Gender and Uveitis - Hindawi Publishing Corporation
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Gender and Uveitis - Hindawi Publishing Corporation
Journal of Ophthalmology Gender and Uveitis Guest Editors: Chi-Chao Chan, Debra A. Goldstein, Janet L. Davis, and H. Nida Sen Gender and Uveitis Journal of Ophthalmology Gender and Uveitis Guest Editors: Chi-Chao Chan, Debra A. Goldstein, Janet L. Davis, and H. Nida Sen Copyright © 2014 Hindawi Publishing Corporation. All rights reserved. This is a special issue published in “Journal of Ophthalmology.” All articles are open access articles distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Editorial Board Monica L. Acosta, New Zealand Hee B. Ahn, Korea Luis Amselem, Spain Usha P. Andley, USA S. Ansari-Shahrezaei, Austria Taras Ardan, Czech Republic F. Arnalich-Montiel, Spain Takayuki Baba, Japan Antonio Benito, Spain Mehmet Borazan, Turkey Gary C. Brown, USA David J. Calkins, USA Francis Carbonaro, Malta Chi-Chao Chan, USA Haoyu Chen, China Lingyun Cheng, USA Chung-Jung Chiu, USA Daniel C. Chung, USA Colin Clement, Australia Miguel Cordero-Coma, Spain Vasilios F. Diakonis, USA Priyanka P. Doctor, India Michel E. Farah, Brazil Paolo Fogagnolo, Italy Farzin Forooghian, Canada Brian A. Francis, USA Joel Gambrelle, France M.-A. Gamulescu, Germany Ian Grierson, UK Vlassis Grigoropoulos, Greece Koray Gumus, Turkey Vishali Gupta, India Takaaki Hayashi, Japan Takeshi Ide, Japan Vishal Jhanji, Hong Kong Thomas Klink, Germany Naoshi Kondo, Japan Bobby S. Korn, USA Ozlem G. Koz, Turkey Rachel W. Kuchtey, USA Hiroshi Kunikata, Japan Toshihide Kurihara, Japan George D. Kymionis, Greece Timothy Y. Lai, Hong Kong Van C. Lansingh, USA Theodore Leng, USA Christopher Leung, Hong Kong Kin S. Lim, UK Paloma B. Liton, USA Marco Lombardo, Italy Tamer A. Macky, Egypt Edward Manche, USA Flavio Mantelli, Italy E. Mencı́a-Gutiérrez, Spain Marcel N. Menke, Switzerland Lawrence S. Morse, USA Darius M. Moshfeghi, USA Majid M. Moshirfar, USA Hermann Mucke, Austria Ramon Naranjo-Tackman, Mexico Magella M. Neveu, UK Neville Osborne, UK Suresh K. Pandey, India Jijing Pang, USA Anand Parthasarathy, Singapore Enrico Peiretti, Italy Pai-Huei Peng, Taiwan David P. Piñero, Spain Pawan Prasher, India Yi Qu, China Antonio Queiros, Portugal Eduardo B. Rodrigues, Brazil Dirk Sandner, Germany Ana R. Santiago, Portugal Patrik Schatz, Sweden Kyoung Y. Seo, Republic of Korea Wisam A. Shihadeh, USA Bartosz Sikorski, Poland Katsuyoshi Suzuki, Japan S. K. Swamynathan, USA Suphi Taneri, Germany Christoph Tappeiner, Switzerland Stephen C Teoh, Singapore P. G. Theodossiadis, Greece Biju B. Thomas, USA Lisa Toto, Italy David A. Wilkie, USA Wai T. Wong, USA Victoria W Y Wong, Hong Kong S. Chien Wong, UK Huseyin Yetik, Turkey Terri L. Young, USA Hyeong Gon Yu, Republic of Korea Hunter Yuen, Hong Kong Vicente Zanon-Moreno, Spain Contents Gender and Uveitis, Chi-Chao Chan, Debra A. Goldstein, Janet L. Davis, and H. Nida Sen Volume 2014, Article ID 818070, 2 pages Sex and Reproduction in the Transmission of Infectious Uveitis, Janet L. Davis Volume 2014, Article ID 683246, 6 pages Sarcoidosis: Sex-Dependent Variations in Presentation and Management, Andrea D. Birnbaum and Lana M. Rifkin Volume 2014, Article ID 236905, 7 pages Gender and Uveitis in Patients with Multiple Sclerosis, Lynn K. Gordon and Debra A. Goldstein Volume 2014, Article ID 565262, 5 pages Gender Differences in Behçet’s Disease Associated Uveitis, Didar Ucar-Comlekoglu, Austin Fox, and H. Nida Sen Volume 2014, Article ID 820710, 8 pages Gender and Ocular Manifestations of Connective Tissue Diseases and Systemic Vasculitides, Maria M. Choudhary, Rula A. Hajj-Ali, and Careen Y. Lowder Volume 2014, Article ID 403042, 8 pages Gender Differences in Vogt-Koyanagi-Harada Disease and Sympathetic Ophthalmia, Yujuan Wang and Chi-Chao Chan Volume 2014, Article ID 157803, 8 pages The Role of Gender in Juvenile Idiopathic Arthritis-Associated Uveitis, Ahmadreza Moradi, Rowayda M. Amin, and Jennifer E. Thorne Volume 2014, Article ID 461078, 7 pages Gender Differences in Birdshot Chorioretinopathy and the White Dot Syndromes: Do They Exist?, Lisa J. Faia Volume 2014, Article ID 146768, 10 pages Uveitis and Gender: The Course of Uveitis in Pregnancy, Nathalie P. Y. Chiam and Lyndell L. P. Lim Volume 2014, Article ID 401915, 10 pages Gender and Spondyloarthropathy-Associated Uveitis, Wendy M. Smith Volume 2013, Article ID 928264, 6 pages Hindawi Publishing Corporation Journal of Ophthalmology Volume 2014, Article ID 818070, 2 pages http://dx.doi.org/10.1155/2014/818070 Editorial Gender and Uveitis Chi-Chao Chan,1 Debra A. Goldstein,2 Janet L. Davis,3 and H. Nida Sen1 1 Laboratory of Immunology, National Eye Institute, Bethesda, MD, USA Department of Ophthalmology, Northwestern Feinberg School of Medicine, Chicago, IL, USA 3 Bascom Palmer Eye Institute, University of Miami, Miami, FL, USA 2 Correspondence should be addressed to Chi-Chao Chan; [email protected] Received 7 July 2014; Accepted 7 July 2014; Published 22 July 2014 Copyright © 2014 Chi-Chao Chan et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Sex differences in medicine include sex-specific diseases occurring only in one sex and sex-related diseases that are more common to one sex. Indeed differences in incidence, presentation, and course of disease between males and females are common. Eye disease is no exception. According to the WHO website, “In every region of the world and at all ages, females have a significantly higher risk of being visually impaired.” WHO estimates that globally there are approximately 314 million people with visual impairment and that women account for more than 64.5%. Even adjusted for age, the overall odds ratio of blind women to men is 1.43, representing a range from 1.39 in Africa to 1.63 in industrialized countries [1]. Gender-based differences refer to hormonal changes in menstrual cycles, pregnancy, menopause, disease susceptibility, and other anatomic or physiologic differences between women and men. Although the exact mechanisms are not fully understood, recent research demonstrates a link between sex hormones and microbial exposure in which microbiome can trigger testosterone-dependent protection from autoimmunity in the nonobese diabetic (NOD) mouse model [2, 3]. Sex hormones, X-chromosome-related effects, and epigenetic and environmental factors also affect activation and differentiation of different immune cells that play important roles in infectious and autoimmune diseases [4]. The differences of ocular diseases between the sexes are nowhere more apparent than in the field of ocular inflammation. Females as a gender group have heightened immune responses not only to foreign antigens but also to selfantigens. Thus there is a greater preponderance of autoimmune disorders including noninfectious uveitis in women than in men. Recently, the Pacific Ocular Inflammation Study reported that, of 217 061 eligible patients, 872 were identified using International Classification of Diseases, Ninth Revision codes, and 224 cases of uveitis were confirmed. The overall uveitis incidence rate was 24.9 cases per 100000 person-years. The annual prevalence rates for 2006 and 2007 were 57.5 and 58.0 per 100000 persons, respectively. No difference in incidence rate was found by sex (𝑃 = 0.63), but female patients had a higher prevalence (𝑃 = 0.008) [5]. This special issue attempts to identify gender- and sex-based differences in various uveitides: infectious and noninfectious autoimmune uveitis, for example, multiple sclerosis in young and middle-aged women, juvenile idiopathic arthritis in girls, and syphilitic uveitis in HIV infected patients in males. Clinical manifestations and courses may appear differently between female and male patients in certain uveitides. Gender-based differences in uveitis should be also considered in care and treatment of the diseases, as well as the underlying genetic background and physical and social environment. Chi-Chao Chan Debra A. Goldstein Janet L. Davis H. Nida Sen References [1] Jenkins, “Gender and Eye Health: Why women are left in the dark,” http://www.aao.org/publications/eyenet/201005. [2] J. G. M. Markle, D. N. Frank, S. Mortin-Toth et al., “Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity,” Science, vol. 339, no. 6123, pp. 1084–1088, 2013. 2 [3] L. Yurkovetskiy, M. Burrows, A. Khan et al., “Gender bias in autoimmunity is influenced by microbiota,” Immunity, vol. 39, no. 2, pp. 400–412, 2013. [4] J. G. Markle and E. N. Fish, “SeXX matters in immunity,” Trends in Immunology, vol. 35, no. 3, pp. 97–104, 2014. [5] N. R. Acharya, V. M. Tham, E. Esterberg et al., “Incidence and prevalence of uveitis: results from the Pacific Ocular Inflammatory Study,” JAMA Ophthalmology, vol. 131, no. 11, pp. 1405–1412, 2013. Journal of Ophthalmology Hindawi Publishing Corporation Journal of Ophthalmology Volume 2014, Article ID 683246, 6 pages http://dx.doi.org/10.1155/2014/683246 Review Article Sex and Reproduction in the Transmission of Infectious Uveitis Janet L. Davis Bascom Palmer Eye Institute, Miller School of Medicine, University of Miami, 900 NW 17th Street, Miami, FL 33136, USA Correspondence should be addressed to Janet L. Davis; [email protected] Received 30 April 2014; Accepted 16 June 2014; Published 1 July 2014 Academic Editor: H. Nida Sen Copyright © 2014 Janet L. Davis. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Current data permit only speculations regarding sex differences in the prevalence of infectious uveitis between women and men because uveitis case surveys do not uniformly report gender data. Differences in prevalence that are reported in the literature could relate to simple differences in the number of women and men at risk for infection or to biological differences between men and women. Compared to other types of uveitis, infectious uveitis may be directly related to occupational exposures or sexual behaviors, which differ between women and men, and may mask actual biological differences in susceptibility to ocular manifestations of the infection and its prognosis. In infectious uveitis for which there is no element of sexual transmission and data is available, prevalence of ocular disease is roughly equal between women and men. Women also have a unique relationship with infectious uveitis in their role as mothers. Vertical transmission of infections such as herpes simplex, toxoplasmosis, and cytomegalovirus can produce severe chorioretinitis in neonates. 1. Introduction Uveitis, especially noninfectious uveitis, is more common in women than in men, in most large surveys, presumably because of the greater frequency of autoimmune diseases in women. The same cannot be presumed to hold true for infectious uveitis. Sex-determined biological variations in type or intensity of response to infections may exist, just as they appear to exist in noninfectious and autoimmune disorders. If anything, the sex differences in infectious uveitis are likely to be greater than in autoimmune disorders because exposure to infections involves behavioral and cultural issues not encountered with the other uveitides. Differences in sexual behaviors between men and women would predict that uveitis associated with sexually transmissible diseases such as HIV and syphilis would be even more likely to show gender disparities than infections transmitted through environmental and occupational exposures. Monogamy and strict adherence to ideals of chastity and faithfulness in some cultures are important social factors that would likely reduce the prevalence of sexually transmitted infectious diseases in women. Examples that would increase risk of infection among women are sex work and heterosexual transmission from bisexual or promiscuous male partners. Greater exposure increases the risk of infectious uveitis, even though uveitis typically arises in only a small percentage of infected individuals. It is unknown whether men or women would have greater susceptibility on a biological basis to uveitis associated with infectious diseases. In general, men seem to be more susceptible to infections in multiple species [1]. The development of uveitis may depend on other factors that would skew prevalence toward one sex or the other. For nonsexually transmitted types of infectious uveitis, the difference between male and female prevalence seems to be small indicating that large hormonal influences are unlikely. For sexually transmitted diseases, behavioral factors are likely to overshadow any biological effects related to sex-specific gene expression. Calculation of odds ratios based on proportions of women with sexually transmitted infectious diseases only versus those with both systemic and ocular manifestations would require more detailed data than is currently available. In addition to unequal transmission of infections predisposing to infectious uveitis, women have additional concerns related to vertical transmission of infections during pregnancy, most commonly those infections included in the TORCH spectrum (toxoplasmosis, cytomegalovirus, and herpes simplex) which can have devastating ocular consequences. 2 It is the purpose of this review to examine infectious uveitis from the standpoint of its relationship to occupational transmission, sexual transmission, and vertical transmission of pathogens. 2. Methods A Medline search was conducted for peer-reviewed articles in English published from 1990 to 2014 that concerned infectious uveitis qualified by search terms such as prevalence, female, congenital, transmission, and HIV. Additional online resources were consulted for information regarding epidemiologic studies. Primary references were scrutinized for other source publications. 3. Results 3.1. Occupationally and Environmentally Transmitted Diseases. Occupational exposure to pathogens that have a high penetrance of ocular involvement may display unequal sex ratios as dramatic as those related to sexually transmitted disease. Leptospira uveitis in India is often associated with farming or other exposures to animals in rural areas, occupations more likely undertaken by men. Other epidemiological patterns include exposure to ground water in tropical climates and rodents in urban areas, which are more likely to affect the general population including women and children [2]. It is estimated that up to 10% of patients with the systemic disease will have ocular manifestations. The male to female ratio of leptospiral uveitis was 3 : 1 in one study [3]. Uveitic manifestations include hypopyon panuveitis, nonocclusive retinal periphlebitis, and neuroretinitis or papillopathy [2]. Sex differences in brucellar uveitis are another example of differing occupational exposures to animal vectors that result in infectious uveitis. Men aged 20–45 years, engaged in butchering or rendering animal carcasses, seem to be at special risk because of exposure to B. abortus or B. suis (http://www.who.int/csr/resources/publications/Brucellosis .pdf, accessed 12 April, 2014). In contrast, women in Peru are twice as likely as men to have brucellar uveitis [4]. This is because the manufacture, distribution, or consumption of sheep and goat milk products places more women and children at risk of exposure to a more virulent species, B. melitensis, (http://www.who.int/csr/resources/publications/ Brucellosis.pdf, accessed 12 April, 2014). In Western Iran, brucellosis is more common in housewives than in farmers [5]; however, in both western and central Iran, the male : female ratio was 2.1 [6]. Ophthalmicmanifestations, especially in chronic brucellosis, include posterior uveitis in about 40% of patients and anterior, intermediate, or panuveitis in another 15% each. Corneal and optic nerve inflammations can occur [4]. Hunters who field dress animals may acquire toxoplasmosis and, unlike the other zoonoses or Lyme disease from ticks, then transmit the disease through household exposure to the meat. Viable T. gondii was isolated from 17%–29% of white-tailed deer hunted in the United States [7]. Women who assume traditional roles of food preparation can be exposed when handling the meat [8]; a social history should Journal of Ophthalmology include the possible exposure to infected wild meat. Raw meat from US supermarkets, especially pork, may contain toxoplasma oocysts [7]. In endemic areas of toxoplasmosis in Brazil, the production and ingestion of contaminated sausage may be a factor in the very high prevalence of toxoplasma chorioretinitis in that population. Clustering of toxoplasma seropositivity among all ages and sexes sharing the same household suggests that foodborne transmission is important in endemic areas of Brazil [9]. Differences in prevalence of nonsexually transmitted infectious uveitis between the sexes would depend on the amount, type, and infectivity of the activities to which each sex was typically exposed in their culture. When all persons are exposed mainly through food, an equal sex ratio would be expected. 3.2. Sexually Transmitted Diseases. The most striking differences between prevalence in men and women would be expected in diseases that are sexually transmitted because exposure involves a large behavioral component. In 2011 in the USA, there were 8.3 per 100,000 primary and secondary syphilis infections in men versus 1.0 per 100,000 in women. A large imbalance in syphilitic uveitis would also be expected. (http://www.cdc.gov/std/stats11/tables.htm, accessed 01 Sep, 2013, 2:00 PM.) The virulence and persistence of syphilis to the point of causing central nervous system or ocular manifestations is influenced by concomitant HIV infection. Among HIV infected patients, syphilitic uveitis is almost exclusively seen in men; in one meta-analysis, 97 of 101 patients were male [10]. This balance may change as the proportion of HIV-infected women grows relative to men. Among non-HIV infected patients the imbalance in syphilitic uveitis is less striking. A small Chinese case series of 14 nonHIV infected patients with syphilitic uveitis showed only a slight male predominance [11]. Regional factors likely play a role in these results. Syphilis may be more evenly distributed between men and women in China because of fewer men having sex with men or other behavioral factors. Access to care for early treatment or frequency of screening may differ between men and women. Penetrance of syphilis infection in the Chinese population may also be less overall than in the West, resulting in a skewed sample from a very small number of patients; epidemiological information about syphilis in China could not be obtained from online resources. In the United States, the CDC does not separately tally syphilitic uveitis, but only tallies total cases of syphilis in men and women. Conversely, cases of syphilitic uveitis are usually reported without background information regarding the number of cases without ocular disease from the same population and without concurrent controls that have syphilis but not uveitis and might also show gender imbalances from which susceptibility to symptomatic ocular disease could be ascertained. Presumably intraocular involvement is considerably rarer than the systemic infection that causes it in any cultural setting, although the uveitis or optic neuropathy can be most symptomatic manifestation of untreated latent disease [12]. An international series of syphilitic uveitis of the posterior placoid variant recorded 9 of 60 (15%) of the newly reported and previously published patients to be females Journal of Ophthalmology 3 men and women [18]. Globally, testing and treatment for HIV infection is now more readily available to women, which may help reduce risk of opportunistic infections such as CMVR. CMV can also be transmitted through household contacts [19], placing women at special risk if they care for infected young children. In general, unlike syphilis, and independent of HIV status, healthy women are more likely to be infected with CMV than men (OR 1.17 [1.14–1.21]) [19]. Figure 1: Right eye of a middle-aged married housewife with the placoid variant of syphilitic uveitis. Contact tracing through the health department indicated presumptive infection through her spouse. Preconceptions about the likelihood of syphilitic uveitis should not defer testing of all uveitis patients for exposure. [13]. HIV infection was confirmed in 9 of the current and 14 of the historical patients (38%). Among HIV negative patients there was a much higher number of women: 8 of 37 HIV negative patients were women (24.3%) versus 1 of the remaining 23 patients (4.3%). The relatively low prevalence of HIV infection in this series of syphilitic uveitis raises the issue of whether the specific ocular manifestations of syphilitic uveitis, such as the posterior placoid variant, could be influenced by transmission to either a healthy or immunocompromised host, with healthier individuals perhaps more likely to have a limited posterior infection without panuveitis, Figure 1. Understanding the relative influences of immune status, particularly HIV infection, sex, and sexual behavior on syphilitic uveitis would depend on publication of more cases from populations with known seroprevalence of prior syphilitic infection and disease frequencies of symptomatic late manifestations. Prospective studies in sexually transmitted disease clinics are not feasible due to the early treatment of most patients and reduction in their risk of later manifestations of infection, such as uveitis. Cytomegalovirus retinitis (CMVR) is of particular interest because the virus is sexually transmitted [14] as well as transmitted by body fluids and was the predominant cause of blindness and visual disability among HIV-infected patients prior to the initiation of highly active antiretroviral treatment (HAART) in 1996. Prior to the introduction of HAART, the incidence of AIDS indicator infections was dependent on the degree of immunodeficiency rather than sex [15]. CMVR was not specifically analyzed in this study. Among HIV positive women in the early years of the AIDS epidemic, only those who had nonsexually transmitted HIV such as injection drug-use had an increased risk (odds ratio 1.43) for cytomegalovirus disease [16]. After the introduction of HAART, data from a large multicenter study of the ocular complications of AIDS documented that the percentage of incident cases of CMVR in women more than doubled after the introduction of HAART (35.4% versus 15.3%), a statistically significant change [17]. Demographic differences were attributed to differences in access to care between men and women. Reanalysis of data in 2012 from the same cohort no longer found a difference in the incidence of CMVR between 3.3. Nonsexually Transmitted Diseases. Infectious uveitis caused by nonsexually transmitted pathogens would be predicted to be associated with fewer sex differences. Nonetheless, infectious uveitis of any type is a concern in HIV patients, the sex ratio of which varies according to geographicregion therefore variably exposing women. In a large cohort study of HIV-infected individuals, herpes class viruses other than CMV (simplex, zoster), toxoplasmosis, Cryptococcus, and atypical Mycobacterium had similar prevalence between men and women [20]. Biologic differences related to sex were therefore not apparent in these variably immunocompromised individuals, although case numbers were low. A large series of 111 non-HIV infected Turkish patients, with herpetic iridocyclitis, showed a slight female predominance of 1.2 : 1.0 [21]. In the United States, women are more commonly affected than men with herpes simplex 2 (http://www.cdc.gov/std/Herpes/STDFact-Herpes.htm, accessed 01 Sept, 2013 2:00 PM). A similar situation may have influenced the sex disparity in the Turkish series; patients were not typed as having HSV 1 or 2. A Hawaiian cohort showed no sex imbalance in prevalent cases of herpes zoster ophthalmicus [22]. Chronic anterior uveitis, associated with rubella, herpes, and cytomegalovirus, was slightly more common in men than women in a cross-sectional study of 166 Saudi patients; population seroprevalence of the candidate viruses was not reported [23]. It is unclear whether small differences of this type are due to the prevalence of the primary infection or somehow related to a sex-based susceptibility to the eye disease. For tuberculosis, there is male predominance although it is among the top three causes of death for women worldwide [24]. Some of this imbalance may be due to the 13% of TB cases that are in HIV-positive individuals; however, most of these are in the African region where the sex balance in HIV infection is more equal than in the European or American regions [24]. In Saudi Arabia, a large survey of uveitis etiologies revealed presumed tuberculous uveitis to be the most common type of uveitis. Male and female prevalence was essentially equal [25], whereas some immunological causes of uveitis were statistically more common (VogtKoyanagi-Harada and multiple-sclerosis related) or less common (Behçet) in women than in men. An excellent review of prior publications in TB uveitis from the same group summarizes clinical manifestations, most commonly posterior, panuveitis, or occlusive retinal periphlebitis [26]. Specific sex imbalances are not mentioned. 3.4. Vertical Transmission. Women also vertically transmit infections during pregnancy that may cause peri- or postnatal infectious uveitis in their children. A recent series 4 of herpes simplex 2 associated acute retinal necrosis in children identified maternal factors such as birth history with the possibility of direct infection through the birth canal or maternal antibodies in the majority of cases [27]. Congenital syphilis remains relatively common in the United States if considered in the light of the good surveillance and treatment of syphilis during pregnancy. (http://www.cdc.gov/std/stats11/tables/1.htm, accessed 01 Sept, 2013 2:00 PM). The number of ocular infections among the 350 annual cases (about 1 in 10,000 live births) is unknown. Cataract, chorioretinal scarring, and optic neuropathy seem to be rare and do not appear in uveitis surveys. Women with positive treponemal tests but negative nontreponemal tests seem to be at a low risk of transmission of congenital syphilis to their children [28]. Rubella infection currently occurs in less than 1 case per 10,000,000 population in the United States [29]. In Oman where rubella is incident in 0.6 of 1000 live births, bilateral chorioretinitis was the most common manifestation [30]. A historical series from the United Kingdom in 1993 also found bilateral retinopathy to be the most common manifestation of congenital rubella syndrome, although it was not related to vision loss [31]. Interestingly, new diagnoses of Fuchs uveitis syndrome, virologically related to rubella [32], declined in US-born patients after institution of the vaccination program in 1959 whereas the percentage of new Fuchs patients that were foreign born increased [33]. Congenital CMV infection is not specifically related to maternal HIV infection and is more common than congenital HIV. The incidence rate of CMVR in HIV infected children was low in the pre-HAART era (0.5 per 100 person-years) and has fallen further in the post-HAART era [34]. Congenital CMVR is therefore not a specifically HIV-related problem. Among non-HIV infected persons, nonwhite women and those in lower socio-economic groups have higher frequencies of CMV seropositivity and therefore are at greater risk of transmitting CMV prenatally if the primary infection occurs during pregnancy [35]. Unlike syphilis, chorioretinitis or other manifestations affecting the visual pathways are present in almost all of the symptomatic congenital CMV infants, who are 5 to 15% of the total born with serological evidence of congenital disease [36]. Preconception immunity does not protect against transmission to the fetus: about half of children with congenital CMV infection are born to preimmune mothers [37]. The ability to infect a fetus even if the primary maternal infection does not occur in pregnancy may relate to periodic reactivations of lifelong CMV infection, similar to other herpes class viruses such as simplex and zoster. Reinfection with other serovars is also possible. The greatest amount of information about vertically transmitted infectious uveitis relates to congenital toxoplasma chorioretinitis. Screening of pregnant women is sometimes undertaken proactively in countries with high frequencies of congenital toxoplasmosis, such as France [38]. This research enabled the establishment of antibiotic regimens for primary prevention of toxoplasma infection in the fetus, if seroconversion occurs during pregnancy. Diagnosis by ocular screening of mothers is not efficient because only Journal of Ophthalmology Figure 2: New lesions in the left eye of a child with known congenital toxoplasmosis. The central scars were long-standing. The peripheral lesions occurred in regions previously felt to be normal. Multifocal reactivation is unusual. 3.8% to 13.7% of mothers of children with congenital toxoplasmosis have chorioretinal lesions consistent with healed toxoplasmosis [39]. As for other infections, screening is performed serologically. Termination of pregnancy is not usually recommended for all women who become infected with toxoplasmosis during the first trimester as only a low percentage of the fetuses will have symptomatic disease [40]. IgG avidity testing can be used to exclude infections that occurred more than 4 months previously despite the persistence of IgM production [41]. Intrauterine sampling can be used to determine if the fetus is infected and ultrasound can detect malformations [42, 43]. Chorioretinitis is the most common ocular lesion in the neonate [44]. If seroconversion is detected in the first trimester, treatment of the mother with antibiotics during pregnancy and the child during infancy can result in good visual outcomes [45]. Postnatal treatment did not prevent the development of new fundus lesions in 34 of 108 (31%) [23–41, 95% C.I.] of affected children [46] but did reduce the incidence of new lesions compared to 18 of 25 (72%) congenitally infected but untreated children [47]. In both groups, about half of the new lesions appeared at age 10 or older, Figure 2. Although in general preimmune women are felt to be incapable of transmitting toxoplasmosis to a fetus, a case has been reported of transmission from a mother who had reactivation of chorioretinitis during pregnancy [48]. As for CMV, reinfection with multiple serovars may be possible. Lymphocytic choriomeningitis (LCM) virus is a less known congenital infection that produces chorioretinal scarring and vision loss; in one study in Chicago, antibodies against LCM were encountered more frequently in severely retarded children with chorioretinal scars than toxoplasmosis, rubella, CMV, or herpes simplex [49]. In some children chorioretinitis was present but serology did not identify candidate infections indicating the likelihood that other infections can produce fetal ocular infections. 4. Conclusion Women are uniquely affected by infectious uveitides. Vulnerability to HIV from infected partners exposes them to risk of cytomegalovirus retinitis. Syphilitic uveitis is also Journal of Ophthalmology strongly associated with HIV infection but can also occur in immunocompetent women. Women are also at risk of transmitting infections such as herpes simplex, cytomegalovirus, toxoplasmosis, and lymphocytic choriomeningitis virus, and herpes simplex that can cause chorioretinitis in neonates. Rubella infection produces a relatively benign chorioretinitis that is being eradicated by vaccination programs. Robust screening and treatment programs for vertical transmission of toxoplasmosis have reduced the impact of toxoplasma chorioretinitis on children. Conflict of Interests The author declares that there is no conflict of interests regarding the publication of this paper. References [1] S. L. Klein, “The effects of hormones on sex differences in infection: from genes to behavior,” Neuroscience and Biobehavioral Reviews, vol. 24, no. 6, pp. 627–638, 2000. [2] D. Shukla, S. R. Rathinam, and E. T. Cunningham Jr., “Leptospiral uveitis in the developing world,” International Ophthalmology Clinics, vol. 50, no. 2, pp. 113–124, 2010. [3] K. M. Chu, R. Rathinam, P. Namperumalsamy, and D. Dean, “Identification of Leptospira species in the pathogenesis of uveitis and determination of clinical ocular characteristics in South India,” The Journal of Infectious Diseases, vol. 177, no. 5, pp. 1314–1321, 1998. [4] I. Rolando, L. Olarte, G. Vilchez et al., “Ocular manifestations associated with brucellosis: a 26-year experience in Peru,” Clinical Infectious Diseases, vol. 46, no. 9, pp. 1338–1345, 2008. [5] H. Kassiri, H. Amani, and M. Lotfi, “Epidemiological, laboratory, diagnostic and public health aspects of human brucellosis in western Iran,” Asian Pacific Journal of Tropical Biomedicine, vol. 3, no. 8, pp. 589–594, 2013. [6] M. Zeinalian Dastjerdi, R. Fadaei Nobari, and J. Ramazanpour, “Epidemiological features of human brucellosis in central Iran, 2006–2011.,” Public Health, vol. 126, no. 12, pp. 1058–1062, 2012. [7] J. L. Jones and J. P. Dubey, “Foodborne toxoplasmosis,” Clinical Infectious Diseases, vol. 55, no. 6, pp. 845–851, 2012. [8] D. F. Lieb, I. U. Scott, H. W. Flynn Jr., J. L. Davis, and S. M. Demming, “Acute acquired toxoplasma retinitis may present similarly to unilateral acute idiopathic maculopathy,” The American Journal of Ophthalmology, vol. 137, no. 5, pp. 940– 942, 2004. [9] R. W. D. Portela, J. Bethony, M. I. Costa et al., “A multihousehold study reveals a positive correlation between age, severity of ocular toxoplasmosis, and levels of glycoinositolphospholipidspecific immunoglobulin A,” The Journal of Infectious Diseases, vol. 190, no. 1, pp. 175–183, 2004. [10] J. D. Tucker, J. Z. Li, G. K. Robbins et al., “Ocular syphilis among HIV-infected patients: a systematic analysis of the literature,” Sexually Transmitted Infections, vol. 87, no. 1, pp. 4–8, 2011. [11] P. Yang, N. Zhang, F. Li, Y. Chen, and A. Kijlstra, “Ocular manifestations of syphilitic uveitis in Chinese patients,” Retina, vol. 32, no. 9, pp. 1906–1914, 2012. [12] A. Anshu, C. L. Cheng, and S.-P. Chee, “Syphilitic uveitis: an Asian perspective,” The British Journal of Ophthalmology, vol. 92, no. 5, pp. 594–597, 2008. 5 [13] C. M. Eandi, P. Neri, R. A. Adelman, L. A. Yannuzzi, and E. T. Cunningham, “Acute syphilitic posterior placoid chorioretinitis: report of a case series and comprehensive review of the literature,” Retina, vol. 32, no. 9, pp. 1915–1941, 2012. [14] S. A. S. Staras, W. D. Flanders, S. C. Dollard, R. F. Pass, J. E. McGowan Jr., and M. J. Cannon, “Influence of sexual activity on cytomegalovirus seroprevalence in the United States, 1988– 1994,” Sexually Transmitted Diseases, vol. 35, no. 5, pp. 472–479, 2008. [15] K. M. Farizo, J. W. Buehler, M. E. Chamberland et al., “Spectrum of disease in persons with human immunodeficiency virus infection in the United States,” The Journal of the American Medical Association, vol. 267, no. 13, pp. 1798–1805, 1992. [16] P. L. Fleming, C. A. Ciesielski, R. H. Byers, K. G. Castro, and R. L. Berkelman, “Gender differences in reported AIDS-indicative diagnoses,” The Journal of Infectious Diseases, vol. 168, no. 1, pp. 61–67, 1993. [17] D. A. Jabs, M. L. Van Natta, J. H. Kempen et al., “Characteristics of patients with cytomegalovirus retinitis in the era of highly active antiretroviral therapy,” The American Journal of Ophthalmology, vol. 133, no. 1, pp. 48–61, 2002. [18] E. A. Sugar, D. A. Jabs, A. Ahuja, J. E. Thorne, R. P. Danis, and C. L. Meinert, “Incidence of cytomegalovirus retinitis in the era of highly active antiretroviral therapy,” American Journal of Ophthalmology, vol. 153, no. 6, pp. 1016–1024, 2012. [19] S. A. S. Staras, W. D. Flanders, S. C. Dollard, R. F. Pass, J. E. McGowan Jr., and M. J. Cannon, “Cytomegalovirus seroprevalence and childhood sources of infection: a population-based study among pre-adolescents in the United States,” Journal of Clinical Virology, vol. 43, no. 3, pp. 266–271, 2008. [20] S. Gangaputra, L. Drye, V. Vaidya, J. E. Thorne, D. A. Jabs, and A. T. Lyon, “Non-cytomegalovirus ocular opportunistic infections in patients with acquired immunodeficiency syndrome,” The American Journal of Ophthalmology, vol. 155, no. 2, pp. 206.e5– 212.e5, 2013. [21] I. Tugal-Tutkun, B. Ötük-Yasar, and E. Altinkurt, “Clinical features and prognosis of herpetic anterior uveitis: a retrospective study of 111 cases,” International Ophthalmology, vol. 30, no. 5, pp. 559–565, 2010. [22] D. S. Borkar, V. M. Tham, E. Esterberg et al., “Incidence of herpes zoster ophthalmicus: results from the pacific ocular inflammation study,” Ophthalmology, vol. 120, no. 3, pp. 451– 456, 2013. [23] Y. S. Al-Mansour, A. A. Al-Rajhi, H. Al-Dhibi, and A. M. Abu El-Asrar, “Clinical features and prognostic factors in Fuchs’ uveitis,” International Ophthalmology, vol. 30, no. 5, pp. 501–509, 2010. [24] World Health Organization, Global Tuberculosis Report 2013, Geneva, Switzerland, 2013. [25] H. S. Al-Mezaine, D. Kangave, and A. M. Abu El-Asrar, “Patterns of uveitis in patients admitted to a university hospital in Riyadh, Saudi Arabia,” Ocular Immunology and Inflammation, vol. 18, no. 6, pp. 424–431, 2010. [26] A. M. Abu El-Asrar, M. Abouammoh, and H. S. Al-Mezaine, “Tuberculous uveitis,” International Ophthalmology Clinics, vol. 50, no. 2, pp. 19–39, 2010. [27] R. A. Silva, A. M. Berrocal, D. M. Moshfeghi, M. S. Blumenkranz, S. Sanislo, and J. L. Davis, “Herpes simplex virus type 2 mediated acute retinal necrosis in a pediatric population: case series and review,” Graefe’s Archive for Clinical and Experimental Ophthalmology, vol. 251, no. 2, pp. 559–566, 2013. 6 [28] T. A. Peterman, D. R. Newman, D. Davis, and J. R. Su, “Do women with persistently negative nontreponemal test results transmit syphilis during pregnancy?” Sexually Transmitted Diseases, vol. 40, no. 4, pp. 311–315, 2013. [29] M. J. Papania, G. S. Wallace, P. A. Rota et al., “Elimination of endemic measles, rubella, and congenital rubella syndrome from the Western hemisphere: the US experience,” JAMA Pediatrics, vol. 168, no. 2, pp. 148–155, 2014. [30] R. Khandekar, S. Al Awaidy, A. Ganesh, and S. Bawikar, “An epidemiological and clinical study of ocular manifestations of congenital rubella syndrome in omani children,” Archives of Ophthalmology, vol. 122, no. 4, pp. 541–545, 2004. [31] K. T. Givens, D. A. Lee, T. Jones, and D. M. Ilstrup, “Congenital rubella syndrome: ophthalmic manifestations and associated systemic disorders,” The British Journal of Ophthalmology, vol. 77, no. 6, pp. 358–363, 1993. [32] L. de Visser, A. Braakenburg, A. Rothova, and J. H. de Boer, “Rubella virus-associated uveitis: clinical manifestations and visual prognosis,” American Journal of Ophthalmology, vol. 146, no. 2, pp. 292–297, 2008. [33] A. D. Birnbaum, H. H. Tessler, K. L. Schultz et al., “Epidemiologic relationship between fuchs heterochromic iridocyclitis and the United States rubella vaccination program,” American Journal of Ophthalmology, vol. 144, no. 3, pp. 424–428, 2007. [34] P. Gona, R. B. Van Dyke, P. L. Williams et al., “Incidence of opportunistic and other infections in HIV-infected children in the HAART era,” Journal of the American Medical Association, vol. 296, no. 3, pp. 292–300, 2006. [35] M. J. Cannon, “Congenital cytomegalovirus (CMV) epidemiology and awareness,” Journal of Clinical Virology, vol. 46, supplement 4, pp. S6–S10, 2009. [36] S. Ghekiere, K. Allegaert, V. Cossey, M. van Ranst, C. Cassiman, and I. Casteels, “Ophthalmological findings in congenital cytomegalovirus infection: when to screen, when to treat?” Journal of Pediatric Ophthalmology and Strabismus, vol. 49, no. 5, pp. 274–282, 2012. [37] A. Ornoy, “Fetal effects of primary and non-primary cytomegalovirus infection in pregnancy: are we close to prevention?” The Israel Medical Association Journal, vol. 9, no. 5, pp. 398–401, 2007. [38] I. Villena, T. Ancelle, C. Delmas et al., “Congenital toxoplasmosis in France in 2007: first results from a national surveillance system,” Eurosurveillance, vol. 15, no. 25, 2010. [39] A. G. Noble, P. Latkany, J. Kusmierczyk et al., “Chorioretinal lesions in mothers of children with congenital toxoplasmosis in the National Collaborative Chicago-Based, Congenital Toxoplasmosis study,” Scientia Medica, vol. 20, no. 1, pp. 20–26, 2010. [40] A. Berrebi, M. Bardou, M. Bessieres et al., “Outcome for children infected with congenital toxoplasmosis in the first trimester and with normal ultrasound findings: a study of 36 cases,” European Journal of Obstetrics Gynecology and Reproductive Biology, vol. 135, no. 1, pp. 53–57, 2007. [41] F. Robert-Gangneux and M. Dardé, “Epidemiology of and diagnostic strategies for toxoplasmosis,” Clinical Microbiology Reviews, vol. 25, no. 2, pp. 264–296, 2012. [42] F. Daffos, F. Forestier, M. Capella-Pavlovsky et al., “Prenatal management of 746 pregnancies at risk for congenital toxoplasmosis,” The New England Journal of Medicine, vol. 318, no. 5, pp. 271–275, 1988. [43] W. Foulon, A. Naessens, T. Mahler, M. de Waele, L. de Catte, and F. de Meuter, “Prenatal diagnosis of congenital toxoplasmosis,” Obstetrics and Gynecology, vol. 76, no. 5, pp. 769–772, 1990. Journal of Ophthalmology [44] K. Vutova, Z. Peicheva, A. Popova, V. Markova, N. Mincheva, and T. Todorov, “Congenital toxoplasmosis: eye manifestations in infants and children,” Annals of Tropical Paediatrics, vol. 22, no. 3, pp. 213–218, 2002. [45] A. P. Brézin, P. Thulliez, J. Couvreur, R. Nobré, R. Mcleod, and M. B. Mets, “Ophthalmic outcomes after prenatal and postnatal treatment of congenital toxoplasmosis,” American Journal of Ophthalmology, vol. 135, no. 6, pp. 779–784, 2003. [46] P. Garcia-Méric, J. Franck, H. Dumon, and R. Piarroux, “Management of congenital toxoplasmosis in France: current data,” Presse Medicale, vol. 39, no. 5, pp. 530–538, 2010. [47] L. Phan, K. Kasza, J. Jalbrzikowski et al., “Longitudinal study of new eye lesions in treated congenital toxoplasmosis,” Ophthalmology, vol. 115, no. 3, pp. 553.e8–559.e8, 2008. [48] G. M. Q. Andrade, D. V. Vasconcelos-Santos, E. V. M. Carellos et al., “Congenital toxoplasmosis from a chronically infected woman with reactivation of retinochoroiditis during pregnancy,” Jornal de Pediatria, vol. 86, no. 1, pp. 85–88, 2010. [49] M. B. Mets, L. L. Barton, A. S. Khan, and T. G. Ksiazek, “Lymphocytic choriomeningitis virus: an underdiagnosed cause of congenital chorioretinitis,” American Journal of Ophthalmology, vol. 130, no. 2, pp. 209–215, 2000. Hindawi Publishing Corporation Journal of Ophthalmology Volume 2014, Article ID 236905, 7 pages http://dx.doi.org/10.1155/2014/236905 Review Article Sarcoidosis: Sex-Dependent Variations in Presentation and Management Andrea D. Birnbaum and Lana M. Rifkin Department of Ophthalmology, Northwestern University Feinberg School of Medicine, 645 North Michigan Avenue, Suite 440, Chicago, IL 60611, USA Correspondence should be addressed to Andrea D. Birnbaum; [email protected] Received 3 October 2013; Accepted 19 May 2014; Published 2 June 2014 Academic Editor: Janet L. Davis Copyright © 2014 A. D. Birnbaum and L. M. Rifkin. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Sarcoidosis is an inflammatory disease with a wide range of clinical presentations. The manifestations and prognosis in sarcoidosis are dependent upon not only organ involvement but also age and sex. The purpose of this review is to describe the systemic and ocular manifestations of sarcoidosis with a specific focus on sex-dependent difference in presentation and management. Sarcoidosis is more common in women, particularly in patients who present after age of 50 years. Women with sarcoidosis are more likely to develop cystoid macular edema and the mortality rate is higher than that of men. 1. Introduction Sarcoidosis is a systemic inflammatory disease of unknown etiology that can target almost any organ of the body. The most commonly involved organs include the lungs, lymph nodes, skin, and eyes [1]. The clinical presentation and disease course can be extremely variable depending upon the patient population and organ involvement. More than half of patients diagnosed with sarcoidosis experience a limited disease course and remission within 3 years [2]. Up to a third of patients develop chronic disease and require long-term therapy [3]. Patients with severe pulmonary disease, cardiac disease, or neurosarcoidosis have an increased mortality risk [4] and often require aggressive immunosuppression. Patients suspected of having sarcoidosis may undergo a battery of diagnostic tests that are not specific for sarcoidosis, but rather markers of granulomatous inflammation. Angiotensin converting enzyme (ACE) may be elevated in 60–70% of patients with sarcoidosis [1]. The serum levels correlate with the disease burden [5]. Lysozyme is another marker of disease activity that, when elevated, might suggest a diagnosis of sarcoidosis. It has a higher sensitivity but lower specificity than ACE for systemic sarcoidosis [6]. Both ACE and lysozyme levels can be elevated in cerebrospinal fluid in neurosarcoidosis [7]. Hypercalcemia and hypercalciuria are present in 10% and 30% of patients, respectively, and are thought to be associated with increased calcium absorption [8]. Vitamin D dysregulation with hypervitaminosis has also been measured in patients with active disease [9]. Because the lungs are the most common site of involvement, chest X-ray or computerized tomography is performed on most patients to aid in diagnosis and identify possible sites for biopsy [10]. Positron emission tomography (PET) is a more comprehensive study that helps clinicians to understand the extent of organ involvement and to identify possible sites for biopsy [11]. While various diagnostic tests can support a diagnosis, none are confirmatory, and, thus, sarcoidosis is considered a diagnosis of exclusion. Experts agree that three criteria must be met prior to assigning a diagnosis of sarcoidosis: (1) clinical or radiologic findings consistent with sarcoidosis, such as pulmonary disease, uveitis, mediastinal hilar lymphadenopathy, or erythema nodosum; (2) tissue biopsy with histologic evidence of noncaseating granulomas; (3) absence of other causes of granulomatous disease [12]. A diagnosis of sarcoidosis can be made based solely on clinical features in select cases, such as Löfgren’s syndrome. The classic triad of Löfgren’s syndrome is fever, bilateral hilar lymphadenopathy, and polyarthralgias [13]; erythema nodosum is now considered additional diagnostic criterion [14]. In these patients, 2 a diagnosis of sarcoidosis can be made in lieu of biopsy [12– 14]. In patients who are unable to undergo biopsy or who do not have appropriate sites for biopsy, the diagnosis is frequently delayed [15]. Ocular involvement occurs in 11–83% of cases of sarcoidosis patients and can lead to significant morbidity [16–18]. The diagnosis of sarcoidosis in patients with ocular disease can be complicated, as intraocular biopsy is not commonly performed for this disease. One retrospective review of patients with biopsy-proven sarcoidosis and uveitis suggested that although the sensitivities of ACE and lysozyme are low in isolation, when both tests are used in combination with chest X-ray, over 80% of patients had at least one marker suggestive of sarcoidosis. The rate increases to over 90% when ACE and lysozyme are combined with a chest CT [19]. Initial management of patients with systemic sarcoidosis is challenging because evidence exists that the use of systemic corticosteroids actually increases the likelihood of relapse [20]. In patients with chronic systemic disease who are effectively treated with corticosteroids, as many as 74% may relapse within 1 month of stopping the medication [2]. In contrast, only approximately 14% of patients who go into spontaneous remission without treatment relapse [2]. In the case of active ocular disease, patients are treated if symptomatic or if they develop vision threatening sequelae of ocular inflammation, such as cystoid macular edema or retinal ischemia. Mild intermediate uveitis does not always require treatment. 2. Differences in Incidence and Prevalence Understanding the epidemiology of sarcoidosis is complicated by the variability in presentation and diagnostic criteria and the disease is certainly underdiagnosed. As an example, one recent study reported sarcoidosis in 22% of patients with mediastinal incidentalomas identified on chest CT [21]. Sarcoidosis presents most often in young adults under the age of 50, with the highest incidence reported in patients between 20 and 39 years of age [22]. Countries with a high prevalence of sarcoidosis include Scandinavian countries [23, 24], which include predominantly white patients, and the United States, where black patients are more often affected [22, 25] and are diagnosed almost 10 years earlier than whites [26]. Black Americans are also more likely to have extrapulmonary disease and a chronic disease course [1, 26]. As with many inflammatory diseases, sarcoidosis affects women more than men. Three population-based studies performed in three different countries have produced similar findings. In Japan, the rates were 1.2 versus 1.4 per 100,000 in males versus females [27] and, in the United States, the rates were 5.9 versus 6.3 cases per 100,000 person-years in males versus females [28]. A much higher incidence was measured in Sweden, and again the rate was higher in females (21.7 per 100,000 person-years) versus males (16.5 per 100,000 person-years) [29]. A more recent study of patients evaluated at a tertiary referral center found that 65.5% were female. Interestingly, men developed symptoms of sarcoidosis and were diagnosed approximately 2 years earlier than women [26]. Journal of Ophthalmology The increased incidence of sarcoidosis in females has led some to hypothesize that hormones may be a compounding factor. The Black Women’s Health Study (BWHS) followed black women between 1995 and 2009 and determined that factors not associated with an increase in incidence of sarcoidosis included age at menarche, age at menopause, and parity. A reduced incidence of sarcoidosis was noted with a later age at first birth, and a weak association was suggested between recent birth and reduced incidence of sarcoidosis [30], although other studies have shown an increase in disease onset in the first postpartum year [31]. One Danish cohort study reported a positive association between the number of children and risk of erythema nodosum [31]. The relative risk of a hospital contact for sarcoidosis was 1.61 in patients with 4 or more children versus women without children [31]. A second trend is the recognized second peak of sarcoidosis diagnosed in patients over 50 years of age [25, 27, 32]. Late-onset sarcoidosis is more common in women than men, which may factor into the increased mean age of diagnosis reported in women versus men [26]. One study reported a rate of 70.3% females in a study of patients with systemic sarcoidosis diagnosed at 70 years of age or older [33]. A second study compared patients with sarcoidosis who were diagnosed at 65 years of age or older with younger patients. In this study, 83.3% of patients in the older cohort were female versus 50% in the younger group (𝑃 = 0.003). Uveitis was more common in the elderly group versus the younger group (33.3% versus 8.6%, resp.; 𝑃 = 0.002), and 80% of the patients with uveitis in the study were female [34]. The relapse rate of systemic sarcoidosis may also be influenced by sex. White males reportedly have a higher relapse rate of sarcoidosis than white females and African Americans of either gender [2]. In this same study, patients with musculoskeletal sarcoidosis as their presenting disease were more likely to develop recurrence, while patients with asymptomatic disease identified on chest imaging were most likely to remain in remission [2]. 3. Gender Differences in Clinical Manifestations 3.1. Systemic Manifestations. The array of clinical manifestations associated with sarcoidosis is quite varied and includes both constitutional and organ-specific presentations. In any patient with suspected sarcoidosis, a complete review of systems is essential to help characterize the systemic disease and direct diagnostic testing and management. Generalized symptoms of sarcoidosis include fatigue, night sweats, weight loss, arthralgia, and exercise intolerance [35]. Gender differences in complaints of fatigue [36], anxiety, or depression [37] have been measured in patients with sarcoidosis, but they ultimately paralleled similar studies of the general population. Therefore, the authors concluded that sex differences are not specific to sarcoidosis. Organ-specific involvement is easier to characterize and several sex differences have been identified in this regard. Males tend to have higher rates of pulmonary and cardiac involvement, while females are more prone to peripheral lymph node, skin, eye, and liver disease [26, 38, 39]. The most Journal of Ophthalmology common cutaneous manifestation is erythema nodosum (EN), which consists of red, tender bumps or nodules on the anterior aspect of the leg. Lupus pernio, a chronic manifestation of sarcoidosis, is characterized by indurated plaques and discoloration of the skin. It often presents on the nose, cheeks, lips, and ears, most commonly in women of African descent. A prospective study of patients with newly diagnosed sarcoidosis conducted in the United States reported that women are more likely to have EN than men, although no significant variation was measured for other cutaneous manifestations [25]. EN can be associated with joint swelling [40], and men with Löfgren’s syndrome are more likely to experience periarticular inflammation or arthritis of the ankles [41]. Endocrine abnormalities are common and possibly underreported in sarcoidosis. Hypercalciuria and hyperprolactinemia have been reported in up to 30% of patients with sarcoidosis [9, 42]. Abnormalities of calcium metabolism are more common in men [25]. Clinical manifestations of hyperprolactinemia are certainly sex-dependent, with men experiencing decreased libido, impotence, and gynecomastia and women complaining of secondary amenorrhea, galactorrhea, or decreased libido [42]. Thyroid disorders have also been described in patients with sarcoidosis. Patients with abnormal 67Ga-citrate uptake at initial presentation of sarcoidosis, particularly females with anti-thyroid peroxidase antibodies, are at risk of aggressive autoimmune thyroiditis and hypothyroidism and should be carefully monitored [43]. Genitourinary sarcoidosis will obviously differ between men and women. Among men, clinical signs include testicular swelling and a painless mass in the scrotum [44], while women may experience granulomatous inflammation of the uterus, abnormal bleeding, or erosion of the cervix [45]. Genitourinary sarcoidosis affects less than 0.2% of men with sarcoidosis, although evidence of subclinical involvement is present in up to 5% of patients [44]. Black men are affected at a frequency 10 times greater than white men. 3.2. Ocular Inflammation. Sarcoidosis can involve almost any ocular structure, including the globe, orbit, and adnexa. As with systemic sarcoidosis, ocular manifestations of the disease are more common in women [46–48]. In African Americans, the combination of ocular and neurologic disease may be evident [26]. Anterior uveitis is the most common ocular manifestation of sarcoidosis [49] and posterior segment involvement carries a worse visual prognosis [50]. Sex-specific differences in posterior segment disease have been described, with a higher rate of cystoid macular edema (CME) and worse visual acuity in women [51, 52] as well as a trend toward a higher rate of periphlebitis vitreous opacity in men [52]. Several studies have demonstrated a second peak of uveitis in patients over the age of 50, and the vast majority of patients in this subset are female [19, 49, 50]. One consideration in any patient over 50 who presents with newly diagnosed uveitis must be malignancy. In one series, nine patients over the age of 50 were initially diagnosed with primary intraocular lymphoma, but the diagnosis was later 3 determined to be ocular sarcoidosis. Seven of the patients had multifocal choroiditis and six had cystoid macular edema, both of which are rare in lymphoma [53]. This highlights two considerations in female patients over the age of 50 that posterior multifocal choroiditis may be more common in women over age of 50 [54] and that chest X-ray is often not sufficient to identify associated pulmonary sarcoidosis. In one study, 11 of 17 patients with a negative chest X-ray had findings suggestive of sarcoidosis on chest computed tomography (CT) [55]. This finding has been supported by others [54] and has led to the recommendation that women over 50 years of age with a clinical presentation consistent with ocular sarcoidosis should undergo chest imaging with CT rather than chest X-ray. 4. Differences in Treatment Patients with sarcoidosis have been successfully treated with numerous anti-inflammatory agents, ranging from topical and systemic corticosteroids to antimetabolites and monoclonal antibodies. Because sarcoidosis often occurs in patients of childbearing age, special considerations must be made in patients who may have planned or unplanned pregnancy. The pregnancy class of many medications used to treat sarcoidosis is listed in Table 1. Several of the systemic agents used to treat sarcoidosis are contraindicated during pregnancy. A recent international poll of sarcoidosis specialists found that 80% of physicians considered MTX their preferred second-line treatment option for sarcoidosis, after systemic corticosteroids [56]. They also reported that, in cases of ocular sarcoidosis refractory to topical corticosteroids, MTX is their preferred first-line drug rather than systemic corticosteroids [56]. Patients should be adequately educated on the risk of birth defects associated with use of MTX and provided with information on appropriate birth control. Although women who plan to get pregnant are at a greater risk of causing direct harm to their unborn fetus, experts agree that both men and women should stop the medication at least 3 months prior to any planned pregnancy [56]. Topical and periocular corticosteroids are commonly used to treat uveitis during pregnancy. In the case of topical administration, patients should be educated on punctual occlusion after administering the medication to reduce systemic absorption. Intravitreal bevacizumab, a class C drug, has reportedly been used for choroidal neovascularization, a potential complication of posterior segment inflammation which can lead to significant and permanent vision loss, in pregnant patients. In a small series of 4 patients treated offlabel with intraocular bevacizumab, vision improved and no adverse events were observed [57]. The use of medications during pregnancy should be individualized and must include discussions regarding the risks and benefits of treatment. 5. Differences in Prognosis Patients with sarcoidosis often report a diminished healthrelated quality of life [58], with a range of symptoms such as emotional distress, lung problems, pain, physical limitations, 4 Journal of Ophthalmology Table 1: Pregnancy classes of medications used to treat systemic sarcoidosis. Category Corticosteroid Antimetabolite Calcineurin inhibitor Monoclonal antibody Alkylating agents Systemic medication Prednisone Methylprednisolone Methotrexate Mycophenolate Azathioprine Cyclosporine Infliximab Adalimumab Etanercept Chlorambucil Cyclophosphamide fatigue, social limitations, eye issues, skin disorders, and sleep disruption [59]. Side effects of treatments for sarcoidosis may also negatively impact quality of life for these patients [60]. Patients with ocular sarcoidosis have a significantly diminished quality of life based on a visual questionnaire when compared to patients without ocular disease. This was particularly true in patients with vision of 20/100 or worse [61]. A prospective, cross-sectional survey study found that women with sarcoidosis showed a greater degree of functional impairment than men, particularly with regard to physical health [62]. There was no difference found in emotional and daily quality of life in men versus women [63]. Extrapulmonary manifestations of sarcoidosis differ by race and sex. Black Americans have a higher prevalence of extrathoracic involvement [30]. A recent study demonstrated that female smokers were more likely to have a reduced diffusion capacity for carbon monoxide than male smokers, and both female sex and smoking are associated with the development of extrapulmonary manifestations of the disease [64]. Death from sarcoidosis is closely associated with respiratory, cardiac, neurologic, and hepatic involvement [4]. A recent report highlighted an increased rate of mortality in recent years, specifically citing a 30% increase in men and 50% increase in women in 2007 compared to 1988 [63]. Although sarcoidosis deaths were most common in younger patients (35–44 years), the increase in mortality was greatest in older individuals (55–74 years), specifically among nonHispanic black females. The cause of death was determined to be sarcoidosis in almost 60% of patients, while other causes included ischemic heart disease, cardiomyopathy, lung cancer, and pneumonia [65]. 6. Proposed Reasons for Sex Differences Women tend to have higher rates of many autoimmune diseases [66], including sarcoidosis. In fact, autoimmune disease is the fifth leading cause of death among women [66]. Proposed reasons for sex differences in incidence of autoimmune disease have included environmental factors such as hormonal and genetic effects, gender-biased activities, occupational exposure, medications, smoking, and vitamin D deficiency in women [67]. Women may be more likely Pregnancy class C C X D D C B B B D D Risk cannot be ruled out Risk cannot be ruled out Should not be used during pregnancy Positive evidence of risk Positive evidence of risk Risk cannot be ruled out No evidence of risk in humans No evidence of risk in humans No evidence of risk in humans Positive evidence of risk Positive evidence of risk to develop autoimmune disease due to hormonal variation during menstruation, pregnancy, and childbirth. The natural breakdown of epithelial tissue that occurs during these events may increase a woman’s exposure to triggers of autoimmune inflammation [68, 69]. In the case of sarcoidosis, this may be of particular importance, as a 2011 study into risk of sarcoidosis among adults exposed to the World Trade Center (WTC) catastrophe found that firefighters, police officers, lower Manhattan residents, area workers, and even passers-by were found to have an increased risk of sarcoidosis. This study specifically concluded that working on the WTC debris pile was associated with an increased rate of post-9/11 sarcoidosis diagnosis [70]. Gender differences may also be related to genetics. A recent Brazilian study found that certain HLA alleles were more likely to be found in mestizos and blacks with sarcoidosis [71]. It is possible that men and women carry these particular haplotypes to varying degrees. Microchimerism and epigenetics have also been implicated in the reason behind female predominance in many autoimmune diseases, including sarcoidosis [72]. 7. Conclusions Almost every aspect of sarcoidosis, from epidemiology and clinical presentation to treatment options and prognosis, is influenced by patient sex. Men are diagnosed at a younger age than women, and the onset of sarcoidosis in women follows a bimodal distribution with a second peak of onset occurring after age of 50. In this older cohort of patients, chest X-ray may not be sensitive enough to identify pulmonary changes and computed tomography is recommended. Women tend to have more CME and a worse overall visual prognosis than men. Women are more likely to have cutaneous involvement than men, and the mortality rate is higher in women. Several medications used to treat sarcoidosis are contraindicated in pregnancy; therefore, discussions regarding birth control should be thorough and repeated at every visit. Conflict of Interests The authors declare that there is no conflict of interests regarding the publication of this paper. Journal of Ophthalmology References [1] M. C. Iannuzzi, B. A. Rybicki, and A. S. Teirstein, “Sarcoidosis,” The New England Journal of Medicine, vol. 357, no. 21, pp. 2153– 2165, 2007. [2] J. E. Gottlieb, H. L. Israel, R. M. Steiner, J. Triolo, and H. Patrick, “Outcome in sarcoidosis: the relationship of relapse to corticosteroid therapy,” Chest, vol. 111, no. 3, pp. 623–631, 1997. [3] “Statement on sarcoidosis. Joint statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS board of directors and by the ERS executive committee,” American Journal of Respiratory and Critical Care Medicine, vol. 160, no. 2, pp. 736–755, 1999. [4] R. P. Baughman, D. B. Winget, E. H. Bowen, and E. E. Lower, “Predicting respiratory failure in sarcoidosis patients,” Sarcoidosis Vasculitis and Diffuse Lung Disease, vol. 14, no. 2, pp. 154–158, 1997. [5] M. A. Judson, “The diagnosis of sarcoidosis,” Clinics in Chest Medicine, vol. 29, no. 3, pp. 415–427, 2008. [6] H. Tomita, S. Sato, R. Matsuda et al., “Serum lysozyme levels and clinical features of sarcoidosis,” Lung, vol. 177, no. 3, pp. 161–167, 1999. [7] A. Nakamura, S. Ohara, K. Maruyama, Y.-I. Takei, M. Shindo, and N. Yanagisawa, “Systemic sarcoidosis: a case with a focal hydrocephalus and elevated lysozyme and angiotensinconverting enzyme in the cerebrospinal fluid,” Journal of Neurology, vol. 246, no. 4, pp. 320–322, 1999. [8] O. P. Sharma, “Vitamin D, calcium, and sarcoidosis,” Chest, vol. 109, no. 2, pp. 535–539, 1996. [9] G. L. Barbour, J. W. Coburn, E. Slatopolsky, A. W. Norman, and R. L. Horst, “Hypercalcemia in an anephric patient with sarcoidosis: evidence for extrarenal generation of 1,25dihydroxyvitamin D,” The New England Journal of Medicine, vol. 305, no. 8, pp. 440–443, 1981. [10] J. Mambretti, “Chest x-ray stages of sarcoidosis,” Journal of Insurance Medicine, vol. 36, no. 1, pp. 91–92, 2004. [11] M. B. Gotway, M. L. Storto, J. A. Golden, G. P. Reddy, and W. R. Webb, “Incidental detection of thoracic sarcoidosis on wholebody 18Fluorine-2- Fluoro-2-Deoxy-D-Glucose positron emission tomography,” Journal of Thoracic Imaging, vol. 15, no. 3, pp. 201–204, 2000. [12] G. W. Hunninghake, U. Costabel, M. Ando et al., “ATS/ERS/ WASOG statement on sarcoidosis. American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and other Granulomatous Disorders,” Sarcoidosis, Vasculitis and Diffuse Lung Diseases, vol. 16, no. 2, pp. 149–173, 1999. [13] S. Löfgren, “Primary pulmonary sarcoidosis. I. Early signs and symptoms,” Acta Medica Scandinavica, vol. 145, no. 6, pp. 424– 431, 1953. [14] J. Mañá, C. Gómez-Vaquero, A. Montero et al., “Lofgren’s syndrome revisited: a study of 186 patients,” American Journal of Medicine, vol. 107, no. 3, pp. 240–245, 1999. [15] M. A. Judson, B. W. Thompson, D. L. Rabin et al., “The diagnostic pathway to sarcoidosis,” Chest, vol. 123, no. 2, pp. 406–412, 2003. [16] C. D. Obenauf, H. E. Shaw, C. F. Sydnor, and G. K. Klintworth, “Sarcoidosis and its ophthalmic manifestations,” American Journal of Ophthalmology, vol. 86, no. 5, pp. 648–655, 1978. 5 [17] L. E. Siltzbach, D. G. James, E. Neville et al., “Course and prognosis of sarcoidosis around the world,” American Journal of Medicine, vol. 57, no. 6, pp. 847–852, 1974. [18] D. G. James, R. Anderson, D. Langley, and D. Ainslie, “Ocular sarcoidosis,” The British Journal of Ophthalmology, vol. 48, pp. 461–470, 1964. [19] A. D. Birnbaum, F. S. Oh, A. Chakrabarti, H. H. Tessler, and D. A. Goldstein, “Clinical features and diagnostic evaluation of biopsy-proven ocular sarcoidosis,” Archives of Ophthalmology, vol. 129, no. 4, pp. 409–413, 2011. [20] T. Izumi, “Are corticosteroids harmful to sarcoidosis?” Sarcoidosis, vol. 11, supplement 1, pp. 119–122, 2012. [21] J. A. Stigt, J. E. Boers, A. H. Oostdijk, J.-W. K. van den Berg, and H. J. M. Groen, “Mediastinal incidentalomas,” Journal of Thoracic Oncology, vol. 6, no. 8, pp. 1345–1349, 2011. [22] B. A. Rybicki, M. Major, J. Popovich Jr., M. J. Maliarik, and M. C. Iannuzzi, “Racial differences in sarcoidosis incidence: a 5-year study in a health maintenance organization,” American Journal of Epidemiology, vol. 145, no. 3, pp. 234–241, 1997. [23] K.-E. Byg, N. Milman, and S. Hansen, “Sarcoidosis in Denmark 1980–1994. A registry-based incidence study comprising 5536 patients,” Sarcoidosis Vasculitis and Diffuse Lung Diseases, vol. 20, no. 1, pp. 46–52, 2003. [24] K. O. Forsén, N. Milman, A. Pietinalho, and O. Selroos, “Sarcoidosis in the Nordic countries 1950–1987,” Sarcoidosis, vol. 9, no. 2, pp. 140–141, 1992. [25] R. P. Baughman, A. S. Teirstein, M. A. Judson et al., “Clinical characteristics of patients in a case control study of sarcoidosis,” American Journal of Respiratory and Critical Care Medicine, vol. 164, no. 10, pp. 1885–1889, 2001. [26] M. A. Judson, A. D. Boan, and D. T. Lackland, “The clinical course of sarcoidosis: presentation, diagnosis, and treatment in a large white and black cohort in the United States,” Sarcoidosis Vasculitis and Diffuse Lung Diseases, vol. 29, no. 2, pp. 119–127, 2012. [27] M. Yamaguchi, Y. Hosoda, R. Sasaki, and K. Aoki, “Epidemiological study on sarcoidosis in Japan. Recent trends in incidence and prevalence rates and changes in epidemiological features,” Sarcoidosis, vol. 6, no. 2, pp. 138–146, 1989. [28] C. E. Henke, G. Henke, L. R. Elveback, C. M. Beard, D. J. Ballard, and L. T. Kurland, “The epidemiology of sarcoidosis in Rochester, Minnesota: a population-based study of incidence and survival,” American Journal of Epidemiology, vol. 123, no. 5, pp. 840–845, 1986. [29] N. Milman and O. Selroos, “Pulmonary sarcoidosis in the Nordic countries 1950–1982. Epidemiology and clinical picture,” Sarcoidosis, vol. 7, no. 1, pp. 50–57, 1990. [30] Y. C. Cozier, J. S. Berman, J. R. Palmer, D. A. Boggs, L. A. Wise, and L. Rosenberg, “Reproductive and hormonal factors in relation to incidence of sarcoidosis in US black women,” American Journal of Epidemiology, vol. 176, no. 7, pp. 635–641, 2012. [31] K. T. Jørgensen, B. V. Pedersen, N. M. Nielsen, S. Jacobsen, and M. Frisch, “Childbirths and risk of female predominant and other autoimmune diseases in a population-based Danish cohort,” Journal of Autoimmunity, vol. 38, no. 2-3, pp. J81–J87, 2012. [32] G. Hillerdal, E. Nou, K. Osterman, and B. Schmekel, “Sarcoidosis: epidemiology and prognosis: a 15-year European study,” American Review of Respiratory Disease, vol. 130, no. 1, pp. 29– 32, 1984. 6 [33] P. Chevalet, R. Clément, O. Rodat, A. Moreau, J.-M. Brisseau, and J.-P. Clarke, “Sarcoidosis diagnosed in elderly subjects: retrospective study of 30 cases,” Chest, vol. 126, no. 5, pp. 1423– 1430, 2004. [34] L. Varron, V. Cottin, A.-M. Schott, C. Broussolle, and P. Sève, “Late-onset sarcoidosis: a comparative study,” Medicine, vol. 91, no. 3, pp. 137–143, 2012. [35] R. G. J. Marcellis, A. F. Lenssen, M. D. P. Elfferich et al., “Exercise capacity, muscle strength and fatigue in sarcoidosis,” European Respiratory Journal, vol. 38, no. 3, pp. 628–634, 2011. [36] A. Hinz, M. Fleischer, E. Brähler, H. Wirtz, and A. Bosse-Henck, “Fatigue in patients with sarcoidosis, compared with the general population,” General Hospital Psychiatry, vol. 33, no. 5, pp. 462– 468, 2011. [37] A. Hinz, E. Brähler, R. Möde, H. Wirtz, and A. Bosse-Henck, “Anxiety and depression in sarcoidosis: the influence of age, gender, affected organs, concomitant diseases and dyspnea,” Sarcoidosis Vasculitis and Diffuse Lung Diseases, vol. 29, no. 2, pp. 139–146, 2012. [38] H. Yanardaǧ, Ö. Nuri Pamuk, and T. Karayel, “Cutaneous involvement in sarcoidosis: analysis of the features in 170 patients,” Respiratory Medicine, vol. 97, no. 8, pp. 978–982, 2003. [39] J. Grunewald and A. Eklund, “Sex-specific manifestations of Löfgren’s syndrome,” American Journal of Respiratory and Critical Care Medicine, vol. 175, no. 1, pp. 40–44, 2007. [40] A. Khaled, A. Souissi, F. Zeglaoui et al., “Cutaneous sarcoidosis in Tunisia,” Giornale Italiano di Dermatologia e Venereologia, vol. 143, no. 3, pp. 181–185, 2008. [41] J. Mañá, C. Gómez-Vaquero, A. Montero et al., “Lofgren’s syndrome revisited: a study of 186 patients,” American Journal of Medicine, vol. 107, no. 3, pp. 240–245, 1999. [42] N. Porter, H. L. Beynon, and H. S. Randeva, “Endocrine and reproductive manifestations of sarcoidosis,” QJM: Monthly Journal of the Association of Physicians, vol. 96, no. 8, pp. 553– 561, 2003. [43] A. Antonelli, P. Fazzi, P. Fallahi, S. M. Ferrari, and E. Ferrannini, “Prevalence of hypothyroidism and Graves disease in sarcoidosis,” Chest, vol. 130, no. 2, pp. 526–532, 2006. [44] C. O. Turk, M. Schacht, and L. Ross, “Diagnosis and management of testicular sarcoidosis,” Journal of Urology, vol. 135, no. 2, pp. 380–381, 1986. [45] A. Chalvardjian, “Sarcoidosis of the female genital tract,” American Journal of Obstetrics and Gynecology, vol. 132, no. 1, pp. 78– 80, 1978. [46] M. Soheilian, K. Heidari, S. Yazdani, M. Shahsavari, H. Ahmadieh, and M. H. Dehghan, “Patterns of uveitis in a tertiary eye care center in Iran,” Ocular Immunology and Inflammation, vol. 12, no. 4, pp. 297–310, 2004. [47] H. Kitamei, N. Kitaichi, K. Namba et al., “Clinical features of intraocular inflammation in Hokkaido, Japan,” Acta Ophthalmologica, vol. 87, no. 4, pp. 424–428, 2009. [48] Y.-M. Chung, Y.-C. Lin, Y.-T. Liu, S.-C. Chang, H.-N. Liu, and W.-H. Hsu, “Uveitis with biopsy-proven sarcoidosis in Chinese—a study of 60 patients in a uveitis clinic over a period of 20 years,” Journal of the Chinese Medical Association, vol. 70, no. 11, pp. 492–496, 2007. [49] K. Ohara, A. Okubo, H. Sasaki, and K. Kamara, “Intraocular manifestations of systemic sarcoidosis,” Japanese Journal of Ophthalmology, vol. 36, no. 4, pp. 452–457, 1992. [50] A. Lobo, K. Barton, D. Minassian, R. M. du Bois, and S. Lightman, “Visual loss in sarcoid-related uveitis,” Clinical and Experimental Ophthalmology, vol. 31, no. 4, pp. 310–316, 2003. Journal of Ophthalmology [51] A. Rothova, C. Alberts, E. Glasius, A. Kijlstra, H. J. Buitenhuis, and A. C. Breebaart, “Risk factors for ocular sarcoidosis,” Documenta Ophthalmologica, vol. 72, no. 3-4, pp. 287–296, 1989. [52] D. Khalatbari, S. Stinnett, R. M. McCallum, and G. J. Jaffe, “Demographic-related variations in posterior segment ocular sarcoidosis,” Ophthalmology, vol. 111, no. 2, pp. 357–362, 2004. [53] A. D. Birnbaum, W. Huang, O. Sahin, H. H. Tessler, and D. A. Goldstein, “Ocular sarcoidosis misdiagnosed as primary intraocular lymphoma,” Retina, vol. 30, no. 2, pp. 310–316, 2010. [54] K. Pathanapitoon, J. H. M. Goossens, T. C. van Tilborg, P. Kunavisarut, J. Choovuthayakorn, and A. Rothova, “Ocular sarcoidosis in Thailand,” Eye, vol. 24, no. 11, pp. 1669–1674, 2010. [55] P. K. Kaiser, C. Y. Lowder, P. Sullivan et al., “Chest computerized tomography in the evaluation of uveitis in elderly women,” American Journal of Ophthalmology, vol. 133, no. 4, pp. 499–505, 2002. [56] J. P. Cremers, M. Drent, A. Bast et al., “Multinational evidencebased World Association of Sarcoidosis and Other Granulomatous Disorders recommendations for the use of methotrexate in sarcoidosis: integrating systematic literature research and expert opinion of sarcoidologists worldwide,” Current Opinion in Pulmonary Medicine, vol. 19, no. 5, pp. 545–561, 2013. [57] R. M. Tarantola, J. C. Folk, H. C. Boldt, and V. B. Mahajan, “Intravitreal bevacizumab during pregnancy,” Retina, vol. 30, no. 9, pp. 1405–1411, 2010. [58] D. F. Cella, “Quality of life: concepts and definition,” Journal of Pain and Symptom Management, vol. 9, no. 3, pp. 186–192, 1994. [59] D. E. Victorson, D. Cella, H. Grund, and M. A. Judson, “A conceptual model of health-related quality of life in sarcoidosis,” Quality of Life Research, vol. 23, no. 1, pp. 89–101, 2014. [60] C. E. Cox, J. F. Donohue, C. D. Brown, Y. P. Kataria, and M. A. Judson, “Health-related quality of life of persons with sarcoidosis,” Chest, vol. 125, no. 3, pp. 997–1004, 2004. [61] L. N. Saligan, G. Levy-Clarke, T. Wu et al., “Quality of life in sarcoidosis: comparing the impact of ocular and non-ocular involvement of the disease,” Ophthalmic Epidemiology, vol. 17, no. 4, pp. 217–224, 2010. [62] C. E. Cox, J. F. Donohue, C. D. Brown, Y. P. Kataria, and M. A. Judson, “The sarcoidosis health questionnaire: a new measure of health-related quality of life,” American Journal of Respiratory and Critical Care Medicine, vol. 168, no. 3, pp. 323–329, 2003. [63] J. M. Bourbonnais and L. Samavati, “Effect of gender on health related quality of life in sarcoidosis,” Sarcoidosis Vasculitis and Diffuse Lung Diseases, vol. 27, no. 2, pp. 96–102, 2010. [64] W. Krell, J. M. Bourbonnais, R. Kapoor, and L. Samavati, “Effect of smoking and gender on pulmonary function and clinical features in sarcoidosis,” Lung, vol. 190, no. 5, pp. 529–536, 2012. [65] J. J. Swigris, A. L. Olson, T. J. Huie et al., “Sarcoidosis-related mortality in the United States from 1988 to 2007,” American Journal of Respiratory and Critical Care Medicine, vol. 183, no. 11, pp. 1524–1530, 2011. [66] S. J. Walsh and L. M. Rau, “Autoimmune diseases: a leading cause of death among young and middle-aged women in the United States,” American Journal of Public Health, vol. 90, no. 9, pp. 1463–1466, 2000. [67] K. M. Pollard, “Gender differences in autoimmunity associated with exposure to environmental factors,” Journal of Autoimmunity, vol. 38, no. 2-3, pp. J177–J186, 2012. [68] E. Tiniakou, K. H. Costenbader, and M. A. Kriegel, “Sex-specific environmental influences on the development of autoimmune diseases,” Clinical Immunology, vol. 149, no. 2, pp. 182–191, 2013. Journal of Ophthalmology [69] S. Sankaran-Walters, M. Macal, I. Grishina et al., “Sex differences matter in the gut: effect on mucosal immune activation and inflammation,” Biology of Sex Differences, vol. 4, no. 1, article 10, 2013. [70] H. T. Jordan, S. D. Stellman, D. Prezant, A. Teirstein, S. S. Osahan, and J. E. Cone, “Sarcoidosis diagnosed after september 11, 2001, among adults exposed to the world trade center disaster,” Journal of Occupational and Environmental Medicine, vol. 53, no. 9, pp. 966–974, 2011. [71] C. H. da Costa, V. L. Silva, G. M. Fabricio-Silva, M. Usnayo, R. Rufino, and L. C. Porto, “HLA in a cohort of Brazilian patients with sarcoidosis,” Human Immunology, vol. 74, no. 10, pp. 1326– 1332, 2013. [72] M. P. Mallampalli, E. Davies, D. Wood, H. Robertson, F. Polato, and C. L. Carter, “Role of environment and sex differences in the development of autoimmune diseases: a roundtable meeting report,” Journal of Women’s Health, vol. 22, no. 7, pp. 578–586, 2013. 7 Hindawi Publishing Corporation Journal of Ophthalmology Volume 2014, Article ID 565262, 5 pages http://dx.doi.org/10.1155/2014/565262 Review Article Gender and Uveitis in Patients with Multiple Sclerosis Lynn K. Gordon1 and Debra A. Goldstein2 1 2 Department of Ophthalmology, Jules Stein Eye Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA Department of Ophthalmology, Northwestern Feinberg School of Medicine, Chicago, IL 60613, USA Correspondence should be addressed to Lynn K. Gordon; [email protected] Received 4 October 2013; Accepted 30 March 2014; Published 7 May 2014 Academic Editor: Janet L. Davis Copyright © 2014 L. K. Gordon and D. A. Goldstein. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Multiple sclerosis (MS), a demyelinating disease of the central nervous system, is more commonly seen in women. It has been associated with both anterior and intermediate uveitis as well as retinal vasculitis. Ocular inflammation may develop concurrent with, prior to, or after the development of neurologic signs and symptoms. Patients with MS have an approximately 1% chance of developing intraocular inflammation. Patients with intermediate uveitis have an 8–12% risk of being diagnosed with MS. This risk is higher in females and in those with bilateral disease. This should be kept in mind when evaluating patients with uveitis, particularly in those patients for whom TNF inhibitor therapy is being considered, as these agents may worsen demyelinating disease. 1. Introduction Multiple sclerosis (MS), a chronic and episodic demyelinating disease of the central nervous system, affects many aspects of vision and ocular health, from afferent to efferent pathways. Ocular signs and symptoms associated with MS range from optic neuritis, the most commonly associated ophthalmologic disease, which occurs in nearly 50% of MS patients, to internuclear ophthalmoplegia, associated with demyelinating lesions of the medial longitudinal fasciculus, and to various types of debilitating nystagmus and, less commonly, ocular inflammatory disease [1–4]. Disability secondary to visual symptoms is an important cause of morbidity among patients with MS [5]. A large sampling of self-reported data from almost 9000 North American patients with MS revealed that nearly 16% of patients reported a visual comorbidity, most occurring after the diagnosis of MS was made [5]. Uveitis was identified by 3% of these individuals as responsible for significant disease morbidity. In this paper we highlight gender differences in MS and review the data regarding MSassociated uveitis. 2. Gender Differences in Prevalence/Incidence Autoimmune diseases are a significant cause of morbidity and mortality, which disproportionately affect young and middle-aged women [6]. For MS, the female to male ratio is estimated to be approximately 3.5 : 1, and the ratio of affected women to affected men has actually increased over the past several decades [7]. The prevalence is estimated to be around 1 per 100,000 individuals. Although the mean age for diagnosis of MS is around 37, the typical age of onset ranges from the early 20s to the mid 40s. However, MS can also occur in children and in older adults; it is just less commonly diagnosed at the extremes of life. There are geographic differences in disease onset, typically with higher incidence in countries further away from the equator and a lower incidence in Asia, possibly implicating environmental factors or infectious agents in disease pathogenesis [8]. However, there are exceptions to this observation and this generalization is not completely valid. Some populations are at high risk in countries close to the equator and others are at low risk in certain northern countries [9]. The risk for disease in these countries may reflect other genetic, epigenetic, or noninfectious environmental factors. In addition to differences in rates of development of MS between men and women, there are differences between the sexes in age at development of the disease and, possibly, in disease course. One large series reported that MS presented, on average, two years later in men than women (31.2 years versus 29.3 years) [10]. As well, there is evidence from 2 some series that males are more likely to develop primaryprogressive MS, although this has not been borne out by a large meta-analysis [11]. Genetic susceptibility factors also play an important role, with an increased concordance of disease among monozygotic twins as compared to dizygotic twins, as well as an increased risk for MS among first-degree relatives of patients with the disease. Risk loci in the human leukocyte antigen (HLA) family of molecules including HLA-DRB1 have been implicated in disease susceptibility [7, 12, 13]. Large genome wide association studies (GWAS) demonstrated additional complex genetic candidates for disease susceptibility; these candidates typically involve genes in immunologic pathways including T-cell differentiation [7]. 3. Clinical Manifestations of Inflammatory Ocular Disease The clinical manifestations of intraocular inflammation in MS include chronic anterior uveitis, intermediate uveitis, and retinal vasculitis [14–18]. In addition to vasculitis and ischemia, granulomatous retinal periphlebitis was found in 4 cases (7 eyes) and focal lymphocytic or granulomatous retinitis was present in 3 cases (5 eyes) of 47 autopsy cases of multiple sclerosis studied pathologically [19]. Complications of inflammation include cataract, elevation in intraocular pressure, hypotony, retinal ischemia, and retinal neovascularization. In one retrospective study, the authors described 16 patients seen in a uveitis service who carried a diagnosis of MS [14]. They observed anterior uveitis in about 30% of eyes and intermediate uveitis and posterior uveitis each in about 20% of eyes. Three of the patients were not known to have MS at the time of their ocular disease onset. In a different study, 3.1% of 1916 uveitis patients seen in a tertiary care clinic had a diagnosis of MS [20]. In this study anterior uveitis accounted for 10% and intermediate uveitis comprised 78% of the uveitis seen in patients with MS; posterior and panuveitis were each seen in a single patient. Of those with both MS and uveitis, 74.6% were female, highlighting the gender disparity of the underlying autoimmune disease. Another study of 1254 patients with uveitis revealed 16 with a concomitant diagnosis of MS, for a prevalence of 1.3%; the majority of these patients had bilateral disease [21]. Nine of these patients had diagnoses of MS that preceded onset of uveitis, three patients had concurrent diagnoses, and four patients developed uveitis prior to the diagnosis of MS. 88% of these patients were female. The mean age for the diagnosis of uveitis was 37.2 and mean age for diagnosis of MS was 35.5 years. Almost half of these patients also had optic neuritis. Granulomatous anterior uveitis was present in 56%, cataract in 38%, intermediate uveitis in 81%, and retinal vasculitis in 56%. Cystoid macular edema was present in about a third of affected patients. Although uveitis is the most common cause of macular edema in MS patients, it must be recognized that fingolimod, an oral agent FDA approved for MS treatment, is itself associated with development in macular edema in approximately 0.05% of patients [22]. 5970 patients with chronic anterior uveitis (CAA) from a different tertiary care uveitis referral center who were Journal of Ophthalmology evaluated over a period of three decades were analyzed for underlying systemic disease [23]. Multiple sclerosis was present in 30 patients (1.6%). Notably, the percentage of patients with MS increased each decade and was associated with 2.36% of all new patients with CAA evaluated between 1995 and 2004. In a cross-sectional study of uveitis patients seen in Vienna between 1995 and 2009, the prevalence of MS was 0.9% [24]. Of the 25 cases of uveitis with MS described in that study, 19 were intermediate, 4 were anterior, and 2 were posterior. The mean age of these patients was 35.9 years but the gender distribution was not reported. Uveitis may be associated with multiple types of neurological disease. A retrospective review of all patients seen in a tertiary care center with a diagnosis of uveitis identified 115 patients with an underlying neurological disease [25]. Fourteen of these patients, or 1% of the total number of patients seen in the referral center over the course of fifteen years, were diagnosed as having MS. Half of these patients (50%) carried a diagnosis of pars planitis and 29% had chronic granulomatous uveitis. Intermediate uveitis typically affects patients in the younger years, ranging from age 5 to 30, and does not typically have associations with either race or gender [26]. Bilateral disease is seen in at least 80%, and complications such as cataract, glaucoma, or cystoid macular edema are common [27]. 4. What Is the Risk for Uveitis If MS Is Diagnosed? Multiple groups have investigated the frequency of uveitis in patients with multiple sclerosis but the estimates vary widely from 0.4% to 28.5% depending on the study [28]. One study prospectively evaluated 50 MS patients, 61.8% of whom were female, with a complete eye examination in order to identify concomitant inflammatory eye disease [29]. None of the patients had a history of eye disease, including optic neuritis. Nine of the patients (18%), 4 female and 5 male, had retinal vascular changes, either venous sheathing or focal cuffing, often with fluorescein angiographic evidence of leakage and inflammation, without overt cells. Interestingly, a similar study was performed in Egypt in which 75 patients with MS were prospectively evaluated with a full ophthalmological examination [30]. This study differs from most studies on MS in that there was not a striking female preponderance (34 males, 41 females), although it is not clear if this reflected the gender distribution of patients in this country with MS. In this cohort, seven patients were diagnosed as having intermediate uveitis and, in contrast to other studies, five of the seven were male and all of the males were young, with a mean age of 20. A separate study performed in Croatia identified intermediate uveitis in 28.5% of a total of 42 patients with MS [31]. This is a very high prevalence of uveitis, higher than other studies, and it would be interesting to understand more about this patient population to determine why their risk for uveitis is so high. A population based study of uveitis prevalence in 4300 patients in the Lyon Multiple Sclerosis cohort was performed using self-reporting of uveitis. The records of 31 identified patients were extracted and evaluated for uveitis Journal of Ophthalmology classification, gender, and timing of MS onset. Three patients who either had Fuchs disease or HLA B27 associated disease were excluded from additional analysis. In the final cohort, 28 individuals were identified, 0.65% of the total number of MS patients. Women comprised 68% of the total patients with uveitis. In 46% of the patients, uveitis preceded the onset of MS. In this series 36% of patients had posterior uveitis whereas intermediate uveitis only was diagnosed in 7% of the patients [28]. Similarly, another review of 1098 patients from an MS clinic revealed a 1% prevalence of uveitis [32]. In a large population based study in the Northern California Kaiser Permanente Medical Care Program, a computer search of records of more than 5,000 patients with MS and age-matched controls was evaluated for prevalence of uveitis, among other autoimmune diseases [33]. Uveitis was diagnosed in 1.3% of patients with MS as compared to 0.6% of controls. Additional information about the demographics or type of uveitis is not available. In this series, uveitis preceded the diagnosis of MS in only 1% of patients. The population based studies on the prevalence of uveitis in MS are large and confirm that 0.65–1.3% of patients with MS will have uveitis. What is less clear is the timing of onset of uveitis relative to MS, with uveitis preceding MS diagnosis in anywhere from 1 to 46% of patients. These reports are somewhat limited by the quality of the available data but underscore the need to consider uveitis in patients with MS. 5. What Is the Risk of MS If Intermediate Uveitis (Pars Planitis) Is Diagnosed? The term intermediate uveitis is a general one that describes uveitis in which the inflammatory cells are primarily located in the vitreous cavity. Pars planitis refers to a specific subset of idiopathic intermediate uveitis in which there is snowball or snowbank formation and no underlying systemic disease responsible for the inflammation [34]. Older studies did not exclude MS patients from the diagnosis of pars planitis, and in this section we therefore report series on intermediate uveitis and on pars planitis. The experience of a large tertiary care center with patients who carry a diagnosis of intermediate uveitis was published in 1993 [27]. In this retrospective study, 7% of patients with intermediate uveitis had MS. Another large series of 53 patients with pars planitis was reported in 1999 [35]. The mean age at diagnosis was 26 years with a range of 5 to 50 years. There were 20 males and 33 females. General medical or neurological data was available for 37 of the patients. Six were diagnosed with MS (11% of all intermediate uveitis patients), three prior to onset of uveitis. The patients with MS and pars planitis tended to be female (83%) and older (mean age of 36) and were also more likely to have vascular sheathing on examination. Another study of patients evaluated at a tertiary care uveitis center identified intermediate uveitis in 22.9% of patients (𝑛 = 438), and 10.3% of these patients had MS [20]. In another prospective clinical study of 21 patients with pars planitis, 47.6% demonstrated demyelinating lesions on MRI and 33.3% were diagnosed with definitive MS. Those patients diagnosed with MS were more likely to be older than the age of 25 [36]. This series 3 reports the highest association with MS in patients with intermediate uveitis. A population based study was performed in Olmsted, County, Minnesota, looking at all patients with a diagnosis of pars planitis who had been evaluated over a 20-year time period [37]. 25 patients with pars planitis who had sufficient medical records, provided authorization for the study, and did not have sarcoidosis or Behcet disease were identified. With longitudinal followup for a mean of 14.3 years, MS was diagnosed in 3 of the patients, for a rate of 12%. Not surprisingly, there is geographic variation in rates of MS diagnosed in patients with intermediate uveitis. A recent study of 87 intermediate uveitis patients in a referral service in Tunisia revealed a lower percentage of patients with underlying MS (2.3%) and a higher association with sarcoidosis (9.2%) [38]. Genetic testing for risk factors in patients with intermediate uveitis reveals association with the IL2RA rs2104286 gene polymorphism [39]. Interestingly this same polymorphism is observed in MS and other autoimmune diseases. Overall, in the majority of studies, 8–12% of patients with intermediate uveitis carry a diagnosis of or will develop MS. Additional risk factors for this diagnosis include female gender and bilateral disease. Although there is a gender disparity in rates of disease, these likely reflect the underlying increase in MS in females. 6. Possible Explanations for Gender Differences in MS The gender differences in rates of MS are not understood, but there are many hypotheses with supporting data that suggest potential mechanisms [40]. There is a large body of literature that explores this topic, and only several of the leading hypotheses are presented here. One possibility is that these differences are mediated by epigenetic DNA modification by either hormonal or environmental stimuli [41]. Other studies implicate the X chromosome in disease susceptibility. For example, in the rodent MS model of experimental autoimmune encephalitis (EAE), having two X chromosomes increases disease susceptibility for unknown reasons [42]. Interestingly, in studies where the EAE disease was transferred from affected mice using purified T lymphocytes, T cells from female donors were more successful in creating disease in the recipient than were T cells from male donors, thus suggesting that there must be sexual differences in activation of the immune response [43]. There was also increased disease in female recipients in contrast to male recipients, implicating increased effector activation that is also determined by gender [44]. Hormonal differences between females and males may also impact disease severity and progression. Pregnancy is well documented to be associated with a decrease in MS relapses [7]. During pregnancy, the high expression of estriol, which is not measurable outside of pregnancy, may be associated with a milder course [26]. Phase II clinical trials are currently ongoing using exogenous estriol as a potential therapy in MS [45, 46]. Vitamin D has also been postulated to play a role in disease pathogenesis. Patients with MS typically 4 have lower levels of vitamin D, and some studies report lower levels of vitamin D in females in comparison to males [47]. In EAE experiments, increasing vitamin D in the diet has been shown to ameliorate the disease [26]. 7. Conclusion These studies suggest that up to 3% of all patients evaluated in uveitis clinics also carry a diagnosis of MS. The uveitis observed in these patients is often bilateral. Intermediate uveitis is the most common, followed by anterior uveitis, which may be characterized by a granulomatous appearance. Retinal vascular changes in the absence of symptoms are seen in a significant percentage of patients. Patients who have known MS carry an approximately 1% risk of developing clinical intraocular inflammatory disease. Conversely, patients with intermediate uveitis are at moderate risk for MS, around 8–12%. The risk is higher in females and in those with bilateral disease. Therefore, these patients should be routinely questioned regarding transient (lasting several weeks) neurologic symptoms that might otherwise be ignored by the patient. Patients with uveitis and MS are more likely to be female, in concordance with the gender predisposition for MS. Importantly some cases of uveitis occur prior to the diagnosis of MS, and in these patients one must be particularly careful to be alert to the possible diagnosis, in particular if biologic immune modulators are contemplated for therapy, as exposure to TNF-alpha inhibitors heightens the risk for demyelinating lesions [48]. Conflict of Interests The authors declare that there is no conflict of interests regarding the publication of this paper. References [1] L. Chen and L. K. Gordon, “Ocular manifestations of multiple sclerosis,” Current Opinion in Ophthalmology, vol. 16, no. 5, pp. 315–320, 2005. [2] J. Graves and L. J. Balcer, “Eye disorders in patients with multiple sclerosis: natural history and management,” Clinical Ophthalmology, vol. 4, no. 1, pp. 1409–1422, 2010. [3] P. Allegri, R. Rissotto, C. P. Herbort, and U. Murialdo, “CNS diseases and uveitis,” Journal of Ophthalmic and Vision Research, vol. 6, no. 4, pp. 284–308, 2011. [4] M. I. Steinlin, S. I. Blaser, D. L. MacGregor, and J. R. Buncic, “Eye problems in children with multiple sclerosis,” Pediatric Neurology, vol. 12, no. 3, pp. 207–212, 1995. [5] R. A. Marrie, G. Cutter, and T. Tyry, “Substantial adverse association of visual and vascular comorbidities on visual disability in multiple sclerosis,” Multiple Sclerosis, vol. 17, no. 12, pp. 1464– 1471, 2011. [6] G. S. Cooper and B. C. Stroehla, “The epidemiology of autoimmune diseases,” Autoimmunity Reviews, vol. 2, no. 3, pp. 119–125, 2003. [7] H. F. Harbo, R. Gold, and M. Tintore, “Sex and gender issues in multiple sclerosis,” Therapeutic Advances in Neurological Disorders, vol. 6, pp. 237–248, 2013. Journal of Ophthalmology [8] G. C. Ebers and A. D. Sadovnick, “The geographic distribution of multiple sclerosis: a review,” Neuroepidemiology, vol. 12, no. 1, pp. 1–5, 1993. [9] G. Rosati, “The prevalence of multiple sclerosis in the world: an update,” Neurological Sciences, vol. 22, no. 2, pp. 117–139, 2001. [10] M. Cossburn, G. Ingram, C. Hirst, Y. Ben-Shlomo, T. P. Pickersgill, and N. P. Robertson, “Age at onset as a determinant of presenting phenotype and initial relapse recovery in multiple sclerosis,” Multiple Sclerosis, vol. 18, no. 1, pp. 45–54, 2012. [11] J. Stellmann, A. Neuhaus, C. Lederer, M. Daumer, and C. Heesen, “PMC3961431 validating predictors of disease progression in a large cohort of primary-progressive multiple sclerosis based on a systematic literature review,” PLoS ONE, vol. 9, no. 3, Article ID e92761, 2014. [12] S. Sawcer, G. Hellenthal, M. Pirinen et al., “Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis,” Nature, vol. 476, pp. 214–219, 2011. [13] N. A. Patsopoulos, L. F. Barcellos, R. Q. Hintzen et al., “Finemapping the genetic association of the major histocompatibility complex in multiple sclerosis: HLA and non-HLA effects,” PLOS Genetics, vol. 9, no. 11, Article ID e1003926. [14] H. M. A. Towler and S. Lightman, “Symptomatic intraocular inflammation in multiple sclerosis,” Clinical and Experimental Ophthalmology, vol. 28, no. 2, pp. 97–102, 2000. [15] M. Zierhut and C. S. Foster, “Multiple sclerosis, sarcoidosis and other diseases in patients with pars planitis,” Developments in ophthalmology, vol. 23, pp. 41–47, 1992. [16] B. C. Breger and I. H. Leopold, “The incidence of uveitis in multiple sclerosis,” American Journal of Ophthalmology, vol. 62, no. 3, pp. 540–545, 1966. [17] C. L. Giles, “Peripheral uveitis in patients with multiple sclerosis,” American Journal of Ophthalmology, vol. 70, no. 1, pp. 17–19, 1970. [18] J. I. Lim, H. H. Tessler, and J. A. Goodwin, “Anterior granulomatous uveitis in patients with multiple sclerosis,” Ophthalmology, vol. 98, no. 2, pp. 142–145, 1991. [19] A. C. Arnold, J. S. Pepose, R. S. Hepler, and R. Y. Foos, “Retinal periphlebitis and retinitis in multiple sclerosis. I. Pathologic characteristics,” Ophthalmology, vol. 91, no. 3, pp. 255–262, 1984. [20] E. Jakob, M. S. Reuland, F. Mackensen et al., “Uveitis subtypes in a German interdisciplinary uveitis center—analysis of 1916 patients,” The Journal of Rheumatology, vol. 36, no. 1, pp. 127– 136, 2009. [21] G. Zein, A. Berta, and C. S. Foster, “Multiple sclerosis-associated uveitis,” Ocular Immunology and Inflammation, vol. 12, no. 2, pp. 137–142, 2004. [22] N. Jain and M. T. Bhatti, “Fingolimod-associated macular edema: incidence, detection, and management,” Neurology, vol. 78, pp. 672–680, 2012. [23] A. D. Birnbaum, D. M. Little, H. H. Tessler, and D. A. Goldstein, “Etiologies of chronic anterior uveitis at a tertiary referral center over 35 years,” Ocular Immunology and Inflammation, vol. 19, no. 1, pp. 19–25, 2011. [24] T. Barisani-Asenbauer, S. M. Maca, L. Mejdoubi et al., “Uveitisa rare disease often associated with systemic diseases and infections- a systematic review of 2619 patients,” Orphanet Journal of Rare Diseases, vol. 7, article 57, 2012. [25] J. R. Smith and J. T. Rosenbaum, “Neurological concomitants of uveitis,” The British Journal of Ophthalmology, vol. 88, no. 12, pp. 1498–1499, 2004. Journal of Ophthalmology [26] A. A. Bonfioli, F. M. Damico, A. L. L. Curi, and F. Orefice, “Intermediate uveitis,” Seminars in Ophthalmology, vol. 20, no. 3, pp. 147–154, 2005. [27] S. A. Boskovich, C. Y. Lowder, D. M. Meisler, and F. A. Gutman, “Systemic diseases associated with intermediate uveitis,” Cleveland Clinic Journal of Medicine, vol. 60, no. 6, pp. 460–465, 1993. [28] J. Le Scanff, P. Sève, C. Renoux et al., “Uveitis associated with multiple sclerosis,” Multiple Sclerosis Journal, vol. 14, pp. 415– 417, 2008. [29] E. M. Graham, D. A. Francis, M. D. Sanders, and P. Rudge, “Ocular inflammatory changes in established multiple sclerosis,” Journal of Neurology Neurosurgery and Psychiatry, vol. 52, no. 12, pp. 1360–1363, 1989. [30] A. M. Karara, T. A. Macky, and M. H. Sharawy, “Pattern of uveitis in an Egyptian population with multiple sclerosis: a hospital-based study,” Ophthalmic Research, vol. 49, pp. 25–29, 2013. [31] T. Vidović, B. Cerovski, and T. Jukić, “The appereance of pars planitis in multiple sclerosis,” Collegium Antropologicum, vol. 29, no. 1, pp. 203–206, 2005. [32] V. Biousse, C. Trichet, E. Bloch-Michel, and E. Roullet, “Multiple sclerosis associated with uveitis in two large clinic-based series,” Neurology, vol. 52, no. 1, pp. 179–181, 1999. [33] A. Langer-Gould, K. B. Albers, S. K. Van Den Eeden, and L. M. Nelson, “Autoimmune diseases prior to the diagnosis of multiple sclerosis: a population-based case-control study,” Multiple Sclerosis, vol. 16, no. 7, pp. 855–861, 2010. [34] D. A. Jabs, R. B. Nussenblatt, and J. T. Rosenbaum, “Standardization of uveitis nomenclature for reporting clinical data. Results of the first international workshop,” American Journal of Ophthalmology, vol. 140, no. 3, pp. 509–516, 2005. [35] S. C. Raja, D. A. Jabs, J. P. Dunn et al., “Pars planitis: clinical features and class II HLA associations,” Ophthalmology, vol. 106, pp. 594–599, 1999. [36] J. F. Prieto, E. Dios, J. M. Gutierrez, A. Mayo, M. Calonge, and J. M. Herreras, “Pars planitis: epidemiology, treatment, and association with multiple sclerosis,” Ocular Immunology and Inflammation, vol. 9, no. 2, pp. 93–102, 2001. [37] M. J. Donaldson, J. S. Pulido, D. C. Herman, N. Diehl, and D. Hodge, “Pars planitis: a 20-year study of incidence, clinical features, and outcomes,” American Journal of Ophthalmology, vol. 144, no. 6, pp. 812–817, 2007. [38] M. Khairallah, K. Hmidi, S. Attia et al., “Clinical characteristics of intermediate uveitis in Tunisian patients,” International Ophthalmology, vol. 30, pp. 531–537, 2010. [39] E. Lindner, M. Weger, G. Steinwender et al., “IL2RA gene polymorphism rs2104286 A>G seen in multiple sclerosis is associated with intermediate uveitis: possible parallel pathways?” Investigative Ophthalmology & Visual Science, vol. 52, no. 11, pp. 8295–8299, 2011. [40] R. Bove and T. Chitnis, “Sexual disparities in the incidence and course of MS,” Clinical Immunology, vol. 149, no. 2, pp. 201–210, 2013. [41] J. J. Kragt, B. M. van Amerongen, J. Killestein et al., “Higher levels of 25-hydroxyvitamin D are associated with a lower incidence of multiple sclerosis only in women,” Multiple Sclerosis, vol. 15, no. 1, pp. 9–15, 2009. [42] D. L. Smith-Bouvier, A. A. Divekar, M. Sasidhar et al., “A role for sex chromosome complement in the female bias in autoimmune disease,” The Journal of Experimental Medicine, vol. 205, pp. 1099–1108, 2008. 5 [43] R. R. Voskuhl, H. Pitchekian-Halabi, A. MacKenzie-Graham, H. F. McFarland, and C. S. Raine, “Gender differences in autoimmune demyelination in the mouse: implications for multiple sclerosis,” Annals of Neurology, vol. 39, no. 6, pp. 724–733, 1996. [44] N. Kawakami, S. Lassmann, Z. Li et al., “The activation status of neuroantigen-specific T cells in the target organ determines the clinical outcome of autoimmune encephalomyelitis,” The Journal of Experimental Medicine, vol. 199, no. 2, pp. 185–197, 2004. [45] R. D. Spence and R. R. Voskuhl, “Neuroprotective effects of estrogens and androgens in CNS inflammation and neurodegeneration,” Frontiers in Neuroendocrinology, vol. 33, no. 1, pp. 105–115, 2012. [46] R. R. Voskuhl and S. M. Gold, “Sex-related factors in multiple sclerosis susceptibility and progression,” Nature Reviews Neurology, vol. 8, pp. 255–263, 2012. [47] N. M. Van Schoor and P. Lips, “Worldwide vitamin D status,” Best Practice and Research: Clinical Endocrinology and Metabolism, vol. 25, no. 4, pp. 671–680, 2011. [48] L. K. Gordon, “Uveitis and neurological diseases,” The British Journal of Ophthalmology, vol. 88, no. 12, pp. 1483–1484, 2004. Hindawi Publishing Corporation Journal of Ophthalmology Volume 2014, Article ID 820710, 8 pages http://dx.doi.org/10.1155/2014/820710 Review Article Gender Differences in Behçet’s Disease Associated Uveitis Didar Ucar-Comlekoglu,1,2 Austin Fox,1,3 and H. Nida Sen1 1 National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA Ophthalmology Department, Cerrahpasa Medical Faculty, Istanbul University, 34080 Istanbul, Turkey 3 College of Medicine, University of South Alabama, Mobile, AL 36688, USA 2 Correspondence should be addressed to H. Nida Sen; [email protected] Received 8 October 2013; Revised 20 March 2014; Accepted 20 March 2014; Published 23 April 2014 Academic Editor: Debra Goldstein Copyright © 2014 Didar Ucar-Comlekoglu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Behçet’s disease is a systemic vasculitis of unknown etiology, characterized by oral and genital ulceration, skin lesions, and uveitis as well as vascular, central nervous system, and gastrointestinal system involvement. It is prevalent in the Middle East, Mediterranean, and Eastern Asia. The aim of this review is to evaluate the gender differences in clinical manifestations of Behçet’s disease, treatment responses, mortality, and morbidity. Behçet’s disease has been reported to be more prevalent in males from certain geographic regions and particular ethnic groups; however, recent reports indicate more even gender distribution across the world. There are gender differences in clinical manifestations and severity of the disease. Ocular manifestations, vascular involvement, and neurologic symptoms are more frequently reported in male patients whereas oral and genital ulcers, skin lesions, and arthritis occur more frequently in female patients. The disease can have a more severe course in males, and overall mortality rate is significantly higher among young male patients. 1. Introduction Behçet’s disease (BD) is a rare immune-mediated small vessel systemic vasculitis of unknown etiology. It is a multisystem disorder that presents with episodes of mucocutaneous lesions, uveitis, arthritis, venous thrombosis, arterial aneurysms, intestinal ulcers, pulmonary lesions, and central nervous system lesions. Between episodes, clinical findings may be completely normal [1]. BD predominantly affects people with lineages from the Silk Road, particularly Turkey and Japan. BD is more prevalent in certain geographic regions and among particular ethnic groups. There is a strong association with HLA-B51 as has been confirmed by recent genome-wide association studies [2]. Studies have also indicated that shared risk loci with other autoimmune and autoinflammatory diseases, such as ankylosing spondylitis, inflammatory bowel disease, and familial Mediterranean fever, implicate shared and complicated pathogenic pathways involving both the innate and adaptive immune system in Behçet’s disease [3–5]. HLA-B51 has been shown to be present in 40–70% of patients from the Middle East and Asia; however, it is found in only 13% of patients in Europe and North America [6]. Patients with HLA-B51 have a sixfold increased risk of BD, and the disease is usually more severe in HLA-B51 positive patients [4]. Familial BD has been reported in 1–18% of patients, mostly in Turkish, Israeli, and Korean populations [6]. Patients often present in their 30 s–40 s with recurrent oral aphthous ulcers, genital ulcers, and uveitis [7]. Children are rarely affected [5]. In contrast to early reports of higher male to female ratios from Turkey and Japan [8–10], this ratio is now nearly equal with the only exception being Arab countries where higher male prevalence persists. A recent large Chinese population-based study showed no significant gender difference in the incidence or prevalence of Behçet’s disease [11, 12]. BD exhibits a more severe course in males as well as in patients with younger age of onset and HLA-B51 positivity [13]. According to the International Study Group (ISG) for Behçet’s disease diagnostic guidelines, the patient must have recurrent oral (aphthous) ulceration (at least three times within a 12-month period) along with 2 out of the following 4 symptoms: recurrent genital ulcers, ocular 2 Journal of Ophthalmology Table 1: Behçet’s disease and gender differences in clinical manifestations. Clinical findings Mucocutaneous lesions Oral ulcers Genital ulcers Skin pathergy test Arthritis and arthralgia Vascular involvement Central nervous system involvement Gastrointestinal manifestation Uveitis ∗ Incidence/prevalence Erythema nodosum more common in females Papulopustular lesions more common in males More in females More in females More in males More in females∗∗ More in males More in males Comparable More in males (anterior uveitis is more common in women; panuveitis is more common in men) Severity∗ Comparable Comparable More severe in females Comparable Comparable More severe in males More severe in males Comparable More severe in males Comparable indicates that the severity of these clinical manifestations were not significantly different in most studies. Some studies indicated arthritis to be more common in females while others showed comparable incidence. ∗∗ inflammation (anterior and/or posterior uveitis, cells in the vitreous, and retinal vasculitis), skin lesions (including erythema nodosum, pseudofolliculitis, papulopustular lesions, and acne in postadolescents not on corticosteroids), and positive pathergy test [14]. Each of these clinical manifestations may affect men and women differently (Table 1). 2. Gender Differences in Extraocular Manifestations of Behçet’s Disease Mucocutaneous lesions are the most frequently observed findings of BD and include oral and genital ulcers, acneiform lesions, papulopustular lesions, erythema nodosum-like lesions, and superficial thrombophlebitis. Cutaneous lesions constitute part of the major criteria for the diagnosis. The most frequent cutaneous manifestations are erythema nodosum-like lesions, papulopustular lesions, erythema multiforme, and extragenital ulcerations. Erythema nodosumlike lesions are more frequently seen in females and typically affect the lower limbs. These lesions usually resolve within 23 weeks with residual pigmentation [15, 16]. Papulopustular lesions are more frequently seen in males [15–17]. Oral aphthous ulcers are typically recurrent painful ulcerations of the oral mucosa that last up to 14 days. Oral ulcer is the most common manifestation of BD (found in 95–100% of patients) and can be the presenting manifestation in about 70% of patients [12, 18–20]. According to ISG for BD criteria, oral ulcers recurring at least three times over a 12 month period are crucial to the diagnosis [14]. In a retrospective review of 3527 BD patients, Oh et al. found that oral ulcers were more common in females and exacerbations correlated with menstrual cycles [21] (Figure 1(a)). Genital ulcers are less likely than oral ulcers to recur, often heal with scarring, and can be found in 62% to almost 100% of BD patients [12, 22, 23]. Similar to oral ulcers, genital ulcers are also more frequent in females [11, 21, 24–28]. In males, scrotum is more likely to be involved whereas in females, genital ulcers are frequently seen on labia majora and minora [29]. Genital ulcers are especially common and larger in females with BD and resemble recurrent aphthous stomatitis [15]. The skin pathergy test is a skin hyperreactivity test induced by a needle prick. Typically, papule formation (>2 mm diameter), ≥24–48 hours following a sterile needle prick to the forearm, is considered a positive response [14]. According to the ISG for BD, pathergy positivity is among the major criteria for the diagnosis. Different pathergy reaction rates have been reported worldwide (6–71%) [30], but it is especially high in Japan (44%) [31] and the Middle East (60– 70%) [32]. Pathergy positivity is more common in males [15, 16] but is not associated with an increased risk for specific mucocutaneous or systemic involvement or a more severe disease course. An epidemiologic study from Korea reported an overall female predominance among BD patients and higher positivity of pathergy test in male patients [33]. Arthritis and arthralgia have been reported in approximately 35–50% of BD patients [34]. Some reports revealed high frequencies in females (56%) [24, 35] whereas some reports indicated similar incidence in both sexes [26]. It is usually mono- or oligoarticular arthritis and typically resolves in a few weeks without deformity or radiological erosions. The knee joint is the most commonly affected followed by ankle, wrist, and elbow joints. Joint manifestations are frequently seen with erythema nodosum and thrombophlebitis and seem to be more common in patients with papulopustular lesions [22, 32]. Vascular involvement can occur in 7.7% to 43% of patients. Even though vasculitis is a significant feature of Behçet’s disease, it is not one of the ISG diagnostic criteria. Both veins and arteries of all sizes can be affected with an associated thrombotic tendency [1, 10, 36–41]. Venous involvement is more common than arterial (88% versus 12%) [39]. Venous thrombosis is the most common vascular manifestation occurring in 6.2% to 33% [42, 43]. Vascular involvement in BD is more common in males and has a more severe course [37]. A review of 137 Turkish BD patients showed vascular involvement in 27.7% with venous involvement in 24% and arterial involvement in 3%. Vascular Journal of Ophthalmology 3 (a) (b) (d) (c) (e) Figure 1: A 36-year-old Iranian female with incomplete Behçet’s disease with history of oral ulcers (a), genital ulcers, and nongranulomatous anterior uveitis. Retinal exam was completely normal with a visual acuity of 20/16 in each eye. Fundus photos ((b) and (c)) and fluorescein angiogram ((d) and (e)) confirm the absence of retinal vasculitis and retinitis ((b)–(e)). involvement was more common in males with a male to female ratio of 4.4 : 1. Additionally, ocular involvement and pathergy positivity were significantly more common among patients with vascular disease [39]. Similarly, a subsequent study of 2,147 Turkish patients with BD also showed that male patients were five times more likely to have vascular complications [10]. Central nervous system (CNS) involvement (neuroBehçet’s) occurs in approximately 5% of patients and is one of the most serious causes of long-term morbidity and mortality [44–47]. Neuro-Behçet’s is more prevalent in males with a male to female ratio of 2 : 1 to 3 : 1. In a large retrospective study from Turkey, the frequency of CNS involvement was 13% in men and 5.6% in women. Among 200 Turkish neuroBehçet’s patients, the male to female ratio was 3.4 : 1. Other groups from Iraq, Tunis, and Italy have also reported higher rates of neuro-Behçet’s in males with a male to female ratio ranging from 1.6 : 1 to 2.8 : 1. In these studies male gender and CNS involvement were also found to be associated with a poor prognosis [46–51]. The age of onset of neuro-Behçet’s is generally 20–40 years, though it has been reported in children [52]. Neurological signs commonly develop a few years after the onset of the other systemic manifestations of BD [46, 50]. Intestinal involvement is rare but can be a common cause of mortality and severe morbidity in BD [53]. Gastrointestinal (GI) manifestations of BD usually occur 4.5–6 years after the onset of oral ulcers. The prevalence of GI involvement is higher (50–60%) in Japan and Korea, while it is much lower in Turkey and Israel (0–5%). The frequency of extraoral GI involvement varies widely among different ethnic groups [25, 53, 54]. Although several studies reported no gender difference in the incidence of GI involvement, male predominance has been reported by some [11, 25, 55]. Ulcerations may occur anywhere from the mouth to the anus in the GI tract; however, the ileocecal region with extension into the ascending colon is the most frequent site of extraoral involvement [56]. 3. Gender Differences in Prevalence, Incidence, and Severity of Behçet’s Disease Associated Uveitis Uveitis in BD (BDU) has been reported in approximately 50% of the patients in multidisciplinary centers and more than 90% in ophthalmology reports [4, 57]. Patients usually present with bilateral nongranulomatous panuveitis and retinal vasculitis. However, it may rarely present as isolated anterior uveitis, particularly in female patients [58] (Figure 1). Episcleritis, scleritis, conjunctival ulcers, keratitis, orbital inflammation, isolated optic neuritis, and extraocular muscle palsies are rare forms of ocular involvement [59]. Uveitis occurs within 3–5 years after the onset of BD; however, ocular manifestations may be the initial manifestation in approximately 10–20% of cases [58, 59]. Similar to vascular and neurologic involvement, BDU is also more common in males [10]. Typically, BDU has a relapsing and remitting course with explosive episodes and quiet periods in between. Sudden onset of uveitis flare-ups and spontaneous resolution are important features of the disease [58]. Anterior uveitis (iridocyclitis) with hypopyon is very characteristic but occurs 4 Journal of Ophthalmology (a) (b) (c) (d) (e) (f) Figure 2: A 30-year-old Jewish male presented with panuveitis, retinitis, and retinal vasculitis and was later diagnosed with Behçet’s disease. Right eye was legally blind with a visual acuity of 20/200 due to a macular retinitis in the past. Left eye visual acuity was 20/640 due to active macular retinitis. Fundus photos and fluorescein angiogram show macular scar (a) in the right eye and active macular retinitis in the left eye (b) with diffuse retinal vascular leakage in both eyes (involving both veins and arteries) and late staining of the retinitis in the left eye ((c) and (d)). Left eye visual acuity improved to 20/50 after treatment with infliximab with resolution of retinitis and retinal vasculitis ((e) and (f)). in only 10–30% of patients. Hypopyon in BD forms a smooth layer and shifts with head positioning. Posterior synechiae, peripheral anterior synechiae, iris atrophy, cataract, and secondary glaucoma can be seen as complications of recurrent anterior uveitis attacks [58]. Anterior uveitis and hypopyon occur more commonly in women whereas panuveitis and severe ocular BD are more common in men [59, 60] (Figure 2). Childhood onset BDU is also more common in males [61]. Posterior uveitis patients present with decreased vision with floaters and/or visual field defects. Diffuse vitritis, retinal infiltrates, sheathing of retinal veins, occlusive vasculitis, swelling of the optic disc, branch retinal vein occlusions, and exudative retinal detachment are common posterior segment findings. The classic posterior uveitis finding is retinal vasculitis, which can affect both arteries and veins. Retinal disease is the most serious form of ocular involvement in BD [58]. Maculopathy and optic atrophy are the most common causes of permanent visual loss [17]. Optic disc involvement can occur in the form of acute anterior neuropathy, papilledema as a result of dural sinus thrombosis or benign intracranial hypertension, neuroretinitis, or retrobulbar optic neuropathy [46, 62]. In a large retrospective study from Turkey, the mean age at onset of uveitis was 28.5 years in males and 30 years in females. Bilateral ocular involvement was seen in 78.1%. Journal of Ophthalmology There was no gender difference in terms of bilaterality and recurrence of uveitis [61]. However, panuveitis was more common in male patients [63]. Sight-threatening fundus lesions and complications were also more common in male BD patients [61]. In a study by Tugal-Tutkun et al., hypopyon, vitritis, retinal vasculitis, retinitis, and retinal hemorrhages were also seen more frequently in male patients while papillitis was more common in females [61]. According to some reports, male patients with BDU have worse visual prognosis likely due to the fact that men with BD are more likely to have panuveitis [17, 61]. 4. Gender Differences in Treatment and Prognosis of Behçet’s Disease There may be gender differences in response to treatment as well. Mat et al. reported that methylprednisolone acetate was effective for erythema nodosum in females but not in males [64]. Similarly, Yurdakul et al. reported in 116 BD patients from Turkey that colchicine had favorable effects on genital ulcers, erythema nodosum, and arthritis in females but only for arthritis in males [65]. Hamuryudan et al. showed that different dosages of thalidomide were effective for oral and genital ulcers and follicular lesions in male patients; however, the study did not assess thalidomide’s effect in females because of its teratogenic effects [66]. Another male-only study reported that azathioprine 2.5 mg/kg daily was effective for the preservation of visual acuity and the prevention of incident ocular BD as well as mucocutaneous lesions and arthritis [67]. Masuda et al. reported cyclosporine 10 mg/kg daily to be more effective than colchicine 1 mg daily for the treatment of ocular disease and oral and genital ulcers in a double-masked randomized trial [68]. Interestingly, treatment side effects also differed between males and females; hirsutism with cyclosporine occurred more commonly in females while neurotoxicity was significantly more common among males [68, 69]. Several reports showed that the overall mortality rate in BD is significantly higher among male patients. The rate is especially high for young males in their 20 s–40 s [47, 70]. Common causes of mortality are pulmonary arterial aneurysms and neurological involvement, which are significantly more common among young male patients [4]. 5. Possible Explanations for Gender Differences in Behçet’s Disease Autoimmune diseases tend to be more common in women of childbearing age. However, Behçet’s disease is equally prevalent among males and females in some geographic regions and more prevalent in males in others [4, 34]. Overall, the disease has a more severe course and higher mortality among male patients [47]. Despite numerous studies indicating notable gender differences in ocular and extraocular manifestations as well as severity and mortality of the disease, there is no clear evidence as to what this difference stems from. Although its etiology is unknown, both genetic and environmental factors (smoking, infection, vitamin D, and 5 immune dysregulation) have been blamed [1, 13]. Whether males are more prone to such environmental risk factors has yet to be determined. Both smoking and cessation of smoking have been implicated in severity of clinical manifestations of BD including vasculitis and mucocutaneous lesions [71–73]. Smoking was more common among male patients with BD in some studies raising the question of possible association [71–73]. Similarly, low vitamin D3 levels have been associated with BD or its severity; however, these studies failed to show significant differences in vitamin D3 levels between male and female BD patients [74, 75]. Both male gender and HLAB51 have been consistently associated with a severe disease course and poor prognosis in BD. In fact, a recent metaanalysis study indicated that HLA-B51 was more common among male BD patients [76], suggesting there could be a genetic basis for poor prognosis among men with BD. While most other autoimmune diseases are more common among women of childbearing age, BD seems to differ with either equal gender distribution or male predominance. The relationship between BD and pregnancy is also poorly studied. Effects of pregnancy on Behçet’s disease in 27 patients showed worsening of disease in 2/3 of patients during pregnancy, particularly in the 1st trimester. This same group also noted exacerbations in oral and genital ulcers during premenstrual periods. These findings suggest that progesterone may play a role in the disease course among women in a complex manner [77]. Whether other reproductive or sex hormones play any role or to what extent has yet to be determined. 6. Conclusion In summary, mucocutaneous involvement is the hallmark of BD and is more common in females. Neurologic involvement and major vessel disease are uncommon, but such involvements are life-threatening and more common in males. Ocular BD is more common in males whereas arthritis is more frequently reported in female patients. Male patients are more likely to be affected at a younger age, have a more severe uveitis, present with worse visual acuity, and suffer vision loss over time [4, 58]. Though bilaterality and recurrence of uveitis are similar between sexes, incidence of panuveitis and vision loss are higher in men [29]. Overall mortality rates are also higher in young male patients [47]. Despite gender differences in severity of ocular and extraocular findings, visual prognosis in BDU has improved over the past decade due to more aggressive use of immunomodulatory therapy [34]. It is intriguing as to why BD is more prevalent, at least in some reports, and more severe among men when most autoimmune diseases are more prevalent or more severe among women [11]. Although some of the aforementioned risk factors may indeed be responsible for more severe disease in men, there are, unfortunately, no studies directly evaluating possible reasons for gender differences in BD. Translational and epidemiologic studies are needed to further address the question of gender in Behçet’s disease. 6 Conflict of Interests The authors declare that there is no conflict of interests regarding the publication of this paper. Acknowledgments This study has been sponsored by the NEI Intramural Research Program and this research was made possible through the National Institutes of Health (NIH) Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer Inc., The Leona M. and Harry B. Helmsley Charitable Trust, and the Howard Hughes Medical Institute, as well as other private donors. For a complete list, please visit the foundation website at http://www.fnih.org/work/programsdevelopment/medical-research-scholars-program. References [1] A. Gül, “Behçet’s disease: an update on the pathogenesis,” Clinical and Experimental Rheumatology, vol. 19, no. 5, supplement 24, pp. S6–S12, 2001. [2] E. F. Remmers, F. Cosan, Y. Kirino et al., “Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behçet’s disease,” Nature Genetics, vol. 42, no. 8, pp. 698–702, 2010. [3] D. McGonagle and M. F. McDermott, “A proposed classification of the immunological diseases,” PLoS Medicine, vol. 3, no. 8, article e297, 2006. [4] H. Yazici, I. Fresko, and S. Yurdakul, “Behçet’s syndrome: disease manifestations, management, and advances in treatment,” Nature Reviews Rheumatology, vol. 3, no. 3, pp. 148–155, 2007. [5] Y. Kirino, Q. Zhou, Y. Ishigatsubo et al., “Targeted resequencing implicates the familial Mediterranean fever gene MEFV and the toll-like receptor 4 gene TLR4 in Behçet disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 20, pp. 8134–8139, 2013. [6] P. Fietta, “Behçet’s disease: familial clustering and immunogenetics,” Clinical and Experimental Rheumatology, vol. 23, no. 4, supplement 38, pp. S96–S105, 2005. [7] H. Yazici, S. Yurdakul, V. Hamuryudan, and I. Fresko, “Behçet’s syndrome,” in Rheumatology, M. C. Hochberg, J. A. Silman, J. S. Smolen, M. E. Weinblatt, and M. H. Weisman, Eds., pp. 1665– 1669, Mosby, London, UK, 3rd edition, 2003. [8] T. Saylan, G. Ozarmagan, G. Azizlerli, C. Ovül, and N. Oke, “Behçet disease in Turkey,” Zeitschrift für Hautkrankheiten, vol. 61, no. 15, pp. 1120–1122, 1986. [9] A. Gürler, A. Boyvat, and U. Türsen, “Clinical manifestations of Behçet’s disease: an analysis of 2147 patients,” Yonsei Medical Journal, vol. 38, no. 6, pp. 423–427, 1997. [10] C. H. C. Zouboulis, D. Djawari, and W. Kirch, “AdamantiadesBehçet’s disease in Germany,” in Behçet’s Disease, P. Godeau and B. Wechsler, Eds., pp. 193–196, Elsevier Science, Amsterdam, The Netherlands, 1st edition, 1993. [11] L. C. See, C. F. Kuo, I. J. Chou, M. J. Chiou, and K. H. Yu, “Sexand age-specific incidence of autoimmune rheumatic diseases in the Chinese population: a Taiwan population-based study,” Seminars in Arthritis and Rheumatism, vol. 43, no. 3, pp. 381– 386, 2013. Journal of Ophthalmology [12] F. Davatchi, F. Shahram, C. Chams-Davatchi et al., “Behçet’s disease: from east to west,” Clinical Rheumatology, vol. 29, no. 8, pp. 823–833, 2010. [13] A. Gül, “Behçet’s disease as an autoinflammatory disorder,” Current Drug Targets: Inflammation & Allergy, vol. 4, no. 1, pp. 81–83, 2005. [14] International Study Group for Behçet’s Disease, “Criteria for diagnosis of Behçet’s disease,” The Lancet, vol. 335, no. 8697, pp. 1078–1080, 1990. [15] E. Alpsoy, C. C. Zouboulis, and G. E. Ehrlich, “Mucocutaneous lesions of Behçet’s disease,” Yonsei Medical Journal, vol. 48, no. 4, pp. 573–585, 2007. [16] E. Alpsoy, L. Donmez, M. Onder et al., “Clinical features and natural course of Behçet’s disease in 661 cases: a multicentre study,” British Journal of Dermatology, vol. 157, no. 5, pp. 901– 906, 2007. [17] H. Yazici, Y. Tüzün, H. Pazarli et al., “Influence of age of onset and patient’s sex on the prevalence and severity of manifestations of Behçet’s syndrome,” Annals of the Rheumatic Diseases, vol. 43, no. 6, pp. 783–789, 1984. [18] E. C. Ebert, “Gastrointestinal manifestations of Behçet’s disease,” Digestive Diseases and Sciences, vol. 54, no. 2, pp. 201–207, 2009. [19] L. Y. Wang, D. B. Zhao, J. Gu, and S. M. Dai, “Clinical characteristics of Behçet’s disease in China,” Rheumatology International, vol. 30, no. 9, pp. 1191–1196, 2010. [20] F. Shahram, F. Davatchi, A. Nadji et al., “Recent epidemiological data on Behçet’s disease in Iran. The 2001 survey,” Advances in Experimental Medicine and Biology, vol. 528, pp. 31–36, 2003. [21] S. H. Oh, E. C. Han, J. H. Lee, and D. Bang, “Comparison of the clinical features of recurrent aphthous stomatitis and Behçet’s disease,” Clinical and Experimental Dermatology, vol. 34, no. 6, pp. e208–e212, 2009. [22] I. Koné-Paut, S. Yurdakul, S. A. Bahabri et al., “Clinical features of Behçet’s disease in children: an international collaborative study of 86 cases,” The Journal of Pediatrics, vol. 132, no. 4, pp. 721–725, 1998. [23] F. Davatchi, F. Shahram, C. Chams-Davatchi et al., “Behcet’s disease: is there a gender influence on clinical manifestations?” International Journal of Rheumatic Diseases, vol. 15, no. 3, pp. 306–314, 2012. [24] H. Ideguchi, A. Suda, M. Takeno, A. Ueda, S. Ohno, and Y. Ishigatsubo, “Behçet disease: evolution of clinical manifestations,” Medicine, vol. 90, no. 2, pp. 125–132, 2011. [25] U. Tursen, A. Gurler, and A. Boyvat, “Evaluation of clinical findings according to sex in 2313 Turkish patients with Behçet’s disease,” International Journal of Dermatology, vol. 42, no. 5, pp. 346–351, 2003. [26] T. Prokaeva, W. Madanat, N. Yermakova, and Z. Alekberova, “Sex dimorphism of Behçet’s disease,” in Behçet’s Disease, P. Godeau and B. Wechsler, Eds., pp. 219–221, Elsevier Science, Amsterdam, The Netherlands, 1993. [27] T. W. O’Neill, A. S. Rigby, S. McHugh, A. Silman, and C. Barnes, “Regional differences in clinical manifestations of Behçet’s disease,” in Behçet’s Disease, P. Godeau and B. Wechsler, Eds., pp. 159–163, Elsevier Science, Amsterdam, The Netherlands, 1993. [28] C. Evereklioglu, “The migration pattern, patient selection with diagnostic methodological flaw and confusing naming dilemma in Behçet disease,” European Journal of Echocardiography, vol. 8, no. 3, pp. 167–174, 2007. Journal of Ophthalmology [29] M. Khairallah, M. Accorinti, C. Muccioli, R. Kahloun, and J. H. Kempen, “Epidemiology of Behçet disease,” Ocular Immunology and Inflammation, vol. 20, no. 5, pp. 324–335, 2012. [30] C. C. Zouboulis, “Epidemiology of Adamantiades-Behçet’s disease,” Annales de Médecine Interne, vol. 150, no. 6, pp. 488– 498, 1999. [31] K. Nakae, F. Masaki, T. Hashimoto, G. Inaba, M. Mochizuki, and T. Sakane, “Recent epidemiological features of Behçet’s disease in Japan,” in Behçet’s Disease, B. Wechsler and P. Godeau, Eds., pp. 145–151, Excerpta Medica, Amsterdam, The Netherlands, 1993. [32] S. Yurdakul and H. Yazici, “Behçet’s syndrome,” Best Practice & Research Clinical Rheumatology, vol. 22, no. 5, pp. 793–809, 2008. [33] D. Bang, J. H. Lee, E.-S. Lee et al., “Epidemiologic and clinical survey of Behçet’s disease in Korea: the first multicenter study,” Journal of Korean Medical Science, vol. 16, no. 5, pp. 615–618, 2001. [34] S. R. Dalvi, R. Yildirim, and Y. Yazici, “Behçet’s Syndrome,” Drugs, vol. 72, no. 17, pp. 2223–2241, 2012. [35] A. Hamzaoui, R. Klii, O. Harzallah, C. Attig, and S. Mahjoub, “Behçet’s disease in women,” La Revue de Médecine Interne, vol. 33, no. 10, pp. 552–555, 2012. [36] T. Sakane, M. Takeno, N. Suzuki, and G. Inaba, “Behçet’s disease,” The New England Journal of Medicine, vol. 341, no. 17, pp. 1284–1291, 1999. [37] M. Zierhut, N. Mizuki, S. Ohno et al., “Immunology and functional genomics of Behçet’s disease,” Cellular and Molecular Life Sciences, vol. 60, no. 9, pp. 1903–1922, 2003. [38] J. T. Lie, “Vascular involvement in Behçet’s disease: arterial and venous and vessels of all sizes,” The Journal of Rheumatology, vol. 19, no. 3, pp. 341–343, 1992. [39] Y. Koç, I. Güllü, G. Akpek et al., “Vascular involvement in Behçet’s disease,” The Journal of Rheumatology, vol. 19, no. 3, pp. 402–410, 1992. [40] A. N. Al-Dalaan, S. R. Al Balaa, K. El Ramahi et al., “Behçet’s disease in Saudi Arabia,” The Journal of Rheumatology, vol. 21, no. 4, pp. 658–661, 1994. [41] H. de Jesus, M. Rosa, and M. V. Queiroz, “Vascular involvement in Behçet’s disease. An analysis of twelve cases,” Clinical Rheumatology, vol. 16, no. 2, pp. 220–221, 1997. [42] A. Nadji, F. Shahram, and F. Davatchi, “Vascular involvement in Behçet’s disease: report of 323 cases,” in Proceedings of the 8th International Congress on Behcet’s Disease, vol. 194 of Program and Abstracts, p. 194, Prex, Milano, Italy, 1998. [43] A. Muftuoglu, S. Yurdakul, H. Yazici et al., “Vascular involvement in Behçet’s disease—a review of 129 cases,” in Recent Advances in Behçet’s Disease, T. Lehner and C. G. Barnes, Eds., vol. 103 of International Congress and Symposium Series, pp. 255–260, Royal Society of Medicine Services, London, UK, 1986. [44] F. Ildan, A. I. Göçer, H. Bağdatoğlu, M. Tuna, and A. Karadayi, “Intracranial arterial aneurysm complicating Behçet’s disease,” Neurosurgical Review, vol. 19, no. 1, pp. 53–56, 1996. [45] S. Nakasu, M. Kaneko, and M. Matsuda, “Cerebral aneurysms associated with Behçet’s disease: a case report,” Journal of Neurology Neurosurgery & Psychiatry, vol. 70, no. 5, pp. 682– 684, 2001. [46] G. Akman-Demir, P. Serdaroglu, and B. Tasçi, “Clinical patterns of neurological involvement in Behçet’s disease: evaluation of 200 patients,” Brain, vol. 122, part 11, pp. 2171–2182, 1999. 7 [47] E. Kural-Seyahi, I. Fresko, N. Seyahi et al., “The long-term mortality and morbidity of Behçet syndrome: a 2-decade outcome survey of 387 patients followed at a dedicated center,” Medicine, vol. 82, no. 1, pp. 60–76, 2003. [48] M. H. Houman, S. Bellakhal, T. B. Salem et al., “Characteristics of neurological manifestations of Behçet’s disease: a retrospective monocentric study in Tunisia,” Clinical Neurology and Neurosurgery, vol. 115, no. 10, pp. 2015–2018, 2013. [49] R. Talarico, A. d’Ascanio, M. Figus et al., “Behçet’s disease: features of neurological involvement in a dedicated centre in Italy,” Clinical and Experimental Rheumatology, vol. 30, no. 3, supplement 72, pp. S69–S72, 2012. [50] A. Al-Araji, K. Sharquie, and Z. Al-Rawi, “Prevalence and patterns of neurological involvement in Behçet’s disease: a prospective study from Iraq,” Journal of Neurology Neurosurgery & Psychiatry, vol. 74, no. 5, pp. 608–613, 2003. [51] A. Al-Araji and D. P. Kidd, “Neuro-Behçet’s disease: epidemiology, clinical characteristics, and management,” The Lancet Neurology, vol. 8, no. 2, pp. 192–204, 2009. [52] D. Uluduz, M. Kürtüncü, Z. Yapıcı et al., “Clinical characteristics of pediatric-onset neuro-Behçet disease,” Neurology, vol. 77, no. 21, pp. 1900–1905, 2011. [53] U. Korman, M. Cantasdemir, S. Kurugoglu et al., “Enteroclysis findings of intestinal Behçet disease: a comparative study with Crohn disease,” Abdominal Imaging, vol. 28, no. 3, pp. 308–312, 2003. [54] S. Yurdakul, N. Tüzüner, I. Yurdakul, V. Hamuryudan, and H. Yazici, “Gastrointestinal involvement in Behçet’s syndrome: a controlled study,” Annals of the Rheumatic Diseases, vol. 55, no. 3, pp. 208–210, 1996. [55] I. Kötter, H. Dürk, G. Fieribeck, U. Pleyer, M. Zierhut, and J. G. Saal, “Behçet’s disease in 39 German and Mediterranean patients,” in Behçet’s Disease, P. Godeau and B. Wechsler, Eds., pp. 197–200, Elsevier Science, Amsterdam, The Netherlands, 1993. [56] J. H. Cheon, D. S. Han, J. Y. Park et al., “Development, validation, and responsiveness of a novel disease activity index for intestinal Behcet’s disease,” Inflammatory Bowel Diseases, vol. 17, no. 2, pp. 605–613, 2011. [57] P. Yang, W. Fang, Q. Meng, Y. Ren, L. Xing, and A. Kijlstra, “Clinical features of chinese patients with Behçet’s disease,” Ophthalmology, vol. 115, no. 2, pp. 312.e4–318.e4, 2008. [58] I. Tugal-Tutkun, “Behçet’s uveitis,” Middle East African Journal of Ophthalmology, vol. 16, no. 4, pp. 219–224, 2009. [59] C. Evereklioglu, “Current concepts in the etiology and treatment of Behçet disease,” Survey of Ophthalmology, vol. 50, no. 4, pp. 297–350, 2005. [60] A. Ramsay and S. Lightman, “Hypopyon uveitis,” Survey of Ophthalmology, vol. 46, no. 1, pp. 1–18, 2001. [61] I. Tugal-Tutkun, S. Onal, R. Altan-Yaycioglu, H. Huseyin Altunbas, and M. Urgancioglu, “Uveitis in Behçet disease: an analysis of 880 patients,” American Journal of Ophthalmology, vol. 138, no. 3, pp. 373–380, 2004. [62] T. Fujikado and K. Imagawa, “Dural sinus thrombosis in Behçet’s disease—a case report,” Japanese Journal of Ophthalmology, vol. 38, no. 4, pp. 411–416, 1994. [63] D. H. Verity, J. E. Marr, S. Ohno, G. R. Wallace, and M. R. Stanford, “Behçet’s disease, the Silk Road and HLA-B51: historical and geographical perspectives,” Tissue Antigens, vol. 54, no. 3, pp. 213–220, 1999. 8 [64] C. Mat, S. Yurdakul, S. Uysal et al., “A double-blind trial of depot corticosteroids in Behçet’s syndrome,” Rheumatology, vol. 45, no. 3, pp. 348–352, 2006. [65] S. Yurdakul, C. Mat, Y. Tüzün et al., “A double-blind trial of colchicine in Behçet’s syndrome,” Arthritis & Rheumatism, vol. 44, no. 11, pp. 2686–2692, 2001. [66] V. Hamuryudan, C. Mat, S. Saip et al., “Thalidomide in the treatment of the mucocutaneous lesions of the Behçet syndrome: a randomized, double-blind, placebo-controlled trial,” Annals of Internal Medicine, vol. 128, no. 6, pp. 443–450, 1998. [67] H. Yazici, H. Pazarli, C. G. Barnes et al., “A controlled trial of azathioprine in Behçet’s syndrome,” The New England Journal of Medicine, vol. 322, no. 5, pp. 281–285, 1990. [68] K. Masuda, A. Nakajima, A. Urayama, K. Nakae, M. Kogure, and G. Inaba, “Double-masked trial of cyclosporin versus colchicine and long-term open study of cyclosporin in Behçet’s disease,” The Lancet, vol. 1, no. 8647, pp. 1093–1096, 1989. [69] G. Akmar-Demir, O. Ayranci, M. Kurtuncu, E. N. Vanli, M. Mutlu, and I. Tugal-Tutkun, “Cyclosporine for Behçet’s uveitis: is it associated with an increased risk of neurological involvement?” Clinical and Experimental Rheumatology, vol. 26, no. 4, supplement 50, pp. S84–S90, 2008. [70] E. Seyahi and H. Yazici, “Prognosis in Behçet’s syndrome,” in Behçet’s Syndrome, Y. Yazici and H. Yazici, Eds., pp. 285–295, Springer, New York, NY, USA, 2010. [71] H. T. Özer, R. Günesaçar, S. Dinkçi, Z. Özbalkan, F. Yildiz, and E. Erken, “The impact of smoking on clinical features of Behçet’s disease patients with glutathione S-transferase polymorphisms,” Clinical and Experimental Rheumatology, vol. 30, no. 3, supplement 72, pp. S14–S17, 2012. [72] S. W. Rizvi and H. McGrath Jr., “The therapeutic effect of cigarette smoking on oral/genital aphthosis and other manifestations of Behçet’s disease,” Clinical and Experimental Rheumatology, vol. 19, no. 5, supplement 24, pp. S77–S78, 2001. [73] K. Aramaki, H. Kikuchi, and S. Hirohata, “HLA-B51 and cigarette smoking as risk factors for chronic progressive neurological manifestations in Behçet’s disease,” Modern Rheumatology, vol. 17, no. 1, pp. 81–82, 2007. [74] M. Can, M. Gunes, O. A. Haliloglu et al., “Effect of vitamin D deficiency and replacement on endothelial functions in Behçet’s disease,” Clinical and Experimental Rheumatology, vol. 30, no. 3, supplement 72, pp. S57–S61, 2012. [75] K. Hamzaoui, I. B. Dhifallah, E. Karray, F. H. Sassi, and A. Hamzaoui, “Vitamin D modulates peripheral immunity in patients with Behçet’s disease,” Clinical and Experimental Rheumatology, vol. 28, no. 4, supplement 60, pp. S50–S57, 2010. [76] C. Maldini, M. P. Lavalley, M. Cheminant, M. de menthon, and A. Mahr, “Relationships of HLA-B51 or B5 genotype with Behçet’s disease clinical characteristics: systematic review and meta-analyses of observational studies,” Rheumatology, vol. 51, no. 5, pp. 887–900, 2012. [77] D. Bang, Y. S. Chun, I. B. Haam, E.-S. Lee, and S. Lee, “The Influence of pregnancy on Behçet’s disease,” Yonsei Medical Journal, vol. 38, no. 6, pp. 437–443, 1997. Journal of Ophthalmology Hindawi Publishing Corporation Journal of Ophthalmology Volume 2014, Article ID 403042, 8 pages http://dx.doi.org/10.1155/2014/403042 Review Article Gender and Ocular Manifestations of Connective Tissue Diseases and Systemic Vasculitides Maria M. Choudhary,1 Rula A. Hajj-Ali,2 and Careen Y. Lowder1 1 2 Cole Eye Institute, 9500 Euclid Avenue, I-10, Cleveland, OH 44195, USA Department of Rheumatology, Cleveland Clinic, 9500 Euclid Avenue, A-50, Cleveland, OH 44195, USA Correspondence should be addressed to Careen Y. Lowder; [email protected] Received 20 October 2013; Accepted 6 February 2014; Published 17 March 2014 Academic Editor: H. Nida Sen Copyright © 2014 Maria M. Choudhary et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Ocular manifestations are present in many connective tissue diseases which are characterized by an immune system that is directed against self. In this paper, we review the ocular findings in various connective tissue diseases and systemic vasculitides and highlight gender differences in each disease. In rheumatoid arthritis, we find that dry eyes affect women nine times more than men. The other extra-articular manifestations of rheumatoid arthritis affect women three times more commonly than men. Systemic lupus erythematosus can involve all ocular structures and women are nine times more affected than men. Systemic sclerosis is a rare disease but, again, it is more common in women with a female to male ratio of 8 : 1. Polymyositis and dermatomyositis also affect women more commonly than men but no gender differences have been found in the incidence or disease course in the systemic vasculitides associated with antineutrophil cytoplasmic antibody such as granulomatosis with polyangiitis (GPA, formerly known as Wegener’s granulomatosis). Finally, Behcet’s disease is more common in males, and male gender is a risk factor for Behcet’s disease. There is a slight female preponderance in sarcoidosis with female gender carrying a worse prognosis in the outcome of ocular disease. 1. Introduction Many connective tissue diseases have abnormal immune system activity with inflammation in tissues as a result of an immune system that is directed against one’s own body tissues (autoimmunity). Ocular inflammation is seen as part of a number of systemic diseases with autoimmune processes heading the list. Inflammation can affect any part of the eye starting from the cornea anteriorly to the retina, uveal tract and sclera posteriorly. In some conditions, uveitis or scleritis is the heralding presentation and in others it determines the need for more aggressive immunosuppressive therapy. The incidence, severity, and disease course of uveitis and scleritis are variable with many factors contributing to the natural history of the disease, including gender, the underlying systemic disease, and the extent of the inflammatory process. The ocular immune process is mediated by T helper cells 1 (TH1). It can be TH1 predominant with proinflammatory cytokines or antibody mediated through TH2 cells. Females have a stronger autoimmune response compared to males with TH1 pathway being more vigorous than TH2 except in pregnancy when TH2 takes over [1]. Studies have shown that administration of sex hormones alters autoimmune processes; estrogen upregulates whereas androgens suppress it [2, 3]. The effect of estrogen however is dose dependent with lower levels being immune-stimulatory and higher levels immune-inhibitory. This has been proposed to be responsible for improvement of certain autoimmune pathologies such as rheumatoid arthritis during pregnancy. Similarly women have higher levels of prolactin and growth hormones compared to males. These pituitary hormones also enhance autoimmunity [1]. The effect of hormonal factor in inflammatory eye disease is complex and is not uniform among all diseases; male patients with Behçet’s syndrome have worse ocular prognosis than their female counterpart. Nonhormonal gender differences such as environmental exposures, drugs (more commonly used by one gender than the other), or infectious organisms can also play a role. 2 Autoimmune diseases affect the eye in different ways. We will summarize the ocular manifestations of the most encountered connective tissue diseases and vasculitides. 2. Rheumatoid Arthritis Rheumatoid arthritis (RA) is an inflammatory arthritis associated with a variety of extra articular manifestations. It is three times more common in women than men. There is a genetic predisposition with more than 90% patients carrying the HLA-DR4 and HLA-DR1 genes [4]. Dry eye syndrome is the most common ophthalmic manifestation; women are 9 times more commonly affected than men. It presents as foreign body/gritty sensation, redness, burning, photophobia, or even fluctuating blurry vision. The severity of dry eye does not parallel underlying rheumatoid arthritis disease activity [5]. Dry eye can be either “aqueous deficient” or “evaporative” type. The aqueous deficient component is more commonly associated with autoimmune conditions. It results from immune mediated destruction of the exocrine glands resulting in decreased tear production by the lacrimal glands, also referred to as secondary Sjogren’s syndrome [6]. Gender plays a key role with 90% of the patients being females. Females with primary Sjogren’s syndrome (without any underlying autoimmune problem) have elevated levels of antinuclear antibody (ANA) and autoantibodies directed against Ro/SSA and La/SSB autoantigens. This is thought to be secondary to higher estrogen levels in women, which, being immunestimulatory, result in accelerated humoral and cell mediated responses. On the other hand, the evaporative type of dry eye is secondary to tear film instability and higher rate of evaporation. This is thought to be due to relative androgen deficiency. Androgens play a role at various stages in lipid metabolism. Meibomian glands are target organs for androgens. Decreased levels of androgens therefore lead to altered lipid component of meibomian secretions. This alters tear film composition and leads to evaporative dry eye [7]. Women with primary and secondary Sjogren’s syndrome are also relatively androgen deficient [8]. Similarly, men on antiandrogen therapy (such as for prostate cancer) are more commonly affected than others. Therefore, female gender has been identified as a risk factor for the development of dry eye [9]. Whether female patients do worse than men on long term follow-up has yet to be studied. Scleritis and episcleritis are the second most common ocular manifestation of rheumatoid arthritis with RA being the most common autoimmune etiology associated with scleritis [10]. Scleritis can be chronic and associated with significant pain and morbidity. The patients complain of typical deep intolerable boring eye pain, redness, photophobia, and classic ocular tenderness [11, 12]. It usually indicates active systemic disease and sometimes can be the heralding sign. Depending on anatomical location scleritis is classified as anterior or posterior. The former is further subdivided into diffuse, sectoral, nodular, or necrotizing variants with diffuse anterior scleritis being the most prevalent [11]. Significant morbidity is associated with the necrotizing variant, more commonly seen in patients with rheumatoid arthritis than other autoimmune diseases. Slit lamp examination shows a Journal of Ophthalmology bluish hue in areas of scleral thinning (coming from underlying choroid). On the other hand scleromalacia perforans represents the other end of the spectrum characterized by a quiet eye on exam with significant thinning of the sclera and even rupture [13]. The conjunctiva and episcleral tissue can be similarly involved. Episcleritis usually presents with painless red eye and preserved vision. Some patients complain of minimal discomfort. On exam dilated vessels are seen superficial to the sclera that are relatively mobile and blanch with phenylephrine instillation [14]. No gender differences have been reported in the disease course of scleral and episcleral inflammation associated with rheumatoid arthritis. Rheumatoid arthritis is the most common autoimmune disease to affect the cornea. Patients typically complain of pain, photophobia, excessive lacrimation, and blurred vision. The cornea does not have its own blood supply and is inaccessible to the inflammatory leukocytes directly. This relatively protects it from immune mediated damage except for the periphery that derives its blood supply from the surrounding episclera. This can cause perilimbal corneal involvement referred to as peripheral ulcerative keratitis (PUK). PUK is often also accompanied with surrounding scleritis. Activation of tissue collagenases results in digestion of corneal stroma with potential loss of the eye [15]. PUK and resultant corneal melt can be seen in a variety of systemic immune destructive processes and is not specific to RA. Presence of PUK or necrotizing scleritis in patients with rheumatoid arthritis indicates severe systemic disease necessitating immunosuppressive therapy [16]. 3. Systemic Lupus Erythematosus Systemic lupus erythematosus (SLE) is an autoimmune disorder that causes immune complex mediated tissue damage affecting a variety of organ systems [17]. It results from interplay of genetic, environmental, and hormonal factors. Gender plays a key role with women being nine times more commonly affected than men. It most commonly affects Asians and African women in their reproductive years [18]. Significant hormonal alterations such as pregnancy and postpartum can cause worsening of disease activity because of increase in the levels of estrogen and progesterone both of which upregulate the TH2 mediated pathway resulting in increased antibody synthesis. Supplemental estrogen in the form of contraceptive pills or hormone replacement therapy has also been proposed to increase the risk of disease flares [19, 20]. Male androgens offer relative protection. Patients with SLE have lower levels of dehydroepiandrosterone (DHEA) and testosterone compared to age matched controls irrespective of the gender [21, 22]. Hypoandrogenism in men has therefore been proposed to increase the incidence and worsen severity of disease activity [23, 24]. The recently revised classification criteria of SLE referred to as the Systemic Lupus International Collaborating Clinics (SLICC) criteria require the presence of at least four of the seventeen criteria for classification of the disease; these should include at least one clinical criterion and one immunologic criterion or biopsy-proven lupus nephritis [25]. Journal of Ophthalmology Ocular pathology secondary to SLE includes a wide range from the adnexa to the retina and optic nerve. Similar to RA, dry eye syndrome is the most common presentation. SLE is the most common underlying autoimmune pathology in patients with secondary Sjogren’s syndrome [26]. It is more frequent in SLE than rheumatoid arthritis and affects more than half of the patients [27, 28]. As in RA, female gender is a risk factor for dry eye syndrome in SLE patients and this is attributed to both the presence of estrogen and lack of androgens. Clinical findings range from abnormal tear film and corneal epithelial changes such as punctate epithelial erosions to more severe forms such as corneal scarring and ulceration. Peripheral ulcerative keratitis as seen in rheumatoid arthritis is uncommon [29, 30]. Retina is the second most commonly involved structure with significant visual morbidity resulting from vascular thrombosis. It can affect as high as a third of all patients with SLE depending on the patient population [29]. The pathogenesis is thought to be an immune mediated endothelial damage and a hypercoagulable milieu leading to vasoocclusive retinopathy. Dilated fundus examination findings can range from cotton wool spots, microaneurysms, and exudates to severe nonperfusion changes such as neovascularization and vitreous hemorrhage [31]. Retinopathy parallels systemic disease activity and simultaneous central nervous system involvement is seen in a vast majority of patients. Significant vision loss as well as increased mortality has been reported in patients with severe retinal vasculitis [32, 33]. Therefore, the presence of retinopathy warrants aggressive systemic therapy even if no obvious signs of systemic disease are seen. Patients with anti-phospholipid antibody are thought to be at a higher risk for developing retinal vasculitis than those who do not carry this antibody [34]; of all the anti-phospholipid antibodies, lupus anticoagulant is associated with the highest risk of arterial and venous thrombosis and resultant vasculitis [35]. Male patients though less commonly affected by SLE have a higher incidence of anti-phospholipid antibodies than females and therefore a higher risk for thrombosis. Male gender has been proposed as a predictor for poor prognosis for extra ocular organ involvement [36]. It is thought that male patients have a higher incidence and more severe retinopathy than their female counterparts, although there have not been epidemiologic studies comparing the ocular manifestations between genders [37, 38]. Scleritis and episcleritis are also common in patients with SLE, but at a less frequent rate than in patients with RA. The pathogenesis is thought to be immune complex mediated tissue destruction of affected tissue [39, 40]. No apparent gender disparities have been reported in terms of incidence or severity of scleral involvement in this patient population. Scleritis can be chronic, relapsing, and sometimes associated with active systemic disease necessitating systemic immunosuppressive therapy [41]. Neuroophthalmic manifestations such as optic neuritis, ischemic optic neuropathy, and chiasmopathy are seen in about 1% of patients with SLE [42]. Patients typically present with painless loss of vision, pupillary defects, and loss/impaired color vision. This can sometimes be the initial 3 manifestation of the disease making the diagnosis difficult. Examination can show disc pallor or edema. This warrants long-term use of systemic immunosuppressive therapy [43, 44]. Given the small population size, no studies are available to comment on gender differences if they exist. 4. Systemic Sclerosis Systemic sclerosis is a rare connective tissue disorder that is characterized by abnormal fibroblast proliferation leading to deposition of extracellular matrix in the skin, blood vessels, and viscera. This results in stiffening of the connective tissue structures in the skin and body organs. Like other autoimmune diseases, it is characterized by interplay of inflammatory cytokines and antibodies [45]. It is more common in women with female to male ratio being 8 : 1 [46]. Most commonly reported ocular pathologies include eye lid stiffness that is seen in more than 50% of the cases and results from deposition of type I collagen in the dermis [47]. Keratoconjunctivitis sicca is the second most common problem seen in 50% of the affected patients [48]. Cases of conjunctivitis, episcleritis, anterior uveitis, and hypertensive retinopathy have also been reported [46, 48–50]. 5. Polymyositis and Dermatomyositis As their names suggest polymyositis and dermatomyositis are a group of autoimmune diseases characterized by inflammation of the skeletal muscles; when there is dermatologic involvement, the condition is referred to as dermatomyositis. Genetic factors play an important role and a strong association has been identified with human leukocyte antigens HLAB8 and DR3 and DR52 [51, 52]. Laboratory testing usually shows elevated creatinine kinase and aldolase levels along with other inflammatory markers [53]. The histopathologic features in dermatomyositis include deposition of immune complexes in a vascular distribution in more than three quarters of the cases. Vasculitis is more commonly seen in the pediatric population [54, 55]. Inflammatory myositis is relatively rare compared to other rheumatologic diseases with around 5 new cases per million being reported annually [56]. Women are more commonly affected than men. Around 15% of the cases are associated with an underlying malignancy [57]. Heliotrope rash or purplish discoloration of the eyelids is the most common ocular manifestation associated with dermatomyositis. Pediatric case reports exist about retinal vasculitis with dermatomyositis [58–60]. Occasional cases of internuclear ophthalmoplegia have also been reported [61, 62]. No gender differences have been observed in the incidence or severity of ocular problems in this patient population. 6. Systemic Vasculitides Classically, the vasculitic syndromes have been classified by the predominant sizes of the blood vessels most commonly involved [63]. 4 Revisions in the commonly used terms for the various vasculitides have been proposed by the 2012 International Chapel Hill Consensus Conference (CHCC) on nomenclature of vasculitides [64]. Notably, the 2012 Chapel Hill Consensus Conference adopted the term antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) for these three disorders: microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA instead of Wegener’s), and eosinophilic granulomatosis with polyangiitis (EGPA instead of ChurgStrauss Syndrome). ANCA associated vasculitides are a group of small to medium vessel inflammatory diseases that cause end organ damage from vessel thrombosis that results from inflammation of the vascular endothelial lining. Ophthalmic manifestations are protean and nonspecific and are secondary to vasculitis of the ophthalmic circulation. GPA patients have a higher likelihood of ocular or orbital involvement than EGPA patients [65, 66]. Conjunctivitis, episcleritis, and scleritis are the most common presentations. The patients typically present with painful red eye except in episcleritis where the condition might be painless and usually self-limiting. Conjunctivitis can sometimes present with granulomas that are often bilateral. Cicatrizing conjunctivitis resulting in symblepharon more commonly of the upper eyelid can be seen in uncontrolled disease [67, 68]. Scleritis associated with systemic vasculitis requires more aggressive treatment than idiopathic scleritis or from other etiologies [69]. Cornea can be affected in the form of exposure keratitis as a result of conjunctival scarring or more seriously as peripheral ulcerative keratitis (PUK). GPA is the second most common cause of PUK after rheumatoid arthritis [70] and has a similar presentation. Vasoocclusive phenomenon of the retinal artery or veins is uncommon but has been described as case reports in both GPA and EGPA [71–75]. Patients present with sudden, painless loss of vision. Retinal arterial involvement can be in the form of central retinal artery occlusion or a branch of it. Involvement of posterior ciliary circulation can cause ischemic optic neuritis. Rarely patients with ANCA vasculitis can present with anterior, posterior, or panuveitis. Uveitis tends to occur in less than 10% of the cases [67, 76, 77] and is thought to be a result of spill-over of inflammation from adjacent scleritis (which can sometimes be the heralding manifestation) or keratitis [78]. No gender differences have been reported in the incidence or disease course of ocular manifestations seen with systemic vasculitides. 7. Behçet’s Disease Behçet’s disease (BD) is a chronic multiorgan occlusive vasculitis that affects venules more than arteries but can affect vessels of any size [79, 80]. It is most prevalent in countries along the historic Silk Route with Far and Middle East having a higher prevalence than Europe [81, 82]. In some countries such as Turkey the prevalence is as high as 80– 300 cases per 100,000 [82]. Hence, much of the current Journal of Ophthalmology literature comes from studies done in Turkey, Iran, and Japan. It usually presents with recurrent oral and genital ulcers, cutaneous inflammation, and relapsing uveitis usually in the third decade of life with male predominance noted in most studies [82–85]. International Study Group for Behçet’s Disease (ICBD) has included ocular involvement as part of the diagnostic criteria [86]. Uveitis is the most common ocular manifestation affecting more than 50–80% of patients with BD [87]. Bilateral panuveitis is the most frequent form irrespective of the patient age group [82, 83]. Behçet disease associated uveitis carries a poor visual prognosis with more than a quarter ending up legally blind [83, 88]. Male gender has been proposed as a risk factor for developing BD related uveitis [89, 90] and has also been found to be associated with worse outcomes in terms of disease course and response to therapy [91, 92]. This is thought to be secondary to a higher incidence of posterior segment involvement and retinal vasculitis in males compared to females. Other prognostic factors include duration of uveitis and age at onset. Like all autoimmune conditions, genetics plays an important role in the disease pathogenesis. Human leukocyte antigens (HLA-) B51 and HLA-A26 have been identified as predisposing factors associated with BD related uveitis. HLAA26 has also been proposed to be associated with worse visual outcomes by increasing the risk of posterior involvement [93, 94] whereas HLA-B51 is associated with earlier onset age of uveitis and male gender [95] in patients with posterior uveitis. Hence male gender serves not only as a risk factor for developing uveitis in patients with Behçet’s disease but also as a marker of poor visual outcome once the uveitis develops. 8. Sarcoidosis Sarcoidosis is characterized by multisystem noncaseating granulomas that result from an exaggerated immune response to self or non-self-antigens [96]. No specific etiology has been identified. Genetics (HLA-B8 is the most common allele that has been associated with sarcoidosis) [97] and infectious agents (mycobacteria, human herpes virus 8) [98, 99] as well as environmental factors have been implicated in the pathogenesis. Inflammation can involve multiple organ systems with the most common ones being lymph nodes, lungs, eyes, and skin. Ocular sarcoidosis can be seen in up to 25–50% of the patients with systemic disease. This can be the unmasking feature leading to the diagnosis [100]. The incidence also varies with race. African-Americans are 10–20 times more commonly affected than Caucasians [101]. It affects both genders similarly with a slight female predominance [102]. A bimodal incidence has been reported with the first peak between the 2nd and 3rd decade and the second between the 5th and 6th decade of life [103, 104]. Bilateral granulomatous uveitis can sometimes be the only sarcoid related pathology. Bilateral ocular involvement is the most common ocular pattern occurring in 30–70% of the cases [105–108]. Anterior uveitis is the most common type; however distribution of uveitis may vary with race. Some studies have reported posterior or panuveitis Journal of Ophthalmology to be more common in Caucasians compared to AfricanAmericans [109–112]. The International Workshop on Ocular Sarcoidosis (IWOS) has identified seven signs “suggestive” for the diagnosis of ocular sarcoidosis. These include (1) mutton-fat/granulomatous keratic precipitates and/or iris nodules (Koeppe/Busacca), (2) trabecular meshwork nodules and/or tent-shaped peripheral anterior synechiae, (3) snowballs/string of pearls vitreous opacities, (4) multiple chorioretinal peripheral lesions (active and/or atrophic), (5) nodular and/or segmental periphlebitis (+/− candlewax drippings) and/or retinal macroaneurysm in an inflamed eye, (6) optic disc nodule(s)/granuloma(s) and/or solitary choroidal nodule, and (7) bilaterality [113]. About 10% of sarcoid associated uveitis cases can have significant visual dysfunction and even blindness [114]. Female gender, Caucasian race, late onset of systemic disease, and presence of multifocal choroiditis or panuveitis have been associated with a worse visual outcome [109, 115–117]. White patients had more posterior segment involvement and white females had frequent occurrence of cystoid macular edema and therefore worse visual outcomes [117]. Keratoconjunctivitis sicca (KCS) is the second most common ocular manifestation followed by adnexal granulomas. KCS or dry eye syndrome results not only from aqueous layer deficiency as a result of lacrimal gland inflammation leading to fibrosis but also from mucin and lipid layer deficiencies. The latter is in fact the main underlying pathology [118]. This is more common in women as mentioned earlier in the Rheumatoid Arthritis section. Clinically, significant lacrimal gland involvement resulting in enlargement of the lacrimal gland is an uncommon finding [112]. Adnexal granulomas most commonly affect the conjunctiva followed by eyelid. Rarely lacrimal gland and orbital granulomas are also seen [112]. According to IOWS diagnostic criteria, they can also be present in the trabecular meshwork (Berlin nodules) and cause an elevated intraocular pressure secondary to angle closure [113, 119]. Like elsewhere histopathology shows noncaseating granulomas and sometimes can help form the diagnosis. Female gender acts as a prognostic factor related to worse visual outcomes in patients with ocular sarcoidosis. Conflict of Interests The authors declare that there is no conflict of interests regarding the publication of this paper. References [1] C. C. Whitacre, S. C. Reingold, P. A. O’Looney et al., “Biomedicine: a gender gap in autoimmunity,” Science, vol. 283, no. 5406, pp. 1277–1278, 1999. [2] N. Talal, M. J. Dauphinee, A. Ahmed, and P. Christados, “Sex factors in immunity and autoimmnity,” Program in Immunology, pp. 1589–1600, 1983. [3] S. A. Ahmed, W. J. Penhale, and N. Talal, “Sex hormones, immune responses, and autoimmune diseases: mechanisms of sex hormone action,” American Journal of Pathology, vol. 121, no. 3, pp. 531–551, 1985. 5 [4] E. M. McDermot and H. McDevitt, “The immunogenetics of rheumatic diseases,” Bulletin on the Rheumatic Diseases, vol. 38, no. 1, 1988. [5] M. Fujita, T. Igarashi, T. Kurai, M. Sakane, S. Yoshino, and H. Takahashi, “Correlation between dry eye and rheumatoid arthritis activity,” American Journal of Ophthalmology, vol. 140, no. 5, pp. 808–813, 2005. [6] M. A. Lemp and R. Mauquardt, Eds., The Dry Eye, Springer, Berlin, Germany, 1992. [7] D. A. Sullivan, B. D. Sullivan, J. E. Evans et al., “Androgen deficiency, meibomian gland dysfunction, and evaporative dry eye,” Annals of the New York Academy of Sciences, vol. 966, pp. 211–222, 2002. [8] D. A. Sullivan, A. Belanger, J. M. Cermak et al., “Are women with Sjogren’s syndrome androgen deficient?” Investigative Ophthalmology & Visual Science, vol. 41, article S1453, 2000. [9] B. Caffery, D. Richter, T. Simpson, D. Fonn, M. Doughty, and K. Gordon, “The prevalence of dry eye in contact lens wearers: part 2 of the Canadian Dry Eye Epidemiology Study (candees),” Investigative Ophthalmology and Visual Science, vol. 37, no. 3, article S72, 1996. [10] E. K. Akpek, J. E. Thorne, F. A. Qazi, D. V. Do, and D. A. Jabs, “Evaluation of patients with scleritis for systemic disease,” Ophthalmology, vol. 111, no. 3, pp. 501–506, 2004. [11] D. A. Jabs, A. Mudun, J. P. Dunn, and M. J. Marsh, “Episcleritis and scleritis: clinical features and treatment results,” American Journal of Ophthalmology, vol. 130, no. 4, pp. 469–476, 2000. [12] W. P. Riono, A. A. Hidayat, and N. A. Rao, “Scleritis: a clinicopathologic study of 55 cases,” Ophthalmology, vol. 106, no. 7, pp. 1328–1333, 1999. [13] A. Mohsenin and J. J. Huang, “Ocular manifestations of systemic inflammatory diseases,” Connecticut Medicine, vol. 76, no. 9, pp. 533–544, 2012. [14] G. P. Riley, R. L. Harrall, P. G. Watson, T. E. Cawston, and B. L. Hazleman, “Collagenase (MMP-1) and TIMP-1 in destructive corneal disease associated with rheumatoid arthritis,” Eye, vol. 9, no. 6, pp. 703–718, 1995. [15] C. S. Foster, S. L. Forstot, and L. A. Wilson, “Mortality rate in rheumatoid arthritis patients developing necrotizing scleritis or peripheral ulcerative keratitis: effects of systemic immunosuppression,” Ophthalmology, vol. 91, no. 10, pp. 1253–1262, 1984. [16] A. Rahman and D. A. Isenberg, “Systemic lupus erythematosus,” The New England Journal of Medicine, vol. 358, no. 9, pp. 929– 939, 2008. [17] D. P. D’Cruz, M. A. Khamashta, and G. R. Hughes, “Systemic lupus erythematosus,” The Lancet, vol. 369, no. 9561, pp. 587– 596, 2007. [18] K. H. Costenbader, D. Feskanich, M. J. Stampfer, and E. W. Karlson, “Reproductive and menopausal factors and risk of systemic lupus erythematosus in women,” Arthritis and Rheumatism, vol. 56, no. 4, pp. 1251–1262, 2007. [19] G. S. Cooper, M. A. Dooley, E. L. Treadwell, E. W. St.Clair, and G. S. Gilkeson, “Hormonal and reproductive risk factors for development of systemic lupus erythematosus: results of a population-based, case-control study,” Arthritis and Rheumatism, vol. 46, no. 7, pp. 1830–1839, 2002. [20] G. S. Cooper, M. A. Dooley, E. L. Treadwell, E. W. St.Clair, and G. S. Gilkeson, “Hormonal and reproductive risk factors for development of systemic lupus erythematosus: results of a population-based, case-control study,” Arthritis and Rheumatism, vol. 46, no. 7, pp. 1830–1839, 2002. 6 [21] R. G. Lahita, “The role of sex hormones in systemic lupus erythematosus,” Current Opinion in Rheumatology, vol. 11, no. 5, pp. 352–356, 1999. [22] N. I. Stahl and J. L. Decker, “Androgenic status of males with systemic lupus erythematosus,” Arthritis and Rheumatism, vol. 21, no. 6, pp. 665–668, 1978. [23] C. C. Mok and C. S. Lau, “Profile of sex hormones in male patients with systemic lupus erythematosus,” Lupus, vol. 9, no. 4, pp. 252–257, 2000. [24] A. Rahman and D. A. Isenberg, “Systemic lupus erythematosus,” The New England Journal of Medicine, vol. 358, no. 9, pp. 929– 939, 2008. [25] M. Petri, A. M. Orbai, G. S. Alarcón et al., “Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus,” Arthritis & Rheumatology, vol. 64, article 2677, 2012. [26] T. Klenjberg and H. V. Moraes Jr., “Ophthalmological alterations in outpatients with systemic lupus erythematosus,” Arquivos Brasileiros de Oftalmologia, vol. 69, pp. 233–237, 2006. [27] J. L. Jensen, H. O. Bergem, I.-M. Gilboe, G. Husby, and T. Axéll, “Oral and ocular sicca symptoms and findings are prevalent in systemic lupus erythematosus,” Journal of Oral Pathology and Medicine, vol. 28, no. 7, pp. 317–322, 1999. [28] J. B. Davies and P. K. Rao, “Ocular manifestations of systemic lupus erythematosus,” Current Opinion in Ophthalmology, vol. 19, no. 6, pp. 512–518, 2008. [29] O. Ushiyama, K. Ushiyama, S. Koarada et al., “Retinal disease in patients with systemic lupus erythematosus,” Annals of the Rheumatic Diseases, vol. 59, no. 9, pp. 705–708, 2000. [30] F. J. Stafford-Brady, M. B. Urowitz, D. D. Gladman, and M. Easterbrook, “Lupus retinopathy. Patterns, associations, and prognosis,” Arthritis and Rheumatism, vol. 31, no. 9, pp. 1105– 1110, 1988. [31] D. A. Jabs, S. L. Fine, and M. C. Hochberg, “Severe retinal vasoocclusive disease in systemic lupus erythematosus,” Archives of Ophthalmology, vol. 104, no. 4, pp. 558–563, 1986. [32] A. Montehermoso, R. Cervera, J. Font et al., “Association of antiphospholipid antibodies with retinal vascular disease in systemic lupus erythematosus,” Seminars in Arthritis and Rheumatism, vol. 28, no. 5, pp. 326–332, 1999. [33] M. Galli, D. Luciani, G. Bertolini, and T. Barbui, “Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature,” Blood, vol. 101, no. 5, pp. 1827–1832, 2003. [34] S. Stefanidou, A. Benos, V. Galanopoulou et al., “Clinical expression and morbidity of systemic lupus erythematosus during a post-diagnostic 5-year follow-up: a male: female comparison,” Lupus, vol. 20, no. 10, pp. 1090–1094, 2011. [35] S. Stefanidou, A. Benos, V. Galanopoulou et al., “Clinical expression and morbidity of systemic lupus erythematosus during a post-diagnostic 5-year follow-up: a male: female comparison,” Lupus, vol. 20, no. 10, pp. 1090–1094, 2011. [36] D. Yan, G. Jian-ping, D. Yi-jun et al., “Gender differences are associated with the clinical features of systemic lupus erythematosus,” Chinese Medical Journal, vol. 125, no. 14, pp. 2477–2481, 2012. [37] P. Frith, S. M. Burge, P. R. Millard, and F. Wojnarowska, “External ocular finidngs in lupus erythematosus: a clinical and immunopathological study,” British Journal of Ophthalmology, vol. 74, no. 3, pp. 163–167, 1990. Journal of Ophthalmology [38] A. Heiligenhaus, J. E. Dutt, and C. Stephen Foster, “Histology and immunopathology of systemic lupus erythematosus affecting the conjunctiva,” Eye, vol. 10, no. 4, pp. 425–432, 1996. [39] C. E. Pavesio and F. M. Meier, “Systemic disorders associated with episcleritis and scleritis,” Current Opinion in Ophthalmology, vol. 12, no. 6, pp. 471–478, 2001. [40] R. R. Sivaraj, O. M. Durrani, A. K. Denniston, P. I. Murray, and C. Gordon, “Ocular manifestations of systemic lupus erythematosus,” Rheumatology, vol. 46, no. 12, pp. 1757–1762, 2007. [41] G. Galindo-Rodrı́guez, J. A. Aviña-Zubieta, S. Pizarro et al., “Cyclophosphamide pulse therapy in optic neuritis due to systemic lupus erythematosus: an open trial,” American Journal of Medicine, vol. 106, no. 1, pp. 65–69, 1999. [42] L. P. Frohman, B. J. Frieman, and L. Wolansky, “Reversible blindness resulting from optic chiasmitis secondary to systemic lupus erythematosus,” Journal of Neuro-Ophthalmology, vol. 21, no. 1, pp. 18–21, 2001. [43] L. I. Sakkas, “New developments in the pathogenesis of systemic sclerosis,” Autoimmunity, vol. 38, no. 2, pp. 113–116, 2005. [44] B. D. A. F. Gomes, M. R. Santhiago, P. Magalhães, N. Kara Jr., M. N. L. de Azevedo, and H. V. Moraes Jr., “Ocular findings in patients with systemic sclerosis,” Clinics, vol. 66, no. 3, pp. 379– 385, 2011. [45] R. Tailor, A. Gupta, A. Herrick, and J. Kwartz, “Ocular manifestations of scleroderma,” Survey of Ophthalmology, vol. 54, no. 2, pp. 292–304, 2009. [46] F. Zulian, C. Vallongo, P. Woo et al., “Localized scleroderma in childhood is not just a skin disease,” Arthritis and Rheumatism, vol. 52, no. 9, pp. 2873–2881, 2005. [47] R. David and M. Ivry, “Focal chorioretinitis and iridocyclitis associated with scleroderma,” Annals of Ophthalmology, vol. 8, no. 2, pp. 199–202, 1976. [48] W. L. Jones and S. M. DeCanio Jr., “Hypertensive retinopathy and generalized scleroderma,” American Journal of Optometry and Physiological Optics, vol. 58, no. 12, pp. 1138–1141, 1981. [49] N. I. Abdou, G. J. Kullman, G. S. Hoffman et al., “Wegener’s granulomatosis: survey of 701 patients in North America. Changes in outcome in the 1990s,” Journal of Rheumatology, vol. 29, no. 2, pp. 309–316, 2002. [50] G. G. Hunder, W. P. Arend, D. A. Bloch et al., “The American College of Rheumatology 1990 criteria for the classification of vasculitis. Introduction,” Arthritis and Rheumatism, vol. 33, no. 8, pp. 1065–1067, 1990. [51] L. A. Love, R. L. Leff, D. D. Fraser et al., “A new approach to the classification of idiopathic inflammatory myopathy: myositis-specific autoantibodies define useful homogeneous patient groups,” Medicine, vol. 70, no. 6, pp. 360–374, 1991. [52] M. J. Garlepp, “Genetics of the idiopathic inflammatory myopathies,” Current Opinion in Rheumatology, vol. 8, no. 6, pp. 514–520, 1996. [53] R. L. Wortmann, “Inflammatory diseases of muscle and other myopathies,” in Kelly’s Textbook of Rheumatology, S. Ruddy, E. D. Harris, C. B. Sledge et al., Eds., pp. 1273–1296, WB Saunders, Philadelphia, Pa, USA, 6th edition, 2001. [54] J. N. Whitaker and W. K. Engel, “Vascular deposits of immunoglobulin and complement in idiopathic inflammatory myopathy,” The New England Journal of Medicine, vol. 286, no. 7, pp. 333–338, 1972. [55] W. E. Crowe, K. E. Bove, J. E. Levinson, and P. K. Hilton, “Clinical and pathogenetic implications of histopathology in childhood polydermatomyositis,” Arthritis and Rheumatism, vol. 25, no. 2, pp. 126–139, 1982. Journal of Ophthalmology [56] M. E. Cronin and P. H. Plotz, “Idiopathic inflammatory myopathies,” Rheumatic Disease Clinics of North America, vol. 16, no. 3, pp. 655–665, 1990. [57] J. P. Callen, J. F. Hyla, G. G. Bole Jr., and D. R. Kay, “The relationship of dermatomyositis and polymyositis to internal malignancy,” Archives of Dermatology, vol. 116, no. 3, pp. 295– 298, 1980. [58] S. Liebman and C. Cook, “Retinopathy with dermatomyositis,” Archives of Ophthalmology, vol. 74, article 704, 1965. [59] J. Zamora, K. Pariser, T. Hedges et al., “Retinal vasculitis in polymyositis-dermatomyositis,” Arthritis & Rheumatology, vol. 30, article S106, 1987. [60] P. Lenoble, P. Desprez, M. Fischbach, J. Flament, and J. Sahel, “Ocular lesion in dermatomyositis: about the case of a fifteen year old girl,” Journal Francais d’Ophtalmologie, vol. 18, no. 4, pp. 312–316, 1995. [61] J. O. Susac, R. Garcia-Mullin, and J. S. Glaser, “Ophthalmoplegia in dermatomyositis,” Neurology, vol. 23, no. 3, pp. 305–310, 1973. [62] A. Ehongo, M. Cordonnier, C. Van Nechel et al., “Internuclear bilateral pseudo-ophthalmoplegia and dermatomyositis,” Bulletin de la Société Belge d’Ophtalmologie, vol. 263, pp. 43–51, 1996. [63] J. C. Jennette, R. J. Falk, P. A. Bacon et al., “2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides,” Arthritis & Rheumatology, vol. 65, no. 1, article 1, 2013. [64] R. A. Watts, D. M. Carruthers, and D. G. I. Scott, “Epidemiology of systemic vasculitis: changing incidence or definition?” Seminars in Arthritis and Rheumatism, vol. 25, no. 1, pp. 28–34, 1995. [65] C. L. Bullen, T. J. Liesegang, T. J. McDonald, and R. A. DeRemee, “Ocular complications of Wegener’s granulomatosis,” Ophthalmology, vol. 90, no. 3, pp. 279–290, 1983. [66] G. S. Hoffman, G. S. Kerr, R. Y. Leavitt et al., “Wegener granulomatosis: an analysis of 158 patients,” Annals of Internal Medicine, vol. 116, no. 6, pp. 488–498, 1992. [67] N. Pakrou, D. Selva, and I. Leibovitch, “Wegener’s granulomatosis: ophthalmic manifestations and management,” Seminars in Arthritis and Rheumatism, vol. 35, no. 5, pp. 284–292, 2006. [68] M. R. Robinson, S. S. Lee, M. C. Sneller et al., “Tarsalconjunctival disease associated with Wegener’s granulomatosis,” Ophthalmology, vol. 110, no. 9, pp. 1770–1780, 2003. [69] J. A. Garritty, “Ocular manifestations of small-vessel vasculitis,” Cleveland Clinic Journal of Medicine, vol. 79, pp. 31–33, 2012. [70] J. G. Ladas and B. J. Mondino, “Systemic disorders associated with peripheral corneal ulceration,” Current Opinion in Ophthalmology, vol. 11, no. 6, pp. 468–471, 2000. [71] M. H. Greenberger, “Central retinal artery closure. In Wegener’s granulomatosis,” American Journal of Ophthalmology, vol. 63, no. 3, pp. 515–516, 1967. [72] M. Wang, R. N. Khurana, and S. R. Sadda, “Central retinal vein occlusion in Wegener’s granulomatosis without retinal vasculitis,” British Journal of Ophthalmology, vol. 90, no. 11, pp. 1435–1436, 2006. [73] T. Lida, R. F. Spaide, J. Kantor et al., “Retinal and choroifal arterial occlusion in Wegener’s granulomatosis,” American Journal of Ophthalmology, vol. 133, pp. 151–152, 2002. [74] L. Rabinowitz Dagi and J. Currie, “Branch retinal artery occlusion in the Churg-Strauss syndrome,” Journal of Clinical NeuroOphthalmology, vol. 5, no. 4, pp. 229–237, 1985. [75] A. Partal, D. M. Moshfeghi, and D. Alcorn, “Churg-Strauss syndrome in a child: retina and optic nerve findings,” British Journal of Ophthalmology, vol. 88, no. 7, pp. 971–972, 2004. 7 [76] C. L. Bullen, T. J. Liesegang, T. J. McDonald, and R. A. DeRemee, “Ocular complications of Wegener’s granulomatosis,” Ophthalmology, vol. 90, no. 3, pp. 279–290, 1983. [77] B. F. Haynes, M. L. Fishman, A. S. Fauci et al., “The ocular manifestations of Wegener’s granulomatosis. Fifteen years experience and review of the literature,” American Journal of Ophthalmology, vol. 44, pp. 789–799, 1957. [78] J. E. Thorne and D. A. Jabs, “Ocular manifestations of vasculitis,” Rheumatic Disease Clinics of North America, vol. 27, no. 4, pp. 761–779, 2001. [79] V. Kontogiannis and R. J. Powell, “Behçet’s disease,” Postgraduate Medical Journal, vol. 76, pp. 629–637, 2000. [80] P. McCluskey and P. R. J. Powell, “The eye in systemic inflammatory diseases,” The Lancet, vol. 364, no. 9451, pp. 2125–2133, 2004. [81] A. Mahr, L. Belarbi, B. Wechsler et al., “Population-based prevalence study of Behçet’s disease: differences by ethnic origin and low variation by age at immigration,” Arthritis and Rheumatism, vol. 58, no. 12, pp. 3951–3959, 2008. [82] M. Citirik, N. Berker, M. S. Songur, S. S. Ozkan, and O. Zilelioglu, “Ocular manifestations of late-onset Behçet disease,” Ophthalmologica, vol. 225, no. 1, pp. 21–26, 2011. [83] I. Tugal-Tutkun, S. Onal, R. Altan-Yaycioglu, H. Huseyin Altunbas, and M. Urgancioglu, “Uveitis in Behçet disease: an analysis of 880 patients,” American Journal of Ophthalmology, vol. 138, no. 3, pp. 373–380, 2004. [84] I. Tugal-Tutkun and M. Urgancioglu, “Childhood-onset uveitis in Behçet disease: a descriptive study of 36 cases,” American Journal of Ophthalmology, vol. 136, no. 6, pp. 1114–1119, 2003. [85] H. Saricaoglu, S. K. Karadogan, N. Bayazit, A. Yucel, K. Dilek, and S. Tunali, “Clinical features of late-onset Behçet’s disease: report of nine cases,” International Journal of Dermatology, vol. 45, no. 11, pp. 1284–1287, 2006. [86] International Study Group for Behcet’s Disease, “Criteria for diagnosis of Behcet’s disease,” The Lancet, vol. 335, pp. 1078– 1080, 1990. [87] E. H. Kang, J. Y. Kim, F. Takeuchi et al., “Associations between the HLA-A polymorphism and the clinical manifestations of Behcet’s disease,” Arthritis Research & Therapy, vol. 13, no. 2, article R49, 2011. [88] N. Kitaichi, A. Miyazaki, D. Iwata et al., “Ocular features of Behçet’s disease: an international collaborative study,” British Journal of Ophthalmology, vol. 91, pp. 1579–1582, 2007. [89] F. Davatchi, F. Shahram, H. Chams et al., “The influence of gender on the severity and the outcome of ocular lesions in Behçet’s disease,” Advances in Experimental Medicine and Biology, vol. 528, pp. 67–71, 2003. [90] F. Davatchi, F. Shahram, H. Shams et al., “Gender influence on ocular manifestations and their outcome in Behcet’s Disease. A long-term follow-up of up to 20 years,” Clinical Rheumatology, vol. 30, no. 4, pp. 541–547, 2011. [91] H. Yazici, Y. Tuzun, and A. B. Tanman, “Male patients with Behcet’s syndrome have stronger pathergy reactions,” Clinical and Experimental Rheumatology, vol. 3, no. 2, pp. 137–141, 1985. [92] S. Ohno, M. Ohguchi, S. Hirose et al., “Close association of HLA-B51 with Behçet’s disease,” Archives of Ophthalmology, vol. 100, pp. 1455–1458, 1982. [93] C. Maldini, M. P. Lavalley, M. Cheminant, M. de menthon, and A. Mahr, “Relationships of HLA-B51 or B5 genotype with Behçet’s disease clinical characteristics: systematic review and meta-analyses of observational studies,” Rheumatology, vol. 51, no. 5, pp. 887–900, 2012. 8 [94] T. Kaburaki, M. Takamoto, J. Numaga et al., “Genetics association of HLA-A∗ 2601 with ocular Behçet’s disease in Japanese patients,” Clinical and Experimental Rheumatology, vol. 28, supplement 60, pp. S39–S44, 2010. [95] E. H. Kang, J. W. Park, C. Park et al., “Genetic and non-genetic factors affecting the visual outcome of ocular Behçet’s disease,” Human Immunology, vol. 74, pp. 1363–1367, 2013. [96] A. Rothova, “Ocular involvement in sarcoidosis,” British Journal of Ophthalmology, vol. 84, no. 1, pp. 110–116, 2000. [97] L. E. Siltzbach, D. G. James, and E. Neville, “Course and prognosis of sarcoidosis around the world,” American Journal of Medicine, vol. 57, no. 6, pp. 847–852, 1974. [98] F. A. K. El-Zaatari, D. Y. Graham, K. Samuelsson, and L. Engstrand, “Detection of Mycobacterium avium complex in cerebrospinal fluid of a sarcoid patient by specific polymerase chain reaction assays,” Scandinavian Journal of Infectious Diseases, vol. 29, no. 2, pp. 202–204, 1997. [99] L. Di Alberti, A. Piattelli, L. Artese et al., “Human herpesvirus 8 variants in sarcoid tissues,” The Lancet, vol. 350, no. 9092, pp. 1655–1661, 1997. [100] A. Heiligenhaus, D. Wefelmeyer, E. Wefelmeyer, M. Rösel, and M. Schrenk, “The eye as a common site for the early clinical manifestation of sarcoidosis,” Ophthalmic Research, vol. 46, no. 1, pp. 9–12, 2011. [101] J. M. Reich, “Course and prognosis of sarcoidosis in AfricanAmericans versus Caucasians,” European Respiratory Journal, vol. 17, no. 4, article 833, 2001. [102] M. Papadia, C. P. Herbort, and M. Mochizuki, “Diagnosis of ocular sarcoidosis,” Ocular Immunology and Inflammation, vol. 18, no. 6, pp. 432–441, 2010. [103] C. W. Fink and R. Cimaz, “Early onset sarcoidosis: not a benign disease,” Journal of Rheumatology, vol. 24, no. 1, pp. 174–177, 1997. [104] D. L. Hoover, J. A. Khan, and J. Giangiacomo, “Pediatric ocular sarcoidosis,” Survey of Ophthalmology, vol. 30, no. 4, pp. 215– 228, 1986. [105] R. P. Crick, C. Hoyle, and H. Smellie, “The eyes in sarcoidosis,” The British Journal of Ophthalmology, vol. 102, pp. 297–301, 1986. [106] D. J. Spalton and M. D. Sanders, “Fundus changes in histologically confirmed sarcoidosis,” British Journal of Ophthalmology, vol. 65, no. 5, pp. 348–358, 1981. [107] T. J. Wolfensberger and C. P. Herbort, “Indocyanine green angiographic features in ocular sarcoidosis,” Ophthalmology, vol. 106, no. 2, pp. 285–289, 1999. [108] U. R. Desai, K. A. Tawansy, B. C. Joondeph, and R. M. Schiffman, “Choroidal granulomas in systemic sarcoidosis,” Retina, vol. 21, no. 1, pp. 40–47, 2001. [109] P. Stavrou, S. Linton, D. W. Young, and P. I. Murray, “Clinical diagnosis of ocular sarcoidosis,” Eye, vol. 11, no. 3, pp. 365–370, 1997. [110] G. S. Kosmorsky, D. M. Meisler, T. W. Rice, M. A. Meziane, and C. Y. Lowder, “Chest computed tomography and mediastinoscopy in the diagnosis of sarcoidosis-associated uveitis,” American Journal of Ophthalmology, vol. 126, no. 1, pp. 132–134, 1998. [111] A. Rothova, C. Alberts, E. Glasius, A. Kijlstra, H. J. Buitenhuis, and A. C. Breebaart, “Risk factors for ocular sarcoidosis,” Documenta Ophthalmologica, vol. 72, no. 3-4, pp. 287–296, 1989. [112] M. Evans, O. Sharma, L. LaBree, R. E. Smith, and N. A. Rao, “Differences in clinical findings between Caucasians and African Americans with biopsy-proven sarcoidosis,” Ophthalmology, vol. 114, no. 2, pp. 325–333, 2007. Journal of Ophthalmology [113] C. P. Herbort, N. A. Rao, and M. Mochizuki, “International criteria for the diagnosis of ocular sarcoidosis: results of the first international workshop on ocular sarcoidosis (IWOS),” Ocular Immunology and Inflammation, vol. 17, no. 3, pp. 160–169, 2009. [114] J. E. Roulston, G. I. O’Malley, and J. G. Douglas, “Effects of prednisolone on angiotensin converting enzyme activity,” Thorax, vol. 39, no. 5, pp. 356–360, 1984. [115] A. Lobo, K. Barton, D. Minassian, R. M. Du Bois, and S. Lightman, “Visual loss in sarcoid-related uveitis,” Clinical and Experimental Ophthalmology, vol. 31, no. 4, pp. 310–316, 2003. [116] D. Khalatbari, S. Stinnett, R. M. McCallum, and G. J. Jaffe, “Demographic-related variations in posterior segment ocular sarcoidosis,” Ophthalmology, vol. 111, no. 2, pp. 357–362, 2004. [117] C. D. Obenauf, H. E. Shaw, C. F. Sydnor, and G. K. Klintworth, “Sarcoidosis and its ophthalmic manifestations,” American Journal of Ophthalmology, vol. 86, no. 5, pp. 648–655, 1978. [118] D. A. Jabs and C. J. Johns, “Ocular involvement in chronic sarcoidosis,” American Journal of Ophthalmology, vol. 102, no. 3, pp. 297–301, 1986. [119] T. Hamanaka, A. Takei, T. Takemura, and M. Oritsu, “Pathological study of cases with secondary open-angle glaucoma due to sarcoidosis,” American Journal of Ophthalmology, vol. 134, no. 1, pp. 17–26, 2002. Hindawi Publishing Corporation Journal of Ophthalmology Volume 2014, Article ID 157803, 8 pages http://dx.doi.org/10.1155/2014/157803 Review Article Gender Differences in Vogt-Koyanagi-Harada Disease and Sympathetic Ophthalmia Yujuan Wang1,2 and Chi-Chao Chan1 1 Immunopathology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, 10 Center Drive, 10/10N103, Bethesda, MD 20892-1857, USA 2 Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China Correspondence should be addressed to Chi-Chao Chan; [email protected] Received 30 September 2013; Revised 13 January 2014; Accepted 31 January 2014; Published 5 March 2014 Academic Editor: Janet L. Davis Copyright © 2014 Y. Wang and C.-C. Chan. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Vogt-Koyanagi-Harada disease (VKH) and sympathetic ophthalmia (SO) are types of T-cell mediated autoimmune granulomatous uveitis. Although the two diseases share common clinical features, they have certain differences in gender predilections. VKH classically has been reported as more prevalent in females than males, yet some studies in Japan and China have not found differences in gender prevalence. Male patients have a higher risk of chorioretinal degeneration, vitiligo, and worse prognosis. Conversely, the changing levels of estrogen/progesterone during pregnancy and the menstrual cycle as well as higher levels of TGF𝛽 show a protective role in females. Potential causes of female predilection for VKH are associated with HLA-DR and HLA-DQ alleles. SO, a bilateral granulomatous uveitis, occurs in the context of one eye after a penetrating injury due to trauma or surgery. In contrast to the female dominance in VKH, males are more frequently affected by SO due to a higher incidence of ocular injury, especially during wartime. However, no gender predilection of SO has been reported in postsurgical cases. No clinically different manifestations are revealed between males and females in SO secondary to either ocular trauma or surgery. The potential causes of the gender difference may provide hints on future treatment and disease evaluation. 1. Introduction Vogt-Koyanagi-Harada disease (VKH) and sympathetic ophthalmia (SO) are both considered ocular T-cell mediated autoimmune diseases. Although the pathogenesis and etiologies are different, the two entities share common clinical manifestations as well as similar pathological and immunohistochemical features [1–3]. Moreover, prompt and thorough treatment is essential for both VKH and SO. Systemic presentations and clinical history are important features that differentiate VKH from SO. Extraocular findings such as dysacusis, vitiligo, poliosis often develop in VKH but are rare in SO. Since females are more susceptible to a variety of autoimmune diseases, such as systemic lupus erythematosus, multiple sclerosis, and rheumatoid arthritis [4–6], this paper reviews the literature of VKH and SO focusing on whether gender predilection exists in these two diseases. 1.1. Clinical Aspects of VKH. VKH disease is a multisystemic disorder that involves the eyes, ears, skin, hair, and meninges. Ocular manifestations are characterized by bilateral granulomatous panuveitis with exudative retinal detachments. In the majority of VKH patients, the second eye becomes involved within 2 weeks after initial presentation. Overall, females are more frequently affected with VKH than males [7–9], although several studies found no such gender predilection [10, 11]. VKH tends to affect patients from Asian, Middle Eastern, Hispanic, and Native American populations [7, 12]. The typical progression of VKH includes 4 stages: the prodromal, uveitic, chronic, and chronic recurrent stages. The prodromal stage occurs 3–5 days before the ocular disease, mimicking a systemic viral-like presentation. The uveitic stage, which may last for several weeks to months, is characterized by acute anterior uveitis with mutton-fat keratic precipitates, aqueous cells and flare, iris nodules, 2 and synechiae. Severe changes in the posterior segment include vitritis, optic disc swelling, retinal edema, hemorrhages, nonrhegmatogenous exudative retinal detachment, subretinal fibrosis, disciform scars, and RPE abnormality. The focal yellowish-white nodular lesions, known as DalenFuchs nodules, are presented at the subretinal pigment epithelium (RPE) level in the peripheral retina. The Hallmark findings in the uveitic stage are multifocal detachments of the neurosensory retina. Depigmentation of the perilimbus (Sugiura’s sign) and a pale fundus (sunset-glow fundus) are revealed in the chronic stage. The chronic recurrent stage often presents other complications such as cataract, glaucoma, subretinal neovascularization, and subretinal fibrosis [13, 14]. Recurrence mainly involves the anterior segment. Extraocular presentations including vitiligo, poliosis, alopecia, and dysacusis may also develop during the chronic or chronic recurrent stages. 1.2. Clinical Aspects of SO. SO is a rare bilateral granulomatous uveitis that occurs after the uvea of one eye is subjected to a penetrating injury due to trauma or surgery. The injury to one eye (known as the exciting eye) also results in an inflammatory response in the noninjured, contralateral eye (known as the sympathizing eye). Unlike the multisystemic involvements of VKH, extraocular manifestations are rare in SO. Due to the rarity of disease and great improvements in modern surgical techniques, the disease rarely occurs; thus, it is difficult to estimate the prevalence of SO. An earlier study published the incidence of SO after a penetrating injury to be approximately 2% prior to 1950 [15]; lower incidences— 0.2–0.5% following ocular trauma and 0.01% following ocular surgery—have been reported in more recent studies [16, 17]. The interval between ocular injury and the SO onset varies to a large extent, ranging from 5 days to 66 years [16, 18, 19]. In general, 65% of SO occurs between 2 weeks and 2 months after injury and 90% occurs within 1 year [16, 20]. The clinical presentations are identical in both traumaand injury-induced SO with an insidious onset. The classic presentation of SO is characterized by an acute granulomatous inflammation in the anterior segment with muttonfat keratic precipitates, aqueous cells and flare, iridocyclitis, and posterior synechiae. Moderate to severe vitritis with choroidal thickening and infiltration as well as optic disc swelling generally occurs in the posterior segment [21–24]. The presence of Dalen-Fuchs nodules, measuring 60 to 700 𝜇m in diameter, is typical and is most often found at the midperipheral retina in SO [25]. In extremely rare situations, patients with SO may experience extraocular symptoms, such as hearing loss, headache, vitiligo, and alopecia [26, 27]. 2. Gender and VKH 2.1. Gender Differences in Prevalence and Incidence. Most studies have reported that females are affected with VKH more frequently than males (Table 1). Earlier studies in North America have noted that 60–78% of VKH patients are females [10, 12, 13, 28, 29]. By reviewing 75 VKH patients seen at the National Eye Institute between 1978 and 1996, 78.7% Journal of Ophthalmology of patients were females [7]. In other areas, the recently reported proportions of affected females with VKH are 78.9% in Mexico [9]; 62.9–75% in Saudi Arabia [8, 30, 31]; 65.3% in Tunisia, North Africa [32]; 73.7% in Japan [33]; 84.44% in South India [34]; 70% in Brazil [35]; and 71.1% in Turkey [36]. Sukavatcharin et al. reported that females constituted 62.5% of patients in 48 case series in a Hispanic population [37]. However, some other studies did not show similar findings. Sasamoto et al. found that only 38% of patients were females in their 47 case series of VKH in a Japanese population [38]. Chen et al. and Hou et al. even reported more male patients in more than 500 Chinese with VKH [11, 39]. However, no gender predisposition of the disease was also reported from the same group in other studies [40–45]. Other VKH studies have also reported no gender differences in prevalence; interestingly, most of these conclusions come from studies of Asian populations [46–49]. These data might indicate that there are geographic variations in the gender predilection in the VKH patients [13]. 2.2. Gender Differences in Clinical Manifestation after the Prevalence/Incidence. Interestingly, ocular manifestations of VKH are variable and race dependent, and the “sunsetglow” appearance is more commonly seen in Hispanic and Asian patients [13]. A study of 134 eyes (67 VKH patients) conducted in Singapore reported that male VKH patients (50 eyes) were clinically associated with a higher risk of chorioretinal degeneration and vitiligo [47]. No other clinical differences have been reported in VKH between male and female patients. 2.3. Gender Differences in Prognosis. Several factors have been related to a better prognosis in female patients with VKH. Pregnancy is reported to play a role in VKH prognosis and has a beneficial effect on disease activity [10, 50–52]. In general, two patterns of prognosis during pregnancy have been described [10, 50–52]. In some females with VKH, the ophthalmic presentations improved during pregnancy, but with recurrence after delivery [10, 51, 53]. Several studies have documented less uveitis reactivity with lower numbers/rates of flare-up during pregnancy, but many of these females experienced a rebound in activity within 6 months of delivery [53– 55]. However, in the other cases, VKH developed in females during pregnancy who were then cured with corticosteroids without recurrence following delivery [50]. Because VKH is a T-cell mediated autoimmune disease, changes in immunity and humoral constituents during pregnancy may account for the remissions in female patients [51]. In addition, Elias et al. showed that better final visual acuity is positively correlated with female patients, whereas male gender in VKH is significantly associated with worse visual acuity [56]. 2.4. Possible Explanations for Gender Differences Found in VKH 2.4.1. Relationship with Hormone Changes. Sex hormones, including estrogen and progesterone, are believed to mediate Journal of Ophthalmology 3 Table 1: Demographic differences of Vogt-Koyanagi-Harada disease (VKH) in the literature. Author/year Total: male (%)/female (%); 𝑃 value Age: mean ± SD (range, years) Race or region African American: 13.7% Oriental: 29.4% American Indian: 7.8% Spanish American: 15.7% White: 29.4% Others: 2 (3.9%) African American: 11 (55%) Hispanic: 7 (35%) White: 2 (10%) White: 60% Darkly pigmented: 24% Sansei: 9% African American: 6% Reference 51: 23 (45.1)/28 (54.9) 𝑃 = 0.4852 NA Snyder and Tessler/1980 20: 8 (40)/12 (60) 𝑃 = 0.3727 39.7 (10–56) Belfort Jr et al./1988 33: 10 (30)/23 (70) 𝑃 = 0.0174∗∗ NA Sasamoto et al./1990 47: 29 (61.7)/18 (38.3) 𝑃 = 0.1057 41.1 (14–64) Beniz et al./1991 48: 15 (31.2)/33 (68.8) 𝑃 = 0.0072∗∗ 33.4 ± 14.5 (15–78) Rubsamen and Gass/1991 22: 5 (22.7)/17 (77.3) 𝑃 = 0.0060∗∗ 35 (13–73) Moorthy et al./1995 65: 17 (26.2)/48 (73.8) 𝑃 = 0.0000∗∗ 32 (7–71) Lertsumitkul et al./1999 75: 16 (21.3)/59 (78.7) 𝑃 = 0.0000∗∗ 32.8 ± 12.6 (11–72) 39: 21 (53.8)/18 (46.2) 𝑃 = 0.6368 19: 5 (26.3)/14 (73.7) 𝑃 = 0.0306∗∗ 31: 19 (61.3)/12 (38.7) 𝑃 = 0.2063 33: 12 (36.4)/21 (63.6) 𝑃 = 0.1142 48: 18 (37.5)/30 (62.5) 𝑃 = 0.0801 39.82 ± 12.38 Taiwan [75] NA Japanese [33] Taiwan Chinese [76] Thai [48] Hispanic [37] Chinese: 75.28% Malays: 14.61% Indians: 5.62% Others: 4.49%; [46] 35 (16–54) North Africa [32] 37 ± 14.2 (14–63) South India [34] 31 ± 14.3 (4–65) Turkish [36] Ohno et al./1977 Sheu et al./2003 Wakabayashi et al./2003 Sheu et al./2004 Tesavibul and Sansanayuth/2005 Sukavatcharin et al./2007 Chee et al./2007 Khairallah et al./2007 Murthy et al./2007 Tugal-Tutkun et al./2007 89: 38 (42.1)/51 (57.9) 𝑃 = 0.1347 49: 17 (34.7)/32 (65.3) 𝑃 = 0.0291∗∗ 45: 7 (15.6)/38 (84.4) 𝑃 = 0.0000∗∗ 45: 13 (28.9)/32 (71.1) 𝑃 = 0.0032∗∗ 38.6 ± 10.6 (20–63) 35 ± 13.4 (17–67) 35 ± 13 41.8 ± 14.7 (SE) Japan Hispanic: 75% White: 10.4% African American: 4.2% Oriental: 10.4% Hispanic: 54% African American: 23% White: 14% Oriental: 9% Hispanic: 51 (78%) Asian: 6 (10%) African American: 4 (6%) Native American: 1 (1.5%) White: 2 (3%) Asian Indian: 1 (1.5%) White/native American: 22.7% African/native: American: 52.0% Hispanic: 12.0% Oriental: 12.0% Asian Indian: 1.3% [12] [10] [35] [38] [28] [29] [13] [7] 4 Journal of Ophthalmology Table 1: Continued. Author/year Kiyomoto et al./2007 Al-Kharashi et al./2007 Hou et al./2008∗ Chee et al./2009 Lai et al./2009 Iqniebi et al./2009 Meng et al./2009∗ Hou et al./2009∗ Hu et al./2010∗ Chee et al./2010 Jiang et al./2010∗ Shu et al./2010∗ ́ Alaez et al./2011 Al-Halafi et al./2011 Chen et al./2012∗ Yang et al./2012 Chen et al./2012∗ Morita et al./2013 Alam et al./2013 ∗ Age: mean ± SD (range, years) Total: male (%)/female (%); 𝑃 value 68: 29 (42.6)/39 (57.4) 𝑃 = 0.2215 68: 17 (25)/51 (75) 𝑃 = 0.0000∗∗ 231: 128 (55.4)/103 (44.6) 𝑃 = 0.1001 67: 27 (40.3)/40 (59.7) 𝑃 = 0.1103 35: 18 (51.4)/17 (48.6) 𝑃 = 0.8694 30: 12 (40)/18 (60) 𝑃 = 0.2727 247: 138 (55.9)/109 (44.1) 𝑃 = 0.0630 307: 171 (55.7)/136 (44.3) 𝑃 = 0.0453∗∗ 379: 197 (51.9)/182 (48.1) 𝑃 = 0.4596 28: 13 (46.4)/15 (53.6) 𝑃 = 0.7055 43.1 ± 14.2 (16–71) Reference Japanese [77] Saudi Arabia [31] Chinese [40] Chinese: 79.1% Others: 20.9% [47] Hong Kong Chinese [78] NA Saudi Arabia [69] 33.6 Chinese [41] 34.3 ± 10.3 Chinese [39] 32.8 ± 9.8 Chinese [43] Chinese: 64.3% Malays: 21.5% Indians: 7.1% Others 7.1% [79] 33.6 ± 12.4 Chinese [42] 34.1 ± 9.6 Chinese [44] Mexican Mestizos [9] Saudi Arabia [8] Chinese [11] Hong Kong Chinese [80] 33.8 ± 9.3 Chinese [45] 47.1 ± 14 Japanese [81] 28 (16–43) Pakistanis: [49] 25 ± 10.3 (7–55) 33.6 ± 12.4 42.3 (5.4–70.9) 42.5 ± 18.4 (10–72) 42.2 (median) (16–77) 382: 210 (55)/172 (45) 𝑃 = 0.0502 385: 201 (52.2)/184 (47.8) 𝑃 = 0.3880 76: 16 (21.1)/60 (78.9) 𝑃 = 0.0000∗∗ 256: 95 (37.1)/161 (62.9) 𝑃 = 0.0000∗∗ 519: 290 (55.9)/229 (44.1) 𝑃 = 0.0070∗∗ 38: 17 (44.7)/21 (55.3) 𝑃 = 0.5152 451: 243 (53.9)/208 (46.1) 𝑃 = 0.0973 85: 37 (43.5)/48 (56.5) 𝑃 = 0.2301 9: 4 (44.4)/5 (55.6) 𝑃 = 0.7440 Race or region 42.1 (11–76) 29 ± 13 30.0 ± 13.5 50 ± 8.4 Study from the same VKH research group in China; ∗∗ 𝑃 < 0.05. the immune response and account for gender differences in the prevalence of autoimmune diseases [57]. An increased incidence or severity of inflammation has been reported in the late phase of the menstrual cycle for women with asthma, rheumatoid arthritis, and psoriatic arthritis [58–61]. As a systemic autoimmune disorder and subtype of uveitis, VKH is also influenced by hormonal factors [61, 62]. Literature showing VKH amelioration during pregnancy has suggested that sex hormones may influence the course of VKH [10, 51]. To further evaluate the protective role of pregnancy, we used the experimental autoimmune uveitis (EAU) mouse model mimicking human uveitis [63]. Our results suggest that protection from EAU during pregnancy is primarily due to a selective reduction of antigen-specific Th1 responses with only marginal enhancement of Th2 function. These effects may in part be secondary to elevated systemic levels of TGF-𝛽. We measured serum levels of the female hormones (estrogen, progesterone, and prolactin), Th1 (IL2 and IFN-𝛾), Th2 (IL-4, IL-5, IL-6, and IL-10), and TGF𝛽 cytokine levels in 4 women with uveitis during their 5 normal, full term pregnancies. Uveitic activities decreased after the first trimester but flared up in early postpartum Journal of Ophthalmology 5 Table 2: Demographic differences of sympathetic ophthalmia (SO) in the literature. Total: male (%)/female (%) 𝑃 value 32: 16 (50)/16 (50) 𝑃 = 1.0000 30: 21 (70)/9 (30) 𝑃 = 0.0235∗ 32.7 ± 23.6 (1–80) Castiblanco and Adelman/2009 86: 62 (72.1)/24 (27.9) 𝑃 = 0.2655 46 (3–83) Galor et al./2009 85: 50 (60)/35 (40) 𝑃 = 0.0633 44 (2–91) 60: 34 (56.7)/26 (43.3) 𝑃 = 0.2992 36 ± 20 (4–90) Author/year Chan et al./1995 Lin and Zhong/1996 Al-Halafi et al./2011 ∗ Age: mean ± SD (range, years) 32.3 (6–66) Cause of SO Race or region Reference NA [74] Chinese [71] NA [72] Trauma: 53 (62.4%) Surgery: 32 (37.6) White: 57% African American: 23% Others: 20% [73] NA Saudi Arabia [8] Trauma: 23 (71.9%) Surgery: 9 (28.1%) Trauma: 24 (80%) Surgery: 6 (20%) Trauma: 40 (46.5%) Surgery: 38 (44.2%) Trauma + surgery: 8 (9.3%) 𝑃 < 0.05. period, suggesting an association of female hormones and elevated TGF-𝛽 with uveitis [64]. In addition, Sanghvi et al. evaluated 76 regularly menstruating women with acute anterior uveitis and found that the disease commences more frequently in the postovulatory phase of the menstrual cycle [61]. They concluded that the onset of the acute anterior uveitis is partially dependent on the levels of estrogen and/or progesterone. The withdrawal of these hormones, with their proven anti-inflammatory effects, may provoke the onset of uveitis. Based on the association of pregnancy and menstrual cycle with VKH, it is important to assess the menstrual history and to consider adjustments of immunosuppressants, such as corticosteroid treatment, during pregnancy and postpartum [51]. 2.4.2. Relationship with HLA-DR Genes. Although the precise mechanism of VKH is still not clear, genetic factors are thought to play an important role in VKH [61, 62]. The associations of HLA-DR53, HLA-DR4, and HLA-DQ4 antigens with VKH have been reported [65–68]. Additionally, a strong association with HLA-DRB1∗04:05 allele has been documented in VKH [69, 70]. Recently, Aláez et al. in Mexico compared 76 VKH patients (78.9% females) and 256 healthy controls using the HLA-DQB1/DRB1 genotyping method [9]. They found that HLA-DRB1∗04:05, HLA-DRB1∗04:04, and HLA-DQB1∗03:02 alleles were restricted only to female gender. This study implies a significant association with female gender and HLA in VKH. slight male predilection of male gender (60%) with a higher incidence of traumatic etiology (62%) [73]. We reviewed 32 patients with SO presented at the National Eye Institute, including 23 patients with SO resulting from trauma and 9 resulting from surgery. The numbers of males and females are equally distributed in the case series from 1982 to 1992 [74]. Al-Halafi et al. reported no gender difference in disease incidence in 34 males and 26 females with SO due to ocular injury during a 10-year period in Saudi Arabia [8]. Table 2 summarizes the demographics of SO patients resulting from trauma and surgery. Interestingly, only one report shows significant male predisposition of 30 SO patients [71]. Overall, no gender predilection of SO has been reported in postsurgical cases. This is due to the fact that intraocular surgeries including glaucoma surgery, cataract extraction, and pars plana vitrectomy are equally performed in both male and female patients [20, 74]. 3.2. Gender Differences in Clinical Manifestation after the Prevalence/Incidence. There are no clinical differences between males and females in SO due to either trauma or ocular surgery. 3.3. Gender Differences in Prognosis. Due to the rarity of SO, it is difficult to compare gender differences in the prognosis of SO. However, because SO and VKH share many clinical and pathological similarities, the role of sex hormone and pregnancy could also affect disease severity and presentation, Further clinical and/or experimental studies are required to draw a conclusion. 3. Gender and SO 3.1. Gender Differences in Prevalence/Incidence and Possible Explanation. In trauma-induced SO, males are reported to have a higher prevalence than females [71]; this gender predominance may be attributable to a higher incidence of ocular injury in males, especially during historical wartime [72]. Galor et al. reviewed 85 patients with SO and showed a 4. Conclusions Both VKH and SO are types of bilateral granulomatous panuveitis that can lead to severe visual loss without effective management. In addition to clinical features, gender predilection in VKH and SO could provide more appropriate therapies for patients. In VKH, with the protective role of 6 estrogen/progesterone, female patients are better protected and have better prognoses. Moreover, the evidence that certain HLA-DR alleles are exclusively associated with VKH in females implies an important genetic background in the pathogenesis of VKH. In SO, although gender differences only exist in the incidence of ocular trauma, we cannot rule out the possible role of gender-based factors in the initiation, progression, and prognosis of SO. Additional gender-based studies may identify other genes or risk factors related to these two autoimmune diseases. Conflict of Interests The authors declare that there is no conflict of interests regarding the publication of this paper. References [1] N. A. Rao and A. R. Irvine Jr., “Mechanisms of inflammatory response in sympathetic ophthalmia and VKH syndrome,” Eye, vol. 11, no. 2, pp. 213–216, 1997. [2] C. C. Chan, S. M. Whitcup, and R. B. Nussenblatt, “Sympathetic ophthalmia and Vogt-Koyanagi-Harada syndrome,” in Duane’s Clinical Ophthalmology, W. Tasman and E. A. Jaeger, Eds., Lippincott, Williams and Wilkins Publishers, Philadelphia, Pa, USA, 2010. [3] R. B. Nussenblatt, “Uveitic conditions not caused by active infection,” in Uveitis: Fundamentals and Clinical Practice, R. B. Nussenblatt and S. M. Whitcup, Eds., pp. 289–318, Mosby, Philadelphia, Pa, USA, 4th edition, 2010. [4] R. Voskuhl, “Sex differences in autoimmune diseases,” Biology of Sex Differences, vol. 2, no. 1, 2011. [5] N. Gleicher and D. H. Barad, “Gender as risk factor for autoimmune diseases,” Journal of Autoimmunity, vol. 28, no. 1, pp. 1–6, 2007. [6] D. L. Jacobson, S. J. Gange, N. R. Rose, and N. M. H. Graham, “Epidemiology and estimated population burden of selected autoimmune diseases in the United States,” Clinical Immunology and Immunopathology, vol. 84, no. 3, pp. 223–243, 1997. [7] S. Lertsumitkul, S. M. Whitcup, R. B. Nussenblatt, and C.-C. Chan, “Subretinal fibrosis and choroidal neovascularization in Vogt-Koyanagi-Harada syndrome,” Graefe’s Archive for Clinical and Experimental Ophthalmology, vol. 237, no. 12, pp. 1039–1045, 1999. [8] A. Al-Halafi, H. A. Dhibi, I. H. Hamade, C. T. Bou Chacra, and K. F. Tabbara, “The association of systemic disorders with Vogt-Koyanagi-Harada and sympathetic ophthalmia,” Graefe’s Archive for Clinical and Experimental Ophthalmology, vol. 249, no. 8, pp. 1229–1233, 2011. [9] C. Aláez, H. Flores-A, L. E. Concha del Rı́o et al., “Major histocompatibility complex and strong human leukocyte antigenDRB1 and gender association with Vogt-Koyanagi-Harada syndrome in Mexican Mestizos,” Human Immunology, vol. 72, no. 12, pp. 1198–1203, 2011. [10] D. A. Snyder and H. H. Tessler, “Vogt-Koyanagi-Harada syndrome,” The American Journal of Ophthalmology, vol. 90, no. 1, pp. 69–75, 1980. [11] F. Chen, S. Hou, Z. Jiang et al., “CD40 gene polymorphisms confer risk of Behçet’s disease but not of Vogt-Koyanagi-Harada syndrome in a Han Chinese population,” Rheumatology, vol. 51, no. 1, Article ID ker345, pp. 47–51, 2012. Journal of Ophthalmology [12] S. Ohno, D. H. Char, S. J. Kimura, and G. R. O’Connor, “VogtKoyanagi-Harada syndrome,” The American Journal of Ophthalmology, vol. 83, no. 5, pp. 735–740, 1977. [13] R. S. Moorthy, H. Inomata, and N. A. Rao, “Vogt-KoyanagiHarada syndrome,” Survey of Ophthalmology, vol. 39, no. 4, pp. 265–292, 1995. [14] H. Inomata and M. Kato, “Vogt-Koyanagi-Harada disease,” in Handbook of Clinical Neurology, P. J. Vinken, G. W. Bruyn, and H. L. Klawans, Eds., pp. 611–626, Elsevier, Amsterdam, The Netherlands, 12th edition, 1989. [15] S. Duke-Elder and E. S. Perkins, “Sympathetic ophthalmitis,” in Diseases of the Uveal Tract, S. Duke-Elder, Ed., pp. 558–593, Mosby, St. Louis, Mo, USA, 9th edition, 1966. [16] M. A. Zaharia, J. Lamarche, and M. Laurin, “Sympathetic uveitis 66 years after injury,” Canadian Journal of Ophthalmology, vol. 19, no. 5, pp. 240–243, 1984. [17] G. E. Marak Jr., “Recent advances in sympathetic ophthalmia,” Survey of Ophthalmology, vol. 24, no. 3, pp. 141–156, 1979. [18] J. R. Lubin, D. M. Albert, and M. Weinstein, “Sixty-five years of sympathetic ophthalmia: a clinicopathological review of 105 cases (1913–1978),” Ophthalmology, vol. 87, no. 2, pp. 109–121, 1980. [19] K. A. McClellan, F. A. Billson, and M. Filipic, “Delayed onset sympathetic ophthalmia,” Medical Journal of Australia, vol. 147, no. 9, pp. 451–454, 1987. [20] H. Goto and N. A. Rao, “Sympathetic ophthalmia and VogtKoyanagi-Harada syndrome,” International Ophthalmology Clinics, vol. 30, no. 4, pp. 279–285, 1990. [21] V. Gupta, A. Gupta, and M. R. Dogra, “Posterior sympathetic ophthalmia: a single centre long-term study of 40 patients from North India,” Eye, vol. 22, no. 12, pp. 1459–1464, 2008. [22] A. M. Abu El-Asrar, H. Al Kuraya, and A. Al-Ghamdi, “Sympathetic ophthalmia after successful retinal reattachment surgery with vitrectomy,” European Journal of Ophthalmology, vol. 16, no. 6, pp. 891–894, 2006. [23] A. M. Abu El-Asrar and S. A. Al-Obeidan, “Sympathetic ophthalmia after complicated cataract surgery and intraocular lens implantation,” European Journal of Ophthalmology, vol. 11, no. 2, pp. 193–196, 2001. [24] X. K. Chu and C. C. Chan, “Sympathetic ophthalmia: to the twenty-first century and beyond,” Journal of Ophthalmic Inflammation and Infection, vol. 3, no. 1, article 49, 2013. [25] M. Reynard, R. S. Riffenburgh, and D. S. Minckler, “Morphological variation of Dalen-Fuchs nodules in sympathetic ophthalmia,” British Journal of Ophthalmology, vol. 69, no. 3, pp. 197–201, 1985. [26] C. T. Chuang, P. S. Huang, S. C. Chen, and S. J. Sheu, “Reversible alopecia in Vogt-Koyanagi-Harada disease and sympathetic ophthalmia,” Journal of Ophthalmic Inflammation and Infection, vol. 3, no. 1, article 41, 2013. [27] D. J. Kilmartin, A. D. Dick, and J. V. Forrester, “Sympathetic ophthalmia risk following vitrectomy: should we counsel patients?” British Journal of Ophthalmology, vol. 84, no. 5, pp. 448–449, 2000. [28] J. Beniz, D. J. Forster, J. S. Lean, R. E. Smith, and N. A. Rao, “Variations in clinical features of the Vogt-Koyanagi-Harada syndrome,” Retina, vol. 11, no. 3, pp. 275–280, 1991. [29] P. E. Rubsamen and J. D. M. Gass, “Vogt-Koyanagi-Harada syndrome: clinical course, therapy, and long-term visual outcome,” Archives of Ophthalmology, vol. 109, no. 5, pp. 682–687, 1991. Journal of Ophthalmology [30] H. S. Al-Mezaine, D. Kangave, and A. M. Abu El-Asrar, “Patterns of uveitis in patients admitted to a university hospital in Riyadh, Saudi Arabia,” Ocular Immunology and Inflammation, vol. 18, no. 6, pp. 424–431, 2010. [31] A. S. Al-Kharashi, H. Aldibhi, H. Al-Fraykh, D. Kangave, and A. M. Abu El-Asrar, “Prognostic factors in Vogt-Koyanagi-Harada disease,” International Ophthalmology, vol. 27, no. 2-3, pp. 201– 210, 2007. [32] M. Khairallah, S. B. Yahia, A. Ladjimi et al., “Pattern of uveitis in a referral centre in Tunisia, North Africa,” Eye, vol. 21, no. 1, pp. 33–39, 2007. [33] T. Wakabayashi, Y. Morimura, Y. Miyamoto, and A. A. Okada, “Changing patterns of intraocular inflammatory disease in Japan,” Ocular Immunology and Inflammation, vol. 11, no. 4, pp. 277–286, 2003. [34] S. I. Murthy, M. R. Moreker, V. S. Sangwan, R. C. Khanna, and S. Tejwani, “The spectrum of Vogt-Koyanagi-Harada disease in South India,” International Ophthalmology, vol. 27, no. 2-3, pp. 131–136, 2007. [35] R. Belfort Jr., M. Nishi, S. Hayashi, M. T. Abreu, A. M. N. Petrilli, and R. C. A. Plut, “Vogt-Koyanagi-Harada’s disease in Brazil,” Japanese Journal of Ophthalmology, vol. 32, no. 3, pp. 344–347, 1988. [36] I. Tugal-Tutkun, Y. Ozyazgan, Y. A. Akova et al., “The spectrum of Vogt-Koyanagi-Harada disease in Turkey: VKH in Turkey,” International Ophthalmology, vol. 27, no. 2-3, pp. 117–123, 2007. [37] S. Sukavatcharin, J. H. Tsai, and N. A. Rao, “Vogt-KoyanagiHarada disease in hispanic patients,” International Ophthalmology, vol. 27, no. 2-3, pp. 143–148, 2007. [38] Y. Sasamoto, S. Ohno, and H. Matsuda, “Studies on corticosteroid therapy in Vogt-Koyanagi-Harada disease,” Ophthalmologica, vol. 201, no. 3, pp. 162–167, 1990. [39] S. Hou, P. Yang, L. Xie, L. Du, H. Zhou, and Z. Jiang, “Monocyte chemoattractant protein (MCP)-1-2518 A/G SNP in Chinese Han patients with VKH syndrome,” Molecular Vision, vol. 15, pp. 1537–1541, 2009. [40] S. Hou, P. Yang, L. Du et al., “Small ubiquitin-like modifier 4 (SUMO4) polymorphisms and Vogt-Koyanagi-Harada (VKH) syndrome in the Chinese Han population,” Molecular Vision, vol. 14, pp. 2597–2603, 2008. [41] Q. Meng, X. Liu, P. Yang et al., “PDCD1 genes may protect against extraocular manifestations in Chinese Han patients with Vogt-Koyanagi-Harada syndrome,” Molecular Vision, vol. 15, pp. 386–392, 2009. [42] Z. Jiang, P. Yang, S. Hou, F. Li, and H. Zhou, “Polymorphisms of IL23R and Vogt-Koyanagi-Harada syndrome in a Chinese Han population,” Human Immunology, vol. 71, no. 4, pp. 414– 417, 2010. [43] K. Hu, P. Yang, Z. Jiang, S. Hou, L. Du, and F. Li, “STAT4 polymorphism in a Chinese Han population with Vogt-KoyanagiHarada syndrome and Behçet’s disease,” Human Immunology, vol. 71, no. 7, pp. 723–726, 2010. [44] Q. Shu, P. Yang, S. Hou et al., “Interleukin-17 gene polymorphism is associated with Vogt-Koyanagi-Harada syndrome but not with Behçet’s disease in a Chinese Han population,” Human Immunology, vol. 71, no. 10, pp. 988–991, 2010. [45] Y. Chen, P. Yang, F. Li et al., “Association analysis of TGFBR3 gene with Vogt-Koyanagi-Harada disease and Behcet’s disease in the Chinese Han population,” Current Eye Research, vol. 37, no. 4, pp. 312–317, 2012. 7 [46] S.-P. Chee, A. Jap, and K. Bacsal, “Spectrum of Vogt-KoyanagiHarada disease in Singapore,” International Ophthalmology, vol. 27, no. 2-3, pp. 137–142, 2007. [47] S.-P. Chee, A. Jap, and K. Bacsal, “Prognostic factors of VogtKoyanagi-Harada disease in Singapore,” The American Journal of Ophthalmology, vol. 147, no. 1, pp. 154.e1–161.e1, 2009. [48] N. Tesavibul and W. Sansanayuth, “Vogt-Koyanagi-Harada disease in thai patients,” Journal of the Medical Association of Thailand, vol. 88, no. 9, pp. S26–S30, 2005. [49] M. Alam, M. Iqbal, B. S. Khan, and I. Hussain, “Vogt Koyanagi Harada disease: treatment and visual prognosis,” Journal of the College of Physicians and Surgeons Pakistan, vol. 23, no. 10, pp. 740–742, 2013. [50] Z. Friedman, M. Granat, and E. Neumann, “The syndrome of Vogt-Koyanagi-Harada and pregnancy,” Metabolic Ophthalmology, vol. 4, no. 3, pp. 147–149, 1980. [51] L. P. Steahly, “Vogt-Koyanagi-Harada syndrome and pregnancy,” Annals of ophthalmology, vol. 22, no. 2, pp. 59–62, 1990. [52] M. Nohara, K. Norose, and K. Segawa, “Vogt-Koyanagi-Harada disease during pregnancy,” British Journal of Ophthalmology, vol. 79, no. 1, pp. 94–95, 1995. [53] N. P. Chiam, A. J. Hall, R. J. Stawell, L. Busija, and L. L. Lim, “The course of uveitis in pregnancy and postpartum,” British Journal of Ophthalmology, vol. 97, no. 10, pp. 1284–1288, 2013. [54] P. K. Rabiah and A. T. Vitale, “Noninfectious uveitis and pregnancy,” The American Journal of Ophthalmology, vol. 136, no. 1, pp. 91–98, 2003. [55] L. I. Kump, R. A. Cervantes-Castañeda, S. N. Androudi, C. S. Foster, and W. G. Christen, “Patterns of exacerbations of chronic non-infectious uveitis in pregnancy and puerperium,” Ocular Immunology and Inflammation, vol. 14, no. 2, pp. 99–104, 2006. [56] A. Elias, M. Gopalakrishnan, S. Bhat, and G. Anantharaman, “Vogt-Koyanagi-Harada disease clinical course, therapy, complications and prognostic factors,” World Journal of Retina and Vitreous, vol. 2, no. 2, pp. 46–52, 2012. [57] D. Fairweather, S. Frisancho-Kiss, and N. R. Rose, “Sex differences in autoimmune disease from a pathological perspective,” The American Journal of Pathology, vol. 173, no. 3, pp. 600–609, 2008. [58] K. S. Tan, “Premenstrual asthma: epidemiology, pathogenesis and treatment,” Drugs, vol. 61, no. 14, pp. 2079–2086, 2001. [59] S. R. Rudge, I. C. Kowanko, and P. L. Drury, “Menstrual cyclicity of finger joint size and grip strength in patients with rheumatoid arthritis,” Annals of the Rheumatic Diseases, vol. 42, no. 4, pp. 425–430, 1983. [60] H. P. Stevens, L. S. Ostlere, C. M. Black, H. S. Jacobs, and M. H. A. Rustin, “Cyclical psoriatic arthritis responding to antioestrogen therapy,” British Journal of Dermatology, vol. 129, no. 4, pp. 458–460, 1993. [61] C. Sanghvi, K. Aziz, and N. P. Jones, “Uveitis and the menstrual cycle,” Eye, vol. 18, no. 5, pp. 451–454, 2004. [62] G. R. O’Connor, “Factors related to the initiation and recurrence of uveitis,” The American Journal of Ophthalmology, vol. 96, no. 5, pp. 577–599, 1983. [63] R. K. Agarwal, C.-C. Chan, B. Wiggert, and R. R. Caspi, “Pregnancy ameliorates induction and expression of experimental autoimmune uveitis,” Journal of Immunology, vol. 162, no. 5, pp. 2648–2654, 1999. [64] C.-C. Chan, G. F. Reed, Y. Kim, E. Agrón, and R. R. Buggage, “A correlation of pregnancy term, disease activity, serum female hormones, and cytokines in uveitis,” British Journal of Ophthalmology, vol. 88, no. 12, pp. 1506–1509, 2004. 8 [65] S. M. Monowarul Islam, J. Numaga, K. Matsuki, Y. Fujino, H. Maeda, and K. Masuda, “Influence of HLA-DRB1 gene variation on the clinical course of Vogt- Koyanagi-Harada disease,” Investigative Ophthalmology and Visual Science, vol. 35, no. 2, pp. 752–756, 1994. [66] S. M. M. Islam, J. Numaga, Y. Fujino et al., “HLA class II genes in Vogt-Koyanagi-Harada disease,” Investigative Ophthalmology and Visual Science, vol. 35, no. 11, pp. 3890–3896, 1994. [67] X. Y. Z. Xiao Yan Zhang, X.-M. Wang, and T.-S. Hu, “Profiling human leukocyte antigens in Vogt-Koyanagi-Harada syndrome,” The American Journal of Ophthalmology, vol. 113, no. 5, pp. 567–572, 1992. [68] J. Numaga, K. Matsuki, K. Tokunaga, T. Juji, and M. Mochizuki, “Analysis of human leukocyte antigen HLA-DR𝛽 amino acid sequence in Vogt-Koyanagi-Harada syndrome,” Investigative Ophthalmology and Visual Science, vol. 32, no. 7, pp. 1958–1961, 1991. [69] A. Iqniebi, A. Gaafar, A. Sheereen et al., “HLA-DRB1 among patients with Vogt-Koyanagi-Harada disease in Saudi Arabia,” Molecular Vision, vol. 15, pp. 1876–1880, 2009. [70] A. C. Goldberg, J. H. Yamamoto, J. M. Chiarella et al., “HLADRB1∗ ,0405 is the predominant allele in Brazilian patients with Vogt-Koyanagi-Harada disease,” Human Immunology, vol. 59, no. 3, pp. 183–188, 1998. [71] X. Lin and X. Zhong, “A clinical analysis of 30 cases of sympathetic ophthalmia,” Yan ke xue bao, vol. 12, no. 4, pp. 191– 192, 1996. [72] C. P. Castiblanco and R. A. Adelman, “Sympathetic ophthalmia,” Graefe’s Archive for Clinical and Experimental Ophthalmology, vol. 247, no. 3, pp. 289–302, 2009. [73] A. Galor, J. L. Davis, H. W. Flynn Jr. et al., “Sympathetic ophthalmia: incidence of ocular complications and vision loss in the sympathizing eye,” The American Journal of Ophthalmology, vol. 148, no. 5, pp. 704.e2–710.e2, 2009. [74] C.-C. Chan, F. G. Roberge, S. M. Whitcup, and R. B. Nussenblatt, “32 cases of sympathetic ophthalmia: a retrospective study at the National Eye Institute, Bethesda, Md, from 1982 to 1992,” Archives of Ophthalmology, vol. 113, no. 5, pp. 597–600, 1995. [75] S.-J. Sheu, H.-K. Kou, and J.-F. Chen, “Prognostic factors for Vogt-Koyanagi-Harada disease,” Journal of the Chinese Medical Association, vol. 66, no. 3, pp. 148–154, 2003. [76] S.-J. Sheu, H.-K. Kou, and J.-F. Chen, “Significant prognostic factors for Vogt-Koyanagi-Harada disease in the early stage,” Kaohsiung Journal of Medical Sciences, vol. 20, no. 3, pp. 97–105, 2004. [77] C. Kiyomoto, M. Imaizumi, K. Kimoto, H. Abe, S. Nakano, and K. Nakatsuka, “Vogt-Koyanagi-Harada disease in elderly Japanese patients,” International Ophthalmology, vol. 27, no. 2-3, pp. 149–153, 2007. [78] T. Y. Y. Lai, R. P. S. Chan, C. K. M. Chan, and D. S. C. Lam, “Effects of the duration of initial oral corticosteroid treatment on the recurrence of inflammation in Vogt-Koyanagi-Harada disease,” Eye, vol. 23, no. 3, pp. 543–548, 2009. [79] S.-P. Chee, A. Jap, and C. M. G. Cheung, “The prognostic value of angiography in Vogt-Koyanagi-Harada disease,” The American Journal of Ophthalmology, vol. 150, no. 6, pp. 888–893, 2010. [80] M. M. Yang, T. Y. Lai, P. O. Tam et al., “Complement factor H and interleukin gene polymorphisms in patients with noninfectious intermediate and posterior uveitis,” Molecular Vision, vol. 18, pp. 1865–1872, 2012. Journal of Ophthalmology [81] S. Morita, Y. Nakamaru, N. Obara, M. Masuya, and S. Fukuda, “Characteristics and prognosis of hearing loss associated with Vogt-Koyanagi-Harada disease,” Audiology and Neurotology, vol. 19, no. 1, pp. 49–56, 2013. Hindawi Publishing Corporation Journal of Ophthalmology Volume 2014, Article ID 461078, 7 pages http://dx.doi.org/10.1155/2014/461078 Review Article The Role of Gender in Juvenile Idiopathic Arthritis-Associated Uveitis Ahmadreza Moradi,1 Rowayda M. Amin,1 and Jennifer E. Thorne1,2 1 The Division of Ocular Immunology, Department of Ophthalmology, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Woods Building, Room 476, Baltimore, MD, USA 2 Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA Correspondence should be addressed to Jennifer E. Thorne; [email protected] Received 13 November 2013; Accepted 6 January 2014; Published 20 February 2014 Academic Editor: Debra Goldstein Copyright © 2014 Ahmadreza Moradi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Uveitis is a common complication of juvenile idiopathic arthritis (JIA) affecting up to 30% of patients with JIA. Although the typical bilateral chronic anterior uveitis associated with the persistent and extended oligoarticular and polyarticular, rheumatoid factor negative variants of JIA occurs predominantly in girls, boys may be more commonly affected in the HLA-B27 positive, enthesitis variant of JIA. While female gender has been associated with the development of the chronic anterior uveitis in children with JIA, the clinical course of JIA-associated uveitis may be worse in boys than in girls. The purpose of this paper is to review the available published literature to determine the role of gender in the clinical presentation and outcomes of patients with JIA-associated uveitis. 1. Introduction Juvenile idiopathic arthritis (JIA) represents a heterogeneous group of chronic arthritides that affect children aged 16 years and under [1–3]. Uveitis is a common complication of JIA, occurring in upwards of 30% of patients who are positive for antinuclear antibody (ANA) [3]. The most typical type of uveitis is a chronic bilateral anterior uveitis with insidious onset and persistent duration. It is this type of uveitis that is thought to confer the greatest risk for structural ocular complications and visual acuity loss among children suffering from JIA-associated uveitis because of its insidious onset, the lack of a red eye, and the onset in preverbal children. However, other types of JIA-associated uveitis may occur, such as the recurrent acute anterior uveitis associated with enthesitis and a positive HLA-B27. These cases typically present as an acutely red, painful and photophobia eye and occur more commonly in boys than in girls. Alternatively, the typical chronic anterior uveitis associated with JIA occurs predominantly in girls. Furthermore, not only does the proportion of girls versus boys vary according to the type of arthritis and the type of uveitis, it is possible that the clinical outcomes in girls and boys may differ within the same subsets of JIA uveitis. The purpose of this paper therefore is to summarize the available literature investigating the role of gender in the clinical and treatment outcomes in JIAassociated uveitis. 2. Prevalence and Incidence of JIA and JIA-Associated Uveitis Multiple cohort and population-based studies have reported the prevalence and/or incidence of juvenile idiopathic arthritis in populations aged 16 and under and are summarized in Table 1. In general, the prevalence of JIA ranges from 16 to 140 per 100,000 population [4–9, 11]. The incidence of JIA ranges from 3 to 23 per 100,000 person-years (PY) [4–8, 11]. The prevalence of JIA-associated uveitis is estimated as high as 30 per 100,000 people in North America and Europe, with incidence rates ranging from 4.3 to 6 per 100,000 PY [11–13]. It has been reported that up to 30% of patients thought to be at high risk for developing uveitis (ANA positivity, oligoarticular Design N/A 29 (N/A) 28 (29.3) 288 (N/A) 144 (N/A) N/A 48 (15.7) 43 (140) 432 (39.7) N/A 262,284 305,198 31,703 2,119,382 255,303 N/A N/A (19.8) 339,095 N/A 15 (16.6) 17 (N/A) N/A N/A N/A N/A N/A Prevalence N of patients, (rate/100,000) Total F M 1,407,315 Population at risk F: female; IR: incidence rate; M: male; N: number. ∗ Per 100,000 person/year. Nordic Countries Prospective Cohort [4] population-based Retrospective Alsace, France epidemiologic Cohort [5] study Estonia Population-based Cohort [6] study CHU de Poitiers Survey among Cohort [7] pediatricians Prague Population-based Cohort [8] study Prospective, Catalonia population-based Cohort [9] study Norwegian Population-based Cohort [10] multicenter study Study 36 (14) 145 (6.9) 4 (13) N/A 162 (21.7) 67 (3.2) 315 (15) 21 (17) 93 (9.0) 2 (2.1) N/A 86 (22.9) N/A 197 15 (11) 52 (4.8) 2 (2.2) N/A 76 (19.3) N/A 118 Incidence N of patients, (IR∗ ) Total F M January 1, 1998 Northernmost of the Baltic States 2004 June 1, 2004 Southeastern Norway March 1, 2012 Northeast Spain Czech Republic 2006 January 1, 2001 Northeastern France Western France July 1, 1997 Beginning Nordic countries Country Table 1: Summary of some of the cohort and population based studies for the prevalence and/or incidence of juvenile idiopathic arthritis-associated uveitis. 1 year 2 years 1 year 3 years 1 year 1.5 years Study period 2 Journal of Ophthalmology Journal of Ophthalmology disease, female gender) will in fact go on to develop chronic anterior uveitis associated with JIA, with approximately 90% of patients being diagnosed within the first five years after the diagnosis of the joint disease [1–3, 12]. Interestingly one study from Italy suggested that the presence of ANA is the strongest risk factor for developing uveitis, with 30% of ANA positive children with JIA developing uveitis regardless of arthritis type and gender [3]; however, other studies [2, 5, 11, 14] have not duplicated these findings. Registry data from Canada [14] and Germany [15] have suggested that the development of uveitis occurs in the smaller proportion of patients, perhaps on the order of 10–15%. This could be due to the use of disease modifying antirheumatic drugs (DMARDs) to treat the joint disease in the last decade lowering the proportion of patients that ultimately develop uveitis or due to the inclusion of children with milder forms of JIA who perhaps are less likely to develop extra-articular complications of JIA such as uveitis. The epidemiologic data typically have not investigated differences between gender in terms of the prevalence and incidence of uveitis; however, certain types of JIA such as enthesitis-related JIA where patients often have the HLA-B27 haplotype typically affect boys more commonly than girls. The estimated ratio of boys to girls in enthesitis-related JIA is 1.5 : 1 [16]. In contrast, girls typically out number boys in the other JIA subtypes in which uveitis is likely to occur, such as persistent and extended oligoarticular disease and polyarticular, rheumatoid factor negative arthritis [14, 15]. Some of the well-documented risk factors for developing uveitis in children with JIA—specifically younger age, female gender, and positive ANA—form the basis for the uveitis screening recommendations for children with JIA [17]. However, data from a Canadian registry of 1047 patients with JIA suggest that the risk of developing uveitis is age-dependent for girls but not so for boys. Although overall the presence of ANA was the strongest single risk factor for developing uveitis in this study, the proportion of boys with uveitis who were ANA positive was statistically significantly less than the proportion of girls with uveitis who were ANA positive (50% versus 73%, boys versus girls, 𝑃 < 0.001). Taken together, the Canadian registry data suggest an interplay between ANA, age, and gender in role of uveitis screening although validity data are not available for these screening recommendations [18]. 3. Clinical Presentation Although the majority of data regarding JIA-related uveitis focuses on patients with chronic bilateral anterior uveitis, HLA-B27-associated recurrent unilateral anterior uveitis may occur associated with the enthesitis subtype of JIA and, as mentioned above, is more common in boys than in girls. Children with this subtype of uveitis typically follow a clinical presentation and course similar to that observed in adult patients with HLA-B27-associated uveitis independent of arthritis. Although these patients typically have recurrent and unilateral uveitis, some patients may evolve into chronic uveitis, and others may develop a bilateral albeit asynchronous uveitis. Interestingly, data from HLAB27 uveitis in adults suggest that atypical courses of the uveitis 3 including evolution to chronic disease and the development of bilateral uveitis occur more frequently in women than in men; however, the data among children are limited [16]. In terms of the clinical presentation of the chronic anterior uveitis associated with JIA, the majority of children that present to tertiary care clinics (from where most of the published data are reported) already have at least one ocular complication at the time of presentation. The literature from tertiary care centers reports that approximately 50 to 70% of eyes will have at least one ocular complication at presentation, including band keratopathy, cataract, elevated eye pressure, glaucoma, macular edema, optic nerve edema, and epiretinal retinal membrane [19, 20]. In the Johns Hopkins cohort of 75 patients, 67% of patients had at least one ocular complication at the time of presentation. The median time from diagnosis of uveitis to presentation in the Hopkins clinic was approximately six years [20]. Furthermore, approximately onethird of eyes had 20/50 or worse vision at presentation and one-quarter of eyes presented with 20/200 or worse vision. Although the main focus of this paper was not about the role of gender in the presentation of JIA-associated uveitis, the authors investigated the risk factors (including gender) for presenting with poor visual acuity and for presenting with uveitis-related ocular complications [20]. In both univariate and multivariate analyses, gender was not a statistically significant risk factor for any of these outcomes [20]. Because other series have suggested that boys present with more severe uveitis [21–23], we performed subanalyses specific to the role of gender in the Johns Hopkins cohort. Although overall we did not find that boys presented with more severe uveitis than girls, there was a suggestion that in earlier years of the cohort (e.g., patients that presented to the clinic prior to 2000 compared to those presenting in the year 2000 or after), boys tended to have more severe uveitis as evidenced by a higher frequency of posterior synechiae at presentation [20]. However, it is possible that this observation was confounded by the fact that boys experienced a delay in referral to our clinic relative to girls as boys had longer disease durations at the time of presentation during this time period as well. Furthermore, no differences according to gender were reported in a study of 327 patients with JIA-associated uveitis from the Systemic Immunosuppressive Therapy for Eye Disease (SITE) Research Group. This multicenter retrospective study that includes 5 tertiary care centers reported on data collected at the initial visit to the SITE study centers and on subsequent visits; thus, the majority of patients had been diagnosed with JIA-associated uveitis prior to the initial SITE visit and a referral bias likely exists (Table 2) [19]. However, studies both in the UK and The Netherlands have suggested that boys may present with a more severe clinical picture and were more likely to have ocular complications at presentation than were girls [21, 23, 25] (Table 3). These studies were undertaken in combined secondary and tertiary settings so the issue of uveitis duration prior to the presenting examination in these studies is less of a concern and add support to the observation that boys may present with more severe disease independent of disease duration or referral bias—a finding that could not be fully supported by data taken from the strictly referral-based studies described above. 6.3 (0–23.2) Y 96.5% 16.2% 68.3% 12% 0 0 3.5% N/R 37.3% 14.1% 21.8% 23.2% 15.5% N/R N/R N/R 4.9% N/R 70% 16% 54% 0 0 30% N/R N/R N/R N/R N/R N/R N/R N/R N/R N/R N/R N/R N/R 17% 3.4% 5.7% 8.3 Y N/R 60.2% N/R 32.1% (126/393)∗ 22.9% (97/423)∗ N/R N/R 24.6 % (125/508)∗ 10.6% (61/577)∗ 10.5% (60/569)∗ 8.9% (50/564)∗ 8.1% (46/567)∗ 36.8% (131/356)∗ 21% (95/452)∗ N/R N/R N/R N/R N/R N/R N/R 2.62 (0–24) Y 4.1 (4 m–16.9) Y Gregory et al. 2013 [19] 9.3%¥ 3%¥ 3.8%¥ 36.4% 23.7% 15.3%¥ 67% N/R 31.5%¥ 27.5 %¥ 22.5%¥ 86.7% N/R N/R N/R 13.3% 0 0 7 (1–36) Y Woreta et al. 2007 [20] 0.09/EY 0.04/EY 0.06/EY 0.10/EY 0.08/EY 0.04/EY 0.05/EY 0.18/EY 67% 0.33 EY 0.08/EY 86.7% N/R N/R N/R 13.3 0 0 3 (1 m–15) Y 7 (1–36) Y N/R 21% N/R N/R 21% 14% N/R N/R N/R N/R N/R 11% 6% N/R N/R N/R N/R N/R N/R N/R 4Y 50 (4–149) m Thorne et al. Edelsten et al. 2007 [24] 2002 [21] EY: eye-year; F: female; F/U: followup; IR: incidence rate; M: male; m: months; N: number; N/R: result not reported; OC: ocular complications; VA: visual acuity; Y: years. ∗ Incidence; ¥ prevalence at presentation. Mean ± SD/median age at the time of 5.2 ± 3.2 Y diagnosis of uveitis Follow-up time for uveitis, 5.6 ± 4.9 Y Mean ± SD/median (range) Type of uveitis Anterior N/R Acute anterior N/R Chronic anterior N/R Anterior recurrent uveitis N/R Intermediate N/R Posterior N/R Panuveitis N/R Structural ocular complications At least one OC at presentation 45% At least one OC after F/U 56% Band keratopathy 29% Posterior synechiae 27% Cataract 26% Glaucoma 8% Ocular hypertension ≥ 21 mm Hg N/R Ocular hypertension ≥ 30 mm Hg N/R Hypotony N/R Cystoid macular edema 6% Epiretinal membrane N/R Final VA < 20/50 (visual impairment) 31% Final VA < 20/200 (Blindness) 12% Heiligenhaus Saurenmann Edelsten et al. et al. et al. 2003 [12] 2005 [11] 2007 [14] Table 2: Summary of ocular complications during followup in some of the noted studies. Sabri et al. 2008 [26] N/R N/R 16% 40% 42% 25% N/R N/R N/R 19% N/R N/R N/R 99% N/R N/R N/R 0 0 1% N/R 3.9% N/R 3.4% 5.7% 13.6% N/R 32.5% 12.3% 17.1% 20.2% 96.5% 16.2% 68.3% 12% 0 0 3.5% M: 4.3 (1.7–13.8) Y N/R F: 4.2 (1.7–16) Y M: 11(1.1–27.5) Y 6.3 (0.1–23.2) Y F: 7.2(1.1–22.9) Y Ayuso et al. 2010 [25] 4 Journal of Ophthalmology Journal of Ophthalmology 5 Table 3: Summary of gender specific findings in patients with JIA-associated uveitis in some of the recent published articles. Author/year Males were more likely to have Females were more likely to have Saurenman et al./2007 [14] (i) Symptomatic uveitis (ii) A shorter interval between diagnosis of arthritis and uveitis (iii) An older age at diagnosis of JIA (iv) Enthesitis-related arthritis and psoriatic JIA. (i) Female sex was a risk factor for the development of uveitis in patients with oligoarticular and persistent oligoarticular JIA, but not in those with the other subtypes. (ii) Females were more likely to have oligoarticular JIA. (i) Only girls had an age-dependent and ANA-associated increased risk of uveitis. (ii) Female sex (LR 8.0, 𝑃 = 0.004) and the combination of female sex and young age at diagnosis (LR 6.7, 𝑃 = 0.009) were significantly associated with the development of uveitis. (iii) Girls had a higher rate of ANA positivity compared with boys, in all age groups (𝑃 < 0.0001). Saurenman et al./2010 [18] Sabri et al./2008 [26] (i) Male patients tended to have a greater rate of uveitis complications (48.3% vs 33.5% in female patients); this difference was not statistically significant (𝑃 = 0.17). (ii) Male patients were more likely to have earlier complications than female patients (𝑃 = 0.008), including earlier synechiae formation (𝑃 = 0.03). Ayuso et al./2010 [25] (i) Male gender appeared to be independently associated with cataract surgery CME and papillitis (𝑃 < 0.05). (ii) Time between the diagnosis of arthritis and uveitis was shorter in boys than in girls (0.3 vs 1.0 years). (iii) Boys presented with uveitis as initial manifestation of JIA more frequently than girls (44% vs 15% of girls). Hoeve et al./2012 [27] Uveitis in boys was more frequently diagnosed before the onset of arthritis. Edelsten et al./2002 [21] (i) Male sex was associated with increased complications in the standard cohort. (ii) Male sex was found to be independently associated with a higher complication rate, and the rate appeared to be higher in the first 4 years. (iii) After 8 years the complication rate was 38.4% for males and 9.7% for females. Zulian et al./2002 [22] Males were more susceptible to severe ocular involvement. Chia et al./2003 [23] (i) Male children are more likely to have severe uveitis at diagnosis. (ii) Male patients developed uveitis at shorter intervals from the onset of arthritis symptoms (median 5 vs 18 months). The majority of patients who developed uveitis (79.6%) was female. Girls were significantly younger than boys at diagnosis of JIA; however, the age at diagnosis of JIA-associated uveitis was similar for boys and girls. Females in the standard cohort had the most benign disease with 5% complication rate and 54% remission rate. CME: cystoid macular edema; JIA: juvenile-associated arthritis; vs: versus. 4. Incidence of Ocular Complications and Visual Acuity Loss and Treatment Outcomes In general, children with JIA-associated chronic anterior uveitis are at high risk for developing ocular complications and visual acuity loss over time. Rates of structural ocular complications (regardless of gender) have ranged from 0.05 to 0.17/PY and rates of loss of visual acuity to the 20/50 or worse and the 20/200 or worse thresholds are estimated as 0.18/eyeyear (EY) or 0.20/person-year (PY) and 0.09/EY or 0.14/PY, respectively [19, 24]. Most of the published data reporting long-term clinical outcomes in JIA-associated uveitis focus primarily on patients with chronic anterior uveitis rather than patients with HLA-B27 positive, enthesitis-related JIA. In 6 these cohorts, the majority of patients are girls with frequencies ranging from 70 to 85% on average [19, 21, 24– 26]. Despite the lower numbers of boys diagnosed with JIArelated chronic anterior uveitis, several reports have demonstrated worse clinical outcomes among boys [21, 25, 26]. Sabri and colleagues [26] found earlier posterior synechiae formation (𝑃 = 0.03) and earlier development of any uveitisrelated ocular complication (𝑃 = 0.008) in boys as compared to girls in their single-center, retrospective study of 142 patients (29 were boys) with JIA-associated uveitis. Despite the increased risks of ocular complication, there were no gender-associated differences in visual acuity outcomes during the follow-up period in their study [26]. Ayuso and colleagues [25] and Hoeve and colleagues [27] both reported worse clinical outcomes in boys with JIA uveitis in The Netherlands. In the study by Ayuso et al., 65 children with JIA-associated uveitis, 18 of whom were boys, were analyzed for the development of ocular complications and loss of visual acuity [25]. In the multivariate analysis, boys appeared to be independently associated with an increased risk of cataract surgery (adjusted hazard ratio [HR] = 4.33; 𝑃 < 0.01), cystoid macular edema (adjusted HR = 4.59; 𝑃 = 0.01), and papillitis (adjusted HR = 4.10; 𝑃 = 0.01). These findings were independent of the presence of the HLA-B27 haplotype at the initial evaluation. In another paper from the Netherlands [27], the authors investigated the level of cellular inflammatory activity and the use of anti-inflammatory and immunosuppressive therapy in 62 children with JIAassociated uveitis, 22 of which were boys. Although the authors observed no gender-related differences in the level of cellular inflammation or use of topical corticosteroids, there was a suggestion of an increased use of immunosuppressive drug therapy in boys, particularly during estimated puberty years (𝑃 = 0.014); however, after correcting for multiple testing using the Bonferroni technique, the findings failed to achieve conventional statistical significance (𝑃 = 0.112). These findings may suggest a lower threshold for the administration of systemic immunosuppression in boys with JIA uveitis. In a study from the United Kingdom, male sex was found to be independently associated with a higher rate of ocular complications (RR = 4.3; 95% CI: 1.1–16.6; 𝑃 = 0.032), and the rate in boys appeared to be higher in the first four years of followup when compared with girls [21]. After 8 years of followup, approximately 40% of the boys had been diagnosed with at least one ocular complication versus 10% of the girls. Boys had an increased risk of ocular complications in the standard cohort (𝑃 = 0.001), which was the group of patients that were diagnosed with uveitis by the authors as a result of their screening program (e.g., incident cases of JIA uveitis). Interestingly, there was no association between the development of ocular complications and gender in the nonstandard cohort in which the patients were diagnosed prior to referral to the authors. Thus the nonstandard cohort was subject to referral bias and included patients referred with ocular complications and those whose uveitis presented prior to or at the same time as the joint disease [12]. Two studies that reported on the incidence of visual loss and ocular complications in JIA uveitis also have suggested that boys are more likely to have uveitis diagnosed before Journal of Ophthalmology or simultaneously to the development of joint disease [25, 27]. Time between the diagnosis of arthritis and uveitis was reported as shorter in boys (0.3 years) than in girls (1.0 years; 𝑃 = 0.02) [25]. Additionally, boys presented with uveitis as the initial manifestation of JIA more frequently than girls (44% of boys versus 15% of girls; 𝑃 = 0.02) [25]. Although studies that specifically look at the differences between clinical outcomes according to gender have been limited, it is possible to make some inferences from additional retrospective cohort studies [19, 20, 24]. For example, Gregory and colleagues reported the clinical outcomes of patients with JIA-associated chronic uveitis from SITE Cohort Study [19]. In this study of 327 patients, active uveitis statistically significantly increased the risk for developing visual acuity loss while use of methotrexate was associated with a reduced risk of developing such visual loss. Both of these findings were independent of gender suggesting that boys and girls had similar risks for developing loss of visual acuity and responded to treatment with methotrexate similarly [19]. Similar findings regarding active uveitis and the effect of methotrexate were reported by Thorne and colleagues in 75 patients with JIA-associated uveitis [24]. Furthermore, we were able to reanalyze the data from the Johns Hopkins cohort with a specific interest in difference in ocular complications and treatment outcomes according to gender. The incidence rates of ocular complications during followup (including ocular hypertension, posterior synechiae, band keratopathy, hypotony, cataract, macular edema, and optic nerve edema) and of visual acuity loss were not statistically significantly different between girls and boys. Again, the studies in which registry data or newly diagnosed JIA uveitis cases were analyzed seemed to suggest higher complication rates in boys compared to girls; however, the type of outcomes differed from study to study making comparisons between studies difficult. Larger prospective studies that would allow for direct comparison of newly diagnosed patients with JIA uveitis and using standardized outcomes and treatment guidelines would provide helpful data to better ascertain any gender-related differences in disease severity and response to therapy. 5. Conclusions Although the typical chronic anterior uveitis associated with JIA occurs predominantly in girls, several reports have demonstrated worse clinical outcomes among boys; however, these findings are not consistent across all studies and limited data are available from prospective or population-based studies. Further studies, particularly studies with prospectively acquired standardized data and outcome measures, are needed to further clarify the role of gender in JIA-associated uveitis and its clinical course. Conflict of Interests The authors declare that there is no conflict of interests regarding the publication of this paper. Journal of Ophthalmology Acknowledgments Jennifer E. Thorne receives funding for this work from the Research to Prevent Blindness Sybil B. Harrington Special Scholars Award and from the Kids Uveitis Research and Education (KURE) fund. References [1] American Academy of Pediatrics Section on Rheumatology and Section on Ophthalmology, “Guidelines for ophthalmologic examinations in children with juvenile rheumatoid arthritis,” Pediatrics, vol. 92, no. 2, pp. 295–296, 1993. [2] Y.-S. Hahn and J.-G. Kim, “Pathogenesis and clinical manifestations of juvenile rheumatoid arthritis,” Korean Journal of Pediatrics, vol. 53, no. 11, pp. 921–930, 2010. [3] A. Ravelli, E. Felici, S. Magni-Manzoni et al., “Patients with antinuclear antibody-positive juvenile idiopathic arthritis constitute a homogeneous subgroup irrespective of the course of joint disease,” Arthritis and Rheumatism, vol. 52, no. 3, pp. 826–832, 2005. [4] L. Berntson, A. B. Gäre, A. Fasth et al., “Incidence of juvenile idiopathic arthritis in the nordic countries. A population based study with special reference to the validity of the ILAR and EULAR criteria,” Journal of Rheumatology, vol. 30, no. 10, pp. 2275–2282, 2003. [5] S. Danner, C. Sordet, J. Terzic et al., “Epidemiology of juvenile idiopathic arthritis in Alsace, France,” Journal of Rheumatology, vol. 33, no. 7, pp. 1377–1381, 2006. [6] C. Pruunsild, K. Uibo, H. Liivamägi, S. Tarraste, T. Talvik, and P. Pelkonen, “Incidence of juvenile idiopathic arthritis in children in Estonia: a prospective population-based study,” Scandinavian Journal of Rheumatology, vol. 36, no. 1, pp. 7–13, 2007. [7] E. Solau-Gervais, C. Robin, C. Gambert et al., “Prevalence and distribution of juvenile idiopathic arthritis in a region of Western France,” Joint Bone Spine, vol. 77, no. 1, pp. 47–49, 2010. [8] P. Hanova, K. Pavelka, C. Dosta, I. Holcatova, and H. Pikhart, “Epidemiology of rheumatoid arthritis, juvenile idiopathic arthritis and gout in two regions of the Czech Republic in a descriptive population-based survey in 2002–2003,” Clinical and Experimental Rheumatology, vol. 24, no. 5, pp. 499–507, 2006. [9] C. Modesto, J. Antón, B. Rodriguez et al., “Incidence and prevalence of juvenile idiopathic arthritis in Catalonia (Spain),” Scandinavian Journal of Rheumatology, vol. 39, no. 6, pp. 472–479, 2010. [10] Ø. R. Riise, K. S. Handeland, M. Cvancarova et al., “Incidence and characteristics of arthritis in Norwegian children: a population-based study,” Pediatrics, vol. 121, no. 2, pp. e299– e306, 2008. [11] A. Heiligenhaus, M. Niewerth, A. Mingels et al., “Epidemiology of uveitis in juvenile idiopathic arthritis from a national paediatric rheumatologic and ophthalmologic database,” Klinische Monatsblatter fur Augenheilkunde, vol. 222, no. 12, pp. 993–1001, 2005. [12] C. Edelsten, M. A. Reddy, M. R. Stanford, and E. M. Graham, “Visual loss associated with pediatric uveitis in english primary and referral centers,” American Journal of Ophthalmology, vol. 135, no. 5, pp. 676–680, 2003. [13] T. Päivönsalo-Hietanen, J. Tuominen, and K. M. Saari, “Uveitis in children: population-based study in Finland,” Acta Ophthalmologica Scandinavica, vol. 78, no. 1, pp. 84–88, 2000. 7 [14] R. K. Saurenmann, A. V. Levin, B. M. Feldman et al., “Prevalence, risk factors, and outcome of uveitis in juvenile idiopathic arthritis: a long-term followup study,” Arthritis and Rheumatism, vol. 56, no. 2, pp. 647–657, 2007. [15] A. Heiligenhaus, C. Heinz, C. Edelsten, K. Kotaniemi, and K. Minden, “Review for disease of the year: epidemiology of juvenile idiopathic arthritis and its associated uveitis: the probable risk factors,” Ocular Immunology and Inflammation, vol. 21, no. 3, pp. 180–191, 2013. [16] M.-L. Tay-Kearney, B. L. Schwam, C. Lowder et al., “Clinical features and associated systemic diseases of HLA-B27 uveitis,” American Journal of Ophthalmology, vol. 121, no. 1, pp. 47–56, 1996. [17] J. Cassidy, J. Kivlin, C. Lindsley et al., “Ophthalmologic examinations in children with juvenile rheumatoid arthritis,” Pediatrics, vol. 117, no. 5, pp. 1843–1845, 2006. [18] R. K. Saurenmann, A. V. Levin, B. M. Feldman, R. M. Laxer, R. Schneider, and E. D. Silverman, “Risk factors for development of uveitis differ between girls and boys with juvenile idiopathic arthritis,” Arthritis and Rheumatism, vol. 62, no. 6, pp. 1824– 1828, 2010. [19] A. C. Gregory, J. H. Kempen, E. Daniel, R. O. Kacmaz, C. S. Foster, D. A. Jabs et al., “Risk factors for loss of visual acuity among patients with uveitis associated with juvenile idiopathic arthritis: the Systemic Immunosuppressive Therapy for Eye Diseases Study,” Ophthalmology, vol. 120, no. 1, pp. 186–192, 2013. [20] F. Woreta, J. E. Thorne, D. A. Jabs, S. R. Kedhar, and J. P. Dunn, “Risk factors for ocular complications and poor visual acuity at presentation among patients with uveitis associated with juvenile idiopathic arthritis,” American Journal of Ophthalmology, vol. 143, no. 4, pp. 647.e1–655.e1, 2007. [21] C. Edelsten, V. Lee, C. R. Bentley, J. J. Kanski, and E. M. Graham, “An evaluation of baseline risk factors predicting severity in juvenile idiopathic arthritis associated uveitis and other chronic anterior uveitis in early childhood,” British Journal of Ophthalmology, vol. 86, no. 1, pp. 51–56, 2002. [22] F. Zulian, G. Martini, F. Falcini et al., “Early predictors of severe course of uveitis in oligoarticular juvenile idiopathic arthritis,” Journal of Rheumatology, vol. 29, no. 11, pp. 2446–2453, 2002. [23] A. Chia, V. Lee, E. M. Graham, and C. Edelsten, “Factors related to severe uveitis at diagnosis in children with juvenile idiopathic arthritis in a screening program,” American Journal of Ophthalmology, vol. 135, no. 6, pp. 757–762, 2003. [24] J. E. Thorne, F. Woreta, S. R. Kedhar, J. P. Dunn, and D. A. Jabs, “Juvenile idiopathic arthritis-associated uveitis: incidence of ocular complications and visual acuity loss,” American Journal of Ophthalmology, vol. 143, no. 5, pp. 840.e2–846.e2, 2007. [25] K. V. Ayuso, H. A. T. Cate, P. van der Does, A. Rothova, and J. H. de Boer, “Male gender as a risk factor for complications in uveitis associated with juvenile idiopathic arthritis,” American Journal of Ophthalmology, vol. 149, no. 6, pp. 994.e5–999.e5, 2010. [26] K. Sabri, R. K. Saurenmann, E. D. Silverman, and A. V. Levin, “Course, complications, and outcome of juvenile arthritisrelated uveitis,” Journal of AAPOS, vol. 12, no. 6, pp. 539–545, 2008. [27] M. Hoeve, V. K. Ayuso, N. E. Schalij-Delfos, L. I. Los, A. Rothova, and J. H. de Boer, “The clinical course of juvenile idiopathic arthritis-associated uveitis in childhood and puberty,” British Journal of Ophthalmology, vol. 96, no. 6, pp. 852–856, 2012. Hindawi Publishing Corporation Journal of Ophthalmology Volume 2014, Article ID 146768, 10 pages http://dx.doi.org/10.1155/2014/146768 Review Article Gender Differences in Birdshot Chorioretinopathy and the White Dot Syndromes: Do They Exist? Lisa J. Faia1,2 1 2 Department of Ophthalmology, Oakland University William Beaumont School of Medicine, Rochester, MI 48309, USA Retina and Uveitis, Associated Retinal Consultants, P.C., Royal Oak, MI 48073, USA Correspondence should be addressed to Lisa J. Faia; [email protected] Received 1 October 2013; Revised 19 December 2013; Accepted 21 December 2013; Published 9 February 2014 Academic Editor: Debra Goldstein Copyright © 2014 Lisa J. Faia. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Inflammatory conditions that affect the posterior pole are diverse. Specifically, birdshot chorioretinopathy and the white dot syndromes present with multiple white dots in the fundus. These diseases appear to affect similar age groups but there is question as to whether or not a difference exists between the genders. This review summarizes the current studies on birdshot chorioretinopathy and the white dot syndromes as they are related to gender, exploring the differences, if any, which may exist between prevalence, clinical presentation, and treatment response for these diseases. Though the specific etiology of these diseases remains unclear, future treatments may be guided as to how these diseases affect the sexes differently. 1. Introduction The spectrum of posterior uveitis disorders is broad. There is a specific group, called the white dot syndromes, which presents with multiple white dots in the fundus. The characteristic inflammatory changes of the choroid and retina are typically yellow-white foci beneath or in the deep retina and include birdshot chorioretinopathy (BCR), acute posterior multifocal placoid pigment epitheliopathy (APMPPE), multiple evanescent white dot syndrome (MEWDS), multifocal choroiditis with panuveitis (MFC), punctate inner choroidopathy (PIC), and acute zonal occult outer retinopathy (AZOOR). These disorders represent a range of presentations, including that of demographics, age, genetic, and gender prevalence. The etiology of these diseases is not completely understood nor is the best approach for treatment of these diseases. The purpose of this review was to assess the current scientific evidence as it is related to the possible gender differences that may exist in birdshot chorioretinopathy and the white dot syndromes. 2. Methods and Materials A systematic review of all the peer-reviewed, English language articles indexed in PubMed about BCR, APMPPE, MEWDS, MFC, PIC, and AZOOR was carried out. For each disease, specific terms were used and reported. Studies with ten or more patients in which patient data included gender and age were reviewed and summarized. Articles were also reviewed for any mention of presentation differences between the sexes and, for those that specified treatment, reviewed to see if differences were noted in the treatment response. 3. Results and Discussion 3.1. BCR. Birdshot chorioretinopathy (BCR) is a rare, chronic, bilateral, posterior inflammatory disease involving the retina and the choroid. The earliest report of this disorder was in 1949 by Franceschaetti and Babel as candle wax spot chorioretinopathy (“la choriorétinite en täche de bougie”) [1]. Ryan and Maumenee coined the term “birdshot retinochoroidopathy” to describe the distinctive lesions seen in the fundus, characterized by multiple, small, white spots that had the appearance of the scatter from a shotgun (Figure 1) [2]. BCR is relatively uncommon, ranging from 1.2 to 7.9% of patients with posterior uveitis [3, 4]. It mostly affects those of Northern European ancestry and those of middle age (average age 48–53), though the range has been reported between 15 and 79 years old [5, 6]. In Shah et al. review, one of 2 Journal of Ophthalmology (a) (b) (c) (d) (e) Figure 1: (a) Wide-field fundus photograph of a 34-year-old Caucasian male (diagnosed with BCR one year prior to presentation) with (b) corresponding fluorescein angiogram demonstrating vasculitis. (c) Magnified view of the classic lesions (blue circles) and (d) magnified view of vasculitis and late optic disc leakage. No prior treatment. (e) In contrast, bilateral fundus photography of a 55-year-old Caucasian woman diagnosed with BCR two years prior to presentation with more impressive lesions and vascular sheathing. No prior treatment. the largest reviews on birdshot chorioretinopathy, there was slight female predominance (54.1%), though there have been other studies that have shown a near equal male : female ratio and some with slight male predominance [6–10]. In evaluating the current literature for BCR, data was obtained from 16 articles (Table 1) [6, 8, 9, 11–23]. In PubMed, the term “birdshot chorioretinopathy,” using all or parts of the term, brought up 112 articles. After reviewing and eliminating reports with less than 10 patients, no specificity on patient data for gender and age, and those in which data was repeated, 16 reports remained. Eleven of the 16 reports revealed female predominance, ranging from 54.1 to 100%. When all patients from these articles were considered (𝑛 = 1157), 669 patients (58%) were female. The mean age was 53.3 years old, with a range from 46.5 to 61 years old. 3.2. APMPPE. APMPPE was first described by Gass in 1968 as a syndrome of multiple, large, placoid lesions at the level of the retinal pigment epithelium that are associated with temporary vision loss [24]. It affects both men and women without preference, usually of good health between the ages of 20 and 50 years old [25]. Vision loss is usually bilateral but may be asymmetric. APMPPE is characterized by bilateral, multifocal yellowish-white placoid lesions usually less than Journal of Ophthalmology 3 Table 1: Reports for birdshot chorioretinopathy. Author Keane et al. [11] Yang and Foster [12] Cervantes-Castaneda et al. [23] Papadia and Herbort [13] Artornsombudh et al. [22] Kuiper et al. [14] Rothova et al. [21] Giuliari et al. [15] Pagnoux et al. [16] Trinh et al. [17] Kappel et al. [18] Thorne et al. [9] Monnet et al. [19] Shah et al. [6] Sobrin et al. [20] Rothova et al. [8] Year published 2013 2013 2013 2013 2013 2011 2011 2010 2010 2009 2009 2008 2006 2005 2005 2004 No. of patients 12 17 49 25 22 16 76 15 118 10 63 55 80 522 23 54 (a) No. of women (%) 5 (42) 8 (47) 28 (57) 19 (76) 17 (77.3) 15 (94) 49 (64) 15 (100) 73 (62) 4 (40) 38 (60) 25 (45) 51 (64) 283 (54.1) 13 (56.5) 26 (48) Average age (years) 59 52 48.8 49.6 53 61 54 52.3 51.5 46.5 60.9 56 55.6 53 49 53 (b) Figure 2: (a) Fundus photograph and corresponding (b) midphase fluorescein angiogram showing blockage of some lesions and the beginning of staining of other lesions as the later phase begins in APMPPE. 1 disc diameter in size found in the posterior pole. Classically, these lesions, on fluorescein angiogram, “block early, stain late (Figure 2).” The lesions fade over 1-2 weeks, usually without significant sequelae. Though the etiology is not well understood, it has been postulated that a possible viral agent may be the inciting factor, as patients report a preceding viral prodrome. In evaluating the current literature for APMPPE, data was obtained from 3 articles (Table 2) [26–28]. In PubMed, the term “acute posterior multifocal placoid pigment epitheliopathy,” using all or parts of the term, brought up 205 articles. After reviewing and eliminating reports with less than 10 patients, no specificity on patient data for gender and age, and those in which data was repeated, 3 reports remained. None of the reports revealed female predominance, ranging from 45.5 to 50%. When all patients from these articles were considered (𝑛 = 405), 185 patients (46%) were female. The mean of the average age was 27.1 years old, with a range from 26.2 to 28.6 years old. 3.3. MEWDS. MEWDS, first described by Jampol et al., presents with numerous small, discrete white lesions in the deep retina or level of the RPE and appears in the posterior pole and extends to the midperiphery [29]. Classically, the fluorescein demonstrates wreath-like lesions and granular appearance to the fovea (Figure 3). Though usually unilateral in young, myopic women ages 20 to 45 years old, there have been bilateral cases described [30]. A preceding viral illness has been reported in approximately 1/3 of cases, and though the cause is unknown, a viral etiology has been suggested. This disease usually resolves spontaneously. In evaluating the current literature for MEWDS, data was obtained from 3 articles (Table 3) [13, 31, 32]. In PubMed, the term “multifocal evanescent white dot syndrome,” using all or parts of the term, brought up 151 articles. After reviewing and eliminating reports with less than 10 patients, no specificity on patient data for gender and age, and those in which data was repeated, 3 reports remained. Two of the three reports revealed female predominance, ranging from 50 to 91%. 4 Journal of Ophthalmology Table 2: Reports for acute posterior multifocal placoid pigment epitheliopathy. Author Thomas et al. [26] Fiore et al. [27] Jones [28] Year published 2012 2009 1995 No. of patients 18 187 200 (a) No. of women (%) 9 (50) 85 (45.5) 91 (45.5) average Age (years) 28.6 26.2 26.5 (b) (c) (d) Figure 3: (a) Fundus photograph and corresponding (b) fluorescein angiogram (FA) demonstrating classic wreath-like patterns in MEWDS. (c) Fundus photograph of the macula of different patient demonstration foveal granularity and (d) magnified view of the wreath-like patterns seen on FA in MEWDS. When all patients from these articles were considered (𝑛 = 77), 57 patients (74%) were female. The mean of the average age was 28.7 years old, with a range from 28–29.9 years old. 3.4. MFC. MFC, unlike classic APMPPE and MEWDS, is more likely to have irreversible visual damage and impairment (Figure 4). This syndrome simulates presumed ocular histoplasmosis (POHS) except that patients present with vitreous cells and inflammation. The punched-out chorioretinal scars with pigmented borders found in the posterior pole and periphery are similar to those in POHS. There is frequent development of choroidal neovascular membranes, which can cause severe vision loss [33]. This disease is usually bilateral with a predilection for patients in their third decade. Though the cause is unknown, it has been hypothesized that an exogenous pathogen may sensitize the individual, with subsequent episodes not requiring the inciting antigen. MFC tends to be a chronic disorder with, generally, a poorer visual prognosis. Some patients require systemic immunosuppression, while other treatments, such as photodynamic therapy and antivascular endothelial growth factor, are used to treat the resultant CNVM [34–36]. In evaluating the current literature for this review for MFC, data was obtained from 22 articles (Table 4) [33– 35, 37–56]. In PubMed, the term “multifocal choroiditis and panuveitis,” using all or part of the term, brought up 184 articles. After reviewing and eliminating reports with less than 10 patients, no specificity on patient data for gender and age, and those reports in which data was repeated, 22 articles remained. All reports revealed female predominance, ranging from 55 to 100%. When all patients from these articles were considered (𝑛 = 538), 406 patients (75%) were female. The mean of the average age was 39.2 years old, with a range from 30.2 to 57 years old. Journal of Ophthalmology 5 Table 3: Reports for multiple evanescent white dot syndrome. Author Asano et al. [31] Reddy et al. [32] Jampol et al. [29] Year 2004 1996 1984 No. of patients 50 16 11 (a) No. of women (%) 39 (78) 8 (50) 10 (91) average Age (years) 29.9 28.1 28 (b) Figure 4: (a) Fluorescein angiogram of a patient with MFC demonstrating concurrent macular edema. (b) Fundus photograph of a patient with MFC requiring systemic immunosuppression. 3.5. PIC. PIC, a possible variant of MFC, was first described by Watzke et al [57]. This disease was originally described in young, myopic women with punched-out lesions of the posterior pole without ocular inflammation. Like MFC, CNVM may develop and contribute to vision loss (Figure 5). In evaluating the current literature for PIC, data was obtained from 13 articles (Table 5) [33, 57–64]. In PubMed, the term “punctate inner choroidopathy,” using all or parts of the term, brought up 76 articles. After reviewing and eliminating reports with less than 10 patients, no specificity on patient data for gender and age, and those in which data was repeated, 13 articles remained. All 13 articles revealed female predominance, ranging from 64 to 100%. When all patients from these articles were considered (𝑛 = 471), 400 patients (85%) were female. The mean of the average age was 33.1 years old, with a range from 26 to 41.5 years old. 3.6. AZOOR. AZOOR, thought of predominantly in young women, includes a rapid loss of one or more large zones of outer retinal function and photopsias with minimal fundus changes. Though the cause is unknown, 28% of patients had associated autoimmune diseases, such as Hasimoto’s thyroiditis and relapsing transverse myelopathy [65]. No treatment has found to be effective. In Gass’ series, 78% of patients with AZOOR had stabilization of the visual field loss and 20% had improvement [65]. In evaluating the current literature for AZOOR, data was obtained from 5 articles (Table 6) [66–70]. In PubMed, the term “acute zonal occult outer retinopathy,” using all or part of the term, brought up 82 articles. After reviewing and eliminating reports with less than 10 patients, no specificity on patient data for gender and age, and those with repeated data, 5 articles remained. All articles revealed female predominance, ranging from 75 to 93%. When all patients from these articles were considered (𝑛 = 190), 150 patients (79%) were female. The mean of the average age was 38 years old, with a range from 33 to 49.1 years old. 3.7. Summary of Gender Differences in Prevalence. A summary of the gathered data from this paper is provided in Table 7. A review of the presented data appears to demonstrate female predominance, in order from most to least, in the following diseases: PIC > AZOOR > MFC > MEWDS. There appeared to be very slight female predominance in BCR in this review. Very slight male predominance was seen in APMPPE in this review. As for age at onset, from youngest to oldest, this review revealed APMPPE > MEWDS > PIC > AZOOR > MFC > BCR. The BCR patients, on average, were twice as old as the patients of the other WDS for age of onset. 3.8. Gender Differences in Clinical Presentations. Though some of the above white dot syndromes have differences in the ratios of involvement of men to women, no clinical differences have been described between the sexes [1–3, 5, 8–15, 17– 20, 24, 26–29, 31–33, 37, 38, 44–47, 50–52, 54–59, 61, 62, 65, 68–71]. In review of the reports, no distinctions were made between the genders in age of onset, initial clinical findings, or severity of disease. 3.9. Gender Differences in Treatment and Prognosis. Though this review revealed female predominance in PIC, AZOOR, MFC, and MEWDS, treatment differences have not been documented between these and the other white dot syndromes [34, 35, 48, 61]. This should be considered in future studies as differences in response to steroids in SLE, another female predominant autoimmune disease (9 : 1), have been noted [72]. Estrogens have been implicated as enhancers of the immune 6 Journal of Ophthalmology Table 4: Reports for multifocal choroiditis and panuveitis. Author Fung et al. [37] Spaide et al. [38] Parodi et al. [39] Mansour et al. [40] Atan et al. [41] Parodi et al. [42] Kotsolis et al. [43] Haen and Spaide [44] Kedhar et al. [45] Thorne et al. [46] MacLaren and Lightman [47] Vianna et al. [48] Parodi et al. [49] Michel et al. [34] Spaide et al. [35] Parnell et al. [50] Vadalà et al. [51] Slakter et al. [52] Brown Jr. et al. [33] Tiedeman [53] Morgan and Schatz [54] Dreyer and Gass [55] ∗ Watzke and Claussen [56] ∗ Year 2013 2013 2013 2012 2011 2010 2010 2008 2007 2006 2006 2006 2004 2002 2002 2001 2001 1997 1996 1987 1986 1984 1981 No. of patients 41 17 14 12 30 27 17 18 66 66 20 19 13 19 17 25 13 14 41 10 11 28 40 No. of women (%) 29 (70.7) 13 (78.3) 9 (64) 9 (75) 20 (67) 18 (67) 14 (82) 15 (83) 50 (75.8) 50 (76) 11 (55) 13 (68) 11 (85) 15 (79) 15 (88) 23 (92) 13 (100) 8 (57) 32 (78) 6 (60) 11 (100) 21 (75) N/A average Age (years) 38.4 33 48 37.8 57 39 42.7 43.2 49 45 37.1 46.2 47 34.8 34.2 31.1 33 31 36 36.6 30.2 33 N/A Not included in data analysis. Table 5: Reports for punctate inner choroidopathy. Author Zhang et al. [58] Spaide et al. [38] Mansour et al. [40] Zhang et al. [60] Zhang et al. [59] Patel et al. [61] Atan et al. [41] Essex et al. [62] Menezo et al. [63] Kedhar et al. [45] Gerstenblith et al. [64] Brown Jr. et al. [33] Watzke et al. [57] Year published 2013 2013 2012 2012 2011 2011 2011 2010 2010 2007 2007 1996 1984 No. of patients 42 13 24 12 75 12 31 136 10 13 77 16 10 No. of women (%) 27 (64) 12 (92) 19 (79) 11 (92) 54 (72) 11 (92) 26 (84) 126 (93) 8 (80) 12 (92) 69 (90) 15 (94) 10 (100) average Age (years) 26 38 41.5 32.9 32 32 40 32 40.7 29 30 30 26.8 Table 6: Reports for acute zonal occult outer retinopathy. Author Jiang et al. [66] Saito et al. [67] Monson and Smith [68] Fujiwara et al. [69] Jacobson et al. [70] Year published 2013 2013 2011 2010 1995 No. of patients 14 11 130 11 24 No. of women (%) 13 (93) 10 (91) 99 (76) 10 (91) 18 (75) average Age (years) 33 35 36.7 49.1 35 Journal of Ophthalmology 7 (a) (c) (b) (d) Figure 5: (a) Fundus photography and corresponding fluorescein angiogram ((b)–(d)) of a young woman with PIC demonstrating leakage consistent with a choroidal neovascular membrane. Table 7: Summary of gathered data. Disease BCR APMPPE MEWDS MFC PIC AZOOR Average age (years) 53.5 27.1 28.7 39.2 33.1 38 Gender analysis (% women) F > M (58%) M > F (46%) F > M (74%) F > M (75%) F > M (85%) F > M (79%) BCR: birdshot chorioretinopathy, APMPPE: acute posterior multifocal placoid pigment epitheliopathy, MEWDS: multiple evanescent white dot syndrome, MFC: multifocal choroiditis and panuveitis, PIC: punctate inner choroidopathy, AZOOR: acute zonal occult outer retinopathy. system (with androgens and progesterone being considered immunosuppressors), and such possible explanations have been given for the differences in steroid response in SLE [72]. The other WDS diseases, without preference or with male predominance, also have not had treatment differences noted in the literature [5, 7, 21–23, 71, 73, 74]. BCR, MFC, and PIC in general have poorer VA prognoses than APMPPE and MEWDS, though systemic immunomodulatory therapy may help to decrease the amount of vision loss in BCR, MFC, and PIC. MFC and MEWDS appear to be female dominant and on the different ends of the spectrum for disease prognosis, suggesting that gender, for these diseases, may have little to no effect on visual prognosis. The most abundant amount of data in the literature on treatment of the white dot syndrome diseases concerns BCR. Articles on the use of intravitreal triamcinolone, intravenous immunoglobulin, cyclosporine alone, cyclosporine plus mycophenolate mofetil, methotrexate, infliximab, and daclizumab can be found in the literature on the treatment of BCR with varying success and no mention of response differences between the genders [5, 7, 21–23, 71, 73, 74]. 3.10. A Hormonal Difference? Sex hormones influence the immune system, resulting in females having higher immunoglobulin levels and mounting stronger immune responses following immunizations or infections than males [75]. However, this also increases woman’s susceptibility to autoimmune diseases [75]. Abnormal hormone levels may trigger disease [75]. BCR tends to involve older patients, including women who may be menopausal. This is less likely to occur in the other WDS diseases, as they tend to be younger. This may be a possible reason why the ratio is much closer in female : male involvement in BCR than such diseases as PIC, AZOOR, MFC, and MEWDS. Unfortunately, this does not explain the near equal development of APMPPE in males and females, as the patients tend to be younger and this disease usually follows a viral prodrome. Clearly, there is something more. Other factors, such as the involvement of HLA A29 factor in BCR, may influence the occurrence of disease [71]. 8 Journal of Ophthalmology 4. Conclusion In conclusion, though in this review PIC, AZOOR, MFC, and MEWD were found to have female predominance, there does not appear to be a significant difference in clinical presentation nor in the treatment of these diseases between the genders. BCR and APMPPE appear to affect both men and women equally and again, both in presentation and treatment, there does not appear to be a significant difference between the genders. Though estrogens have been implicated in the manipulations of the immune system, further work is needed to truly elicit how estrogen levels may affect prevalence, presentation, and treatment in these ocular diseases. [13] [14] [15] Conflict of Interests [16] The author declares that there is no conflict of interests regarding the publication of this paper. [17] References [1] A. Franceschaetti and J. Babel, “La choriorétinite en täche de bougie, manifestation de la maladie de Besnier-Boeck,” Ophthalmologica, vol. 118, pp. 701–710, 1949. [2] S. J. Ryan and A. E. Maumenee, “Birdshot retinochoroidopathy,” American Journal of Ophthalmology, vol. 89, no. 1, pp. 31–45, 1980. [3] D. E. Henderly, A. J. Genstler, R. E. Smith, and N. A. Rao, “Changing patterns of uveitis,” American Journal of Ophthalmology, vol. 103, no. 2, pp. 131–136, 1987. [4] A. Rodriguez, M. Calonge, M. Pedroza-Seres et al., “Referral patterns of uveitis in a tertiary eye care center,” Archives of Ophthalmology, vol. 114, no. 5, pp. 593–599, 1996. [5] A. T. Gasch, J. A. Smith, and S. M. Whitcup, “Birdshot retinochoroidopathy,” British Journal of Ophthalmology, vol. 83, no. 2, pp. 241–249, 1999. [6] K. H. Shah, R. D. Levinson, F. Yu et al., “Birdshot chorioretinopathy,” Survey of Ophthalmology, vol. 50, no. 6, pp. 519– 541, 2005. [7] S. Kiss, M. Ahmed, E. Letko, and C. S. Foster, “Long-term follow-up of patients with birdshot retinochoroidopathy treated with corticosteroid-sparing systemic immunomodulatory therapy,” Ophthalmology, vol. 112, no. 6, pp. 1066–1071, 2005. [8] A. Rothova, T. T. J. M. Berendschot, K. Probst, B. Van Kooij, and G. S. Baarsma, “Birdshot chorioretinopathy: long-term manifestations and visual prognosis,” Ophthalmology, vol. 111, no. 5, pp. 954–959, 2004. [9] J. E. Thorne, D. A. Jabs, S. R. Kedhar, G. B. Peters, and J. P. Dunn, “Loss of visual field among patients with birdshot chorioretinopathy,” American Journal of Ophthalmology, vol. 145, no. 1, pp. 23–28, 2008. [10] J. E. Thorne, D. A. Jabs, G. B. Peters, D. Hair, J. P. Dunn, and J. H. Kempen, “Birdshot retinochoroidopathy: ocular complications and visual impairment,” American Journal of Ophthalmology, vol. 140, no. 1, pp. 45.e1–45.e7, 2005. [11] P. A. Keane, M. Allie, S. J. Turner et al., “Characterization of birdshot chorioretinopathy using extramacular enhanced depth optical coherence tomography,” JAMA Ophthalmology, vol. 131, no. 3, pp. 341–350, 2013. [12] P. Yang and C. S. Foster, “Interleukin 21, interleukin 23, and transforming growth factor 𝛽1 in HLA-A29-associated birdshot [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] retinochoroidopathy,” American Journal of Ophthalmology, vol. 156, no. 2, pp. 400–406, 2013. M. Papadia and C. P. Herbort, “Reappraisal of birdshot retinochoroiditis (BRC): a global approach,” Graefe’s Archive for Clinical and Experimental Ophthalmology, vol. 251, no. 3, pp. 861– 869, 2013. J. J. W. Kuiper, T. Mutis, W. De Jager, J. D. F. De GrootMijnes, and A. Rothova, “Intraocular interleukin-17 and proinflammatory cytokines in HLA-A-29-associated birdshot chorioretinopathy,” American Journal of Ophthalmology, vol. 152, no. 2, pp. 177–182, 2011. G. P. Giuliari, S. Pujari, M. Shaikh, D. Marvell, and C. S. Foster, “Microperimetry findings in patients with birdshot chorioretinopathy,” Canadian Journal of Ophthalmology, vol. 45, no. 4, pp. 399–403, 2010. C. Pagnoux, A. Mahr, A. Aouba et al., “Extraocular manifestations of birdshot chorioretinopathy in 118 French patients,” Presse Medicale, vol. 39, no. 5, pp. e97–e102, 2010. L. Trinh, B. Bodaghi, C. Fardeau et al., “Clinical features, treatment methods, and evolution of birdshot chorioretinopathy in 5 different families,” American Journal of Ophthalmology, vol. 147, no. 6, pp. 1042–1047, 2009. P. J. Kappel, D. Monnet, F. Yu, A. P. Brezin, R. D. Levinson, and G. N. Holland, “Contrast sensitivity among patients with birdshot chorioretinopathy,” American Journal of Ophthalmology, vol. 147, no. 2, pp. 351–356, 2009. D. Monnet, A. P. Brézin, G. N. Holland et al., “Longitudinal cohort study of patients with birdshot chorioretinopathy. I. Baseline clinical characteristics,” American Journal of Ophthalmology, vol. 141, no. 1, pp. 135–142, 2006. L. Sobrin, B. L. Lam, M. Liu, W. J. Feuer, and J. L. Davis, “Electroretinographic monitoring in birdshot chorioretinopathy,” American Journal of Ophthalmology, vol. 140, no. 1, pp. 52–64, 2005. A. Rothova, A. Ossewaarde-Van Norel, L. I. Los, and T. T. J. M. Berendschot, “Efficacy of low-dose methotrexate treatment in birdshot chorioretinopathy,” Retina, vol. 31, no. 6, pp. 1150–1155, 2011. P. Artornsombudh, O. Gevorgyan, A. Payal, S. Siddique, and C. S. Foster, “Infliximab treatment of patients with birdshot retinochoroidopathy,” Ophthalmology, vol. 120, pp. 588–592, 2013. R. A. Cervantes-Castaneda, L. A. Gonzalez-Gonzalez, and M. Cordero-Coma, “Combined therapy of cyclosporine A and mycophenolate mofetil for the treatment of birdshot retinochoroidopathy: a 12-month follow-up,” British Journal of Ophthalmology, vol. 97, pp. 637–643, 2013. J. D. Gass, “Acute posterior multifocal placoid pigment epitheliopathy,” Archives of Ophthalmology, vol. 80, no. 2, pp. 177–185, 1968. D. A. Quillen, J. B. Davis, J. L. Gottlieb et al., “The white dot syndromes,” American Journal of Ophthalmology, vol. 137, no. 3, pp. 538–550, 2004. B. C. Thomas, C. Jacobi, M. Korporal, M. D. Becker, B. Wildemann, and F. Mackensen, “Ocular outcome and frequency of neurological manifestations in patients with acute posterior multifocal placoid pigment epitheliopathy (APMPPE),” Journal of Ophthalmic Inflammation and Infection, vol. 2, no. 3, pp. 125– 131, 2012. T. Fiore, B. Iaccheri, S. Androudi et al., “Acute posterior multifocal placoid pigment epitheliopathy: outcome and visual prognosis,” Retina, vol. 29, no. 7, pp. 994–1001, 2009. Journal of Ophthalmology [28] N. P. Jones, “Acute posterior multifocal placoid pigment epitheliopathy,” British Journal of Ophthalmology, vol. 79, no. 4, pp. 384–389, 1995. [29] L. M. Jampol, P. A. Sieving, and D. Pugh, “Multiple evanescent white dot syndrome. I. Clinical findings,” Archives of Ophthalmology, vol. 102, no. 5, pp. 671–674, 1984. [30] T. M. Aaberg, R. V. Campo, and L. Joffe, “Recurrences and bilaterality in the multiple evanescent white-dot syndrome,” American Journal of Ophthalmology, vol. 100, no. 1, pp. 29–37, 1985. [31] T. Asano, M. Kondo, N. Kondo, S. Ueno, H. Terasaki, and Y. Miyake, “High prevalence of myopia in Japanese patients with multiple evanescent white dot syndrome,” Japanese Journal of Ophthalmology, vol. 48, no. 5, pp. 486–489, 2004. [32] C. V. Reddy, J. Brown Jr., J. C. Folk et al., “Enlarged blind spots in chorioretinal inflammatory disorders,” Ophthalmology, vol. 103, no. 4, pp. 606–617, 1996. [33] J. Brown Jr., J. C. Folk, C. V. Reddy, and A. E. Kimura, “Visual prognosis of multifocal choroiditis, punctate inner choroidopathy, and the diffuse subretinal fibrosis syndrome,” Ophthalmology, vol. 103, no. 7, pp. 1100–1105, 1996. [34] S. S. Michel, A. Ekong, S. Baltatzis, and C. S. Foster, “Multifocal choroiditis and panuveitis: Immunomodulatory therapy,” Ophthalmology, vol. 109, no. 2, pp. 378–383, 2002. [35] R. F. Spaide, K. B. Freund, J. Slakter, J. Sorenson, L. A. Yannuzzi, and Y. Fisher, “Treatment of subfoveal choroidal neovascularization associated with multifocal choroiditis and panuveitis with photodynamic therapy,” Retina, vol. 22, no. 5, pp. 545–549, 2002. [36] D. A. Cionni, S. A. Lewis, M. R. Petersen et al., “Analysis of outcomes for intravitreal bevacizumab in the treatment of choroidal neovascularization secondary to ocular histoplasmosis,” Ophthalmology, vol. 119, no. 2, pp. 327–332, 2012. [37] A. T. Fung, S. Pal, N. A. Yannuzzi et al., “MULTIFOCAL CHOROIDITIS WITHOUT PANUVEITIS: clinical characteristics and progression,” Retina, vol. 34, no. 1, pp. 98–107, 2014. [38] R. F. Spaide, N. Goldberg, and K. B. Freund, “Redefining multifocal choroiditis and panuveitis and punctate inner choroidopathy through multimodal imaging,” Retina, vol. 33, no. 7, pp. 1315–1324, 2013. [39] M. B. Parodi, P. Iacono, A. Mansour et al., “Intravitreal bevacizumab for juxtafoveal choroidal neovascularization secondary to multifocal choroiditis,” Retina, vol. 33, no. 5, pp. 953– 956, 2013. [40] A. M. Mansour, J. F. Arevalo, C. Fardeau et al., “Three-year visual and anatomic results of administrating intravitreal bevacizumab in inflammatory ocular neovascularization,” Canadian Journal of Ophthalmology, vol. 47, no. 3, pp. 269–274, 2012. [41] D. Atan, S. Fraser-Bell, J. Plskova et al., “Punctate inner choroidopathy and multifocal choroiditis with panuveitis share haplotypic associations with IL10 and TNF loci,” Investigative Ophthalmology & Visual Science, vol. 52, no. 6, pp. 3573–3581, 2011. [42] M. B. Parodi, P. Iacono, D. S. Kontadakis, I. Zucchiatti, M. L. Cascavilla, and F. Bandello, “Bevacizumab vs photodynamic therapy for choroidal neovascularization in multifocal choroiditis,” Archives of Ophthalmology, vol. 128, no. 9, pp. 1100– 1103, 2010. [43] A. I. Kotsolis, F. A. Killian, I. D. Ladas, and L. A. Yannuzzi, “Fluorescein angiography and optical coherence tomography concordance for choroidal neovascularisation in multifocal choroidtis,” British Journal of Ophthalmology, vol. 94, no. 11, pp. 1506–1508, 2010. 9 [44] S. P. Haen and R. F. Spaide, “Fundus autofluorescence in multifocal choroiditis and panuveitis,” American Journal of Ophthalmology, vol. 145, no. 5, pp. 847–853, 2008. [45] S. R. Kedhar, J. E. Thorne, S. Wittenberg, J. P. Dunn, and D. A. Jabs, “Multifocal choroiditis with panuveitis and punctate inner choroidopathy: comparison of clinical characteristics at presentation,” Retina, vol. 27, no. 9, pp. 1174–1179, 2007. [46] J. E. Thorne, S. Wittenberg, D. A. Jabs et al., “Multifocal choroiditis with panuveitis. Incidence of ocular complications and of loss of visual acuity,” Ophthalmology, vol. 113, no. 12, pp. 2310– 2316, 2006. [47] R. E. MacLaren and S. L. Lightman, “Variable phenotypes in patients diagnosed with idiopathic multifocal choroiditis,” Clinical and Experimental Ophthalmology, vol. 34, no. 3, pp. 233– 238, 2006. [48] R. N. G. Vianna, P. C. Özdal, J. Deschênes, and M. N. Burnier Jr., “Combination of azathioprine and corticosteroids in the treatment of serpiginous choroiditis,” Canadian Journal of Ophthalmology, vol. 41, no. 2, pp. 183–189, 2006. [49] M. B. Parodi, L. Di Crecchio, P. Lanzetta, A. Polito, F. Bandello, and G. Ravalico, “Photodynamic therapy with verteporfin for subfoveal choroidal neovascularization associated with multifocal choroiditis,” American Journal of Ophthalmology, vol. 138, no. 2, pp. 263–269, 2004. [50] J. R. Parnell, L. M. Jampol, L. A. Yannuzzi, J. D. M. Gass, and M. K. Tittl, “Differentiation between presumed ocular histoplasmosis syndrome and multifocal choroiditis with panuveitis based on morphology of photographed fundus lesions and fluorescein angiography,” Archives of Ophthalmology, vol. 119, no. 2, pp. 208–212, 2001. [51] M. Vadalà, G. Lodato, and S. Cillino, “Multifocal choroiditis: indocyanine green angiographic features,” Ophthalmologica, vol. 215, no. 1, pp. 16–21, 2001. [52] J. S. Slakter, A. Giovannini, L. A. Yannuzzi et al., “Indocyanine green angiography of multifocal choroiditis,” Ophthalmology, vol. 104, no. 11, pp. 1813–1819, 1997. [53] J. S. Tiedeman, “Epstein-Barr viral antibodies in multifocal choroiditis and panuveitis,” American Journal of Ophthalmology, vol. 103, no. 5, pp. 659–663, 1987. [54] C. M. Morgan and H. Schatz, “Recurrent multifocal choroiditis,” Ophthalmology, vol. 93, no. 9, pp. 1138–1147, 1986. [55] R. F. Dreyer and J. D. M. Gass, “Multifocal choroiditis and panuveitis: a syndrome that mimics ocular histoplasmosis,” Archives of Ophthalmology, vol. 102, no. 12, pp. 1776–1784, 1984. [56] R. C. Watzke and R. W. Claussen, “The long-term course of multifocal choroiditis (presumed ocular histoplasmosis),” American Journal of Ophthalmology, vol. 91, no. 6, pp. 750–760, 1981. [57] R. C. Watzke, A. J. Packer, and J. C. Folk, “Punctate inner choroidopathy,” American Journal of Ophthalmology, vol. 98, no. 5, pp. 572–584, 1984. [58] X. Zhang, C. Zuo, M. Li, H. Chen, S. Huang, and F. Wen, “Spectral-domain optical coherence tomographic findings at each stage of punctate inner choroidopathy,” Ophthalmology, vol. 120, no. 12, pp. 2678–2683, 2013. [59] X. Zhang, F. Wen, C. Zuo et al., “Clinical features of punctate inner choroidopathy in Chinese patients,” Retina, vol. 31, no. 8, pp. 1680–1691, 2011. [60] H. Zhang, Z.-L. Liu, P. Sun, and F. Gu, “Intravitreal bevacizumab as primary treatment of choroidal neovascularization secondary to punctate inner choroidopathy: results of a 1-year prospective trial,” Retina, vol. 32, no. 6, pp. 1106–1113, 2012. 10 [61] K. H. Patel, A. D. Birnbaum, H. H. Tessler, and D. A. Goldstein, “Presentation and outcome of patients with punctate inner choroidopathy at a tertiary referral center,” Retina, vol. 31, no. 7, pp. 1387–1391, 2011. [62] R. W. Essex, J. Wong, S. Fraser-Bell et al., “Punctate inner choroidopathy: clinical features and outcomes,” Archives of Ophthalmology, vol. 128, no. 8, pp. 982–987, 2010. [63] V. Menezo, F. Cuthbertson, and S. M. Downes, “Positive response to intravitreal ranibizumab in the treatment of choroidal neovascularization secondary to punctate inner choroidopathy,” Retina, vol. 30, no. 9, pp. 1400–1404, 2010. [64] A. T. Gerstenblith, J. E. Thorne, L. Sobrin et al., “Punctate inner choroidopathy: a survey analysis of 77 persons,” Ophthalmology, vol. 114, no. 6, pp. 1201–1204, 2007. [65] J. D. Gass, A. Agarwal, and I. U. Scott, “Acute zonal occult outer retinopathy: a long-term follow-up study,” American Journal of Ophthalmology, vol. 134, no. 3, pp. 329–339, 2002. [66] L. B. Jiang, C. Y. Shen, F. Chen, W. Y. Yan, T. Y. Lai, and N. L. Wang, “Clinical features of retinal diseases masquerading as retrobulbar optic neuritis,” Chinese Medical Journal, vol. 126, no. 17, pp. 3301–3306, 2013. [67] M. Saito, W. Saito, Y. Hashimoto et al., “Correlation between decreased choroidal blood flow velocity and the pathogenesis of acute zonal occult outer retinopathy,” Clinical & Experimental Ophthalmology, 2013. [68] D. M. Monson and J. R. Smith, “Acute zonal occult outer retinopathy,” Survey of Ophthalmology, vol. 56, no. 1, pp. 23–35, 2011. [69] T. Fujiwara, Y. Imamura, V. J. Giovinazzo, and R. F. Spaide, “Fundus autofluorescence and optical coherence tomographic findings in acute zonal occult outer retinopathy,” Retina, vol. 30, no. 8, pp. 1206–1216, 2010. [70] S. G. Jacobson, D. S. Morales, X. K. Sun et al., “Pattern of retinal dysfunction in acute zonal occult outer retinopathy,” Ophthalmology, vol. 102, no. 8, pp. 1187–1198, 1995. [71] R. D. Levinson and C. R. Gonzales, “Birdshot retinochoroidopathy: immunopathogenesis, evaluation, and treatment,” Ophthalmology Clinics of North America, vol. 15, no. 3, pp. 343–350, 2002. [72] V. Rider and N. I. Abdou, “Gender differences in autoimmunity: molecular basis for estrogen effects in systemic lupus erythematosus,” International Immunopharmacology, vol. 1, no. 6, pp. 1009–1024, 2001. [73] A. Shah and M. Branley, “Use of intravitreal triamcinolone in the management of birdshot retinochoroidopathy associated with cystoid macular oedema: a case study over a three-year period,” Clinical and Experimental Ophthalmology, vol. 33, no. 4, pp. 442–444, 2005. [74] P. LeHoang, N. Cassoux, F. George, N. Kullmann, and M. D. Kazatchkine, “Intravenous immunoglobulin (IVIg) for the treatment of birdshot retinochoroidopathy,” Ocular Immunology and Inflammation, vol. 8, no. 1, pp. 49–57, 2000. [75] D. Verthelyi, “Sex hormones as immunomodulators in health and disease,” International Immunopharmacology, vol. 1, no. 6, pp. 983–993, 2001. Journal of Ophthalmology Hindawi Publishing Corporation Journal of Ophthalmology Volume 2014, Article ID 401915, 10 pages http://dx.doi.org/10.1155/2014/401915 Review Article Uveitis and Gender: The Course of Uveitis in Pregnancy Nathalie P. Y. Chiam and Lyndell L. P. Lim Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, 32 Gisborne Street, East Melbourne, VIC 3002, Australia Correspondence should be addressed to Lyndell L. P. Lim; [email protected] Received 25 September 2013; Accepted 9 December 2013; Published 9 January 2014 Academic Editor: H. Nida Sen Copyright © 2014 N. P. Y. Chiam and L. L. P. Lim. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The hormonal and immunological changes in pregnancy have a key role in maintaining maternal tolerance of the semiallogeneic foetus. These pregnancy-associated changes may also influence the course of maternal autoimmune diseases. Noninfectious uveitis tends to improve during pregnancy. Specifically, uveitis activity tends to ameliorate from the second trimester onwards, with the third trimester being associated with the lowest disease activity. The mechanism behind this phenomenon is likely to be multifactorial and complex. Possible mechanisms include Th1/Th2 immunomodulation, regulatory T-cell phenotype plasticity, and immunosuppressive cytokines. This clearly has management implications for patients with chronic sight threatening disease requiring systemic treatment, as most medications are not recommended during pregnancy due to lack of safety data or proven teratogenicity. Given that uveitis activity is expected to decrease in pregnancy, systemic immunosuppressants could be tapered during pregnancy in these patients, with flare-ups being managed with local corticosteroids till delivery. In the postpartum period, as uveitis activity is expected to rebound, patients should be reviewed closely and systemic medications recommenced, depending on uveitis activity and the patient’s breastfeeding status. This review highlights the current understanding of the course of uveitis in pregnancy and its management to help guide clinicians in managing their uveitis patients during this special time in life. 1. Introduction Pregnancy is associated with various hormonal and immunological changes that facilitate the survival of the semiallogeneic foetus. These physiological changes influence the course of various maternal autoimmune diseases [1, 2]. The effect of pregnancy on noninfectious uveitis has not been as extensively studied; however, to date it has been well described by a few authors. It is essential to understand the course of uveitis in pregnancy as uveitis has a peak incidence in young adults and it is not uncommon for female patients with known uveitis to become pregnant. This review will examine the literature on the course of uveitis in pregnancy and its management. This summary would hopefully help guide clinicians in the management of uveitis during pregnancy and the postpartum period. 2. Theories on How Pregnancy Influences Uveitis During pregnancy, the tolerance of the semiallogeneic foetus is made possible by the various hormonal and immunological changes in pregnancy. These physiological changes also have a role in influencing the course of maternal autoimmune diseases [1, 2]. The increased levels of oestrogen and progesterone during pregnancy result in the suppression of Th1 associated immunity but the upregulation of Th2 associated immune responses [3–5]. As such, pregnancy often ameliorates Th1 associated autoimmune diseases, like rheumatoid arthritis, but exacerbates Th2 associated autoimmune conditions, like systemic lupus erythematosus [2–9]. The association between uveitis amelioration and Th1 suppression/Th2 upregulation 2 has been demonstrated by serum studies in Chan et al.’s [10] prospective case study on four pregnant uveitis patients. Agarwal et al. [11] have also reported similar findings for experimental autoimmune uveitis (EAU) in mice. When EAU susceptible mice (C57BL/6) were immunised with interphotoreceptor retinoid binding protein, the incidence and severity of EAU were lower in the pregnant mice, as compared to nonpregnant controls. The pregnant mice were also found to have reduced levels of interferon gamma, IL 12 P40 but unchanged levels of TNF alpha, IL4, IL5, and IL10, which suggested a Th2 bias in their immune system [11]. This Th2 bias in pregnancy probably augments the Th1 predominant response in noninfectious uveitis, resulting in disease amelioration [12]. Although still uncertain, the recently discovered subset of T helper cells, Th17, may also play a role in altered autoimmune activity in pregnancy [13– 17]. Th17 cells are proinflammatory and associated with the pathogenesis of autoimmune diseases like systemic lupus erythematosus [18],Vogt-Koyanagi-Harada (VKH) disease [19], irritable bowel disease [20], rheumatoid arthritis [21], and multiple sclerosis [22]. During pregnancy, Th17 cells are elevated in preeclampsia [9, 23]. The hormonal and associated cytokine changes in pregnancy influence autoimmune disease activity and may inspire future therapeutic options. Interestingly, studies have shown that oral oestradiol may decrease disease activity in multiple sclerosis [24, 25]; however, its implications in uveitis management are uncertain. Several other pregnancy-associated changes may influence the course of maternal autoimmune conditions. For instance, regulatory T cells demonstrate phenotype plasticity and are able to switch between a tolerant or aggressive phenotype in response to circulating foetal cells or infectious agents accordingly [17, 26]. The elevated levels of immunosuppressive cytokines and hormones, such as melanocytestimulating hormone [27, 28], early pregnancy factor [29], and alpha-fetoprotein [30, 31] have also been implicated in the improvement of various autoimmune conditions during pregnancy. The mechanism for altered activity of autoimmune uveitis in pregnancy is likely to be multifactorial. The available literature seems to suggest that uveitis activity begins to improve in mid pregnancy and reaches its lowest level in the third trimester (see below). This may be due to the various pregnancy-associated changes, such as the Th1/Th2 immune shift, becoming increasingly pronounced with the progress of pregnancy [6, 32]. These findings are in keeping with the accepted theory that most forms of non-infectious uveitis are Th1 mediated diseases [12]. After delivery, the rate of flare-up seems to return to prepregnancy levels. This may be explained by the reversal of various pregnancy-associated changes within one to two months of delivery [33]. 3. The Effect of Pregnancy on the Course of Uveitis There have only been a few studies that investigated pregnancy’s effect on noninfectious uveitis. Previous publications on uveitis in pregnancy include a few case reports [10, 34–36], a retrospective case series by Rabiah and Vitale [37] in 2003, Journal of Ophthalmology and a retrospective cohort study by Kump et al. [38] in 2006. The authors of this review have also recently conducted a retrospective case series on uveitis in pregnancy [39]. As uveitis is an uncommon condition [40], studies on uveitis in pregnancy are constrained by the limited number of eligible patients and are largely restricted to retrospective studies. The general consensus is that uveitis activity improves in pregnancy, with significantly decreased disease activity from the mid pregnancy onwards. However, in the postpartum period, uveitis activity tends to relapse. The findings from previous case reports and small case series (𝑛 ≤ 4) [10, 34–36] have limited generalizability due to the small numbers of patients studied. Even so, they reported that uveitis improves in pregnancy, especially in the mid and late trimesters while postpartum period was associated with activity relapse, which was reflected by other larger studies. The retrospective case series by Rabiah and Vitale [37] was based in Saudi Arabia. It included 76 pregnancies among 50 women. Their subjects had VKH associated uveitis (46%), Behcet’s disease associated uveitis (20%), and idiopathic uveitis (34%), which reflected the regional epidemiology in Saudi Arabia. The study investigated the probability of at least one flare-up in the periods three months before pregnancy, during pregnancy, and up to six months postpartum. They reported that the probability of uveitis flaring-up was lower during pregnancy as compared to three months prepregnancy and six months postpartum. It should be noted that the duration of followup in prepregnancy, pregnancy, and postpartum was unequal. As such, a larger number of patients may experience a flare-up when the duration of followup was longer; thus their findings should be interpreted with this in mind. The retrospective cohort study by Kump et al. [38] was based in the United States of America. It involved 32 pregnant self-controls and 32 nonpregnant female controls who were matched for age, ethnicity, and anatomical location of uveitis. Most subjects had idiopathic uveitis (72%). They reported that the annual rate of flare-up was significantly lower during pregnancy (1.0 per year) as compared to nonpregnant periods (2.4 per year) and non-pregnant controls (3.1 per year), 𝑃 < 0.001. During pregnancy, rates of flare-up decreased significantly in the second and third trimester (2.3, 0.5, 0.4 per year for the first, second, and third trimesters, resp.). Chiam et al.’s retrospective study was based in Australia and included 47 subjects [39]. Uveitis activity one year prepregnancy, during pregnancy and one year postpartum was evaluated. The reported flare-up rates were 1.188, 0.540, 0.972 per person year in prepregnancy, gestation, and postpartum, respectively. (𝑃 < 0.001 for comparison between pre-pregnancy and pregnancy; 𝑃 = 0.009 for comparison between pregnancy and postpartum). The rate of flare-up was 1.188, 0.264, 0.096 per person year for the first, second, and third trimesters, respectively. Rates in the second trimester were significantly lower than rates in the first trimester, 𝑃 = 0.002; meanwhile rates in the third trimester did not differ significantly from the second trimester, 𝑃 = 0.338. After delivery, rates of flare-up rebounded, as flare-up rates six months postpartum were not significantly different from prepregnancy rates (𝑃 = 0.306). Journal of Ophthalmology Interestingly, the severity of uveitis flare-ups does not seem to be influenced by the course of pregnancy. Chiam et al. reported that when uveitis severity was evaluated based on anterior chamber cell count, the severity of flare-ups was not significantly different between pregnancy and nonpregnant periods [39]. In Rabiah and Vitale’s study [37], surrogate markers of disease severity including flare-up duration and type of therapy prescribed were also not significantly different in pregnancy and nonpregnant periods. Other factors have also been studied with regard to their possible influence on uveitis activity during this period. These include the effect of breastfeeding, the possible relationship between multiple pregnancies in the same individual and various host factors such as type of uveitis. Lactation has been suggested to aggravate some autoimmune diseases. After delivery, elevated prolactin levels from pregnancy will decline unless breastfeeding occurs. As prolactin is a proinflammatory hormone that promotes Th1immune responses [2], Th1-dominant immunopathologies like rheumatoid arthritis have been shown to be aggravated by lactation [8, 41–45]. Although breastfeeding has not been found to have a significant influence on the likelihood of uveitis flare-up in the postpartum period, this is likely to be due to the small numbers of subjects available for analysis [37–39]. Similarly, although uveitis activity in pregnancy does not seem to be correlated between different pregnancies within multiparous individuals [37, 39], the small numbers of subjects available for analysis in these studies were again limited. In general, the course of uveitis varies across uveitis aetiologies. However, it is interesting to note that in our study, host variables such as uveitis aetiology, anatomical location of uveitis, course of uveitis activity, medication used, and sex of child were not found to be associated with flare-up rates in pre-pregnancy, gestation, or postpartum period. In particular, it is interesting to note that uveitis activity seems to improve during pregnancy across most uveitis aetiologies. This is supported by other studies that analysed the effect of pregnancy according to uveitis diagnosis, where uveitis activity was found to improve from the second trimester onwards across the various uveitis aetiologies [37, 39]. Uveitis aetiologies analysed in these studies included HLA-B27 associated uveitis, VKH disease, Behcet’s disease, and idiopathic uveitis. Articles focusing on systemic autoimmune diseases in pregnancy have also suggested that the associated uveitis tends to improve for most of these conditions [3, 4, 7, 41, 42, 46–52]; however, the opposite applies to systemic lupus erythematosus, where ocular inflammation has been reported to increase in pregnancy [7, 51]. Meanwhile reports have been contradictory for VKH associated uveitis [53–58]. Rabiah and Vitale’s retrospective study reported that their VKH subjects (𝑛 = 33) mostly experienced an early pregnancy flare-up, with approximately half experiencing a postpartum flare-up [37]. However, this has not been a consistent pattern amongst prior studies. Two case reports have described VKH patients experiencing flare-ups in mid and late pregnancy [55, 58]. Meanwhile, other case reports have described VKH activity in early pregnancy, with cases of VKH being first diagnosed 3 between 10 and 16 weeks [56, 57]. There have also been case reports on VKH generally improving during pregnancy [53, 54]. It is therefore difficult to ascertain the course of VKH on pregnancy as the existing literature is restricted to case reports which describe inconsistent experiences. The use of anti-inflammatory medications has not been found to be associated with rates of flare-up during pregnancy [37, 39]. However, this may be due to selection bias, as patients who did not receive treatment probably had relatively inactive uveitis, whereas those on medication likely had more aggressive disease that required treatment. On the other hand, the lack of association could also be due to the relatively small sample sizes (type II error) in these studies. 4. The Management of Uveitis in Pregnancy The management of non-infectious uveitis in pregnancy attracts special interest as non-infectious uveitis is often managed with immunosuppressive agents that may affect fertility and the viability of pregnancies. The management of uveitis in pregnant women is therefore an area of uncertainty for clinicians due to the limited information available. Wakefield et al. [59] recently published a review on the treatment of severe inflammatory eye disease in pregnancy and young patients of reproductive age. They advised that both male and female patients should be informed about the risks of infertility, miscarriage, and foetal abnormalities. Measures to address these adverse effects of immunosuppressants include sperm banking for male patients, oocyte cryopreservation for female patients, the use of double contraception (barrier and hormonal), and enforcing a drug washout period before conception is attempted. Female patients who become pregnant should be encouraged to inform their doctors as soon as possible so that their treatment may be modified if required for the safety of the pregnancy [59]. In general, principles in the management of uveitis in pregnancy include collaboration between the obstetrician, ophthalmologist, and the patient to evaluate the risks and benefit for the mother and child [59, 60]. Although many immunosuppressive agents are not recommended during pregnancy due to the lack of safety data rather than due to proven teratogenicity, some have proven adverse effects on the fetus and must be avoided. Specifically, methotrexate is contraindicated during pregnancy and lactation, as it results in both miscarriage and fetal anomalies. Similarly, cyclophosphamide and mycophenolate mofetil (MMF) should also be avoided in pregnancy. MMF has been associated with a high rate of fetal anomalies and miscarriages and has therefore resulted in the development of a risk evaluation and mitigation strategy (REMS) for this drug as mandated by the Food and Drug Administration [61]. Cyclophosphamide use poses fetal malformation risks and developmental delay and is absolutely contraindicated in early pregnancy [62, 63]. Although azathioprine and cyclosporine can be used with caution during pregnancy [63], there is currently insufficient data regarding the use of tumour necrosis factor blockers, anakinra and rituximab in pregnancy and lactation [59, 62, 63]. Table 1 summarises the current recommendations 4 Journal of Ophthalmology Table 1: Immunosuppressive drugs in pregnancy and lactation (adapted from reviews on immunomodulatory agents in pregnancy) [59, 62– 65]. Class Prednisolone Side effects on pregnancy and foetus Corticosteroids (i) Foetal: cleft palate/lip, foetal growth retardation, adrenal suppression, neonate cataract [99, 100] (ii) Maternal: glucose intolerance, hypertension, osteopenia Recommendations (i) Food and Drug Administration Category B drug (ii) May be used in pregnancy and breastfeeding (iii) Ideally use prednisolone doses of ≤10 mg/day (iv) May need stress dosing (hydrocortisone/methylprednisolone) at labour, delivery, immediate postpartum period [63, 101] (v) Prednisolone level in milk is <0.1% of the prednisolone dose ingested by the mother Minimise exposure by nursing 4 hours after dose is taken if daily dose exceeds 20 mg [102, 103] Antimetabolites Azathioprine 6-Mercaptopurine Methotrexate (MTX) Mycophenolate mofetil (MMF) (i) Foetal: the foetal liver lacks the enzyme, inosinate pyrophosphorylase, which converts azathioprine to active metabolites; therefore the fetus is protected from the adverse effects of azathioprine (especially early pregnancy) [104] (ii) Paternal: male fertility and pregnancy do not seem to be affected [105] (i) Food and Drug Administration Category D drug (ii) Has been used in pregnancy for many years [64] (iii) Ideally use doses <2 mg/kg/day. Consider decreasing dose at 32 weeks [63] (iv) Breastfeeding is not recommended [106] (i) Foetal: miscarriage, congenital malformations (limb defects, cranial and central nervous system abnormalities) especially in first trimester (ii) Paternal: oligospermia (may be irreversible) (i) Food and Drug Administration Category X drug (ii) Cease 3 months before conception (male and females), continue folic acid after stopping MTX and during pregnancy (iii) Not considered safe in breastfeeding due to inadequate data (i) Foetal: congenital malformations (distinctive MMF embryopathy), abortions (especially in first trimester) (ii) Paternal: male fertility and pregnancy do not seem to be affected (i) Food and Drug Administration Category D drug (ii) Avoid in pregnancy (iii) Use of MMF in pregnancy has not been widely studied; however available reports suggest avoiding MMF if possible during pregnancy [107–109] (iv) Cease >6 weeks before conception attempted [63] (v) MMF is often switched to azathioprine during pregnancy [65] (vi) Breastfeeding is not recommended [65] T-cell inhibitors Cyclosporine Tacrolimus (i) Foetal: infant T-, B-, NK-cell development abnormalities [110] (ii) Maternal: renal impairment, hypertension, lymphoma (iii) Paternal: male fertility and pregnancy do not seem to be affected (i) Foetal: risk of congenital malformations and abortions (i) Food and Drug Administration Category C drug (ii) May be used during pregnancy (iii) Dosage 2.5–5 mg/kg/day—not recommended for use in breastfeeding. However, there have been reports of use in breastfeeding without adverse effects [111] (i) Food and Drug Administration Category C drug (ii) Insufficient information to recommend use in pregnancy (iii) Avoid breast feeding Journal of Ophthalmology 5 Table 1: Continued. Class Interferon-2a Side effects on pregnancy and foetus Interferon (i) Foetal: not teratogenic in animal studies Recommendations (i) Food and Drug Administration Category C drug (ii) American College of Paediatricians classifies interferon-2a as safe in pregnancy and breastfeeding (iii) However, given the limited data on human studies, it should be avoided in pregnancy ideally Anti-TNF Infliximab Adalimumab Etanercept (i) Foetal: possible risk of VACTERL (vertebral anomalies, anal atresia, cardiac defects, tracheoesophageal fistula, esophageal atresia, renal anomalies, limb dysplasia). Currently effects are still uncertain [62, 112–115] (ii) TNF antagonists may affect fertility [116] (i) Food and Drug Administration Category B drug (ii) Not recommended for use in pregnancy and breastfeeding, unless potential benefits outweigh the potential risks [63] (iii) Limited data on infliximab use in lactation, therefore should avoid breastfeeding (iv) Cease infliximab for 6 months before starting breastfeeding Anti-CD 20 B-cell inhibitor Rituximab (i) Foetal: case reports of granulocytopenia and lymphopenia (i) Food and Drug Administration Category C drug (ii) Not recommended for use in pregnancy and breastfeeding, unless potential benefits outweigh the potential risks (iii) Cease 1 year before attempting conception Interleukin-1 receptor antagonist Anakinra (i) Foetal: no toxicity demonstrated in animal studies (i) Food and Drug Administration Category B drug (ii) Only use in pregnancy and lactation if needed to suppress disease activity Alkylating agents Cyclophosphamide Sulfasalazine (i) Foetal: congenital malformation (craniofacial and distal limb defects), developmental delay [117] (ii) Maternal: infertility, amenorrhoea, ovarian failure (iii) Paternal: oligospermia (may be irreversible) [118–120] (i) Food and Drug Administration Category X drug (ii) Absolutely contraindicated in the first trimester but may be used in latter half of pregnancy [64] (iii) Cease 3 months before attempting conception (iv) Contraindicated in breastfeeding [121] Dihydrofolate reductase inhibitor (i) Foetal: kernicterus, agranulocytosis, no (i) Food and Drug Administration Category B significant increase in congenital abnormalities drug [62, 122–124] (ii) Probably safe for use in pregnancy [124] and (ii) Paternal: oligospermia (reversible) breastfeeding [125, 126] Intravenous Immunoglobulin therapy (i) Food and Drug Administration Category C drug (ii) Good safety profile in use during pregnancy (in studies on autoimmune conditions, other than uveitis) regarding the use of various immunosuppressive drugs in pregnancy, as advised in previous reviews [59, 62–65]. Wakefield et al.’s review proposed a stepwise therapeutic regimen for the management of uveitis in pregnancy according to disease severity. In mild uveitis, treatment could consist of topical or local steroid injections, followed by oral prednisolone (<50 mg/day), azathioprine (2 mg/kg/day), or cyclosporine (2.5–5 mg/kg/day). Higher doses of prednisolone (1 mg/kg/day) were recommended for more severe uveitis, with the addition of azathioprine and/or 6 cyclosporine if needed. In the event where triple therapy with steroids, azathioprine, and cyclosporine was insufficient for the control of inflammation, the addition of intravenous immunoglobulin therapy or biological agents could then be considered [59]. In addition, for those patients taking chronic corticosteroids during pregnancy, Wakefield et al. recommended that the dose should be increased prior to delivery (24, 12, and 1 hour prior to delivery) to counteract the stress of childbirth. However, as we and others have found that uveitis is generally less active during pregnancy than during the prepregnancy and postpartum periods, given the questionable safety of several systemic agents used in the treatment of noninfectious uveitis, an alternative approach would be to taper and/or cease systemic treatments during pregnancy in favour of locally delivered treatment. The use of locally delivered treatment (such as periocular sustained release corticosteroid injections or intravitreal steroids) in non-infectious uveitis is not new and its use has been extensively described in a large range of non-infectious ocular inflammatory conditions. Periocular corticosteroids of triamcinolone and methylprednisolone have been effective in managing vitritis, posterior segment inflammation, and moderate macular oedema [66–73]. They confer the advantages of achieving higher drug levels in the posterior segment of the eye as compared to systemic steroids and lower risks of systemic side effects [74]. However, potential complications include ptosis, orbital fat protrusion, and other steroid induced ocular complications such as cataracts and raised intraocular pressure (IOP) [66, 73, 75, 76]. Intravitreal triamcinolone acetate (IVTA) is commonly used to treat vitritis and associated cystoid macular oedema [77–82]. Specifically, IVTA has been effectively used to treat uveitis associated with Behcet’s disease [83–85], VKH syndrome [86], serpinginous choroiditis [87], and sympathetic ophthalmia [88–91]. These studies have shown that IVTA may be used alone or as an adjuvant to reduce the dose of systemic immunosuppression required. As compared to other forms of steroids, IVTA has been shown to be more effective than orbital floor and sub-Tenon triamcinolone [92, 93] and comparably as effective as oral steroids in managing posterior uveitis. However, side effects associated with IVTA include relatively high risks of steroid induced cataracts (15– 30%) and IOP rise (25–45%), particularly in younger patients [81, 94]. This should be kept in mind when considering regionally delivered corticosteroids in uveitis patients during pregnancy. Other less common side effects include postinjection infectious endophthalmitis, pseudoendophthalmitis, and rhegmatogenous retinal detachments [95]. In most of these cases, the use of periocular or intravitreal steroid injections has been for the treatment of acute exacerbations, often in combination with the commencement of systemic treatment to prevent the relapse of disease when the sustained release steroid is exhausted. However, due to their limited duration of effect, this modality of treatment tends not to be used as the sole treatment in chronic disease. However, their use during pregnancy would appear ideal, as they have very little (if any) systemic toxicity and only a limited and finite number of repeated administrations would Journal of Ophthalmology be needed (if required) during the course of the pregnancy, after which systemic treatments could be reconsidered after delivery. Alternatively, newer forms of sustained release corticosteroid therapy such as Ozurdex (Allergan, Irvine, CA) and Retisert (Bausch and Lomb, Rochester, NY) could also be considered during this time, given their longer durations of effect in chronic active posterior or panuveitis, with similar efficacy to systemic treatment [96, 97]. A suggested approach in the management of patients with chronic uveitis who become pregnant would therefore be the tapering and cessation of systemic treatments during pregnancy, as the activity of the patient’s uveitis would be expected to decrease during this time. Any flare-ups of disease could then be managed locally with either topical, sub-Tenons, or intravitreal sustained release corticosteroid as required until delivery. For those with sight-threatening disease, repeated prophylactic local injections could be considered; however, this would be a more contentious approach, given that disease activity is expected to reduce during pregnancy and common side effects such as raised IOP and cataracts are higher in younger patients [81, 94]. Upon delivery, recommencement of systemic agents (being mindful of the patient’s breastfeeding status) and closer review of patients would then be recommended, given that uveitis activity is likely to rebound back to prepregnancy levels. For patients with chronic, sight-threatening disease where the cessation of systemic treatment is deemed particularly risky, an alternative option is the use of either the Ozurdex or Retisert sustained release corticosteroid devices. In those patients planning for multiple children, Retisert may be particularly advantageous, given its much longer duration of effect [98]. 5. Conclusion The influence of pregnancy on the course of uveitis is a fascinating phenomenon. The general consensus is that uveitis improves during pregnancy, especially from mid pregnancy onwards, while the postpartum period is associated with uveitis activity relapse. This has key implications on the management of pregnant uveitis patients. Clinicians may consider decreasing uveitis medications during pregnancy to minimise medication associated side effects on the foetus. After delivery, followup should also be intensified in anticipation of postpartum relapse. It would be interesting to see if future studies on the mechanisms behind uveitis amelioration in pregnancy would inspire new therapeutic options for uveitis. Conflict of Interests The authors have no conflict of interests in any aspect of this paper. Acknowledgment CERA receives Operational Infrastructure Support from the Victorian Government. Journal of Ophthalmology References [1] J. P. Buyon, J. L. Nelson, and M. D. Lockshin, “The effects of pregnancy on autoimmune diseases,” Clinical Immunology and Immunopathology, vol. 78, no. 2, pp. 99–104, 1996. [2] R. L. Wilder, “Hormones, pregnancy, and autoimmune diseases,” Annals of the New York Academy of Sciences, vol. 840, pp. 45–50, 1998. [3] J. P. Buyon, “The effects of pregnancy on autoimmune diseases,” Journal of Leukocyte Biology, vol. 63, no. 3, pp. 281–287, 1998. [4] A. Doria, L. Iaccarino, S. Arienti et al., “Th2 immune deviation induced by pregnancy: the two faces of autoimmune rheumatic diseases,” Reproductive Toxicology, vol. 22, no. 2, pp. 234–241, 2006. [5] I. J. Elenkov, J. Hoffman, and R. L. Wilder, “Does differential neuroendocrine control of cytokine production govern the expression of autoimmune diseases in pregnancy and the postpartum period?” Molecular Medicine Today, vol. 3, no. 9, pp. 379–383, 1997. [6] I. J. Elenkov, R. L. Wilder, V. K. Bakalov et al., “IL-12, TNF-𝛼, and hormonal changes during late pregnancy and early postpartum: implications for autoimmune disease activity during these times,” Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 10, pp. 4933–4938, 2001. [7] S. O. Keeling and A. E. Oswald, “Pregnancy and rheumatic disease: “by the book” or ‘by the doc’,” Clinical Rheumatology, vol. 28, no. 1, pp. 1–9, 2009. [8] L. J. Jara, O. Vera-Lastra, J. M. Miranda, M. Alcala, and J. Alvarez-Nemegyei, “Prolactin in human systemic lupus erythematosus,” Lupus, vol. 10, no. 10, pp. 748–756, 2001. [9] M. Østensen, P. M. Villiger, and F. Förger, “Interaction of pregnancy and autoimmune rheumatic disease,” Autoimmunity Reviews, vol. 11, no. 6-7, pp. A437–A446, 2012. [10] C.-C. Chan, G. F. Reed, Y. Kim, E. Agrón, and R. R. Buggage, “A correlation of pregnancy term, disease activity, serum female hormones, and cytokines in uveitis,” British Journal of Ophthalmology, vol. 88, no. 12, pp. 1506–1509, 2004. [11] R. K. Agarwal, C.-C. Chan, B. Wiggert, and R. R. Caspi, “Pregnancy ameliorates induction and expression of experimental autoimmune uveitis,” Journal of Immunology, vol. 162, no. 5, pp. 2648–2654, 1999. [12] E. F. Foxman, M. Zhang, S. D. Hurst et al., “Inflammatory mediators in uveitis: differential induction of cytokines and chemokines in Th1- versus Th2-mediated ocular inflammation,” Journal of Immunology, vol. 168, no. 5, pp. 2483–2492, 2002. [13] M. Akdis, O. Palomares, W. van de Veen, M. van Splunter, and C. A. Akdis, “TH17 and TH22 cells: a confusion of antimicrobial response with tissue inflammation versus protection,” Journal of Allergy and Clinical Immunology, vol. 129, pp. 1438–1449, 2012. [14] E. Bettelli, M. Oukka, and V. K. Kuchroo, “TH-17 cells in the circle of immunity and autoimmunity,” Nature Immunology, vol. 8, no. 4, pp. 345–350, 2007. [15] J. Furuzawa-Carballeda, M. I. Vargas-Rojas, and A. R. Cabral, “Autoimmune inflammation from the Th17 perspective,” Autoimmunity Reviews, vol. 6, no. 3, pp. 169–175, 2007. [16] M. B. Torchinsky and J. M. Blander, “T helper 17 cells: discovery, function, and physiological trigger,” Cellular and Molecular Life Sciences, vol. 67, no. 9, pp. 1407–1421, 2010. [17] J. Ernerudh, G. Berg, and J. Mjösberg, “Regulatory T helper cells in pregnancy and their roles in systemic versus local immune tolerance,” American Journal of Reproductive Immunology, vol. 66, no. 1, pp. 31–43, 2011. 7 [18] C. K. Wong, C. Y. Ho, E. K. Li, and C. W. K. Lam, “Elevation of proinflammatory cytokine (IL-18, IL-17, IL-12) and Th2 cytokine (IL-4) concentrations in patients with systemic lupus erythematosus,” Lupus, vol. 9, no. 8, pp. 589–593, 2000. [19] C. Wang, Y. Tian, B. Lei et al., “Decreased IL-27 expression in association with an increased Th17 response in Vogt-KoyanagiHarada disease.,” Investigative Ophthalmology & Visual Science, vol. 53, pp. 4668–4675, 2012. [20] D. Yen, J. Cheung, H. Scheerens et al., “IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6,” Journal of Clinical Investigation, vol. 116, no. 5, pp. 1310– 1316, 2006. [21] W. Wang, S. Shao, Z. Jiao, M. Guo, H. Xu, and S. Wang, “The Th17/Treg imbalance and cytokine environment in peripheral blood of patients with rheumatoid arthritis,” Rheumatology International, vol. 32, no. 4, pp. 887–893, 2012. [22] L. Klotz, S. Burgdorf, I. Dani et al., “The nuclear receptor PPAR𝛾 selectively inhibits Th17 differentiation in a T cellintrinsic fashion and suppresses CNS autoimmunity,” Journal of Experimental Medicine, vol. 206, no. 10, pp. 2079–2089, 2009. [23] G. Toldi, J. Rigó Jr., B. Stenczer, B. Vásárhelyi, and A. Molvarec, “Increased prevalence of IL-17-producing peripheral blood lymphocytes in pre-eclampsia,” American Journal of Reproductive Immunology, vol. 66, no. 3, pp. 223–229, 2011. [24] W.-H. Zhu, C.-Z. Lu, Y.-M. Huang, H. Link, and B.-G. Xiao, “A putative mechanism on remission of multiple sclerosis during pregnancy: estrogen-induced indoleamine 2,3-dioxygenase by dendritic cells,” Multiple Sclerosis, vol. 13, no. 1, pp. 33–40, 2007. [25] S. S. Soldan, A. I. A. Retuerto, N. L. Sicotte, and R. R. Voskuhl, “Immune modulation in multiple sclerosis patients treated with the pregnancy hormone estriol,” Journal of Immunology, vol. 171, no. 11, pp. 6267–6274, 2003. [26] Z. Williams, “Inducing tolerance to pregnancy,” The New England Journal of Medicine, vol. 367, pp. 1159–1161, 2012. [27] J. M. Lipton and A. Catania, “Anti-inflammatory actions of the neuroimmunomodulator 𝛼-MSH,” Immunology Today, vol. 18, no. 3, pp. 140–145, 1997. [28] J. M. Lipton, “Modulation of host defense by the neuropeptide 𝛼-MSH,” Yale Journal of Biology and Medicine, vol. 63, no. 2, pp. 173–182, 1990. [29] J. Harness, A. Cavanagh, H. Morton, and P. McCombe, “A protective effect of early pregnancy factor on experimental autoimmune encephalomyelitis induced in Lewis rats by inoculation with myelin basic protein,” Journal of the Neurological Sciences, vol. 216, no. 1, pp. 33–41, 2003. [30] T. B. Tomasi Jr., “Structure and function of alpha-fetoprotein,” Annual Review of Medicine, vol. 28, pp. 453–465, 1977. [31] E. Matsuura, Y. Kang, H. Kitakawa et al., “Modulation of T cell function by alpha-fetoprotein: an in vivo study on porcine thyroid peroxidase-induced experimental autoimmune thyroiditis in transgenic mice producing human alpha-fetoprotein,” Tumor Biology, vol. 20, no. 3, pp. 162–171, 1999. [32] S. Vassiliadis, A. Ranella, L. Papadimitriou, A. Makrygiannakis, and I. Athanassakis, “Serum levels of pro- and antiinflammatory cytokines in non-pregnant women, during pregnancy, labour and abortion,” Mediators of Inflammation, vol. 7, no. 2, pp. 69–72, 1998. [33] M. Ostensen, R. Lundgren, G. Husby, and O. P. Rekvig, “Studies on humoral immunity in pregnancy: immunoglobulins, alloantibodies and autoantibodies in healthy pregnant women and in pregnant women with rheumatoid disease,” Journal of Clinical and Laboratory Immunology, vol. 11, no. 3, pp. 143–147, 1983. 8 [34] C. Taguchi, E. Ikeda, N. Hikita, and M. Mochizuki, “A report of two cases suggesting positive influence of pregnancy on uveitis activity,” Nippon Ganka Gakkai zasshi, vol. 103, no. 1, pp. 66–71, 1999. [35] A. Kubicka-Trz¸ska, “Endogenous uveitis during pregnancy—a report of 4 cases,” Klinika Oczna, vol. 106, no. 3, pp. 328–331, 2004. [36] K. Yamada, K. Kimoto, J. Ikewaki, K. Nakatsuka, and H. Yatsuka, “A case of recurrent uveitis with remission during pregnancies,” Japanese Journal of Clinical Ophthalmology, vol. 57, no. 3, pp. 311–315, 2003. [37] P. K. Rabiah and A. T. Vitale, “Noninfectious uveitis and pregnancy,” American Journal of Ophthalmology, vol. 136, no. 1, pp. 91–98, 2003. [38] L. I. Kump, R. A. Cervantes-Castañeda, S. N. Androudi, C. S. Foster, and W. G. Christen, “Patterns of exacerbations of chronic non-infectious uveitis in pregnancy and puerperium,” Ocular Immunology and Inflammation, vol. 14, no. 2, pp. 99–104, 2006. [39] N. P. Chiam, A. J. Hall, R. J. Stawell, L. Busija, and L. L. Lim, “The course of uveitis in pregnancy and postpartum,” The British Journal of Ophthalmology, vol. 97, no. 10, pp. 1284–1288, 2013. [40] D. A. Jabs, “Epidemiology of uveitis,” Ophthalmic Epidemiology, vol. 15, no. 5, pp. 283–284, 2008. [41] J. H. Barrett, P. Brennan, M. Fiddler, and A. Silman, “Breastfeeding and postpartum relapse in women with rheumatoid and inflammatory arthritis,” Arthritis & Rheumatism, vol. 43, pp. 1010–1015, 2000. [42] J. H. Barrett, P. Brennan, M. Fiddler, and A. J. Silman, “Does rheumatoid arthritis remit during pregnancy and relapse postpartum? Results from a nationwide study in the United Kingdom performed prospectively from late pregnancy,” Arthritis & Rheumatism, vol. 42, pp. 1219–1227, 1999. [43] L. Matera, M. Mori, M. Geuna, S. Buttiglieri, and G. Palestro, “Prolactin in autoimmunity and antitumor defence,” Journal of Neuroimmunology, vol. 109, no. 1, pp. 47–55, 2000. [44] S. E. Walker, D. Miller, D. Hill, and G. R. Komatireddy, “Prolactin, a pituitary hormone that modifies immune responses. Proceedings of the Mini-symposium on Prolactin and SLE, held at the 5th International Conference on Systemic Lupus Erythematosus, Cancun, Mexico.,” Lupus, vol. 7, no. 6, pp. 371– 375, 1998. [45] K. B. Elbourne, D. Keisler, and R. W. McMurray, “Differential effects of estrogen and prolactin on autoimmune disease in the NZB/NZW F1 mouse model of systemic lupus erythematosus,” Lupus, vol. 7, no. 6, pp. 420–427, 1998. [46] J. L. Nelson and M. Ostenson, “Pregnancy and rheumatoid arthritis,” Rheumatic Disease Clinics of North America, vol. 23, no. 1, pp. 195–212, 1997. [47] M. Østensen and P. M. Villiger, “Immunology of pregnancy— pregnancy as a remission inducing agent in rheumatoid arthritis,” Transplant Immunology, vol. 9, no. 2–4, pp. 155–160, 2002. [48] S. H. Zrour, R. Boumiza, N. Sakly et al., “The impact of pregnancy on rheumatoid arthritis outcome: the role of maternofetal HLA class II disparity,” Joint Bone Spine, vol. 77, no. 1, pp. 36–40, 2010. [49] E. Musiej-Nowakowska and R. Ploski, “Pregnancy and early onset pauciarticular juvenile chronic arthritis,” Annals of the Rheumatic Diseases, vol. 58, no. 8, pp. 475–480, 1999. [50] M. Ostensen, “Pregnancy in patients with a history of juvenile rheumatoid arthritis,” Arthritis and Rheumatism, vol. 34, no. 7, pp. 881–887, 1991. Journal of Ophthalmology [51] C. Gordon, “Pregnancy and autoimmune diseases,” Best Practice & Research Clinical Rheumatology, vol. 18, pp. 359–379, 2004. [52] R. L. Mayock, R. D. Sullivan, R. R. Greening, and R. Jones Jr., “Sarcoidosis and pregnancy,” Journal of the American Medical Association, vol. 164, no. 2, pp. 158–163, 1957. [53] D. A. Snyder and H. H. Tessler, “Vogt-Koyanagi-Harada syndrome,” American Journal of Ophthalmology, vol. 90, no. 1, pp. 69–75, 1980. [54] L. P. Steahly, “Vogt-Koyanagi-Harada syndrome and pregnancy,” Annals of Ophthalmology, vol. 22, no. 2, pp. 59–62, 1990. [55] Z. Friedman, M. Granat, and E. Neumann, “The syndrome of Vogt-Koyanagi-Harada and pregnancy,” Metabolic Ophthalmology, vol. 4, no. 3, pp. 147–149, 1980. [56] M. Nohara, K. Norose, and K. Segawa, “Vogt-Koyanagi-Harada disease during pregnancy,” British Journal of Ophthalmology, vol. 79, no. 1, pp. 94–95, 1995. [57] M. Doi, H. Matsubara, and Y. Uji, “Vogt-Koyanagi-Harada syndrome in a pregnant patient treated with high-dose systemic corticosteroids,” Acta Ophthalmologica Scandinavica, vol. 78, no. 1, pp. 93–96, 2000. [58] N. Miyata, M. Sugita, S. Nakamura et al., “Treatment of VogtKoyanagi- Harada’s disease during pregnancy,” Japanese Journal of Ophthalmology, vol. 45, no. 2, pp. 177–180, 2001. [59] D. Wakefield, A. Abu El-Asrar, and P. McCluskey, “Treatment of severe inflammatory eye disease in patients of reproductive age and during pregnancy,” Ocular Immunology and Inflammation, vol. 20, pp. 277–287, 2012. [60] C. Y. Chung, A. K. H. Kwok, and K. L. Chung, “Use of opthalmic medications during pregnancy,” Hong Kong Medical Journal, vol. 10, no. 3, pp. 191–195, 2004. [61] Mycophenolate REMS, “Food and Drug Administration,” 2012, https://www.mycophenolaterems.com/HCPOverview.aspx. [62] M. Barbhaiya and B. L. Bermas, “Evaluation and management of systemic lupus erythematosus and rheumatoid arthritis during pregnancy,” Clinical Immunology, vol. 149, pp. 225–235, 2013. [63] K. K. Temprano, R. Bandlamudi, and T. L. Moore, “Antirheumatic drugs in pregnancy and lactation,” Seminars in Arthritis and Rheumatism, vol. 35, no. 2, pp. 112–121, 2005. [64] A. B. Elliott and E. F. Chakravarty, “Immunosuppressive medications during pregnancy and lactation in women with autoimmune diseases,” Women’s Health, vol. 6, no. 3, pp. 431– 442, 2010. [65] M. Petri, “Immunosuppressive drug use in pregnancy,” Autoimmunity, vol. 36, no. 1, pp. 51–56, 2003. [66] S. R. J. Taylor, H. Isa, L. Joshi, and S. Lightman, “New developments in corticosteroid therapy for uveitis,” Ophthalmologica, vol. 224, supplement 1, pp. 46–53, 2010. [67] P. Ferrante, A. Ramsey, C. Bunce, and S. Lightman, “Clinical trial to compare efficacy and side-effects of injection of posterior sub-Tenon triamcinolone versus orbital floor methylprednisolone in the management of posterior uveitis,” Clinical and Experimental Ophthalmology, vol. 32, no. 6, pp. 563–568, 2004. [68] P. Riordan-Eva and S. Lightman, “Orbital floor steroid injections in the treatment of uveitis,” Eye, vol. 8, part 1, pp. 66–69, 1994. [69] C. J. Helm and G. N. Holland, “The effects of posterior subtenon injection of triamcinolone acetonide in patients with intermediate uveitis,” American Journal of Ophthalmology, vol. 120, no. 1, pp. 55–64, 1995. [70] I. G. M. Duguid, R. L. Ford, S. E. Horgan, H. M. A. Towler, and S. L. Lightman, “Combined orbital floor betamethasone and Journal of Ophthalmology [71] [72] [73] [74] [75] [76] [77] [78] [79] [80] [81] [82] [83] [84] [85] depot methylprednisolone in uveitis,” Ocular Immunology and Inflammation, vol. 13, no. 1, pp. 19–24, 2005. M. L. Dafflon, V. T. Tran, Y. Guex-Crosier, and C. P. Herbort, “Posterior sub-Tenon’s steroid injections for the treatment of posterior ocular inflammation: indications, efficacy and side effects,” Graefe’s Archive for Clinical and Experimental Ophthalmology, vol. 237, no. 4, pp. 289–295, 1999. V. Tanner, J. J. Kanski, and P. A. Frith, “Posterior sub-Tenon’s triamcinolone injections in the treatment of uveitis,” Eye, vol. 12, part 4, pp. 679–685, 1998. M. Roesel, M. Gutfleisch, C. Heinz, B. Heimes, B. Zurek-Imhoff, and A. Heiligenhaus, “Orbital floor triamcinolone acetonide injections for the management of active non-infectious uveitis,” Eye, vol. 23, no. 4, pp. 910–914, 2009. S. Raghava, M. Hammond, and U. B. Kompella, “Periocular routes for retinal drug delivery,” Expert Opinion on Drug Delivery, vol. 1, no. 1, pp. 99–114, 2004. Y. S. Byun and Y.-H. Park, “Complications and safety profile of posterior subtenon injection of triamcinolone acetonide,” Journal of Ocular Pharmacology and Therapeutics, vol. 25, no. 2, pp. 159–162, 2009. M. Roesel, M. Gutfleisch, C. Heinz, B. Heimes, B. ZurekImhoff, and A. Heiligenhaus, “Intravitreal and orbital floor triamcinolone acetonide injections in noninfectious uveitis: a comparative study,” Ophthalmic Research, vol. 42, no. 2, pp. 81– 86, 2009. R. J. Antcliff, D. J. Spalton, M. R. Stanford, E. M. Graham, T. J. Fytche, and J. Marshall, “Intravitreal triamcinolone for uveitic cystoid macular edema: an optical coherence tomography study,” Ophthalmology, vol. 108, no. 4, pp. 765–772, 2001. S. Young, G. Larkin, M. Branley, and S. Lightman, “Safety and efficacy of intravitreal triamcinolone for cystoid macular oedema in uveitis,” Clinical and Experimental Ophthalmology, vol. 29, no. 1, pp. 2–6, 2001. S. Androudi, E. Letko, M. Meniconi, T. Papadaki, M. Ahmed, and C. S. Foster, “Safety and efficacy of intravitreal triamcinolone acetonide for uveitic macular edema,” Ocular Immunology and Inflammation, vol. 13, no. 2-3, pp. 205–212, 2005. R. I. Angunawela, C. J. Heatley, T. H. Williamson et al., “Intravitreal triamcinalone acetonide for refractory uveitic cystoid macular oedema: longterm management and outcome,” Acta Ophthalmologica Scandinavica, vol. 83, no. 5, pp. 595–599, 2005. H. Kok, C. Lau, N. Maycock, P. McCluskey, and S. Lightman, “Outcome of intravitreal triamcinolone in uveitis,” Ophthalmology, vol. 112, no. 11, pp. 1916.e1–1916.e7, 2005. M. C. Gillies, J. M. Simpson, F. A. Billson et al., “Safety of an intravitreal injection of triamcinolone: results from a randomized clinical trial,” Archives of Ophthalmology, vol. 122, no. 3, pp. 336–340, 2004. S. Tuncer, S. Yilmaz, M. Urgancioglu, and I. Tugal-Tutkun, “Results of Intravitreal Triamcinolone Acetonide (IVTA) injection for the treatment of panuveitis attacks in patients with Behçet disease,” Journal of Ocular Pharmacology and Therapeutics, vol. 23, no. 4, pp. 395–401, 2007. M. Kramer, R. Ehrlich, M. Snir et al., “Intravitreal injections of triamcinolone acetonide for severe vitritis in patients with incomplete Behcet’s disease,” American Journal of Ophthalmology, vol. 138, no. 4, pp. 666–667, 2004. M. Karacorlu, B. Mudun, H. Ozdemir, S. A. Karacorlu, and E. Burumcek, “Intravitreal triamcinolone acetonide for the treatment of cystoid macular edema secondary to Behçet 9 [86] [87] [88] [89] [90] [91] [92] [93] [94] [95] [96] [97] [98] [99] [100] [101] disease,” American Journal of Ophthalmology, vol. 138, no. 2, pp. 289–291, 2004. M. Karacorlu, S. Arf Karacorlu, and H. Ozdemir, “Intravitreal triamcinolone acetonide in Vogt-Koyanagi-Harada syndrome,” European Journal of Ophthalmology, vol. 16, no. 3, pp. 481–483, 2006. S. Karacorlu, H. Ozdemir, and M. Karacorlu, “Intravitreal triamcinolone acetonide in serpiginous choroiditis,” Japanese Journal of Ophthalmology, vol. 50, no. 3, pp. 290–291, 2006. H. Ozdemir, M. Karacorlu, and S. Karacorlu, “Intravitreal triamcinolone acetonide in sympathetic ophthalmia,” Graefe’s Archive for Clinical and Experimental Ophthalmology, vol. 243, no. 7, pp. 734–736, 2005. R. V. P. Chan, B. D. Seiff, H. A. Lincoff, and D. J. Coleman, “Rapid recovery of sympathetic ophthalmia with treatment augmented by intravitreal steroids,” Retina, vol. 26, no. 2, pp. 243–247, 2006. J. B. Jonas, “Intravitreal triamcinolone acetonide for treatment of sympathetic ophthalmia,” American Journal of Ophthalmology, vol. 137, no. 2, pp. 367–368, 2004. J. B. Jonas and U. H. M. Spandau, “Repeated intravitreal triamcinolone acetonide for chronic sympathetic ophthalmia,” Acta Ophthalmologica Scandinavica, vol. 84, no. 3, p. 436, 2006. M. Roesel, C. Tappeiner, C. Heinz, J. M. Koch, and A. Heiligenhaus, “Comparison between intravitreal and orbital floor triamcinolone acetonide after phacoemulsification in patients with endogenous uveitis,” American Journal of Ophthalmology, vol. 147, no. 3, pp. 406–412, 2009. S. Choudhry and S. Ghosh, “Intravitreal and posterior subtenon triamcinolone acetonide in idiopathic bilateral uveitic macular oedema,” Clinical and Experimental Ophthalmology, vol. 35, no. 8, pp. 713–718, 2007. A. Sallam, R. M. Comer, J. H. Chang et al., “Short-term safety and efficacy of intravitreal triamcinolone acetonide for uveitic macular edema in children,” Archives of Ophthalmology, vol. 126, no. 2, pp. 200–205, 2008. Y. Tao and J. B. Jonas, “Intravitreal triamcinolone,” Ophthalmologica, vol. 225, no. 1, pp. 1–20, 2011. J. H. Kempen, M. M. Altaweel, J. T. Holbrook et al., “Randomized comparison of systemic anti-inflammatory therapy versus fluocinolone acetonide implant for intermediate, posterior, and panuveitis: the multicenter uveitis steroid treatment trial,” Ophthalmology, vol. 118, no. 10, pp. 1916–1926, 2011. C. Lowder, R. Belfort Jr., S. Lightman et al., “Dexamethasone intravitreal implant for noninfectious intermediate or posterior uveitis,” Archives of Ophthalmology, vol. 129, no. 5, pp. 545–553, 2011. L. L. Lim, J. R. Smith, and J. T. Rosenbaum, “Retisert Bausch & Lomb/control delivery systems,” Current Opinion in Investigational Drugs, vol. 6, no. 11, pp. 1159–1167, 2005. M. Østensen, “Antirheumatic therapy and reproduction. The influence on fertility, pregnancy and breast feeding,” Zeitschrift fur Rheumatologie, vol. 65, no. 3, pp. 217–224, 2006. L. Park-Wyllie, P. Mazzotta, A. Pastuszak et al., “Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies,” Teratology, vol. 62, pp. 385–392, 2000. P. A. Rosandich, J. T. Kelley III, and D. L. Conn, “Perioperative management of patients with rheumatoid arthritis in the era of biologic response modifiers,” Current Opinion in Rheumatology, vol. 16, no. 3, pp. 192–198, 2004. 10 [102] P. A. Greenberger, Y. K. Odeh, M. C. Frederiksen, and A. J. Atkinson Jr., “Pharmacokinetics of prednisolone transfer to breast milk,” Clinical Pharmacology and Therapeutics, vol. 53, no. 3, pp. 324–328, 1993. [103] L. Ost, G. Wettrell, I. Bjorkhem, and A. Rane, “Prednisolone excretion in human milk,” Journal of Pediatrics, vol. 106, no. 6, pp. 1008–1011, 1985. [104] B. Nørgård, L. Pedersen, K. Fonager, S. N. Rasmussen, and H. T. Sørensen, “Azathioprine, mercaptopurine and birth outcome: a population-based cohort study,” Alimentary Pharmacology and Therapeutics, vol. 17, no. 6, pp. 827–834, 2003. [105] C. Dejaco, C. Mittermaier, W. Reinisch et al., “Azathioprine treatment and male fertility in inflammatory bowel disease,” Gastroenterology, vol. 121, no. 5, pp. 1048–1053, 2001. [106] C. B. Coulam, T. P. Moyer, N. S. Jiang, and H. Zincke, “Breastfeeding after renal transplantation,” Transplantation Proceedings, vol. 14, no. 3, pp. 605–609, 1982. [107] V. T. Armenti, J. S. Radomski, M. J. Moritz et al., “Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation,” Clinical transplants, pp. 97–105, 2001. [108] P. E. Pergola, A. Kancharla, and D. J. Riley, “Kidney transplantation during the first trimester of pregnancy: immunosuppression with mycophenolate mofetil, tacrolimus, and prednisone,” Transplantation, vol. 71, no. 7, pp. 994–997, 2001. [109] C. Le Ray, A. Coulomb, E. Elefant, R. Frydman, and F. Audibert, “Mycophenolate mofetil in pregnancy after renal transplantation: a case of major fetal malformations,” Obstetrics and Gynecology, vol. 103, no. 5, pp. 1091–1094, 2004. [110] S. Di Paolo, A. Schena, L. F. Morrone et al., “Immunologic evaluation during the first year of life of infants born to cyclosporine-treated female kidney transplant recipients: analysis of lymphocyte subpopulations and immunoglobulin serum levels,” Transplantation, vol. 69, no. 10, pp. 2049–2054, 2000. [111] M. E. Moretti, M. Sgro, D. W. Johnson et al., “Cyclosporine excretion into breast milk,” Transplantation, vol. 75, no. 12, pp. 2144–2146, 2003. [112] J. A. Katz, C. Antoni, G. F. Keenan, D. E. Smith, S. J. Jacobs, and G. R. Lichtenstein, “Outcome of pregnancy in women receiving infliximab for the treatment of Crohn’s disease and rheumatoid arthritis,” American Journal of Gastroenterology, vol. 99, no. 12, pp. 2385–2392, 2004. [113] U. Mahadevan, S. Kane, W. J. Sandborn et al., “Intentional infliximab use during pregnancy for induction or maintenance of remission in Crohn’s disease,” Alimentary Pharmacology and Therapeutics, vol. 21, no. 6, pp. 733–738, 2005. [114] B. P. Giroir, K. Peppel, M. Silva, and B. Beutler, “The biosynthesis of tumor necrosis factor during pregnancy: studies with a CAT reporter transgene and TNF inhibitors,” European Cytokine Network, vol. 3, no. 6, pp. 533–538, 1992. [115] K. L. Hyrich, D. P. M. Symmons, K. D. Watson, and A. J. Silman, “Pregnancy outcome in women who were exposed to antitumor necrosis factor agents: results from a national population register,” Arthritis and Rheumatism, vol. 54, no. 8, pp. 2701–2702, 2006. [116] D. J. Wallace and M. H. Weisman, “The use of etanercept and other tumor necrosis factor-𝛼 blockers in infertility: it’s time to get serious,” Journal of Rheumatology, vol. 30, no. 9, pp. 1897– 1899, 2003. [117] G. M. Enns, E. Roeder, R. T. Chan, Z. Ali-Khan Catts, V. A. Cox, and M. Golabi, “Apparent cyclophosphamide, (cytoxan) Journal of Ophthalmology [118] [119] [120] [121] [122] [123] [124] [125] [126] embryopathy: a distinct phenotype?” American Journal of Medical Genetics, vol. 86, pp. 237–241, 1999. J. Penso, B. Lippe, R. Ehrlich, and F. G. Smith, “Testicular function in prepubertal and pubertal male patients treated with cyclophosphamide for nephrotic syndrome,” Journal of Pediatrics, vol. 84, no. 6, pp. 831–836, 1974. W. H. B. Wallace, S. M. Shalet, M. Lendon, and P. H. MorrisJones, “Male fertility in long-term survivors of childhood acute lymphoblastic leukaemia,” International Journal of Andrology, vol. 14, no. 5, pp. 312–319, 1991. V. Papadakis, E. Vlachopapadopoulou, K. van Syckle et al., “Gonadal function in young patients successfully treated for Hodgkin disease,” Medical and Pediatric Oncology, vol. 32, pp. 366–372, 1999. P. H. Wiernik and J. H. Duncan, “Cyclophosphamide in human milk,” The Lancet, vol. 1, no. 7705, article 912, 1971. R. Rahimi, S. Nikfar, A. Rezaie, and M. Abdollahi, “Pregnancy outcome in women with inflammatory bowel disease following exposure to 5-aminosalicylic acid drugs: a meta-analysis,” Reproductive Toxicology, vol. 25, no. 2, pp. 271–275, 2008. B. Nørgård, A. E. Czeizel, M. Rockenbauer, J. Olsen, and H. T. Sørensen, “Population-based case control study of the safety of sulfasalazine use during pregnancy,” Alimentary Pharmacology and Therapeutics, vol. 15, no. 4, pp. 483–486, 2001. M. Mogadam, W. O. Dobbins III, B. I. Korelitz, and S. W. Ahmed, “Pregnancy in inflammatory bowel disease: effect of sulfasalazine and corticosteroids on fetal outcome,” Gastroenterology, vol. 80, no. 1, pp. 72–76, 1981. E. Esbjorner, G. Jarnerot, and L. Wranne, “Sulphasalazine and sulphapyridine serum levels in children to mothers treated with sulphasalazine during pregnancy and lactation,” Acta Paediatrica Scandinavica, vol. 76, no. 1, pp. 137–142, 1987. G. Jarnerot and M.-B. Into-Malmberg, “Sulphasalazine treatment during breast feeding,” Scandinavian Journal of Gastroenterology, vol. 14, no. 7, pp. 869–871, 1979. Hindawi Publishing Corporation Journal of Ophthalmology Volume 2013, Article ID 928264, 6 pages http://dx.doi.org/10.1155/2013/928264 Review Article Gender and Spondyloarthropathy-Associated Uveitis Wendy M. Smith Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA Correspondence should be addressed to Wendy M. Smith; [email protected] Received 4 October 2013; Accepted 11 December 2013 Academic Editor: H. Nida Sen Copyright © 2013 Wendy M. Smith. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Spondyloarthropathies encompass a group of inflammatory diseases with arthritis and other features such as enthesitis and dermatologic and gastrointestinal involvement. Up to 37% of spondyloarthropathy patients may develop uveitis which is typically bilateral asynchronous acute anterior uveitis. Spondyloarthropathies with and without uveitis are more prevalent among males; the reasons for gender imbalance are unclear. This review will focus on gender differences in the prevalence, incidence, clinical manifestations, and prognosis of uveitis associated with spondyloarthropathies. 1. Introduction Spondyloarthropathies are a group of inflammatory diseases with overlapping features including arthritis of the axial skeleton and/or peripheral joints, inflammatory back pain, enthesitis, and dermatologic and gastrointestinal involvement. The majority of these syndromes are more prevalent in males although the reasons for this gender imbalance are unclear. The concept of individualized medicine has become increasingly important; therefore, a better understanding of gender differences in uveitis may help us provide better care and prevent vision loss. This review will focus on gender differences in the prevalence, incidence, clinical manifestations, and prognosis of uveitis in spondyloarthropathies. Most spondyloarthropathy patients are positive for the human leukocyte antigen (HLA)-B27 allele, although the prevalence varies: 90% ankylosing spondylitis, 40–80% reactive arthritis, 40–50% psoriatic arthritis, 35–75% enteropathic arthritis, and 70% undifferentiated spondyloarthropathy [1, 2]. Uveitis may occur in up to 37% of spondyloarthropathy patients [1, 2] and typically manifests as bilateral asynchronous acute anterior uveitis although posterior segment manifestations including vitritis, papillitis, and cystoid macular edema may occur in 20–30% of cases [3, 4]. HLA-B27associated acute anterior uveitis (AAU) is one of the most common types of uveitis in the United States and other Western countries, accounting for approximately 30% of uveitis cases and 50–80% of anterior uveitis [2, 5–8]. Since most patients with spondyloarthropathies and uveitis are HLA-B27 positive, studies assessing the demographics, clinical course, management, complication rates, and prognosis generally make comparisons to HLA-B27-negative uveitis patients. 2. Gender Differences in Prevalence and Incidence In general, multiple studies have shown that males are more likely to develop HLA-B27-associated AAU than females with male-to-female ratios ranging from 1.1 to 2.5 to 1 [2, 3, 9– 17]. A few studies have reported higher ratios (i.e., 3.5 to 1 by Wakefield et al.) [9] Table 1 summarizes the studies reviewed in this paper. 3. Gender Differences in Clinical Manifestations Many, but not all, patients with HLA-B27-associated AAU have spondyloarthropathy at the time of uveitis diagnosis; systemic inflammatory disease can also develop after the onset of uveitis. Men are more likely to develop ankylosing spondylitis and commonly have a more severe course of disease in terms of radiographic changes [18]. Women usually have a milder course of systemic disease with less typical features such as peripheral arthritis [2]. 2 Journal of Ophthalmology Table 1: Summary of studies reporting data on gender in spondyloarthropathy and uveitis. Study Total number of patients Female (%) 40 21/40 (52.5%) 41 9/41 (22%) HLA-B27-associated AU∗ 8/18 (44%) Idiopathic HLA-B27-associated AU Wakefield et al. 1984 [9] Rothova et al. 1992 [7] Linssen and Meenken 1995 [11] 73 0/11 (0%) AU + ankylosing spondylitis 1/4 (25%) AU + seronegative arthritis 0/1 (0%) AU + IBD 35 18/35 (51%) 43/119 (36%) HLA-B27-associated AU∗ 24/40 (60%) Idiopathic HLA-B27-associated AU∗ 16/44 (36%) AU + ankylosing spondylitis∗ 8/35 (23%) AU + AS-related spondyloarthropathy∗ HLA-B27-associated AU∗ 17 21/73 (29%) † 59 /148 (40%) 14/37 (38%) AU + ankylosing spondylitis 4/22 (18%) AU + Reiters syndrome 5/9 (55.5%) AU + incomplete Reiters syndrome 1/5 (20%) AU + psoriatic arthritis and/or spondylitis 2/3 (67%) AU + IBD and/or spondylitis 4/7 (57%) AU + undifferentiated spondyloarthropathy Uveitis + IBD 14/17 (82%) 89‡ 29/89 (33%) 191 86/191 (45%) Uveitis + spondyloarthropathy HLA-B27-associated AU 52/97 (54%) AU without systemic disease 17/51 (33%) AU + ankylosing spondylitis 5/26 (19%) AU + Reiters syndrome 4/5 (80%) AU + psoriatic arthritis Power et al. 1998 [3] Paiva et al. 2000 [20] 2/5 (40%) AU + ulcerative colitis 6/7 (86%) 5/16 (31%) AU + Crohn’s disease Uveitis + psoriatic arthritis (PsA) 5/8 (62.5%) Uveitis + PsA, and peripheral arthritis 0/8 (0%) ‡ Monnet et al. 2004 [13] AU + Reiters syndrome 119 Tay-Kearney et al. 1996 [12] Queiro et al. 2002 [21] 0/7 (0%) HLA-B27-associated AU HLA-B27-negative AU 148 Lyons and Rosenbaum 1997 [19] Type of spondyloarthropathy (if any) HLA-B27-negative AU Uveitis + PsA, peripheral and/or axial arthritis 89 13 29/89 (33%) N.A.∗∗ 175 76/175 (43%) Uveitis + spondyloarthropathy Uveitis + psoriatic arthritis HLA-B27-associated AU 22/39 (56%) AU without spondyloarthropathy† 54/136 (40%) AU with spondyloarthropathy† 42/98 (43%) AU + ankylosing spondylitis or presumed AS 8/21 (38%) AU + undifferentiated spondyloarthropathy 0/2 (0%) AU + psoriatic arthritis 2/6 (33%) AU + reactive arthritis 1/5 (20%) AU + spondyloarthropathy and Behçet’s disease 1/4 (25%) AU + inflammatory bowel disease Journal of Ophthalmology 3 Table 1: Continued. Study Total number of patients Female (%) 177 81/177 (46%) Type of spondyloarthropathy (if any) HLA-B27-associated AU 15/39 (38%) AU + HLA-B27-associated systemic disease 10/30 (33%) AU + ankylosing spondylitis HLA-B27-associated AU Braakenburg et al. 2008 [14] 504 169/504 (33.5%) 47/117 (40%) Chung et al. 2009 [15] 46/214 (21.5%) AU + ankylosing spondylitis 69/150 (46%) AU + undifferentiated spondyloarthropathy 4/10 (40%) 3/11 (27%) 0/2 (0%) Loh and Acharya 2010 [17] 99 43/99 (43%) 18/44 (41%) Agnani et al. 2010 [16] 207 91/207 (44%) 55/126 (44%) 240 Zheng et al. 2012 [22] AU without spondyloarthropathy AU + psoriatic arthritis AU + reactive arthritis AU + inflammatory bowel disease HLA-B27-associated AU AU + HLA-B27-associated systemic disease AU + HLA-B27 or axial spondyloarthritis 71/240 (30%) AU + axial spondyloarthritis HLA-B27-associated AU (6 were HLA-B27 negative) 19/108 (18%) AU + ankylosing spondylitis 9/16 (56%) AU + undifferentiated spondyloarthropathy AU: anterior uveitis, IBD: inflammatory bowel disease, AS: ankylosing spondylitis, PsA: psoriatic arthritis. ∗ All patients had HLA B27-associated AU plus one of the categories indicated. † Data not available on systemic disease for all patients. ‡ Same population of patients with uveitis and spondyloarthropathy used in each study. ∗∗ Number and percentage of females cannot be determined from publication. Wakefield et al. [9] identified 41 consecutive patients with HLA-B27 and anterior uveitis at an Australian clinic; some also had posterior uveitis, panuveitis, or retinal vasculitis. The HLA-B27-positive males were more likely to have spondyloarthropathy than the B27-positive females and the B27negative patients. In a study from The Netherlands, Linssen and Meenken [11] performed a prospective study comparing 119 patients with HLA-B27-positive AAU to 35 B27-negative cases. The HLA-B27-positive AAU patients were more likely to be male. Initially, about half of the HLA-B27-positive patients also had spondyloarthropathy; after nine years, two-thirds had been diagnosed with spondyloarthropathy. Among the females without ankylosing spondylitis, there was a nonstatistically significant trend towards older age at onset of AAU. A total of 148 patients with HLA-B27-associated uveitis from two uveitis practices in Ohio and Maryland were assessed in a retrospective study by Tay-Kearney et al. [12] There was no gender difference in the onset of uveitis (acute versus insidious) or the presence of hypopyon, increased intraocular pressure, posterior synechiae, cataract, or cystoid macular edema. There was also no association between gender and the presence of systemic disease although women seemed more likely to have atypical spondyloarthropathies such as incomplete Reiters syndrome or undifferentiated spondyloarthropathy. Lyons and Rosenbaum [19] reported the characteristics of eye disease in 17 patients with uveitis and inflammatory bowel disease (IBD) from a university clinic in Oregon. In comparison to 89 uveitis patients with spondyloarthropathy, uveitis associated with IBD was more likely to occur in females 82% (𝑃 < 0.001) and less likely to be associated with HLA-B27 (𝑃 < 0.01). The inflammation was also more likely to be insidious rather than sudden onset (𝑃 < 0.001) and chronic (𝑃 < 0.001). Uveitis with IBD was often bilateral and simultaneous with a significant posterior component. Cataract and glaucoma were more commonly associated with IBD and uveitis versus spondyloarthropathyrelated uveitis. In another study from the Oregon group, Paiva et al. [20] assessed 16 patients with uveitis and psoriatic arthritis in comparison to 89 uveitis patients with spondyloarthropathy. The psoriatic arthritis patients with uveitis and only axial joint involvement were more likely to be male (8 of 8) and HLAB27 positive (6 of 6 tested) compared to those with uveitis and peripheral arthritis only. The difference between the cohorts was very small. Queiro et al. [21] conducted a retrospective study of 71 psoriatic arthritis patients in Spain and found 13 (18%) with uveitis. Among the small number of patients with uveitis, there was a slight predominance of females. Interestingly, multivariate analysis showed a significant association between psoriatic arthritis patients with uveitis and HLADR13 (𝑃 = 0.0056), bilateral sacroiliitis, and syndesmophytes. HLA-B27 was associated in a univariate analysis (𝑃 = 0.026) but did not reach statistical significance in a logistic 4 regression model. The number of uveitis cases was very small in this study as well. In an observational case series from France, Monnet et al. [13] studied the ocular and extraocular manifestations in 99 patients with HLA-B27-associated uveitis. Although the male-to-female ratio in the group of patients with spondyloarthropathy and uveitis was higher than in those without spondyloarthropathy, the difference was not statistically significant in a Chi square test (𝑃 = 0.06). Braakenburg et al. [14] investigated gender differences in HLA-B27-associated AAU through a retrospective study of 177 patients with at least one year of followup at a university practice in The Netherlands. The male-to-female ratio was 1.1 : 1. There was no difference between males and females in terms of average age at onset of uveitis; however, the onset of systemic HLA-B27-associated systemic disease occurred earlier in men than in women (30 versus 37 years; 𝑃 = 0.021) and men were more likely to develop ankylosing spondylitis. Men were also more likely to develop systemic disease prior to the onset of uveitis whereas systemic disease in women was often diagnosed after uveitis. Over time, the gender differences in risk of systemic HLA-B27-associated disease diminished as more patients were diagnosed. A retrospective study of 504 Chinese/Taiwanese patients with HLA-B27 uveitis was conducted by Chung et al. with longitudinal followup over 18 years [15]. In this cohort, males were significantly older than females at the onset of uveitis (𝑃 = 0.004). 76.8% of patients had spondyloarthropathy; among these patients, ankylosing spondylitis occurred more frequently in males (50.1% versus 27.2%, 𝑃 < 0.001) whereas undifferentiated spondyloarthropathy was more common in females (40.8% versus 24.2%, 𝑃 < 0.001). Uveitis without spondyloarthropathy showed no predilection for gender. In a California study, Loh and Acharya [17] found that HLA-B27-associated systemic diseases were slightly more common in men (46%) than in women (41%) with acute and chronic HLA-B27-associated uveitis although the difference was not statistically significant. Finally, Zheng et al. [22] studied 240 Chinese patients with HLA-B27-associated AAU. The mean age of onset was younger in the male patients (36.0 versus 39.5, 𝑃 < 0.05). Male patients were also more likely to have concomitant spondyloarthropathy, especially ankylosing spondylitis. In summary, HLA-B27-associated uveitis patients are more likely to be male and to have systemic inflammatory disease, in particular ankylosing spondylitis. Male patients also tend to be younger at the onset of uveitis. Women might be more prone to atypical or undifferentiated spondyloarthropathies. These gender differences may lessen as time elapses from initial uveitis presentation, since male patients seem to be more likely to have systemic disease prior to the onset of uveitis, but, as more female patients develop systemic manifestations after uveitis onset, the ratio becomes nearly equal. Small studies of uveitis patients with psoriatic arthritis and IBD show trends towards a female predominance, uveitis onset more insidious than typical HLAB27-associated AAU, less association with HLA-B27, and atypical spondyloarthropathy. The different and sometimes conflicting conclusions may be due to variable cohort sizes, Journal of Ophthalmology different methods of diagnosing spondyloarthropathies, and the inclusion or exclusion of chronic uveitis. 4. Gender Differences in Treatment and Prognosis Some studies have suggested that HLA-B27-associated uveitis has a poorer prognosis than HLA-B27-negative uveitis [3, 10]. Power et al. [3] studied 191 consecutive HLA-B27-positive uveitis patients with and without systemic inflammatory disease and compared them to 72 patients with idiopathic HLA-B27-negative uveitis. The HLA-B27-associated uveitis patients had significantly higher mean recurrence rates and more complications such as cystoid macular edema, extensive and persistent posterior synechiae, secondary glaucoma, vitritis, and papillitis. Not unexpectedly, these patients required more periocular and systemic corticosteroids as well as surgical interventions. Finally, there was a higher rate of legally blind eyes among the HLA-B27-positive uveitis cases. In contrast, other studies have shown a higher rate of complications in HLA-B27-negative uveitis plus more recalcitrant inflammation [11, 23]. Differences between the genders in terms of prognosis and treatment of HLA-B27-associated uveitis are even less well defined. Wakefield et al. [9] found that uveitis in HLA-B27positive males with spondyloarthropathy occurred at a younger age but with fewer recurrences compared to the B27positive females without associated rheumatologic disease. The statistical significance of this data was not stated, and the number of patients in each group was small (HLA-B27 and associated rheumatologic disease: 22 males, 1 female. HLAB27 and no associated rheumatologic disease: 10 males and 8 females). Monnet et al. [13] observed no significant gender differences in rates of hypopyon, posterior synechiae, cataract, intraocular pressure, papillitis, cystoid macular edema, final visual acuity, or treatments. Family history of spondyloarthropathy with or without uveitis and extraocular symptoms were also similar between the genders. Uy et al. [24] also found no relationship between gender and the risk of cystoid macular edema. Braakenburg et al. [14] determined that the average number of attacks of AAU per year was not affected by gender although women did require longer topical treatment of active episodes. Over time there was a nonsignificant trend towards more attacks in women. Bilateral involvement occurred more frequently in women, although there were no gender differences in the rates of developing chronic uveitis or attacks longer than six months. Clinical manifestations or complications of inflammation such as posterior synechia, anterior chamber fibrin, hypopyon, vitritis, and cystoid macular edema were equally likely in men and women. Occlusive retinal vasculitis did occur more frequently in men (8% versus zero, 𝑃 = 0.39), three of whom had HLA-B27-associated systemic disease, but not inflammatory bowel disease or Behçet’s disease. There was no difference in the rates of secondary glaucoma, cataract, vision loss, and surgical interventions. In terms of treatment, periocular Journal of Ophthalmology steroids, systemic steroids, and nonsteroid systemic immunosuppressants were used equally in male and female patients. Chung et al. [15] found no gender difference in the mean number of recurrent attacks of AAU in a cohort of Taiwanese patients; however, the frequency of attacks was significantly higher among women (80/100 patient-years versus 68, 𝑃 = 0.002). In the first five years after the initial attack, there was no difference in the frequency of attacks. More than five years afterward, a higher rate of recurrence occurred in female patients (52/100 patient-years versus 39, 𝑃 = 0.008). In a retrospective study Agnani et al. [16] identified 207 patients with acute anterior uveitis who were HLA-B27 positive or who had a diagnosis with axial spondyloarthritis. The probability of recurrence within a year was similar between men and women by Kaplan-Meier estimates. Univariate analysis with a Cox proportional hazards model showed that male gender was significantly associated with a shorter time interval between attacks of recurrent anterior uveitis. Loh and Acharya [17] performed a retrospective chart review of 99 HLA-B27-associated uveitis patients. They found no statistically significant gender difference in the rate of developing chronic uveitis versus recurrent disease. Male gender was a risk factor for vision loss (20/50 or worse on a single visit) in a backward stepwise multivariate regression. In summary, although males are probably more likely to develop HLA-B27-associated uveitis at a younger age, females may have more frequent recurrences of inflammation and may require longer topical treatment. In contrast, some studies found that males might be more prone to recurrent attacks of inflammation. One study found that male gender is a risk factor for single visit vision loss of 20/50 or worse, and another found that males were more likely to have occlusive vasculitis. Otherwise, there appeared to be no gender differences in the risks of hypopyon, vitritis, papillitis, cataract, cystoid macular edema, intraocular pressure, secondary glaucoma, or final visual acuity. There were also no significant differences in types of treatments. 5. Possible Explanations for the Gender Differences It is difficult to determine the precise mechanism(s) for these differences as few studies have been specifically designed to investigate gender, and the available studies are not in consensus. Since HLA-B27 molecules are major histocompatibility complex class I gene products which interact with T cells, in particular CD8+ T cells, it is conceivable that gender-related differences in immune response could play a role in the different manifestations of HLA-B27-associated uveitis. However, not all spondyloarthropathy patients with uveitis are positive for HLA-B27, so it seems likely that other factors are also important. Variable environmental exposures, either endogenous (i.e., sex hormone milieu) or exogenous (tendency towards exposure to infectious agents through lifestyle or different susceptibilities), might be expected to play roles as well. None of the studies collected data on pregnancy and its relationship to uveitis onset of recurrence in spondyloarthropathy patients. It is possible that hormonal 5 fluctuations during and after the reproductive years play a role in gender differences as well. Again, these questions have not been investigated in the context of spondyloarthropathy and uveitis. 6. Conclusion Few studies have investigated gender and spondyloarthropathy-associated uveitis. It is not surprising that males and females have different clinical characteristics, although we do not have much information to explain these differences or evaluate their importance. We do know that males are generally more likely to develop spondyloarthropathy and associated uveitis, probably at a younger age. Females who develop uveitis may have less classic HLA-B27-associated uveitis (i.e., insidious rather than abrupt onset) as well as atypical spondyloarthropathies (perhaps because “typical” was initially defined in male patients). Females also might be more likely to have frequent attacks of recurrent inflammation which require longer treatment. Fortunately, despite these clinical differences the rate of complications and vision loss seems to be unaffected. As we strive to develop a concept individualized medicine for uveitis patients, a better understanding of gender differences in clinical presentation, prognosis, and response to treatment may help us to provide better care and to prevent vision loss. Conflict of Interests The author declares that there is no conflict of interests regarding the publication of this paper. References [1] E. B. Suhler, T. M. Martin, and J. T. Rosenbaum, “HLA-B27associated uveitis: overview and current perspectives,” Current Opinion in Ophthalmology, vol. 14, no. 6, pp. 378–383, 2003. [2] J. H. Chang, P. J. McCluskey, and D. Wakefield, “Acute anterior uveitis and HLA-B27,” Survey of Ophthalmology, vol. 50, no. 4, pp. 364–388, 2005. [3] W. J. Power, A. Rodriguez, M. Pedroza-Seres, and C. S. Foster, “Outcomes in anterior uveitis associated with the HLA-B27 haplotype,” Ophthalmology, vol. 105, no. 9, pp. 1646–1651, 1998. [4] E. M. Dodds, C. Y. Lowder, and D. M. Meisler, “Posterior segment inflammation in HLA-B27+ acute anterior uveitis: clinical characteristics,” Ocular Immunology and Inflammation, vol. 7, no. 2, pp. 85–92, 1999. [5] C. A. McCannel, G. N. Holland, C. J. Helm et al., “Causes of uveitis in the general practice of ophthalmology,” American Journal of Ophthalmology, vol. 121, no. 1, pp. 35–46, 1996. [6] A. Rodriguez, M. Calonge, M. Pedroza-Seres et al., “Referral patterns of uveitis in a tertiary eye care center,” Archives of Ophthalmology, vol. 114, no. 5, pp. 593–599, 1996. [7] A. Rothova, H. J. Buitenhuis, C. Meenken et al., “Uveitis and systemic disease,” British Journal of Ophthalmology, vol. 76, no. 3, pp. 137–141, 1992. [8] V. T. Tran, C. Auer, Y. Guez-Crosier, N. Pittet, and C. P. Herbort, “Epidemiology of uveitis in Switzerland,” Ocular Immunology and Inflammation, vol. 2, no. 3, pp. 169–176, 1994. 6 [9] D. Wakefield, J. Easter, and R. Penny, “Clinical features of HLAB27 anterior uveitis,” Australian Journal of Ophthalmology, vol. 12, no. 1, pp. 191–196, 1984. [10] A. Rothova, W. G. van Veenendaal, and A. Linssen, “Clinical features of acute anterior uveitis,” American Journal of Ophthalmology, vol. 103, no. 2, pp. 137–145, 1987. [11] A. Linssen and C. Meenken, “Outcomes of HLA-B27-positive and HLA-B27-negative acute anterior uveitis,” American Journal of Ophthalmology, vol. 120, no. 3, pp. 351–361, 1995. [12] M.-L. Tay-Kearney, B. L. Schwam, C. Lowder et al., “Clinical features and associated systemic diseases of HLA-B27 uveitis,” American Journal of Ophthalmology, vol. 121, no. 1, pp. 47–56, 1996. [13] D. Monnet, M. Breban, C. Hudry, M. Dougados, and A. P. Brézin, “Ophthalmic findings and frequency of extraocular manifestations in patients with HLA-B27 uveitis: a study of 175 cases,” Ophthalmology, vol. 111, no. 4, pp. 802–809, 2004. [14] A. M. D. Braakenburg, H. W. de Valk, J. de Boer, and A. Rothova, “Human leukocyte antigen-B27-associated uveitis: long-term follow-up and gender differences,” American Journal of Ophthalmology, vol. 145, no. 3, pp. 472–479, 2008. [15] Y.-M. Chung, H.-T. Liao, K.-C. Lin et al., “Prevalence of spondyloarthritis in 504 Chinese patients with HLA-B27-associated acute anterior uveitis,” Scandinavian Journal of Rheumatology, vol. 38, no. 2, pp. 84–90, 2009. [16] S. Agnani, D. Choi, T. M. Martin et al., “Gender and laterality affect recurrences of acute anterior uveitis,” British Journal of Ophthalmology, vol. 94, no. 12, pp. 1643–1647, 2010. [17] A. R. Loh and N. R. Acharya, “Incidence rates and risk factors for ocular complications and vision loss in HLA-B27-associated uveitis,” American Journal of Ophthalmology, vol. 150, no. 4, pp. 534.e2–542.e2, 2010. [18] W. Lee, J. D. Reveille, J. C. Davis Jr., T. J. Learch, M. M. Ward, and M. H. Weisman, “Are there gender differences in severity of ankylosing spondylitis? Results from the PSOAS cohort,” Annals of the Rheumatic Diseases, vol. 66, no. 5, pp. 633–638, 2007. [19] J. L. Lyons and J. T. Rosenbaum, “Uveitis associated with inflammatory bowel disease compared with uveitis associated with spondyloarthropathy,” Archives of Ophthalmology, vol. 115, no. 1, pp. 61–64, 1997. [20] E. S. Paiva, D. C. Macaluso, A. Edwards, and J. T. Rosenbaum, “Characterisation of uveitis in patients with psoriatic arthritis,” Annals of the Rheumatic Diseases, vol. 59, no. 1, pp. 67–70, 2000. [21] R. Queiro, J. C. Torre, J. Belzunegui et al., “Clinical features and predictive factors in psoriatic arthritis-related uveitis,” Seminars in Arthritis and Rheumatism, vol. 31, no. 4, pp. 264–270, 2002. [22] M. Q. Zheng, Y. Q. Wang, X. Y. Lu et al., “Clinical analysis of 240 patients with HLA-B27 associated acute anterior uveitis,” Yan Ke Xue Bao, vol. 27, no. 4, pp. 169–172, 2012. [23] S. Tuncer, Y. S. Adam, M. Urgancioglu, and I. Tugal-Tutkun, “Clinical features and outcomes of HLA-B27-positive and HLAB27-negative acute anterior uveitis in a Turkish patient population,” Ocular Immunology and Inflammation, vol. 13, no. 5, pp. 367–373, 2005. [24] H. S. Uy, W. G. Christen, and C. S. Foster, “HLA-B27-associated uveitis and cystoid macular edema,” Ocular Immunology and Inflammation, vol. 9, no. 3, pp. 177–183, 2001. Journal of Ophthalmology