Gender and Uveitis - Hindawi Publishing Corporation

Commenti

Transcript

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

Documenti analoghi