Leishmaniasis and Biologic Therapies for

ARTICLE IN PRESS
Leishmaniasis and Biologic Therapies for Rheumatologic Diseases
I
n his article in Seminars in Arthritis and Rheumatism,
Furst (1) provides an accurate analysis of the infections that are related to the use of biologic therapies
for rheumatoid arthritis. We would like to add Leishmania spp to the list of the infectious agents that can cause
disease during the course of biologic therapies.
Eight cases of leishmaniasis have been diagnosed during biologic therapies for rheumatoid arthritis or other
There was no financial support for this research.
The authors have no conflicts of interest to declose.
Address reprint requests to: Antonio Cascio, MD, PhD, UO Medicina Tropicale e
Parassitologia, Policlinico “G. Martino”, Via Consolare Valeria n. 1, 98125 Messina,
Italia. E-mail: [email protected].
rheumatologic diseases (Table 1) (2-9). We found the
above cases through a MEDLINE search of the international literature combining the terms (leishmaniasis OR
leishmania) AND (antitumor necrosis factor OR infliximab OR adalimumab OR rituximab OR alemtuzumab
OR etanercept OR efalizumab OR IL-1RA agonist).
Leishmaniases is a group of parasitic diseases encompassing cutaneous, mucocutaneous, and visceral manifestations caused by obligate intracellular protozoa of the
genus Leishmania (10). In endemic countries, the number
of asymptomatic visceral leishmaniasis (VL) infections is
greater than the number of clinically apparent VL disease
cases, and among immunocompetent people it is estimated
that only 1 in every 5 or 10 develops clinically overt VL (11).
Table 1 Clinical characteristics, therapy,* and outcome of rheumatologic patients receiving biologic drugs and suffering
from Leishmaniasis
Author, yr, country
(ref)
Age/sex
Disease
Biological drug (dose)
and duration
Immunosuppressive
agents associated
with biological drug
Previous
immunosuppressive
agents
Romaní-Costa et al.
2004 Spain (2)
55/M
Psoriatic arthritis Infliximab (3 mg/kg)
9 mo
NR
NR for 300 mo
Fabre et al. 2005
France (3)
53/F
Rheumatoid
arthritis
Infliximab (3 mg/kg)
9 mo
Steroids, azathioprine NR
(100 mg/d)
Bassetti et al. 2006
Italy (5)
69/F
Rheumatoid
arthritis
Bagalas et al. 2006
Greece (4)
60/F
Rheumatoid
arthritis
Adalimumab (40 mg
MTX (7.5 mg weekly)
every other week)
and prednisone (5
25 mo
mg/d) 360 mo
Etanercept for 18 mo-24 NR
mo before VL;
Anakinra, for 2 to 3
weeks 6 mo before VL
Koné-Paut et al.
2007 France (6)
9/F
Tektonidou and
Skopouli 2008
Greece (7)
Balato et al. 2008
Italy (9)
45/M
Garcia-Vidal et al.
2009 Spain (8)
NR
Steroids and
cyclosporine for
7 yr
NR
Etanercept (to cure an
episode of MAS), then
anakinra (1 mg/kg/d)
6 mo
Psoriatic arthritis Infliximab (3 and then 5 MTX, prednisolone
mg/kg) 3 yr
for 3 yr
Steroids, MTX,
cyclosporine.
42/M
Psoriasis
Efalizumab (1 mg/kg/
wk) 3 mo
NR
Cyclosporine for 1 mo
55/M
Rheumatoid
arthritis
Infliximab (Tot 40 mg/
kg) 11 mo
MTX, steroids
MTX, steroids,
azathioprine,
cyclosporine for
10 yr
Systemic
juvenile
arthritis
NR
F, female; IFAT, immunofluorescent antibody test; L-amB, liposomal amphotericin B; M, male; MAS, macrophage activation syndrome;
MTX, methotrexate; Neg, negative; ND, not done; NR, not reported; PCR, polymerase chain reaction; Pos, positive; VL, visceral
leishmaniasis.
*Dosage of the drugs and duration of therapy are reported in those cases in which this information was noted in the original paper.
0049-0172/09/$-see front matter © 2009 Published by Elseiver Inc.
doi:10.1016/j.semarthrit.2009.07.001
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2
7 cases. Culture of bone marrow was positive in 2 cases.
Polymerase chain reaction on peripheral blood samples
and/or bone marrow blood sample was positive in all 4
patients in which the test was performed. Of note, in the
cases in which both serology and bone marrow microscopy were negative, laboratory diagnosis was made by
polymerase chain reaction (7) or by a positive culture (6).
In all patients biologic drugs were stopped when VL
was diagnosed, and only in 1 case was it reintroduced after
VL was cured (3). VL was treated with a single cycle of
liposomal amphotericin B in 4 cases, of meglumine antimoniate in 2 cases, and of amphotericin B deoxycholate in
1 case. In 1 case antileishmania therapy was not administered; nevertheless the patient was cured (9). All but 1
patient recovered from VL; that patient died from pneumonia and other opportunistic infection (4).
Considering the concomitant long-term use of other
immunosuppressants, it is not possible to determine the
Malnutrition and immunosuppression may reactivate latent
Leishmania infection and, among human immunodeficiency virus/acquired immunodeficiency syndrome infected
patients, the risk of clinical VL is increased 100 to 1000 times
(12). Transplant patients living or traveling to areas where
the disease is endemic are also at risk (13). Leishmaniasis is a
granulomatosis disease and granulomas represent the tissue
expression of the successful T-cell-dependent immune response (14). Analysis of the retrieved cases showed that the
median duration of biologic drug treatment was 11 months
(range, 3-36 months).
All 8 patients suffered from VL, and in 6 of them VL
presented with the classical symptoms: fever, splenomegaly, and pancytopenia. In 1 case splenomegaly was not
present (5); in another case leukocytosis instead of leukopenia was reported (6). Serology was positive in 4 of 5 in
which this information was available. The search of leishmania amastigotes in bone marrow smears was positive in
LV symptoms
Amastigotes in bone
marrow smears
Letter to the Editor
IFAT
PCR
Therapy
Outcome
Fever, asthenia,
hepatosplenomegaly,
pancytopenia
Fever, splenomegaly, and
pancytopenia. Inflammatory
markers increased
Pos
ND
ND
Meglumine antimoniate
(840 mg/d for 28 d)
Cure
Neg; Pos a 2nd bone
marrow aspirate
1:5120
Pos
Cure—The patient was
then treated for 1 yr
with etanercept
Fluctuant fever with several
peaks at 39°C, pancytopenia
Pos
1/160
Pos
Temperature up to 39.5°C
every 3 to 4 days,
pancytopenia, splenomegaly
Pos
Pos
ND
Fever, scarlet fever-like pruritic
rash and
hepatosplenomegaly,
anemia, thrombocytopenia
High-grade fever,
splenomegaly, acute reactive
proteins, pancytopenia
Intermittent fever,
hepatosplenomegaly,
pancytopenia
NR
Neg
NR
ND
Amphotericin B (0.7
mg/kg/d for 15 days,
then 0.7 mg/kg every
15 d)
L-amB (3 mg/kg/d for
5 d, and 3 mg/kg on
d 10).
L-amB (4 mg kg/d,
then, due to acute
renal failure, 1 mg
kg/d, which was
gradually increased)
L-amB steroids to cover
the risk of MAS
Neg
Neg
Pos
Cure
Pos
1:640
Pos
L-amB (3 mg/kg/d for
5 d, and 3 mg/kg on
d 20)
No anti-leishmania
drugs were given
Pos
NR
ND
Meglumine antimoniate
Cure
Cure—MTX was
started again after
30 d
Death due to severe
pulmonary infection
Cure
Cure
A. Cascio, M. Iaria, and C. Iaria
ARTICLE IN PRESS
role played by biologic drugs in the development of leishmaniasis. Indeed, there are at least 7 cases of leishmaniasis
that occurred in patients with rheumatoid arthritis or
other rheumatologic diseases who were treated with classical immunosuppressive drugs (15-21).
Although pancytopenia or thrombocytopenia may be
due to lupus or rheumatoid arthritis, dysplasia and lymphoma, or side effects of methotrexate or other drugs, the
association of fever, asthenia, splenomegaly, and pancytopenia should prompt the search for VL in patients living
in endemic leishmaniasis areas and treated with biologic
therapies (3).
In immunocompromised patients, atypical forms of
VL (for example, without splenomegaly or fever or with
negative serology or with leukocytosis) may occur or mucocutaneous disease may develop in geographic regions
where the typical mucocutaneous leishmaniasis is not endemic.
Antonio Cascio, MD, PhD
Tropical and Parasitological Diseases Unit
Department of Human Pathology
University of Messina
Messina, Italy
Maurizio Iaria, MD
Division of General Surgery
Department of Human Pathology
University of Messina
Messina, Italy
Chiara Iaria, MD
Department of Infectious and Tropical Diseases
“La Sapienza” University
Rome, Italy
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