Annals of Clinical & Laboratory Science 39:192-195 (2009)
© 2009 Association of Clinical Scientists
Anti-Tumor Necrosis Factor-alpha Therapy Provokes Latent Leishmaniasis in a Patient with Rheumatoid Arthritis
Gillian Franklin1,
Joel Greenspan2 and
Sheng Chen1
1 Departments of Pathology and 2 Medicine, Long Island Jewish Medical Center, The Long Island Campus of Albert Einstein College of Medicine, New Hyde Park, New York
Address correspondence to Sheng Chen, M.D., Ph.D., Department of Pathology, Long Island Jewish Medical Center, 270-05 76th Avenue, New Hyde Park, NY 11040, USA; tel 718 470 7490; fax 718 347 9171; e-mail schen{at}nshs.edu.
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Abstract
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It has been reported that anti-tumor necrosis factor-
therapy increases the risk of opportunistic infections including rare case reports of leishmaniasis. Here we report a case of latent cutaneous leishmaniasis, which was provoked by anti-tumor necrosis factor- therapy in a patient with rheumatoid arthritis.
Keywords: anti-TNF- monoclonal antibody, adalimumab, leishmaniasis, rheumatoid arthritis
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Introduction
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Leishmania encompasses a group of ubiquitous protozoa that are obligate intramacrophage mammalian parasitic organisms, the causative agents of leishmaniasis [1]. This infection can be localized to the skin (cutaneous leishmaniasis, CL) and mucous membranes (mucosal leishmaniasis, ML), or disseminated in the reticuloendothelial system (visceral leishmaniasis). Transmission of the disease to humans, the incidental hosts, occurs usually on exposed skin through the bite of a female sandfly infected with Leishmania parasites [2,3]. Small mammals are the usual reservoir in endemic urban cases.
CL is endemic in >80 countries, presenting a serious public problem in many tropical and subtropical parts of the world [4,5]. There are >200 million people at risk with an annual incidence rate of approximately 1–1.5 million [4]. In the New World, CL is seen from southern Texas to northern Argentina. Old World endemic areas include India, East Africa, and the Middle East. In the USA, infection rates are highest among immigrants.
Many individuals with CL are asymptomatic or manifest mild, nonspecific symptoms. CL may remain a dormant infection, but activation of latent infection can be disfiguring in immunocompromised patients. Here we report a case of latent CL provoked by anti-tumor necrosis factor-alpha (TNF- ) monoclonal antibody therapy in a patient with rheumatoid arthritis (RA).
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Case Report
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A 42-yr-old woman with a history of RA, treated with adalimumab (an anti-TNF- monoclonal antibody) in September 2004, presented in December 2004 with a small, red, itchy area, which she first noted in November 2004, on the right side of her nose after plucking a nasal hair. The area was cultured and grew methicillin-resistant Staphylococcus aureus. The patient was treated with antibiotics, but showed no improvement. From 2004 to 2007, despite visits to several physicians and multiple biopsies, the nasal lesion progressed to a well-defined, 4.0 x 2.5 cm ulcer, with a raised erythematous border and a central zone of granulation tissue (Fig. 1
).
The clinical differential diagnosis included nares abscess with sinusitis, staphylococcal folliculitis, sarcoidosis, lupus erythematosus, mycobacterial infection, lethal midline granuloma, rhinoscleroma, leishmaniasis, pyoderma gangrenosum, and fungal infection. The histopathological differential diagnosis on biopsies reported by outside laboratories included perifolliculitis, interstitial dermatitis, suppurative granulomatous dermatitis, sarcoidosis, T-cell lymphoma, and lupus erythematosus.
The patient was a Brazilian who had immigrated to the USA in 1999 and had visited the Mediterranean coast of Spain and Italy 11 and 4 mo, respectively, after the initial appearance of the nasal lesion. She had been treated for 4 yr with low-dose prednisone, non-steroidal anti-inflammatory agents, and methotrexate therapy for RA. The correct diagnosis of cutaneous leishmaniasis was made in June 2007 following another biopsy, which revealed numerous Leishmania amastigotes within macrophages. The dot-like amastigotes were visible in histiocytes on both H&E- and Giemsa-stained tissue sections (Fig. 2). PAS and AFB stains were negative for fungal organisms and mycobacteria.
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Fig. 2. Intracellular amastigotes of Leishmania in biopsy of the nasal lesion. The left panel (a) shows clusters of amastigotes (blue ovals) stained with H&E, x1000; the right panel (b) shows a cluster of amastigotes (red oval) with Giemsa’s stain, x1000.
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An indirect immunofluorescence assay on serum (performed by the Centers for Disease Control and Prevention, Atlanta, GA) revealed a titer of 1:16 IgG antibody for the Leishmania donovani complex. Subsequent culture studies and DNA amplification by PCR with species typing identified the organisms as Leishmania chagasi. Following treatment with liposomal amphotericin B, the patient’s nasal lesion resolved, leaving an atrophic scar (Fig. 3).
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Discussion
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It is well documented in the literature that patients treated with anti-TNF- agents have increased risk for opportunistic infections [6–9]. The 3 FDA-approved TNF- antagonists used to treat inflammatory diseases such as RA are entanercept, infliximab, and adalimumab [10]. Various opportunistic infections such as Pneumocystis jiroveci (carinii) pneumonia and tuberculosis have been reported in patients treated with TNF- antagonists [11]. Of the 3 forms of leishmaniasis, the visceral type has been primarily reported in RA patients using entanercept [12] and infliximab [11,13,14]. VL has been reported in RA patients on the TNF- antagonist adalimumab [15], but, to our knowledge, CL has not been reported in RA patients treated with adalimumab.
TNF- antagonists used clinically have been associated with increased susceptibility to reactivation of granulomatous infectious diseases [16]. TNF- has been implicated in cytokine-induced macrophage activation and tissue granuloma formation and maintenance, the key components of host defense against intracellular pathogens [17]. Our patient was treated with adalimumab, a fully humanized monoclonal antibody specific for TNF- which neutralizes both extracellular and membrane forms of TNF- a cytokine with a key role in the pathophysiology of RA [18].
In endemic areas, patients with CL or mucocutaneous leishmaniasis usually present with a small red, itchy area at the site of the bite, which becomes ulcerated. There is usually no associated fever, chills, anorexia, weight loss, or discharge. There may be pain at the site. The lesions develop into disfiguring sores and gaping holes involving the nasal septum, soft palate, nasal cavity, and oral cavity.
Since Leishmania chagasi is endemic only in the New World, we believe that our patient contracted her disease in Brazil before she immigrated to the USA in 1999, and that her infection remained latent until 2004. Furthermore, this case of CL occurred 2 to 3 mo after the patient started anti- TNF- therapy for RA. TNF- is an intermediate agent in host protection against CL [19,20]. We believe that this is an example of CL that was incited from latency by anti-TNF- therapy with adalimumab. The patient was also treated with other immunosuppressive medications during the course of her RA and they may have helped to reactivate her infection.
To the best of our knowledge, this is the first reported case of CL reported in a RA patient treated with the TNF- antagonist, adalimumab.
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Acknowledgments
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We thank Dr. John Garofalo for providing one of the photographs (Fig. 1
) and Francis J. Steurer, M.S., for providing the serology information.
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References
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Abstract
Introduction
