Rheumatology Advance Access originally published online on August 3, 2006
Rheumatology 2006 45(11):1446-1448; doi:10.1093/rheumatology/kel235
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Visceral leishmaniasis infection in a rheumatoid arthritis patient treated with adalimumab
1Division of Infectious Diseases, S. Martino Hospital and University of Genoa School of Medicine, 2Research Laboratory, Division of Rheumatology, Department of Internal Medicine, University of Genoa and 3Department of Infectious, Parasitic and Immunomediated Diseases, Istituto Superiore di Sanità, Rome, Italy
Correspondence to: Matteo Bassetti, MD, PhD, Clinica Malattie Infettive Azienda Ospedaliera Universitaria San Martino di Genova, Largo R.Benzi 10, 16132 Genova, Italy. E-mail: mattba{at}tin.it; matteo.bassetti{at}hsanmartino.it
SIR, Anti-tumour necrosis factor-
(TNF-)-based therapies represent an important innovation in rheumatoid arthritis (RA) treatment, demonstrating efficacy in reducing disease activity and in retarding radiographic progression. Three different TNF- blockers have been approved for the treatment of these conditions: infliximab, adalimumab and etanercept. TNF- is essential for granuloma formation and maintenance, which are key components of host defences against intracellular pathogens [1]. The clinical use of TNF- blockers has been associated with an increased risk of reactivation of granulomatous infectious diseases [2]. Visceral leishmaniasis (VL) is a disseminated protozoan infection caused by Leishmania donovani and Leishmania infantum. The acute form of the disease is almost 100% fatal if left untreated. In endemic areas, any individual showing fever, hepatosplenomegaly, pancytopenia and hypergammaglobulinaemia should be suspected for VL. Standard diagnosis includes parasite demonstration in bone marrow or splenic aspirate smears, and/or the detection of significant levels of antileishmanial antibodies by serological techniques [3]. In experimental VL, TNF- plays an important role in cytokine-induced macrophage activation and tissue granuloma formation, two activities linked to control of intracellular infection caused by L. donovani [4]. VL is an extremely rare event in RA patients treated with TNF- antagonists, and only two cases, both under infliximab treatment, have been described [5, 6]. Here, we report a case of a 69-yr-old Caucasian woman living in Genoa area (northwest Italy), who was diagnosed as affected by RA in 1976 and from that time was treated for long time with methotrexate (MTX) (7.5 mg weekly) and corticosteroids (5 mg prednisone daily). Since the patient was poorly responsive to the combination of MTX and prednisone, it was decided to introduce the anti-TNF- treatment (adalimumab—40 mg every other week). At that time, all diagnostic tests for latent tuberculosis were negative. However, after 25 months of consecutive combination therapy with adalimumab, the patient showed intermittent daily fever (maximum 38.5°C) for a week and severe asthenia. Adalimumab and methotrexate administration were promptly stopped. Laboratory test analysis showed a C-reactive protein of 240 mg/l, an erythrocyte sedimentation rate of 100 and a pancytopenia [haemoglobin: 10 g/dl, white blood cells (WBCs): 2900 and platelets: 72 000]. During hospitalization she presented a fluctuant fever with several peaks at 39°C. Physical examination did not reveal splenomegaly or hepatomegaly. A computed tomography (CT) scan and 99mTc-HMPAO WBC scintigraphy did not reveal any infection localization. A bone marrow examination (smear and core biopsy) revealed a non-specific reactive lympho-plasmacellular infiltration with no myelodisplasia. Finally, the examination of Giemsa-stained smears from a second bone marrow aspirate detected Leishmania parasites (Fig. 1), and indirect fluorescent antibody test (IFAT) serology tested positive at the titre of 1/160 (cut-off: 1/80). A polymerase chain reaction (PCR) for the amplification of Leishmania genomic sequences in peripheral blood confirmed the diagnosis. Three patient's serum samples stored in 2002 (2) and in 2003 (1) were available for serodiagnosis, and all tested negative at IFAT. The patient was treated intravenously with liposomal amphotericin B for a total dose of 18 mg/kg (3 mg/kg per day for 5 days, followed by 3 mg/kg on day 10). She did not develop any adverse events and 15 days after the treatment, the Leishmania PCR on blood no longer revealed parasites. The treatment with MTX was started again at the previous dosage 30 days after adalimumab and MTX were stopped. Treatment with prednisone was stable during this time. Six months after adalimumab was stopped, the patient is clinically stable and the laboratory/imaging tests did not reveal RA progression. Currently, no further clinical or biological symptoms of leishmaniasis were detected.
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To our knowledge, this is the first case of VL reported in a patient treated with adalimumab. This confirms the risk of opportunistic infections and the difficulties of diagnosis in patients treated with anti-TNF-
blockers (i.e. monoclonal antibodies). Of course, this patient received several immunosuppressive drugs during the course of her disease and, taken together, might have played a predisposing role to the infection. With appropriate treatment VL was controlled [7]. Spleen and/or liver enlargement is commonly seen in adults, being reported in 70–100% of VL cases including those with HIV co-infection and during infliximab therapy [5, 6, 8, 9]. The clinical picture of our VL case was characterized by fever, asthenia and pancytopenia, but there was no hepato- or splenomegaly. This case raises the issue of a possible atypical presentation in patients treated with adalimumab, probably due to the lack of an effective inflammatory response. The patient was living in Liguria, northwest Italy, which has long been known to be endemic for VL [10]. As widely known, patients undergoing therapy with anti-TNF- monoclonal antibodies should be screened for a history of tuberculosis, both anamnestically and with a tuberculin test, and positive cases should be treated pre-emptively. The same cannot be recommended for VL because of the low incidence rate of this disease, although the possibility of VL should always be taken into account, at least for patients living in endemic areas. The authors have declared no conflicts of interest.
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