Rheumatology Advance Access originally published online on March 12, 2008
Rheumatology 2008 47(5):737-738; doi:10.1093/rheumatology/ken072
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Visceral leishmaniasis mimicking disease activity in mixed connective tissue disease
Musculoskeletal Unit, Department of Rheumatology, Freeman Hospital, Newcastle Upon Tyne, UK.
Correspondence to: A. Lorenzi, Musculoskeletal Unit, Department of Rheumatology, Freeman Hospital, Freeman Road, Newcastle Upon Tyne, Tyne and Wear NE7 7DN, UK. E-mail: a.r.lorenzi{at}ncl.ac.uk
SIR, We present the case of a patient well-known to our department with a firmly established diagnosis of MCTD, who became progressively unwell from a cause we did not suspect, which mimicked the established pattern of her disease flares.
A 23-yr-old female presented in 1996 with lymphadenopathy, polyarthralgia, myalgia and RPs. MCTD was diagnosed on the basis of positive ANA (1 : 1024), RNP antibody and a raised IgG (19.4 g/l). HCQ was started, but by 1998 an erosive arthritis had developed and MTX was added. She remained well for 5 yrs with occasional episodes of mild neutropenia attributed to MCTD activity. In 2004, she spent a week on holiday in Greece and remained well other than a single, slowly healing ‘mosquito bite’. Later that year, she wanted to conceive and MTX was stopped. She remained well for 8 months but was then admitted, 8 weeks pregnant, with high fever, pleuritic pain and breathlessness. Pleural and pericardial effusions were present but there was no lymphadenopathy or hepatosplenomegaly. Investigations were unremarkable other than an elevated CRP. Two days later she spontaneously miscarried. Her symptoms resolved on 60 mg oral prednisolone and MTX was successfully reintroduced as the steroid dose was tapered.
In 2006, our patient independently stopped MTX. Four months later, dyspnoea, cough arthralgia and a high, swinging fever (40°C) recurred. Splenomegaly had developed. Despite prednisolone (30–60 mg) and restarting MTX at her previous dose she remained unwell. AZA was introduced, but later stopped due to leucopenia (despite normal thiopurine methyl transferase levels). In March 2007, she was admitted with persistent symptoms and with a marked pancytopenia (haemoglobin 5.5 g/dl, neutrophils <0.1 x 109/l, CD4+ 69 cells/µl, CD8+ 163 cells/µl and platelets 40 x 109/l). Serial blood and urine cultures were negative as was viral serology (EBV, CMV, parvovirus B19, HIV I & II, Hep-B and -C). The auto antibody profile was unchanged [ANA+ (1:640) RNP+; dsDNA negative, Sm negative, ENA negative, anti-cardiolipin (IgG and IgM) negative, lupus anticoagulant negative] and complement pathways were normal [CH100 normal, C3 normal, C4 < 0.1 IU (as previously documented in 1996) and alternative pathway components normal], but IgG was further raised (34.5 g/l). CT confirmed splenomegaly with multiple low attenuation lesions but was otherwise unremarkable, and in particular there was no lymphadenopathy. Review of her travel history identified only weekend breaks in European cities and a 3 day stay in five star accommodation in Morocco (when she had remained well) in addition to her week in Greece. An initial bone marrow aspirate showed hypoplastic appearances in all three cell lines with signs of early granulopoietic recovery—features attributed to the previous AZA therapy. The neutropenia only temporarily responded to filgrastrim (Neupogen, Amgen, Cambridge, UK). She continued to deteriorate with weight loss, arthralgia and fevers, which were not improved by intravenous immunoglobulin or high-dose steroid. We therefore considered rituximab (Mabthera, Roche, Hertfordshire, UK) since there was evidence of polyclonal B-cell activation with a high IgG titre and relative preservation of the B-cell count. Her other blood count parameters had, however, continued to fall and so a repeat bone marrow biopsy was performed. Unexpectedly, widespread, double-dot nuclei amastigotes within bone marrow macrophages, consistent with Leishman-Donovan bodies typical of leishmaniasis were seen. Leishmania fluorescent antibody test was positive (1:102400) and antibody to antigen K39 was detected by ELISA. Despite an episode of neutropenic sepsis, she recovered following liposomal amphotericin and her blood count parameters normalized. It was considered that she had acquired the disease in 2004 whilst on a holiday in Greece.
Visceral leishmaniasis is transmitted from a variety of mammalian reservoir species to humans by sand flies, an obligate vector in the life cycle of this protozoan. Promastigotes in the sand fly gut pass to humans when the female fly feeds. Macrophages phagocytose the promastigotes, which transform to amastigotes. Infected macrophages die, releasing progeny that infect cells of the reticulo-endothelial system [1] (Fig. 1). Visceral leishmaniasis is endemic in over 60 countries [2], including popular tourist destinations in southern Europe [3, 4]. The incubation period ranges from 3 months to 3 yrs with infection characterized by fever, splenomegaly, pancytopenia and hyper-gammaglobulinaemia. The untreated mortality is 75–95% [5]. MCTD is characterized by antibodies to U1-RNP and shares clinical features with visceral leishmaniasis, in particular, leucopenia and hypergammaglobulinaemia [6]. There is no published cross-reactivity between leishmania antibody and the U1-RNP antigen tested for in MCTD and our patient's serological profile did not change with leishmania infection. Fever is frequently a feature of CTD and splenomegaly is not unusual. A similar presentation in a patient with SLE has been reported [7] and there is an increasing incidence in patients immunocompromised by HIV/AIDS [4]. In an era where powerful immunosuppressants with long-lasting immunological effects, such as rituximab, are commonly used to treat refractory autoimmune disease, our patient serves as a reminder of the importance of opportunistic infectious diseases as differential diagnoses. Rheumatologists should be alert to the presentations of these infectious diseases in patients, even years after visits to apparently benign tourist destinations.
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The authors are grateful to Dr B. Wilkins for preparation of the images used in Fig. 1 and to Dr P. Kesteven for critical review of the manuscript.
Disclosure statement: The authors have declared no conflicts of interest.
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