Rheumatology Advance Access originally published online on January 5, 2005
Rheumatology 2005 44(3):406; doi:10.1093/rheumatology/keh470
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Rheumatology Vol. 44 No. 3 © British Society for Rheumatology 2005; all rights reserved
LETTER TO THE EDITOR |
Serum sickness associated with rituximab in a patient with hepatitis C virus-related mixed cryoglobulinaemia
Division of Rheumatology, University ‘La Sapienza’, Rome, Italy
Correspondence to: M. Catuogno. E-mail: manuela.catuogno{at}libero.it
SIR, We report the case of a 60-yr-old woman who developed serum sickness after rituximab.
At the age of 56 yr, a routine blood test showed a moderate increase of transaminases. Anti-hepatitis C virus (HCV) antibodies were demonstrated, the genotype was subtype 1b and the virus actively replicated (600 000 IU/ml). In spite of persistent elevation of transaminases, the patient refused liver biopsy. Within 18 months lower limb sensory polyneuropathy developed, followed by motor involvement. Transaminases were still high and rheumatoid factor (RF) and a small serum monoclonal component (IgM
) were present in the absence of Bence-Jones proteinuria. A liver biopsy was performed showing signs of chronic active hepatitis while a bone marrow biopsy excluded a lymphoproliferative disease. Prednisone (1 mg/kg/day) and pegylated-IFN
(80 µg weekly) associated with ribavirin (1 g/day) were started with clinical improvement and normalization of transaminases. Nevertheless, any effort to taper steroids induced a flare of neuropathy. Within 1 yr the patient developed a cushingoid aspect and severe osteoporosis. At the age of 59 yr, deep skin ulcers of the leg appeared; initially the patient was treated with plasmapheresis and subsequently i.v. immunoglobulins with little clinical benefit. After 2 yr of treatment, antiviral therapy was stopped due to progressive leucopenia and anaemia, both improving within 1 month of withdrawal.
At the age of 60 yr, the patient was admitted to our division; she was still taking prednisone (37.5 mg/day). Physical examination showed a steppage walk, livedo reticularis and wide skin ulcers of the legs involving the right calf, right external malleolus and left heel; the patient refused skin biopsy. Laboratory examinations showed high erythrocyte sedimentation rate, C-reactive protein and fibrinogen, normal renal and liver function, low viral activity (HCV RNA <3000 IU/ml), IgM 453 mg/dl with a monoclonal component IgM (0.26 g/dl), RF positivity (Ra-test, FII latex, Waaler–Rose) and the presence of type II cryoglobulins, C4<5 mg/dl (normal range 20–55).
Rituximab is an anti-CD20 human–mouse chimeric monoclonal antibody that showed encouraging results in two series including 35 patients with mixed cryoglobulinaemia resistant to traditional approaches [1, 2]. Therefore, we performed a first infusion of the drug (375 mg/m2), which was well tolerated. However, 7 days after, shivering fever (38.5°C) and polyarthralgias presented. The next day fever was higher (39.3°C) and associated with diffuse urticaria. Symptoms and signs completely remitted after administration of betametasone 4 mg/i.v. and H1-blockers. Haemoculture and urinoculture were sterile.
We hypothesized an acute serum sickness which, as far as we know, has never been reported in association with rituximab in patients with lymphoproliferative diseases [3] while it has been previously described in three cases of autoimmune diseases (autoimmune polyneuropathy, autoimmune thrombocytopenia, systemic lupus erythematosus) [4–6]. It is possible to speculate that some factors related to autoimmune disorders are involved in the pathogenesis of serum sickness such as a reduced clearance of immunocomplexes and/or an increased production of autoantibodies. As a matter of fact, high titres of antibodies directed against the murine F(ab') fragments were detected in the first reported case of serum sickness after rituximab [4]. On the other hand, patients with lymphoproliferative disorders are usually treated with polychemotherapy, which could prevent the development of serum sickness. This is the first case of serum sickness associated with rituximab in a patient with HCV-related mixed cryoglobulinaemia. In this condition RF could bind to the human Fc(
) fragment of the chimeric antibody and form immunocomplexes, possibly inducing a third-type immune reaction. A further possible pathogenetic factor is the previous administration of i.v. immunoglobulins, which might have sensitized our patient, explaining the occurrence of serum sickness after the first infusion of rituximab. With the expansion in the therapeutic use of monoclonal antibodies in a widening spectrum of disorders, it is advisable to take into consideration not only immediate reactions but also delayed ones.
The authors have declared no conflicts of interest.
References
- Sansonno D, De Re V, Lauletta G, Tucci FA, Boiocchi M, Dammacco F. Monoclonal antibody treatment of mixed cryoglobulinemia resistant to interferon- with an anti-CD20. Blood 2003;101:3818–26.
[Abstract/Free Full Text] - Zaja F, De Vita S, Mazzaro C et al. Efficacy and safety of rituximab in type II mixed cryoglobulinemia. Blood 2003;101:3827–34.
[Abstract/Free Full Text] - Grillo-Lopez AJ, White CA, Varns C et al. Overview of the clinical development of rituximab: first monoclonal antibody approved for the treatment of lymphoma. Semin Oncol 1999;26(S14):66–73.
- D’Arcy CA, Mannick M. Serum sickness secondary to treatment with the murine-human chimeric antibody IDEC-C2B8 (rituximab). Arthritis Rheum 2001;44:1717–8.[CrossRef][Medline]
- Herishanu Y. Rituximab-induced serum sickness. Am J Hematol 2002;70:329.[Medline]
- Hellerstedt B, Ahmed A. Delayed-type hypersensitivity reaction or serum sickness after rituximab treatment. Ann Oncol 2003;14:1792.
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