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Neil Mo, Senthil Muthu, Margaret O’Sullivan, Regression of lymphoma after withdrawal of infliximab alone in an infliximab/methotrexate-treated RA patient, Rheumatology, Volume 50, Issue 4, April 2011, Pages 808–810, https://doi.org/10.1093/rheumatology/keq417
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Sir, The risk of lymphoma in RA patients treated with anti-TNF agents has been debated, with some discrepancy between studies [1, 2]. Previous reports describing tumour regression post-anti-TNF withdrawal have involved concurrent MTX cessation or EBV infection [3, 4]. We describe lymphoma occurring at an unusual site, which regressed on stopping infliximab alone.
A 62-year-old man diagnosed with sero-positive RA in 1984 and Crohn’s disease in 1988, was initially treated with prednisolone 10 mg/day. Active RA prompted multiple disease-modifying drug use, including penicillamine, SSZ, MTX and LEF, all of which failed due to inefficacy or adverse effects. Infliximab with MTX was started in 2002, resulting in a DAS reduction from 8.34 to 3.22 within a month. In June 2009, the patient noticed excessive lacrimation from his left eye. He was found to have a swelling over the inner canthus of the eye, present for 1 month. Infliximab treatment was discontinued given the unknown aetiology of the swelling but MTX 10 mg/week was continued. An MRI scan demonstrated a soft-tissue mass arising from the lacrimal sac (Fig. 1). A biopsy of the lesion confirmed a non-Hodgkin’s follicular lymphoma (World Health Organization Grade 3a). Immunophenotyping revealed positive CD10, CD20 and BCL-6. Other markers including CD3, CD5 CD21, BCL-2, MUM 1, cyclin D1 and EBV by EBV encoded RNA in situ hybridization were negative. FISH studies did not find evidence of IGH/BCL-2 gene rearrangement corresponding to lack of protein by immunohistochemistry. Bone marrow aspirate and trephine biopsy were normal. A whole-body CT scan did not demonstrate lymphadenopathy. No treatment was considered as indicated apart from the withdrawal of infliximab. A repeat MRI scan 5 months later demonstrated a marked regression of the tumour. The patient was seen recently in the clinic. He remains in clinical remission 9 months after the diagnosis was made. This case points to the incrimination of infliximab in the development of lymphoma, as demonstrated by tumour regression on discontinuing infliximab while continuing MTX. Lymphoma induced by MTX has been previously reported to regress on withdrawal [5]. However, the absence of EBV in this case is significant as previous reports of reversible lymphoma with MTX and etanercept have been linked to EBV [4, 6]. One further case report of Hodgkin’s lymphoma regression after cessation of infliximab alone was described in Japan [7]. The significant difference in that case was the definite association of EBV, with viral RNA and DNA detected through in situ hybridization and Southern blotting. The mechanism of EBV-induced lymphoma in immunosuppressed RA patients is controversial. The idea of drug-induced immune dysfunction postulated by the earlier cases of EBV-associated lymphomas has been questioned. One study of RA patients on MTX and/or anti-TNF examining the EBV load in peripheral blood mononuclear cells did not demonstrate a significantly increased viral EBV load due to these drugs [8]. The same authors also earlier demonstrated a 10-fold increase in viral load due to rheumatoid disease itself, which equates to similar levels found in healthy organ transplant recipients.
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