A Clinical, Pathological and Genetic Characterization of Methotrexate-Associated Lymphoproliferative Disorders

Abstract

Background Methotrexate (MTX)-associated lymphoproliferative disorder (LPD) is a lymphoid proliferation or lymphoma in a patient immunosuppressed with MTX. As MTX has recently gained acceptance as a first-line therapy for rheumatoid arthritis (RA), the incidence of MTX-LPD is expected to increase. Epstein-Barr virus (EBV) infection is considered to play an important role in the pathogenesis of MTX-LPD, although EBV can only be detected on histopathological examination in only about half cases of MTX-LPD. Recently, LPD with EBV-positive mucocutaneous ulcer (EBVMCU) has been reported as a distinct disease entity with a self-limiting and indolent clinical course (1). EBVMCU is found in various conditions of immunosuppression, including MTX-LPD or in age-related immunosenescence. Although MTX-LPD often shows spontaneous regression, it is not clear whether MTX-LPD with EBVMCU has a better prognosis. Objectives The aim of this study is to clarify the clinical, histological and genetic factors that predict outcomes in patients with MTX-LPD. Methods Patients with MTX-LPD diagnosed between 2000 and 2012 were analyzed retrospectively regarding their clinical course, site of biopsy, histological type, Epstein-Barr virus (EBV) immunostaining and human leukocyte antigen (HLA) typing. Results Twenty-one patients, including 20 with RA and one with polymyositis were analyzed. The mean dose of MTX was 6.1 mg/week and the mean duration of treatment was 71.1 months. Clinically, five patients were diagnosed with EBV-positive mucocutaneous ulcer (EBVMCU). All had polymorphic histological findings and were more successfully treated solely by withdrawal of MTX than the other cases (75% versus 7.7%, P = 0.015). Genetically, the HLA-B15:11 haplotype was more frequent in patients with MTX-LPD than in healthy Japanese controls (P = 0.0043). EBV latency classification and HLA typing were not associated with the prognosis of MTX-LPD. Conclusions Our data demonstrate that EBVMCU, a specific clinical subgroup of MTX-LPD, had a better clinical outcome when MTX was withdrawn than other patients with MTX-LPD. References Dojcinov SD, Venkataraman G, Raffeld M, Pittaluga S, Jaffe ES. EBV positive mucocutaneous ulcer--a study of 26 cases associated with various sources of immunosuppression. Am J Surg Pathol. 2010 Mar;34(3):405-17. Acknowledgements The authors thank Dr. Toda, of the Center for Anatomical Studies at the Kyoto University Graduate School of Medicine for performing immunostaining studies and Dr. Inoko, of the Tokai University Department of Molecular Science, Division of Molecular Medical Science and Molecular Medicine for kindly providing the HLA data of Japanese patients with rheumatoid arthritis. Disclosure of Interest None Declared