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Methotrexate Implicated in Lymphoma Development in Patient With Rheumatoid Arthritis

Patients with highly active rheumatoid arthritis (RA) might be at risk of developing malignant lymphoma if they are treated with oral methotrexate, according to the authors of a new case study.

Takahisa Gono, MD, with the Third Department of Medicine, at the Shinshu University School of Medicine, Matsumoto, Japan, and colleagues describe the case of a 59-year-old man with RA who initially presented with low-grade fever and polyarthralgia. His symptoms did not improve despite administration of non-steroidal anti-inflammatory drugs.

He was admitted to hospital and was treated with oral prednisolone 30 mg/day and salazosulfapyridine 1000 mg/day. The patient was allergic to salazosulfapyridine, so he was treated with methotrexate 4 mg/week. Approximately 3 weeks later, the arthritis began to worsen and multiple rheumatic nodules appeared. Oral prednisone was increased to 50 mg/day and methotrexate was increased to 6 mg/week.

His arthritis appeared to improve. Oral prednisolone was tapered to 35 mg/day and his hospital discharge date was scheduled for 5 months after admission.

Just before discharge, however, the right submandibular lymph node appeared swollen. Open biopsy demonstrated extensive infiltration of immature lymphocytes. Cells were positive for CD79a and CD20 but negative for CD3 and CD45RO, leading to a diagnosis of malignant lymphoma of diffuse large B-cell type.

Despite cessation of methotrexate, the lymph nodes remained swollen. The patient was treated with 3 courses of CHOP therapy (cyclophosphamide, doxorubicin, vincristine, and prednisolone) followed by irradiation at a total dose of 40 Gy. About 6 months later, magnetic resonance imaging of the neck indicated that the lymphadenopathy had disappeared.

The patient "has since been treated with oral prednisolone alone at a dose of around 20 mg/d, and has been in a good general condition without recurrence of lymphadenopathy and arthralgia due to RA," the researchers write.

They believe that the pathogenesis of associated malignant lymphoma in this patient was related mainly to the highly activated RA itself, but they add that methotrexate might have modified the patient's immune system and promoted development of malignant lymphoma.

"Methotrexate should be used carefully, keeping in mind the possible development of malignant lymphoma as well as other serious complications, particularly when the disease is highly active," they conclude.


Intern Med 2004;43:135-138. "Malignant lymphoma associated with rheumatoid arthritis, developing shortly after initiation of oral methotrexate"

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