Methotrexate induced neurotoxicity in a patient with rheumatoid arthritis on rituximab therapy: a case-based review

Rheumatoid arthritis (RA) is a systemic inflammatory disease treated with conventional and biologic disease-modifying drugs. Methotrexate is the anchor drug for the treatment of RA and is also frequently used for various autoimmune diseases. Adverse events are common and generally easy to manage, involving mainly the gastrointestinal tract and the liver function. However, neurotoxicity is very uncommon in adults with rheumatic diseases. B cell depletion with rituximab is another therapy approach particularly in patients with refractory RA. Whistle leukoencephalopathy – namely progressive multifocal leukoencephalopathy—is an infrequent but well-described side effect of rituximab. In contrast, central nervous system toxicity due to methotrexate is extremely rare especially in RA individuals under oral or subcutaneous low dose on weekly basis. We present a challenging case of a RA patient on treatment with methotrexate and rituximab presenting with leukoencephalopathy. The patient was diagnosed with methotrexate-induced leukoencephalopathy which reversed after treatment discontinuation. We comment on the symptoms and diagnostic workout and we review the available literature on this issue based on recommendations for narrative reviews.