Hematological Side Effects of Methotrexate in Rheumatoid Arthritis: A Systematic Review

Methotrexate (MTX) is a cornerstone therapy for rheumatoid arthritis (RA), yet its hematological toxicity remains a significant clinical concern. This systematic review synthesizes evidence on MTX-induced hematological side effects to inform safer management.

A comprehensive search of Medline/PubMed (1991 to 2024), SCOPUS (1995 to 2024), and the Cochrane Library identified 108 studies reporting hematological adverse events associated with MTX in RA patients. Search terms included "RA," "MTX," and "hematologic side effects". Exclusion criteria included the use of biologics or other DMARDs, other rheumatic diseases, and studies focusing on non-hematological side effects.

Hematological disorders represent the second most prevalent adverse outcome following gastroenterological disorders. The side effects often include complications such as leukopenia, thrombocytopenia, megaloblastic anemia, and pancytopenia. Risk factors were consistently identified across studies and include renal failure, advanced age, hypoalbuminemia, folate deficiency, dosing errors, and concomitant use of medications. Pancytopenia emerges as a potentially fatal complication, requiring careful monitoring and timely intervention with folinic acid (leucovorin).

Low-dose MTX, though effective for RA, can lead to significant hematologic side effects such as anemia, leukopenia, thrombocytopenia, and pancytopenia, with reported incidence rates of 2.4-5.6%, exceeding earlier estimates. Dosage errors by patients or healthcare providers demonstrate the potential for fatal outcomes. Risk factors include renal impairment, hypoalbuminemia, infections, advanced age, and inadequate folic acid supplementation. Side effects typically resolve after discontinuation, and MTX can be safely resumed under appropriate monitoring and dose adjustment protocols.

Our study summarizes evidence indicating that hematological disorders are commonly reported adverse events following gastroenterological disorders. Pancytopenia represents a potentially fatal complication requiring careful monitoring and timely intervention. This work provides an integrative clinical synthesis of evidence across diverse study designs to inform risk stratification and clinical management.