Fatigue during leflunomide therapy: A narrative review of an overlooked adverse effect in autoimmune rheumatic diseases

Fatigue is one of the most prevalent and disabling symptoms in patients with autoimmune rheumatic diseases, significantly impairing physical functioning, work productivity, and quality of life. Although disease-modifying antirheumatic drugs (DMARDs) are essential for controlling inflammatory activity and may improve fatigue indirectly, pharmacologic therapies themselves may influence fatigue through metabolic, immunologic, or systemic effects. Leflunomide is a widely used conventional synthetic DMARD for rheumatoid arthritis and other autoimmune inflammatory diseases; however, fatigue occurring during leflunomide therapy has received limited attention in the literature. The objective of this study was to review the available evidence regarding fatigue reported during treatment with leflunomide in patients with autoimmune rheumatic diseases. A narrative review of the literature was conducted using major biomedical databases. Evidence from randomized clinical trials, observational studies, pharmacovigilance reports, and case reports describing fatigue or related systemic symptoms in patients treated with leflunomide was analyzed qualitatively to explore potential associations and possible mechanisms. Available evidence suggests that fatigue or fatigue-related symptoms, including malaise, weakness, and unexplained tiredness, may occur in a subset of patients receiving leflunomide. However, fatigue has rarely been evaluated as a predefined outcome in clinical studies. Reported fatigue is likely multifactorial, reflecting disease activity, psychosocial factors, metabolic alterations, comorbidities, or drug-related complications such as hepatic dysfunction, hematologic abnormalities, or infection. Fatigue during leflunomide therapy appears to be an underrecognized clinical issue. Greater awareness may help clinicians evaluate unexplained fatigue during treatment. Prospective studies using validated fatigue assessment tools are needed to clarify its prevalence and clinical relevance.