Methotrexate (MTX) has long been the cornerstone of first-line therapy in rheumatoid arthritis (RA), particularly in early disease. While it is well-established in controlling inflammation and preventing joint damage, concerns about immunosuppression and a perceived increased risk of infections have persisted. However, new evidence from a large UK-based study challenges this traditional view.
A recent analysis by Adas et al., published in Rheumatology, utilized real-world data from the National Early Inflammatory Arthritis Audit (NEIAA) to evaluate the risk of serious infections in patients with newly diagnosed RA. This study, among the most comprehensive to date, included 17,472 adults across England and Wales diagnosed between 2018 and 2023.
The analysis examined the relationship between initial treatment choices—methotrexate, other conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), and corticosteroids—and the occurrence of serious infections. These infections were rigorously defined as those requiring hospitalization or resulting in death.
During a follow-up of 43,232 person-years (mean duration 2.62 years), 1,307 serious infection events were recorded, with an overall incidence rate of 3.02 per 100 person-years (95% CI: 2.86–3.19). Patients started on methotrexate-based treatment had a significantly lower risk of serious infections than those treated with other csDMARDs. The adjusted hazard ratio was 0.72 (95% CI: 0.63–0.82), indicating a 28 percent reduction in risk.
Although corticosteroid use initially appeared linked to a higher infection risk, this association was not statistically significant after adjusting for confounding factors (adjusted HR: 0.99, 95% CI: 0.87–1.12).
The study also identified patient-related and disease-specific predictors of infection risk. Older age, current or former smoking, comorbidities, seropositivity, and higher baseline Disease Activity Score using 28 joints (DAS28) were all independently associated with an increased likelihood of serious infections. Notably, each unit increase in DAS28 score corresponded to a 10 percent higher risk, underscoring the role of disease activity and individual characteristics rather than the immunosuppressive action of methotrexate.
Emerging evidence suggests that methotrexate, when used early in RA, may lower the incidence of serious infections. According to Dr. Shinji Izuka, effective inflammation control through methotrexate may help restore immune balance, reduce comorbidity burden, and ultimately decrease infection risk. Methotrexate’s mechanism of action involves inhibition of dihydrofolate reductase, reducing proliferation of activated immune cells. At the low doses used in RA, this results in immune modulation rather than broad suppression, possibly helping to normalize immune function and reduce susceptibility to infections.
These insights have important implications for clinical practice. Concerns about infection risk often delay initiation or continuation of methotrexate, which can lead to poor adherence and inadequate disease control. Reframing methotrexate as not only an effective anti-inflammatory but also a potentially protective agent strengthens the rationale for early use within a treat-to-target strategy.
The findings further reinforce methotrexate’s role as the primary therapeutic agent in RA management, particularly in early disease. Despite the growing availability of targeted biologics and JAK inhibitors, methotrexate remains the most commonly used conventional disease-modifying therapy worldwide due to its cost-effectiveness and extensive clinical evidence.
In conclusion, the data presented by Adas et al. represent a significant advancement in understanding infection risk in early RA. Rather than contributing to infection vulnerability, methotrexate may reduce it when appropriately initiated. This real-world evidence, along with expert perspectives, supports a re-evaluation of methotrexate’s risk-benefit profile and affirms its central role in contemporary RA treatment. As RA care evolves toward more personalized and data-informed approaches, studies like this help refine therapeutic decisions and challenge outdated assumptions.
References
- Adas MA, Bechman K, Russell MD, et al. Risk of infection in patients with early inflammatory arthritis: results from a large UK prospective observational cohort study. Rheumatology. 2025;keaf312. doi:10.1093/rheumatology/keaf312
- Izuka S. More than an immunosuppressant—lower serious infection rates with methotrexate in early rheumatoid arthritis. Rheumatology. 2025 Jun 27;keaf354.