Reevaluating Methotrexate in RA: Can Less Be More in Combination Therapy?

In the ongoing effort to fine-tune rheumatoid arthritis (RA) treatment, a new randomized controlled trial is challenging long-held assumptions about combination therapy—specifically, the role of methotrexate alongside biologic agents like certolizumab pegol.

Traditionally, methotrexate has served as a cornerstone of RA management, often paired with biologics to enhance efficacy. But its well-documented side effects—from gastrointestinal discomfort to hepatotoxicity—frequently complicate long-term adherence. Now, new trial data suggest that for some patients, stopping methotrexate may not mean sacrificing disease control.

The trial, led by investigators evaluating certolizumab pegol, compared outcomes in patients who either continued or discontinued methotrexate. Results revealed a notable divergence: while both groups maintained clinical responses, those who stopped methotrexate experienced fewer adverse events. The implication? For select patients, monotherapy with certolizumab pegol may offer a therapeutic sweet spot—preserving disease control while minimizing drug-related toxicity.

These findings arrive amid growing interest in personalizing RA treatment regimens. As biologic and targeted synthetic DMARDs gain traction, clinicians are increasingly focused on tailoring therapy not only to disease activity but also to patient tolerability and quality of life. Methotrexate, despite its efficacy, remains a common source of treatment burden, especially for patients with comorbidities or low tolerance thresholds.

Evidence from this trial aligns with post hoc analyses and prior observational data suggesting that certolizumab pegol’s efficacy does not hinge entirely on methotrexate co-administration. In studies cited in Frontiers in Medicine and repositories like PMC, the biologic’s anti-TNF activity demonstrated sustained benefit as a standalone agent, further reinforcing the case for individualized treatment strategies.

From a clinical standpoint, the implications are significant. Rheumatologists may begin to reassess the necessity of continuing methotrexate indefinitely in patients who achieve remission or low disease activity on combination therapy. For patients struggling with methotrexate-induced fatigue, nausea, or lab abnormalities, deprescribing may now be a viable, evidence-based option.

However, the findings also raise important questions. Which patients can safely discontinue methotrexate without risking flare-ups? Are there biomarkers or clinical characteristics that predict success with biologic monotherapy? Addressing these questions will be critical in translating trial data into practice. Future trials and real-world studies will need to stratify patients more precisely to understand who benefits most from combination versus monotherapy approaches.

For now, the message is one of cautious optimism. Methotrexate has earned its place in the RA treatment algorithm—but as this new trial illustrates, stepping back from it under the right conditions might offer patients both relief and results. As RA management moves further into the era of personalized medicine, such data serve as a welcome guidepost for clinicians navigating the balance between efficacy and tolerability.