New research reveals surprising patterns in methotrexate maintenance when combined with advanced rheumatoid arthritis therapies, challenging conventional treatment approaches.
For the millions of people living with rheumatoid arthritis (RA), treatment often follows a familiar path. When the disease strikes, physicians typically reach for a time-tested medication called methotrexate—a drug that has formed the bedrock of RA treatment for decades. But what happens when methotrexate alone isn't enough to control the painful joint inflammation and stiffness that characterizes this autoimmune condition?
The standard approach has been to add more advanced "targeted therapies" to the mix while ideally continuing methotrexate. This strategy presents a complex puzzle for rheumatologists and patients alike: does maintaining methotrexate alongside these newer drugs truly benefit patients, or is it simply adding unnecessary side effects? The answers have been surprisingly elusive—until now.
of RA patients don't respond adequately to methotrexate alone
Methotrexate has been the first-line RA treatment
Standard of care recommended by rheumatology organizations
Methotrexate boasts a fascinating history. Originally developed as a cancer chemotherapy agent, researchers discovered that at much lower doses, it could effectively calm the overactive immune response in rheumatoid arthritis. Today, it's recognized as the first-line treatment for RA worldwide, with professional organizations like EULAR (European Alliance of Associations for Rheumatology) recommending it as the initial anchor drug for most patients.
Methotrexate prescribed as first-line therapy for most RA patients
Evaluation of treatment response; approximately 30-40% show inadequate response
Addition of bDMARDs or tsDMARDs while considering methotrexate continuation
Regular assessment of combination therapy effectiveness and side effects
To address this treatment dilemma head-on, French researchers designed the STRATEGE 2 study—a prospective, observational investigation conducted across 53 sites in France. Between February 2019 and December 2020, the study enrolled 186 RA patients who had been on methotrexate for at least three months but required an additional targeted therapy due to insufficient disease control.
Unlike tightly controlled clinical trials that often exclude complex real-world patients, STRATEGE 2 aimed to capture what actually happens in routine clinical practice. The researchers followed 180 patients with analyzable data—mostly women (73.4%) with an average age of 56.4 years who had lived with RA for approximately 5.6 years. At the study's start, these patients were taking an average methotrexate dose of 19.9 mg per week, with most (71.7%) receiving it via subcutaneous injection 1 .
The study's primary goal was to assess how many patients maintained their methotrexate unchanged within twelve months of starting the new targeted therapy. The researchers defined "non-maintenance" broadly: permanently discontinuing methotrexate, reducing the dose, or switching from subcutaneous to oral administration.
After following patients for approximately one year, the STRATEGE 2 findings painted a fascinating picture of real-world treatment patterns. The results revealed that therapeutic adjustments to methotrexate are far more common than previously recognized.
At the initial consultation when the targeted therapy was started, rheumatologists maintained methotrexate unchanged in 76.1% of patients. However, by the twelve-month mark, this picture had changed dramatically. When applying the composite endpoint (considering any dose reduction, route change, or discontinuation as non-maintenance), only 40.9% of patients remained on unchanged methotrexate therapy 1 .
| Adaptation Type | Percentage of Patients |
|---|---|
| Permanent discontinuation | 30% |
| Dose decrease only | 44% |
| Route change only (subcutaneous to oral) | 3% |
| Both dose decrease and route change | 23% |
Perhaps surprisingly, these frequent adjustments occurred alongside significant improvements in disease activity. The average DAS28 score (a composite measure of arthritis activity) improved from 4.3 at baseline to 2.6 at twelve months, then further to 2.4 at twenty-four months. This indicates that despite methotrexate adaptations, patients' arthritis was generally well-controlled 7 .
The STRATEGE 2 findings gain even more significance when viewed alongside other recent research on methotrexate patterns across the globe.
Examined 889 RA patients starting b/tsDMARDs while on methotrexate.
tapered or discontinued methotrexate within 2 years
No worsening of arthritis control with methotrexate tapering/discontinuation 9 .
Revealed higher methotrexate maintenance rates than other studies.
maintenance at 1 year
maintenance at 5 years
Side effects were primary reason for discontinuation (75%) 4 .
These divergent patterns across different healthcare systems highlight:
The findings emphasize that one-size-fits-all approaches are inadequate for RA management.
The findings from STRATEGE 2 and related studies carry significant implications for clinical practice and the lived experience of rheumatoid arthritis.
Looking ahead, researchers are exploring even more sophisticated approaches to RA treatment. Scientists at the National Center for Advancing Translational Sciences (NCATS) are developing retooled versions of methotrexate called PROTACs that might offer similar benefits with fewer side effects. One candidate, "versortrexate," works by marking the target protein for destruction rather than just inhibiting it, potentially representing a next-generation approach to methotrexate therapy 2 .
As research continues to refine our understanding of optimal RA management, studies like STRATEGE 2 provide the crucial real-world evidence needed to balance treatment efficacy, safety, and quality of life for people living with this chronic condition. The methotrexate puzzle isn't completely solved, but we're gaining ever-clearer pieces to guide both patients and clinicians in their treatment decisions.