(Vienna, 21-04-2026) Methotrexate (MTX) remains the cornerstone of treatment for rheumatoid arthritis (RA), yet many patients fail to achieve remission with standard therapy. A new international clinical trial led by researchers at the Division of Rheumatology, Department of Medicine III, Medical University of Vienna, now aims to address this gap by systematically optimizing how MTX is used in clinical practice. The study protocol of the MethMax trial has been published in Trials.
The MethMax study is led by Karolina Anderle and Helga Lechner-Radner from the Division of Rheumatology at the Department of Medicine III at MedUni Vienna and conducted across multiple European centers. The trial investigates whether adjusting both the dose and route of administration of MTX can significantly improve treatment outcomes in patients with active disease. "Methotrexate is highly effective, but in many patients its full potential is not realized in routine care," explains first author Karolina Anderle. "With MethMax, we aim to systematically test whether optimizing dose and administration route can improve remission rates. " – "This trial addresses a very practical and clinically relevant question," adds Helga Lechner-Radner. "By refining how we use an established therapy, we may be able to improve outcomes without immediately escalating to more complex and costly treatments."
Optimizing a cornerstone therapy
Methotrexate is widely recommended as first-line treatment in RA due to its proven efficacy, safety, and affordability. However, limitations in real-world use—such as insufficient dose escalation or delayed switch to subcutaneous administration—may reduce its effectiveness.
The MethMax trial directly addresses these challenges by comparing optimized oral MTX dosing and subcutaneous MTX administration at the same target dose. The primary goal is to determine whether these strategies increase the proportion of patients achieving remission after 24 weeks.
A structured, multicenter trial design
The study is a prospective, randomized, assessor-blinded, multicenter trial enrolling 182 patients across seven European countries. All participants receive a standardized treatment approach, including weekly MTX at a target dose of 25 mg, a short-term glucocorticoid bridging regimen and regular follow-up assessments over 24 weeks. Clinical outcomes, safety, and patient-reported measures are systematically evaluated throughout the study.
In addition to clinical endpoints, the MethMax trial explores novel biomarkers and treatment adherence, including Methotrexate polyglutamates in blood, metabolites measured from finger sweat and digital and patient-reported adherence measures. These innovative approaches aim to provide deeper insight into how patients metabolise and respond to MTX in real-world settings.
Part of a broader European research effort
The MethMax trial is one of several studies conducted within the framework of the SQUEEZE consortium, funded by the European Union’s Horizon Europe program. By combining clinical trials with translational research, the initiative seeks to improve treatment strategies and personalize care in rheumatic diseases. By focusing on optimizing an established therapy, the MethMax study aims to provide practical guidance for clinicians and improve outcomes for patients with RA. The results are expected to inform future treatment strategies and help ensure that patients fully benefit from one of the most widely used therapies in rheumatology.
Publication: Trials
An international, multicentre, interventional, randomised, assessor-blinded trial to MAXimise the METHotrexate therapy potential in patients with active rheumatoid arthritis (MethMax trial): Study protocol
Karolina Anderle et al.
https://link.springer.com/article/10.1186/s13063-026-09519-4