A Phase 4 interventional study of Methotrexate and Sulfasalazine in Rheumatoid Arthritis, Stiffness, Aortic and Endothelial Dysfunction, sponsored by Flinders University. Completed at 1 site in Australia. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2025-02-26.
Sponsored by Flinders University · Phase 4, Interventional, and Treatment
The investigators will study the effects of methotrexate on blood pressure, arterial stiffness and endothelial function in patients with rheumatoid arthritis.
Patients with rheumatoid arthritis have an increased risk of stroke and heart attack when compared to the rest of the population. Recent studies have shown that methotrexate, a disease-modifying antirheumatic drug (DMARDs) commonly prescribed for rheumatoid arthritis, reduces this risk. However, the mechanisms responsible for the protective effects of methotrexate on the heart and the brain are unknown.
The investigators have recently completed an observational study in participants with rheumatoid arthritis treated with either methotrexate or with other DMARDs. Participants on methotrexate had lower blood pressure and 'healthier' blood vessels than participants treated with other DMARDs. These differences were maintained over a period of 8 months. These results suggest that methotrexate lowers blood pressure and exerts salutary effects on blood vessels, which might explain the reduced risk of stroke and heart attack with this drug. However, the observational nature of this study does not allow establishing a clear cause-effect relationship between methotrexate treatment and the observed changes in blood pressure and blood vessels.
In order to address this issue, the investigators will recruit participants that have been recently diagnosed with rheumatoid arthritis and are about to start treatment with either methotrexate (Group 1) or another DMARD (Group 2). Then, the investigators will assess their blood pressure and blood vessels for 6 months. The investigators will use an injectable (subcutaneous) form of methotrexate because this might provide better effects on blood pressure and blood vessels. The investigators will also study a third group (Group 3) of rheumatoid arthritis participants already on treatment (> 1 year) with oral methotrexate, with or without other DMARDs. They will be switched to subcutaneous methotrexate, but continuing all their other medications, for 6 months to see whether the subcutaneous form can further reduce blood pressure and provide additional salutary effects on blood vessels. Finally, the investigators will study a fourth group (Group 4) of participants with rheumatoid arthritis already on treatment (> 1 year) with DMADRs other than methotrexate who will continue with the same medications for 6 months, to assess possible fluctuations in blood pressure and blood vessel markers over time.
Each participant will attend three study visits (baseline, 1 and 6 months), each lasting between 60 and 90 min.
Exclusion Criteria:
Newly diagnosed RA patients started on subcutaneous MTX - open randomisation vs. sulfasalazine. In this group, use of NSAIDs, steroids, and/or other DMARDs, is allowed, if indicated, for symptom control. The overall management, tests and outpatient rheumatology visits schedule will be similar to other patients with RA, in accordance to standard practice .
Drug: Methotrexate
Newly diagnosed RA patients started on sulfasalazine - open randomisation vs. subcutaneous MTX. In this group, use of NSAIDs, steroids, and/or other DMARDs (except MTX), is allowed, if indicated, for symptom control. The overall management, tests and outpatient rheumatology visits schedule will be similar to other patients with RA, in accordance to standard practice.
Drug: Sulfasalazine
RA patients on long-term treatment (\> 1 year) with oral MTX, with or without other DMARDs, NSAIDs and/or steroids, switched to subcutaneous MTX (same dose). In these patients, treatment with other DMARDs, NSAIDs and/or steroids will continue. The overall management, tests and outpatient rheumatology visits schedule will be similar to other patients with RA, in accordance to standard practice.
Drug: Methotrexate
RA patients on stable treatment (\> 1 year) with other (non-MTX) DMARDs, with or without NSAIDs and/or steroids, and continued on the same treatment. The overall management, tests and outpatient rheumatology visits schedule will be similar to other patients with RA, in accordance to standard practice.
Drug: Other DMARDs
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Change in peripheral systolic blood pressure
Change in peripheral systolic blood pressure
Time frame: Change from baseline peripheral systolic blood pressure at 6 months
Change in peripheral and central blood pressure
Change in peripheral and central blood pressure
Time frame: Change from baseline peripheral and central blood pressure at 6 months
Change in arterial stiffness
Change in pulse wave velocity
Time frame: Change from baseline pulse wave velocity at 6 months
Change in arterial wave reflection
Change in augmentation index
Time frame: Change from baseline augmentation index at 6 months
Change in adenosine
Change in adenosine concentrations
Time frame: Change from baseline adenosine concentrations at 6 months
Change in arginine metabolites
Change in ADMA concentrations
Time frame: Change from baseline ADMA concentrations at 6 months
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Flinders University