What Was Studied
A new controlled comparative study, published in Annals of Medicine, examined effects of methotrexate on arterial blood pressure in patients with newly diagnosed rheumatoid arthritis (RA) who had not previously been treated with disease-modifying antirheumatic drugs (DMARDs). PubMed+2PMC+2
Two groups (n = 62 total): 31 patients put on subcutaneous methotrexate and 31 on sulfasalazine (another csDMARD). PubMed+2PMC+2
Blood pressures (systolic and diastolic), augmentation index (a measure of arterial stiffness), and RA disease activity were measured at baseline, 1 month, and at 6 months. PMC+2PubMed+2
Main Findings
After six months, the methotrexate group had a significantly greater reduction in systolic blood pressure (SBP) compared to sulfasalazine: a mean difference of −7.4 mm Hg (95% CI −14.0 to −0.8; p = 0.03). PubMed+2PMC+2
There were no statistically significant between-group differences in diastolic BP (DBP), nor in measures of arterial stiffness via augmentation index (AIx), or in RA disease activity (DAS28-CRP) at six months. PMC+1
The BP drop was not tied to big changes in disease activity or stiffness (AIx), suggesting other mechanisms might be involved. PMC+1
Another study (a repeated cross-sectional design) comparing RA patients on methotrexate versus those on other DMARDs also found that the methotrexate group had lower clinic and 24-hour peripheral and central SBP and DBP, as well as lower pulse wave velocity (a measure of arterial stiffness) compared to those not on methotrexate. PubMed+1
Also, a bigger set of data from Veterans’ Affairs in the U.S. showed that after initiation of DMARD therapy, especially methotrexate (and hydroxychloroquine), SBP and DBP tend to decline over six months. PubMed
Strengths & Limitations of the Evidence
Strengths
Prospective follow-up and comparative design: In the main study, treatment-naïve patients allowed for a clearer view of changes over time, and the use of a comparator (sulfasalazine) helps isolate effect associated with methotrexate. PubMed+1
Clinical relevance: A fall of ~7 mm Hg in SBP is meaningful. Even modest reductions in SBP are known in hypertension studies to reduce cardiovascular event risk. PMC+1
Pharmacogenetic component: The study also looked at single-nucleotide polymorphisms (SNPs) — specifically in MTHFR (rs1801133) and ABCG2 (rs2231142) — which modulated BP response. This suggests that individual genetic variation may influence how much benefit a patient gets. PMC+2PubMed+2
Limitations
Non-random assignment: Although newly diagnosed and treatment-naïve, patients were not randomized to methotrexate vs sulfasalazine; the choice was made by their treating rheumatologists. This leaves the possibility of confounding by indication — meaning unmeasured differences might bias results. PMC+1
Small sample size: Only 31 in each arm, with some dropouts. So the power is limited. PMC
No change in arterial stiffness (AIx) or disease activity: The lack of change in stiffness or RA activity suggests mechanisms are unclear. Might mean the BP change is independent of these, but also raises question of what’s causing it. PMC+1
Shorter follow-up: Six months is a moderate timeframe; longer-term outcomes (e.g. cardiovascular event rates) were not evaluated.
Biological Plausibility & Possible Mechanisms
While the precise mechanism by which methotrexate lowers SBP isn’t yet established, several possibilities are discussed:
Anti-inflammatory effect: RA involves systemic inflammation, which contributes to endothelial dysfunction, increased vascular resistance, and hypertension. Methotrexate reduces inflammation, possibly improving vascular tone. PMC+2SAGE Journals+2
Effect on vascular stiffness: Some evidence (from cross-sectional study) links methotrexate with lower pulse wave velocity (PWV), though in the comparative study the non-significant change in AIx suggests stiffness-related improvements are partial or delayed. PubMed+1
Genetic modulators: SNPs in certain genes (e.g. MTHFR, ABCG2) may modulate the metabolism of methotrexate, folate pathways, or how the drug interacts with vascular tissue or inflammation. Such genetic variation might influence how much BP drops. PMC+1
Implications & What It Could Mean in Practice
Cardiovascular risk reduction: RA patients have elevated cardiovascular risk. If methotrexate lowers SBP meaningfully (≈7 mm Hg), that could translate into reduced risks of heart attack, stroke, etc.
Treatment choice: When selecting among DMARDs, the potential BP‐lowering effect of methotrexate (versus alternatives) may factor in, especially in RA patients with or at risk for hypertension or cardiovascular disease.
Personalisation of therapy: Genetic testing (for relevant SNPs) may enable predicting which patients are more likely to benefit in terms of BP lowering.
Need for larger, randomized trials: To confirm causality, longer‐term clinical outcomes, and to better understand mechanisms; also to see whether these benefits are seen in diverse populations.
Summary
In sum, recent evidence shows that methotrexate, when used in treatment-naïve RA patients, reduces systolic blood pressure by about 7.4 mm Hg over six months compared to sulfasalazine. The effect appears independent of changes in disease activity or arterial stiffness (as measured by augmentation index), although reductions in pulse wave velocity in other studies suggest some vascular benefit. Genetic variation may influence the degree of BP reduction. While promising, these findings still require confirmation by randomized trials, and mechanistic understanding is incomplete. If confirmed, the BP-lowering effects of methotrexate might add to its value in reducing the high cardiovascular risk burden seen in RA.
