Effect of methotrexate on endothelial function in psoriasis patients

Psoriasis is not just a skin disease — it is linked to serious cardiovascular complications including hardening of the arteries and higher rates of heart disease. This Brazilian pilot study asked whether methotrexate (MTX), a widely used psoriasis treatment, could improve the health of blood vessel linings (endothelial function) in addition to clearing skin. Over 12 weeks, patients received 15 mg of MTX weekly and were tested before and after for skin severity, cholesterol levels, blood vessel flexibility, and a panel of inflammation markers tied to a cellular alarm system called the NLRP3 inflammasome. The good news: MTX significantly improved skin scores and lipid profiles. The less expected finding: blood vessel function and the inflammatory markers — including gasdermin D, IL-1β, NLRP3, and VCAM-1 — did not meaningfully change. The authors suggest that patients enrolled here may not have had pre-existing endothelial dysfunction, so there was little room for improvement to be detected. The study concludes that MTX appears cardiovascularly safe in this population, but cannot be credited with vascular benefit over this short timeframe. Longer trials with larger, higher-risk cohorts are needed before any vascular claims can be made.

• MTX therapy (15 mg/week for 12 weeks) significantly improved psoriasis clinical severity scores (PASI, BSA, DLQI), with results reaching statistical significance at p ≤ 0.024.
• Lipid profile parameters improved significantly after 12 weeks of MTX, suggesting a favorable metabolic effect beyond skin clearance.
• No significant changes were detected in flow-mediated dilation (FMD1 or FMD2), nitric oxide bioavailability (NOx), or pro-inflammatory biomarkers including GSDMD, IL-1β, NLRP3 inflammasome activation, LOX-1 receptor, and VCAM-1.

This was a prospective, open-label, single-arm pilot study conducted in Brazil, enrolling psoriasis patients who were assessed at baseline and after 12 weeks of methotrexate therapy at 15 mg/week. Endothelial function was measured non-invasively via flow-mediated dilation (FMD) at two time points. Nitric oxide bioavailability was estimated through serum nitrate and nitrite (NOx) levels. Pro-inflammatory biomarkers — gasdermin D (GSDMD), IL-1β, NLRP3, LOX-1, and VCAM-1 — were measured alongside standard clinical scores (PASI, BSA, DLQI) and a lipid panel; exact sample size is not reported in the available abstract.

As a 12-week open-label pilot without a placebo control arm, the study cannot distinguish MTX-specific vascular effects from natural disease fluctuation or regression to the mean. The enrolled population appears to have had intact endothelial function at baseline, creating a floor effect that would mask any protective vascular benefit — a higher-risk cohort with documented endothelial dysfunction would be the critical next population to study. Sample size is not disclosed in the abstract, raising concerns about statistical power to detect modest changes in biomarkers. A longer follow-up (ideally ≥ 52 weeks) with a parallel control group would be needed to determine whether lipid improvements eventually translate into measurable vascular benefit.

This study extends [§45], which targets the NLRP3 inflammasome pathway with a dedicated oral inhibitor (ruvonoflast) in individuals at elevated cardiovascular risk — here, MTX fails to suppress the same NLRP3/IL-1β axis in psoriasis patients over 12 weeks, suggesting that anti-inflammatory drugs not primarily designed as inflammasome inhibitors may be insufficient to shift these biomarkers in a short window. It parallels [§30], which similarly examines how a systemic anti-inflammatory intervention (vitamin D) modulates oxidative stress and inflammation in a chronic disease model, finding that mechanistic biomarker changes do not always follow clinical improvement — a pattern echoed in the present MTX findings. The absence of endothelial functional change also invites comparison with [§70], where a metabolic intervention (tirzepatide) in HIV-related chronic inflammation did produce systemic inflammatory shifts, raising the question of whether baseline inflammatory burden and patient selection drive biomarker responsiveness more than the drug itself. Collectively, this article occupies an important cautionary position in the corpus: clinical skin clearance and lipid improvement do not guarantee concurrent resolution of the vascular inflammatory milieu.

• Anti-inflammatory effects of oral NLRP3 inhibition with ruvonoflast among individuals at elevated cardiovascular risk
  Directly targets the same NLRP3/IL-1β pathway studied here, but with a purpose-built inflammasome inhibitor in a cardiovascular-risk population — comparing outcomes reveals whether pathway-specific targeting outperforms MTX's broader immunosuppression for vascular biomarkers.
• 1,25-Dihydroxyvitamin D3 mitigates high glucose-induced oxidative stress, inflammation, and extracellular matrix accumulation in glomerular mesangial cells via the ROS/TXNIP/NLRP3 pathway
  Also tests a systemic anti-inflammatory agent (vitamin D) on inflammation and oxidative stress biomarkers in a chronic disease context, providing a mechanistic parallel for understanding why clinical improvement can dissociate from biomarker change.
• Effects of Tirzepatide on Weight Loss and Chronic Inflammation in People With HIV
  Examines how a metabolic-plus-anti-inflammatory intervention (tirzepatide) shifts chronic inflammation markers in a different high-cardiovascular-risk population (HIV), offering a contrast case where systemic inflammatory biomarkers did respond — highlighting the role of baseline disease burden and patient selection.
• Ligature-induced periodontitis in mice potentially accelerates CD4+ T-cell senescence and exacerbates rheumatoid arthritis
  Explores immune-mediated chronic inflammation and T-cell dysregulation in a separate disease context (periodontitis/rheumatoid arthritis), useful for contextualising whether the NLRP3/inflammasome unresponsiveness seen here is psoriasis-specific or a broader feature of short-term immunomodulatory treatment.