OBJECTIVE: Our objective was to assess the incidence of major adverse cardiovascular events (MACEs) in patients with rheumatoid arthritis (RA) treated with JAK inhibitors (JAKi), tumor necrosis factor inhibitors (TNFi), or biologic disease-modifying antirheumatic drugs with other modes of action (bDMARD-OMA) in a multicountry, real-world population. METHODS: Patients with RA from 15 registries in the JAK-pot collaboration were included. MACE incidence was analyzed using two approaches: a within-registry analysis aggregating country-specific estimates from registers with >25 incident MACEs through meta-analysis and an individual-level data combined analysis. We used adjusted linear mixed Poisson regression to obtain incidence rate ratios (IRRs) of MACEs between treatment groups, accounting for multiple treatment courses. RESULTS: The study included 73,008 treatment courses (16,417 JAKi, 35,373 TNFi, and 21,218 bDMARD-OMA) and 828 incident MACEs among 51,233 patients. Median follow-up time was 1.3 years, with most of the follow-up concentrated in the first two years of treatment. Incidence rates were 7.0, 7.6, and 11.8 per 1,000 person-years for JAKi, TNFi, and bDMARD-OMA, respectively. Compared to TNFi, JAKi (within-registry adjusted IRR 0.89, 95% confidence interval [CI] 0.63-1.25) had similar incidence rates of MACEs and bDMARD-OMA had higher rates (within-registry adjusted IRR 1.35, 95% CI 1.10-1.66). Combined analysis showed similar results. CONCLUSION: Observational data from the JAK-pot collaboration show no evidence of an increase in cardiovascular events during the first two years of use with JAKi compared to TNFi in the general RA population.

• MeSH
• Antirheumatic Agents * therapeutic use   adverse effects   MeSH
• Biological Products * therapeutic use   adverse effects   MeSH
• Adult MeSH
• Incidence MeSH
• Janus Kinase Inhibitors * therapeutic use   adverse effects   MeSH
• Tumor Necrosis Factor Inhibitors therapeutic use   adverse effects   MeSH
• Cardiovascular Diseases * epidemiology   chemically induced   MeSH
• Middle Aged MeSH
• Humans MeSH
• Registries MeSH
• Arthritis, Rheumatoid * drug therapy   MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Comparative Study MeSH
• Names of Substances
• Antirheumatic Agents * MeSH
• Biological Products * MeSH
• Janus Kinase Inhibitors * MeSH
• Tumor Necrosis Factor Inhibitors MeSH

This commentary explores the potential cardiovascular (CV) benefits of combining methotrexate (MTX) and Janus kinase inhibitors (JAKis) in the treatment of rheumatoid arthritis (RA). While European guidelines recommend MTX as first-line treatment, concerns about the CV risks associated with JAKis have emerged. This article reviews the existing literature to assess the role of concomitant MTX in reducing CV risk when used with JAKis. Clinical trials confirm the efficacy of JAKis in combination with MTX in terms of treatment outcomes in RA. However, the number of major adverse cardiovascular events (MACEs) reported is too low to draw conclusions on adverse CV outcomes. Indirect evidence does, however, suggest potential protective effects of MTX on CV outcomes, as several mechanisms may contribute to MTX's cardioprotective effects, including reduced inflammation, adenosine monophosphate-activated protein kinase (AMPK) activation, increased cholesterol efflux, and adenosine accumulation. These mechanisms and the available data may support the case for CV benefits of concomitant MTX when JAKis are used in the treatment of patients with RA, although further research is needed. In particular, the lipid paradox associated with RA highlights the complex relationship between RA treatments (MTX, JAKis, tumor necrosis factor (TNF) inhibitors, and interleukin (IL)-6 receptor inhibitors), inflammation, different lipid profiles, and CV risk. In the absence of contraindications and when MTX is tolerated, this commentary suggests the concomitant use of MTX and JAKis as a preferred option for optimizing CV protection in patients with RA.

• Keywords
• Cardiovascular, Combination therapy, Janus kinase inhibitors, Methotrexate, Rheumatoid arthritis,
• Publication type
• Journal Article MeSH

BACKGROUND: In a clinical trial setting, patients with rheumatoid arthritis (RA) taking the Janus kinase inhibitor (JAKi) tofacitinib demonstrated higher adverse events rates compared with those taking the tumour necrosis factor inhibitors (TNFi) adalimumab or etanercept. OBJECTIVE: Compare treatment discontinuations for adverse events (AEs) among second-line therapies in an international real-world RA population. METHODS: Patients initiating JAKi, TNFi or a biological with another mode of action (OMA) from 17 registers participating in the 'JAK-pot' collaboration were included. The primary outcome was the rate of treatment discontinuation due to AEs. We used unadjusted and adjusted cause-specific Cox proportional hazard models to compare treatment discontinuations for AEs among treatment groups by class, but also evaluating separately the specific type of JAKi. RESULTS: Of the 46 913 treatment courses included, 12 523 were JAKi (43% baricitinib, 40% tofacitinib, 15% upadacitinib, 2% filgotinib), 23 391 TNFi and 10 999 OMA. The adjusted cause-specific hazard rate of treatment discontinuation for AEs was similar for TNFi versus JAKi (1.00, 95% CI 0.92 to 1.10) and higher for OMA versus JAKi (1.11, 95% CI 1.01 to 1.23), lower with TNFi compared with tofacitinib (0.81, 95% CI 0.71 to 0.90), but higher for TNFi versus baricitinib (1.15, 95% CI 1.01 to 1.30) and lower for TNFi versus JAKi in patients 65 or older with at least one cardiovascular risk factor (0.79, 95% CI 0.65 to 0.97). CONCLUSION: While JAKi overall were not associated with more treatment discontinuations for AEs, subgroup analyses suggest varying patterns with specific JAKi, such as tofacitinib, compared with TNFi. However, these observations should be interpreted cautiously, given the observational study design.

• Keywords
• Antirheumatic Agents, Arthritis, Rheumatoid, Biological Therapy, Epidemiology,
• MeSH
• Antirheumatic Agents * therapeutic use   MeSH
• Azetidines * MeSH
• Janus Kinase Inhibitors * therapeutic use   MeSH
• Tumor Necrosis Factor Inhibitors therapeutic use   MeSH
• Humans MeSH
• Purines * MeSH
• Pyrazoles * MeSH
• Arthritis, Rheumatoid * drug therapy   MeSH
• Sulfonamides * MeSH
• Tumor Necrosis Factor-alpha MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Observational Study MeSH
• Names of Substances
• Antirheumatic Agents * MeSH
• Azetidines * MeSH
• baricitinib MeSH Browser
• Janus Kinase Inhibitors * MeSH
• Tumor Necrosis Factor Inhibitors MeSH
• Purines * MeSH
• Pyrazoles * MeSH
• Sulfonamides * MeSH
• Tumor Necrosis Factor-alpha MeSH