Background/Purpose: Disease activity was linked to cardiovascular (CV) risk in rheumatoid arthritis (RA). Anticitrullinated protein antibody (ACPA) positivity associated with greater synovial inflammation, tumor necrosis factor production and CV risk. We hypothesized that the effect of disease activity on CV risk may vary between ACPA positive and negative patients. Methotrexate is generally the initial treatment prescribed upon RA diagnosis, is shown to decrease proinflammatory cytokines and may lower CV risk. We postulated that the effect of disease activity on CV risk may differ across methotrexate users and nonusers. Moreover, methotrexate was reported to be less effective in seronegative compared to seropositive RA. We here explored whether the relationship between RA activity and CV risk varied according to ACPA status and methotrexate use.

Methods: We evaluated 3958 patients free of CV disease upon enrollment to an international consortium. Main outcome was major adverse cardiovascular events (MACE) defined as non-fatal myocardial infarction, non-fatal stroke, or CV death. Missing data were imputed using multiple imputation by chained equations with 10 repetitions. Multivariable Cox models stratified by center risk explored the impact of disease activity on 28-joint counts and C-reactive protein (DAS28CRP), ACPA positivity, methotrexate use and the two- and three-way interactions of DAS28CRP with ACPA positivity and/or methotrexate use on risk of MACE, after adjusting for age, gender, hypertension, diabetes, smoking, family history of CV disease, total cholesterol to high-density lipoprotein ratio, and disease duration.

Results: Of 3958 patients, 2373 (59.95%) were ACPA positive, 1323 (33.43%) used methotrexate, and mean (standard deviation) DAS28CRP was 3.74 (1.28). Throughout 22,749 patient years, 185 first MACE were recorded. There was a main effect of DAS28CRP (HR 1.18, 95% CI 1.03-1.30, p=0.019) and ACPA positivity (HR 1.44, 95% CI 1.04-1.99, p=0.027) but not methotrexate use (HR 0.78, 95% CI 0.47-1.30, p=0.341) on risk of MACE overall after multivariable adjustment. A significant three-way interaction between DAS28CRP, ACPA positivity and methotrexate use on the risk of MACE was observed (p-interaction=0.011) suggesting that the influence of methotrexate use on the association of RA activity with MACE differed between ACPA negative and positive patients. Among ACPA negative patients (Figure 1A), the methotrexate × DAS28CRP interaction was significant (p=0.038) such that higher disease activity associated with increased risk of MACE in methotrexate nonusers (HR 1.35, 95% CI 1.02-1.77, p=0.033) but not users (HR 0.40, 95% CI 0.15-1.09, p=0.073). Among ACPA positive patients (Figure 1B), the methotrexate × DAS28CRP interaction (p=0.237), main effect of DAS28CRP (HR 1.15, 95% CI 0.98-1.36, p=0.093), and main effect of methotrexate use (HR 0.80, 95% CI 0.43-1.47, p=0.464) were not significant.

Conclusion: Among ACPA negative patients, RA activity associated with MACE risk only in methotrexate nonusers. In contrast, there were no interaction or main effects of RA activity and methotrexate in ACPA positive patients, perhaps due to competing MACE risk conferred by ACPA positivity.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/methotrexate-use-influenced-the-effect-of-inflammation-on-cardiovascular-risk-differently-in-anticitrullinated-protein-antibody-negative-and-positive-patients-with-rheumatoid-arthritis/