Influence of body mass index on cardiovascular risk in rheumatoid arthritis varies across anti-citrullinated protein antibody status and biologic use

Abstract

Objectives: The impact of body mass index (BMI) on cardiovascular risk in rheumatoid arthritis (RA) is unclear. RA characteristics may influence the association between BMI and risk. Disease activity, which predicts cardiovascular risk, is associated with obesity only among anticitrullinated antibody (ACPA)-positive patients. Biologics alter body composition and mitigate cardiovascular risk in RA. We explored the association of BMI with cardiovascular risk and whether this varied across ACPA status and biologic use.

Methods: We evaluated 3982 patients from an international observational cohort. Outcomes included (a) first major adverse cardiovascular event (MACE) encompassing myocardial infarction, stroke or cardiovascular death; and (b) all events comprising MACE, angina, revascularisation, transient ischaemic attack, peripheral arterial disease and heart failure. Multivariable Cox models stratified by centre risk evaluated the impact of BMI, ACPA, biologics and their two- and three-way interactions on outcomes.

Results: We recorded 192 MACE and 319 total events. No main effects of BMI, ACPA or biologics were observed. A three-way interaction between them on MACE (p-interaction<0.001) and all events (p-interaction=0.028) was noted. Among ACPA negative patients, BMI was inversely associated with MACE (HR 0.38 (95% CI 0.25 to 0.57)) and all events (HR 0.67 (0.49 to 0.92)) in biologic users but not non-users (p-for-interaction <0.001 and 0.012). Among ACPA-positive patients, BMI was associated with MACE (HR 1.04 [1.01-1.07]) and all events (HR 1.03 (1.00 to 1.06)) independently of biologic use.

Conclusions: BMI is inversely associated with cardiovascular risk only among ACPA-negative biologic users. In contrast, BMI is associated with cardiovascular risk in ACPA-positive patients independently of biologic use.

Keywords: Anti-Citrullinated Protein Antibodies; Arthritis, Rheumatoid; Biological Therapy; Cardiovascular Diseases.

Figure 1. Main effects of BMI, ACPA positivity and bDMARD use on cardiovascular event risk. All models adjust for age, hypertension, diabetes, family history of cardiovascular disease, smoking, total cholesterol/high-density lipoprotein cholesterol ratio, rheumatoid arthritis duration and 28-joint disease activity score with erythrocyte sedimentation rate. BMI, body mass index; bDMARD, biologic disease-modifying anti-rheumatic drug; ACPA, anti-citrullinated protein antibodies; CVEs, cardiovascular events.

Figure 2. Cumulative hazard of MACE in ACPA-positive patients at low BMI (one SD below the mean) and high BMI (one SD above the mean). ACPA, anti-citrullinated protein antibodies; BMI, body mass index; MACE, major adverse cardiovascular event.

Figure 3. Effect of BMI on cardiovascular risk in ACPA-negative patients stratified by bDMARD use in unweighted models, models with inverse probability weighting and unweighted models limited to sample enrolment from 2000 forward. All models adjust for age, hypertension, diabetes, family history of cardiovascular disease, smoking, total cholesterol/high-density lipoprotein cholesterol ratio, rheumatoid arthritis duration and 28-joint disease activity score with erythrocyte sedimentation rate. ACPA, anti-citrullinated protein antibodies; bDMARD, biologic disease modifying anti-rheumatic drug; BMI, body mass index; CVEs: cardiovascular events; IP-weighted, inverse probability weighted analyses.

Figure 4. Cumulative hazard plots of all cardiovascular events in ACPA-negative bDMARD users and non-users at low BMI (one SD below the mean) and high BMI (one SD above the mean). ACPA, anti-citrullinated protein antibodies; bDMARD, biologic disease modifying antirheumatic drug; BMI, body mass index, Cum, cumulative, CVEs, cardiovascular events.

Figure 5. (A) Effect of inverted BMI on cardiovascular risk in ACPA-negative patients stratified by bDMARD use. All models adjust for age, hypertension, diabetes, family history of cardiovascular disease, smoking, total cholesterol/high-density lipoprotein cholesterol ratio, rheumatoid arthritis duration and 28-joint disease activity score with erythrocyte sedimentation rate. (B) Competing risk regression analysis for MACE and all cardiovascular events accounting for the competing risk of non-cardiovascular disease-related death. BMI, body mass index; ACPA, anti-citrullinated protein antibodies; bDMARD, biologic disease modifying anti-rheumatic drug; SHR, sub-hazard ratio; CVEs, cardiovascular events; MACE, major adverse cardiovascular events.