Elevated BMI and antibodies to citrullinated proteins interact to increase rheumatoid arthritis risk and shorten time to diagnosis: A nested case-control study of women in the Nurses' Health Studies.

OBJECTIVE Overweight/obesity and anti-citrullinated protein antibodies (ACPA) increase rheumatoid arthritis (RA) risk. We investigated the relationship between body mass index (BMI) and ACPA, tested for an interaction between BMI and ACPA for RA risk, and examined effects of BMI and ACPA on time to RA diagnosis. DESIGN Within the Nurses' Health Studies, blood samples were collected before diagnosis from medical record-confirmed incident RA cases and matched controls. Multiplex assays measured 7 ACPA subtypes (biglycan, clusterin, enolase, fibrinogen, histone 2A, histone 2B, and vimentin). Logistic regression analyses tested the association of BMI and ACPA and for a multiplicative interaction between BMI groups (≥25 vs. <25kg/m2) and ACPA positivity (≥2 vs. <2 subtypes), adjusting for age, smoking, alcohol use, and HLA-shared epitope. In case-only analyses, log-rank tests compared time from blood draw to RA onset by cross-classified BMI/ACPA status. RESULTS Among 255 pre-RA cases and 778 matched controls, 15.7% vs. 2.1% (p<0.001) had ≥2 ACPA and 49.4% vs. 40.2% (p<0.01) were overweight/obese. Continuous BMI was not associated with presence of ≥2 ACPA [OR per kg/m2 unit BMI: 1.03 (95% CI: 0.97-1.09)]. However, there was a multiplicative interaction between elevated BMI and the presence of ≥2 ACPA for RA risk (p = 0.027). Women with BMI≥25kg/m2 and ≥2 ACPA had OR 22.7 (95% CI: 6.64-77.72) for RA. Median time to RA differed by BMI/ACPA group (overall log-rank p<0.001) and was shortest among women with ≥2 ACPA and BMI≥25kg/m2 [45.0 months, IQR: 17.5-72.5] and longest in women with <2 ACPA and BMI<25kg/m2 [125.0 months, IQR: 72.0-161.0] (pairwise log-rank p = 0.002). CONCLUSION Elevated BMI and presence of ACPA interacted to increase RA risk. Time to RA onset was shortest among overweight/obese women with ≥2 ACPA.