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 Nursesʼ Health Studies

Abstract

Objective Overweight/obesity and anti-citrullinated protein antibodies (ACPA) increase 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 seven ACPA subtypes (biglycan, clusterin, enolase, fibrinogen, histone 2A, histone 2B, vimentin). Logistic regression analyses tested the association of BMI and ACPA and for a multiplicative interaction between BMI groups (≥25 vs. <25 kg/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 presence of ≥2 ACPA for RA risk (p=0.027). Women with BMI ≥25 kg/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 ≥25 kg/m2 (45.0 months, IQR [17.5-72.5]) and longest in women with <2 ACPA and BMI <25 kg/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.

Obesity and the risk of systemic lupus erythematosus among women in the Nurses’ Health Studies

“…33 Obesity has been identified as a risk factor for several other autoimmune diseases, including rheumatoid arthritis, psoriasis, psoriatic arthritis, inflammatory bowel disease, and sarcoidosis. 16,17,34–39 Murine models of SLE-prone mice (NZB/WF1 females) also support the hypothesis that obesity may be associated with increased SLE risk, as these mice have higher body weight and greater visceral fat compared to control mice. 40 …”

The importance of differences; On environment and its interactions with genes and immunity in the causation of rheumatoid arthritis

“…Most studies on the effects of obesity on risk to develop RA have demonstrated a certain increased risk for RA in individuals with obesity [109,110]. Dietary factors have for a long time been in the focus of many studies on development and disease course of RA, but results have in most cases remained inconclusive and difficult to reproduce.…”

Elevated adiponectin predicts the development of rheumatoid arthritis in subjects with obesity

“…The Swedish Obese Subjects (SOS) study is a longitudinal non-randomized controlled study designed to examine the effect of bariatric surgery on obesityassociated morbidity and overall mortality (24)(25)(26). In this cohort of subjects with obesity, we have previously analysed the effect of bariatric surgery on the future development of RA, since obesity is thought to be a risk factor for the development of the disease, in particular if combined with other factors (27,28). However, we were not able to detect any association between bariatric surgery and the incidence of RA (29).…”