title: 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.
abstract: 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.
  
  
  
  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.
  
  
  
  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/m2unit 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/m2and ≥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).
  
  
  
  Elevated BMI and presence of ACPA interacted to increase RA risk. Time to RA onset was shortest among overweight/obese women with ≥2 ACPA.
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115. Electronic address: stedeschi1@partners.org.
authors.forename: Sara K
authors.initials: SK
authors.lastname: Tedeschi
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115.
authors.forename: Jing
authors.initials: J
authors.lastname: Cui
authors.affiliation: Department of Medicine, Karolinska Institutet, Solna, Stockholm, Sweden.
authors.forename: Elizabeth V
authors.initials: EV
authors.lastname: Arkema
authors.affiliation: Division of Immunology and Rheumatology, Stanford University, Palo Alto, CA.
authors.forename: William H
authors.initials: WH
authors.lastname: Robinson
authors.affiliation: Division of Immunology and Rheumatology, Stanford University, Palo Alto, CA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Sokolove
authors.affiliation: Division of Immunology and Rheumatology, Stanford University, Palo Alto, CA.
authors.forename: Nithya
authors.initials: N
authors.lastname: Lingampalli
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Sparks
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115.
authors.forename: Elizabeth W
authors.initials: EW
authors.lastname: Karlson
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115.
authors.forename: Karen H
authors.initials: KH
authors.lastname: Costenbader
mesh_terms: D000328:Adult; D000075422:Anti-Citrullinated Protein Antibodies / Q000097:blood* / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000175:diagnosis / Q000209:etiology* / Q000276:immunology; D015992:Body Mass Index; D016022:Case-Control Studies; D000939:Epitopes; D005260:Female; D006801:Humans; D008875:Middle Aged; D009726:Nurses; D012307:Risk Factors; D013997:Time Factors
chemical_list: D000075422:Anti-Citrullinated Protein Antibodies; D000939:Epitopes
keywords: ACPA; Autoantibodies; Obesity; Rheumatoid arthritis