TY - JOUR T1 - Determining in which pre-arthritis stage HLA-shared epitope alleles and smoking exert their effect on the development of rheumatoid arthritis JF - Annals of the Rheumatic Diseases JO - Ann Rheum Dis DO - 10.1136/annrheumdis-2021-220546 SP - annrheumdis-2021-220546 AU - Fenne Wouters AU - Marc P Maurits AU - Laurette van Boheemen AU - Marloes Verstappen AU - Kulveer Mankia AU - Xanthe M E Matthijssen AU - Annemarie L Dorjée AU - Paul Emery AU - Rachel Knevel AU - Dirkjan van Schaardenburg AU - René E M Toes AU - Annette H M van der Helm-van Mil Y1 - 2021/07/20 UR - http://ard.bmj.com/content/early/2021/07/19/annrheumdis-2021-220546.abstract N2 - Objectives The human leukocyte antigen-shared epitope (HLA-SE) alleles and smoking are the most prominent genetic and environmental risk factors for rheumatoid arthritis (RA). However, at which pre-arthritis stage (asymptomatic/symptomatic) they exert their effect is unknown. We aimed to determine whether HLA-SE and smoking are involved in the onset of autoantibody positivity, symptoms (clinically suspect arthralgia (CSA)) and/or progression to clinical arthritis.Methods We performed meta-analyses on results from the literature on associations of HLA-SE and smoking with anti-citrullinated protein antibodies (ACPAs) in the asymptomatic population. Next, we studied associations of HLA-SE and smoking with autoantibody positivity at CSA onset and with progression to clinical inflammatory arthritis (IA) during follow-up. Associations in ACPA-positive patients with CSA were validated in meta-analyses with other arthralgia cohorts. Analyses were repeated for rheumatoid factor (RF), anti-carbamylated protein antibodies (anti-CarP) and anti-acetylated protein antibodies (AAPA).Results Meta-analyses showed that HLA-SE is not associated with ACPA positivity in the asymptomatic population (OR 1.06 (95% CI:0.69 to 1.64)), whereas smoking was associated (OR 1.37 (95% CI: 1.15 to 1.63)). At CSA onset, both HLA-SE and smoking associated with ACPA positivity (OR 2.08 (95% CI: 1.24 to 3.49), OR 2.41 (95% CI: 1.31 to 4.43)). During follow-up, HLA-SE associated with IA development (HR 1.86 (95% CI: 1.23 to 2.82)), in contrast to smoking. This was confirmed in meta-analyses in ACPA-positive arthralgia (HR 1.52 (95% CI: 1.08 to 2.15)). HLA-SE and smoking were not associated with RF, anti-CarP or AAPA-positivity at CSA onset. Longitudinally, AAPA associated with IA development independent from ACPA and RF (HR 1.79 (95% CI: 1.02 to 3.16)), anti-CarP did not.Conclusions HLA-SE and smoking act at different stages: smoking confers risk for ACPA and symptom development, whereas HLA-SE mediates symptom and IA development. These data enhance the understanding of the timing of the key risk factors in the development of RA.Data can be requested from the corresponding author. ER -