Determining in which pre-arthritis stage HLA-shared epitope alleles and smoking exert their effect on the development of rheumatoid arthritis

• Published in: Annals of the rheumatic diseases Vol. 81; no. 1; p. 48
• Main Authors: Wouters, Fenne, Maurits, Marc P, van Boheemen, Laurette, Verstappen, Marloes, Mankia, Kulveer, Matthijssen, Xanthe M E, Dorjée, Annemarie L, Emery, Paul, Knevel, Rachel, van Schaardenburg, Dirkjan, Toes, René E M, van der Helm-van Mil, Annette H M
• Format: Journal Article
• Language: English
• Published: England 01-01-2022
• Subjects: Alleles; Anti-Citrullinated Protein Antibodies - blood; Arthralgia - blood; Arthritis, Rheumatoid - blood; Arthritis, Rheumatoid - etiology; Arthritis, Rheumatoid - genetics; Arthritis, Rheumatoid - immunology; Asymptomatic Diseases; Disease Progression; Epitopes - genetics; HLA Antigens - genetics; Humans; Rheumatoid Factor - blood; Risk Factors; Tobacco Smoking; anti-citrullinated protein antibodies; arthritis; autoantibodies; rheumatoid; smoking
• ISSN: 1468-2060
• DOI: 10.1136/annrheumdis-2021-220546

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.
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).
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.
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.