A predominant involvement of the triple seropositive patients and others with rheumatoid factor in the association of smoking with rheumatoid arthritis

Cristina Regueiro,Ana M Ortiz,Laura Nuño,Antonio Mera-Varela,Benjamı́n Fernández-Gutiérrez ,A Villalba ,Alejandro Balsa,Miguel A González‐Gay ,Raquel López‐Mejías ,Alfonso Corrales,Ana Triguero‐Martínez ,Luis Rodríguez‐Rodríguez ,Yolanda López-Golán ,Carmen Conde,Eva Pérez‐Pampín ,Sara Remuzgo‐Martínez ,Ana Martínez‐Feito ,Isidoro González‐Álvaro ,Eva Herranz,Lydia Abásolo ,Antonio G González

doi:10.1038/s41598-020-60305-x

Abstract

The major environmental risk factor for rheumatoid arthritis (RA) is smoking, which according to a widely accepted model induces protein citrullination in the lungs, triggering the production of anti-citrullinated protein antibodies (ACPA) and RA development. Nevertheless, some research findings do not fit this model. Therefore, we obtained six independent cohorts with 2253 RA patients for a detailed analysis of the association between smoking and RA autoantibodies. Our results showed a predominant association of smoking with the concurrent presence of the three antibodies: rheumatoid factor (RF), ACPA and anti-carbamylated protein antibodies (ACarPA) (3 Ab vs. 0 Ab: OR = 1.99, p = 2.5 × 10–8). Meta-analysis with previous data (4491 patients) confirmed the predominant association with the concurrent presence of the three antibodies (3 Ab vs. 0 Ab: OR = 2.00, p = 4.4 ×10–16) and revealed that smoking was exclusively associated with the presence of RF in patients with one or two antibodies (RF+1+2vs. RF−0+1+2: OR = 1.32, p = 0.0002). In contrast, no specific association with ACPA or ACarPA was found. Therefore, these results showed the need to understand how smoking favors the concordance of RA specific antibodies and RF triggering, perhaps involving smoking-induced epitope spreading and other hypothesized mechanisms.

Highlights

The major environmental risk factor for rheumatoid arthritis (RA) is smoking, which according to a widely accepted model induces protein citrullination in the lungs, triggering the production of anticitrullinated protein antibodies (ACPA) and RA development
We did not find significant associations of smoking with the specific presence of ACPA or anti-carbamylated protein antibodies (ACarPA). These results indicate that smoking promotes pathways leading to the concurrent presence of the three RA autoantibodies and, in its defect, to the production of rheumatoid factor (RF)
Smoking was associated with the presence of RF in the RA patients carrying two positive antibodies (2 Ab) (Supplementary Table S4)

Summary

Introduction

The major environmental risk factor for rheumatoid arthritis (RA) is smoking, which according to a widely accepted model induces protein citrullination in the lungs, triggering the production of anticitrullinated protein antibodies (ACPA) and RA development. Our results showed a predominant association of smoking with the concurrent presence of the three antibodies: rheumatoid factor (RF), ACPA and anti-carbamylated protein antibodies (ACarPA) (3 Ab vs 0 Ab: OR = 1.99, p = 2.5 × 10–8). In the ACPA positive patients, the risk is potentiated by interaction with the HLA-DRB1 shared epitope (SE)[8–10] This interaction together with protein citrullination in the bronchoalveolar lavage (BAL) cells of smokers has been at the basis of an influential pathogenic model[11]. We did not find significant associations of smoking with the specific presence of ACPA or ACarPA These results indicate that smoking promotes pathways leading to the concurrent presence of the three RA autoantibodies and, in its defect, to the production of RF

Methods

Results

Discussion

Conclusion