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

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 anticitrullinated 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+2 vs. 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. Rheumatoid arthritis (RA) is a systemic autoimmune disease that can be divided in two pathogenic subgroups 1,2. The largest subgroup comprises the patients presenting RA specific autoantibodies. These antibodies include the rheumatoid factor (RF), which is directed against the Fc of the IgG, and antibodies against some post-translational protein modifications. The best characterized are anti-citrullinated protein antibodies (ACPA), which in the clinic are assayed as anti-cyclic citrullinated peptides or anti-CCP, and the anti-carbamylated protein antibodies (ACarPA), which are not yet analyzed beyond research studies. The antibody positive patients are known as seropositive and they represent more than two thirds of the total, while the remaining are the seronegative patients.

Improved classification of rheumatoid arthritis with a score including anti-acetylated ornithine antibodies

“…Another aspect that could affect the reproducibility of the findings pertains to differences in the patient populations. In this respect, the frequency of smokers was lower in our patients than in some other European EA cohorts [37][38][39] . However, we did not find that smoking alters the association of antibody concordance with the RA classification.…”

“…The same report showed that the distinction in RF levels added little to classification. This could be explained by the correlation between high RF levels and anti-CCP presence observed in our patients ( Supplementary Table S6) and in other sets of RA patients [38][39][40] . Therefore, the lack of reliance on the RF and anti-CCP levels will permit increasing reproducibility of the RA classification based on anti-AcOrn concordance without losing accuracy.…”

“…Unfortunately, this seems to be the common outcome with the autoantibodies given their concordant presence in the RA patients [16][17][18] . Even, the concordance may reflect shared underlying pathways, as suggested by the recent work indicating that smoking predisposes primarily to RA with multiple autoantibodies [37][38][39] .…”

Impact of Posttranslational Modification in Pathogenesis of Rheumatoid Arthritis: Focusing on Citrullination, Carbamylation, and Acetylation

“…Studies have shown that carbamylation plays a role that is like citrullination in RA [ 249 , 254 , 255 ]. Similar to RF and ACPAs, anti-CarP antibodies show an association with risk when combined with smoking [ 256 ]. The presence of RF is associated with positivity for both ACPAs and anti-CarP antibodies [ 257 ].…”

Causal risk and protective factors in rheumatoid arthritis: A genetic update

“…Exposition to free crystalline silica represents another air pollutant risk-factor retrieved to be associated with RA development (OR = 1.94; CI95: 1.46–2.58), and such association is additive among tobacco smokers seropositive for ACPA and/or RF in men (OR = 3.30; CI95: 2.40–4.54) [ 15 , 64 ]. The underlying pathways leading to the development of RA within individuals exposed to tobacco smoking and air pollutants is still unclear and several models have been proposed: (i) an impaired innate immune system that relies on the positive association between smoking and P. gingivalis [ 65 ]; (ii) an affected adaptive immune response explaining that never smoker RA patients possess elevated protective anti- P. gingivalis and anti-PPAD antibody titers [ 66 ]; (iii) a deregulated PAD4 expression in the lung based on the observation that RA patients with ILD have increase PAD4 expression at transcriptional and protein level in bronchoalveolar granulocytes and monocytes among smokers [ 67 ]; (iv) a higher systemic inflammation as retrieved in the elevated tobacco consumption subgroup [ 17 ]; and (v) an association with RF-positivity (OR = 2.35; IC95: 1.64–3.35) independent from ACPA/CarpA status [ 15 , 68 ]. Although all these explanations are plausible, more studies are warranted to elucidate the mechanisms and their interplay.…”