Associations With Smoking and Shared Epitope Differ Between IgA‐ and IgG‐Class Antibodies to Cyclic Citrullinated Peptides in Early Rheumatoid Arthritis

Abstract

Objective Smoking and HLA–DRB1/shared epitope (SE) alleles are risk factors for rheumatoid arthritis (RA) characterized by seropositivity for antibodies targeting citrullinated proteins (ACPAs)/cyclic citrullinated peptides (anti‐CCP). Previously, mainly IgG‐class antibodies have been studied. IgA‐class antibodies are to a great extent related to mucosal immunity. The aim of this study was to explore interrelations between cigarette smoking, presence of SE, and seropositivity for circulating IgA and/or IgG anti‐CCP antibodies among patients with early RA, to determine whether ACPAs of the IgA subclass are regulated by different mechanisms than those of the IgG subclass. Methods Two cohorts of patients with early RA, from the first Epidemiological Investigations of RA trial (n = 1,663) and the second Early Intervention in RA trial (n = 199), were grouped into 4 subsets based on anti‐CCP subclass status (IgG−/IgA−, IgG−/IgA+, IgG+/IgA−, and IgG+/IgA+), and each subset was compared with regard to associations with smoking (current and former) and presence of SE. Interaction between smoking and SE was calculated using the attributable proportion (AP) due to interaction (assessing deviation from additivity of effects). Results Smoking was overrepresented among IgA anti‐CCP–positive RA patients, regardless of whether IgG anti‐CCP were present, whereas in patients with IgG anti‐CCP alone, no association with smoking was found. SE alleles were overrepresented among IgG anti‐CCP–positive patients, regardless of IgA anti‐CCP status, and was not seen in patients with IgA anti‐CCP alone. An interaction between ever smoking and SE was found with regard to the risk of IgG+/IgA+ RA (AP 0.5, 95% confidence interval 0.4, 0.6). No significant interaction was observed with regard to the risk of IgG−/IgA+ RA or IgG+/IgA− RA. Conclusion In patients with RA, a history of ever smoking was associated with seropositivity for IgA anti‐CCP antibodies, whereas presence of SE was associated with seropositivity for IgG anti‐CCP antibodies. An interaction between ever smoking and the SE was limited to the RA subset characterized by seropositivity for both IgG and IgA anti‐CCP. These findings provide novel evidence that anti‐CCP–positive RA can be divided into at least 3 serologically distinct subsets associated with different risk factors, indicating different modes of pathogenesis in RA.

Smoking and Air Pollution as Pro-Inflammatory Triggers for the Development of Rheumatoid Arthritis

“…This contention is supported by findings of structural abnormalities of lung parenchyma in patients with untreated, early ACPA-positive RA [41]. These were 5 associated with high concentrations of ACPA in bronchoalveolar lavage fluid relative to those of blood [35,39].…”

“…The smoking/SE allele interaction is, however, complex [40]. This is clearly illustrated by the findings of a recent study which reported that ever-smoking per se is associated with production of ACPA of the IgA isotype, possibly consistent with a pulmonary origin, while SE in the absence of smoking is associated with ACPA of the IgG isotype, and the combination of smoking and SE with seropositivity for both isotypes [41].…”

Anti-citrullinated protein antibodies cause arthritis by cross-reactivity to joint cartilage

“…In the present study, we used part of the TIRA2 cohort (n = 504), which enrolled patients with recent-onset RA between 2006 and 2009 (37). Symptom duration was at least 6 weeks but less than 12 months.…”

Anti-phospholipid Antibodies and Smoking: An Overview

“…These results were confirmed by Manfredsdittor et al [129] in a prospective study that showed that IgA RF was associated with a poor prognosis. Svärd et al reported that in anti-CCPpositive patients with RA, a history of Bever smokingŵ as associated only with IgA antibodies [130], and the same group reported in 2016 that circulating secretory IgA antibodies against cyclic citrullinated peptides in early rheumatoid arthritis associate with inflammatory activity and smoking [131]. Mikuls et al [132] examined cigarette smoking and RA-related features in African Americans.…”