Asthma and elevation of anti-citrullinated protein antibodies prior to the onset of rheumatoid arthritis

Abstract

BackgroundAnti-citrullinated protein antibodies (ACPA) are central to rheumatoid arthritis (RA) pathogenesis and may develop at inflamed mucosa. We investigated whether asthma, a disease of airway mucosal inflammation, was associated with elevated ACPA before RA diagnosis.MethodsWe performed a nested case-control study among women in two prospective cohorts, the Nurses’ Health Study (NHS; 1976–2014) and NHSII (1989–2015). Blood was obtained on a subset (NHS: 1989–1990; NHSII: 1996–1999). Cases met 1987 ACR or 2010 ACR/EULAR RA criteria by medical record review and were classified as seropositive (ACPA+ or rheumatoid factor positivity) or seronegative by clinical laboratory testing at diagnosis. We identified RA cases with blood drawn before the date of RA diagnosis (index date), matching each to three controls by age, cohort, year, time from blood draw to index date, and menopause. Pre-RA ACPA elevation for cases was defined as >99th percentile of the control distribution on a research assay composed of autoantibodies targeting citrullinated protein epitopes or positivity on the second-generation commercial assay for cyclic citrullinated peptide. Asthma status and covariates were obtained through biennial questionnaires before blood draw. Conditional logistic regression estimated ORs and 95%CIs for RA by pre-RA ACPA and clinical serostatus, adjusted for matching factors, smoking pack-years, passive smoking, and body mass index (BMI).ResultsWe identified 284 incident RA cases and 849 matched controls; mean age at the index date was 61.2 years (SD 10.1). Blood was drawn 9.7 years (mean; SD 5.8) before the index date. We identified 96 (33.8%) RA cases with elevated pre-RA ACPA. At blood draw, 17.7% of pre-RA ACPA+ cases and 6.3% of matched controls (p = 0.0008) reported clinician-diagnosed asthma. After adjusting for matching factors, smoking pack-years, passive smoking, and BMI, asthma was significantly associated with pre-RA ACPA+ RA (OR 3.57, 95%CI 1.58,8.04). Asthma was not associated with overall RA (OR 1.45, 95%CI 0.91,2.31), but was significantly associated with seropositive RA (OR 1.79, 95%CI 1.01,3.18).ConclusionsAsthma was strongly associated with ACPA elevation in blood drawn prior to RA diagnosis, independent of smoking. Chronic mucosal airway inflammation may contribute to ACPA development and RA pathogenesis.

Respiratory Diseases as Risk Factors for Seropositive and Seronegative Rheumatoid Arthritis and in Relation to Smoking

“…The primary finding that a history of respiratory disease was associated with developing RA aligns with the growing body of evidence supporting a connection between the lungs and RA. The association between chronic lower respiratory diseases and overall RA risk is consistent with existing data for asthma (9)(10)(11)(12)(13)(14)(15)18,19,25), COPD (10,(15)(16)(17)20), and ILD (27,28), which is mixed but mostly positive. Novel to our analysis were the associations between RA and acute upper respiratory diseases (e.g., sinusitis and pharyngitis), chronic upper respiratory diseases (e.g., rhinitis), and acute lower respiratory diseases (e.g., influenza and pneumonia), which have never been reported.…”

“…In newly diagnosed RA as well as RA prior to clinical diagnosis, smoking has been associated with citrullination and production of ACPAs in the lungs in the presence of subtle airway abnormalities, but in the absence of diagnosed airway disease (21)(22)(23). Other studies have demonstrated increased citrullination and/or ACPA production in patients with COPD (24), asthma (25), and interstitial lung disease (ILD) (26), also in the absence of smoking. These studies raise the question as to what extent the association between airway disease and RA may be attributable to smoking as a common risk factor and to what extent airway disease confers a risk of RA in the absence of smoking.…”

An assessment of anti-citrullinated protein antibody in systemically healthy individuals with or without chronic periodontitis: A case–control study

“…The biologic effect of smoking or other inhalants on RA risk may be due to induction of local pulmonary mucosal inflammation at the bronchioles and alveoli, leading to protein citrullination, loss of immune tolerance, and the apparent formation of ACPA preceding RA symptoms. [ 20 ]…”

Lung inflammation in the pathogenesis of rheumatoid arthritis

“…Several recent epidemiologic studies have also identified significant increases in the prevalence of lung disease, particularly AD, during pre‐RA, supporting lung disease as a risk factor for developing RA . Specifically, Zaccardelli et al found that a clinical diagnosis of asthma was present in 18% of serum ACPA + subjects who later developed classified RA compared to only 6% in matched controls.…”

“…70 Several recent epidemiologic studies have also identified significant increases in the prevalence of lung disease, particularly AD, during pre-RA, supporting lung disease as a risk factor for developing RA. 29,87 Specifically, Zaccardelli et al 87…”