Anti-Citrullinated Protein Antibody Presence in RA Linked to Prior Asthma Diagnosis

Woman using asthma inhaler
Investigators analyzed the potential link between asthma and elevated anti-citrullinated antibody presence before diagnosis of rheumatoid arthritis.

Asthma may be strongly associated with elevated levels of anti-citrullinated protein antibody (ACPA) before rheumatoid arthritis (RA) diagnosis, according to research results published in Arthritis Research and Therapy. This association was found to be independent of patient smoking status.

Using data from 2 large prospective cohorts, researchers performed a nested case-control study to examine whether an asthma diagnosis was associated with elevated levels of ACPA before RA diagnosis. They collected data from the Nurses’ Health Study and the Nurses’ Health Study II and matched each RA case with 3 healthy controls. Investigators collected blood samples from both groups and used laboratory assays to evaluate the presence of ACPA in these samples.

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The study cohort included data of 1133 women: 96 with RA and 286 matched healthy controls. In total, 58.3% of pre-RA ACPA-positive cases were cyclic citrullinated peptide (CCP)-positive, 70.8% were rheumatoid factor-positive, and 79.2% were seropositive for either biomarker. Among pre-RA ACPA-negative patients, 9.4% were CCP-positive, 52.7% were rheumatoid factor-positive, and 53.7% were seropositive for either biomarker.

In the pre-RA ACPA-positive RA group, compared with no asthma, asthma was shown to have an odds ratio (OR) of 3.70 (95% CI, 1.7-8.05); this association remained after additional adjustment in a multivariable model (OR, 3.57; 95% CI, 1.58-8.04). Researchers noted no association between asthma and pre-RA ACPA-negative RA; however, they observed a significant difference in the associations between asthma and RA (P =.004), according to pre-RA ACPA status. Using a more specific definition of ACPA positivity in a secondary analysis, researchers identified a “similar but attenuated association” between asthma and pre-RA ACPA-positive RA (unadjusted OR, 2.75; 95% CI, 1.11-6.85; multivariable OR, 2.27; 95% CI, 0.84-6.16).

Investigators also assessed how smoking factored into their study results. After restricting their subgroup analysis to never smokers, asthma continued to be associated with pre-RA ACPA-positive RA (OR, 4.62; 95% CI, 1.28-16.64). Compared with asthma-free patients who smoked ≤10 packs per year, those with asthma and >10 pack-years of smoking resulted in a multivariable OR of 6.33 (95% CI, 1.43-27.95) for pre-RA ACPA-positive RA.

Among 36 cases, researchers identified data of patients who were pre-RA ACPA-positive within 5 years of RA diagnosis. After restricting analysis to this subgroup of patients and their matched healthy controls, women with asthma had a multivariable OR of 4.29 (95% CI, 0.95-19.77) for pre-RA ACPA-positive RA.

Study limitations included the use of a questionnaire rather than formal medical evaluation to collect asthma data, a small sample size, and possible changes in the formal definition of asthma over the last few decades.

“We showed that asthma may be important in the pathogenesis of ACPA+ RA independent of smoking,” the researchers concluded. “Our study provides evidence that airways may be important in RA-related autoantibody development and adds to the mucosal paradigm for RA pathogenesis.” They added, “Further research is warranted to understand the link between pulmonary abnormalities, autoimmunity, and RA.”

Disclosure: One study author declared an affiliation with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Zaccardelli A, Liu X, Ford JA, et al. Asthma and elevation of anti-citrullinated protein antibodies prior to the onset of rheumatoid arthritis. Arthritis Res Ther. 2019;21(1):246.