Elevated Anti-Citrullinated Protein Antibody Levels Before RA Diagnosis Associated With COPD Risk

Researchers investigated the association between elevated anti-citrullinated protein antibody levels before rheumatoid arthritis diagnosis and the risks for chronic obstructive pulmonary disease or asthma.

Women with elevated levels of anti-citrullinated protein antibodies (ACPA) before rheumatoid arthritis (RA) diagnosis experience increased risk of developing chronic obstructive pulmonary disease (COPD), according to study results published in Arthritis Care and Research. In addition, researchers observed that women who later developed RA were more likely to develop asthma, regardless of ACPA status before RA diagnosis.

Researchers conducted a matched-cohort nested study to assess whether elevated ACPA levels in pre-RA banked blood was associated with a subsequent risk for either COPD or asthma. Data from the Nurses’ Health Study and Nurses’ Health Study II were used for the study. Every patient with RA was matched with 3 healthy control participants who had never reported either RA or other connective tissue diseases and who had donated blood. All participants were asked to self-report asthma diagnoses. Two separate laboratory assays were used to test for ACPA levels.

The total cohort included 283 women and 842 matched control participants. Investigators examined 1125 study samples for the COPD analysis and 951 for the asthma analysis. Average age was similar between the pre-RA ACPA+ and pre-RA ACPA- group and their matching control groups. The mean time between blood draw and diagnosis or match date was 6.4 years (median, 4.8 years) and 10.6 years (median, 10.6 years) for the pre-RA ACPA+ and pre-RA ACPA- groups, respectively. Compared with the control participants, patients in the pre-RA ACPA+ group had numerically higher, but statistically nonsignificant, smoking pack-years (mean, 19.3 vs 21.5 pack-years, respectively).

During 21,489 person-years of follow-up, the researchers noted 107 cases of incident COPD. Mean age at diagnosis was 64.5±11.4 years; 74.8% of these patients were smokers. Among women in the pre-RA ACPA+ group, 22.0% developed COPD, with 46.2% of the COPD cases developing before RA diagnosis. During 18,365 person-years of follow-up, researchers noted 105 cases of incident asthma, with a mean age of 59.4±9.5 years at diagnosis. A total of 34 patients reported diagnoses of both COPD and asthma, 73 reported only COPD, 71 reported only asthma, and 153 reported either COPD or asthma or both.

In a model adjusting only for matching factors, pre-RA ACPA+ was significantly associated with incident COPD (hazard ratio [HR], 3.02; 95% CI, 1.42-6.43); results were similar in a multivariable model that additionally adjusted for smoking pack-years, body mass index, income, and asthma (HR, 3.04; 95% CI, 1.33-7.00). After further adjusting for smoking status and including a quadratic term for continuous smoking pack-years, the results remained consistent (HR, 2.91; 95% CI, 1.28-6.64).

Study results showed that pre-RA ACPA- was not associated with COPD (HR, 1.07; 95% CI, 0.65-1.75). Among patients with pre-RA ACPA- RA within 5 years of blood draw, there was no association with COPD (HR, 0.49; 95% CI, 0.10-2.39). Investigators also noted no association of all pre-RA women with COPD (HR, 1.39; 95% CI, 0.92-2.09) and no statistical interaction between pre-RA or control status and ACPA status for COPD risk. In only the pre-RA analysis, compared with pre-RA ACPA-, pre-RA ACPA+ was significantly associated with increased risk for incident COPD (HR, 2.22; 95% CI, 1.12-4.41).

Asthma analyses indicated that, compared with participants without RA, women who developed RA had an increased asthma risk (HR, 1.65; 95% CI, 1.11-2.46). Pre-RA ACPA- also led to an increased risk for asthma compared with control participants (HR, 1.62; 95% CI, 1.04-2.55), and although pre-RA ACPA+ was not statistically associated with asthma diagnosis, an estimate of effect size was similar (HR, 1.74; 95% CI, 0.72-4.24). All pre-RA patients had an increased risk for asthma compared with controls (HR, 1.70; 95% CI, 1.01-2.88).

Analyses stratified by smoking status demonstrated results that were generally consistent with the primary study results.

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Study limitations included potential misclassification because of the use of 2 assays, an inability to phenotype COPD and asthma based on severity, subtype, or treatment, and a limited number of patients available for this particular cohort.

“Overall, our results emphasize that clinicians should closely monitor seropositive patients for airway abnormalities, even [before] RA onset,” the researchers concluded. “Future work is needed to elucidate the bidirectional link between RA and chronic airway diseases.”

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Zaccardelli A, Lui X, Ford JA, et al. Elevated anti-citrullinated protein antibodies prior to rheumatoid arthritis diagnosis and risks for chronic obstructive pulmonary disease or asthma [published online January 21, 2020]. Arthritis Care Res. doi:10.1002/acr.24140