Association of rheumatoid arthritis-related autoantibodies with pulmonary function test abnormalities in a rheumatoid arthritis registry

  • Sicong HuangEmail author
  • Xintong He
  • Tracy J. Doyle
  • Alessandra Zaccardelli
  • Allison A. Marshall
  • H. Maura Friedlander
  • Rachel B. Blaustein
  • Elisabeth A. Smith
  • Jing Cui
  • Christine K. Iannaccone
  • Taysir G. Mahmoud
  • Michael E. Weinblatt
  • Paul F. Dellaripa
  • Nancy A. Shadick
  • Jeffrey A. SparksEmail author
Original Article



We investigated whether rheumatoid arthritis (RA)-related autoantibodies were associated with abnormalities on pulmonary function tests (PFTs).


We studied RA serostatus and PFT abnormalities within a RA registry. RA serostatus was assessed by research assays for cyclic citrullinated peptide (CCP) and rheumatoid factor (RF). Outcomes were abnormalities on clinically indicated PFTs, including restriction, obstruction, and diffusion abnormality. Logistic regression was used to obtain ORs and 95% CIs for the PFT abnormalities by RA serologic phenotypes independent of lifestyle and RA characteristics.


Among 1272 analyzed subjects, mean age was 56.3 years (SD 14.1), 82.2% were female, and 69.5% were seropositive. There were 100 subjects with abnormal PFTs. Compared with seronegativity, seropositivity was associated with increased odds of any PFT abnormality (multivariable OR 2.29, 95% CI 1.30–4.03). When analyzing type of PFT abnormality, seropositivity was also associated with restriction, obstruction, and diffusion abnormalities; multivariable ORs were 2.48 (95% CI 1.26–4.87), 3.12 (95% CI 1.28–7.61), and 2.30 (95% CI 1.09–4.83), respectively. When analyzing by CCP and RF status, the associations were stronger for RF+ than for CCP+ (any PFT abnormality OR 1.99, 95% CI 1.21–3.27 for RF+ vs. RF−; OR 1.67, 95% CI 1.03–2.69 for CCP+ vs. CCP−) with a dose effect of higher RF titer increasing odds for each PFT abnormality (p for trend < 0.05).


Seropositive RA patients had two-fold increased risk for abnormalities on PFTs performed for clinical indications compared with seronegative RA. Patients with seropositive RA, particularly those with high-titer RF positivity, may be more likely to have obstructive and restrictive abnormalities, independent of smoking.

Key points

• Due to the known excess pulmonary morbidity/mortality in RA, we studied the relationship of rheumatoid arthritis (RA)-related autoantibodies with pulmonary function test (PFT) abnormalities using a large RA registry.

• We evaluated whether presence and levels of cyclic citrullinated peptide (CCP) and rheumatoid factor (RF) were associated with restriction, obstruction, and diffusion abnormalities on PFTs among 1272 subjects with RA.

• Seropositivity was associated with two-fold increased risk for any PFT abnormality, independent of confounders including smoking. Higher titers of RF conferred greatest risk for all PFT outcomes: obstruction, restriction, and diffusion abnormality.

• These results provide evidence that patients with RA should be closely monitored for pulmonary involvement, particularly those with high-titer RF seropositivity.


CCP Pulmonary disease RF Rheumatoid arthritis Serostatus 



The authors thank Elizabeth W. Karlson, MD, MS for her support and guidance. We thank Vivi Feathers for the assistance in data management and statistical analysis. We thank the dedicated RA participants and staff of the Brigham Rheumatoid Arthritis Sequential Study (BRASS) at Brigham and Women’s Hospital for their continued participation in this longitudinal research study.

Author contributions

All authors were involved in drafting the article or revising it critically for important intellectual contact, and all authors approved the final version to be published. Huang, He, Shadick, and Sparks were involved in the study conception and design; Huang, Zaccardelli, Marshall, Friedlander, Blaustein, Smith, Cui, Iannaccone, Mahmoud, Weinblatt, Shadick and Sparks in acquisition of data; and Huang, He, Doyle, Zaccardelli, Marshall, Friedlander, Cui, Iannaccone, Mahmoud, Weinblatt, Dellaripa, Shadick and Sparks in data analysis and interpretation. Dr. Huang had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Funding information

This work was supported by the Rheumatology Research Foundation K Supplement Award and the National Institutes of Health (grant numbers K23 AR069688, K23 HL119558, R03 AR075886, L30 AR066953, R01 AR049880, P30 AR070253, and P30 AR072577). The Brigham Rheumatoid Arthritis Sequential Study is funded by grants from Bristol-Myers Squibb, Crescendo Bioscience, and Sanofi/Regeneron. The funders had no role in study design, data collection, analysis, decision to publish, or preparation of the manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard University, its affiliated academic health care centers, or the National Institutes of Health.

Compliance with ethical standards

The study protocol and informed consent document were reviewed and approved by the Partners HealthCare Institutional Review Board. All subjects provided written informed consent before participating in the BRASS registry.

Conflict of interest

Tracy J. Doyle reports research funding from Bristol-Myers Squibb and involvement in a clinical trial funded by Genentech. Paul F. Dellaripa reports research funding from Bristol-Myers Squibb and involvement in a clinical trial funded by Genentech. Michael E. Weinblatt reports research grants from Amgen, Crescendo Bioscience, Sanofi/Regeneron, and Bristol-Myers Squibb; consultancy to Abbvie, Amgen, Bristol-Myers Squibb, Canfite, Corrona, Crescendo Bioscience, GlaxoSmithKline, Gilead, Lilly, Lycera, Merck, Novartis, Pfizer, Roche, Samsung, Set Point, and Scipher; and stock options in Lycera, Canfite, Scipher, Vorso, and Inmedix. Nancy A. Shadick reports research funding from Bristol-Myers Squibb, Crescendo Biosciences, Sanofi Regeneron, and Mallinckrodt; and consultancy to Bristol-Myers Squibb. Jeffrey A. Sparks reports research funding from Bristol-Myers Squibb and Amgen and consultancy to Optum.

Supplementary material

10067_2019_4733_MOESM1_ESM.docx (31 kb)
ESM 1 (DOCX 30 kb)


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Copyright information

© International League of Associations for Rheumatology (ILAR) 2019

Authors and Affiliations

  • Sicong Huang
    • 1
    • 2
    Email author
  • Xintong He
    • 1
  • Tracy J. Doyle
    • 2
    • 3
  • Alessandra Zaccardelli
    • 1
  • Allison A. Marshall
    • 1
    • 4
  • H. Maura Friedlander
    • 1
  • Rachel B. Blaustein
    • 1
  • Elisabeth A. Smith
    • 1
  • Jing Cui
    • 1
  • Christine K. Iannaccone
    • 1
  • Taysir G. Mahmoud
    • 1
  • Michael E. Weinblatt
    • 1
    • 2
  • Paul F. Dellaripa
    • 1
    • 2
  • Nancy A. Shadick
    • 1
    • 2
  • Jeffrey A. Sparks
    • 1
    • 2
    Email author
  1. 1.Division of Rheumatology, Immunology and AllergyBrigham and Women’s HospitalBostonUSA
  2. 2.Harvard Medical SchoolBostonUSA
  3. 3.Division of Pulmonary and Critical Care MedicineBrigham and Women’s HospitalBostonUSA
  4. 4.Tufts School of MedicineBostonUSA

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