Advertisement

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

Abstract

Introduction

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

Methods

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.

Results

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).

Conclusions

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.

Keywords

CCP Pulmonary disease RF Rheumatoid arthritis Serostatus 

Notes

Acknowledgments

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)

References

  1. 1.
    Turesson C, O’Fallon WM, Crowson CS, Gabriel SE, Matteson EL (2003) Extra-articular disease manifestations in rheumatoid arthritis: incidence trends and risk factors over 46 years. Ann Rheum Dis 62(8):722–727CrossRefGoogle Scholar
  2. 2.
    Nannini C, Ryu JH, Matteson EL (2008) Lung disease in rheumatoid arthritis. Curr Opin Rheumatol 20(3):340–346CrossRefGoogle Scholar
  3. 3.
    Shaw M, Collins BF, Ho LA, Raghu G (2015) Rheumatoid arthritis-associated lung disease. Eur Respir Rev 24(135):1–16CrossRefGoogle Scholar
  4. 4.
    Bongartz T, Nannini C, Medina-Velasquez YF, Achenbach SJ, Crowson CS, Ryu JH, Vassallo R, Gabriel SE, Matteson EL (2010) Incidence and mortality of interstitial lung disease in rheumatoid arthritis: a population-based study. Arthritis Rheum 62(6):1583–1591CrossRefGoogle Scholar
  5. 5.
    Liao KP, Sparks JA, Hejblum BP, Kuo IH, Cui J, Lahey LJ, Cagan A, Gainer VS, Liu W, Cai TT, Sokolove J, Cai T (2017) Phenome-wide association study of autoantibodies to citrullinated and noncitrullinated epitopes in rheumatoid arthritis. Arthritis Rheumatol 69(4):742–749CrossRefGoogle Scholar
  6. 6.
    Shadick NA, Fanta CH, Weinblatt ME, O’Donnell W, Coblyn JS (1994) Bronchiectasis. A late feature of severe rheumatoid arthritis. Medicine (Baltimore) 73(3):161–170CrossRefGoogle Scholar
  7. 7.
    Doyle TJ, Dellaripa PF (2017) Lung manifestations in the rheumatic diseases. Chest. 152(6):1283–1295CrossRefGoogle Scholar
  8. 8.
    Hassan WU, Keaney NP, Holland CD, Kelly CA (1994) Bronchial reactivity and airflow obstruction in rheumatoid arthritis. Ann Rheum Dis 53(8):511–514CrossRefGoogle Scholar
  9. 9.
    Kelly CA, Saravanan V, Nisar M, Arthanari S, Woodhead FA, Price-Forbes AN, Dawson J, Sathi N, Ahmad Y, Koduri G, Young A, on behalf of the British Rheumatoid Interstitial Lung (BRILL) Network (2014) Rheumatoid arthritis-related interstitial lung disease: associations, prognostic factors and physiological and radiological characteristics--a large multicentre UK study. Rheumatology (Oxford) 53(9):1676–1682CrossRefGoogle Scholar
  10. 10.
    Brown KK (2007) Roger S. Mitchell Lecture. Rheumatoid Lung Disease. Proc Am Thorac Soc 4(5):443–448CrossRefGoogle Scholar
  11. 11.
    Pappas DA, Giles JT, Connors G, Lechtzin N, Bathon JM, Danoff SK (2010) Respiratory symptoms and disease characteristics as predictors of pulmonary function abnormalities in patients with rheumatoid arthritis: an observational cohort study. Arthritis Res Ther 12(3):R104CrossRefGoogle Scholar
  12. 12.
    Wilsher M, Voight L, Milne D, Teh M, Good N, Kolbe J, Williams M, Pui K, Merriman T, Sidhu K, Dalbeth N (2012) Prevalence of airway and parenchymal abnormalities in newly diagnosed rheumatoid arthritis. Respir Med 106(10):1441–1446CrossRefGoogle Scholar
  13. 13.
    Hwang J, Song JU, Ahn JK (2016) Decline of pulmonary function is associated with the presence of rheumatoid factor in Korean health screening subjects without clinically apparent lung disease: a cross-sectional study. Medicine (Baltimore) 95(19):e3668CrossRefGoogle Scholar
  14. 14.
    Robles-Perez A, Luburich P, Rodriguez-Sanchon B, Dorca J, Nolla JM, Molina-Molina M, Narvaez-Garcia J (2016) Preclinical lung disease in early rheumatoid arthritis. Chron Respir Dis 13(1):75–81CrossRefGoogle Scholar
  15. 15.
    Aubart F, Crestani B, Nicaise-Roland P, Tubach F, Bollet C, Dawidowicz K et al (2011) High levels of anti-cyclic citrullinated peptide autoantibodies are associated with co-occurrence of pulmonary diseases with rheumatoid arthritis. J Rheumatol 38(6):979–982CrossRefGoogle Scholar
  16. 16.
    Paschalaki KE, Jacob J, Wells AU (2016) Monitoring of lung involvement in rheumatologic disease. Respiration. 91(2):89–98CrossRefGoogle Scholar
  17. 17.
    Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS et al (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31(3):315–324CrossRefGoogle Scholar
  18. 18.
    Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd et al (2010) 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis 69(9):1580–1588CrossRefGoogle Scholar
  19. 19.
    Iannaccone CK, Lee YC, Cui J, Frits ML, Glass RJ, Plenge RM, Solomon DH, Weinblatt ME, Shadick NA (2011) Using genetic and clinical data to understand response to disease-modifying anti-rheumatic drug therapy: data from the Brigham and Women’s Hospital Rheumatoid Arthritis Sequential Study. Rheumatology (Oxford) 50(1):40–46CrossRefGoogle Scholar
  20. 20.
    Doyle TJ, Dellaripa PF, Batra K, Frits ML, Iannaccone CK, Hatabu H, Nishino M, Weinblatt ME, Ascherman DP, Washko GR, Hunninghake GM, Choi AMK, Shadick NA, Rosas IO (2014) Functional impact of a spectrum of interstitial lung abnormalities in rheumatoid arthritis. Chest. 146(1):41–50CrossRefGoogle Scholar
  21. 21.
    Doyle TJ, Patel AS, Hatabu H, Nishino M, Wu G, Osorio JC, Golzarri MF, Traslosheros A, Chu SG, Frits ML, Iannaccone CK, Koontz D, Fuhrman C, Weinblatt ME, el-Chemaly SY, Washko GR, Hunninghake GM, Choi AMK, Dellaripa PF, Oddis CV, Shadick NA, Ascherman DP, Rosas IO (2015) Detection of rheumatoid arthritis-interstitial lung disease is enhanced by serum biomarkers. Am J Respir Crit Care Med 191(12):1403–1412CrossRefGoogle Scholar
  22. 22.
    Bohler C, Radner H, Smolen JS, Aletaha D (2013) Serological changes in the course of traditional and biological disease modifying therapy of rheumatoid arthritis. Ann Rheum Dis 72(2):241–244CrossRefGoogle Scholar
  23. 23.
    Vogelmeier CF, Criner GJ, Martinez FJ, Anzueto A, Barnes PJ, Bourbeau J, Celli BR, Chen R, Decramer M, Fabbri LM, Frith P, Halpin DMG, López Varela MV, Nishimura M, Roche N, Rodriguez-Roisin R, Sin DD, Singh D, Stockley R, Vestbo J, Wedzicha JA, Agustí A (2017) Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report. GOLD executive summary. Am J Respir Crit Care Med 195(5):557–582CrossRefGoogle Scholar
  24. 24.
    Johnson JD, Theurer WM (2014) A stepwise approach to the interpretation of pulmonary function tests. Am Fam Physician 89(5):359–366Google Scholar
  25. 25.
    Radner H, Yoshida K, Mjaavatten MD, Aletaha D, Frits M, Lu B, Iannaccone C, Shadick N, Weinblatt M, Hmamouchi I, Dougados M, Smolen JS, Solomon DH (2015) Development of a multimorbidity index: impact on quality of life using a rheumatoid arthritis cohort. Semin Arthritis Rheum 45(2):167–173CrossRefGoogle Scholar
  26. 26.
    Quinn T, Bs MF, von Heideken J, Iannaccone C, Shadick NA, Weinblatt M et al (2017) Validity of the nurses’ health study physical activity questionnaire in estimating physical activity in adults with rheumatoid arthritis. BMC Musculoskelet Disord 18(1):234CrossRefGoogle Scholar
  27. 27.
    Prevoo ML, van 't Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL (1995) Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 38(1):44–48CrossRefGoogle Scholar
  28. 28.
    Pincus T, Swearingen C, Wolfe F (1999) Toward a multidimensional health assessment questionnaire (MDHAQ): assessment of advanced activities of daily living and psychological status in the patient-friendly health assessment questionnaire format. Arthritis Rheum 42(10):2220–2230CrossRefGoogle Scholar
  29. 29.
    Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R et al (2005) Interpretative strategies for lung function tests. Eur Respir J 26(5):948–968CrossRefGoogle Scholar
  30. 30.
    Barrera P, Laan RF, van Riel PL, Dekhuijzen PN, Boerbooms AM, van de Putte LB (1994) Methotrexate-related pulmonary complications in rheumatoid arthritis. Ann Rheum Dis 53(7):434–439CrossRefGoogle Scholar
  31. 31.
    Perez T, Remy-Jardin M, Cortet B (1998) Airways involvement in rheumatoid arthritis: clinical, functional, and HRCT findings. Am J Respir Crit Care Med 157(5 Pt 1):1658–1665CrossRefGoogle Scholar
  32. 32.
    Youssef AA, Machaly SA, El-Dosoky ME, El-Maghraby NM (2012) Respiratory symptoms in rheumatoid arthritis: relation to pulmonary abnormalities detected by high-resolution CT and pulmonary functional testing. Rheumatol Int 32(7):1985–1995CrossRefGoogle Scholar
  33. 33.
    Perry E, Kelly C, Eggleton P, De Soyza A, Hutchinson D (2014) The lung in ACPA-positive rheumatoid arthritis: an initiating site of injury? Rheumatology (Oxford) 53(11):1940–1950CrossRefGoogle Scholar
  34. 34.
    Zhu J, Zhou Y, Chen X, Li J (2014) A metaanalysis of the increased risk of rheumatoid arthritis-related pulmonary disease as a result of serum anticitrullinated protein antibody positivity. J Rheumatol 41(7):1282–1289CrossRefGoogle Scholar
  35. 35.
    Mori S, Koga Y, Sugimoto M (2012) Different risk factors between interstitial lung disease and airway disease in rheumatoid arthritis. Respir Med 106(11):1591–1599CrossRefGoogle Scholar
  36. 36.
    Fischer A, Solomon JJ, du Bois RM, Deane KD, Olson AL, Fernandez-Perez ER, Huie TJ, Stevens AD, Gill MB, Rabinovitch AM, Lynch DA, Burns DA, Pineiro IS, Groshong SD, Duarte Achcar RD, Brown KK, Martin RJ, Swigris JJ (2012) Lung disease with anti-CCP antibodies but not rheumatoid arthritis or connective tissue disease. Respir Med 106(7):1040–1047CrossRefGoogle Scholar
  37. 37.
    Tuomi T, Heliovaara M, Palosuo T, Aho K (1990) Smoking, lung function, and rheumatoid factors. Ann Rheum Dis 49(10):753–756CrossRefGoogle Scholar
  38. 38.
    Ford JA, Liu X, Marshall AA, Zaccardelli A, Prado MG, Wiyarand C, Lu B, Karlson EW, Schur PH, Deane KD, Sparks JA (2018) Impact of cyclic citrullinated peptide antibody level on progression to rheumatoid arthritis in clinically tested CCP-positive patients without RA. Arthritis Care Res (Hoboken)Google Scholar
  39. 39.
    Bergstrom U, Jacobsson LT, Nilsson JA, Berglund G, Turesson C (2011) Pulmonary dysfunction, smoking, socioeconomic status and the risk of developing rheumatoid arthritis. Rheumatology (Oxford) 50(11):2005–2013CrossRefGoogle Scholar
  40. 40.
    Karlson EW, Chibnik LB, Cui J, Plenge RM, Glass RJ, Maher NE, Parker A, Roubenoff R, Izmailova E, Coblyn JS, Weinblatt ME, Shadick NA (2008) Associations between human leukocyte antigen, PTPN22, CTLA4 genotypes and rheumatoid arthritis phenotypes of autoantibody status, age at diagnosis and erosions in a large cohort study. Ann Rheum Dis 67(3):358–363CrossRefGoogle Scholar
  41. 41.
    Balsa A, Cabezon A, Orozco G, Cobo T, Miranda-Carus E, Lopez-Nevot MA et al (2010) Influence of HLA DRB1 alleles in the susceptibility of rheumatoid arthritis and the regulation of antibodies against citrullinated proteins and rheumatoid factor. Arthritis Res Ther. 12(2):R62CrossRefGoogle Scholar
  42. 42.
    van der Helm-van Mil AH, Verpoort KN, Breedveld FC, Huizinga TW, Toes RE, de Vries RR (2006) The HLA-DRB1 shared epitope alleles are primarily a risk factor for anti-cyclic citrullinated peptide antibodies and are not an independent risk factor for development of rheumatoid arthritis. Arthritis Rheum 54(4):1117–1121CrossRefGoogle Scholar
  43. 43.
    Klareskog L, Stolt P, Lundberg K, Kallberg H, Bengtsson C, Grunewald J et al (2006) A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum 54(1):38–46CrossRefGoogle Scholar
  44. 44.
    Luukkainen R, Saltyshev M, Pakkasela R, Nordqvist E, Huhtala H, Hakala M (1995) Relationship of rheumatoid factor to lung diffusion capacity in smoking and non-smoking patients with rheumatoid arthritis. Scand J Rheumatol 24(2):119–120CrossRefGoogle Scholar
  45. 45.
    Tseng HJ, Henry TS, Veeraraghavan S, Mittal PK, Little BP (2017) Pulmonary function tests for the radiologist. Radiographics. 37(4):1037–1058CrossRefGoogle Scholar

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

Personalised recommendations