Skip to main content

Comprehensive Understanding of Interstitial Lung Disease in Rheumatoid Arthritis

  • Chapter
  • First Online:

Abstract

Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is complicated in approximately 10% of RA patients. High titers of rheumatoid factor or anti-citrullinated protein antibodies (ACPAs), smoking, male gender, older age, longer disease duration, and higher articular disease activity are factors associated with the development of RA-ILD. Genetic factors such as human leukocyte antigen and peptidyl-arginine deiminase (PADI) and environmental factors such as smoking and periodontal disease could be associated with the activation of autoimmunity against citrullinated proteins, the synthesis of ACPAs, and the development of RA or RA-ILD. Metalloproteinase 7 and interferon-r-inducible protein 10 are serum novel biomarkers for the identification of RA-ILD, although surfactant protein A (SP-A), SP-D, and KL-6 are useful conventional biomarkers for the evaluation of RA-ILD. Novel antibodies against the PADI enzyme isoforms 3 and 4 or citrullinated heat shock protein (Hsp) 90a and Hsp90b are associated with RA-ILD and could be useful for predicting the development of RA-ILD. ILD is one of the main causes of mortality in RA. Therefore, prompt management of ILD in RA is necessary. To provide a better prognosis for RA-ILD patients, more efforts need to be made to determine the pathophysiology and the biomarkers for RA-ILD and the causal relationship between the development of ILD and DMARDs.

This is a preview of subscription content, log in via an institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Nakajima A, Saito K, Kojima T, Amano K, Yoshio T, Fukuda W, Inoue E, Taniguchi A, Momohara S, Minota S, Takeuchi T, Ishiguro N, Tanaka Y, Yamanaka H. No increased mortality in patients with rheumatoid arthritis treated with biologics: results from the biologics register of six rheumatology institutes in Japan. Mod Rheumatol. 2013;23:945–52.

    Google Scholar 

  2. Bongartz T, Nannini C, Medina-Velasquez YF, Achenbach SJ, Crowson CS, Ryu JH, Vassallo R, Gabriel SE, Matteson EL. Incidence and mortality of interstitial lung disease in rheumatoid arthritis: a population-based study. Arthritis Rheum. 2010;62:1583–91.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Chen J, Shi Y, Wang X, Huang H, Ascherman D. Asymptomatic preclinical rheumatoid arthritis-associated interstitial lung disease. Clin Dev Immunol. 2013;2013:406927.

    PubMed  PubMed Central  Google Scholar 

  4. Mori S, Koga Y, Sugimoto M. Different risk factors between interstitial lung disease and airway disease in rheumatoid arthritis. Respir Med. 2012;106:1591–9.

    Article  PubMed  Google Scholar 

  5. Mori S, Cho I, Koga Y, Sugimoto M. Comparison of pulmonary abnormalities on high-resolution computed tomography in patients with early versus longstanding rheumatoid arthritis. J Rheumatol. 2008;35:1513–21.

    PubMed  Google Scholar 

  6. Gochuico BR, Avila NA, Chow CK, Novero LJ, Wu HP, Ren P, MacDonald SD, Travis WD, Stylianou MP, Rosas IO. Progressive preclinical interstitial lung disease in rheumatoid arthritis. Arch Intern Med. 2008;168:159–66.

    Article  CAS  PubMed  Google Scholar 

  7. Wang JX, Du CG. A retrospective study of clinical characteristics of interstitial lung disease associated with rheumatoid arthritis in Chinese patients. Med Sci Monit. 2015;21:708–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Shidara K, Hoshi D, Inoue E, Yamada T, Nakajima A, Taniguchi A, Hara M, Momohara S, Kamatani N, Yamanaka H. Incidence of and risk factors for interstitial pneumonia in patients with rheumatoid arthritis in a large Japanese observational cohort, IORRA. Mod Rheumatol. 2010;20:280–6.

    Article  PubMed  Google Scholar 

  9. Pérez-Dórame R, Mejía M, Mateos-Toledo H, Rojas-Serrano J. Rheumatoid arthritis-associated interstitial lung disease: lung inflammation evaluated with high resolution computed tomography scan is correlated to rheumatoid arthritis disease activity. Reumatol Clin. 2015;11:12–6.

    Article  PubMed  Google Scholar 

  10. Koduri G, Norton S, Young A, Cox N, Davies P, Devlin J, Dixey J, Gough A, Prouse P, Winfield J, Williams P, ERAS (Early Rheumatoid Arthritis Study). Interstitial lung disease has a poor prognosis in rheumatoid arthritis: results from an inception cohort. Rheumatology (Oxford). 2010;49:1483–9.

    Article  Google Scholar 

  11. Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, Colby TV, Cordier JF, Flaherty KR, Lasky JA, Lynch DA, Ryu JH, Swigris JJ, Wells AU, Ancochea J, Bouros D, Carvalho C, Costabel U, Ebina M, Hansell DM, Johkoh T, Kim DS, King TE, Kondoh Y, Myers J, Müller NL, Nicholson AG, Richeldi L, Selman M, Dudden RF, Griss BS, Protzko SL, Schünemann HJ, ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183:788–824.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Suda T. Up-to-date information on rheumatoid arthritis-associated interstitial lung disease. Clin Med Insights Circ Respir Pulm Med. 2015;9:155–62.

    PubMed  Google Scholar 

  13. Kelly CA, Saravanan V, Nisar M, Arthanari S, Woodhead FA, Price-Forbes AN, Dawson J, Sathi N, Ahmad Y, Koduri G, Young A, British Rheumatoid Interstitial Lung (BRILL) Network. Rheumatoid arthritis-related interstitial lung disease: associations, prognostic factors and physiological and radiological characteristics—a large multicentre UK study. Rheumatology (Oxford). 2014;53:1676–82.

    Article  CAS  Google Scholar 

  14. Hozumi H, Nakamura Y, Johkoh T, Sumikawa H, Colby TV, Kono M, Hashimoto D, Enomoto N, Fujisawa T, Inui N, Suda T, Chida K. Acute exacerbation in rheumatoid arthritis-associated interstitial lung disease: a retrospective case control study. BMJ Open. 2013;3:e003132.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Assayag D, Lubin M, Lee JS, King TE, Collard HR, Ryerson CJ. Predictors of mortality in rheumatoid arthritis-related interstitial lung disease. Respirology. 2014;19:493–500.

    Article  PubMed  Google Scholar 

  16. Kim EJ, Elicker BM, Maldonado F, Webb WR, Ryu JH, Van Uden JH, Lee JS, King TE, Collard HR. Usual interstitial pneumonia in rheumatoid arthritis-associated interstitial lung disease. Eur Respir J. 2010;35:1322–8.

    Article  CAS  PubMed  Google Scholar 

  17. Dixon WG, Hyrich KL, Watson KD, Lunt M, Symmons DP, BSRBR Control Centre Consortium, British Society for Rheumatology Biologics Register. Influence of anti-TNF therapy on mortality in patients with rheumatoid arthritis-associated interstitial lung disease: results from the British Society for Rheumatology Biologics Register. Ann Rheum Dis. 2010;69:1086–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Solomon JJ, Ryu JH, Tazelaar HD, Myers JL, Tuder R, Cool CD, Curran-Everett D, Fischer A, Swigris JJ, Brown KK. Fibrosing interstitial pneumonia predicts survival in patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Respir Med. 2013;107:1247–52.

    Article  PubMed  Google Scholar 

  19. Takayanagi N. Biological agents and respiratory infections: causative mechanisms and practice management. Respir Investig. 2015;53:185–200.

    Article  PubMed  Google Scholar 

  20. Zamora-Legoff JA, Krause ML, Crowson CS, Ryu JH, Matteson EL. Risk of serious infection in patients with rheumatoid arthritis-associated interstitial lung disease. Clin Rheumatol. 2016;35:2585–9.

    Article  PubMed  Google Scholar 

  21. Roubille C, Haraoui B. Interstitial lung diseases induced or exacerbated by DMARDS and biologic agents in rheumatoid arthritis: a systematic literature review. Semin Arthritis Rheum. 2014;43:613–26.

    Article  CAS  PubMed  Google Scholar 

  22. Ohnishi H, Yokoyama A, Kondo K, Hamada H, Abe M, Nishimura K, Hiwada K, Kohno N. Comparative study of KL-6, surfactant protein-A, surfactant protein-D, and monocyte chemoattractant protein-1 as serum markers for interstitial lung diseases. Am J Respir Crit Care Med. 2002;165:378–81.

    Article  PubMed  Google Scholar 

  23. Nakajima H, Harigai M, Hara M, Hakoda M, Tokuda H, Sakai F, Kamatani N, Kashiwazaki S. KL-6 as a novel serum marker for interstitial pneumonia associated with collagen diseases. J Rheumatol. 2000;27:1164–70.

    CAS  PubMed  Google Scholar 

  24. Lee YS, Kim HC, Lee BY, Lee CK, Kim MY, Jang SJ, Lee HS, Moon J, Colby TV, Kim DS. The value of biomarkers as predictors of outcome in patients with rheumatoid arthritis-associated usual interstitial pneumonia. Sarcoidosis Vasc Diffuse Lung Dis. 2016;33:216–23.

    PubMed  Google Scholar 

  25. Richards TJ, Eggebeen A, Gibson K, Yousem S, Fuhrman C, Gochuico BR, Fertig N, Oddis CV, Kaminski N, Rosas IO, Ascherman DP. Characterization and peripheral blood biomarker assessment of anti-Jo-1 antibody-positive interstitial lung disease. Arthritis Rheum. 2009;60:2183–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Chen J, Doyle TJ, Liu Y, Aggarwal R, Wang X, Shi Y, Ge SX, Huang H, Lin Q, Liu W, Cai Y, Koontz D, Fuhrman CR, Golzarri MF, Hatabu H, Nishino M, Araki T, Dellaripa PF, Oddis CV, Rosas IO, Ascherman DP. Biomarkers of rheumatoid arthritis-associated interstitial lung disease. Arthritis Rheumatol. 2015;67:28–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Richards TJ, Kaminski N, Baribaud F, Flavin S, Brodmerkel C, Horowitz D, Li K, Choi J, Vuga LJ, Lindell KO, Klesen M, Zhang Y, Gibson KF. Peripheral blood proteins predict mortality in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2012;185:67–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Fujishima S, Shiomi T, Yamashita S, Yogo Y, Nakano Y, Inoue T, Nakamura M, Tasaka S, Hasegawa N, Aikawa N, Ishizaka A, Okada Y. Production and activation of matrix metalloproteinase 7 (matrilysin 1) in the lungs of patients with idiopathic pulmonary fibrosis. Arch Pathol Lab Med. 2010;134:1136–42.

    CAS  PubMed  Google Scholar 

  29. Salmela MT, Pender SL, Karjalainen-Lindsberg ML, Puolakkainen P, Macdonald TT, Saarialho-Kere U. Collagenase-1 (MMP-1), matrilysin-1 (MMP-7), and stromelysin-2 (MMP-10) are expressed by migrating enterocytes during intestinal wound healing. Scand J Gastroenterol. 2004;39:1095–104.

    Article  CAS  PubMed  Google Scholar 

  30. Zuo F, Kaminski N, Eugui E, Allard J, Yakhini Z, Ben-Dor A, Lollini L, Morris D, Kim Y, DeLustro B, Sheppard D, Pardo A, Selman M, Heller RA. Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans. Proc Natl Acad Sci U S A. 2002;99:6292–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Shen H, Xia L, Lu J. Interleukin-4 in rheumatoid arthritis patients with interstitial lung disease: a pilot study. Indian J Med Res. 2013;138:919–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Jian XD, Guo GR, Ruan YJ, Zhao B, Wang YC, Ning Q, Zhang YC. [Clinical observation of rheumatoid arthritis associated interstitial lung disease patients and changes of serum cytokines thereof]. Zhonghua Yi Xue Za Zhi. 2008;88:1884–7.

    Google Scholar 

  33. Xiangyang Z, Lutian Y, Lin Z, Liping X, Hui S, Jing L. Increased levels of interleukin-33 associated with bone erosion and interstitial lung diseases in patients with rheumatoid arthritis. Cytokine. 2012;58:6–9.

    Article  PubMed  Google Scholar 

  34. Giles JT, Darrah E, Danoff S, Johnson C, Andrade F, Rosen A, Bathon JM. Association of cross-reactive antibodies targeting peptidyl-arginine deiminase 3 and 4 with rheumatoid arthritis-associated interstitial lung disease. PLoS One. 2014;9:e98794.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Harlow L, Rosas IO, Gochuico BR, Mikuls TR, Dellaripa PF, Oddis CV, Ascherman DP. Identification of citrullinated hsp90 isoforms as novel autoantigens in rheumatoid arthritis-associated interstitial lung disease. Arthritis Rheum. 2013;65:869–79.

    Article  CAS  PubMed  Google Scholar 

  36. Bernstein EJ, Barr RG, Austin JH, Kawut SM, Raghu G, Sell JL, Hoffman EA, Newell JD, Watts JR, Nath PH, Sonavane SK, Bathon JM, Majka DS, Lederer DJ. Rheumatoid arthritis-associated autoantibodies and subclinical interstitial lung disease: the Multi-Ethnic Study of Atherosclerosis. Thorax. 2016;71:1082–90.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Paulin F, Doyle TJ, Fletcher EA, Ascherman DP, Rosas IO. Rheumatoid arthritis-associated interstitial lung disease and idiopathic pulmonary fibrosis: shared mechanistic and phenotypic traits suggest overlapping disease mechanisms. Rev Investig Clin. 2015;67:280–6.

    Google Scholar 

  38. Reynisdottir G, Karimi R, Joshua V, Olsen H, Hensvold AH, Harju A, Engström M, Grunewald J, Nyren S, Eklund A, Klareskog L, Sköld CM, Catrina AI. Structural changes and antibody enrichment in the lungs are early features of anti-citrullinated protein antibody-positive rheumatoid arthritis. Arthritis Rheumatol. 2014;66:31–9.

    Article  CAS  PubMed  Google Scholar 

  39. Giles JT, Danoff SK, Sokolove J, Wagner CA, Winchester R, Pappas DA, Siegelman S, Connors G, Robinson WH, Bathon JM. Association of fine specificity and repertoire expansion of anticitrullinated peptide antibodies with rheumatoid arthritis associated interstitial lung disease. Ann Rheum Dis. 2014;73:1487–94.

    Article  CAS  PubMed  Google Scholar 

  40. Sokolove J, Bromberg R, Deane KD, Lahey LJ, Derber LA, Chandra PE, Edison JD, Gilliland WR, Tibshirani RJ, Norris JM, Holers VM, Robinson WH. Autoantibody epitope spreading in the pre-clinical phase predicts progression to rheumatoid arthritis. PLoS One. 2012;7:e35296.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Furukawa H, Oka S, Shimada K, Sugii S, Ohashi J, Matsui T, Ikenaka T, Nakayama H, Hashimoto A, Takaoka H, Arinuma Y, Okazaki Y, Futami H, Komiya A, Fukui N, Nakamura T, Migita K, Suda A, Nagaoka S, Tsuchiya N, Tohma S. Association of human leukocyte antigen with interstitial lung disease in rheumatoid arthritis: a protective role for shared epitope. PLoS One. 2012;7:e33133.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Laki J, Lundström E, Snir O, Rönnelid J, Ganji I, Catrina AI, Bengtsson C, Saevarsdottir S, Wick MC, Alfredsson L, Klareskog L, Padyukov L. Very high levels of anti-citrullinated protein antibodies are associated with HLA-DRB1*15 non-shared epitope allele in patients with rheumatoid arthritis. Arthritis Rheum. 2012;64:2078–84.

    Article  CAS  PubMed  Google Scholar 

  43. Ikari K, Kuwahara M, Nakamura T, Momohara S, Hara M, Yamanaka H, Tomatsu T, Kamatani N. Association between PADI4 and rheumatoid arthritis: a replication study. Arthritis Rheum. 2005;52:3054–7.

    Article  CAS  PubMed  Google Scholar 

  44. Scher JU, Abramson SB. Periodontal disease, Porphyromonas gingivalis, and rheumatoid arthritis: what triggers autoimmunity and clinical disease? Arthritis Res Ther. 2013;15:122.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Scher JU, Ubeda C, Equinda M, Khanin R, Buischi Y, Viale A, Lipuma L, Attur M, Pillinger MH, Weissmann G, Littman DR, Pamer EG, Bretz WA, Abramson SB. Periodontal disease and the oral microbiota in new-onset rheumatoid arthritis. Arthritis Rheum. 2012;64:3083–94.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Mikuls TR, Payne JB, Yu F, Thiele GM, Reynolds RJ, Cannon GW, Markt J, McGowan D, Kerr GS, Redman RS, Reimold A, Griffiths G, Beatty M, Gonzalez SM, Bergman DA, Hamilton BC, Erickson AR, Sokolove J, Robinson WH, Walker C, Chandad F, O’Dell JR. Periodontitis and Porphyromonas gingivalis in patients with rheumatoid arthritis. Arthritis Rheumatol. 2014;66:1090–100.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Hitchon CA, Chandad F, Ferucci ED, Willemze A, Ioan-Facsinay A, van der Woude D, Markland J, Robinson D, Elias B, Newkirk M, Toes RM, Huizinga TW, El-Gabalawy HS. Antibodies to porphyromonas gingivalis are associated with anticitrullinated protein antibodies in patients with rheumatoid arthritis and their relatives. J Rheumatol. 2010;37:1105–12.

    Article  CAS  PubMed  Google Scholar 

  48. Makrygiannakis D, Hermansson M, Ulfgren AK, Nicholas AP, Zendman AJ, Eklund A, Grunewald J, Skold CM, Klareskog L, Catrina AI. Smoking increases peptidylarginine deiminase 2 enzyme expression in human lungs and increases citrullination in BAL cells. Ann Rheum Dis. 2008;67:1488–92.

    Article  CAS  PubMed  Google Scholar 

  49. Gabbay E, Tarala R, Will R, Carroll G, Adler B, Cameron D, Lake FR. Interstitial lung disease in recent onset rheumatoid arthritis. Am J Respir Crit Care Med. 1997;156:528–35.

    Article  CAS  PubMed  Google Scholar 

  50. Moazedi-Fuerst FC, Kielhauser S, Brickmann K, Tripolt N, Meilinger M, Lufti A, Graninger W. Sonographic assessment of interstitial lung disease in patients with rheumatoid arthritis, systemic sclerosis and systemic lupus erythematosus. Clin Exp Rheumatol. 2015;33:S87–91.

    PubMed  Google Scholar 

  51. Cogliati C, Antivalle M, Torzillo D, Birocchi S, Norsa A, Bianco R, Costantino G, Ditto MC, Battellino M, Sarzi Puttini PC, Montano N. Standard and pocket-size lung ultrasound devices can detect interstitial lung disease in rheumatoid arthritis patients. Rheumatology (Oxford). 2014;53:1497–503.

    Article  Google Scholar 

  52. Nakashita T, Ando K, Takahashi K, Motojima S. Possible effect of abatacept on the progression of interstitial lung disease in rheumatoid arthritis patients. Respir Investig. 2016;54:376–9.

    Article  PubMed  Google Scholar 

  53. Wang Y, Xu SQ, Xu JH, Ding C. Treatment with etanercept in a patient with rheumatoid arthritis-associated interstitial lung disease. Clin Med Insights Case Rep. 2011;4:49–52.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Hartung W, Maier J, Pfeifer M, Fleck M. Effective treatment of rheumatoid arthritis-associated interstitial lung disease by B-cell targeted therapy with rituximab. Case Reports Immunol. 2012;2012:272303.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Horai Y, Miyamura T, Shimada K, Takahama S, Minami R, Yamamoto M, Suematsu E. Eternacept for the treatment of patients with rheumatoid arthritis and concurrent interstitial lung disease. J Clin Pharm Ther. 2012;37:117–21.

    Article  CAS  PubMed  Google Scholar 

  56. Nakashita T, Ando K, Kaneko N, Takahashi K, Motojima S. Potential risk of TNF inhibitors on the progression of interstitial lung disease in patients with rheumatoid arthritis. BMJ Open. 2014;4:e005615.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Akiyama M, Kaneko Y, Yamaoka K, Kondo H, Takeuchi T. Association of disease activity with acute exacerbation of interstitial lung disease during tocilizumab treatment in patients with rheumatoid arthritis: a retrospective, case-control study. Rheumatol Int. 2016;36:881–9.

    Article  CAS  PubMed  Google Scholar 

  58. Atkins SR, Turesson C, Myers JL, Tazelaar HD, Ryu JH, Matteson EL, Bongartz T. Morphologic and quantitative assessment of CD20+ B cell infiltrates in rheumatoid arthritis-associated nonspecific interstitial pneumonia and usual interstitial pneumonia. Arthritis Rheum. 2006;54:635–41.

    Article  PubMed  Google Scholar 

Download references

Acknowledgment

I would like to thank Naohiro Sugitani for providing the chest imaging.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Takahisa Gono M.D., Ph.D. .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Gono, T. (2018). Comprehensive Understanding of Interstitial Lung Disease in Rheumatoid Arthritis. In: Gono, T., Tokuda, H., Sakai, F., Takemura, T. (eds) Lung Disease Associated with Rheumatoid Arthritis. Springer, Singapore. https://doi.org/10.1007/978-981-10-6750-1_6

Download citation

  • DOI: https://doi.org/10.1007/978-981-10-6750-1_6

  • Published:

  • Publisher Name: Springer, Singapore

  • Print ISBN: 978-981-10-6749-5

  • Online ISBN: 978-981-10-6750-1

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics