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Mechanisms of lung disease development in rheumatoid arthritis

Nature Reviews Rheumatology volume 15, pages 581–596 (2019)Cite this article

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Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disorder that causes joint inflammation and damage. Extra-articular manifestations occur in many patients and can include lung involvement in the form of airway or parenchymal inflammation and fibrosis. Although the pathophysiology of articular RA has been extensively investigated, the mechanisms causing airway and parenchymal lung disease are not well defined. Infections, cigarette-smoking, mucosal dysbiosis, host genetics and premature senescence are all potentially important contributors to the development of lung disease in patients with RA. RA-associated lung disease (which can predate the onset of articular disease by many years) probably originates from chronic airway and alveolar epithelial injury that occurs in an individual with a genetic background that permits the development of autoimmunity, leading to chronic inflammation and subsequent airway and lung parenchymal remodelling and fibrosis. Further investigations into the specific mechanisms by which lung disease develops in RA will be crucial for the development of effective therapies. Identifying mechanisms by which environmental and host factors cooperate in the induction of autoimmunity in the lung might also help to establish the order of early events in RA.

Key points

  • Rheumatoid arthritis (RA) is a systemic autoimmune disease that can present with a variety of lung manifestations including airway disease and interstitial lung disease.

  • Seropositive RA develops following an asymptomatic pre-RA phase characterized by the emergence of autoantibodies and systemic immune activation that might be initiated at mucosal surfaces such as the lung.

  • Cigarette smoking, host genetic factors, dysbiosis in the oral cavity and airways and senescence are all potentially important in the pathogenesis of lung disease in RA.

  • Identifying specific mechanisms that permit the breakdown of tolerance and generation of disease in the lung are important for the development of therapies that address lung complications in RA.

  • Screening individuals with RA at risk of lung complications is now feasible and should be the focus of future studies.

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Fig. 1: The natural history of RA-associated lung disease.
Fig. 2: The spectrum of RA-associated lung disease.
Fig. 3: Proposed mechanism of RA-associated lung disease development.

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References

  1. Smolen, J. S., Aletaha, D. & McInnes, I. B. Rheumatoid arthritis. Lancet 388, 2023–2038 (2016).

    CAS  PubMed  Google Scholar 

  2. Myasoedova, E., Crowson, C. S., Turesson, C., Gabriel, S. E. & Matteson, E. L. Incidence of extraarticular rheumatoid arthritis in Olmsted County, Minnesota, in 1995–2007 versus 1985–1994: a population-based study. J. Rheumatol. 38, 983–989 (2011).

    PubMed  PubMed Central  Google Scholar 

  3. Holers, V. M. et al. Rheumatoid arthritis and the mucosal origins hypothesis: protection turns to destruction. Nat. Rev. Rheumatol. 14, 542–557 (2018).

    PubMed  PubMed Central  Google Scholar 

  4. Deane, K. D. et al. The number of elevated cytokines and chemokines in preclinical seropositive rheumatoid arthritis predicts time to diagnosis in an age-dependent manner. Arthritis Rheum. 62, 3161–3172 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Reynisdottir, G. et al. Signs of immune activation and local inflammation are present in the bronchial tissue of patients with untreated early rheumatoid arthritis. Ann. Rheum. Dis. 75, 1722–1727 (2016).

    CAS  PubMed  Google Scholar 

  6. Nielen, M. M. et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum. 50, 380–386 (2004).

    PubMed  Google Scholar 

  7. Willis, V. C. et al. Sputum autoantibodies in patients with established rheumatoid arthritis and subjects at risk of future clinically apparent disease. Arthritis Rheum. 65, 2545–2554 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Arnett, F. C. et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 31, 315–324 (1988).

    CAS  PubMed  Google Scholar 

  9. Kallberg, H. et al. Smoking is a major preventable risk factor for rheumatoid arthritis: estimations of risks after various exposures to cigarette smoke. Ann. Rheum. Dis. 70, 508–511 (2011).

    PubMed  Google Scholar 

  10. Quirke, A. M. et al. Bronchiectasis is a model for chronic bacterial infection inducing autoimmunity in rheumatoid arthritis. Arthritis Rheumatol. 67, 2335–2342 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Vassallo, R. et al. Cellular and humoral immunity in arthritis are profoundly influenced by the interaction between cigarette smoke effects and host HLA-DR and DQ genes. Clin. Immunol. 152, 25–35 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Saag, K. G. et al. Cigarette smoking and rheumatoid arthritis severity. Ann. Rheum. Dis. 56, 463–469 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Hutchinson, D., Shepstone, L., Moots, R., Lear, J. T. & Lynch, M. P. Heavy cigarette smoking is strongly associated with rheumatoid arthritis (RA), particularly in patients without a family history of RA. Ann. Rheum. Dis. 60, 223–227 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Bidkar, M. et al. Cigarette smoke induces immune responses to vimentin in both, arthritis-susceptible and -resistant humanized mice. PLOS ONE 11, e0162341 (2016).

    PubMed  PubMed Central  Google Scholar 

  15. Stolt, P. et al. Silica exposure is associated with increased risk of developing rheumatoid arthritis: results from the Swedish EIRA study. Ann. Rheum. Dis. 64, 582–586 (2005).

    CAS  PubMed  Google Scholar 

  16. Karlson, E. W. & Deane, K. Environmental and gene-environment interactions and risk of rheumatoid arthritis. Rheum. Dis. Clin. North Am. 38, 405–426 (2012).

    PubMed  PubMed Central  Google Scholar 

  17. Norton, S. et al. A study of baseline prevalence and cumulative incidence of comorbidity and extra-articular manifestations in RA and their impact on outcome. Rheumatology 52, 99–110 (2013).

    Google Scholar 

  18. Wilsher, M. et al. Prevalence of airway and parenchymal abnormalities in newly diagnosed rheumatoid arthritis. Respir. Med. 106, 1441–1446 (2012).

    PubMed  Google Scholar 

  19. Cavagna, L. et al. The multifaceted aspects of interstitial lung disease in rheumatoid arthritis. Biomed. Res. Int. 2013, 759760 (2013).

    PubMed  PubMed Central  Google Scholar 

  20. de Lauretis, A., Veeraraghavan, S. & Renzoni, E. Review series: aspects of interstitial lung disease: connective tissue disease-associated interstitial lung disease: how does it differ from IPF? How should the clinical approach differ? Chron. Respir. Dis. 8, 53–82 (2011).

    PubMed  Google Scholar 

  21. Chen, J. J., Branstetter, B. F. T. & Myers, E. N. Cricoarytenoid rheumatoid arthritis: an important consideration in aggressive lesions of the larynx. AJNR Am. J. Neuroradiol. 26, 970–972 (2005).

    PubMed  Google Scholar 

  22. Bongartz, T. et al. Incidence and mortality of interstitial lung disease in rheumatoid arthritis: a population based study. Arthritis Rheum. 62, 1583–1591 (2010).

    PubMed  PubMed Central  Google Scholar 

  23. Graney, B. A. & Fischer, A. Interstitial pneumonia with autoimmune features. Ann. Am. Thorac. Soc. 16, 525–533 (2019).

    PubMed  Google Scholar 

  24. Lee, H. K. et al. Histopathologic pattern and clinical features of rheumatoid arthritis-associated interstitial lung disease. Chest 127, 2019–2027 (2005).

    PubMed  Google Scholar 

  25. Olson, A. L. et al. Rheumatoid arthritis-interstitial lung disease-associated mortality. Am J Respir Crit Care Med 183, 372–378 (2011).

    PubMed  PubMed Central  Google Scholar 

  26. Perez, T., Remy-Jardin, M. & Cortet, B. Airways involvement in rheumatoid arthritis: clinical, functional, and HRCT findings. Am. J. Respir. Crit. Care Med. 157, 1658–1665 (1998).

    CAS  PubMed  Google Scholar 

  27. Doyle, T. J. et al. A roadmap to promote clinical and translational research in rheumatoid arthritis-associated interstitial lung disease. Chest 145, 454–463 (2014).

    PubMed  PubMed Central  Google Scholar 

  28. Shaw, M., Collins, B. F., Ho, L. A. & Raghu, G. Rheumatoid arthritis-associated lung disease. Eur. Respir. Rev. 24, 1–16 (2015).

    PubMed  Google Scholar 

  29. Gauhar, U. A., Gaffo, A. L. & Alarcon, G. S. Pulmonary manifestations of rheumatoid arthritis. Semin. Respir. Crit. Care Med. 28, 430–440 (2007).

    PubMed  Google Scholar 

  30. Balbir-Gurman, A., Yigla, M., Nahir, A. M. & Braun-Moscovici, Y. Rheumatoid pleural effusion. Semin. Arthritis Rheum. 35, 368–378 (2006).

    PubMed  Google Scholar 

  31. Cortet, B. et al. Use of high resolution computed tomography of the lungs in patients with rheumatoid arthritis. Ann. Rheum. Dis. 54, 815–819 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Portner, M. M. & Gracie, W. A. Jr. Rheumatoid lung disease with cavitary nodules, pneumothorax and eosinophilia. N. Engl. J. Med. 275, 697–700 (1966).

    CAS  PubMed  Google Scholar 

  33. Kim, E. J. et al. Usual interstitial pneumonia in rheumatoid arthritis-associated interstitial lung disease. Eur. Respir. J. 35, 1322–1328 (2010).

    PubMed  Google Scholar 

  34. Nurmi, H. M. et al. Several high-resolution computed tomography findings associate with survival and clinical features in rheumatoid arthritis-associated interstitial lung disease. Respir. Med. 134, 24–30 (2018).

    PubMed  Google Scholar 

  35. Solomon, J. J. et al. Predictors of mortality in rheumatoid arthritis-associated interstitial lung disease. Eur. Respir. J. 47, 588–596 (2016).

    PubMed  Google Scholar 

  36. Tsuchiya, Y. et al. Lung diseases directly associated with rheumatoid arthritis and their relationship to outcome. Eur. Respir. J. 37, 1411–1417 (2011).

    CAS  PubMed  Google Scholar 

  37. Hamblin, M. J. & Horton, M. R. Rheumatoid arthritis-associated interstitial lung disease: diagnostic dilemma. Pulm. Med. 2011, 872120 (2011).

    PubMed  PubMed Central  Google Scholar 

  38. Kim, E. J., Collard, H. R. & King, T. E. Jr. Rheumatoid arthritis-associated interstitial lung disease: the relevance of histopathologic and radiographic pattern. Chest 136, 1397–1405 (2009).

    PubMed  PubMed Central  Google Scholar 

  39. Inui, N. et al. Anti-cyclic citrullinated peptide antibodies in lung diseases associated with rheumatoid arthritis. Clin. Biochem. 41, 1074–1077 (2008).

    CAS  PubMed  Google Scholar 

  40. Chen, J. et al. Biomarkers of rheumatoid arthritis-associated interstitial lung disease. Arthritis Rheumatol. 67, 28–38 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. National Cancer Institute. Lung Cancer Screening (PDQ®)–Health Professional Version. Cancer.gov https://www.cancer.gov/types/lung/hp/lung-screening-pdq (2019).

  42. Audiger, C., Rahman, M. J., Yun, T. J., Tarbell, K. V. & Lesage, S. The importance of dendritic cells in maintaining immune tolerance. J. Immunol. 198, 2223–2231 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Albano, S. A., Santana-Sahagun, E. & Weisman, M. H. Cigarette smoking and rheumatoid arthritis. Semin. Arthritis Rheum. 31, 146–159 (2001).

    CAS  PubMed  Google Scholar 

  44. Baka, Z., Buzas, E. & Nagy, G. Rheumatoid arthritis and smoking: putting the pieces together. Arthritis Res. Ther. 11, 238 (2009).

    PubMed  PubMed Central  Google Scholar 

  45. Criswell, L. A. et al. Cigarette smoking and the risk of rheumatoid arthritis among postmenopausal women: results from the Iowa Women’s Health Study. Am. J. Med. 112, 465–471 (2002).

    PubMed  Google Scholar 

  46. Damgaard, D. et al. Smoking is associated with increased levels of extracellular peptidylarginine deiminase 2 (PAD2) in the lungs. Clin. Exp. Rheumatol. 33, 405–408 (2015).

    PubMed  Google Scholar 

  47. Mori, S., Koga, Y. & Sugimoto, M. Different risk factors between interstitial lung disease and airway disease in rheumatoid arthritis. Respir. Med. 106, 1591–1599 (2012).

    PubMed  Google Scholar 

  48. Juge, P. A. et al. MUC5B promoter variant and rheumatoid arthritis with interstitial lung disease. N. Engl. J. Med. 379, 2209–2219 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Centers for Disease Control and Prevention (CDC). Smoking-attributable mortality, years of potential life lost, and productivity losses – United States, 2000–2004. MMWR Morb. Mortal Wkly. Rep. 57, 1226–1228 (2008).

    Google Scholar 

  50. Antoniou, K. M. et al. Smoking-related emphysema is associated with idiopathic pulmonary fibrosis and rheumatoid lung. Respirology 18, 1191–1196 (2013).

    PubMed  Google Scholar 

  51. Jacob, J. et al. Prevalence and effects of emphysema in never-smokers with rheumatoid arthritis interstitial lung disease. EbioMedicine 28, 303–310 (2018).

    PubMed  PubMed Central  Google Scholar 

  52. Anaya, J. M., Ramirez-Santana, C., Alzate, M. A., Molano-Gonzalez, N. & Rojas-Villarraga, A. The autoimmune ecology. Front. Immunol. 7, 139 (2016).

    PubMed  PubMed Central  Google Scholar 

  53. Morse, D. & Rosas, I. O. Tobacco smoke-induced lung fibrosis and emphysema. Annu. Rev. Physiol. 76, 493–513 (2014).

    CAS  PubMed  Google Scholar 

  54. Rahman, I., Biswas, S. K. & Kode, A. Oxidant and antioxidant balance in the airways and airway diseases. Eur. J. Pharmacol. 533, 222–239 (2006).

    CAS  PubMed  Google Scholar 

  55. Arnson, Y., Shoenfeld, Y. & Amital, H. Effects of tobacco smoke on immunity, inflammation and autoimmunity. J. Autoimmun. 34, J258–J265 (2010).

    CAS  PubMed  Google Scholar 

  56. Lee, J., Taneja, V. & Vassallo, R. Cigarette smoking and inflammation: cellular and molecular mechanisms. J. Dent. Res. 91, 142–149 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Nguyen, N. T., Hanieh, H., Nakahama, T. & Kishimoto, T. The roles of aryl hydrocarbon receptor in immune responses. Int. Immunol. 25, 335–343 (2013).

    CAS  PubMed  Google Scholar 

  58. Kazantseva, M. G., Highton, J., Stamp, L. K. & Hessian, P. A. Dendritic cells provide a potential link between smoking and inflammation in rheumatoid arthritis. Arthritis Res. Ther. 14, R208 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Nakahama, T. et al. Aryl hydrocarbon receptor deficiency in T cells suppresses the development of collagen-induced arthritis. Proc. Natl Acad. Sci. USA 108, 14222–14227 (2011).

    CAS  PubMed  Google Scholar 

  60. Su, H. H. et al. Aryl hydrocarbon receptor-ligand axis mediates pulmonary fibroblast migration and differentiation through increased arachidonic acid metabolism. Toxicology 370, 116–126 (2016).

    CAS  PubMed  Google Scholar 

  61. Woeller, C. F., Roztocil, E., Hammond, C. L., Feldon, S. E. & Phipps, R. P. The aryl hydrocarbon receptor and its ligands inhibit myofibroblast formation and activation: implications for thyroid eye disease. Am. J. Pathol. 186, 3189–3202 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Chen, K. et al. IL-17RA is required for CCL2 expression, macrophage recruitment, and emphysema in response to cigarette smoke. PLOS ONE 6, e20333 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Nguyen, N. T. et al. Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism. Proc. Natl Acad. Sci. U. S. A. 107, 19961–19966 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Yang, Y. et al. Regulatory effect of nicotine on collagen-induced arthritis and on the induction and function of in vitro-cultured Th17 cells. Mod. Rheumatol. 24, 781–787 (2014).

    CAS  PubMed  Google Scholar 

  65. Lee, J. et al. Nicotine drives neutrophil extracellular traps formation and accelerates collagen-induced arthritis. Rheumatology 56, 644–653 (2017).

    CAS  PubMed  Google Scholar 

  66. Yu, H., Yang, Y. H., Rajaiah, R. & Moudgil, K. D. Nicotine-induced differential modulation of autoimmune arthritis in the lewis rat involves changes in interleukin-17 and anti-cyclic citrullinated peptide antibodies. Arthritis Rheum. 63, 981–991 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Lee, K. H. et al. Neutrophil extracellular traps (NETs) in autoimmune diseases: a comprehensive review. Autoimmun. Rev. 16, 1160–1173 (2017).

    CAS  PubMed  Google Scholar 

  68. Li, P. et al. PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps. J. Exp. Med. 207, 1853–1862 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Jensen, K. et al. General mechanisms of nicotine-induced fibrogenesis. FASEB J. 26, 4778–4787 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Ahmad, S. et al. Acute pulmonary effects of aerosolized nicotine. Am. J. Physiol. Lung Cell Mol. Physiol. 316, L94–L104 (2019).

    PubMed  Google Scholar 

  71. Zou, W., Zou, Y., Zhao, Z., Li, B. & Ran, P. Nicotine-induced epithelial-mesenchymal transition via Wnt/beta-catenin signaling in human airway epithelial cells. Am. J. Physiol. Lung Cell Mol. Physiol. 304, L199–L209 (2013).

    CAS  PubMed  Google Scholar 

  72. Upham, J. W. & Xi, Y. Dendritic cells in human lung disease: recent advances. Chest 151, 668–673 (2017).

    PubMed  Google Scholar 

  73. Kroening, P. R. et al. Cigarette smoke-induced oxidative stress suppresses generation of dendritic cell IL-12 and IL-23 through ERK-dependent pathways. J. Immunol. 181, 1536–1547 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Robbins, C. S. et al. Cigarette smoke decreases pulmonary dendritic cells and impacts antiviral immune responsiveness. Am. J. Respir. Cell Mol. Biol. 30, 202–211 (2004).

    CAS  PubMed  Google Scholar 

  75. Vassallo, R. et al. Cigarette smoke promotes dendritic cell accumulation in COPD; a Lung Tissue Research Consortium study. Respir. Res. 11, 45 (2010).

    PubMed  PubMed Central  Google Scholar 

  76. Givi, M. E., Folkerts, G., Wagenaar, G. T., Redegeld, F. A. & Mortaz, E. Cigarette smoke differentially modulates dendritic cell maturation and function in time. Respir. Res. 16, 131 (2015).

    PubMed  PubMed Central  Google Scholar 

  77. Van Hove, C. L., Moerloose, K., Maes, T., Joos, G. F. & Tournoy, K. G. Cigarette smoke enhances Th-2 driven airway inflammation and delays inhalational tolerance. Respir. Res. 9, 42 (2008).

    PubMed  PubMed Central  Google Scholar 

  78. Van Pottelberge, G. R. et al. Plasmacytoid dendritic cells in pulmonary lymphoid follicles of patients with COPD. Eur. Respir. J. 36, 781–791 (2010).

    PubMed  Google Scholar 

  79. Checa, M. et al. Cigarette smoke enhances the expression of profibrotic molecules in alveolar epithelial cells. PLOS ONE 11, e0150383 (2016).

    PubMed  PubMed Central  Google Scholar 

  80. John, G. et al. The composition of cigarette smoke determines inflammatory cell recruitment to the lung in COPD mouse models. Clin. Sci. 126, 207–221 (2014).

    CAS  Google Scholar 

  81. Moret, F. M. et al. Thymic stromal lymphopoietin, a novel proinflammatory mediator in rheumatoid arthritis that potently activates CD1c+ myeloid dendritic cells to attract and stimulate T cells. Arthritis Rheumatol. 66, 1176–1184 (2014).

    CAS  PubMed  Google Scholar 

  82. Sendo, S. et al. CD11b+Gr-1(dim) tolerogenic dendritic cell-like cells are expanded in interstitial lung disease in SKG mice. Arthritis Rheumatol. 69, 2314–2327 (2017).

    CAS  PubMed  Google Scholar 

  83. Rangel-Moreno, J. et al. Inducible bronchus-associated lymphoid tissue (iBALT) in patients with pulmonary complications of rheumatoid arthritis. J. Clin. Invest. 116, 3183–3194 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Marin, N. D., Dunlap, M. D., Kaushal, D. & Khader, S. A. Friend or foe: the protective and pathological roles of inducible bronchus-associated lymphoid tissue in pulmonary diseases. J. Immunol. 202, 2519–2526 (2019).

    CAS  PubMed  Google Scholar 

  85. Heesters, B. A., Myers, R. C. & Carroll, M. C. Follicular dendritic cells: dynamic antigen libraries. Nat. Rev. Immunol. 14, 495–504 (2014).

    CAS  PubMed  Google Scholar 

  86. Stastny, P. HLA-D and Ia antigens in rheumatoid arthritis and systemic lupus erythematosus. Arthritis Rheum. 21, S139–S143 (1978).

    CAS  PubMed  Google Scholar 

  87. Karlson, E. W. et al. Gene-environment interaction between HLA-DRB1 shared epitope and heavy cigarette smoking in predicting incident rheumatoid arthritis. Ann. Rheum. Dis. 69, 54–60 (2010).

    CAS  PubMed  Google Scholar 

  88. Padyukov, L., Silva, C., Stolt, P., Alfredsson, L. & Klareskog, L. A gene-environment interaction between smoking and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis. Arthritis Rheum. 50, 3085–3092 (2004).

    CAS  PubMed  Google Scholar 

  89. Mattey, D. L. et al. Relationship among the HLA-DRB1 shared epitope, smoking, and rheumatoid factor production in rheumatoid arthritis. Arthritis Rheum. 47, 403–407 (2002).

    CAS  PubMed  Google Scholar 

  90. Lundstrom, E., Kallberg, H., Alfredsson, L., Klareskog, L. & Padyukov, L. Gene-environment interaction between the DRB1 shared epitope and smoking in the risk of anti-citrullinated protein antibody-positive rheumatoid arthritis: all alleles are important. Arthritis Rheum. 60, 1597–1603 (2009).

    PubMed  Google Scholar 

  91. Makrygiannakis, D. et al. Smoking increases peptidylarginine deiminase 2 enzyme expression in human lungs and increases citrullination in BAL cells. Ann. Rheum. Dis. 67, 1488–1492 (2008).

    CAS  PubMed  Google Scholar 

  92. Dieude, P. et al. Rheumatoid arthritis seropositive for the rheumatoid factor is linked to the protein tyrosine phosphatase nonreceptor 22-620W allele. Arthritis Res. Ther. 7, R1200–R1207 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Chang, H. H., Dwivedi, N., Nicholas, A. P. & Ho, I. C. The W620 polymorphism in PTPN22 disrupts its interaction with peptidylarginine deiminase type 4 and enhances citrullination and NETosis. Arthritis Rheumatol. 67, 2323–2334 (2015).

    CAS  PubMed  Google Scholar 

  94. Gregersen, P. K. Pathways to gene identification in rheumatoid arthritis: PTPN22 and beyond. Immunol. Rev. 204, 74–86 (2005).

    CAS  PubMed  Google Scholar 

  95. Budding, K. et al. The autoimmune-associated single nucleotide polymorphism within PTPN22 correlates with clinical outcome after lung transplantation. Front. Immunol. 9, 3105 (2018).

    CAS  PubMed  Google Scholar 

  96. Furukawa, H. et al. Association of human leukocyte antigen with interstitial lung disease in rheumatoid arthritis: a protective role for shared epitope. PLOS ONE 7, e33133 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Oka, S. et al. Association of human leukocyte antigen alleles with chronic lung diseases in rheumatoid arthritis. Rheumatology 55, 1301–1307 (2016).

    CAS  PubMed  Google Scholar 

  98. Tsui, J. L. et al. Analysis of pulmonary features and treatment approaches in the COPA syndrome. ERJ Open Res. 4, 00017–02018 (2018).

    PubMed  PubMed Central  Google Scholar 

  99. Watkin, L. B. et al. COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis. Nat. Genet. 47, 654–660 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Wei, J., Rahman, S., Ayaub, E. A., Dickhout, J. G. & Ask, K. Protein misfolding and endoplasmic reticulum stress in chronic lung disease. Chest 143, 1098–1105 (2013).

    CAS  PubMed  Google Scholar 

  101. Chen, J. et al. An expansion of rare lineage intestinal microbes characterizes rheumatoid arthritis. Genome Med. 8, 43 (2016).

    PubMed  PubMed Central  Google Scholar 

  102. Zhang, X. et al. The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nat. Med. 21, 895–905 (2015).

    CAS  PubMed  Google Scholar 

  103. Scher, J. U. et al. The lung microbiota in early rheumatoid arthritis and autoimmunity. Microbiome 4, 60 (2016).

    PubMed  PubMed Central  Google Scholar 

  104. Mikuls, T. R., Payne, J. B., Deane, K. D. & Thiele, G. M. Autoimmunity of the lung and oral mucosa in a multisystem inflammatory disease: The spark that lights the fire in rheumatoid arthritis? J. Allergy Clin. Immunol. 137, 28–34 (2016).

    CAS  PubMed  Google Scholar 

  105. Ruane, D. et al. Microbiota regulate the ability of lung dendritic cells to induce IgA class-switch recombination and generate protective gastrointestinal immune responses. J. Exp. Med. 213, 53–73 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Gomez, A. et al. Loss of sex and age driven differences in the gut microbiome characterize arthritis-susceptible 0401 mice but not arthritis-resistant 0402 mice. PLOS ONE 7, e36095 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Bradley, C. P. et al. Segmented filamentous bacteria provoke lung autoimmunity by inducing gut-lung axis Th17 cells expressing dual TCRs. Cell Host Microbe 22, 697–704 e694 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Mikuls, T. R. et al. Periodontitis and Porphyromonas gingivalis in patients with rheumatoid arthritis. Arthritis Rheumatol. 66, 1090–1100 (2014).

    PubMed  PubMed Central  Google Scholar 

  109. Marchesan, J. T. et al. Porphyromonas gingivalis oral infection exacerbates the development and severity of collagen-induced arthritis. Arthritis Res. Ther. 15, R186 (2013).

    PubMed  PubMed Central  Google Scholar 

  110. Jung, H. et al. Arthritic role of Porphyromonas gingivalis in collagen-induced arthritis mice. PLOS ONE 12, e0188698 (2017).

    PubMed  PubMed Central  Google Scholar 

  111. Fidler, L., Sitzer, N., Shapera, S. & Shah, P. S. Treatment of gastroesophageal reflux in patients with idiopathic pulmonary fibrosis: a systematic review and meta-analysis. Chest 153, 1405–1415 (2018).

    PubMed  Google Scholar 

  112. Chen, B. et al. Chronic microaspiration of bile acids induces lung fibrosis through multiple mechanisms in rats. Clin. Sci. 131, 951–963 (2017).

    CAS  Google Scholar 

  113. Zhang, Y., Li, H., Wu, N., Dong, X. & Zheng, Y. Retrospective study of the clinical characteristics and risk factors of rheumatoid arthritis-associated interstitial lung disease. Clin. Rheumatol. 36, 817–823 (2017).

    PubMed  Google Scholar 

  114. Assayag, D. et al. Rheumatoid arthritis-associated interstitial lung disease: radiologic identification of usual interstitial pneumonia pattern. Radiology 270, 583–588 (2014).

    PubMed  PubMed Central  Google Scholar 

  115. Taylor, P., Gartemann, J., Hsieh, J. & Creeden, J. A systematic review of serum biomarkers anti-cyclic citrullinated peptide and rheumatoid factor as tests for rheumatoid arthritis. Autoimmune Dis. 2011, 815038 (2011).

    PubMed  PubMed Central  Google Scholar 

  116. Bongartz, T. et al. Citrullination in extra-articular manifestations of rheumatoid arthritis. Rheumatology 46, 70–75 (2007).

    CAS  Google Scholar 

  117. Aubart, F. et al. High levels of anti-cyclic citrullinated peptide autoantibodies are associated with co-occurrence of pulmonary diseases with rheumatoid arthritis. J. Rheumatol. 38, 979–982 (2011).

    CAS  PubMed  Google Scholar 

  118. Giles, J. T. et al. Association of fine specificity and repertoire expansion of anticitrullinated peptide antibodies with rheumatoid arthritis associated interstitial lung disease. Ann. Rheum. Dis. 73, 1487–1494 (2014).

    CAS  PubMed  Google Scholar 

  119. del Val del Amo, N., Ibanez Bosch, R., Fito Manteca, C., Gutierrez Polo, R. & Loza Cortina, E. Anti-cyclic citrullinated peptide antibody in rheumatoid arthritis: relation with disease aggressiveness. Clin. Exp. Rheumatol. 24, 281–286 (2006).

    PubMed  Google Scholar 

  120. Clavel, C. et al. Induction of macrophage secretion of tumor necrosis factor α through Fcγ receptor IIa engagement by rheumatoid arthritis-specific autoantibodies to citrullinated proteins complexed with fibrinogen. Arthritis Rheum. 58, 678–688 (2008).

    CAS  PubMed  Google Scholar 

  121. Khandpur, R. et al. NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci. Transl Med. 5, 178ra140 (2013).

    Google Scholar 

  122. Matteson, E. L. et al. Open-label, pilot study of the safety and clinical effects of rituximab in patients with rheumatoid arthritis-associated interstitial pneumonia. Open J. Rheumatol. Autoimmune Dis. 2, 6 (2012).

    PubMed  PubMed Central  Google Scholar 

  123. Chartrand, S., Swigris, J. J., Peykova, L. & Fischer, A. Rituximab for the treatment of connective tissue disease-associated interstitial lung disease. Sarcoidosis Vasc. Diffuse Lung Dis. 32, 296–304 (2016).

    PubMed  Google Scholar 

  124. Md Yusof, M. Y. et al. Effect of rituximab on the progression of rheumatoid arthritis-related interstitial lung disease: 10 years’ experience at a single centre. Rheumatology 56, 1348–1357 (2017).

    PubMed  Google Scholar 

  125. Baumgartner, K. B., Samet, J. M., Stidley, C. A., Colby, T. V. & Waldron, J. A. Cigarette smoking: a risk factor for idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 155, 242–248 (1997).

    CAS  PubMed  Google Scholar 

  126. Kelly, C. A. et al. Rheumatoid arthritis-related interstitial lung disease: associations, prognostic factors and physiological and radiological characteristics – a large multicentre UK study. Rheumatology 53, 1676–1682 (2014).

    CAS  PubMed  Google Scholar 

  127. Assayag, D. et al. Predictors of mortality in rheumatoid arthritis-related interstitial lung disease. Respirology 19, 493–500 (2014).

    PubMed  Google Scholar 

  128. Guenther, A. et al. The European IPF registry (eurIPFreg): baseline characteristics and survival of patients with idiopathic pulmonary fibrosis. Respir. Res. 19, 141 (2018).

    PubMed  PubMed Central  Google Scholar 

  129. Hancock, L. A. et al. Muc5b overexpression causes mucociliary dysfunction and enhances lung fibrosis in mice. Nat. Commun. 9, 5363 (2018).

    PubMed  PubMed Central  Google Scholar 

  130. Seibold, M. A. et al. A common MUC5B promoter polymorphism and pulmonary fibrosis. N. Engl. J. Med. 364, 1503–1512 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Peljto, A. L. et al. Association between the MUC5B promoter polymorphism and survival in patients with idiopathic pulmonary fibrosis. JAMA 309, 2232–2239 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Stock, C. J. et al. Mucin 5B promoter polymorphism is associated with idiopathic pulmonary fibrosis but not with development of lung fibrosis in systemic sclerosis or sarcoidosis. Thorax 68, 436–441 (2013).

    PubMed  Google Scholar 

  133. Borie, R. et al. The MUC5B variant is associated with idiopathic pulmonary fibrosis but not with systemic sclerosis interstitial lung disease in the european caucasian population. PLOS ONE 8, e70621 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Peljto, A. L. et al. The pulmonary fibrosis-associated MUC5B promoter polymorphism does not influence the development of interstitial pneumonia in systemic sclerosis. Chest 142, 1584–1588 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Johnson, C. et al. Exploration of the MUC5B promoter variant and ILD risk in patients with autoimmune myositis. Respir. Med. 130, 52–54 (2017).

    PubMed  Google Scholar 

  136. Juge, P. A. et al. Shared genetic predisposition in rheumatoid arthritis-interstitial lung disease and familial pulmonary fibrosis. Eur. Respir. J. 49, 1602314 (2017).

    PubMed  Google Scholar 

  137. Nureki, S. I. et al. Expression of mutant Sftpc in murine alveolar epithelia drives spontaneous lung fibrosis. J. Clin. Invest. 128, 4008–4024 (2018).

    PubMed  PubMed Central  Google Scholar 

  138. Turesson, C. et al. Increased CD4+ T cell infiltrates in rheumatoid arthritis-associated interstitial pneumonitis compared with idiopathic interstitial pneumonitis. Arthritis Rheum. 52, 73–79 (2005).

    PubMed  Google Scholar 

  139. Zhang, J. et al. Pro-fibrotic effects of IL-17A and elevated IL-17RA in IPF and RA-ILD support a direct role for IL-17A/IL-17RA in human fibrotic interstitial lung disease. Am. J. Physiol. Lung Cell Mol. Physiol. 316, L487–L497 (2019).

  140. Broekelmann, T. J., Limper, A. H., Colby, T. V. & McDonald, J. A. Transforming growth factor beta 1 is present at sites of extracellular matrix gene expression in human pulmonary fibrosis. Proc. Natl Acad. Sci. U. S. A. 88, 6642–6646 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Mangan, P. R. et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 441, 231–234 (2006).

    CAS  Google Scholar 

  142. van den Berg, W. B. & Miossec, P. IL-17 as a future therapeutic target for rheumatoid arthritis. Nat. Rev. Rheumatol. 5, 549–553 (2009).

    PubMed  Google Scholar 

  143. Wilson, M. S. et al. Bleomycin and IL-1beta-mediated pulmonary fibrosis is IL-17A dependent. J. Exp. Med. 207, 535–552 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Harley, C. B., Futcher, A. B. & Greider, C. W. Telomeres shorten during ageing of human fibroblasts. Nature 345, 458–460 (1990).

    CAS  PubMed  Google Scholar 

  145. d’Adda di Fagagna, F. et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 426, 194–198 (2003).

    PubMed  Google Scholar 

  146. Schafer, M. J. et al. Cellular senescence mediates fibrotic pulmonary disease. Nat. Commun. 8, 14532 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Fujii, H., Shao, L., Colmegna, I., Goronzy, J. J. & Weyand, C. M. Telomerase insufficiency in rheumatoid arthritis. Proc. Natl. Acad. Sci. U. S. A. 106, 4360–4365 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Zamora-Legoff, J. A., Krause, M. L., Crowson, C. S., Ryu, J. H. & Matteson, E. L. Patterns of interstitial lung disease and mortality in rheumatoid arthritis. Rheumatology 56, 344–350 (2017).

    CAS  PubMed  Google Scholar 

  149. US National Library of Medicine ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02999178 (2019).

  150. US National Library of Medicine ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02808871 (2019).

  151. Dawson, J. K., Fewins, H. E., Desmond, J., Lynch, M. P. & Graham, D. R. Fibrosing alveolitis in patients with rheumatoid arthritis as assessed by high resolution computed tomography, chest radiography, and pulmonary function tests. Thorax 56, 622–627 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Gabbay, E. et al. Interstitial lung disease in recent onset rheumatoid arthritis. Am. J. Respir. Crit. Care Med. 156, 528–535 (1997).

    CAS  PubMed  Google Scholar 

  153. Gochuico, B. R. et al. Progressive preclinical interstitial lung disease in rheumatoid arthritis. Arch. Intern. Med. 168, 159–166 (2008).

    CAS  PubMed  Google Scholar 

  154. Tanaka, N. et al. Rheumatoid arthritis-related lung diseases: CT findings. Radiology 232, 81–91 (2004).

    PubMed  Google Scholar 

  155. Mori, S., Koga, Y. & Sugimoto, M. Small airway obstruction in patients with rheumatoid arthritis. Mod. Rheumatol. 21, 164–173 (2011).

    PubMed  Google Scholar 

  156. Schreiber, J. et al. Rheumatoid pneumoconiosis (Caplan’s syndrome). Eur. J. Intern. Med. 21, 168–172 (2010).

    CAS  PubMed  Google Scholar 

  157. Jurik, A. G., Pedersen, U. & Noorgard, A. Rheumatoid arthritis of the cricoarytenoid joints: a case of laryngeal obstruction due to acute and chronic joint changes. Laryngoscope 95, 846–848 (1985).

    CAS  PubMed  Google Scholar 

  158. Charlin, B., Brazeau-Lamontagne, L., Levesque, R. Y. & Lussier, A. Cricoarytenoiditis in rheumatoid arthritis: comparison of fibrolaryngoscopic and high resolution computerized tomographic findings. J. Otolaryngol. 14, 381–386 (1985).

    CAS  PubMed  Google Scholar 

  159. Lawry, G. V. et al. Laryngeal involvement in rheumatoid arthritis. A clinical, laryngoscopic, and computerized tomographic study. Arthritis Rheum. 27, 873–882 (1984).

    CAS  PubMed  Google Scholar 

  160. Devouassoux, G. et al. Characterisation of severe obliterative bronchiolitis in rheumatoid arthritis. Eur. Respir. J. 33, 1053–1061 (2009).

    CAS  PubMed  Google Scholar 

  161. Udayakumar, N., Venkatesan, S. & Rajendiran, C. Pulmonary hypertension in rheumatoid arthritis – relation with the duration of the disease. Int. J. Cardiol. 127, 410–412 (2008).

    CAS  PubMed  Google Scholar 

  162. Keser, G. et al. Pulmonary hypertension in rheumatoid arthritis. Scand. J. Rheumatol. 33, 244–245 (2004).

    CAS  PubMed  Google Scholar 

  163. Dawson, J. K., Goodson, N. G., Graham, D. R. & Lynch, M. P. Raised pulmonary artery pressures measured with doppler echocardiography in rheumatoid arthritis patients. Rheumatology 39, 1320–1325 (2000).

    CAS  PubMed  Google Scholar 

  164. Voskuyl, A. E. et al. Factors associated with the development of vasculitis in rheumatoid arthritis: results of a case-control study. Ann. Rheum. Dis. 55, 190–192 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Schwarz, M. I. et al. Isolated pulmonary capillaritis and diffuse alveolar hemorrhage in rheumatoid arthritis and mixed connective tissue disease. Chest 113, 1609–1615 (1998).

    CAS  PubMed  Google Scholar 

  166. Walker, W. C. & Wright, V. Rheumatoid pleuritis. Ann. Rheum. Dis. 26, 467–474 (1967).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Sharma, S. S. & Reynolds, P. M. Broncho-pleural fistula complicating rheumatoid lung disease. Postgrad. Med. J. 58, 187–189 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Ayzenberg, O., Reiff, D. B. & Levin, L. Bilateral pneumothoraces and pleural effusions complicating rheumatoid lung disease. Thorax 38, 159–160 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Martel, W., Abell, M. R., Mikkelsen, W. M. & Whitehouse, W. M. Pulmonary and pleural lesions in rheumatoid disease. Radiology 90, 641–653 (1968).

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Rheumatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China

    Dan Wang

  2. Division of Pulmonary Medicine, Department of Medicine, Chongqing General Hospital, Chongqing, China

    Jie Zhang

  3. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, USA

    Jessica Lau, Shaohua Wang & Robert Vassallo

  4. Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA

    Veena Taneja

  5. Division of Rheumatology, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, USA

    Eric L. Matteson

  6. Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA

    Robert Vassallo

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Contributions

D.W., J.Z., J.L. and R.V. researched data for this article. All authors provided substantial contributions to discussions of content and wrote this article. D.W., J.Z., J.L., E.L.M. and R.V. reviewed and/or edited the manuscript before submission.

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Correspondence to Robert Vassallo.

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Competing interests

V.T. declares that she has received research funding from Evelo Biosciences and Jansen Biotech for research unrelated to this Review. E.L.M. declares that he has served as an adviser to Boeringher-Ingelheim (<$10,000). R.V. declares that he has received grant funding from Bristol-Myers-Squibb, Pfizer and Sun Pharmaceuticals. R.V. is also an investigator on a multicentre clinical trial funded by Genentech into rheumatoid arthritis-associated interstitial lung disease (TRAIL-1). The other authors declare no competing interests.

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Glossary

Bronchoalveolar lavage

(BAL). A medical procedure during which a bronchoscope is guided from the oral cavity or nose into the lungs for the purpose of instilling sterile fluid into a region of the lung and then aspirating back the fluid for examination.

Bronchiectasis

A chronic disorder of the airways characterized by bronchial wall thickening and impaired mucous clearance, often associated with secondary colonization with various types of bacteria and other microorganisms.

Interstitial lung disease

(ILD). A large collection of diseases that affect the interstitial spaces within the lungs.

Rheumatoid nodules

Well-demarcated, subcutaneous lumps that vary in size and usually occur adjacent to joints on extensor surfaces, such as the elbow; they can also occur internally, such as in the sclera of the eyes, lungs or vocal cords.

Pulmonary hypertension

A medical condition associated with an elevated pressure (hypertension) in the pulmonary arteries.

Cricoarytenoiditis

Inflammation of the cricoarytenoid joint (a synovial joint located between the arytenoid and cricoid cartilages in the neck), which can occur in rheumatoid arthritis.

Constrictive bronchiolitis

A histopathological term for the bronchiolar (small airway) disorder characterized by fibroproliferative thickening of the bronchiolar walls causing narrowing of the bronchioles.

Follicular bronchiolitis

A bronchiolar disorder associated with bronchiolar narrowing as a result of inflammation and lymphoid hyperplasia of bronchus-associated lymphoid tissue.

Obliterative bronchiolitis

The clinical term used to describe constrictive small-airway bronchiolar diseases that can occur in a variety of clinical contexts, including rheumatoid arthritis; the corresponding histopathological entity to obliterative bronchiolitis is constrictive bronchiolitis.

Pleural effusion

Excessive fluid build-up that happens between visceral and parietal pleura.

Usual interstitial pneumonia

A form of interstitial lung disease associated with a characteristic histopathological pattern on lung biopsy and radiological pattern on chest CT.

Non-specific interstitial pneumonia

A distinct subgroup of interstitial lung disease with characteristic histopathological findings in lung tissue.

Clubbing

A deformity of the fingers and/or toes associated with enlargement of the fingertips and increased curvature of the nails that is associated with a number of lung and other disorders.

Pack-years

Each pack-year is the equivalent of a pack of 20 cigarettes smoked every day for 1 year.

Emphysema

A lung disorder associated with the destruction of alveolar units that clinically results in shortness of breath and exercise limitation.

Dysbiosis

An altered microbiome composition linked with the transition from healthy mucosal tissue to a state of dysfunction.

Diffusing capacity for carbon monoxide measurement

A physiological parameter of gas transfer efficiency in the lungs.

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Wang, D., Zhang, J., Lau, J. et al. Mechanisms of lung disease development in rheumatoid arthritis. Nat Rev Rheumatol 15, 581–596 (2019). https://doi.org/10.1038/s41584-019-0275-x

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