Skip to main content
SpringerLink
Log in
Book cover

Lung Disease in Rheumatoid Arthritis pp 31–43Cite as

The Lungs as the Site of Initiation of RA

  • Chapter
  • First Online:

  • 857 Accesses

Part of the book series: Respiratory Medicine ((RM))

Abstract

It has long been known that the lung can be involved in rheumatoid arthritis (RA). However, there are also emerging data that the lung may be a site of initial generation of RA-related autoimmunity even prior to the development of the clinically apparent joint disease during a period called “preclinical RA.” Herein, we will discuss an overall model of RA development where disease is initiated at a mucosal surface and specifically the lung. We will also discuss the biologic mechanisms, epidemiologic factors, and clinical and research findings that support that the lung may be an initial site of generation of RA-related autoimmunity. We will conclude by discussing a research agenda for further studies in this area.

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

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   79.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   99.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   99.99
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. Brown KK. Rheumatoid lung disease. Proc Am Thorac Soc. 2007;4(5):443–8.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Demoruelle MK, Weisman MH, Simonian PL, Lynch DA, Sachs PB, Pedraza IF, et al. Brief report: airways abnormalities and rheumatoid arthritis-related autoantibodies in subjects without arthritis: early injury or initiating site of autoimmunity? Arthritis Rheum. 2012;64(6):1756–61.

    Article  CAS  PubMed  Google Scholar 

  3. Wilsher M, Voight L, Milne D, Teh M, Good N, Kolbe J, et al. Prevalence of airway and parenchymal abnormalities in newly diagnosed rheumatoid arthritis. Respir Med. 2012;106(10):1441–6.

    Article  PubMed  Google Scholar 

  4. Deane KD, El-Gabalawy H. Pathogenesis and prevention of rheumatic disease: focus on preclinical RA and SLE. Nat Rev Rheumatol. 2014;10(4):212–28.

    Article  CAS  PubMed  Google Scholar 

  5. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American rheumatism association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31(3):315–24.

    Article  CAS  PubMed  Google Scholar 

  6. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, et al. Rheumatoid arthritis classification criteria: an American College of Rheumatology/European league against rheumatism collaborative initiative. Ann Rheum Dis. 2010;69(9):1580–8.

    Article  PubMed  Google Scholar 

  7. Gan RW, Trouw LA, Shi J, Toes RE, Huizinga TW, Demoruelle MK, et al. Anti-carbamylated protein antibodies are present prior to rheumatoid arthritis and are associated with its future diagnosis. J Rheumatol. 2015;42(4):572–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kolfenbach JR, Deane KD, Derber LA, O'Donnell CI, Gilliland WR, Edison JD, et al. Autoimmunity to peptidyl arginine deiminase type 4 precedes clinical onset of rheumatoid arthritis. Arthritis Rheum. 2010;62(9):2633–9.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Kokkonen H, Soderstrom I, Rocklov J, Hallmans G, Lejon K, Rantapaa Dahlqvist S. Up-regulation of cytokines and chemokines predates the onset of rheumatoid arthritis. Arthritis Rheum. 2010;62(2):383–91.

    CAS  PubMed  Google Scholar 

  10. Deane KD. Preclinical rheumatoid arthritis (autoantibodies): an updated review. Curr Rheumatol Rep. 2014;16(5):419.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Bos WH, Wolbink GJ, Boers M, Tijhuis GJ, de Vries N, Van der Horst-Bruinsma IE, et al. Arthritis development in patients with arthralgia is strongly associated with anti-citrullinated protein antibody status: a prospective cohort study. Ann Rheum Dis. 2010;69(3):490–4.

    Article  CAS  PubMed  Google Scholar 

  12. Demoruelle MK, Parish MC, Derber LA, Kolfenbach JR, Hughes-Austin JM, Weisman MH, et al. Performance of anti-cyclic citrullinated peptide assays differs in subjects at increased risk of rheumatoid arthritis and subjects with established disease. Arthritis Rheum. 2013;65(9):2243–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Demoruelle MK, Parish MC, Derber LA, Kolfenbach JR, Hughes-Austin JM, Weisman MH, et al. Anti-cyclic citrullinated peptide assays differ in subjects at elevated risk for rheumatoid arthritis and subjects with established disease. Arthritis Rheum. 2013;65(9):2243–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Sokolove J, Bromberg R, Deane KD, Lahey LJ, Derber LA, Chandra PE, et al. Autoantibody epitope spreading in the pre-clinical phase predicts progression to rheumatoid arthritis. PLoS One. 2012;7(5):e35296.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. van der Woude D, Rantapaa-Dahlqvist S, Ioan-Facsinay A, Onnekink C, Schwarte CM, Verpoort KN, et al. Epitope spreading of the anti-citrullinated protein antibody response occurs before disease onset and is associated with the disease course of early arthritis. Ann Rheum Dis. 2010;69(8):1554–61.

    Article  PubMed  Google Scholar 

  16. Johansson L, Pratesi F, Brink M, Arlestig L, D'Amato C, Bartaloni D, et al. Antibodies directed against endogenous and exogenous citrullinated antigens pre-date the onset of rheumatoid arthritis. Arthritis Res Ther. 2016;18(1):127.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Deane KD, O'Donnell CI, Hueber W, Majka DS, Lazar AA, Derber LA, 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. 2010;62(11):3161–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ercan A, Cui J, Chatterton DE, Deane KD, Hazen MM, Brintnell W, et al. Aberrant IgG galactosylation precedes disease onset, correlates with disease activity, and is prevalent in autoantibodies in rheumatoid arthritis. Arthritis Rheum. 2010;62(8):2239–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ioan-Facsinay A, Willemze A, Robinson DB, Peschken CA, Markland J, van der Woude D, et al. Marked differences in fine specificity and isotype usage of the anti-citrullinated protein antibody in health and disease. Arthritis Rheum. 2008;58(10):3000–8.

    Article  PubMed  Google Scholar 

  20. James EA, Rieck M, Pieper J, Gebe JA, Yue BB, Tatum M, et al. Citrulline-specific Th1 cells are increased in rheumatoid arthritis and their frequency is influenced by disease duration and therapy. Arthritis Rheumatol. 2014;66(7):1712–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kinslow JD, Blum LK, Deane KD, Demoruelle MK, Okamoto Y, Parish MC, et al. Elevated IgA Plasmablast levels in subjects at risk of developing rheumatoid arthritis. Arthritis Rheumatol. 2016;68(10):2372–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Quirke AM, Perry E, Cartwright A, Kelly C, De Soyza A, Eggleton P, et al. Bronchiectasis is a model for chronic bacterial infection inducing autoimmunity in rheumatoid arthritis. Arthritis Rheumatol. 2015;67(9):2335–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Masson-Bessiere C, Sebbag M, Durieux JJ, Nogueira L, Vincent C, Girbal-Neuhauser E, et al. In the rheumatoid pannus, anti-filaggrin autoantibodies are produced by local plasma cells and constitute a higher proportion of IgG than in synovial fluid and serum. Clin Exp Immunol. 2000;119(3):544–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. van de Stadt LA, Bos WH, Meursinge Reynders M, Wieringa H, Turkstra F, van der Laken CJ, et al. The value of ultrasonography in predicting arthritis in auto-antibody positive arthralgia patients: a prospective cohort study. Arthritis Res Ther. 2010;12(3):R98.

    Article  PubMed  PubMed Central  Google Scholar 

  25. de Hair MJ, van de Sande MG, Ramwadhdoebe TH, Hansson M, Landewe R, van der Leij C, et al. Features of the synovium of individuals at risk of developing rheumatoid arthritis: implications for understanding preclinical rheumatoid arthritis. Arthritis Rheumatol. 2014;66(3):513–22.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Karlson EW, Deane K. Environmental and gene-environment interactions and risk of rheumatoid arthritis. Rheum Dis Clin N Am. 2012;38(2):405–26.

    Article  Google Scholar 

  27. Klareskog L, Stolt P, Lundberg K, Kallberg H, Bengtsson C, Grunewald J, et al. 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. 2006;54(1):38–46.

    Article  CAS  PubMed  Google Scholar 

  28. Catrina AI, Deane KD, Scher JU. Gene, environment, microbiome and mucosal immune tolerance in rheumatoid arthritis. Rheumatology (Oxford). 2016;55(3):391–402.

    CAS  Google Scholar 

  29. Kokkonen H, Mullazehi M, Berglin E, Hallmans G, Wadell G, Ronnelid J, et al. Antibodies of IgG, IgA and IgM isotypes against cyclic citrullinated peptide precede the development of rheumatoid arthritis. Arthritis Res Ther. 2011;13(1):R13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Barra L, Scinocca M, Saunders S, Bhayana R, Rohekar S, Racape M, et al. Anti-citrullinated protein antibodies in unaffected first-degree relatives of rheumatoid arthritis patients. Arthritis Rheum. 2013;65(6):1439–47.

    Article  CAS  PubMed  Google Scholar 

  31. Rangel-Moreno J, Hartson L, Navarro C, Gaxiola M, Selman M, Randall TD. Inducible bronchus-associated lymphoid tissue (iBALT) in patients with pulmonary complications of rheumatoid arthritis. J Clin Invest. 2006;116(12):3183–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Willis VC, Demoruelle MK, Derber LA, Chartier-Logan CJ, Parish MC, Pedraza IF, et al. Sputum autoantibodies in patients with established rheumatoid arthritis and subjects at risk of future clinically apparent disease. Arthritis Rheum. 2013;65(10):2545–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Hwang JY, Randall TD, Silva-Sanchez A. Inducible bronchus-associated lymphoid tissue: taming inflammation in the lung. Front Immunol. 2016;7:258.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Moyron-Quiroz JE, Rangel-Moreno J, Kusser K, Hartson L, Sprague F, Goodrich S, et al. Role of inducible bronchus associated lymphoid tissue (iBALT) in respiratory immunity. Nat Med. 2004;10(9):927–34.

    Article  CAS  PubMed  Google Scholar 

  35. Gould SJ, Isaacson PG. Bronchus-associated lymphoid tissue (BALT) in human fetal and infant lung. J Pathol. 1993;169(2):229–34.

    Article  CAS  PubMed  Google Scholar 

  36. Mori M, Andersson CK, Svedberg KA, Glader P, Bergqvist A, Shikhagaie M, et al. Appearance of remodelled and dendritic cell-rich alveolar-lymphoid interfaces provides a structural basis for increased alveolar antigen uptake in chronic obstructive pulmonary disease. Thorax. 2013;68(6):521–31.

    Article  PubMed  Google Scholar 

  37. Sato A, Hayakawa H, Uchiyama H, Chida K. Cellular distribution of bronchus-associated lymphoid tissue in rheumatoid arthritis. Am J Respir Crit Care Med. 1996;154(6 Pt 1):1903–7.

    Article  CAS  PubMed  Google Scholar 

  38. Klareskog L, Gregersen PK, Huizinga TW. Prevention of autoimmune rheumatic disease: state of the art and future perspectives. Ann Rheum Dis. 2010;69(12):2062–6.

    Article  CAS  PubMed  Google Scholar 

  39. Stolt P, Bengtsson C, Nordmark B, Lindblad S, Lundberg I, Klareskog L, et al. Quantification of the influence of cigarette smoking on rheumatoid arthritis: results from a population based case-control study, using incident cases. Ann Rheum Dis. 2003;62(9):835–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kokkonen H, Brink M, Hansson M, Lassen E, Mathsson-Alm L, Holmdahl R, et al. Associations of antibodies against citrullinated peptides with human leukocyte antigen-shared epitope and smoking prior to the development of rheumatoid arthritis. Arthritis Res Ther. 2015;17:125.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Karlson EW, Ding B, Keenan BT, Liao K, Costenbader KH, Klareskog L, et al. Association of environmental and genetic factors and gene-environment interactions with risk of developing rheumatoid arthritis. Arthritis Care Res (Hoboken). 2013;65(7):1147–56.

    Article  Google Scholar 

  42. Al-Zalabani AH, Stewart KF, Wesselius A, Schols AM, Zeegers MP. Modifiable risk factors for the prevention of bladder cancer: a systematic review of meta-analyses. Eur J Epidemiol. 2016;31(9):811–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Gizinski AM, Mascolo M, Loucks JL, Kervitsky A, Meehan RT, Brown KK, et al. Rheumatoid arthritis (RA)-specific autoantibodies in patients with interstitial lung disease and absence of clinically apparent articular RA. Clin Rheumatol. 2009;28(5):611–3.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Fischer A, Solomon JJ, du Bois RM, Deane KD, Olson AL, Fernandez-Perez ER, et al. Lung disease with anti-CCP antibodies but not rheumatoid arthritis or connective tissue disease. Respir Med. 2012;106(7):1040–7.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Reynisdottir G, Olsen H, Joshua V, Engstrom M, Forsslund H, Karimi R, 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. 2015;75(9):1722–7.

    Article  PubMed  Google Scholar 

  46. Harlow L, Rosas IO, Gochuico BR, Mikuls TR, Dellaripa PF, Oddis CV, et al. Identification of citrullinated hsp90 isoforms as novel autoantigens in rheumatoid arthritis-associated interstitial lung disease. Arthritis Rheum. 2013;65(4):869–79.

    Article  CAS  PubMed  Google Scholar 

  47. Schiotz PO, Egeskjold EM, Hoiby N, Permin H. Autoantibodies in serum and sputum from patients with cystic fibrosis. Acta Pathol Microbiol Scand C. 1979;87(5):319–24.

    CAS  PubMed  Google Scholar 

  48. Sokolove J, Johnson DS, Lahey LJ, Wagner CA, Cheng D, Thiele GM, et al. Rheumatoid factor as a potentiator of anti-citrullinated protein antibody-mediated inflammation in rheumatoid arthritis. Arthritis Rheumatol. 2014;66(4):813–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Makrygiannakis D, Hermansson M, Ulfgren AK, Nicholas AP, Zendman AJ, Eklund A, et al. Smoking increases peptidylarginine deiminase 2 enzyme expression in human lungs and increases citrullination in BAL cells. Ann Rheum Dis. 2008;67(10):1488–92.

    Article  CAS  PubMed  Google Scholar 

  50. Hill JA, Southwood S, Sette A, Jevnikar AM, Bell DA, Cairns E. Cutting edge: the conversion of arginine to citrulline allows for a high-affinity peptide interaction with the rheumatoid arthritis-associated HLA-DRB1*0401 MHC class II molecule. J Immunol. 2003;171(2):538–41.

    Article  CAS  PubMed  Google Scholar 

  51. Hemminki K, Li X, Sundquist J, Sundquist K. Familial associations of rheumatoid arthritis with autoimmune diseases and related conditions. Arthritis Rheum. 2009;60(3):661–8.

    Article  PubMed  Google Scholar 

  52. Stack RJ, van Tuyl LH, Sloots M, van de Stadt LA, Hoogland W, Maat B, et al. Symptom complexes in patients with seropositive arthralgia and in patients newly diagnosed with rheumatoid arthritis: a qualitative exploration of symptom development. Rheumatology (Oxford). 2014;53(9):1646–53.

    Article  CAS  Google Scholar 

  53. Kharlamova N, Jiang X, Sherina N, Potempa B, Israelsson L, Quirke AM, et al. Antibodies to Porphyromonas gingivalis indicate interaction between oral infection, smoking, and risk genes in rheumatoid arthritis etiology. Arthritis Rheumatol. 2016;68(3):604–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Oldham JM, Adegunsoye A, Valenzi E, Lee C, Witt L, Chen L, et al. Characterisation of patients with interstitial pneumonia with autoimmune features. Eur Respir J. 2016;47(6):1767–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kolfenbach JR, Deane KD, Derber LA, O'Donnell C, Weisman MH, Buckner JH, et al. A prospective approach to investigating the natural history of preclinical rheumatoid arthritis (RA) using first-degree relatives of probands with RA. Arthritis Rheum. 2009;61(12):1735–42.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Catrina AI, Ytterberg AJ, Reynisdottir G, Malmstrom V, Klareskog L. Lungs, joints and immunity against citrullinated proteins in rheumatoid arthritis. Nat Rev Rheumatol. 2014;10(11):645–53.

    Article  CAS  PubMed  Google Scholar 

  57. Reynisdottir G, Karimi R, Joshua V, Olsen H, Hensvold AH, Harju A, et al. Structural changes and antibody enrichment in the lungs are early features of anti-citrullinated protein antibody-positive rheumatoid arthritis. Arthritis Rheumatol. 2014;66(1):31–9.

    Article  CAS  PubMed  Google Scholar 

  58. Shilling RA, Williams JW, Perera J, Berry E, Wu Q, Cummings OW, et al. Autoreactive T and B cells induce the development of bronchus-associated lymphoid tissue in the lung. Am J Respir Cell Mol Biol. 2013;48(4):406–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Rheumatology, University of Colorado Denver, Aurora, CO, USA

    Lindsay B. Kelmenson MD, M. Kristen Demoruelle MD, PhD & Kevin D. Deane MD, PhD

  2. Denver Veterans Affairs Medical Center, Denver, CO, USA

    Kevin D. Deane MD, PhD

Authors
  1. Lindsay B. Kelmenson MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Kristen Demoruelle MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kevin D. Deane MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kevin D. Deane MD, PhD .

Editor information

Editors and Affiliations

  1. Division of Rheumatology, Division of Pulmonary Sciences and Critical Care, Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA

    Aryeh Fischer

  2. Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA

    Joyce S. Lee

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Kelmenson, L.B., Kristen Demoruelle, M., Deane, K.D. (2018). The Lungs as the Site of Initiation of RA. In: Fischer, A., Lee, J. (eds) Lung Disease in Rheumatoid Arthritis. Respiratory Medicine. Humana Press, Cham. https://doi.org/10.1007/978-3-319-68888-6_3

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-68888-6_3

  • Published:

  • Publisher Name: Humana Press, Cham

  • Print ISBN: 978-3-319-68887-9

  • Online ISBN: 978-3-319-68888-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation