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Interstitial lung disease in rheumatoid arthritis – current events
Vol. 33 No. 3 (2026), Review articles
Vol. 33 No. 3 (2026)

Interstitial lung disease in rheumatoid arthritis – current events

Review articles
https://doi.org/10.35465/rbj.rbj.411
Published February 27, 2026
Valentina Simeonova Reshkova
University Hospital St. Ivan Rilski, Sofia, Bulgaria
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Keywords

rheumatoid arthritis,ILD , biomarkers, course and relationship

How to Cite

Reshkova, V. (2026). Interstitial lung disease in rheumatoid arthritis – current events. Rheumatology (Bulgaria), 33(3), 24-38. https://doi.org/10.35465/rbj.rbj.411
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Abstract

Rheumatoid arthritis (RA) is an autoimmune inflammatory joint disease with a chronic-progressive course. It occurs with progressive, symmetrical, erosive arthritis and extraarticular manifestations. The incidence of RA is 1 - 2% of the population. It affects women and men in a ratio of 9:1. Extra-articular manifestations are found in about 50% of patients with RA: consumptive and astheno-adynamic syndrome, splenomegaly, pericarditis, vasculitis, subcutaneous nodules, pulmonary involvement. Pulmonary involvement is found in 4 to 68% of patients with RA. The earliest pulmonary complications are respiratory manifestations – interstitial lung disease (ILD), bronchiolitis and cylindrical bronchiectasis. ILD in the course of rheumatoid arthritis occurs twice as often in men between 50 and 60 years of age. Several studies confirm that the most common radiographic presentation of ILD in patients with RA is usual interstitial pneumonia (UIP), with peripheral reticular opacities and honeycombing seen on high-resolution computed tomography (HRCT). Important for the occurrence, clinical course, and prevention of pulmonary fibrosis manifestations is to assess the presence of biomarkers in the serum of these patients with rheumatoid arthritis. 98 articles were found investigating biomarkers in interstitial lung disease associated with rheumatoid arthritis (ILD-RA), with 83 studies being of high quality, 15 being of moderate quality. The biomarkers studied were C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), anti-cyclic citrullinated antibody (anti-CCP), rheumatoid factor (RF), Krebs von den Lungen 6 (KL-6), surfactant protein D (SP-D), carcinoembryonic antigen (CEA), carbohydrate antigen 19-9. (CA19-9), matrix metalloproteinase 7 (MMP-7), chemokine ligand 10 (CXCL-10), neutrophil to lymphocyte ratio (NLR) in patients with rheumatoid arthritis only and in patients with ILD-RA. Treatment of the disease includes corticosteroids, immunosuppressants, biological therapy, kinase inhibitors. These medications are used to treat not only rheumatoid arthritis, but also systemic manifestations.

https://doi.org/10.35465/rbj.rbj.411
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References

  1. Hochberg M, Silman A, Smolen J, et al. Rheumatology 5th edition, vol. 2, 2011; Expert Consult Premium, sec. 10 Connective tissue disorders, 1223-1339.
  2. Marigliano B, Soriano A, Margiotta D et al. Lung involvement in connective tissue diseases: A comprehensive review and a focus on rheumatoid arthritis. Autoimmune reviews 2013; 12: 1076-1084. doi: 10.1016/j.autrev.2013.05.001. Epub 2013 May 15.
  3. Kim Dong Soon, Harold RC, Talmadge EK. Classification and natural history of the idiopathic interstial pneumonias. Proc Am Thorac Soc 2006; 3 (4): 285-292. doi: 10.1513/pats.200601-005TK.
  4. Eric L Matteson. Rheumatoid Arthritis-Associated Interstitial Lung Disease - Medscape - Jun 14, 2022
  5. Horton MR. Rheumatoid arthritis associated interstitial lung disease. Crit Rev Comput Tomogr 2004; 45:429-440. Doi: 10.3109/10408370490905325
  6. Bernstein EJ, Barr RG, Austin JH, Kawut SM, Raghu G, Sell JL et al. Rheumatoid arthritis associated autoantibodies and subclinical interstitial lung disease: the Multi-Ethnic Study of Atherosclerosis. Thorax. 2016; 71(12):1082-90. doi: 10.1136/thoraxjnl-2016-208932
  7. Katsumata M, Hozumi H, Yasui H, Suzuki Y, Kono M, Karayama M et al. Frequency and clinical relevance of anti-cyclic citrullinated peptide antibody in idiopathic interstitial pneumonias. Respir Med. 2019; 154:102-8. doi: 10.1016/j.rmed.2019.06.016. Epub 2019 Jun 19
  8. Hyldgaard C, Hilberg O, Pedersen AB, Ulrichsen SP, Løkke A, Bendstrup E et al. A population-based cohort study of rheumatoid arthritis-associated interstitial lung disease: comorbidity and mortality. Ann Rheum Dis. 2017; 76(10):1700-6. doi: 10.1136/annrheumdis-2017-211138. Epub 2017 Jun 13
  9. Mohning MP, Amigues I, Demoruelle MK, Pérez ERF, Huie TJ, Keith RK et al. Duration of rheumatoid arthritis and the risk of developing interstitial lung disease. ERJ Open Research. 2021; 7(1). doi: 10.1183/23120541.00633-2020
  10. Samhouri BF, Vassallo R, Achenbach SJ, Kronzer VL, Davis III JM, Myasoedova E et al. The Incidence, Risk Factors, and Mortality of Clinical and Subclinical Rheumatoid Arthritis‐associated Interstitial Lung Disease: A Population‐based Cohort. Arthritis Care & Research. 2022. doi: 10.1002/acr.24856. Epub 2022 Aug 10
  11. Solomon JJ, Matson S, Kelmenson LB, Chung JH, Hobbs SB, Rosas IO et al. IgA antibodies directed against citrullinated protein antigens are elevated in patients with idiopathic pulmonary fibrosis. Chest. 2020; 157(6):1513-21. doi: 10.1016/j.chest.2019.12.005. Epub 2019 Dec 23
  12. Holers VM, Demoruelle MK, Kuhn KA, Buckner JH, Robinson WH, Okamoto Y et al. Rheumatoid arthritis and the mucosal origins hypothesis: protection turns to destruction. Nature Reviews Rheumatology. 2018; 14(9):542-57. doi: 10.1038/s41584-018-0070-0
  13. Verpoort KN, Jol‐Van Der Zijde, C M, Papendrecht‐Van Der Voort E, Ioan‐Facsinay A, Drijfhout JW, Van Tol M et al. Isotype distribution of anti–cyclic citrullinated peptide antibodies in undifferentiated arthritis and rheumatoid arthritis reflects an ongoing immune response. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology. 2006; 54(12):3799-808. doi: 10.1002/art.22279
  14. Klareskog L, Stolt P, Lundberg K, Källberg 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 & Rheumatism: Official Journal of the American College of Rheumatology. 2006; 54(1):38-46. doi: 10.1002/art.21575
  15. Makrygiannakis D, Hermansson M, Ulfgren A, 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. doi: 10.1136/ard.2007.075192
  16. 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. doi: 10.1172/JCI28756
  17. Ytterberg AJ, Joshua V, Reynisdottir G, Tarasova NK, Rutishauser D, Ossipova E et al. Shared immunological targets in the lungs and joints of patients with rheumatoid arthritis: identification and validation. Ann Rheum Dis. 2015; 74(9):1772-7. doi: 10.1136/annrheumdis-2013-204912
  18. Giles JT, Danoff SK, Sokolove J, Wagner CA, Winchester R, Pappas DA et al. Association of fine specificity and repertoire expansion of anticitrullinated peptide antibodies with rheumatoid arthritis associated interstitial lung disease. Ann Rheum Dis. 2014; 73(8):1487-94. doi: 10.1136/annrheumdis-2012-203160
  19. 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. doi: 10.1371/journal.pone.0035296.
  20. Konig MF, Abusleme L, Reinholdt J, Palmer RJ, Teles RP, Sampson K et al. Aggregatibacter actinomycetemcomitans–induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis. Science translational medicine. 2016; 8(369):369ra176. doi: 10.1126/scitranslmed.aaj1921
  21. Engström M, Eriksson K, Lee L, Hermansson M, Johansson A, Nicholas AP et al. Increased citrullination and expression of peptidylarginine deiminases independently of P. gingivalis and A. actinomycetemcomitans in gingival tissue of patients with periodontitis. Journal of translational medicine. 2018; 16(1):1-14. doi: 10.1186/s12967-018-1588-2
  22. Olson AL, Swigris JJ, Sprunger DB, Fischer A, Fernandez-Perez ER, Solomon J, et al. Rheumatoid arthritis–interstitial lung disease–associated mortality. American journal of respiratory and critical care medicine. 2011; 183(3):372-8. doi: 10.1164/rccm.201004-0622OC
  23. Solomon JJ, Danoff SK, Woodhead FA, Hurwitz S, Maurer R, Glaspole I, et al. Safety, tolerability, and efficacy of pirfenidone in patients with rheumatoid arthritis-associated interstitial lung disease: a randomised, double-blind, placebo-controlled, phase 2 study. The Lancet Respiratory Medicine. 2023 Jan; 11 (1):87-96. doi: 10.1016/S2213-2600(22)00260-0
  24. Olivia CL, Leticia Kawano-Dourado, Ian SD, Quint JK, Solomon JJ, Borie R, Crestani B, Wain LV, Jenkins RJ, Dieudé F, Minelli C. Rheumatoid arthritis and idiopathic pulmonary fibrosis: a bidirectional Mendelian randomisation study. doi: https://doi.org/10.1101/2022.09.27.22280286 doi: 10.1136/thorax-2023-220856
  25. American Thoracic Society/European Respiratory Society. International multidisciplinary consensus classification of the idiopathic interstial pneumonias. Am J Respir Crit Care Med 2002; 165 (2): 277-304. doi: 10.1164/ajrccm.165.2.ats01
  26. Demedts M, Costabel U. ATS/ERS International multidisciplinary consensus classification of the idiopathic interstial pneumonias. Eur Respir J 2002; 19 (5): 794-796. doi: 10.1183/09031936.02.00492002
  27. MacDonald SL, Rubens MB, Hansell DM et al. Nonspecific interstial pneumonia and usual interstial pneumonia; comparative appearances at and diagnostic accurancy of thin-section CT. Radiology 2001; 221: 600-605. doi: 10.1148/radiol.2213010158
  28. Sundaram B, Gross BH, Martinez FJ et al. Accuracy of high-resolution Ct in the diagnosis of diffuse lung disease: effect of predominance and distribution findings. Am J Roentgenol 2008; 191: 1032-1039. doi: 10.2214/AJR.07.3177
  29. Kligerman SJ, Groshong S, Brown KK et al. Nonspecific interstial pneumonia: radiological, clinical and pathological considerations. Radiographics 2009; 29: 73-87.
  30. Camus P, Bonniaud P, Fanton A, et al. Drug-induced and iatrogenic infiltrative lung disease. Clin Chest Med 2004; 25:479-519. doi: 10.1148/rg.291085096
  31. Carson CW, Cannon GW, Egger MJ et al. Pulmonary disease during the treatment of rheumatoid arthritis with low dose pulse methotrexate. Semin Arthritis Rheum 1987; 16:186-195. doi: 10.1016/0049-0172(87)90021-7
  32. Searles G, McKendry RJ. Methotrexate pneumonitis in rheumatoid arthritis: potential risk factors: four case reports and a review of the literature. J Rheumatol 1987; 14:1164-1171.
  33. Aniruddh Kapoor, MBBS; Chief Editor: Zab Mosenifar, MD et Al., Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD), Aug 06, 2020
  34. Saravanan V, Kelly CA. Survival in fibrosing alveolitis associated with rheumatoid arthritis is better than cryptogenic fibrosing alveolitis. Rheumatology (Oxford) 2003; 42:603-604, author reply 604-605.
  35. Smolen J. S., Aletaha D., McInnes I. B. Rheumatoid arthritis. Lancet. (2016) 388:2023–38. doi: 10.1016/S0140-6736(16)30173-8
  36. Jee AS, Sahhar J, Youssef P, Bleasel J, Adelstein S, Nguyen M, et al. Review: Serum biomarkers in idiopathic pulmonary fibrosis and systemic sclerosis associated interstitial lung disease - frontiers and horizons. Pharmacol Ther. (2019) 202:40–52. doi: 10.1016/j.pharmthera.2019.05.014
  37. Beketov VD, Lebedeva MV, Mukhin NA, Serova AG, Ponomarev AB, Popova EN, et al. Clinical significance of the determination of surfactant proteins A and D in assessing the activity of lung sarcoidosis. Ter Arkh. (2018) 90:42–6. doi: 10.26442/terarkh201890342-46
  38. Chung C, Kim J, Cho HS, Kim HC. Baseline serum Krebs von den Lungen-6 as a biomarker for the disease progression in idiopathic pulmonary fibrosis. Sci Rep. (2022) 12:8564. doi: 10.1038/s41598-022-12399-8
  39. Roque W, Boni A, Martinez-Manzano J, Romero F. A tale of two proteolytic machines: matrix metalloproteinases and the ubiquitin-proteasome system in pulmonary fibrosis. Int J Mol Sci. (2020) 21(11):3878. doi: 10.3390/ijms21113878
  40. Zamora-Legoff JA, Krause ML, Crowson CS, Ryu JH, Matteson EL. Progressive decline of lung function in rheumatoid arthritis-associated interstitial lung disease. Arthritis Rheumatol. (2017) 69:542–9. doi: 10.1002/art.39971
  41. George PM et al. Progressive fibrosing interstitial lung disease: clinical uncertainties, consensus recommendations, and research priorities. Lancet Respir Med 2020; 8(9):925-934. doi: 10.1016/S2213-2600(20)30355-6

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