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Interstitial Pneumonia with Autoimmune Features: 8 Years after Nomenclature and Classification—Where are We Not and Where Are We Headed?

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Abstract

Purpose of Review

The term interstitial pneumonia with autoimmune features (IPAF) was proposed by an international task force as a research classification to standardize nomenclature for patients with idiopathic interstitial pneumonia (IIP) and features of connective tissue disease (CTD). This review aims to discuss the advances made in understanding this research classification and the clinical implications of this term.

Recent Findings

Multiple cohort studies have described the clinical presentation of patients meeting criteria for IPAF with heterogeneity noted particularly in the morphologic domain as compared to clinical and serologic domains. Treating these patients according to their clinical presentation and features remains the key expert opinion given the paucity of data to inform therapeutic strategies in IPAF.

Summary

There are still several challenges and unresolved questions which preclude the application of IPAF as a clinical diagnosis. Whether IPAF represents a clinical diagnosis distinct from CTD-ILD or IIPs or precursor or an overlap of these conditions remains controversial and warrants further investigation.

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References

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  1. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, et al. 2010 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 

  2. van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, et al. 2013 Classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum. 2013;65(11):2737–47.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Lundberg IE, Tjarnlund A, Bottai M, Werth VP, Pilkington C, Visser M, et al. 2017 European League Against Rheumatism/American College of Rheumatology classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups. Ann Rheum Dis. 2017;76(12):1955–64.

    Article  PubMed  Google Scholar 

  4. Kinder BW, Collard HR, Koth L, Daikh DI, Wolters PJ, Elicker B, et al. Idiopathic nonspecific interstitial pneumonia: lung manifestation of undifferentiated connective tissue disease? Am J Respir Crit Care Med. 2007;176(7):691–7.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Fischer A, West SG, Swigris JJ, Brown KK, du Bois RM. Connective tissue disease-associated interstitial lung disease: a call for clarification. Chest. 2010;138(2):251–6.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Vij R, Noth I, Strek ME. Autoimmune-featured interstitial lung disease: a distinct entity. Chest. 2011;140(5):1292–9.

    Article  PubMed  PubMed Central  Google Scholar 

  7. •• Fischer A, Antoniou KM, Brown KK, Cadranel J, Corte TJ, du Bois RM, et al. An official European Respiratory Society/American Thoracic Society research statement: interstitial pneumonia with autoimmune features. Eur Respir J. 2015;46(4):976–87. Research statement discussing the rationale and definition of IPAF.

  8. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62(9):2569–81.

    Article  PubMed  Google Scholar 

  9. Kumar Y, Bhatia A, Minz RW. Antinuclear antibodies and their detection methods in diagnosis of connective tissue diseases: a journey revisited. Diagn Pathol. 2009;4:1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. • Hazarika K, Sahoo RR, Mohindra N, Wakhlu A, Manoj M, Bafna P, et al. Clinical, radiologic and serologic profile of patients with interstitial pneumonia with autoimmune features: a cross-sectional study. Rheumatol Int. 2022;42(8):1431–41. More recent study describing the characteristics and presentation of patients with IPAF.

  11. 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 

  12. Chartrand S, Swigris JJ, Stanchev L, Lee JS, Brown KK, Fischer A. Clinical features and natural history of interstitial pneumonia with autoimmune features: a single center experience. Respir Med. 2016;119:150–4.

    Article  PubMed  Google Scholar 

  13. Ahmad K, Barba T, Gamondes D, Ginoux M, Khouatra C, Spagnolo P, et al. Interstitial pneumonia with autoimmune features: clinical, radiologic, and histological characteristics and outcome in a series of 57 patients. Respir Med. 2017;123:56–62.

    Article  PubMed  Google Scholar 

  14. Ito Y, Arita M, Kumagai S, Takei R, Noyama M, Tokioka F, et al. Serological and morphological prognostic factors in patients with interstitial pneumonia with autoimmune features. BMC Pulm Med. 2017;17(1):111.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Dai J, Wang L, Yan X, Li H, Zhou K, He J, et al. Clinical features, risk factors, and outcomes of patients with interstitial pneumonia with autoimmune features: a population-based study. Clin Rheumatol. 2018;37(8):2125–32.

    Article  PubMed  Google Scholar 

  16. Kelly BT, Moua T. Overlap of interstitial pneumonia with autoimmune features with undifferentiated connective tissue disease and contribution of UIP to mortality. Respirology. 2018;23(6):600–5.

    Article  PubMed  Google Scholar 

  17. Kim HC, Lee JH, Chae EJ, Song JS, Song JW. Long-term clinical course and outcome of interstitial pneumonia with autoimmune features. Respirology. 2020;25(6):636–43.

    Article  PubMed  Google Scholar 

  18. Sebastiani M, Cassone G, De Pasquale L, Cerri S, Della Casa G, Vacchi C, et al. Interstitial pneumonia with autoimmune features: a single center prospective follow-up study. Autoimmun Rev. 2020;19(2):102451.

    Article  PubMed  Google Scholar 

  19. Jee AS, Parker MJS, Bleasel JF, Troy LK, Lau EM, Jo HE, et al. Baseline characteristics and survival of an australian interstitial pneumonia with autoimmune features cohort. Respiration. 2021;100(9):853–64.

    Article  CAS  PubMed  Google Scholar 

  20. Collins BF, Spiekerman CF, Shaw MA, Ho LA, Hayes J, Spada CA, et al. Idiopathic interstitial pneumonia associated with autoantibodies: a large case series followed over 1 year. Chest. 2017;152(1):103–12.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Khanna D, Tashkin DP, Denton CP, Lubell MW, Vazquez-Mateo C, Wax S. Ongoing clinical trials and treatment options for patients with systemic sclerosis-associated interstitial lung disease. Rheumatology (Oxford). 2019;58(4):567–79.

    Article  CAS  PubMed  Google Scholar 

  22. Kawano-Dourado L, Lee JS. Management of connective tissue disease-associated interstitial lung disease. Clin Chest Med. 2021;42(2):295–310.

    Article  PubMed  Google Scholar 

  23. Matson SM, Demoruelle MK. Connective tissue disease associated interstitial lung disease. Immunol Allergy Clin North Am. 2023;43(2):229–44.

    Article  PubMed  Google Scholar 

  24. Dsouza KG, Alexander AS, Watts JR Jr, Kulkarni T. Management of interstitial lung disease in patients with autoimmune disease-related interstitial lung disease. Multidiscip Respir Med. 2023;18(1). https://doi.org/10.4081/mrm.2023.890.

  25. Tashkin DP, Elashoff R, Clements PJ, Goldin J, Roth MD, Furst DE, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med. 2006;354(25):2655–66.

    Article  CAS  PubMed  Google Scholar 

  26. Tashkin DP, Roth MD, Clements PJ, Furst DE, Khanna D, Kleerup EC, et al. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial. Lancet Respir Med. 2016;4(9):708–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. •• Maher TM, Tudor VA, Saunders P, Gibbons MA, Fletcher SV, Denton CP, et al. Rituximab versus intravenous cyclophosphamide in patients with connective tissue disease-associated interstitial lung disease in the UK (RECITAL): a double-blind, double-dummy, randomised, controlled, phase 2b trial. Lancet Respir Med. 2023;11(1):45–54. First RCT reporting the efficacy of rituximab in patients with progressive CTD-ILD.

  28. Khanna D, Lin CJF, Furst DE, Goldin J, Kim G, Kuwana M, et al. Tocilizumab in systemic sclerosis: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med. 2020;8(10):963–74.

    Article  CAS  PubMed  Google Scholar 

  29. • Joerns EK, Adams TN, Newton CA, Bermas B, Karp D, Batra K, et al. Variables associated with response to therapy in patients with interstitial pneumonia with autoimmune features. J Clin Rheumatol. 2022;28(2):84–8. This study is one of the few small studies reporting treatment patterns for IPAF.

  30. McCoy SS, Mukadam Z, Meyer KC, Kanne JP, Meyer CA, Martin MD, et al. Mycophenolate therapy in interstitial pneumonia with autoimmune features: a cohort study. Ther Clin Risk Manag. 2018;14:2171–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Nieto MA, Sanchez-Pernaute O, Vadillo C, Rodriguez-Nieto MJ, Romero-Bueno F, Lopez-Muniz B, et al. Functional respiratory impairment and related factors in patients with interstitial pneumonia with autoimmune features (IPAF): multicenter study from NEREA registry. Respir Res. 2023;24(1):19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. D'Silva KM, Ventura IB, Bolster MB, Castelino FV, Sharma A, Little BP, et al. Rituximab for interstitial pneumonia with autoimmune features at two medical centres. Rheumatol Adv Pract. 2021;5(Suppl 2):ii1–ii9.

  33. Wiertz IA, van Moorsel CHM, Vorselaars ADM, Quanjel MJR, Grutters JC. Cyclophosphamide in steroid refractory unclassifiable idiopathic interstitial pneumonia and interstitial pneumonia with autoimmune features (IPAF). Eur Respir J. 2018;51(4).

  34. King TE Jr, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2083–92.

    Article  PubMed  Google Scholar 

  35. Richeldi L, Cottin V, Flaherty KR, Kolb M, Inoue Y, Raghu G, et al. Design of the INPULSIS trials: two phase 3 trials of nintedanib in patients with idiopathic pulmonary fibrosis. Respir Med. 2014;108(7):1023–30.

    Article  PubMed  Google Scholar 

  36. Distler O, Highland KB, Gahlemann M, Azuma A, Fischer A, Mayes MD, et al. Nintedanib for systemic sclerosis-associated interstitial lung disease. N Engl J Med. 2019;380(26):2518–28.

    Article  CAS  PubMed  Google Scholar 

  37. Flaherty KR, Wells AU, Cottin V, Devaraj A, Walsh SLF, Inoue Y, et al. Nintedanib in progressive fibrosing interstitial lung diseases. N Engl J Med. 2019;381(18):1718–27.

    Article  CAS  PubMed  Google Scholar 

  38. Behr J, Prasse A, Kreuter M, Johow J, Rabe KF, Bonella F, et al. Pirfenidone in patients with progressive fibrotic interstitial lung diseases other than idiopathic pulmonary fibrosis (RELIEF): a double-blind, randomised, placebo-controlled, phase 2b trial. Lancet Respir Med. 2021;9(5):476–86.

    Article  CAS  PubMed  Google Scholar 

  39. Maher TM, Corte TJ, Fischer A, Kreuter M, Lederer DJ, Molina-Molina M, et al. Pirfenidone in patients with unclassifiable progressive fibrosing interstitial lung disease: a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Respir Med. 2020;8(2):147–57.

    Article  CAS  PubMed  Google Scholar 

  40. Raghu G, Remy-Jardin M, Richeldi L, Thomson CC, Inoue Y, Johkoh T, et al. Idiopathic Pulmonary fibrosis (an update) and progressive pulmonary fibrosis in adults: an official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med. 2022;205(9):e18–47.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Yamano Y, Kataoka K, Takei R, Sasano H, Yokoyama T, Matsuda T, et al. Interstitial pneumonia with autoimmune features and histologic usual interstitial pneumonia treated with anti-fibrotic versus immunosuppressive therapy. Respir Investig. 2023;61(3):297–305.

    Article  CAS  PubMed  Google Scholar 

  42. Martinez FJ, Flaherty KR. Comprehensive and individualized patient care in idiopathic pulmonary fibrosis: refining approaches to diagnosis, prognosis, and treatment. Chest. 2017;151(5):1173–4.

    Article  PubMed  Google Scholar 

  43. King CS, Nathan SD. Idiopathic pulmonary fibrosis: effects and optimal management of comorbidities. Lancet Respir Med. 2017;5(1):72–84.

    Article  PubMed  Google Scholar 

  44. Lee JS, Kim EJ, Lynch KL, Elicker B, Ryerson CJ, Katsumoto TR, et al. Prevalence and clinical significance of circulating autoantibodies in idiopathic pulmonary fibrosis. Respir Med. 2013;107(2):249–55.

    Article  PubMed  Google Scholar 

  45. Fischer A, Pfalzgraf FJ, Feghali-Bostwick CA, Wright TM, Curran-Everett D, West SG, et al. Anti-th/to-positivity in a cohort of patients with idiopathic pulmonary fibrosis. J Rheumatol. 2006;33(8):1600–5.

    PubMed  Google Scholar 

  46. Moua T, Maldonado F, Decker PA, Daniels CE, Ryu JH. Frequency and implication of autoimmune serologies in idiopathic pulmonary fibrosis. Mayo Clin Proc. 2014;89(3):319–26.

    Article  PubMed  Google Scholar 

  47. Goobie GC, Ford-Sahibzada CA, Fritzler MJ, Johannson KA, Fell CD. Autoantibody status is not associated with change in lung function or survival in patients with idiopathic pulmonary fibrosis. Respir Med. 2019;153:85–90.

    Article  PubMed  Google Scholar 

  48. Kulkarni T, Newton C, Gupta S, Ko J, Samara K, Bernstein EJ. Baseline characteristics and clinical outcomes in patients with idiopathic pulmonary fibrosis (IPF) by autoantibody status: an exploratory analysis from the ASCEND study. Am J Res Crit Care Med. 2022;205:A2717.

  49. Alevizos MK, Giles JT, Patel NM, Bernstein EJ. Risk of progression of interstitial pneumonia with autoimmune features to a systemic autoimmune rheumatic disease. Rheumatology (Oxford). 2020;59(6):1233–40.

    Article  CAS  PubMed  Google Scholar 

  50. Decker P, Sobanski V, Moulinet T, Launay D, Hachulla E, Valentin V, et al. Interstitial pneumonia with autoimmune features: evaluation of connective tissue disease incidence during follow-up. Eur J Intern Med. 2022;97:62–8.

    Article  CAS  PubMed  Google Scholar 

  51. Sambataro G, Ferrara CA, Torrisi SE, Spadaro C, Vignigni G, Vancheri A, et al. “Usual” interstitial pneumonia with autoimmune features: a prospective study on a cohort of idiopathic pulmonary fibrosis patients. Clin Exp Rheumatol. 2022;40(7):1324–9.

    PubMed  Google Scholar 

  52. Raghu G, Remy-Jardin M, Myers JL, Richeldi L, Ryerson CJ, Lederer DJ, et al. Diagnosis of idiopathic pulmonary fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med. 2018;198(5):e44–e68.

  53. Graham J, Bauer Ventura I, Newton CA, Lee C, Boctor N, Pugashetti JV, et al. Myositis-specific antibodies identify a distinct interstitial pneumonia with autoimmune features phenotype. Eur Respir J. 2020.

  54. Adegunsoye A, Oldham JM, Valenzi E, Lee C, Witt LJ, Chen L, et al. Interstitial pneumonia with autoimmune features: value of histopathology. Arch Pathol Lab Med. 2017;141(7):960–9.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Chung JH, Cox CW, Montner SM, Adegunsoye A, Oldham JM, Husain AN, et al. CT Features of the usual interstitial pneumonia pattern: differentiating connective tissue disease-associated interstitial lung disease from idiopathic pulmonary fibrosis. AJR Am J Roentgenol. 2018;210(2):307–13.

    Article  PubMed  Google Scholar 

  56. Chung JH, Montner SM, Adegunsoye A, Lee C, Oldham JM, Husain AN, et al. CT findings, radiologic-pathologic correlation, and imaging predictors of survival for patients with interstitial pneumonia with autoimmune features. AJR Am J Roentgenol. 2017;208(6):1229–36.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Lasky JA, Case A, Unterman A, Kreuter M, Scholand MB, Chaudhary S, et al. The Impact of the Envisia genomic classifier in the diagnosis and management of patients with idiopathic pulmonary fibrosis. Ann Am Thorac Soc. 2022;19(6):916–24.

    Article  PubMed  Google Scholar 

  58. Raghu G, Flaherty KR, Lederer DJ, Lynch DA, Colby TV, Myers JL, et al. Use of a molecular classifier to identify usual interstitial pneumonia in conventional transbronchial lung biopsy samples: a prospective validation study. Lancet Respir Med. 2019;7(6):487–96.

    Article  PubMed  Google Scholar 

  59. Richeldi L, Scholand MB, Lynch DA, Colby TV, Myers JL, Groshong SD, et al. Utility of a molecular classifier as a complement to high-resolution computed tomography to identify usual interstitial pneumonia. Am J Respir Crit Care Med. 2021;203(2):211–20.

    Article  CAS  PubMed  Google Scholar 

  60. Chaudhary S, Weigt SS, Ribeiro Neto ML, Benn BS, Pugashetti JV, Keith R, et al. Interstitial lung disease progression after genomic usual interstitial pneumonia testing. Eur Respir J. 2023;61(4).

  61. Lancaster LH, Ryerson CJ, Johnson M, Huang J, Burbanksivey J, Morrie E, Lofaro L, Bulman W, Kennedy G, Raghu G, Wells A, Scholand MB, et al., editors. Positive Envisia genomic classifier result predicts clinical progression in fibrotic interstitial lung disease. CHEST. 2022;162(4):Supplement A2630–32. https://doi.org/10.1016/j.chest.2022.08.2149.

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  1. Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, 1900 University Blvd, Tinsley Harrison Tower 422, AL, Birmingham, USA

    Tejaswini Kulkarni

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TK reports speaker and consultation fees from Boehringer Ingelheim Inc. and consultation fees from United Therapeutics Corp and PureTech Lyt-100 Inc. unrelated to submitted work.

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Kulkarni, T. Interstitial Pneumonia with Autoimmune Features: 8 Years after Nomenclature and Classification—Where are We Not and Where Are We Headed?. Curr Pulmonol Rep 12, 144–150 (2023). https://doi.org/10.1007/s13665-023-00312-1

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