Guidelines Summary

Idiopathic Pulmonary Fibrosis (IPF)

In 2018, the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society released their clinical practice guidelines on the diagnosis of idiopathic pulmonary fibrosis, as outlined below.^{[97, 98]}

Obtain a detailed history for possible environmental exposures or medication use to exclude potential causes of interstitial lung disease (ILD).

Perform serologic testing to exclude connective-tissue disease.

With newly diagnosed ILD, perform high-resolution CT (HRCT) scanning of the chest; determine if findings indicate a pattern of (1) usual interstitial pneumonia (UIP), (2) probable UIP, (3) indeterminate of UIP, or (4) alternate diagnosis.

For probable UIP, indeterminate findings, or alternate diagnosis, bronchoalveolar lavage and surgical lung biopsy are recommended; evidence is insufficient to recommend for or against transbronchial lung biopsy or lung cryobiopsy.

For a UIP pattern, bronchoalveolar lavage (cellular analysis) and surgical lung biopsy are not recommended (risks outweigh benefits); guidelines strongly recommend against transbronchial lung biopsy or lung cryobiopsy in this situation.

Multidisciplinary discussions (MDDs) should include interactions between pulmonologists, possibly rheumatologists (on a case-by-case basis), pathologists, and radiologists. MDDs are recommended with newly detected ILD of an unknown cause in patients whose findings clinically suggest idiopathic pulmonary fibrosis. MDDs likely provide the greatest benefit in situations in which HRCT patterns indicate probable UIP, indeterminate findings, or alternative diagnoses, or when clinical, histologic, or radiologic data are incongruous.

For serum biomarker measurements, measuring serum matrix metalloproteinase 7, chemokine ligand 18, Krebs von den Lungen-6, or surfactant protein D is not recommended solely to distinguish idiopathic pulmonary fibrosis from other ILDs, owing to high false-positive and false-negative results.

Interstitial pneumonia with autoimmune features (IPAF)

In 2015, the European Respiratory Society and American Thoracic Society released a joint consensus statement proposing the term interstitial pneumonia with autoimmune features (IPAF) be used for idiopathic interstitial pneumonia (IIP) with clinical features that suggest an underlying autoimmune process. Proposed classification criteria include the presence of interstitial pneumonia (by HRCT or surgical lung biopsy); alternative etiologies are excluded and the patient does not meet the criteria for a connective tissue disease; and at least one feature from two domains (clinical, serologic, morphologic) is present.^[10]

The clinical domain includes specific features suggestive of an underlying CTD. While they are specific findings, their presence alone does not meet the criteria for the diagnosis of a defined CTD. These features include distal digital fissuring (ie, “mechanic hands”), distal digital tip ulceration, inflammatory arthritis or polyarticular morning joint stiffness ≥60 min, palmar telangiectasia, Raynaud's phenomenon, unexplained digital edema, unexplained fixed rash on the digital extensor surfaces (Gottron sign).^[10]

The serologic domain includes circulating autoantibodies known to be associated with CTDs. (See Table 2 in Workup) Less specific serologic markers, such as a low-titer antinuclear antibody (ANA), low-titer rheumatoid factor (RF), erythrocyte sedimentation rate, C-reactive protein or creatine phosphokinase, are not included.^[10]

The morphology domain is divided into three sections: interstitial pneumonia patterns suggested by HRCT imaging, histopathologic features identified by surgical lung biopsy, or evidence of additional thoracic compartment involvement as determined by diagnostic imaging, histopathologic findings, right heart catheterization (RHC) or pulmonary function testing.^[10]

When these proposed criteria were applied to 422 patients previously diagnosed with idiopathic interstitial pneumonia (IIP) or undifferentiated CTD-ILD (UCTD), 144 (34%) met IPAF criteria. The mean age was 63.2 years with a slight female predominance. IPAF cohort survival was marginally better than patients with idiopathic pulmonary fibrosis but worse than CTD-ILD. A non-usual interstitial pneumonia pattern was associated with improved survival, as was the presence of the clinical domain. A modified IPAF cohort of those meeting the clinical domain and a radiographic or histological feature within the morphological domain displayed survival similar to those with CTD-ILD.^[9]

Medication

Furukawa H, Oka S, Shimada K, et al. Autoantibody profiles in collagen disease patients with interstitial lung disease (ILD): antibodies to major histocompatibility complex class I-related chain A (MICA) as markers of ILD. Biomark Insights. 2015. 10:63-73. [QxMD MEDLINE Link]. [Full Text].
Self SE. Autoantibody testing for autoimmune disease. Clin Chest Med. 2010 Sep. 31(3):415-22. [QxMD MEDLINE Link].
Strange C, Highland KB. Interstitial lung disease in the patient who has connective tissue disease. Clin Chest Med. 2004 Sep. 25(3):549-59, vii. [QxMD MEDLINE Link].
Koo SM, Uh ST. Treatment of connective tissue disease-associated interstitial lung disease: the pulmonologist's point of view. Korean J Intern Med. 2017 Jul. 32 (4):600-10. [QxMD MEDLINE Link]. [Full Text].
Olson AL, Swigris JJ, Sprunger DB, et al. Rheumatoid arthritis-interstitial lung disease-associated mortality. Am J Respir Crit Care Med. 2011 Feb 1. 183 (3):372-8. [QxMD MEDLINE Link]. [Full Text].
Marie I, Hachulla E, Cherin P, et al. Interstitial lung disease in polymyositis and dermatomyositis. Arthritis Rheum. 2002 Dec 15. 47 (6):614-22. [QxMD MEDLINE Link]. [Full Text].
Tzelepis GE, Toya SP, Moutsopoulos HM. Occult connective tissue diseases mimicking idiopathic interstitial pneumonias. Eur Respir J. 2008 Jan. 31(1):11-20. [QxMD MEDLINE Link].
Atzeni F, Gerardi MC, Barilaro G, Masala IF, Benucci M, Sarzi-Puttini P. Interstitial lung disease in systemic autoimmune rheumatic diseases: a comprehensive review. Expert Rev Clin Immunol. 2018 Jan. 14 (1):69-82. [QxMD MEDLINE Link].
Oldham JM, Adegunsoye A, Valenzi E, et al. Characterisation of patients with interstitial pneumonia with autoimmune features. Eur Respir J. 2016 Jun. 47 (6):1767-75. [QxMD MEDLINE Link]. [Full Text].
[Guideline] Fischer A, Antoniou KM, Brown KK, et al. An official European Respiratory Society/American Thoracic Society research statement: interstitial pneumonia with autoimmune features. Eur Respir J. 2015 Oct. 46 (4):976-87. [QxMD MEDLINE Link]. [Full Text].
Jindal SK, Agarwal R. Autoimmunity and interstitial lung disease. Curr Opin Pulm Med. 2005 Sep. 11(5):438-46. [QxMD MEDLINE Link].
Wells AU, Denton CP. Interstitial lung disease in connective tissue disease--mechanisms and management. Nat Rev Rheumatol. 2014 Dec. 10(12):728-39. [QxMD MEDLINE Link].
Meyer KC, Decker C, Baughman R. Toxicity and monitoring of immunosuppressive therapy used in systemic autoimmune diseases. Clin Chest Med. 2010 Sep. 31(3):565-88. [QxMD MEDLINE Link].
Castelino FV, Varga J. Interstitial lung disease in connective tissue diseases: evolving concepts of pathogenesis and management. Arthritis Res Ther. 2010. 12 (4):213. [QxMD MEDLINE Link]. [Full Text].
Wells AU, Steen V, Valentini G. Pulmonary complications: one of the most challenging complications of systemic sclerosis. Rheumatology (Oxford). 2009 Jun. 48 suppl 3:iii40-4. [QxMD MEDLINE Link].
Walker UA, Tyndall A, Czirjak L, et al. Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials And Research group database. Ann Rheum Dis. 2007 Jun. 66 (6):754-63. [QxMD MEDLINE Link].
DeHoratius RJ, Abruzzo JL, Williams RC Jr. Immunofluorescent and immunologic studies of rheumatoid lung. Arch Intern Med. 1972 Mar. 129 (3):441-6. [QxMD MEDLINE Link].
Tanaka N, Kim JS, Newell JD, et al. Rheumatoid arthritis-related lung diseases: CT findings. Radiology. 2004 Jul. 232(1):81-91. [QxMD MEDLINE Link].
Antin-Ozerkis D, Evans J, Rubinowitz A, Homer RJ, Matthay RA. Pulmonary manifestations of rheumatoid arthritis. Clin Chest Med. 2010 Sep. 31(3):451-78. [QxMD MEDLINE Link].
Kamen DL, Strange C. Pulmonary manifestations of systemic lupus erythematosus. Clin Chest Med. 2010 Sep. 31(3):479-88. [QxMD MEDLINE Link].
Pego-Reigosa JM, Medeiros DA, Isenberg DA. Respiratory manifestations of systemic lupus erythematosus: old and new concepts. Best Pract Res Clin Rheumatol. 2009 Aug. 23 (4):469-80. [QxMD MEDLINE Link].
Kalluri M, Oddis CV. Pulmonary manifestations of the idiopathic inflammatory myopathies. Clin Chest Med. 2010 Sep. 31(3):501-12. [QxMD MEDLINE Link].
Connors GR, Christopher-Stine L, Oddis CV, Danoff SK. Interstitial lung disease associated with the idiopathic inflammatory myopathies: what progress has been made in the past 35 years?. Chest. 2010 Dec. 138 (6):1464-74. [QxMD MEDLINE Link].
Ito I, Nagai S, Kitaichi M, et al. Pulmonary manifestations of primary Sjogren's syndrome: a clinical, radiologic, and pathologic study. Am J Respir Crit Care Med. 2005 Mar 15. 171 (6):632-8. [QxMD MEDLINE Link].
Khan MA, Mathieu A, Sorrentino R, Akkoc N. The pathogenetic role of HLA-B27 and its subtypes. Autoimmun Rev. 2007 Jan. 6(3):183-9. [QxMD MEDLINE Link].
Furukawa H, Oka S, Shimada K, Tsuchiya N, Tohma S. Genetics of interstitial lung disease: Vol de nuit (night flight). Clin Med Insights Circ Respir Pulm Med. 2015. 9 (suppl 1):1-7. [QxMD MEDLINE Link]. [Full Text].
Furukawa H, Oka S, Shimada K, et al. Role of deleterious rare alleles for acute-onset diffuse interstitial lung disease in collagen diseases. Clin Med Insights Circ Respir Pulm Med. 2019. 13:1179548419866443. [QxMD MEDLINE Link].
Cooper GS, Dooley MA, Treadwell EL, St Clair EW, Parks CG, Gilkeson GS. Hormonal, environmental, and infectious risk factors for developing systemic lupus erythematosus. Arthritis Rheum. 1998 Oct. 41(10):1714-24. [QxMD MEDLINE Link].
Saag KG, Kolluri S, Koehnke RK, et al. Rheumatoid arthritis lung disease. Determinants of radiographic and physiologic abnormalities. Arthritis Rheum. 1996 Oct. 39(10):1711-9. [QxMD MEDLINE Link].
Tamaki T, Mori S, Takehara K. Epidemiological study of patients with systemic sclerosis in Tokyo. Arch Dermatol Res. 1991. 283(6):366-71. [QxMD MEDLINE Link].
Maricq HR, Weinrich MC, Keil JE, et al. Prevalence of scleroderma spectrum disorders in the general population of South Carolina. Arthritis Rheum. 1989 Aug. 32(8):998-1006. [QxMD MEDLINE Link].
Kurland LT, Hauser WA, Ferguson RH, Holley KE. Epidemiologic features of diffuse connective tissue disorders in Rochester, Minn., 1951 through 1967, with special reference to systemic lupus erythematosus. Mayo Clin Proc. 1969 Sep. 44(9):649-63. [QxMD MEDLINE Link].
Arnett FC, Howard RF, Tan F, et al. Increased prevalence of systemic sclerosis in a Native American tribe in Oklahoma. Association with an Amerindian HLA haplotype. Arthritis Rheum. 1996 Aug. 39 (8):1362-70. [QxMD MEDLINE Link].
Stojan G, Petri M. Epidemiology of systemic lupus erythematosus: an update. Curr Opin Rheumatol. 2018 Mar. 30 (2):144-50. [QxMD MEDLINE Link]. [Full Text].
Dorner T, Furie R. Novel paradigms in systemic lupus erythematosus. Lancet. 2019 Jun 8. 393 (10188):2344-58. [QxMD MEDLINE Link].
Spector TD. Rheumatoid arthritis. Rheum Dis Clin North Am. 1990 Aug. 16(3):513-37. [QxMD MEDLINE Link].
Kellgren JH. Epidemiology of rheumatoid arthritis. Arthritis Rheum. 1966 Oct. 9(5):658-74. [QxMD MEDLINE Link].
Gladman DD, Anhorn KA. HLA and disease manifestations in rheumatoid arthritis--a Canadian experience. J Rheumatol. 1986. Apr;13(2):274-6. [QxMD MEDLINE Link].
Patel R, Shahane A. The epidemiology of Sjögren's syndrome. Clin Epidemiol. 2014. 6:247-55. [QxMD MEDLINE Link]. [Full Text].
Oddis CV, Conte CG, Steen VD, Medsger TA Jr. Incidence of polymyositis-dermatomyositis: a 20-year study of hospital diagnosed cases in Allegheny County, PA 1963-1982. J Rheumatol. 1990 Oct. 17(10):1329-34. [QxMD MEDLINE Link].
Kapoor A, Vaidyan P, Jalil B, Upaluri C. Novel case of anti-synthetase syndrome. Eur J Rheumatol. 2018 Dec. 5 (4):275-7. [QxMD MEDLINE Link].
Hakala M. Poor prognosis in patients with rheumatoid arthritis hospitalized for interstitial lung fibrosis. Chest. 1988 Jan. 93(1):114-8. [QxMD MEDLINE Link].
Suzuki A, Kondoh Y, Fischer A. Recent advances in connective tissue disease related interstitial lung disease. Expert Rev Respir Med. 2017 Jul. 11(7):591-603. [QxMD MEDLINE Link].
Kang EH, Lee EB, Shin KC, et al. Interstitial lung disease in patients with polymyositis, dermatomyositis and amyopathic dermatomyositis. Rheumatology (Oxford). 2005 Oct. 44(10):1282-6. [QxMD MEDLINE Link].
Park JH, Kim DS, Park IN, et al. Prognosis of fibrotic interstitial pneumonia: idiopathic versus collagen vascular disease-related subtypes. Am J Respir Crit Care Med. 2007 Apr 1. 175(7):705-11. [QxMD MEDLINE Link].
Takizawa H, Suzuki N, Yanagawa T, et al. [Importance of interstitial lung disease in collagen vascular disease: analysis of outcome] [Japanese]. Nihon Kyobu Shikkan Gakkai Zasshi. 1996 Nov. 34 (11):1177-81. [QxMD MEDLINE Link].
Vij R, Strek ME. Diagnosis and treatment of connective tissue disease-associated interstitial lung disease. Chest. 2013 Mar. 143 (3):814-24. [QxMD MEDLINE Link]. [Full Text].
Lawrence RC, Hochberg MC, Kelsey JL, et al. Estimates of the prevalence of selected arthritic and musculoskeletal diseases in the United States. J Rheumatol. 1989 Apr. 16(4):427-41. [QxMD MEDLINE Link].
Matthay RA, Schwarz MI, Petty TL, et al. Pulmonary manifestations of systemic lupus erythematosus: review of twelve cases of acute lupus pneumonitis. Medicine (Baltimore). 1975 Sep. 54(5):397-409. [QxMD MEDLINE Link].
Martens J, Demedts M, Vanmeenen MT, Dequeker J. Respiratory muscle dysfunction in systemic lupus erythematosus. Chest. 1983 Aug. 84(2):170-5. [QxMD MEDLINE Link].
Owens GR, Follansbee WP. Cardiopulmonary manifestations of systemic sclerosis. Chest. 1987 Jan. 91(1):118-27. [QxMD MEDLINE Link].
Keane MP, Lynch JP 3rd. Pleuropulmonary manifestations of systemic lupus erythematosus. Thorax. 2000 Feb. 55(2):159-66. [QxMD MEDLINE Link].
Onomura K, Nakata H, Tanaka Y, Tsuda T. Pulmonary hemorrhage in patients with systemic lupus erythematosus. J Thorac Imaging. 1991 Apr. 6(2):57-61. [QxMD MEDLINE Link].
Won Huh J, Soon Kim D, Keun Lee C, et al. Two distinct clinical types of interstitial lung disease associated with polymyositis-dermatomyositis. Respir Med. 2007 Aug. 101(8):1761-9. [QxMD MEDLINE Link].
Wiener-Kronish JP, Solinger AM, Warnock ML, Churg A, Ordonez N, Golden JA. Severe pulmonary involvement in mixed connective tissue disease. Am Rev Respir Dis. 1981 Oct. 124(4):499-503. [QxMD MEDLINE Link].
Dimachkie MM, Barohn RJ, Amato AA. Idiopathic inflammatory myopathies. Neurol Clin. 2014 Aug. 32 (3):595-628, vii. [QxMD MEDLINE Link]. [Full Text].
Vegh J, Szilasi M, Soos G, et al. [Interstitial lung disease in mixed connective tissue disease]. Orv Hetil. 2005 Nov 27. 146(48):2435-43. [QxMD MEDLINE Link].
Epler GR, Carrington CB, Gaensler EA. Crackles (rales) in the interstitial pulmonary diseases. Chest. 1978. 333-9. [QxMD MEDLINE Link]. [Full Text].
Fenlon HM, Casserly I, Sant SM, Breatnach E. Plain radiographs and thoracic high-resolution CT in patients with ankylosing spondylitis. AJR Am J Roentgenol. 1997 Apr. 168(4):1067-72. [QxMD MEDLINE Link].
Gabbay E, Tarala R, Will R, et al. Interstitial lung disease in recent onset rheumatoid arthritis. Am J Respir Crit Care Med. 1997 Aug. 156(2 Pt 1):528-35. [QxMD MEDLINE Link].
Franquet T, Gimenez A, Monill JM, Diaz C, Geli C. Primary Sjögren's syndrome and associated lung disease: CT findings in 50 patients. AJR Am J Roentgenol. 1997 Sep. 169(3):655-8. [QxMD MEDLINE Link].
Song G, Bae SC, Lee YH. Diagnostic accuracy of lung ultrasound for interstitial lung disease in patients with connective tissue diseases: a meta-analysis. Clin Exp Rheumatol. 2016 Jan-Feb. 34 (1):11-6. [QxMD MEDLINE Link].
Xie HQ, Zhang WW, Sun S, et al. A simplified lung ultrasound for the diagnosis of interstitial lung disease in connective tissue disease: a meta-analysis. Arthritis Res Ther. 2019 Apr 11. 21 (1):93. [QxMD MEDLINE Link]. [Full Text].
Wang Y, Gargani L, Barskova T, Furst DE, Cerinic MM. Usefulness of lung ultrasound B-lines in connective tissue disease-associated interstitial lung disease: a literature review. Arthritis Res Ther. 2017 Sep 18. 19 (1):206. [QxMD MEDLINE Link]. [Full Text].
Ferro F, Delle Sedie A. The use of ultrasound for assessing interstitial lung involvement in connective tissue diseases. Clin Exp Rheumatol. 2018 Sep-Oct. 36 suppl 114 (5):165-70. [QxMD MEDLINE Link].
Frongillo E, Gaudioso G, Feragalli B. Ultrasound and interstitial lung disease: use and limitations. Radiol Med. 2020 Jan. 125 (1):66-7. [QxMD MEDLINE Link].
Cortet B, Perez T, Roux N, et al. Pulmonary function tests and high resolution computed tomography of the lungs in patients with rheumatoid arthritis. Ann Rheum Dis. 1997 Oct. 56(10):596-600. [QxMD MEDLINE Link].
Herzog CA, Miller RR, Hoidal JR. Bronchiolitis and rheumatoid arthritis. Am Rev Respir Dis. 1981 Nov. 124(5):636-9. [QxMD MEDLINE Link].
Corrin B, Turner-Warwick M, Geddes DM, Brewerton DA. Bronchiolitis obliterans. A new form of rheumatoid lung?. Chest. 1978 Feb. 73(2):244. [QxMD MEDLINE Link].
Cortet B, Flipo RM, Remy-Jardin M, et al. Use of high resolution computed tomography of the lungs in patients with rheumatoid arthritis. Ann Rheum Dis. 1995 Oct. 54(10):815-9. [QxMD MEDLINE Link].
Caplan A. Certain unusual radiological appearances in the chest of coal-miners suffering from rheumatoid arthritis. Thorax. 1953 Mar. 8(1):29-37. [QxMD MEDLINE Link].
Jolles H, Moseley PL, Peterson MW. Nodular pulmonary opacities in patients with rheumatoid arthritis. A diagnostic dilemma. Chest. 1989 Nov. 96(5):1022-5. [QxMD MEDLINE Link].
Gabazza E, Taguchi O, Yamakami T, Machishi M, Ibata H, Suzuki S. [Usefulness of DLco for the early diagnosis of pulmonary involvement in collagen diseases] [Japanese]. Nihon Kyobu Shikkan Gakkai Zasshi. 1993 Apr. 31 (4):480-5. [QxMD MEDLINE Link].
Spagnolo P, Cordier JF, Cottin V. Connective tissue diseases, multimorbidity and the ageing lung. Eur Respir J. 2016 May. 47 (5):1535-58. [QxMD MEDLINE Link]. [Full Text].
Chhajed PN, Doshi KP, Athavale AU, Bichile LS, Shah AC. Bronchoalveolar lavage (BAL) in newly diagnosed patients with collagen vascular diseases. Indian J Chest Dis Allied Sci. 1998 Oct-Dec. 40 (4):243-50. [QxMD MEDLINE Link].
Popp W, Braun O, Ritschka L, et al. Chest X-ray in collagen vascular diseases. A comparison of chest X-ray with bronchoalveolar lavage and transbronchial forceps biopsy. Respiration. 1994. 61(3):138-43. [QxMD MEDLINE Link].
Nagai S, Satake N, Kitaichi M, Izumi T. [Interstitial pneumonia associated with collagen vascular diseases: histological findings, and cells in bronchoalveolar lavage fluid] [Japanese]. Nihon Kyobu Shikkan Gakkai Zasshi. 1995 Dec. 33 Suppl:258-63. [QxMD MEDLINE Link].
Tanaka N, Newell JD, Brown KK, Cool CD, Lynch DA. Collagen vascular disease-related lung disease: high-resolution computed tomography findings based on the pathologic classification. J Comput Assist Tomogr. 2004 May-Jun. 28(3):351-60. [QxMD MEDLINE Link].
Grubben MJ, Kerstens PJ, Wiersma JM, Boerbooms AM, Festen J. Pleuro-pulmonary involvement in patients with connective tissue disease. The role of open lung biopsy. Neth J Med. 1993 Dec. 43(5-6):269-76. [QxMD MEDLINE Link].
Sato T, Fujita J, Yamadori I, et al. Non-specific interstitial pneumonia; as the first clinical presentation of various collagen vascular disorders. Rheumatol Int. 2006 Apr. 26(6):551-5. [QxMD MEDLINE Link].
Tashkin DP, Elashoff R, Clements PJ, et al, for the Scleroderma Lung Study Research Group. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med. 2006 Jun 22. 354 (25):2655-66. [QxMD MEDLINE Link].
Guillevin L, Cordier JF, Lhote F, et al. A prospective, multicenter, randomized trial comparing steroids and pulse cyclophosphamide versus steroids and oral cyclophosphamide in the treatment of generalized Wegener's granulomatosis. Arthritis Rheum. 1997 Dec. 40 (12):2187-98. [QxMD MEDLINE Link].
Tashkin DP, Roth MD, Clements PJ, et al, for the Sclerodema Lung Study II Investigators. 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 Sep. 4 (9):708-19. [QxMD MEDLINE Link].
Jayne D, Rasmussen N, Andrassy K, et al, European Vasculitis Study Group. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med. 2003 Jul 3. 349 (1):36-44. [QxMD MEDLINE Link].
Hiemstra TF, Walsh M, Mahr A, et al, for the European Vasculitis Study Group (EUVAS). Mycophenolate mofetil vs azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized controlled trial. JAMA. 2010 Dec 1. 304 (21):2381-8. [QxMD MEDLINE Link].
Guillevin L, Pagnoux C, Karras A, et al, for the French Vasculitis Study Group. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med. 2014 Nov 6. 371 (19):1771-80. [QxMD MEDLINE Link].
John H. Stone, M.D., M.P.H., Peter A. Merkel, M.D., M.P.H., et al. Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis. NEJM. July 15, 2010. 363:221-232.
Rituximab versus cyclophosphamide in connective tissue disease-ILD (RECITAL). ClinicalTrials.gov. Available at http://clinicaltrials.gov/ct2/show/NCT01862926. Updated: May 22, 2020; Accessed: August 7, 2020.
Fink SD, Kremer JM. Successful treatment of interstitial lung disease in systemic lupus erythematosus with methotrexate. J Rheumatol. 1995 May. 22(5):967-9. [QxMD MEDLINE Link].
Hagiwara K, Sato T, Takagi-Kobayashi S, Hasegawa S, Shigihara N, Akiyama O. Acute exacerbation of preexisting interstitial lung disease after administration of etanercept for rheumatoid arthritis. J Rheumatol. 2007 May. 34(5):1151-4. [QxMD MEDLINE Link].
US Food and Drug Administration. FDA approves first treatment for patients with rare type of lung disease [press release]. Available at http://fda.gov/news-events/press-announcements/fda-approves-first-treatment-patients-rare-type-lung-disease. September 6, 2019; Accessed: September 9, 2019.
Distler O, Highland KB, Gahlemann M, et al, for the SENSCIS Trial Investigators. Nintedanib for systemic sclerosis-associated interstitial lung disease. N Engl J Med. 2019 Jun 27. 380 (26):2518-28. [QxMD MEDLINE Link].
Flaherty KR, Wells AU, Cottin V, et al, for the INBUILD Trial Investigators. Nintedanib in progressive fibrosing interstitial lung diseases. N Engl J Med. 2019 Oct 31. 381 (18):1718-27. [QxMD MEDLINE Link].
[Guideline] Galie N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Rev Esp Cardiol (Engl Ed). 2016 Feb. 69 (2):177. [QxMD MEDLINE Link]. [Full Text].
Walker UA, Saketkoo LA, Distler O. Haematopoietic stem cell transplantation in systemic sclerosis. RMD Open. 2018. 4 (1):e000533. [QxMD MEDLINE Link].
Park JE, Kim SY, Song JH, et al. Comparison of short-term outcomes for connective tissue disease-related interstitial lung disease and idiopathic pulmonary fibrosis after lung transplantation. J Thorac Dis. 2018 Mar. 10 (3):1538-47. [QxMD MEDLINE Link].
[Guideline] Raghu G, Remy-Jardin M, Myers JL, et al, for the American Thoracic Society, European Respiratory Society, et al. Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med. 2018 Sep 1. 198 (5):e44-e68. [QxMD MEDLINE Link]. [Full Text].
Phillips D. New guideline updates diagnostic criteria for IPF. Medscape Medical News. Available at http://medscape.com/viewarticle/901860. September 12, 2018; Accessed: August 7, 2020.
Chartrand S, Fischer A. Management of connective tissue disease-associated interstitial lung disease. Rheum Dis Clin North Am. 2015 May. 41(2):279-94. [QxMD MEDLINE Link].
Castagnaro A, Chetta A, Marangio E, Zompatori M, Olivieri D. The lung in immune-mediated disorder: rheumatoid arthritis. Curr Drug Targets Inflamm Allergy. Dec; 2004. 3(4):449-54. [QxMD MEDLINE Link].
Olson AL, Swigris JJ. Idiopathic pulmonary fibrosis: diagnosis and epidemiology. Clin Chest Med. 2012 Mar. 33(1):41-50. [QxMD MEDLINE Link].
Antin-Ozerkis D, Rubinowitz A, Evans J, Homer RJ, Matthay RA. Interstitial lung disease in the connective tissue diseases. Clin Chest Med. 2012 Mar. 33(1):123-49. [QxMD MEDLINE Link].
Tanriverdi H, Erboy F, Altinsoy B, et al. Bronchoalveolar lavage fluid characteristics of patients with sarcoidosis and nonsarcoidosis interstitial lung diseases: ten-year experience of a single center in Turkey. Iran Red Crescent Med J. 2015 Oct. 17(10):e31103. [QxMD MEDLINE Link].
Hagaman JT, Panos RJ, McCormack FX, et al. Vitamin D deficiency and reduced lung function in connective tissue-associated interstitial lung diseases. Chest. 2011 Feb. 139(2):353-60. [QxMD MEDLINE Link]. [Full Text].
Wallace B, Vummidi D, Khanna D. Management of connective tissue diseases associated interstitial lung disease: a review of the published literature. Curr Opin Rheumatol. 2016 May. 28 (3):236-45. [QxMD MEDLINE Link]. [Full Text].
Ruiz-Irastorza G, Khamashta MA, Castellino G, Hughes GR. Systemic lupus erythematosus. Lancet. 2001 Mar 31. 357(9261):1027-32. [QxMD MEDLINE Link].
Youinou P, Moutsopoulos HM, Pennec YL. Clinical features of Sjögren's syndrome. Curr Opin Rheumatol. 1990 Oct. 2(5):687-93. [QxMD MEDLINE Link].
Fessel WJ. Epidemiology of systemic lupus erythematosus. Rheum Dis Clin North Am. 1988 Apr. 14(1):15-23. [QxMD MEDLINE Link].
Kim DS. Interstitial lung disease in rheumatoid arthritis: recent advances. Curr Opin Pulm Med. 2006 Sep. 12(5):346-53. [QxMD MEDLINE Link].
Mouthon L, Berezne A, Brauner M, Valeyre D, Guillevin L. [Interstitial lung disease in connective tissue disorders] [French]. Rev Pneumol Clin. 2005 Jun. 61(3):211-9. [QxMD MEDLINE Link].
Kocheril SV, Appleton BE, Somers EC, et al. Comparison of disease progression and mortality of connective tissue disease-related interstitial lung disease and idiopathic interstitial pneumonia. Arthritis Rheum. 2005 Aug 15. 53(4):549-57. [QxMD MEDLINE Link].
Singh P, Thakur B, Mohapatra AK, Padhan P. Clinical features and outcome of acute exacerbation in connective tissue disease-associated interstitial lung disease: A single-center study from India. Int J Rheum Dis. 2019 Sep. 22 (9):1741-5. [QxMD MEDLINE Link].
Takizawa H, Suzuki N, Yanagawa T, et al. [Pulmonary involvement of collagen vascular diseases: studies on prognostic factors from basic and clinical viewpoints] [Japanese]. Nihon Kyobu Shikkan Gakkai Zasshi. 1995 Dec. 33 suppl:291-5. [QxMD MEDLINE Link].
Kuwana M. [Collagen diseases with pulmonary involvement]. Nihon Rinsho Meneki Gakkai Kaishi. 2004 Jun. 27(3):118-26. [QxMD MEDLINE Link].
Maeda H, Kanzaki M, Sakamoto K, et al. Effect of collagen vascular disease-associated interstitial lung disease on the outcomes of lung cancer surgery. Surg Today. 2017 Sep. 47 (9):1072-9. [QxMD MEDLINE Link]. [Full Text].

Media Gallery

Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD). Pulmonary hypertension is a complication of various collagen vascular diseases, referred to as connective tissue diseases. This lung biopsy specimen demonstrates severe interstitial fibrosis and medial fibrosis, as well as smooth muscle hyperplasia of a pulmonary arteriole, features that are compatible with pulmonary hypertension.
Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD). Note the heliotrope rash in a woman with dermatomyositis.
Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD). This image reveals Gottron papules and nail-fold telangiectasia in a patient with dermatomyositis.
Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD). This image shows the classic malar rash (butterfly rash), with distribution over the cheeks and nasal bridge. Note that the fixed erythema (sometimes associated with mild induration, as seen here) characteristically spares the nasolabial folds.
Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD). The high-resolution computed tomography scan of advanced-stage pulmonary fibrosis demonstrates reticular opacities with honeycombing in a predominantly subpleural distribution. This pattern can be present in rheumatoid arthritis–related interstitial lung disease, Sjögren syndrome, and scleroderma.
Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD). Ground-glass opacification (GGO) may correlate with active alveolitis and a favorable response to therapy. GGO is among the earliest features of rheumatoid arthritis–induced interstitial lung disease.
Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD). This chest radiograph was obtained from a patient with lymphocytic interstitial pneumonia.
Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD). The histologic image is from a patient with usual interstitial pneumonitis. Subpleural and paraseptal inflammation are present, with the appearance of temporal heterogeneity. Patchy scarring of the lung parenchyma and normal (or nearly normal) alveoli interspersed between fibrotic areas are hallmarks of this disease. In addition, the lung architecture is completely destroyed. This pattern can be present in rheumatoid arthritis–induced interstitial lung disease and is generally associated with a poor prognosis.
Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD). In reviewing a retrospective database, Odham et al (Chicago cohort), showed a significant difference in mortality for patients with and without autoimmune features. CTD-ILD = Connective tissue disease-associated interstitial lung disease; IPAF = interstitial pneumonia with autoimmune features; IPF = idiopathic pulmonary fibrosis; UIP = usual interstitial pneumonia. Reproduced with permission of the © ERS 2019. Eur Resp J. 2016 Jun:47(6):1767-75. DOI: 10.1183/13993003.01565-2015. Published 31 May 2016. PMID: 27103387.

of 9

Table 1. Important Physical Findings in Connective Tissue Diseases

CTD	Skin and Musculoskeletal System	Lungs	Heart	Salivary Glands	Eyes
RA^*	Subcutaneous nodules, digital ulcers, nail-fold infarcts	Bibasilar Velcro crackles, signs of pulmonary hypertension, pleural effusion	Pericarditis, myocarditis	N/A	N/A
SLE^*	Malar rash, alopecia, livedo reticularis, erythema, telangiectasia, capillary infarcts, polyarthritis	Pleural effusion or rub, pneumonitis, cor pulmonale, diaphragmatic weakness	Pericarditis, myocarditis, CAD	N/A	N/A
SD	Thickening of skin of face, fingers, and hands; Raynaud phenomenon and ischemic changes of fingertips	Cor pulmonale, inspiratory "Velcro crackles" at lung bases	Restrictive pericardial disease, conduction defects, CHF	N/A	N/A
SS^*	Secondary SS can manifest similarly to RA and SLE	Secondary SS can manifest similarly to RA and SLE	N/A	Xerostomia, parotid gland swelling	Keratoconjunctivitis sicca
PM	Proximal muscle weakness	Respiratory muscle failure	N/A	N/A	N/A
DM	Heliotrope rash of eyelids, Gottron papules	Respiratory muscle failure	N/A	N/A	N/A
AS	Sacroiliitis	Restriction in chest expansion, pulmonary apical fibrosis	Aortic insufficiency	N/A	Anterior uveitis
^* Mixed connective tissue disease (MCTD) can manifest with the signs and symptoms of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), or Sjögren syndrome (SS). AS = ankylosing spondylitis; CAD = coronary artery disease; CHF = congestive heart failure; CTD = connective-tissue disease; DM = dermatomyositis; PM = polymyositis; SD = scleroderma.

Table 2. Autoantibodies in Connective Tissue Diseases

Autoantibody	RA	SLE	SD	SS	PM/DM	AS	MCTD	IPAF #^[10]
RF	+	+	+	+	Rare	-	+	Possible
ANA	+	+	+	+	Rare	-	+ (speckled)	Possible
ds-DNA	-	+	-	-	-	-	-	Possible
Anti centromere	-	-	+ (limited)	Rare	Rare	-	-	Possible
Scl-70	-	-	+ (diffuse)		Rare	-	-	Possible
Anti-Jo	-	-	-	Rare	+ (ILD)	-	-	Possible
ANCA	Rare	Rare	-	-	-	-	-	-
Smith antibody	-	+	-	-	-	-	-	Possible
Anti-Ro/SSA and anti-La/SSB	-	-	-	+	-	-	-	Possible
Anti-U1-RNP and anti-UN-70 kd	-	-	-	-	-	-	+	Possible
Anti-CCP	+	-	-	-	-	-	-	Possible
ANA = antinuclear antibody; ANCA = antineutrophilic cytoplasmic antibody; AS = ankylosing spondylitis; CCP = cyclic citrullinated peptide; DM = dermatomyositis; ds-DNA = double-stranded DNA antibody; ILD = interstitial lung disease; IPAF = interstitial pneumonia with autoimmune features; MCTD = mixed connective-tissue disease; PM = polymyositis; RA = rheumatoid arthritis; RF = rheumatoid factor; RNP = ribonucleoprotein; SD = scleroderma; SLE = systemic lupus erythematosus; SS = Sjögren syndrome.

Table 3. Radiologic Patterns of Connective Tissue Diseases

Radiologic Pattern	RA	SLE	SD	Secondary SS	PM/DM	AS	MCTD	IPAF ^[10]
Pleural effusion	+	+	+	±	-	-	+	May be present
Interstitial pneumonitis, fibrosis	UIP and NSIP patterns	+	LIP pattern	±	+	Upper apical fibrosis^[59]	+	NISP, OP, LIP or NISP with OP overlap pattern
BOOP	±	+	+	+	+	±	±
Pulmonary nodules	Rheumatoid pulmonary nodules; uncommon, maybe 1-5 mm, single or multiple, may cavitate	-	-	Follicular lymphoid hyperplasia or lymphoma can present as lung nodules	+	-	-
Bronchiectasis	+	+	+	+	+	+	+	unexplained airflow obstruction, bronchiolitis or bronchiectasis.
Caplan syndrome	Coal worker pneumoconiosis, rheumatoid nodules	-	-	-	-	-	±
Diffuse pulmonary hemorrhage	-	+	-	-	-	-	±
Shrinking lung syndrome	-	Loss of lung volume at bases with no parenchymal pathology	-	-	-	-	±
Diaphragmatic dysfunction	-	+	-	May be present	+	-	±
Cysts, honeycombing	10% of patients have subpleural honeycombing; compared with IPF, it is more anterior and involves upper lobes	Uncommon	+	Present, especially in LIP	+	Upper-lobe cyst may become infected with Aspergillus species	-
GGO	Present, especially in NSIP	+	+	+	+	-	±
AS = ankylosing spondylitis; BOOP = bronchiolitis obliterans organizing pneumonia; DM = dermatomyositis; GGO = ground-glass opacification; IPAF = interstitial pneumonia with autoimmune features; IPF = idiopathic pulmonary fibrosis; LIP = lymphoid interstitial pneumonia; MCTD = mixed connective-tissue disease; NSIP = nonspecific interstitial pneumonia; OP = organizing pneumonia; PM = polymyositis; RA = rheumatoid arthritis; SD = scleroderma; SLE = systemic lupus erythematosus; SS = Sjögren syndrome; UIP = usual interstitial pneumonia.

Back to List

Author

Aniruddh Kapoor, MBBS Fellow in Pulmonary Disease and Critical Care Medicine, St Louis University Hospital

Disclosure: Nothing to disclose.

Coauthor(s)

Setu K Patolia, MD, MPH Assistant Professor of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Director of Interventional Pulmonary Services, Associate Program Director for Pulmonary and Critical Care Fellowship, St Louis University School of Medicine

Setu K Patolia, MD, MPH is a member of the following medical societies: American Association for Bronchology and Interventional Pulmonology, American College of Chest Physicians, American Thoracic Society, Society of Critical Care Medicine

Disclosure: Nothing to disclose.

David Picker, MD, MBA Attending Physician, Department of Pulmonary Disease and Critical Care Medicine, St Louis University School of Medicine

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Zab Mosenifar, MD, FACP, FCCP Geri and Richard Brawerman Chair in Pulmonary and Critical Care Medicine, Professor and Executive Vice Chairman, Department of Medicine, Medical Director, Women's Guild Lung Institute, Cedars Sinai Medical Center, University of California, Los Angeles, David Geffen School of Medicine

Zab Mosenifar, MD, FACP, FCCP is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Federation for Medical Research, American Thoracic Society

Disclosure: Nothing to disclose.

Additional Contributors

Daniel R Ouellette, MD, FCCP Associate Professor of Medicine, Wayne State University School of Medicine; Medical Director, Pulmonary Medicine General Practice Unit (F2), Senior Staff and Attending Physician, Division of Pulmonary and Critical Care Medicine, Henry Ford Hospital

Daniel R Ouellette, MD, FCCP is a member of the following medical societies: American College of Chest Physicians, American Thoracic Society, Society of Critical Care Medicine

Disclosure: Received research grant from: Sanofi Pharmaceutical.

Arshad Ali, MD Attending Physician, Department of Pulmonary and Critical Care Medicine, Mercy General Hospital of Sacramento

Arshad Ali, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Thoracic Society

Disclosure: Nothing to disclose.

Danilo A Enriquez, MD, FCCP Clinical Assistant Professor of Medicine, State University of New York Health Science Center at Brooklyn; Associate Program Director of Internal Medicine Residency Program, Interfaith Medical Center

Danilo A Enriquez, MD, FCCP is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Medical Association

Disclosure: Nothing to disclose.

Isabel F Pedraza, MD Director, Respiratory Intensive Care Unit, Faculty Physician, Department of Medicine, Division of Pulmonary/Critical Care Medicine, Women's Guild Lung Institute, Cedars-Sinai Medical Center

Disclosure: Nothing to disclose.

Acknowledgements

Om Prakash Sharma, MD, FRCP, FCCP, DTM&H Professor, Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Southern California Keck School of Medicine

Om Prakash Sharma, MD, FRCP, FCCP, DTM&H is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Chest Physicians, American College of Physicians, American Federation for Medical Research, American Osler Society, American Thoracic Society, New York Academy of Medicine, and Royal Society of Medicine

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment