Medscape is available in 5 Language Editions – Choose your Edition here.


Interstitial Lung Disease Associated With Collagen-Vascular Disease Differential Diagnoses

  • Author: Isabel F Pedraza, MD; Chief Editor: Zab Mosenifar, MD, FACP, FCCP  more...
Updated: Sep 20, 2013

Diagnostic Considerations

Proper diagnosis of interstitial lung disease (ILD) in persons with collagen-vascular disease (CVD) is important. In most cases, treatment is not very successful, and the medications themselves can cause ILD.

Methotrexate-induced pulmonary toxicity can manifest as an acute onset of fever, dyspnea, hypoxia, and patchy interstitial infiltrates, making it indistinguishable from rheumatoid arthritis (RA)-related ILD. The presence of lymphocytes in bronchoalveolar lavage (BAL) fluid, granuloma in lung biopsy specimens, and peripheral eosinophilia can distinguish methotrexate toxicity from RA-related ILD.

In addition to the conditions listed in the differential diagnosis, other problems to be considered include the following:

  • Human immunodeficiency virus
  • Antiphospholipid antibody syndrome
  • Undifferentiated connective-tissue disease

Differential Diagnoses

Contributor Information and Disclosures

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.


Daniel R Ouellette, MD, FCCP Associate Professor of Medicine, Wayne State University School of Medicine; Chair of the Clinical Competency Committee, Pulmonary and Critical Care Fellowship Program, Senior Staff and Attending Physician, Division of Pulmonary and Critical Care Medicine, Henry Ford Health System; Chair, Guideline Oversight Committee, American College of Chest Physicians

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

Disclosure: Nothing to disclose.

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.

Hina Arif, MD 

Disclosure: Nothing to disclose.

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.


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

  1. Self SE. Autoantibody testing for autoimmune disease. Clin Chest Med. 2010 Sep. 31(3):415-22. [Medline].

  2. 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. [Medline].

  3. Tzelepis GE, Toya SP, Moutsopoulos HM. Occult connective tissue diseases mimicking idiopathic interstitial pneumonias. Eur Respir J. 2008 Jan. 31(1):11-20. [Medline].

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

  5. 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. [Medline].

  6. Olson AL, Swigris JJ. Idiopathic pulmonary fibrosis: diagnosis and epidemiology. Clin Chest Med. 2012 Mar. 33(1):41-50. [Medline].

  7. Jindal SK, Agarwal R. Autoimmunity and interstitial lung disease. Curr Opin Pulm Med. Sep;2005. 11(5):438-46. [Medline].

  8. 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. [Medline].

  9. 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. [Medline].

  10. 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. [Medline].

  11. Kamen DL, Strange C. Pulmonary manifestations of systemic lupus erythematosus. Clin Chest Med. 2010 Sep. 31(3):479-88. [Medline].

  12. Tanaka N, Kim JS, Newell JD, Brown KK, Cool CD, Meehan R, et al. Rheumatoid arthritis-related lung diseases: CT findings. Radiology. Jul;2004 Epub 2004 May 27. 232(1):81-91. [Medline].

  13. 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. [Medline].

  14. Kalluri M, Oddis CV. Pulmonary manifestations of the idiopathic inflammatory myopathies. Clin Chest Med. 2010 Sep. 31(3):501-12. [Medline].

  15. Khan MA, Mathieu A, Sorrentino R, Akkoc N. The pathogenetic role of HLA-B27 and its subtypes. Autoimmun Rev. Jan;2007 Epub 2006 Dec. 6(3):183-9. [Medline].

  16. 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. Oct;1998. 41(10):1714-24. [Medline].

  17. Saag KG, Kolluri S, Koehnke RK, Georgou TA, Rachow JW, Hunninghake GW, et al. Rheumatoid arthritis lung disease. Determinants of radiographic and physiologic abnormalities. Arthritis Rheum. Oct;1996. 39(10):1711-9. [Medline].

  18. 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. [Medline]. [Full Text].

  19. Ruiz-Irastorza G, Khamashta MA, Castellino G, Hughes GR. Systemic lupus erythematosus. Lancet. Mar 31;2001. 357(9261):1027-32. [Medline].

  20. Tamaki T, Mori S, Takehara K. Epidemiological study of patients with systemic sclerosis in Tokyo. Arch Dermatol Res. 1991;. 283(6):366-71. [Medline].

  21. Maricq HR, Weinrich MC, Keil JE, Smith EA, Harper FE, Nussbaum AI, et al. Prevalence of scleroderma spectrum disorders in the general population of South Carolina. Arthritis Rheum. Aug;. 32(8):1989:998-1006. [Medline].

  22. 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. Sep;1969. 44(9):649-63. [Medline].

  23. Oddis CV, Conte CG, Steen VD, Medsger TA. Incidence of polymyositis-dermatomyositis: a 20-year study of hospital diagnosed cases in Allegheny County, PA 1963-1982. J Rheumatol. Oct;1990. 17(10):1329-34. [Medline].

  24. Spector TD. Rheumatoid arthritis. Rheum Dis Clin North Am. Aug;1990. 16(3):513-37. [Medline].

  25. Kellgren JH. Epidemiology of rheumatoid arthritis. Arthritis Rheum. Oct;1966. 9(5):658-74. [Medline].

  26. Youinou P, Moutsopoulos HM, Pennec YL. Clinical features of Sjögren's syndrome. Curr Opin Rheumatol. Oct;1990. 2(5):687-93. [Medline].

  27. Fessel WJ. Epidemiology of systemic lupus erythematosus. Rheum Dis Clin North Am. Apr;. 14(1): 1988:15-23. [Medline].

  28. Lawrence RC, Hochberg MC, Kelsey JL, McDuffie FC, Medsger TA, Felts WR, et al. Estimates of the prevalence of selected arthritic and musculoskeletal diseases in the United States. J Rheumatol. Apr;1989. 16(4):427-41. [Medline].

  29. 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. May;2007 Epub 2007 Apr 15. 34(5):1151-4. [Medline].

  30. Kim DS. Interstitial lung disease in rheumatoid arthritis: recent advances. Curr Opin Pulm Med. Sep;. 12(5):2006:346-53. [Medline].

  31. Mouthon L, Berezné A, Brauner M, Valeyre D, Guillevin L. Interstitial lung disease in connective tissue disorders. Rev Pneumol Clin. Jun;2005. 61(3):211-9. [Medline].

  32. 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. [Medline].

  33. 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. [Medline].

  34. Takizawa H, Suzuki N, Yanagawa T, Okazaki H, Satoh M, Akiyama N, et al. Importance of interstitial lung disease in collagen vascular disease: analysis of outcome. Nihon Kyobu Shikkan Gakkai Zasshi. Nov;1996. 34(11):1177-81. [Medline].

  35. Hakala M. Poor prognosis in patients with rheumatoid arthritis hospitalized for interstitial lung fibrosis. Chest. Jan;1988. 93(1):114-8. [Medline].

  36. Kang EH, Lee EB, Shin KC, Im CH, Chung DH, Han SK, et al. Interstitial lung disease in patients with polymyositis, dermatomyositis and amyopathic dermatomyositis. Rheumatology (Oxford). Oct: 2005;Epub 2005 Jun 21. 44(10):1282-6. [Medline].

  37. Takizawa H, Suzuki N, Yanagawa T, Okazaki H, Satoh M, Akiyama N, et al. Pulmonary involvement of collagen vascular diseases: studies on prognostic factors from basic and clinical viewpoints. Nihon Kyobu Shikkan Gakkai Zasshi. Dec;1995. 33 Suppl:291-5. [Medline].

  38. Matthay RA, Schwarz MI, Petty TL, Stanford RE, Gupta RC, Sahn SA, et al. Pulmonary manifestations of systemic lupus erythematosus: review of twelve cases of acute lupus pneumonitis. Medicine (Baltimore). Sep;1975. 54(5):397-409. [Medline].

  39. Martens J, Demedts M, Vanmeenen MT, Dequeker J. Respiratory muscle dysfunction in systemic lupus erythematosus. Chest. Aug;1983. 84(2):170-5. [Medline].

  40. Owens GR, Follansbee WP. Cardiopulmonary manifestations of systemic sclerosis. Chest. Jan;1987. 91(1):118-27. [Medline].

  41. Keane MP, Lynch JP. Pleuropulmonary manifestations of systemic lupus erythematosus. Thorax. Feb;2000. 55(2):159-66. [Medline].

  42. Onomura K, Nakata H, Tanaka Y, Tsuda T. Pulmonary hemorrhage in patients with systemic lupus erythematosus. J Thorac Imaging. Apr;1991. 6(2):57-61. [Medline].

  43. Won Huh J, Soon Kim D, Keun Lee C, Yoo B, Bum Seo J, Kitaichi M, et al. Two distinct clinical types of interstitial lung disease associated with polymyositis-dermatomyositis. Respir Med. Aug;2007:Epub 2007 Apr 10. 101(8):1761-9. [Medline].

  44. 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. Oct;1981. 124(4):499-503. [Medline].

  45. Végh J, Szilasi M, Soós G, Dévényi K, Dezso B, Soltész P, et al. Interstitial lung disease in mixed connective tissue disease. Orv Hetil. Nov 27;2005. 146(48):2435-43. [Medline].

  46. Fenlon HM, Casserly I, Sant SM, Breatnach E. Plain radiographs and thoracic high-resolution CT in patients with ankylosing spondylitis. AJR Am J Roentgenol. Apr;1997. 168(4):1067-72. [Medline].

  47. Gabbay E, Tarala R, Will R, Carroll G, Adler B, Cameron D, et al. Interstitial lung disease in recent onset rheumatoid arthritis. Am J Respir Crit Care Med. Aug;1997. 156(2 Pt 1):528-35. [Medline].

  48. Cortet B, Perez T, Roux N, Flipo RM, Duquesnoy B, Delcambre B, et al. Pulmonary function tests and high resolution computed tomography of the lungs in patients with rheumatoid arthritis. Ann Rheum Dis. Oct;1997. 56(10):596-600. [Medline].

  49. Herzog CA, Miller RR, Hoidal JR. Bronchiolitis and rheumatoid arthritis. Am Rev Respir Dis. Nov;1981. 124(5):636-9. [Medline].

  50. Corrin B, Turner-Warwick M, Geddes DM, Brewerton DA. Bronchiolitis obliterans. A new form of rheumatoid lung?. Chest. Feb;1978. 73(2):244. [Medline].

  51. Cortet B, Flipo RM, Rémy-Jardin M, Coquerelle P, Duquesnoy B, Rêmy J, et al. Use of high resolution computed tomography of the lungs in patients with rheumatoid arthritis. Ann Rheum Dis. Oct;1995. 54(10):815-9. [Medline].

  52. CAPLAN A. Certain unusual radiological appearances in the chest of coal-miners suffering from rheumatoid arthritis. Thorax. Mar;1953. 8(1):29-37. [Medline].

  53. Jolles H, Moseley PL, Peterson MW. Nodular pulmonary opacities in patients with rheumatoid arthritis. A diagnostic dilemma. Chest. Nov;1989. 96(5):1022-5. [Medline].

  54. Franquet T, Giménez A, Monill JM, Díaz C, Geli C. Primary Sjögren's syndrome and associated lung disease: CT findings in 50 patients. AJR Am J Roentgenol. Sep;1997. 169(3):655-8. [Medline].

  55. 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. Nihon Kyobu Shikkan Gakkai Zasshi. Apr;1993. 31(4):480-5. [Medline].

  56. 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. Oct-Dec;1998. 40(4):243-50. [Medline].

  57. Popp W, Braun O, Ritschka L, Scherak O, Kolarz G, Rauscher H, 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. [Medline].

  58. Nagai S, Satake N, Kitaichi M, Izumi T. Interstitial pneumonia associated with collagen vascular diseases: histological findings, and cells in bronchoalveolar lavage fluid. Nihon Kyobu Shikkan Gakkai Zasshi. Dec;1995. 33 :Suppl:258-63. [Medline].

  59. 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. May-Jun; 2004. 28(3):351-60. [Medline].

  60. 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. Dec;1993. 43(5-6):269-76. [Medline].

  61. Sato T, Fujita J, Yamadori I, Ohtsuki Y, Yoshinouchi T, Bandoh S, et al. Non-specific interstitial pneumonia; as the first clinical presentation of various collagen vascular disorders. Rheumatol Int. Apr; 2006: Epub 2005 Nov 8. 26(6):551-5. [Medline].

  62. Kuwana M. Collagen diseases with pulmonary involvement. Nihon Rinsho Meneki Gakkai Kaishi. Jun; 2004. 27(3):118-26. [Medline].

  63. Fink SD, Kremer JM. Successful treatment of interstitial lung disease in systemic lupus erythematosus with methotrexate. J Rheumatol. May;1995. 22(5):967-9. [Medline].

Pulmonary hypertension is complication of various collagen-vascular diseases. Lung biopsy specimen demonstrates severe interstitial fibrosis and medial fibrosis and smooth muscle hyperplasia of pulmonary arteriole, compatible with pulmonary hypertension.
Heliotrope rash in woman with dermatomyositis.
Gottron papules and nail-fold telangiectasia in patient with dermatomyositis.
Classic malar rash (butterfly rash) with distribution over cheeks and nasal bridge. Note that fixed erythema (sometimes associated with mild induration, as here) characteristically spares nasolabial folds.
High-resolution CT scan of advanced-stage pulmonary fibrosis demonstrating reticular opacities with honeycombing in predominantly subpleural distribution. This pattern can be present in rheumatoid arthritis–related interstitial lung disease, Sjögren syndrome, and scleroderma.
Ground-glass opacification (GGO) may correlate with active alveolitis and favorable response to therapy. GGO is among earliest features of rheumatoid arthritis–induced interstitial lung disease.
Patient with lymphocytic interstitial pneumonia.
Usual interstitial pneumonitis. Subpleural and paraseptal inflammation are present, with appearance of temporal heterogeneity. Patchy scarring of lung parenchyma and normal (or nearly normal) alveoli interspersed between fibrotic areas are hallmarks of this disease. In addition, lung architecture is completely destroyed. This pattern can be present in rheumatoid arthritis–induced interstitial lung disease and generally is associated with poor prognosis.
Table 1. Important Physical Findings in Collagen-Vascular Diseases
CVD Skin and Musculoskeletal System Lungs Heart Salivary Glands Eyes
RA*Subcutaneous nodules, digital ulcers, nail-fold infarctsBibasilar Velcro crackles, signs of pulmonary hypertension, pleural effusionPericarditis, myocarditisN/AN/A
SLE*Malar rash, alopecia, livedo reticularis, erythema, telangiectasia, capillary infarcts, polyarthritisPleural effusion or rub, pneumonitis, cor pulmonale, diaphragmatic weaknessPericarditis, myocarditis, CADN/AN/A
SDThickening of skin of face, fingers, and hands; Raynaud phenomenon and ischemic changes of fingertipsCor pulmonale, inspiratory Velcro crackles at lung basesRestrictive pericardial disease, conduction defects, CHFN/AN/A
SS*Secondary SS can manifest similarly to RA and SLESecondary SS can manifest similarly to RA and SLEN/AXerostomia, parotid gland swellingKeratoconjunctivitis sicca
PMProximal muscle weaknessRespiratory muscle failureN/AN/AN/A
DMHeliotrope rash of eyelids, Gottron papules,Respiratory muscle failureN/AN/AN/A
ASSacroiliitisRestriction in chest expansion, pulmonary apical fibrosisAortic insufficiencyN/AAnterior uveitis
* MCTD can manifest with the signs and symptoms of RA, SLE, or SS.

AS = ankylosing spondylitis; CAD = coronary artery disease; CHF = congestive heart failure; CVD = collagen-vascular disease; DM = dermatomyositis; PM = polymyositis; RA = rheumatoid arthritis; SD = scleroderma; SLE = systemic lupus erythematosus; SS = Sjögren syndrome.

Table 2. Autoantibodies in Collagen-Vascular Diseases


Anticentromere--+ (limited)RareRare--
Scl-70--+ (diffuse) Rare--
Anti-Jo---Rare+ (ILD)--
Smith antibody-+-----
Anti-Ro/SSA and anti-La/SSB---+---
Anti-U1-RNP and anti-UN-70 kd------+
ANA = antinuclear antibody; ANCA = antineutrophilic cytoplasmic antibody; AS = ankylosing spondylitis; DM = dermatomyositis; ds-DNA = double-stranded DNA antibody; ILD = interstitial lung disease; MCTD = mixed connective-tissue disease; PM = polymyositis; RA = rheumatoid arthritis; RF = rheumatoid factor; RNP = ribonucleoprotein; SD = scleroderma; SLE = systemic lupus erythematosus; SS = Sjögren syndrome; CCP = cyclic citrullinated peptide.
Table 3. Radiographic Patterns of Collagen-Vascular Diseases
Radiologic Pattern RA SLE SD Secondary SS PM/DM AS MCTD
Pleural effusion+++±--+
Interstitial pneumonitis, fibrosisUIP and NSIP patterns+LIP pattern±+Upper apical fibrosis[46] +
Pulmonary nodulesRheumatoid pulmonary nodules; uncommon, may be 1-5 mm, single or multiple, may cavitate--Follicular lymphoid hyperplasia or lymphoma can present as lung nodules+--
Caplan syndromeCoal worker’s 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, honeycombing10% of patients have subpleural honeycombing; compared with IPF, it is more anterior and involves upper lobesUncommon+Present, especially in LIP+Upper-lobe cyst may become infected with Aspergillus species-
GGOPresent, especially in NSIP++++-±
AS = ankylosing spondylitis; BOOP = bronchiolitis obliterans organizing pneumonia; DM = dermatomyositis; GGO = ground-glass opacification; IPF = idiopathic pulmonary fibrosis; LIP = lymphoid interstitial pneumonia; MCTD = mixed connective-tissue disease; NSIP = nonspecific interstitial pneumonia; PM = polymyositis; RA = rheumatoid arthritis; SD = scleroderma; SLE = systemic lupus erythematosus; SS = Sjögren syndrome; UIP = usual interstitial pneumonia.
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.