SYMPOSIUM REVIEW ARTICLE
The Spectrum of Interstitial Lung Disease in Connective Tissue Disease Travis S. Henry, MD,* Brent P. Little, MD,* Srihari Veeraraghavan, MD,w Sanjeev Bhalla, MD,z and Brett M. Elicker, MDy
Abstract: Interstitial lung disease (ILD) is a common cause of morbidity and mortality in patients with connective tissue disease (CTD). In a minority of patients the ILD may be the presenting (or only) manifestation of an underlying CTD. Diagnosis of CTDrelated ILD relies on a multidisciplinary team including pulmonologists, pathologists, radiologists, and rheumatologists, as the imaging and pathologic findings may be indistinguishable from idiopathic interstitial pneumonias. Moreover, many patients with ILD are suspected of having an underlying CTD but do not meet all of the necessary criteria for a specific disorder. This article provides a pattern-based approach to the imaging of CTD-related ILD and also reviews relevant clinical, pathologic, and serologic data that radiologists should be familiar with as part of a multidisciplinary team. Key Words: connective tissue disease, interstitial lung disease, antisynthetase syndrome, interstitial pneumonia with autoimmune features, nonspecific interstitial pneumonia, usual interstitial pneumonia
(J Thorac Imaging 2016;31:65–77)
C
onnective tissue diseases (CTD), also known as collagen vascular diseases or systemic rheumatic diseases, are a heterogenous assortment of autoimmune disorders that affect almost any organ system, including the lung. The most common CTDs that affect the lung include rheumatoid arthritis (RA), systemic sclerosis (SSc), Sjo¨gren syndrome (SjS), idiopathic inflammatory myopathies (IIM), systemic lupus erythematosus (SLE), and mixed CTD (MCTD). The primary lung manifestation is interstitial lung disease (ILD), a leading cause of mortality in many CTD patients. Diagnosis of CTD-related ILD (CTD-ILD) is complex, with a growing emphasis on multidisciplinary teams including pulmonologists, pathologists, radiologists, and rheumatologists to reach a consensus diagnosis. Despite the best efforts, in a minority of patients a consensus diagnosis cannot be reached, underscoring the difficulty in diagnosing these disorders and leaving questions
From the *Department of Radiology and Imaging Sciences, Cardiothoracic Division; wDepartment of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Emory University School of Medicine, Atlanta, GA; zMallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO; and yDepartment of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA. Travis S. Henry’s spouse is an employee of Genentech. The remaining authors declare no conflicts of interest. Correspondence to: Travis S. Henry, MD, 1755 Alabama St., San Francisco, CA 94110 (e-mail: [email protected]). Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/RTI.0000000000000191
J Thorac Imaging
Volume 31, Number 2, March 2016
as to whether some patients have unclassifiable CTDs or idiopathic interstitial pneumonia (IIP). Since the IIPs were classified in 2002 (and updated in 2013), several publications have described the high-resolution computed tomographic (HRCT) appearance of the IIPs in great detail.1–4 Moreover, many recent review articles have nicely illustrated the imaging manifestations of common CTDs, including ILD and other thoracic manifestations.5–10 However, as any experienced thoracic imager knows, many cases do not fit into a single classification, with >1 pattern present on the same imaging study [eg, mixed nonspecific interstitial pneumonia (NSIP) and organizing pneumonia (OP)], and it is these patients that often turn out to have a previously undiagnosed CTD. Although this paper will provide a detailed appraisal of typical imaging findings in CTDs, it also serves as a review of the broader clinical context of CTDs. This article will first provide a primer for radiologists on the diagnosis of CTDs, including relevant laboratory and physical examination findings, and then address 2 specific questions that will hopefully advance the reader’s understanding of CTD-ILD, enhancing the radiologist’s value to a multidisciplinary team. (1) A patient with CTD has an abnormal HRCT. Is the lung involvement a manifestation of the CTD? (2) A patient has findings of ILD on HRCT. Do they have an IIP or could it be the initial presentation of a CTD? Important points that will be emphasized in this text include the following: Clinicians currently face a diagnostic dilemma, as the existence of ILD is not included in the criteria for the diagnosis of a CTD (except for SSc where it is part of the 2013 criteria).11 If these patients present with ILD before other clinical manifestations of a CTD, they may be incorrectly diagnosed as having an IIP.12 Despite the growing battery of tests available, many cases of presumed IIP may be secondary to undiagnosed CTD [interstitial pneumonia with autoimmune features (IPAF)]. These patients tend to be younger, more often female, and have better baseline lung function. On HRCT, patients may have a mixed pattern (eg, NSIP + OP) or an unclassifiable pattern. These patients often have an underlying CTD. Idiopathic NSIP (iNSIP) is probably less common than originally thought. An NSIP pattern should prompt evaluation for an underlying CTD.13 Usual interstitial pneumonia (UIP), OP, lymphocytic interstitial pneumonia (LIP), and diffuse alveolar damage (DAD) patterns can also be seen in the setting of underlying CTDs. Distinction of UIP from NSIP is crucial, especially in the setting of a confident diagnosis where biopsy may be obviated and a diagnosis of idiopathic pulmonary fibrosis (IPF) assigned to the patient (ie, definite UIP). www.thoracicimaging.com |
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
65
J Thorac Imaging
Henry et al
In practice, many cases of NSIP are misdiagnosed as UIP, which alters therapy and prognosis. IIPs and CTD-ILD can have identical imaging appearances; however, they should not be considered identical diseases. Different therapeutic options are available in each group, and prognosis varies. For example, CTDUIP has improved survival compared with IPF-UIP.14
DIAGNOSIS OF CTDs Although pulmonologists and rheumatologists diagnose CTDs on the basis of clinical and laboratory guidelines, ILD, a significant cause of morbidity and mortality in these patients, is not a part of the diagnostic criteria except for SSc.11 This is especially troublesome in patients for whom ILD is the presenting (or only) symptom of a CTD.11 Diagnosing a CTD (and CTD-ILD) versus an IIP affects management and prognosis, as CTD-ILD patients are managed differently and have improved survival compared with patients with IPF.13,14 Findings suggestive of CTD include younger age (compared with IPF) and female sex, a history of Raynaud phenomenon or inflammatory arthritis, or subtle physical examination findings such as “mechanic’s hands” or abnormal findings at nailfold capillaroscopy.15 When clinicians are suspicious of CTD, serologic evaluation is generally the next step, and clinicians have an everexpanding battery of tests that can be ordered. Because of the overlap in imaging with IIPs and CTD-ILD, many clinicians will order these laboratory tests when a patient initially presents with an HRCT suggestive of ILD. A full review of autoantibodies associated with CTDs is beyond the scope of this manuscript, but basic tests with which all thoracic imagers should be familiar are presented here.
Acute Phase Proteins Acute phase proteins are defined as those whose plasma concentrations change by >25% during inflammatory states.16 Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are 2 of the most common tests that measure acute phase proteins and are useful in the setting of suspected CTD when considered in the appropriate context. These tests are not specific for CTD, as almost any cause of inflammation (eg, infection, vasculitis), malignancy, and other systemic illnesses can cause elevation, but serum levels do tend to correlate with disease activity (although ESR tends to lag response to treatment more than CRP).16 ESR also increases with age, obesity, and female sex.17 Unfortunately, these tests are imperfect, as up to 10% of patients with active RA, as well as patients with other active CTDs, may have normal ESR and CRP values.17,18
Volume 31, Number 2, March 2016
CTDs. The ANA test detects the presence of various autoantibodies and is often a first-line test when CTD is suspected. There are different ANA testing methods that vary in sensitivity and specificity, and the 2 most common tests are the enzyme-linked immunosorbent assay (ELISA) and indirect fluorescent antibody (IFA). At most institutions the ELISA is the first screening test, and an IFA is performed only if the ELISA is positive. The ANA ELISA is an automated, qualitative examination that detects the presence or absence of one of many antigens that are pooled into a sample. This makes the ELISA a good initial screening test, as it is more sensitive and cheaper than the IFA test.20 The sensitivity is at least 95% for SLE, and other CTDs including RA, IIM, SSc, and SjS may produce a positive ANA result in at least 50% of patients.15 The IFA is more specific, but less sensitive, and is generally performed to confirm a positive ELISA. The IFA is usually reported in terms of titer and pattern. The titer is the most dilute sample at which the ANA is detectable, and a value of 1:40 or greater is generally considered low-level positive but has overlap with healthy patients; values of 1:160 or greater are more suggestive of an underlying CTD.16,21 The different patterns of reactivity include speckled, homogenous/diffuse, rim/peripheral, nucleolar, or centromeric20 and may help improve specificity in some instances. For example, a nucleolar pattern is more suggestive of SSc than other patterns.15
Rheumatoid Factor (RF) and Anti–Cyclic Citrullinated Peptide (CCP) Antibody RF has limited sensitivity and specificity for RA of about 70% each. RF-positive patients tend to have more aggressive disease, with higher rates of vasculitis, rheumatoid nodules, Felty syndrome, and secondary SjS.16,21 RF, like ANA, may be positive in other autoimmune diseases (eg, SjS, SLE, SSc) and, also important for the imager, may be positive in other causes of lung disease, including sarcoidosis, silicosis, tuberculosis, and chronic obstructive pulmonary disease.16,21 Autoantibody to CCP is a more recent biomarker with increased specificity for RA (B95%) and similar sensitivity to RF. Anti-CCP can serve as a useful marker for progression of disease.21 Anti-CCP may also be elevated in SLE, SjS, IIMs, and tuberculosis.16 Performing RF and anti-CCP tests together is a strategy to maximize sensitivity for detection of RA.21
Specific ANAs A positive ANA IFA usually prompts further testing for specific ANAs. Relevant antibodies for the diagnosis of CTDs are discussed below.
AUTOANTIBODIES The presence of specific autoantibodies may support a diagnosis in the clinical context of a specific CTD. However, it is important to realize that false positives occur in healthy patients, degrees of sensitivity and specificity vary widely by test, and there is cross-reactivity among different diseases (Table 1).19 Therefore, these tests are most meaningful when there is a high pretest probability of CTD.
Antinuclear Antibodies (ANAs) ANAs bind to many antigens within the cell (proteins and nucleic acids) and are often elevated in the setting of
Anti-dsDNA and Anti-Sm Anti-dsDNA (double-stranded DNA) and anti-Sm (anti-Smith) are useful for confirming a diagnosis of SLE. A weighted analysis by Kavanaugh and colleagues reported a specificity of anti-dsDNA of 97.4% for the diagnosis of SLE, but a sensitivity of 57.3%.22 Anti-dsDNA has been reported in other CTDs but is positive in 1 AS at the same time is extremely rare), other CTDs may coexist (eg, RA, SSc, SjS).42,71 Anti-Jo-1 is the most common subtype of AS and represents 60% to 80% of all AS cases.72,73 ILD is the most frequent complication of AS, occurs in up to 90% of cases, and is the leading cause of morbidity and mortality in these patients.74 Moreover, ILD is the first manifestation in at least half of these patients and many may be misdiagnosed as an IIP either due to subclinical myositis or a negative ANA screening panel that prevents further serologic testing.75 Although anti-Jo-1 is the most common cause of AS, antiPL-7 and anti-PL-12 tend to have higher rates of ILD (up to 90%) and worse prognosis.73,75 Other AS antibodies occur
FIGURE 9. AS syndrome (anti-Jo-1) in a 53-year-old man who presented with 6 weeks of worsening dyspnea, arthralgia, and fever. Axial CT images demonstrate peripheral and peribronchovascular consolidation, reticulation, and traction bronchiectasis/bronchiolectasis (mixed NSIP and OP) almost exclusively affecting the lower lobes. The appearance of the CT, and the clinical presentation prompted extensive autoimmunity evaluation that was positive for anti-Jo-1 antibodies.
74 | www.thoracicimaging.com Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
J Thorac Imaging
Volume 31, Number 2, March 2016
The Spectrum of ILD in CTD
FIGURE 10. Imaging findings of a 42-year-old man with AS syndrome. Axial CT (A, B) was obtained at the time of hospitalization for dyspnea at an outside hospital and demonstrates peripheral GGO, reticulation, and traction bronchiectasis/bronchiolectasis in a lower lobe distribution with mild subpleural sparing. Lymphadenopathy is also visible (asterisk, A), and the patient was presumptively diagnosed with sarcoidosis. He initially responded to steroids but developed worsening dyspnea and was referred to our multidisciplinary ILD conference where the possibility of a CTD-ILD was raised. Extensive serologic testing was positive for anti-PL-7 and confirmed the diagnosis of AS syndrome.
much less frequently and are also associated with ILD but have only been described in small number of cases.71 AS-ILD may present with either acute respiratory failure or gradual and progressive respiratory symptoms.73,74 Tillie-Leblond et al74 reported that 47% of patients with anti-Jo-1 antibodies had an acute presentation of respiratory insufficiency and fever, attributable to infection, pulmonary hemorrhage, or an acute interstitial pneumonia–like illness with basal-predominant reticulation, consolidation, and GGOs. Recognition of this acute form of ILD required treatment with high-dose steroids or immunosuppressive agents to prevent respiratory failure and death and led the authors to conclude that
“anti-Jo-1 antibodies be sought and CK determined in cases of ILD with an acute presentation.”74 In patients with the more gradual or subacute onset of AS-ILD, the most frequent imaging findings are NSIP, OP, or mixed NSIP-OP42,73–75 (Figs. 9, 10). Moreover, the imaging abnormalities in these patients often have “extreme” basilar predominance that “hug” or “pancake” the diaphragm and may be a clue to the presence of AS versus other causes of NSIP or a mixed pattern44 (Fig. 11). Consolidation tends to decrease with immunosuppressive treatment, but fibrosis (mainly reticulation and traction bronchiectasis) may stabilize or progress, and a minority of patients may have honeycombing with a UIP pattern.74,75
FIGURE 11. Imaging findings of a 42-year-old man with anti-PL-7 AS syndrome. Axial (A) and sagittal (B) images demonstrate the extreme basilar distribution of an NSIP pattern of fibrosis that is often seen in AS syndrome.
Copyright
r
2015 Wolters Kluwer Health, Inc. All rights reserved.
www.thoracicimaging.com |
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
75
J Thorac Imaging
Henry et al
CONCLUSIONS HRCT plays an essential role in the multidisciplinary approach to diagnosis and management of CTD-ILD. Any IIP pattern (UIP, NSIP, cryptogenic organizing pneumonia, LIP, DAD, desquamative interstitial pneumonia) may be seen in CTDs, and certain clues (an unclassifiable or mixed pattern, young or middle-aged patient, especially female) should raise the suspicion of one of these diagnoses. Merely suggesting the possibility of CTD as the cause of abnormalities on a CT may drastically alter the management of a patient, especially as ILD may be the initial manifestation of CTD in a minority of patients. REFERENCES 1. Lynch DA, Travis WD, Muller NL, et al. Idiopathic interstitial pneumonias: CT features. Radiology. 2005;236:10–21. 2. Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/ JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183:788–824. 3. Travis WD, Hunninghake G, King TE Jr., et al. Idiopathic nonspecific interstitial pneumonia: report of an American Thoracic Society project. Am J Respir Crit Care Med. 2008; 177:1338–1347. 4. American Thoracic S, European Respiratory S. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med. 2002;165:277–304. 5. Jokerst C, Purdy H, Bhalla S. An overview of collagen vascular disease-associated interstitial lung disease. Semin Roentgenol. 2015;50:31–39. 6. Nair A, Walsh SL, Desai SR. Imaging of pulmonary involvement in rheumatic disease. Rheum Dis Clin North Am. 2015; 41:167–196. 7. Capobianco J, Grimberg A, Thompson BM, et al. Thoracic manifestations of collagen vascular diseases. Radiographics. 2012;32:33–50. 8. Gutsche M, Rosen GD, Swigris JJ. Connective tissue diseaseassociated interstitial lung disease: a review. Curr Respir Care Rep. 2012;1:224–232. 9. Antin-Ozerkis D, Rubinowitz A, Evans J, et al. Interstitial lung disease in the connective tissue diseases. Clin Chest Med. 2012;33:123–149. 10. Lynch DA. Lung disease related to collagen vascular disease. J Thorac Imaging. 2009;24:299–309. 11. Fischer A, West SG, Swigris JJ, et al. Connective tissue diseaseassociated interstitial lung disease: a call for clarification. Chest. 2010;138:251–256. 12. Kinder BW, Collard HR, Koth L, et al. Idiopathic nonspecific interstitial pneumonia: lung manifestation of undifferentiated connective tissue disease? Am J Respir Crit Care Med. 2007;176:691–697. 13. Mittoo S, Gelber AC, Christopher-Stine L, et al. Ascertainment of collagen vascular disease in patients presenting with interstitial lung disease. Respir Med. 2009;103:1152–1158. 14. 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;175:705–711. 15. Fischer A, Richeldi L. Cross-disciplinary collaboration in connective tissue disease-related lung disease. Semin Respir Crit Care Med. 2014;35:159–165. 16. Castro C, Gourley M. Diagnostic testing and interpretation of tests for autoimmunity. J Allergy Clin Immunol. 2010;125: S238–S247. 17. Colglazier CL, Sutej PG. Laboratory testing in the rheumatic diseases: a practical review. South Med J. 2005;98:185–191.
Volume 31, Number 2, March 2016
18. Tozzoli R, Bizzaro N, Tonutti E, et al. Guidelines for the laboratory use of autoantibody tests in the diagnosis and monitoring of autoimmune rheumatic diseases. Am J Clin Pathol. 2002;117:316–324. 19. Habash-Bseiso DE, Yale SH, Glurich I, et al. Serologic testing in connective tissue diseases. Clin Med Res. 2005;3:190–193. 20. Kavanaugh A, Tomar R, Reveille J, et al. Guidelines for clinical use of the antinuclear antibody test and tests for specific autoantibodies to nuclear antigens. American College of Pathologists. Arch Pathol Lab Med. 2000;124:71–81. 21. Waits JB. Rational use of laboratory testing in the initial evaluation of soft tissue and joint complaints. Prim Care. 2010;37:673–689. 22. Kavanaugh AF, Solomon DH. American College of Rheumatology Ad Hoc Committee on Immunologic Testing G. Guidelines for immunologic laboratory testing in the rheumatic diseases: anti-DNA antibody tests. Arthritis Rheum. 2002;47:546–555. 23. Benito-Garcia E, Schur PH, Lahita R. American College of Rheumatology Ad Hoc Committee on Immunologic Testing G. Guidelines for immunologic laboratory testing in the rheumatic diseases: anti-Sm and anti-RNP antibody tests. Arthritis Rheum. 2004;51:1030–1044. 24. Goeb V, Salle V, Duhaut P, et al. Clinical significance of autoantibodies recognizing Sjogren’s syndrome A (SSA), SSB, calpastatin and alpha-fodrin in primary Sjogren’s syndrome. Clin Exp Immunol. 2007;148:281–287. 25. Reveille JD, Solomon DH. American College of Rheumatology Ad Hoc Committee of Immunologic Testing G. Evidence-based guidelines for the use of immunologic tests: anticentromere, Scl70, and nucleolar antibodies. Arthritis Rheum. 2003;49:399–412. 26. Fischer A, Pfalzgraf FJ, Feghali-Bostwick CA, et al. Anti-th/ to-positivity in a cohort of patients with idiopathic pulmonary fibrosis. J Rheumatol. 2006;33:1600–1605. 27. Katzap E, Barilla-LaBarca ML, Marder G. Antisynthetase syndrome. Curr Rheumatol Rep. 2011;13:175–181. 28. Marguerie C, Bunn CC, Beynon HL, et al. Polymyositis, pulmonary fibrosis and autoantibodies to aminoacyl-tRNA synthetase enzymes. Q J Med. 1990;77:1019–1038. 29. Miller SA, Glassberg MK, Ascherman DP. Pulmonary complications of inflammatory myopathy. Rheum Dis Clin North Am. 2015;41:249–262. 30. Wells AU. Pulmonary function tests in connective tissue disease. Semin Respir Crit Care Med. 2007;28:379–388. 31. Marie I, Hachulla E, Cherin P, et al. Interstitial lung disease in polymyositis and dermatomyositis. Arthritis Rheum. 2002;47: 614–622. 32. Wells AU, Cullinan P, Hansell DM, et al. Fibrosing alveolitis associated with systemic sclerosis has a better prognosis than lone cryptogenic fibrosing alveolitis. Am J Respir Crit Care Med. 1994;149:1583–1590. 33. Hwang JH, Misumi S, Sahin H, et al. Computed tomographic features of idiopathic fibrosing interstitial pneumonia: comparison with pulmonary fibrosis related to collagen vascular disease. J Comput Assist Tomogr. 2009;33:410–415. 34. Swartz JS, Chatterjee S, Parambil JG. Desquamative interstitial pneumonia as the initial manifestation of systemic sclerosis. J Clin Rheumatol. 2010;16:284–286. 35. Esmaeilbeigi F, Juvet S, Hwang D, et al. Desquamative interstitial pneumonitis in a patient with systemic lupus erythematosus. Can Respir J. 2012;19:50–52. 36. Silva CI, Muller NL. Interstitial lung disease in the setting of collagen vascular disease. Semin Roentgenol. 2010;45:22–28. 37. Desai SR, Veeraraghavan S, Hansell DM, et al. CT features of lung disease in patients with systemic sclerosis: comparison with idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia. Radiology. 2004;232:560–567. 38. Kligerman SJ, Groshong S, Brown KK, et al. Nonspecific interstitial pneumonia: radiologic, clinical, and pathologic considerations. Radiographics. 2009;29:73–87. 39. Travis WD, Costabel U, Hansell DM, et al. An official American Thoracic Society/European Respiratory Society
76 | www.thoracicimaging.com Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
J Thorac Imaging
40.
41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51.
52. 53. 54.
55.
56.
57.
Volume 31, Number 2, March 2016
statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2013;188:733–748. Lee HY, Lee KS, Jeong YJ, et al. High-resolution CT findings in fibrotic idiopathic interstitial pneumonias with little honeycombing: serial changes and prognostic implications. Am J Roentgenol. 2012;199:982–989. Kim SJ, Lee KS, Ryu YH, et al. Reversed halo sign on highresolution CT of cryptogenic organizing pneumonia: diagnostic implications. Am J Roentgenol. 2003;180:1251–1254. Debray MP, Borie R, Revel MP, et al. Interstitial lung disease in anti-synthetase syndrome: initial and follow-up CT findings. Eur J Radiol. 2015;84:516–523. Douglas WW, Tazelaar HD, Hartman TE, et al. Polymyositisdermatomyositis-associated interstitial lung disease. Am J Respir Crit Care Med. 2001;164:1182–1185. Fischer A, Swigris JJ, Du Bois RM, et al. Anti-synthetase syndrome in ANA and anti-Jo-1 negative patients presenting with idiopathic interstitial pneumonia. Respir Med. 2009;103:1719–1724. Walsh SL, Hansell DM. Diffuse interstitial lung disease: overlaps and uncertainties. Eur Radiol. 2010;20:1859–1867. Lee HK, Kim DS, Yoo B, et al. Histopathologic pattern and clinical features of rheumatoid arthritis-associated interstitial lung disease. Chest. 2005;127:2019–2027. Alhamad EH. Clinical characteristics and survival in idiopathic pulmonary fibrosis and connective tissue disease-associated usual interstitial pneumonia. J Thorac Dis. 2015;7:386–393. Kim EJ, Elicker BM, Maldonado F, et al. Usual interstitial pneumonia in rheumatoid arthritis-associated interstitial lung disease. Eur Respir J. 2010;35:1322–1328. Song JW, Do KH, Kim MY, et al. Pathologic and radiologic differences between idiopathic and collagen vascular diseaserelated usual interstitial pneumonia. Chest. 2009;136:23–30. Flaherty KR, Colby TV, Travis WD, et al. Fibroblastic foci in usual interstitial pneumonia: idiopathic versus collagen vascular disease. Am J Respir Crit Care Med. 2003;167:1410–1415. Kono M, Nakamura Y, Enomoto N, et al. Usual interstitial pneumonia preceding collagen vascular disease: a retrospective case control study of patients initially diagnosed with idiopathic pulmonary fibrosis. PLoS One. 2014;9:e94775. Cha SI, Fessler MB, Cool CD, et al. Lymphoid interstitial pneumonia: clinical features, associations and prognosis. Eur Respir J. 2006;28:364–369. Egashira R, Kondo T, Hirai T, et al. CT findings of thoracic manifestations of primary Sjogren syndrome: radiologicpathologic correlation. Radiographics. 2013;33:1933–1949. Jeong YJ, Lee KS, Chung MP, et al. Amyloidosis and lymphoproliferative disease in Sjogren syndrome: thin-section computed tomography findings and histopathologic comparisons. J Comput Assist Tomogr. 2004;28:776–781. Desai SR, Nicholson AG, Stewart S, et al. Benign pulmonary lymphocytic infiltration and amyloidosis: computed tomographic and pathologic features in three cases. J Thorac Imaging. 1997;12:215–220. Koyama M, Johkoh T, Honda O, et al. Pulmonary involvement in primary Sjogren’s syndrome: spectrum of pulmonary abnormalities and computed tomography findings in 60 patients. J Thorac Imaging. 2001;16:290–296. Baqir M, Kluka EM, Aubry MC, et al. Amyloid-associated cystic lung disease in primary Sjogren’s syndrome. Respir Med. 2013;107:616–621.
Copyright
r
The Spectrum of ILD in CTD
58. Johkoh T, Muller NL, Pickford HA, et al. Lymphocytic interstitial pneumonia: thin-section CT findings in 22 patients. Radiology. 1999;212:567–572. 59. Silva CI, Muller NL, Fujimoto K, et al. Acute exacerbation of chronic interstitial pneumonia: high-resolution computed tomography and pathologic findings. J Thorac Imaging. 2007; 22:221–229. 60. Parambil JG, Myers JL, Ryu JH. Diffuse alveolar damage: uncommon manifestation of pulmonary involvement in patients with connective tissue diseases. Chest. 2006;130:553–558. 61. Homma Y, Ohtsuka Y, Tanimura K, et al. Can interstitial pneumonia as the sole presentation of collagen vascular diseases be differentiated from idiopathic interstitial pneumonia? Respiration. 1995;62:248–251. 62. Fujita J, Ohtsuki Y, Yoshinouchi T, et al. Idiopathic nonspecific interstitial pneumonia: as an “autoimmune interstitial pneumonia”. Respir Med. 2005;99:234–240. 63. Romagnoli M, Nannini C, Piciucchi S, et al. Idiopathic nonspecific interstitial pneumonia: an interstitial lung disease associated with autoimmune disorders? Eur Respir J. 2011;38: 384–391. 64. 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;26:551–555. 65. Vij R, Noth I, Strek ME. Autoimmune-featured interstitial lung disease: a distinct entity. Chest. 2011;140:1292–1299. 66. Cottin V. Interstitial lung disease: are we missing formes frustes of connective tissue disease? Eur Respir J. 2006;28: 893–896. 67. Castelino FV, Goldberg H, Dellaripa PF. The impact of rheumatological evaluation in the management of patients with interstitial lung disease. Rheumatology (Oxford). 2011;50: 489–493. 68. Pereira DA, Dias OM, de Almeida GE, et al. Lung-dominant connective tissue disease among patients with interstitial lung disease: prevalence, functional stability, and common extrathoracic features. J Bras Pneumol. 2015;41:151–160. 69. Ryerson CJ, Urbania TH, Richeldi L, et al. Prevalence and prognosis of unclassifiable interstitial lung disease. Eur Respir J. 2013;42:750–757. 70. 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;46:976–987. 71. Koreeda Y, Higashimoto I, Yamamoto M, et al. Clinical and pathological findings of interstitial lung disease patients with anti-aminoacyl-tRNA synthetase autoantibodies. Intern Med. 2010;49:361–369. 72. Hallowell RW, Ascherman DP, Danoff SK. Pulmonary manifestations of polymyositis/dermatomyositis. Semin Respir Crit Care Med. 2014;35:239–248. 73. Marie I, Josse S, Decaux O, et al. Comparison of long-term outcome between anti-Jo1- and anti-PL7/PL12 positive patients with antisynthetase syndrome. Autoimmun Rev. 2012;11:739–745. 74. Tillie-Leblond I, Wislez M, Valeyre D, et al. Interstitial lung disease and anti-Jo-1 antibodies: difference between acute and gradual onset. Thorax. 2008;63:53–59. 75. Kalluri M, Sahn SA, Oddis CV, et al. Clinical profile of antiPL-12 autoantibody. Cohort study and review of the literature. Chest. 2009;135:1550–1556.
2015 Wolters Kluwer Health, Inc. All rights reserved.
www.thoracicimaging.com |
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
77
The Spectrum of Interstitial Lung Disease in Connective Tissue Disease Travis S. Henry, MD,* Brent P. Little, MD,* Srihari Veeraraghavan, MD,w Sanjeev Bhalla, MD,z and Brett M. Elicker, MDy
Abstract: Interstitial lung disease (ILD) is a common cause of morbidity and mortality in patients with connective tissue disease (CTD). In a minority of patients the ILD may be the presenting (or only) manifestation of an underlying CTD. Diagnosis of CTDrelated ILD relies on a multidisciplinary team including pulmonologists, pathologists, radiologists, and rheumatologists, as the imaging and pathologic findings may be indistinguishable from idiopathic interstitial pneumonias. Moreover, many patients with ILD are suspected of having an underlying CTD but do not meet all of the necessary criteria for a specific disorder. This article provides a pattern-based approach to the imaging of CTD-related ILD and also reviews relevant clinical, pathologic, and serologic data that radiologists should be familiar with as part of a multidisciplinary team. Key Words: connective tissue disease, interstitial lung disease, antisynthetase syndrome, interstitial pneumonia with autoimmune features, nonspecific interstitial pneumonia, usual interstitial pneumonia
(J Thorac Imaging 2016;31:65–77)
C
onnective tissue diseases (CTD), also known as collagen vascular diseases or systemic rheumatic diseases, are a heterogenous assortment of autoimmune disorders that affect almost any organ system, including the lung. The most common CTDs that affect the lung include rheumatoid arthritis (RA), systemic sclerosis (SSc), Sjo¨gren syndrome (SjS), idiopathic inflammatory myopathies (IIM), systemic lupus erythematosus (SLE), and mixed CTD (MCTD). The primary lung manifestation is interstitial lung disease (ILD), a leading cause of mortality in many CTD patients. Diagnosis of CTD-related ILD (CTD-ILD) is complex, with a growing emphasis on multidisciplinary teams including pulmonologists, pathologists, radiologists, and rheumatologists to reach a consensus diagnosis. Despite the best efforts, in a minority of patients a consensus diagnosis cannot be reached, underscoring the difficulty in diagnosing these disorders and leaving questions
From the *Department of Radiology and Imaging Sciences, Cardiothoracic Division; wDepartment of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Emory University School of Medicine, Atlanta, GA; zMallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO; and yDepartment of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA. Travis S. Henry’s spouse is an employee of Genentech. The remaining authors declare no conflicts of interest. Correspondence to: Travis S. Henry, MD, 1755 Alabama St., San Francisco, CA 94110 (e-mail: [email protected]). Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/RTI.0000000000000191
J Thorac Imaging
Volume 31, Number 2, March 2016
as to whether some patients have unclassifiable CTDs or idiopathic interstitial pneumonia (IIP). Since the IIPs were classified in 2002 (and updated in 2013), several publications have described the high-resolution computed tomographic (HRCT) appearance of the IIPs in great detail.1–4 Moreover, many recent review articles have nicely illustrated the imaging manifestations of common CTDs, including ILD and other thoracic manifestations.5–10 However, as any experienced thoracic imager knows, many cases do not fit into a single classification, with >1 pattern present on the same imaging study [eg, mixed nonspecific interstitial pneumonia (NSIP) and organizing pneumonia (OP)], and it is these patients that often turn out to have a previously undiagnosed CTD. Although this paper will provide a detailed appraisal of typical imaging findings in CTDs, it also serves as a review of the broader clinical context of CTDs. This article will first provide a primer for radiologists on the diagnosis of CTDs, including relevant laboratory and physical examination findings, and then address 2 specific questions that will hopefully advance the reader’s understanding of CTD-ILD, enhancing the radiologist’s value to a multidisciplinary team. (1) A patient with CTD has an abnormal HRCT. Is the lung involvement a manifestation of the CTD? (2) A patient has findings of ILD on HRCT. Do they have an IIP or could it be the initial presentation of a CTD? Important points that will be emphasized in this text include the following: Clinicians currently face a diagnostic dilemma, as the existence of ILD is not included in the criteria for the diagnosis of a CTD (except for SSc where it is part of the 2013 criteria).11 If these patients present with ILD before other clinical manifestations of a CTD, they may be incorrectly diagnosed as having an IIP.12 Despite the growing battery of tests available, many cases of presumed IIP may be secondary to undiagnosed CTD [interstitial pneumonia with autoimmune features (IPAF)]. These patients tend to be younger, more often female, and have better baseline lung function. On HRCT, patients may have a mixed pattern (eg, NSIP + OP) or an unclassifiable pattern. These patients often have an underlying CTD. Idiopathic NSIP (iNSIP) is probably less common than originally thought. An NSIP pattern should prompt evaluation for an underlying CTD.13 Usual interstitial pneumonia (UIP), OP, lymphocytic interstitial pneumonia (LIP), and diffuse alveolar damage (DAD) patterns can also be seen in the setting of underlying CTDs. Distinction of UIP from NSIP is crucial, especially in the setting of a confident diagnosis where biopsy may be obviated and a diagnosis of idiopathic pulmonary fibrosis (IPF) assigned to the patient (ie, definite UIP). www.thoracicimaging.com |
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
65
J Thorac Imaging
Henry et al
In practice, many cases of NSIP are misdiagnosed as UIP, which alters therapy and prognosis. IIPs and CTD-ILD can have identical imaging appearances; however, they should not be considered identical diseases. Different therapeutic options are available in each group, and prognosis varies. For example, CTDUIP has improved survival compared with IPF-UIP.14
DIAGNOSIS OF CTDs Although pulmonologists and rheumatologists diagnose CTDs on the basis of clinical and laboratory guidelines, ILD, a significant cause of morbidity and mortality in these patients, is not a part of the diagnostic criteria except for SSc.11 This is especially troublesome in patients for whom ILD is the presenting (or only) symptom of a CTD.11 Diagnosing a CTD (and CTD-ILD) versus an IIP affects management and prognosis, as CTD-ILD patients are managed differently and have improved survival compared with patients with IPF.13,14 Findings suggestive of CTD include younger age (compared with IPF) and female sex, a history of Raynaud phenomenon or inflammatory arthritis, or subtle physical examination findings such as “mechanic’s hands” or abnormal findings at nailfold capillaroscopy.15 When clinicians are suspicious of CTD, serologic evaluation is generally the next step, and clinicians have an everexpanding battery of tests that can be ordered. Because of the overlap in imaging with IIPs and CTD-ILD, many clinicians will order these laboratory tests when a patient initially presents with an HRCT suggestive of ILD. A full review of autoantibodies associated with CTDs is beyond the scope of this manuscript, but basic tests with which all thoracic imagers should be familiar are presented here.
Acute Phase Proteins Acute phase proteins are defined as those whose plasma concentrations change by >25% during inflammatory states.16 Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are 2 of the most common tests that measure acute phase proteins and are useful in the setting of suspected CTD when considered in the appropriate context. These tests are not specific for CTD, as almost any cause of inflammation (eg, infection, vasculitis), malignancy, and other systemic illnesses can cause elevation, but serum levels do tend to correlate with disease activity (although ESR tends to lag response to treatment more than CRP).16 ESR also increases with age, obesity, and female sex.17 Unfortunately, these tests are imperfect, as up to 10% of patients with active RA, as well as patients with other active CTDs, may have normal ESR and CRP values.17,18
Volume 31, Number 2, March 2016
CTDs. The ANA test detects the presence of various autoantibodies and is often a first-line test when CTD is suspected. There are different ANA testing methods that vary in sensitivity and specificity, and the 2 most common tests are the enzyme-linked immunosorbent assay (ELISA) and indirect fluorescent antibody (IFA). At most institutions the ELISA is the first screening test, and an IFA is performed only if the ELISA is positive. The ANA ELISA is an automated, qualitative examination that detects the presence or absence of one of many antigens that are pooled into a sample. This makes the ELISA a good initial screening test, as it is more sensitive and cheaper than the IFA test.20 The sensitivity is at least 95% for SLE, and other CTDs including RA, IIM, SSc, and SjS may produce a positive ANA result in at least 50% of patients.15 The IFA is more specific, but less sensitive, and is generally performed to confirm a positive ELISA. The IFA is usually reported in terms of titer and pattern. The titer is the most dilute sample at which the ANA is detectable, and a value of 1:40 or greater is generally considered low-level positive but has overlap with healthy patients; values of 1:160 or greater are more suggestive of an underlying CTD.16,21 The different patterns of reactivity include speckled, homogenous/diffuse, rim/peripheral, nucleolar, or centromeric20 and may help improve specificity in some instances. For example, a nucleolar pattern is more suggestive of SSc than other patterns.15
Rheumatoid Factor (RF) and Anti–Cyclic Citrullinated Peptide (CCP) Antibody RF has limited sensitivity and specificity for RA of about 70% each. RF-positive patients tend to have more aggressive disease, with higher rates of vasculitis, rheumatoid nodules, Felty syndrome, and secondary SjS.16,21 RF, like ANA, may be positive in other autoimmune diseases (eg, SjS, SLE, SSc) and, also important for the imager, may be positive in other causes of lung disease, including sarcoidosis, silicosis, tuberculosis, and chronic obstructive pulmonary disease.16,21 Autoantibody to CCP is a more recent biomarker with increased specificity for RA (B95%) and similar sensitivity to RF. Anti-CCP can serve as a useful marker for progression of disease.21 Anti-CCP may also be elevated in SLE, SjS, IIMs, and tuberculosis.16 Performing RF and anti-CCP tests together is a strategy to maximize sensitivity for detection of RA.21
Specific ANAs A positive ANA IFA usually prompts further testing for specific ANAs. Relevant antibodies for the diagnosis of CTDs are discussed below.
AUTOANTIBODIES The presence of specific autoantibodies may support a diagnosis in the clinical context of a specific CTD. However, it is important to realize that false positives occur in healthy patients, degrees of sensitivity and specificity vary widely by test, and there is cross-reactivity among different diseases (Table 1).19 Therefore, these tests are most meaningful when there is a high pretest probability of CTD.
Antinuclear Antibodies (ANAs) ANAs bind to many antigens within the cell (proteins and nucleic acids) and are often elevated in the setting of
Anti-dsDNA and Anti-Sm Anti-dsDNA (double-stranded DNA) and anti-Sm (anti-Smith) are useful for confirming a diagnosis of SLE. A weighted analysis by Kavanaugh and colleagues reported a specificity of anti-dsDNA of 97.4% for the diagnosis of SLE, but a sensitivity of 57.3%.22 Anti-dsDNA has been reported in other CTDs but is positive in 1 AS at the same time is extremely rare), other CTDs may coexist (eg, RA, SSc, SjS).42,71 Anti-Jo-1 is the most common subtype of AS and represents 60% to 80% of all AS cases.72,73 ILD is the most frequent complication of AS, occurs in up to 90% of cases, and is the leading cause of morbidity and mortality in these patients.74 Moreover, ILD is the first manifestation in at least half of these patients and many may be misdiagnosed as an IIP either due to subclinical myositis or a negative ANA screening panel that prevents further serologic testing.75 Although anti-Jo-1 is the most common cause of AS, antiPL-7 and anti-PL-12 tend to have higher rates of ILD (up to 90%) and worse prognosis.73,75 Other AS antibodies occur
FIGURE 9. AS syndrome (anti-Jo-1) in a 53-year-old man who presented with 6 weeks of worsening dyspnea, arthralgia, and fever. Axial CT images demonstrate peripheral and peribronchovascular consolidation, reticulation, and traction bronchiectasis/bronchiolectasis (mixed NSIP and OP) almost exclusively affecting the lower lobes. The appearance of the CT, and the clinical presentation prompted extensive autoimmunity evaluation that was positive for anti-Jo-1 antibodies.
74 | www.thoracicimaging.com Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
J Thorac Imaging
Volume 31, Number 2, March 2016
The Spectrum of ILD in CTD
FIGURE 10. Imaging findings of a 42-year-old man with AS syndrome. Axial CT (A, B) was obtained at the time of hospitalization for dyspnea at an outside hospital and demonstrates peripheral GGO, reticulation, and traction bronchiectasis/bronchiolectasis in a lower lobe distribution with mild subpleural sparing. Lymphadenopathy is also visible (asterisk, A), and the patient was presumptively diagnosed with sarcoidosis. He initially responded to steroids but developed worsening dyspnea and was referred to our multidisciplinary ILD conference where the possibility of a CTD-ILD was raised. Extensive serologic testing was positive for anti-PL-7 and confirmed the diagnosis of AS syndrome.
much less frequently and are also associated with ILD but have only been described in small number of cases.71 AS-ILD may present with either acute respiratory failure or gradual and progressive respiratory symptoms.73,74 Tillie-Leblond et al74 reported that 47% of patients with anti-Jo-1 antibodies had an acute presentation of respiratory insufficiency and fever, attributable to infection, pulmonary hemorrhage, or an acute interstitial pneumonia–like illness with basal-predominant reticulation, consolidation, and GGOs. Recognition of this acute form of ILD required treatment with high-dose steroids or immunosuppressive agents to prevent respiratory failure and death and led the authors to conclude that
“anti-Jo-1 antibodies be sought and CK determined in cases of ILD with an acute presentation.”74 In patients with the more gradual or subacute onset of AS-ILD, the most frequent imaging findings are NSIP, OP, or mixed NSIP-OP42,73–75 (Figs. 9, 10). Moreover, the imaging abnormalities in these patients often have “extreme” basilar predominance that “hug” or “pancake” the diaphragm and may be a clue to the presence of AS versus other causes of NSIP or a mixed pattern44 (Fig. 11). Consolidation tends to decrease with immunosuppressive treatment, but fibrosis (mainly reticulation and traction bronchiectasis) may stabilize or progress, and a minority of patients may have honeycombing with a UIP pattern.74,75
FIGURE 11. Imaging findings of a 42-year-old man with anti-PL-7 AS syndrome. Axial (A) and sagittal (B) images demonstrate the extreme basilar distribution of an NSIP pattern of fibrosis that is often seen in AS syndrome.
Copyright
r
2015 Wolters Kluwer Health, Inc. All rights reserved.
www.thoracicimaging.com |
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
75
J Thorac Imaging
Henry et al
CONCLUSIONS HRCT plays an essential role in the multidisciplinary approach to diagnosis and management of CTD-ILD. Any IIP pattern (UIP, NSIP, cryptogenic organizing pneumonia, LIP, DAD, desquamative interstitial pneumonia) may be seen in CTDs, and certain clues (an unclassifiable or mixed pattern, young or middle-aged patient, especially female) should raise the suspicion of one of these diagnoses. Merely suggesting the possibility of CTD as the cause of abnormalities on a CT may drastically alter the management of a patient, especially as ILD may be the initial manifestation of CTD in a minority of patients. REFERENCES 1. Lynch DA, Travis WD, Muller NL, et al. Idiopathic interstitial pneumonias: CT features. Radiology. 2005;236:10–21. 2. Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/ JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183:788–824. 3. Travis WD, Hunninghake G, King TE Jr., et al. Idiopathic nonspecific interstitial pneumonia: report of an American Thoracic Society project. Am J Respir Crit Care Med. 2008; 177:1338–1347. 4. American Thoracic S, European Respiratory S. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med. 2002;165:277–304. 5. Jokerst C, Purdy H, Bhalla S. An overview of collagen vascular disease-associated interstitial lung disease. Semin Roentgenol. 2015;50:31–39. 6. Nair A, Walsh SL, Desai SR. Imaging of pulmonary involvement in rheumatic disease. Rheum Dis Clin North Am. 2015; 41:167–196. 7. Capobianco J, Grimberg A, Thompson BM, et al. Thoracic manifestations of collagen vascular diseases. Radiographics. 2012;32:33–50. 8. Gutsche M, Rosen GD, Swigris JJ. Connective tissue diseaseassociated interstitial lung disease: a review. Curr Respir Care Rep. 2012;1:224–232. 9. Antin-Ozerkis D, Rubinowitz A, Evans J, et al. Interstitial lung disease in the connective tissue diseases. Clin Chest Med. 2012;33:123–149. 10. Lynch DA. Lung disease related to collagen vascular disease. J Thorac Imaging. 2009;24:299–309. 11. Fischer A, West SG, Swigris JJ, et al. Connective tissue diseaseassociated interstitial lung disease: a call for clarification. Chest. 2010;138:251–256. 12. Kinder BW, Collard HR, Koth L, et al. Idiopathic nonspecific interstitial pneumonia: lung manifestation of undifferentiated connective tissue disease? Am J Respir Crit Care Med. 2007;176:691–697. 13. Mittoo S, Gelber AC, Christopher-Stine L, et al. Ascertainment of collagen vascular disease in patients presenting with interstitial lung disease. Respir Med. 2009;103:1152–1158. 14. 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;175:705–711. 15. Fischer A, Richeldi L. Cross-disciplinary collaboration in connective tissue disease-related lung disease. Semin Respir Crit Care Med. 2014;35:159–165. 16. Castro C, Gourley M. Diagnostic testing and interpretation of tests for autoimmunity. J Allergy Clin Immunol. 2010;125: S238–S247. 17. Colglazier CL, Sutej PG. Laboratory testing in the rheumatic diseases: a practical review. South Med J. 2005;98:185–191.
Volume 31, Number 2, March 2016
18. Tozzoli R, Bizzaro N, Tonutti E, et al. Guidelines for the laboratory use of autoantibody tests in the diagnosis and monitoring of autoimmune rheumatic diseases. Am J Clin Pathol. 2002;117:316–324. 19. Habash-Bseiso DE, Yale SH, Glurich I, et al. Serologic testing in connective tissue diseases. Clin Med Res. 2005;3:190–193. 20. Kavanaugh A, Tomar R, Reveille J, et al. Guidelines for clinical use of the antinuclear antibody test and tests for specific autoantibodies to nuclear antigens. American College of Pathologists. Arch Pathol Lab Med. 2000;124:71–81. 21. Waits JB. Rational use of laboratory testing in the initial evaluation of soft tissue and joint complaints. Prim Care. 2010;37:673–689. 22. Kavanaugh AF, Solomon DH. American College of Rheumatology Ad Hoc Committee on Immunologic Testing G. Guidelines for immunologic laboratory testing in the rheumatic diseases: anti-DNA antibody tests. Arthritis Rheum. 2002;47:546–555. 23. Benito-Garcia E, Schur PH, Lahita R. American College of Rheumatology Ad Hoc Committee on Immunologic Testing G. Guidelines for immunologic laboratory testing in the rheumatic diseases: anti-Sm and anti-RNP antibody tests. Arthritis Rheum. 2004;51:1030–1044. 24. Goeb V, Salle V, Duhaut P, et al. Clinical significance of autoantibodies recognizing Sjogren’s syndrome A (SSA), SSB, calpastatin and alpha-fodrin in primary Sjogren’s syndrome. Clin Exp Immunol. 2007;148:281–287. 25. Reveille JD, Solomon DH. American College of Rheumatology Ad Hoc Committee of Immunologic Testing G. Evidence-based guidelines for the use of immunologic tests: anticentromere, Scl70, and nucleolar antibodies. Arthritis Rheum. 2003;49:399–412. 26. Fischer A, Pfalzgraf FJ, Feghali-Bostwick CA, et al. Anti-th/ to-positivity in a cohort of patients with idiopathic pulmonary fibrosis. J Rheumatol. 2006;33:1600–1605. 27. Katzap E, Barilla-LaBarca ML, Marder G. Antisynthetase syndrome. Curr Rheumatol Rep. 2011;13:175–181. 28. Marguerie C, Bunn CC, Beynon HL, et al. Polymyositis, pulmonary fibrosis and autoantibodies to aminoacyl-tRNA synthetase enzymes. Q J Med. 1990;77:1019–1038. 29. Miller SA, Glassberg MK, Ascherman DP. Pulmonary complications of inflammatory myopathy. Rheum Dis Clin North Am. 2015;41:249–262. 30. Wells AU. Pulmonary function tests in connective tissue disease. Semin Respir Crit Care Med. 2007;28:379–388. 31. Marie I, Hachulla E, Cherin P, et al. Interstitial lung disease in polymyositis and dermatomyositis. Arthritis Rheum. 2002;47: 614–622. 32. Wells AU, Cullinan P, Hansell DM, et al. Fibrosing alveolitis associated with systemic sclerosis has a better prognosis than lone cryptogenic fibrosing alveolitis. Am J Respir Crit Care Med. 1994;149:1583–1590. 33. Hwang JH, Misumi S, Sahin H, et al. Computed tomographic features of idiopathic fibrosing interstitial pneumonia: comparison with pulmonary fibrosis related to collagen vascular disease. J Comput Assist Tomogr. 2009;33:410–415. 34. Swartz JS, Chatterjee S, Parambil JG. Desquamative interstitial pneumonia as the initial manifestation of systemic sclerosis. J Clin Rheumatol. 2010;16:284–286. 35. Esmaeilbeigi F, Juvet S, Hwang D, et al. Desquamative interstitial pneumonitis in a patient with systemic lupus erythematosus. Can Respir J. 2012;19:50–52. 36. Silva CI, Muller NL. Interstitial lung disease in the setting of collagen vascular disease. Semin Roentgenol. 2010;45:22–28. 37. Desai SR, Veeraraghavan S, Hansell DM, et al. CT features of lung disease in patients with systemic sclerosis: comparison with idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia. Radiology. 2004;232:560–567. 38. Kligerman SJ, Groshong S, Brown KK, et al. Nonspecific interstitial pneumonia: radiologic, clinical, and pathologic considerations. Radiographics. 2009;29:73–87. 39. Travis WD, Costabel U, Hansell DM, et al. An official American Thoracic Society/European Respiratory Society
76 | www.thoracicimaging.com Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
J Thorac Imaging
40.
41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51.
52. 53. 54.
55.
56.
57.
Volume 31, Number 2, March 2016
statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2013;188:733–748. Lee HY, Lee KS, Jeong YJ, et al. High-resolution CT findings in fibrotic idiopathic interstitial pneumonias with little honeycombing: serial changes and prognostic implications. Am J Roentgenol. 2012;199:982–989. Kim SJ, Lee KS, Ryu YH, et al. Reversed halo sign on highresolution CT of cryptogenic organizing pneumonia: diagnostic implications. Am J Roentgenol. 2003;180:1251–1254. Debray MP, Borie R, Revel MP, et al. Interstitial lung disease in anti-synthetase syndrome: initial and follow-up CT findings. Eur J Radiol. 2015;84:516–523. Douglas WW, Tazelaar HD, Hartman TE, et al. Polymyositisdermatomyositis-associated interstitial lung disease. Am J Respir Crit Care Med. 2001;164:1182–1185. Fischer A, Swigris JJ, Du Bois RM, et al. Anti-synthetase syndrome in ANA and anti-Jo-1 negative patients presenting with idiopathic interstitial pneumonia. Respir Med. 2009;103:1719–1724. Walsh SL, Hansell DM. Diffuse interstitial lung disease: overlaps and uncertainties. Eur Radiol. 2010;20:1859–1867. Lee HK, Kim DS, Yoo B, et al. Histopathologic pattern and clinical features of rheumatoid arthritis-associated interstitial lung disease. Chest. 2005;127:2019–2027. Alhamad EH. Clinical characteristics and survival in idiopathic pulmonary fibrosis and connective tissue disease-associated usual interstitial pneumonia. J Thorac Dis. 2015;7:386–393. Kim EJ, Elicker BM, Maldonado F, et al. Usual interstitial pneumonia in rheumatoid arthritis-associated interstitial lung disease. Eur Respir J. 2010;35:1322–1328. Song JW, Do KH, Kim MY, et al. Pathologic and radiologic differences between idiopathic and collagen vascular diseaserelated usual interstitial pneumonia. Chest. 2009;136:23–30. Flaherty KR, Colby TV, Travis WD, et al. Fibroblastic foci in usual interstitial pneumonia: idiopathic versus collagen vascular disease. Am J Respir Crit Care Med. 2003;167:1410–1415. Kono M, Nakamura Y, Enomoto N, et al. Usual interstitial pneumonia preceding collagen vascular disease: a retrospective case control study of patients initially diagnosed with idiopathic pulmonary fibrosis. PLoS One. 2014;9:e94775. Cha SI, Fessler MB, Cool CD, et al. Lymphoid interstitial pneumonia: clinical features, associations and prognosis. Eur Respir J. 2006;28:364–369. Egashira R, Kondo T, Hirai T, et al. CT findings of thoracic manifestations of primary Sjogren syndrome: radiologicpathologic correlation. Radiographics. 2013;33:1933–1949. Jeong YJ, Lee KS, Chung MP, et al. Amyloidosis and lymphoproliferative disease in Sjogren syndrome: thin-section computed tomography findings and histopathologic comparisons. J Comput Assist Tomogr. 2004;28:776–781. Desai SR, Nicholson AG, Stewart S, et al. Benign pulmonary lymphocytic infiltration and amyloidosis: computed tomographic and pathologic features in three cases. J Thorac Imaging. 1997;12:215–220. Koyama M, Johkoh T, Honda O, et al. Pulmonary involvement in primary Sjogren’s syndrome: spectrum of pulmonary abnormalities and computed tomography findings in 60 patients. J Thorac Imaging. 2001;16:290–296. Baqir M, Kluka EM, Aubry MC, et al. Amyloid-associated cystic lung disease in primary Sjogren’s syndrome. Respir Med. 2013;107:616–621.
Copyright
r
The Spectrum of ILD in CTD
58. Johkoh T, Muller NL, Pickford HA, et al. Lymphocytic interstitial pneumonia: thin-section CT findings in 22 patients. Radiology. 1999;212:567–572. 59. Silva CI, Muller NL, Fujimoto K, et al. Acute exacerbation of chronic interstitial pneumonia: high-resolution computed tomography and pathologic findings. J Thorac Imaging. 2007; 22:221–229. 60. Parambil JG, Myers JL, Ryu JH. Diffuse alveolar damage: uncommon manifestation of pulmonary involvement in patients with connective tissue diseases. Chest. 2006;130:553–558. 61. Homma Y, Ohtsuka Y, Tanimura K, et al. Can interstitial pneumonia as the sole presentation of collagen vascular diseases be differentiated from idiopathic interstitial pneumonia? Respiration. 1995;62:248–251. 62. Fujita J, Ohtsuki Y, Yoshinouchi T, et al. Idiopathic nonspecific interstitial pneumonia: as an “autoimmune interstitial pneumonia”. Respir Med. 2005;99:234–240. 63. Romagnoli M, Nannini C, Piciucchi S, et al. Idiopathic nonspecific interstitial pneumonia: an interstitial lung disease associated with autoimmune disorders? Eur Respir J. 2011;38: 384–391. 64. 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;26:551–555. 65. Vij R, Noth I, Strek ME. Autoimmune-featured interstitial lung disease: a distinct entity. Chest. 2011;140:1292–1299. 66. Cottin V. Interstitial lung disease: are we missing formes frustes of connective tissue disease? Eur Respir J. 2006;28: 893–896. 67. Castelino FV, Goldberg H, Dellaripa PF. The impact of rheumatological evaluation in the management of patients with interstitial lung disease. Rheumatology (Oxford). 2011;50: 489–493. 68. Pereira DA, Dias OM, de Almeida GE, et al. Lung-dominant connective tissue disease among patients with interstitial lung disease: prevalence, functional stability, and common extrathoracic features. J Bras Pneumol. 2015;41:151–160. 69. Ryerson CJ, Urbania TH, Richeldi L, et al. Prevalence and prognosis of unclassifiable interstitial lung disease. Eur Respir J. 2013;42:750–757. 70. 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;46:976–987. 71. Koreeda Y, Higashimoto I, Yamamoto M, et al. Clinical and pathological findings of interstitial lung disease patients with anti-aminoacyl-tRNA synthetase autoantibodies. Intern Med. 2010;49:361–369. 72. Hallowell RW, Ascherman DP, Danoff SK. Pulmonary manifestations of polymyositis/dermatomyositis. Semin Respir Crit Care Med. 2014;35:239–248. 73. Marie I, Josse S, Decaux O, et al. Comparison of long-term outcome between anti-Jo1- and anti-PL7/PL12 positive patients with antisynthetase syndrome. Autoimmun Rev. 2012;11:739–745. 74. Tillie-Leblond I, Wislez M, Valeyre D, et al. Interstitial lung disease and anti-Jo-1 antibodies: difference between acute and gradual onset. Thorax. 2008;63:53–59. 75. Kalluri M, Sahn SA, Oddis CV, et al. Clinical profile of antiPL-12 autoantibody. Cohort study and review of the literature. Chest. 2009;135:1550–1556.
2015 Wolters Kluwer Health, Inc. All rights reserved.
www.thoracicimaging.com |
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
77
