Diagnostic Considerations

As previously mentioned, a multidisciplinary approach to the diagnosis and treatment of connective tissue disease-associated interstitial lung disease (CTD-ILD) is of paramount importance. A thorough history and physical examination should be supplemented by chest radiography, serum biomarkers and, occasionally, histopathology.

It is essential to make an effort to exclude the diagnosis of underlying CTD or interstitial pneumonia with autoimmune features (IPAF) in a patient presenting with ILD, as previous data have shown improved outcomes regardless of the histopathologic diagnosis.^{[9, 45]}

Differential Diagnoses

Chronic Obstructive Pulmonary Disease (COPD)
Coal Workers' Pneumoconiosis (Black Lung Disease)
Cryptogenic Organizing Pneumonia
Diaphragmatic Paralysis
Drug-Induced Pulmonary Toxicity
Eosinophilic Pneumonia
Hypersensitivity Pneumonitis
Idiopathic Nonspecific Interstitial Lung Disease
Idiopathic Pulmonary Fibrosis (IPF)
Lymphocytic Interstitial Pneumonia
Idiopathic Pulmonary Arterial Hypertension
Restrictive Lung Disease
Sarcoidosis
Silicosis

Workup

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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.

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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.

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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