Collagen-Vascular Disease Associated With Interstitial Lung Disease Workup

Author: Arshad Ali, MD; Chief Editor: Zab Mosenifar, MD more...

Updated: Apr 12, 2012

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Laboratory Studies
Plain Radiography and Computed Tomography
Pulmonary Function Tests
Other Tests
Bronchoalveolar Lavage
Biopsy
Histologic Findings
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Laboratory Studies

Laboratory studies are helpful in the setting of collagen-vascular disease (CVD) associated with interstitial lung disease (ILD). Various antibodies detected in the serum of patients with CVD help in determining the diagnosis and the prognosis (see Table 2 below).

Table 2. Autoantibodies in Collagen-Vascular Diseases (Open Table in a new window)

Autoantibody	RA	SLE	SD	SS	PM/DM	AS	MCTD
RF	+	+	+	+	Rare	-	+
ANA	+	+	+	+	Rare	-	+ (speckled)
ds-DNA	-	+	-	-	-	-	-
Anticentromere	-	-	+ (limited)	Rare	Rare	-	-
Scl-70	-	-	+ (diffuse)		Rare	-	-
Anti-Jo	-	-	-	Rare	+ (ILD)	-	-
ANCA	Rare	Rare	-	-	-	-	-
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.

Anemia of chronic disease can be found in persons with rheumatoid arthritis (RA), whereas systemic lupus erythematosus (SLE) can cause leukopenia, lymphopenia, thrombosis, and thrombocytopenia. The erythrocyte sedimentation rate (ESR) and creatine kinase levels may be high in patients with polymyositis (PM)/dermatomyositis (DM). Total complement levels and a high ESR may be present in SLE patients who present with an acute lupus flare.

Plain Radiography and Computed Tomography

Radiologically, CVDs may manifest as a focal or a diffuse pulmonary abnormality. The type and frequency of the lung abnormalities vary with the specific disease (see Table 2 below).

Table 3. Radiographic Patterns of Collagen-Vascular Diseases (Open Table in a new window)

Radiologic Pattern	RA	SLE	SD	Secondary SS	PM/DM	AS	MCTD
Pleural effusion	+	+	+	±	-	-	+
Interstitial pneumonitis, fibrosis	UIP and NSIP patterns	+	LIP pattern	±	+	Upper apical fibrosis^[37]	+
BOOP	±	+	+	+	+	±	±
Pulmonary nodules	Rheumatoid pulmonary nodules; uncommon, may be 1-5 mm, single or multiple, may cavitate	-	-	Follicular lymphoid hyperplasia or lymphoma can present as lung nodules	+	-	-
Bronchiectasis	+	+	+	+	+	+	+
Caplan syndrome	Coal 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, 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; 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.

RA, SLE, scleroderma (SD), Sjögren syndrome (SS), and PM/DM all can cause an interstitial fibrosis similar to interstitial pulmonary fibrosis (IPF). All CVDs like IPF involve lung bases and are subpleural, except for ankylosing spondylitis (AS), which involves the upper lobes, and RA-induced ILD. RA-ILD is differentiated from IPF on the basis of greater upper-lobe involvement, an anterior location, and the presence of reticular infiltrates finer than those associated with IPF (see the image below).

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.

Initially, chest radiographs may be normal^[38]; however, in later stages of the disease, they may show fine reticulation. Depending on the type of CVD present, radiography may reveal pleural effusion, nodules, bronchiectasis, bronchiolitis obliterans organizing pneumonia (BOOP), loss of lung volume, or prominent pulmonary vessels.

Numerous studies show correlation high-resolution computed tomography (HRCT) findings and pulmonary function test (PFT) results correlate with underlying lung histopathology in patients with CVD.^[39]Ground-glass opacities (GGOs) and consolidation may reflect the presence of interstitial pneumonia on computed tomography (CT) of the chest (see the image below). Pulmonary fibrosis is uncommon in SLE patients; if it occurs, it usually is patchy.

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.

RA is associated with the following 4 CT patterns:

Usual interstitial pneumonia (UIP)
Nonspecific interstitial pneumonia (NSIP)
Bronchiolitis^[40]
Organizing pneumonia^[41]

The most common CT features of RA-related lung disease are GGOs and reticulation.^{[6, 42]}RA can manifest as rheumatoid nodules, Caplan syndrome (rheumatoid nodules up to 5 cm, mostly involving the upper lungs in coal miners and resembling coal worker’s pneumoconiosis).^[43]In a smoker who has RA and presents with lung nodules, lung cancer should be ruled out first.^[44]

In patients with SD, HRCT scanning frequently shows evidence of interstitial pneumonitis and fibrosis, mainly involving the lower lobes, in a predominantly peripheral and posterior distribution.

PM/DM-induced lung disease is rare (5%). The most common pattern of ILD is symmetric and predominantly basal reticulation. HRCT scanning is remarkable for revealing prominent interlobular septa, patchy consolidation, and honeycombing. Patients with an acute presentation have GGOs and consolidation, in contrast to the reticulation and honeycombing seen in patients with the chronic type of ILD.

SS is manifested by a reticulonodular pattern of infiltrates involving lower lung zones. This finding may reflect the presence of lymphocytic interstitial fibrosis (see the image below). HRCT scans may reveal GGOs and bronchiolitis obliterans.^[45]

Patient with lymphocytic interstitial pneumonia.

Radiologic features of MCTD vary across different studies. Radiologic abnormalities include subpleural honeycombing, BOOP, and pleural effusion.

Pulmonary Function Tests

PFTs include spirometry, lung volumes, diffusion capacity of the lung for carbon monoxide (DLCO), and arterial blood gas (ABG) measurements.

Most CVDs cause a restrictive lung disease pattern with a decrease in total lung capacity (TLC), residual volume (RV), functional residual capacity, and DLCO.^[46]Forced expiratory volume in 1 second (FEV₁) and forced vital capacity (FVC) (ie, the FEV₁/FVC ratio) may be normal or increased. However, bronchiolitis obliterans may cause an obstructive ventilatory defect (reduced FEV₁/FVC ratio and FEV₁, increased RV and RV/TLC ratio).

ABG analysis may reveal hypoxemia at rest. Arterial oxygen desaturation may occur with exercise. A 6-minute walk test with pulse oximetry provides a measure of oxygen desaturation and helps to detect disease progression.

Schirmer and Rose Bengal stain

The Schirmer test may be used to screen for dry eyes secondary to decreased tear production in patients with SS. Similarly, Rose Bengal staining of the cornea can detect keratitis associated with SS.

Echocardiography

Echocardiography can help detect cardiac involvement, which is useful in patients presenting with heart failure and in patients with suspected pulmonary hypertension.

Gallium scanning

Gallium scanning results may be abnormal in patients with CVDs, probably as a consequence of alveolitis. However, the role of gallium scanning in the diagnosis or prognosis of CVDs is not well established.

Bronchoalveolar Lavage

Bronchoalveolar lavage (BAL) results are not diagnostic in patients with CVDs, but they are helpful in determining the prognosis and guiding treatment.

Studies have been performed to determine the importance of cell counts in BAL samples; patients with increased neutrophil counts tend to have worse prognoses than those with increased lymphocyte counts.^[47]BAL results seem to correlate with the underlying lung pathology.^{[48, 49]}Similarly, BAL lymphocytosis may predict corticosteroid responsiveness. Most patients with underlying ILD have lymphocytosis in BAL fluid. Finally, BAL is valuable for excluding infections that can mimic CVDs.

Biopsy

As with other ILDs, a transbronchial biopsy is usually inadequate for diagnosis, and often, open lung biopsy is required.

HRCT results correlate well with the pathology of the underlying CVD.^[50]However, open lung biopsy is needed in atypical cases,^[51]depending on the clinical and functional status of the patient. Video-assisted thoracoscopic surgery is usually preferred.

Histologic Findings

The most common histopathologic findings in patients with CVDs are UIP, NSIP, BOOP, follicular bronchiolitis, diffuse alveolar hemorrhage (DAH), and lymphoid interstitial pneumonia (LIP).

Usual interstitial pneumonia

Histologic findings in UIP include fibroblastic foci with alternate areas of normal lung tissue, fibrosis, and honeycombing (see the image below). Distribution is peripheral, subpleural, and basal. These findings may be seen in SLE, RA, DM/PM, and MCTD.

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.

Nonspecific interstitial pneumonia

Histologic findings in NSIP^[52]include varying proportions of interstitial inflammation and fibrosis, which may be divided into cellular and fibrosing and are patchy with intervening normal lung tissue. Distribution is peripheral, subpleural, basal, and symmetric. These findings may be seen in SLE, RA, DM/PM, and MCTD.

Lymphoid interstitial pneumonia

Histologic findings in LIP include infiltration of T cells, plasma cells, and macrophages, as well as lymphoid hyperplasia that is usually diffuse and predominantly septal. Distribution is diffuse. These findings may be seen in SS and MCTD.

Bronchiolitis obliterans organizing pneumonia

Histologic findings in BOOP include patchy intraluminal organizing fibrosis in air spaces with preservation of lung architecture. Distribution is bronchovascular. These findings may be seen in SLE, SD, SS, and PM/DM.

Diffuse alveolar hemorrhage

Histologic findings in DAH include hyaline membrane formation, damaged type II pneumocytes, alveolar edema, and fibroblastic proliferation. Distribution is diffuse. These findings may be seen in SLE, RA, SD, and PM/DM.

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Contributor Information and Disclosures

Author

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

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

Disclosure: Nothing to disclose.

Coauthor(s)

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, and American Medical Association

Disclosure: Nothing to disclose.

Hina Arif, MD Research Assistant, Interfaith Medical Center

Disclosure: Nothing to disclose.

Chief Editor

Zab Mosenifar, MD Director, Division of Pulmonary and Critical Care Medicine, Director, Women's Guild Pulmonary Disease Institute, Professor and Executive Vice Chair, Department of Medicine, Cedars Sinai Medical Center, University of California, Los Angeles, David Geffen School of Medicine

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

Disclosure: Nothing to disclose.

Additional Contributors

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

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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.