Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD) Workup

Updated: Aug 07, 2020
  • Author: Aniruddh Kapoor, MBBS; Chief Editor: Zab Mosenifar, MD, FACP, FCCP  more...
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Workup

Laboratory Studies

Laboratory studies are helpful in the setting of connective tissude disease-associated (CTD) interstitial lung disease (ILD) (CTD-ILD). At least 15% of patients with ILD have evidence of underlying CTD. [3]

Antibody testing

Various antibodies detected in the serum of patients with CTD help in determining the diagnosis and the prognosis (see Table 2 below).

Table 2. Autoantibodies in Connective Tissue Diseases (Open Table in a new window)

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.

 

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 patients with SLE who present with an acute lupus flare.

Schirmer and Rose Bengal staining

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

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Radiology

Radiologically, connective tissue disease (CTDs) 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 3 below).

Table 3. Radiologic Patterns of Connective Tissue Diseases (Open Table in a new window)

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.

 

Rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), scleroderma (SD), Sjögren syndrome (SS), and polymyositis/dermatomyositis (PM/DM) can cause interstitial fibrosis similar to idiopathic pulmonary fibrosis (IPF). All CTDs like IPF involve the lung bases and are subpleural, except for ankylosing spondylitis (AS), which involves the upper lobes, and RA-induced interstital lung disease (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).

Connective Tissue Disease-Associated Interstitial 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.

Radiologic features of mixed connective tissue disease (MCTD) vary across different studies. Radiologic abnormalities include subpleural honeycombing, bronchiolitis obliterans organizing pneumonia (BOOP), and pleural effusion.

Chest radiography

Chest radiographs can detect ILD; however, these may be normal initially. [60] Thus, high-resolution computed tomography (CT) scanning remains the standard when it comes to the evaluation of CTD-related ILD (CTD-ILD). Depending on the type of CTD present and the extent of lung involvement, radiography may reveal a plethora of findings, including but not limited to ground-glass opacities, reticulations, pleural effusions, pulmonary nodules, bronchiectasis, volume loss, and prominent pulmonary vessels.

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 ground-glass opacities (GGOs) and bronchiolitis obliterans. [61]

Connective Tissue Disease-Associated Interstitial Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD). This chest radiograph was obtained from a patient with lymphocytic interstitial pneumonia.

Ultrasonography

Although not yet adopted as a gold standard, data exists to suggest a role for the use of lung ultrasonography. [62, 63, 64, 65] [66]

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

Computed tomography (CT) scanning

Numerous studies show high-resolution (HR) CT findings and pulmonary function test (PFT) results correlate with underlying lung histopathology in patients with CTD. [67] GGOs and consolidation may reflect the presence of interstitial pneumonia on CT scanning of the chest (see the image below). Pulmonary fibrosis is uncommon in patients with SLE; if present, it is usually patchy. The abnormalities occur mainly at the periphery of the lung and can be associated with traction bronchiectasis and honeycombing. The HRCT findings in CTD-ILD can be indistinguishable from those found in idiopathic interstitial pneumonia.

Connective Tissue Disease-Associated Interstitial 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.

RA is associated with the following four CT scan patterns:

  • Usual interstitial pneumonia (UIP)

  • Nonspecific interstitial pneumonia (NSIP)

  • Bronchiolitis [68]

  • Organizing pneumonia (OP) [69]

The most common CT scan features of RA-related lung disease are GGOs and reticulation. [18, 70] RA can manifest as rheumatoid nodules, Caplan syndrome (rheumatoid nodules ≤5 cm, mostly involving the upper lungs in coal miners and resembling coal worker pneumoconiosis). [71] In a smoker who has RA and presents with lung nodules, lung cancer should be ruled out first. [72]

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.

Nuclear imaging

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

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Pulmonary Function Tests

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

Most connective tissue diseases (CTDs) cause a restrictive lung disease pattern with a decrease in total lung capacity (TLC), residual volume (RV), functional residual capacity (FRC), and DLCO. [73] 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).

Arterial blood gas (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.

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Bronchoalveolar Lavage

Bronchoalveolar lavage (BAL) results are not diagnostic in patients with connective tissue diseases (CTDs), but they are diagnositic in excluding infections and can help narrow a differerential diagnosis. [74]

Studies have been performed to determine the importance of cell counts in BAL samples; patients with increased neutrophil counts tend to have a worse prognosis than those with increased lymphocyte counts. [75] BAL results seem to correlate with the underlying lung pathology. [76, 77] Similarly, BAL lymphocytosis may predict responsiveness to corticosteroids. Most patients with underlying interstitial lung disease (ILD) have lymphocytosis in BAL fluid. Finally, BAL is valuable for excluding infections that can mimic CTDs.

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Biopsy

As with other interstitial lung diseases (ILDs), a transbronchial biopsy is usually inadequate for diagnosis, given the often patchy distribution of histologic findings. Alhough lung biopsies would provide a histopathologic diagnosis, they are often not required.

High-resolution computed tomography (HRCT) scanning results correlate well with the pathology of the underlying connective tissue disease (CTD). [78] However, open lung biopsy is needed in atypical cases, [79] depending on the clinical and functional status of the patient. Video-assisted thoracoscopic surgery is usually preferred.

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Histologic Findings

The most common histopathologic findings in patients with connective disease tissues (CTDs) are nterstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), organizing pneumonia (OP), 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). The distribution is peripheral, subpleural, and basal. These findings may be seen in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), polymyositis/dermatomyositis (DM/PM), and mixed connective tissue disease (MCTD).

Connective Tissue Disease-Associated Interstitial 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.

Nonspecific interstitial pneumonia

Histologic findings in NSIP include varying proportions of interstitial inflammation and fibrosis, which may be divided into cellular and fibrosing and are patchy with intervening normal lung tissue. [80] The 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. The distribution is diffuse. These findings may be seen in Sjögren syndrome (SS) and MCTD.

Organizing pneumonia

Histologic findings in OP include patchy intraluminal organizing fibrosis in air spaces, with preservation of lung architecture. The distribution is bronchovascular. These findings may be seen in SLE, scleroderma (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.

Interstitial pneumonia with autoimmune features (IPAF)

The histopathologic features included within the morphologic domain criteria for IPAF are only those considered to be highly associated with, but not diagnostic for, the presence of CTDs. These are the primary patterns of NSIP, OP and LIP and the secondary features of interstitial lymphoid aggregates with germinal centers and diffuse lymphoplasmacytic infiltration, with or without lymphoid follicles. [10]

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