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      News & Perspective Drugs & Diseases CME & Education Academy Video Decision Point
      Drugs & Diseases > Pulmonology

      Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD) Clinical Presentation

      Updated: Aug 06, 2020
      • Author: Aniruddh Kapoor, MBBS; Chief Editor: Zab Mosenifar, MD, FACP, FCCP  more...
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      Presentation

      History

      A thorough history including present respiratory symptoms, their onset and duration, as well as other systemic manifestations are crucial in diagnosing connective tissue disease-associated interstitial lung disease (CTD-ILD). Chronic cough and dyspnea, especially dyspnea on exertion, represent the initial presenting complaints in patients with CTD-ILD. However, patients are often asymptomatic early in the disease course.

      Furthermore, a careful history of occupation, environmental exposures, smoking, radiation exposure, and drug use is needed to make a correct diagnosis. Actively seek extrapulmonary symptoms, including—but not limited to—rashes, telangiectasias, skin thickening, and nail pitting (which can be found in scleroderma); musculoskeletal or joint pain (which can be found in RA); and Raynaud symptoms (discoloration of the fingers and/or toes in response to triggers such as cold or stress). It has been suggested that a multidisciplinary approach, including consultation with a pulmonologist and rheumatologist, is the gold standard for the diagnosis of ILD. [47]

      A history of smoking is important because this habit can exacerbate the underlying CTD. A detailed history of previously used medications is also needed to exclude the possibility of drug-induced lung disease. Certain CTDs (eg, systemic lupus erythematosus [SLE]) run in families; therefore, a detailed family history is important in these cases. A patient’s previous employment history and environmental exposures may be helpful to differentiate CTD from ILD that is secondary to occupational exposure.

      The clinical manifestations of CTD depend on the underlying CTD (see below); as a group, almost all CTDs cause diffuse ILD. Predominant symptoms of all CTDs include insidious onset of dyspnea, cough, hypoxia and, in the later stages of ILD, hypoxemia. Occasional chest pain is also reported.

      Systemic lupus erythematosus

      The clinical diagnosis of SLE is based on the presence of at least 4 of the following 10 features:

      • Rash

      • Discoid lupus

      • Photosensitivity

      • Oral ulcers

      • Arthritis

      • Serositis

      • Renal disorders

      • Neurologic disorders

      • Hematologic disorders

      • Immunologic disorders

      SLE can involve any part of the respiratory system [48] and can cause acute pneumonitis (1-9% of cases), ILD (25%), pleuritis and pleural effusions (50-80%), an increased incidence of bacterial pneumonia, diffuse alveolar damage (1-2%), pulmonary hypertension (9%) and thromboembolism, diaphragmatic dysfunction with reduced lung volumes, [49] shrinking lung syndrome, and acute reversible hypoxemia syndrome. [50]

      Pleural disease is the most common lung abnormality; effusion occurs in 50-70% of cases. [51] Pleural effusions are usually small, bilateral, and exudative. Fibrothorax due to lupus pleuritis is a rare complication.

      Pneumonia, usually of bacterial origin, is the most common cause of pulmonary infiltrates in SLE patients. It may be related to immunosuppression by the disease itself or it may be due to the drugs used for its treatment. Lupus pneumonitis occurs in 5% of cases and is characterized by fever, cough, pleurisy, dyspnea, pulmonary infiltrates on radiography, hypoxia, and pleural effusion.

      Diffuse alveolar hemorrhage (DAH) due to capillaritis is rare (occurring in 1-2% of cases) and associated with high mortality. [52, 53] It is characterized by fever, cough, dyspnea, hypoxia, and hemoptysis. The presentation is similar to that of acute lupus pneumonitis; however, in DAH, the diffusion capacity of the lung for carbon monoxide (DLCO) is usually high, and lupus nephritis is present. The diagnosis is typically made by bronchoscopy with bronchoalveolar lavage, which shows progressively bloody lavage fluid and hemosiderin-laden macrophages.

      Diaphragmatic dysfunction or pleuritic chest pain with restriction of respiration has been suggested but not confirmed as a cause of shrinking lung syndrome. Patients have shortness of breath, and chest radiographs show loss of lung volume with no evidence of interstitial fibrosis or significant pleural disease. Furthermore, patients with chronic interstitial pneumonitis usually present with an insidious onset of dyspnea, chronic hypoxia, nonproductive cough, and recurrent pleuritic chest pain.

      Pulmonary hypertension is less common with SLE than with other CTDs (eg, scleroderma [SD] or mixed connective-tissue disease [MCTD]). Symptoms of pulmonary hypertension include dyspnea (which increases with exercise), fatigue, weakness, and right-side heart failure.

      Acute reversible hypoxemia is rare in SLE patients; it manifests as acute hypoxia with negative chest radiography findings and no evidence of pulmonary emboli. Pulmonary leukoaggregation and complement activation are thought to be the causes of this acute hypoxemia. Antiphospholipid antibodies can cause thromboembolic events in patients with SLE.

      See Systemic Lupus Erythematosus for more information.

      Rheumatoid arthritis

      Rheumatoid arthritis (RA) is commonly associated with pleural disease (in 20-40% of cases), interstitial pneumonitis (5-10%), nodules (1%), interstitial fibrosis (similar to idiopathic pulmonary fibrosis [IPF]), bronchiolitis obliterans organizing pneumonia (BOOP), and pulmonary vasculitis. Pleural effusions in RA, unlike those in SLE, are usually small, unilateral, and asymptomatic.

      RA-ILD occurs most commonly in middle-aged men and is usually associated with severe arthritis and high serum levels of rheumatoid factor (RF). Risk factors include male sex, older age, and a history of cigarette smoking. Clinically, patients develop an insidious onset of dyspnea with occasional dry cough.

      The underlying pathologic pattern is usually nonspecific interstitial pneumonia (NSIP) or usual interstitial pneumonia (UIP). Pulmonary vasculitis can cause pulmonary hypertension. RA-ILD is usually slowly progressive; however, approximately 10% of patients die of progressive respiratory failure. Also, the findings of ILD can be present before the onset of articular disease.

      See Rheumatoid Arthritis for more information.

      Scleroderma

      The lungs are the second most common organ involved in scleroderma (SD) (also referred to as progressive systemic sclerosis [PSS]), after the esophagus. SD can be divided into two types: limited (CREST syndrome [calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia]) and diffuse. ILD is more prevalent in diffuse SD (30-90%), whereas pulmonary hypertension is more common in limited SD (10%).

      ILD in SD patients manifests as an insidious onset of dyspnea, hypoxia, and fatigue. Later, as the disease progresses, it becomes indistinguishable from IPF. It should be noted that SD-ILD follows a less progressive course than IPF does and has a better long-term prognosis.

      Pulmonary hypertension (see the image below) is fatal in SD patients. It can occur alone or in combination with ILD. Dyspnea on exertion is the most common symptom, followed by syncope or right-sided chest pain.

      Connective Tissue Disease-Associated Interstitial 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.
      View Media Gallery

      Less commonly, SD can cause pleural disease, aspiration pneumonia, spontaneous pneumothorax, bronchiectasis, and drug-induced pulmonary toxicity (eg, methotrexate-mediated ILD).

      See Scleroderma for more information.

      Sjögren syndrome

      Sjögren syndrome (SS) consists of the triad of keratoconjunctivitis sicca, xerostomia, and parotid swelling. It can be divided into two forms: primary (when other connective-tissue diseases are not present) and secondary (when other connective-tissue diseases are present). Pulmonary involvement (eg, pleuritis or vasculitis) is more common in secondary SS, whereas ILD is more common in primary SS.

      Pleuropulmonary manifestations of SS include tracheobronchial gland inflammation, pleuritis, lymphoid interstitial pneumonia (LIP), NSIP, UIP, BOOP, and follicular bronchiolitis. Focal lymphoid hyperplasia (pseudolymphoma, a nonmalignant extraglandular lesion characterized by infiltrates of mature lymphocytes) and lymphoma (non-Hodgkin lymphoma) are more common in these patients.

      See Sjogren Syndrome for more information.

      Polymyositis/dermatomyositis

      Polymyositis (PM)/dermatomyositis (DM) is less commonly associated with pulmonary lung disease. [54, 55] ILD occurs in 10% of patients with PM/DM (PM/DM-ILD). Patients with PM/DM-ILD tend to have shorter survival than patients without lung involvement. These patients present acutely with normal creatine kinase levels despite myositis. [55, 56]

      Infections are the most common form of pulmonary disease in PM/DM patients. [54, 55] Several mechanisms have been proposed, including weakness of the respiratory muscles, aspiration, lymphocytopenia, and immunosuppression from the drugs used to treat PM/DM.

      See Polymyositis and Dermatomyositis for more information.

      Mixed connective-tissue disease

      Mixed connective tissue disease (MCTD) is a rare autoimmune disorder that causes signs and symptoms of other CTDs. Clinical and laboratory findings overlap those of PSS, SLE, and PM/DM. For this reason, MCTD is sometimes referred to as an overlap disease.

      The lungs are commonly affected in persons with MCTD; most patients are asymptomatic, but they may present with an insidious onset of dyspnea, dry cough, and chest pain. Pulmonary hypertension is the most common cause of death in patients with MCTD. [57]

      See Mixed Connective-Tissue Disease for more information.

      Ankylosing spondylitis

      Ankylosing spondylitis (AS) involves the lungs in 1% of patients (AS-ILD). Upper lobe and apical lung fibrosis is seen, usually 10 years or more after the onset of the disease. In 3.5% of cases, AS can cause aortic root dilatation and aortic valve regurgitation.

      See Ankylosing Spondylitis and Undifferentiated Spondyloarthropathy for more information.

      Next:

      Physical Examination

      In addition to a detailed history, a thorough physical examination has a central role in the early diagnosis patients with CTDs.

      Although often obscure, "velcro crackles" are an easily identifiable and key physical examination finding in the diagnosis of CTD-associated ILD (CTD-ILD). Previous data suggest that crackles, or rales, are auscultated in 60% of patients with biopsy-proven interstitial pneumonias. [58]

      Specific physical findings depend on the underlying CTD, and they may be limited to the chest or may involve other body organs (see the images and Table 1 below).

      Connective Tissue Disease-Associated Interstitial Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD). Note the heliotrope rash in a woman with dermatomyositis.
      View Media Gallery
      Connective Tissue Disease-Associated Interstitial Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD). This image reveals Gottron papules and nail-fold telangiectasia in a patient with dermatomyositis.
      View Media Gallery
      Connective Tissue Disease-Associated Interstitial 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.
      View Media Gallery

      Table 1. Important Physical Findings in Connective Tissue Diseases (Open Table in a new window)

      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.

      Interstitial pneumonia with autoimmune features (IPAF)

      in IPAF associated with CTD, specific clinical features suggestive of an underlying CTD are present, but they do not allow for the diagnosis of a defined CTD. For example, Raynaud phenomenon, palmar telangiectasia, distal digital tip ulceration, and digital edema are specific physical findings that are often seen in systemic sclerosis (SS) but rarely seen in idiopathic interstitial pneumonia (IIP). Similarly, the features of digital fissuring (“mechanic hands”) and a fixed rash on the digital extensor surfaces (Gottron sign) are hallmarks of the anti-synthetase syndrome or SS-myositis overlap associated with PM-Scl antibody positivity. Inflammatory arthropathy is characterized by symptoms or signs of peripheral joint synovitis, but joint pain alone lacks specificity. [10]

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