eMedicine Specialties > Pulmonology > Interstitial Lung Diseases
Collagen-Vascular Disease Associated With Interstitial Lung Disease
Updated: Sep 24, 2008
Introduction
Background
Collagen-vascular diseases (CVDs) are a heterogeneous group of autoimmune disorders of unknown etiology. Many CVDs involve the lungs directly or involve them as a complication of treatment of the CVD. Several different components of the respiratory system may be involved, including airways, vessels, parenchyma, pleura, and/or respiratory muscles. Interstitial lung disease (ILD) is the most common pulmonary complication of the CVDs. CVDs include systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), progressive systemic sclerosis (PSS) or scleroderma (SD), dermatomyositis (DM) and polymyositis (PM), ankylosing spondylitis (AS), Sjögren syndrome (SS), and mixed connective-tissue disease (MCTD).1
Felizardo et al2 conducted a study to find out the incidence of ILD in CVD patients in an outpatient setting. They found that 30% patients had ILD, and in these patients, the distribution of CVDs was that 8% had SD, 1% had CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome, 34% had RA, 4.3% had SLE, 6.4% had DM, 10.6% had primary syndromes, and 8.5% had secondary SS.
The incidence of ILD is increasing in CVD patients.3 This can be mainly attributed to the increased use of invasive techniques such as bronchoscopy and video-assisted thoracoscopic surgery and, in part, to the use of high-resolution computed tomography (HRCT) and pulmonary function tests (PFTs). Because the prognosis, degree of reversibility, and optimal therapy differ for each disease presentation, a thorough knowledge of the pulmonary clinical picture of each connective-tissue disease is important.
Related eMedicine articles include Systemic Lupus Erythematosus, Rheumatoid Arthritis, Systemic Sclerosis, Scleroderma, Dermatomyositis/Polymyositis, Ankylosing Spondylitis, Sjogren Syndrome, and Mixed Connective-Tissue Disease.
Pathophysiology
The etiology and pathogenesis of connective-tissue diseases is unknown. The role of autoimmunity in ILDs associated with connective-tissue disorders such as systemic sclerosis, SLE, and RA is well established.4
CVD can cause a variety of pathological lung abnormalities, including usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), organizing pneumonia, diffuse alveolar damage, lymphoid interstitial pneumonia (LIP), bronchiectasis, constrictive bronchiolitis, follicular bronchiolitis, alveolar hemorrhage, pulmonary hypertension,5 and drug-induced lung disease. The frequency of each lung disease is different among underlying CVDs. Some of the pathologic characteristics of CVDs are as follows:
- Lungs are involved in more than 50% of patients with systemic sclerosis. A diffuse interstitial and alveolar fibrosis may appear with variable fibrous thickening of small pulmonary vessels.
- Pleuritis and pleural effusions are the most common pulmonary manifestations of SLE. Less commonly, evidence of alveolar injury in the form of edema and hemorrhage is present. In some cases, chronic interstitial fibrosis is noted.
- The most common interstitial pathologic pattern in patients with RA is diffuse fibrosis with inflammation.6 Follicular bronchiolitis (ie, development of the lymphoid follicles with germinal centers) can be associated with significant airway obstruction. Pulmonary vasculitis7 causing pulmonary hypertension is also reported.
- The pulmonary complications of PM/DM may occur by 3 mechanisms: primary interstitial pneumonitis, aspiration pneumonia secondary to hypotonic esophagus, and hypostatic pneumonia secondary to chest wall involvement.
Risk factors for the development of CVDs are as follows:
- Genetic susceptibility can play a role. Many individuals are predisposed genetically to develop CVDs. For example, in persons with SD class II, major histocompatibility complex associations increase the risk of interstitial pulmonary fibrosis (IPF). A genetic predisposition is found in persons with SS, including familial clustering and an association with HLA-Dw2 and HLA-Dw3. Further, AS is strongly associated with HLA-B27.8
- Hormonal influence can be a factor. Pregnancy exacerbates various CVDs, including SLE and RA, suggesting that hormones (especially estrogen) play an important role.9
- High titers of rheumatoid factor (RF) and the presence of rheumatoid nodules are also associated with an increased prevalence of pulmonary fibrosis in persons with RA.
- Cigarette smoking (>25 pack-year) increases the risk of ILD in patients with RA.10
Frequency
United States
The exact frequency of CVD is unknown. The incidence and prevalence vary depending on various epidemiological studies. However, the fact that 10-90% of patients with CVDs (depending on the type of CVD) will have lung involvement in their lifetime is well known.
- In the United States, SLE is a fairly common autoimmune disease and affects 1-2 in 2000 people.11
- RA affects 0.3-1.5% of the North American population.
- The prevalence of SD is 26 cases per 100,000 population in the United States.12,13,14
- The prevalence of SS is 0.5-0.3%.
- PM/DM is relatively rare, affecting 2-3 in 100,000 people.15
International
- RA is a common disease with a worldwide prevalence of approximately 1% and an annual incidence of approximately 3 in 10,000 adults.16,17
- SS affects 1 in 1250 individuals.18
- SLE affects approximately 1 in 2000 individuals.19
- PSS and limited SD affect 1 in 5,000-20,000 individuals.
- PM and DM are relatively rare; they affect 1 in 100,000-200,000 individuals per year in the world.
Mortality/Morbidity
In general, CVD-associated ILD causes significant morbidity and mortality. PM/DM and systemic sclerosis have high mortality rates compared with other CVDs. In one study, the diagnostic Kaplan-Meier analysis showed that patients with PM/DM and those with systemic sclerosis did not survive as long as patients with other types of CVD.
Mortality is high in patients with CVD who develop ILD and pulmonary hypertension. Takizawa et al20 found that in 715 patients with CVDs, ILD and pulmonary hypertension were found to be important causes of death (37.5% and 6%, respectively).
In patients with RA and SLE who develop ILD, the mortality rate is 3-4 times higher compared with the general population.
Race
RA is more common in adult whites. The prevalence of SLE is higher among Asians, African Americans, and Hispanic Americans.21
Sex
SLE, RA, PM/DM, SS, and MCTD are more common in females. However, note that RA occurs predominantly in women but RA-related ILD is more common in middle-aged men. AS is more common in men, with a male-to-female ratio of 3:1.
Age
In general, CVDs are rare in children; the primary peak age of onset is middle age (ie, for RA, SLE, PSS, and AS). DM affecting older individuals (ie, >50-60 y) may be associated with malignancy.
Clinical
History
A thorough history is key for the diagnosis of CVDs. It should include present symptoms, the onset and duration of symptoms, other body systems involvement (other than the lungs), and past medical conditions. A careful history of occupation, environmental exposures, smoking, radiation exposure, and drug use is needed to make a correct diagnosis.
A history of smoking is important because it can exacerbate the underlying CVD. A detailed history of previously used medications is needed to exclude the possibility of drug-induced lung disease. Certain CVDs (eg, SLE) run in families, and a detailed family history is important in these cases. A patient’s previous employment history and environmental exposures may be helpful to differentiate CVD from ILDs secondary to occupational exposure.
The clinical manifestations of CVD depend on the underlying CVD; as a group, almost all CVDs cause diffuse ILD. Predominant symptoms of all CVDs include an insidious onset of dyspnea, cough, hypoxia, and, in the later stages of ILD, hypoxemia. Occasional chest pain is also reported.
The clinical patient presentations of individual CVDs are as follows:
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
- Neurological disorders
- Hematologic disorders
- Immunologic disorders
Pleural disease is the most common lung abnormality; pleural effusion occurs in 50-70% of cases.24 Effusions are usually small, bilateral, and exudative. Fibrothorax due to lupus pleuritis is a rare complication.
Pneumonia, usually bacterial in origin, is the most common cause of pulmonary infiltrates in SLE patients. It may be related to immunosuppression by the disease itself or may be due to the drug treatment. Lupus pneumonitis occurs in 5% of cases and is characterized by fever, cough, pleurisy, dyspnea, pulmonary infiltrates on radiographs, hypoxia, and pleural effusion.
Diffuse pulmonary hemorrhage (DAH)25 due to capillaritis is rare (1-2%). It is characterized by fever, cough, dyspnea, hypoxia, and hemoptysis. The presentation is similar to acute lupus pneumonitis; however, in DAH, diffusion capacity for carbon monoxide (DLCO) is usually high and lupus nephritis is present.
Diaphragmatic dysfunction or pleuritic chest pain with restriction of respiration can cause 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 compared with other CVDs (eg, SD, MCTD). Symptoms of pulmonary hypertension are dyspnea (which increases with exercise), fatigue, weakness, and right-sided heart failure. Acute reversible hypoxemia is a rare entity 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.
Rheumatoid arthritis
RA is commonly associated with pleural disease (20-40%), interstitial pneumonitis (5-10%), nodules (1%), interstitial fibrosis (similar to IPF), bronchiolitis obliterans-organizing pneumonia (BOOP), and pulmonary vasculitis. Pleural effusions, unlike in SLE, are usually small, unilateral, and asymptomatic.ILD occurs most commonly in middle-aged men and is usually associated with severe arthritis and high serum levels of RF. Clinically, patients develop an insidious onset of dyspnea with occasional dry cough. The underlying pathologic pattern is usually NSIP or UIP. Pulmonary vasculitis can cause pulmonary hypertension.
Scleroderma
The lungs are the second most common organ involved in SD, after the esophagus. SD can be divided into limited (CREST syndrome) and diffuse. ILD is more prevalent in diffuse SD (30-90%), and pulmonary hypertension is more common in limited SD (10%).ILD in SD patients manifests as an insidious onset dyspnea, hypoxia, and fatigue. Later, as the disease progresses, it becomes indistinguishable from IPF. Importantly, note that ILD associated with SD follows a less progressive course and has a better long-term prognosis than IPF.
Pulmonary hypertension is fatal in SD patients. It can occur alone or in combination with ILD. Dyspnea upon exertion is the most common symptom, followed by syncope or right-sided chest pain. See the image below.
Pulmonary hypertension is a complication of various collagen-vascular diseases. The image shows a lung biopsy specimen demonstrating severe interstitial fibrosis and medial fibrosis and smooth muscle hyperplasia of a pulmonary arteriole compatible with pulmonary hypertension.
Less commonly, SD can cause pleural disease, aspiration pneumonia, spontaneous pneumothorax, bronchiectasis, and drug-induced pulmonary toxicity (eg, methotrexate-mediated ILD).
Sjögren syndrome
SS consists of the triad of keratoconjunctivitis sicca, xerostomia, and parotid swelling. It can be divided into primary SS (when other connective-tissue diseases are not present) and secondary SS (when other connective-tissue diseases are present). Pulmonary involvement (eg, pleuritis, vasculitis) is more common in secondary SS and ILD is more common in primary SS.
Pleuropulmonary manifestations of SS include tracheobronchial gland inflammation, pleuritis, LIP, NSIP, UIP, BOOP, and follicular bronchiolitis. Focal lymphoid hyperplasia (pseudolymphoma; nonmalignant extraglandular lesion characterized by infiltrates of mature lymphocytes) and lymphoma (non-Hodgkin lymphoma) are more common in these patients.
Polymyositis/dermatomyositis
PM/DM is less commonly associated with pulmonary lung disease. ILD occurs in 10% of patients with PM/DM. Patients with ILD tend to have shorter survival than patients without lung involvement. These patients present acutely with normal creatine kinase levels despite myositis.26Infections are the most common form of pulmonary disease in PM/DM patients. Several mechanisms have been proposed, such as weakness of the respiratory muscles, aspiration, lymphocytopenia, and immunosuppression from the drugs used to treat PM/DM.
Mixed connective-tissue diseases
MCTD is a rare autoimmune disorder that causes signs and symptoms of other connective-tissue diseases. 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 MCTD27 ; most patients are asymptomatic, but they may present with an insidious onset of dyspnea, dry cough, and chest pain. Pulmonary hypertension28 is the most common cause of death in patients with MCTD.
Ankylosing spondylitis
AS involves the lungs in 1% of patients. 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 dilation and aortic valve regurgitation.Physical
Physical examination is important in patients with CVDs. Physical findings may be limited to the chest or may involve other body organs, as demonstrated in the images below.
Heliotrope rash in a woman with dermatomyositis.
Gottron papules and nailfold telangiectasia are present in this patient with dermatomyositis.
The classic malar rash, also known as a butterfly rash, with distribution over the cheeks and nasal bridge. Note that the fixed erythema, sometimes with mild induration as seen here, characteristically spares the nasolabial folds.
Important physical findings are outlined in Table 1 below.
Table 1. Important Findings in the Physical Examination of CVD Patients
Open table in new window
Table
| CVDs | 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 and 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, and coronary artery disease | N/A | N/A |
| SD | Thickening of the skin of face, fingers, and hands; Raynaud phenomenon and ischemic changes of the finger tips | Cor pulmonale, inspiratory Velcro crackles at the lung bases | Restrictive pericardial disease, conduction defects, congestive heart failure | N/A | N/A |
| SS | Secondary SS can manifest similar to RA and SLE | Secondary SS can manifest similar to RA, SLE | N/A | Xerostomia, parotid gland swelling | Keratoconjunctivitis sicca |
| Polymyositis | 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 |
| Spondylitis | Sacroiliitis | Restriction in chest expansion, pulmonary apical fibrosis | Aortic insufficiency | N/A | Anterior uveitis |
| CVDs | 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 and 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, and coronary artery disease | N/A | N/A |
| SD | Thickening of the skin of face, fingers, and hands; Raynaud phenomenon and ischemic changes of the finger tips | Cor pulmonale, inspiratory Velcro crackles at the lung bases | Restrictive pericardial disease, conduction defects, congestive heart failure | N/A | N/A |
| SS | Secondary SS can manifest similar to RA and SLE | Secondary SS can manifest similar to RA, SLE | N/A | Xerostomia, parotid gland swelling | Keratoconjunctivitis sicca |
| Polymyositis | 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 |
| Spondylitis | Sacroiliitis | Restriction in chest expansion, pulmonary apical fibrosis | Aortic insufficiency | N/A | Anterior uveitis |
Causes
The exact cause of CVDs is unknown. However, many agents, as described below, can cause the disease or can exacerbate the underlying ILD.
Infections
Various viruses have been implicated as causes of SLE. Epstein-Barr virus is a prime suspect, but other viruses and bacteria are also important, such as retroviruses, parvoviruses, mycobacteria, Mycoplasma species, and Borrelia species. Infectious agents are thought to act as potent antigens, and they cross-react with the collagen, suppressing T-suppresser cells and inducing T-cell activation.
Immunologic factors
Alteration and derangement of immune mechanisms are also suggested as causes of CVDs. The most characteristic derangement in SLE is autoantibodies directed against components of the nucleus, double- and single-stranded DNA, nuclear ribonucleoprotein, and Smith antigen. Whether these antibodies are the cause of the disease of just the markers is still debatable. SS is associated with several autoantibodies.
Anti-SS-A and anti-SS-B are the 2 most common antibodies considered to be important serologic markers of this disorder.
Role of inflammatory mediators
A wide variety of cytokines identified in bronchoalveolar lavage (BAL) fluid clearly contribute to the cascade of inflammation in the lungs. The most striking of these are interleukin 8 (neutrophil chemoattractant and activator), tumor necrosis factor-alpha (an early cytokine involved in many pathologic processes), macrophage inflammatory protein-1alpha (important in neutrophil chemotaxis), RANTES (regulated on activation normal T-cell expressed and secreted; important in T-cell and eosinophil recruitment and activation), transforming growth factor-beta, and endothelin-1.
Genetic factors
Family members of SLE patients have an increased risk of developing SLE; a higher rate of concordance (24%) is recognized in monozygotic twins compared with dizygotic twins (1-3%).Genetic predisposition is clearly a major determinant of susceptibility to RA. A high rate of concordance is recognized between monozygotic twins and a well-defined familial predisposition. Most individuals who develop RA are HLA-DR4, HLA-DR1, or both.
Environmental factors
Drugs such as hydralazine, procainamide, and D-penicillamine can induce SLE-like responses in humans. Exposure to ultraviolet light is another environmental factor that exacerbates SLE in many individuals. Ultraviolet light induces keratinocytes to produce interleukin 1, a factor known to influence the immune response. Finally, sex hormones seem to exert an important influence on the occurrence of SLE; the frequency of SLE is 10 times greater in women than in men.
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Further Reading
Keywords
systemic lupus erythematosus, SLE, SS, RA, SD, inflammatory myopathies, rheumatoid arthritis, scleroderma, Sjögren syndrome, Sjögren’s syndrome, autoimmune disease, connective-tissue disease, connective tissue disease, pulmonary vascular disease, collagen-vascular disease, collagen vascular disease, dermatomyositis, polymyositis, ankylosing spondylitis, progressive systemic sclerosis, pulmonary hypertension, pulmonary vasculitis, interstitial pneumonia, antibodies in connective tissue diseases, usual interstitial pneumonia, nonspecific interstitial pneumonia, lymphocytic interstitial pneumonia, diffuse alveolar hemorrhage, mixed connective tissue diseases, bronchiolitis obliterans-organizing pneumonia, BOOP
