You are in: eMedicine Specialties > Pulmonology > Interstitial Lung Diseases Collagen-Vascular Disease Associated With Interstitial Lung DiseaseArticle Last Updated: Jun 11, 2008AUTHOR AND EDITOR INFORMATIONSection 1 of 11
  Author: Arshad Ali, MD, Fellow in Pulmonary Diseases, Interfaith Medical Center, State University of New York Downstate Arshad Ali is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and American Thoracic Society 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 Editors: Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; 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; Timothy D Rice, MD, Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, Saint Louis University School of Medicine; Zab Mosenifar, MD, Director, Division of Pulmonary and Critical Care Medicine, Director, Women's Guild Pulmonary Disease Institute, Executive Vice Chair, Department of Medicine, Cedars Sinai Medical Center; Professor of Medicine, David Geffen School of Medicine at UCLA Author and Editor Disclosure Synonyms and related 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 INTRODUCTIONSection 2 of 11
  BackgroundCollagen-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
In addition, the Medscape CME course Interstitial Lung Disease and Pulmonary Hypertension may be of interest. PathophysiologyThe 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
Risk factors for the development of CVDs are as follows:
FrequencyUnited StatesThe 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.
International
Mortality/MorbidityIn 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. RaceRA is more common in adult whites. The prevalence of SLE is higher among Asians, African Americans, and Hispanic Americans.21 SexSLE, 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. AgeIn 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. CLINICALSection 3 of 11
HistoryA 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. Systemic lupus erythematosus The clinical diagnosis of SLE is based on the presence of at least 4 of the following 10 features:
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 Media File 1. 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.PhysicalPhysical examination is important in patients with CVDs. Physical findings may be limited to the chest or may involve other body organs. See Media Files 2-4. Important physical findings are outlined in Table 1 below.
CausesThe exact cause of CVDs is unknown. However, many agents, as described below, can cause the disease or can exacerbate the underlying ILD. 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. DIFFERENTIALSSection 4 of 11
Other Problems to Be Considered
WORKUPSection 5 of 11
Lab StudiesLaboratory studies are helpful. Various antibodies detected in the serum of patients with CVD help in determining the diagnosis and the prognosis.
†Double-stranded DNA antibody ‡Antineutrophilic cytoplasmic antibody §Antiribonucleoprotein antibody Imaging StudiesRadiologically, CVDs may manifest as a focal or diffuse pulmonary abnormality. The type and frequency of the lung abnormalities vary with the specific disease.
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