Interstitial Lung Disease Associated With Collagen-Vascular Disease
- Author: Isabel F Pedraza, MD; Chief Editor: Zab Mosenifar, MD, FACP, FCCP more...
Collagen-vascular diseases (CVDs) are a heterogeneous group of autoimmune disorders characterized by the presence of autoantibodies. They include systemic lupus erythematosus (SLE),rheumatoid arthritis (RA), progressive systemic sclerosis (PSS), dermatomyositis (DM)/polymyositis (PM),ankylosing spondylitis (AS),Sjögren syndrome (SS), and mixed connective-tissue disease (MCTD). Many experts include the ANCA-related vasculitides and Goodpasture syndrome in this group because of the presence of autoantibodies.
Many CVDs involve the lungs either directly or as a complication of treatment of the CVD. Several different components of the respiratory system may be involved, including the airways, vessels, parenchyma, pleura, and respiratory muscles. Interstitial lung diseases (ILD) are common pulmonary complications of the CVDs.
Approximately 15% of patients with an interstitial lung disease have an underlying connective-tissue disease. Almost all autoimmune conditions have been associated with the occurrence of ILD. ILD may be the initial manifestation of a connective-tissue disease. It has been suggested that some patients who have ILD but who do not meet clinical criteria for connective-tissue disorders may have a lung-predominant form of a connective-tissue disease.
Some evidence suggests that the incidence of ILD is increasing in CVD patients. To some degree, this increase may be related to an increased detection bias owing to the increased use of diagnostic techniques to include bronchoscopy, video-assisted thoracoscopic surgery, high-resolution computed tomography (HRCT), and pulmonary function tests (PFTs). However, it should be noted that, in general, the incidence, prevalence, and mortality rate associated with ILD have all been increasing. The increased incidence of ILD in CVD patients may reflect this overall trend. 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.
The pathogenesis of connective-tissue diseases is unknown. The role of autoimmunity in ILD associated with connective-tissue disorders such as systemic sclerosis, SLE, and RA is well established.
ILD associated with CVD may display a variety of histological subtypes, including usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), organizing pneumonia, diffuse alveolar damage, lymphoid interstitial pneumonia (LIP), bronchiectasis, constrictive bronchiolitis, follicular bronchiolitis, and alveolar hemorrhage. ILD related to CVD may be associated with pulmonary hypertension. Patients with CVD who develop drug-induced ILD may also manifest a variety of histologic patterns in lung biopsy specimens. The frequency of each histologic pattern varies, depending on the underlying CVD.
The lungs are involved in more than 50% of patients with systemic sclerosis. While clinical examination reveals that 28% of patients with systemic sclerosis have ILD, HRCT demonstrates consistent findings in more than 65% of patients, and PFTs are abnormal in 93% of patients. 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. Infections and venous thromboembolic disease are also common pulmonary complications of SLE.
The most common interstitial pathologic pattern in patients with RA is diffuse fibrosis with inflammation. Follicular bronchiolitis (ie, development of the lymphoid follicles with germinal centers) can be associated with significant airway obstruction. Other common thoracic disorders associated with RA include rheumatoid nodules and pleural effusions. Vasculitis and pulmonary hypertension have been reported.
Pulmonary complications of PM/DM are frequent, occurring in 40% of patients. Manifestations include ILD, aspiration, pneumonia, and ventilator muscle weakness. Pulmonary disease can be seen in patients without overt muscle abnormalities. Patients may also develop pulmonary arterial hypertension, vasculitis, and diffuse alveolar hemorrhage.
Risk factors for the development of CVDs are as follows:
Genetic susceptibility – Many individuals are predisposed genetically to develop CVDs; in persons with SD class II, major histocompatibility complex (MHC) 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 human leukocyte antigen (HLA)-Dw2 and HLA-Dw3; AS is strongly associated with HLA-B27 
Hormonal influence – Pregnancy exacerbates various CVDs, including SLE and RA, suggesting that hormones (especially estrogen) play an important role 
High titers of rheumatoid factor (RF) and the presence of rheumatoid nodules – These are also associated with an increased prevalence of pulmonary fibrosis in persons with RA
Cigarette smoking (>25 pack-year) – This increases the risk of ILD in patients with RA 
The exact cause of CVDs is unknown. However, many factors can either cause the disease or exacerbate the ILD.
Various viruses have been implicated as causes of SLE. Epstein-Barr virus (EBV) is a prime suspect, but other viruses and bacteria (eg, retroviruses, parvoviruses, mycobacteria, Mycoplasma species, and Borrelia species) are also important. Infectious agents are thought to act as potent antigens, and they cross-react with the collagen, suppressing T-suppressor cells and inducing T-cell activation. See Systemic Lupus Erythematosus for more information.
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 or just the markers is still being debated. 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. See Systemic Lupus Erythematosus for more information.
Role of inflammatory mediators
A wide variety of cytokines identified in bronchoalveolar lavage (BAL) fluid appear to contribute to the cascade of inflammation in the lungs. The most striking of these are the following:
Interleukin (IL)–8 (a neutrophil chemoattractant and activator)
Tumor necrosis factor-α (TNF-α, an early cytokine involved in many pathologic processes)
Macrophage inflammatory protein-1α (a cytokine that is important in neutrophil chemotaxis)
RANTES (regulated on activation normal T-cell expressed and secreted, a cytokine that is important in T-cell and eosinophil recruitment and activation)
Transforming growth factor-β (TGF-β)
Family members of SLE patients have an increased risk of developing SLE; a higher rate of concordance (24%) is recognized in monozygotic twins than in dizygotic twins (1-3%). In addition, 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.
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 IL-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.
Hagaman et al found that vitamin D deficiency was associated with reduced lung function in patients with connective tissue disease and may play a role in the pathogenesis of ILD.
United States statistics
The exact frequency of CVD is unknown. The incidence and prevalence vary depending on various epidemiologic studies. However, it is well known that 10-90% of patients with CVDs (depending on the type of CVD) will have lung involvement in their lifetime.
In the United States, SLE is a fairly common autoimmune disease and affects 1-2 in 2000 people. 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.[20, 21, 22] The prevalence of SS is 0.5-0.3%. PM/DM is relatively rare, affecting 2-3 in 100,000 people.
Outside the United States, RA is a common disease, with a worldwide prevalence of approximately 1% and an annual incidence of approximately 3 in 10,000 adults.[24, 25] SS affects 1 in 1250 individuals. SLE affects approximately 1 in 2000 individuals. PSS and limited SD affect 1 in 5,000-20,000 individuals. PM and DM are relatively rare, affecting 1 in 100,000-200,000 individuals per year in the world.
Age-, sex-, and race-related demographics
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 years) may be associated with malignancy.
SLE, RA, PM/DM, SS, and MCTD are more common in females. It should be noted, however, that whereas 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.
RA is more common in adult whites. The prevalence of SLE is higher among Asians, African Americans, and Hispanic Americans.
CVD-associated ILD causes significant morbidity and mortality. In general, the prognosis for CVD-ILD is worse than that for IPF (if the underlying histologic pattern is UIP and the patient has concomitant pulmonary hypertension), except in RA-related ILD (with underlying NSIP pattern), which has a better prognosis than IPF.[29, 30, 31] Most forms of CVD-related ILD have a better prognosis than idiopathic ILD. An exception is RA-related ILD with UIP findings.[32, 33] However, CVDs are more indolent in progression than IPF.
Mortality is high in patients with CVD who develop ILD and pulmonary hypertension. Takizawa et al found that in 715 patients with CVDs, ILD and pulmonary hypertension were important causes of death (37.5% and 6%, respectively).
In patients with RA and SLE who develop ILD, mortality is 3-4 times higher than that in the general population. The median survival of all patients with RA-related ILD has been reported to be approximately 5 years.
PM/DM and systemic sclerosis are associated with higher mortalities than 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. Kang et al found that in Korean patients with PM/DM, ILD was observed in 40.3% and was associated with poor survival. The 3-year survival rate for patients with systemic sclerosis and pulmonary hypertension is 56%.
In general, indicators of poor survival include the following:
Diffusing capacity of the lung for carbon monoxide (DLCO) below 50% of predicted
PM/DM-associated ILD with normal creatine kinase values, negative anti-Jo antibody findings, and pulmonary hypertension [34, 36]
Male sex and lung fibrosis in RA-related ILD 
Patients with SD – Antitopoisomerase and antiribonucleoprotein polymerase antibodies are associated with pulmonary hypertension.
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|CVD||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|
|* MCTD can manifest with the signs and symptoms of RA, SLE, or SS.
AS = ankylosing spondylitis; CAD = coronary artery disease; CHF = congestive heart failure; CVD = collagen-vascular disease; DM = dermatomyositis; PM = polymyositis; RA = rheumatoid arthritis; SD = scleroderma; SLE = systemic lupus erythematosus; SS = Sjögren syndrome.
|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; CCP = cyclic citrullinated peptide.|
|Radiologic Pattern||RA||SLE||SD||Secondary SS||PM/DM||AS||MCTD|
|Interstitial pneumonitis, fibrosis||UIP and NSIP patterns||+||LIP pattern||±||+||Upper apical fibrosis||+|
|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||+||-||-|
|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.|