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Interstitial Lung Disease Associated With Collagen-Vascular Disease

  • Author: Isabel F Pedraza, MD; Chief Editor: Zab Mosenifar, MD, FACP, FCCP  more...
Updated: Sep 20, 2013


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.[1]

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.[2] Almost all autoimmune conditions have been associated with the occurrence of ILD. ILD may be the initial manifestation of a connective-tissue disease.[3] 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.[4]

Some evidence suggests that the incidence of ILD is increasing in CVD patients.[5] 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.[6] 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.[7]

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.[8] Patients with CVD who develop drug-induced ILD may also manifest a variety of histologic patterns in lung biopsy specimens.[9] 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.[10] 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.[11] 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.[12] 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.[13]

Pulmonary complications of PM/DM are frequent, occurring in 40% of patients.[14] 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 [15]
  • Hormonal influence – Pregnancy exacerbates various CVDs, including SLE and RA, suggesting that hormones (especially estrogen) play an important role [16]
  • 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 [17]


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.

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 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)
  • 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 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.

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 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.[18]



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.[19] 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.[23]

International statistics

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.[26] SLE affects approximately 1 in 2000 individuals.[27] 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.[28]



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[34] 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.[35]

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[30] 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 [37]
  • Patients with SD – Antitopoisomerase and antiribonucleoprotein polymerase antibodies are associated with pulmonary hypertension.
Contributor Information and Disclosures

Isabel F Pedraza, MD Director, Respiratory Intensive Care Unit, Faculty Physician, Department of Medicine, Division of Pulmonary/Critical Care Medicine, Women's Guild Lung Institute, Cedars-Sinai Medical Center

Disclosure: Nothing to disclose.


Daniel R Ouellette, MD, FCCP Associate Professor of Medicine, Wayne State University School of Medicine; Chair of the Clinical Competency Committee, Pulmonary and Critical Care Fellowship Program, Senior Staff and Attending Physician, Division of Pulmonary and Critical Care Medicine, Henry Ford Health System; Chair, Guideline Oversight Committee, American College of Chest Physicians

Daniel R Ouellette, MD, FCCP is a member of the following medical societies: American College of Chest Physicians, Society of Critical Care Medicine, American Thoracic Society

Disclosure: Nothing to disclose.

Arshad Ali, MD Attending Physician, Department of Pulmonary and Critical Care Medicine, Mercy General Hospital of Sacramento

Arshad Ali, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Thoracic Society

Disclosure: Nothing to disclose.

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

Danilo A Enriquez, MD, FCCP is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Medical Association

Disclosure: Nothing to disclose.

Hina Arif, MD 

Disclosure: Nothing to disclose.

Chief Editor

Zab Mosenifar, MD, FACP, FCCP Geri and Richard Brawerman Chair in Pulmonary and Critical Care Medicine, Professor and Executive Vice Chairman, Department of Medicine, Medical Director, Women's Guild Lung Institute, Cedars Sinai Medical Center, University of California, Los Angeles, David Geffen School of Medicine

Zab Mosenifar, MD, FACP, FCCP is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Federation for Medical Research, American Thoracic Society

Disclosure: Nothing to disclose.


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

Om Prakash Sharma, MD, FRCP, FCCP, DTM&H is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Chest Physicians, American College of Physicians, American Federation for Medical Research, American Osler Society, American Thoracic Society, New York Academy of Medicine, and Royal Society of Medicine

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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Pulmonary hypertension is complication of various collagen-vascular diseases. Lung biopsy specimen demonstrates severe interstitial fibrosis and medial fibrosis and smooth muscle hyperplasia of pulmonary arteriole, compatible with pulmonary hypertension.
Heliotrope rash in woman with dermatomyositis.
Gottron papules and nail-fold telangiectasia in patient with dermatomyositis.
Classic malar rash (butterfly rash) with distribution over cheeks and nasal bridge. Note that fixed erythema (sometimes associated with mild induration, as here) characteristically spares nasolabial folds.
High-resolution CT scan of advanced-stage pulmonary fibrosis demonstrating reticular opacities with honeycombing in predominantly subpleural distribution. This pattern can be present in rheumatoid arthritis–related interstitial lung disease, Sjögren syndrome, and scleroderma.
Ground-glass opacification (GGO) may correlate with active alveolitis and favorable response to therapy. GGO is among earliest features of rheumatoid arthritis–induced interstitial lung disease.
Patient with lymphocytic interstitial pneumonia.
Usual interstitial pneumonitis. Subpleural and paraseptal inflammation are present, with appearance of temporal heterogeneity. Patchy scarring of lung parenchyma and normal (or nearly normal) alveoli interspersed between fibrotic areas are hallmarks of this disease. In addition, lung architecture is completely destroyed. This pattern can be present in rheumatoid arthritis–induced interstitial lung disease and generally is associated with poor prognosis.
Table 1. Important Physical Findings in Collagen-Vascular Diseases
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.

Table 2. Autoantibodies in Collagen-Vascular Diseases
RF + + + + Rare - +
ANA + + + + Rare - +


ds-DNA - + - - - - -
Anticentromere - - + (limited) Rare Rare - -
Scl-70 - - + (diffuse)   Rare - -
Anti-Jo - - - Rare + (ILD) - -
ANCA Rare Rare - - - - -
Smith antibody - + - - - - -
Anti-Ro/SSA and anti-La/SSB - - - + - - -
Anti-U1-RNP and anti-UN-70 kd - - - - - - +
Anti-CCP + - - - - - -
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.
Table 3. Radiographic Patterns of Collagen-Vascular Diseases
Radiologic Pattern RA SLE SD Secondary SS PM/DM AS MCTD
Pleural effusion + + + ± - - +
Interstitial pneumonitis, fibrosis UIP and NSIP patterns + LIP pattern ± + Upper apical fibrosis[46] +
BOOP ± + + + + ± ±
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 + - -
Bronchiectasis + + + + + + +
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.
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