Collagen-Vascular Disease Associated With Interstitial Lung Disease 

Collagen-vascular diseases (CVDs) are a heterogeneous group of autoimmune disorders of unknown etiology. They include systemic lupus erythematosus (SLE),rheumatoid arthritis (RA), progressive systemic sclerosis (PSS), scleroderma (SD),dermatomyositis (DM)/polymyositis (PM),ankylosing spondylitis (AS),Sjögren syndrome (SS), and mixed connective-tissue disease (MCTD).^[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 airways, vessels, parenchyma, pleura, and respiratory muscles. Interstitial lung disease (ILD) is the most common pulmonary complication of the CVDs.

Felizardo et al conducted a study to determine the incidence of ILD in CVD patients in an outpatient setting and found that 30% of patients had ILD.^[2] Among 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 increase is attributable mainly 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.

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.^[4]

CVD can cause a variety of pathologic 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 varies, depending on the underlying CVD.

The 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 vasculitis^[7] 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 – 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^[8]
• Hormonal influence – 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 – 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^[10]

The exact cause of CVDs is unknown. However, many factors can either cause the disease or exacerbate the ILD.

Infections

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.

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.

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 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.^[11]

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.^[12] 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.^{[13, 14, 15]} The prevalence of SS is 0.5-0.3%. PM/DM is relatively rare, affecting 2-3 in 100,000 people.^[16]

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.^{[17, 18]} SS affects 1 in 1250 individuals.^[19] SLE affects approximately 1 in 2000 individuals.^[20] 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.^[21]

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.^{[22, 23, 24]} 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^[25] 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.^[26]

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^[23] 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^{[27, 25]}
• Male sex and lung fibrosis in RA-related ILD^[28]
• Patients with SD – Antitopoisomerase and antiribonucleoprotein polymerase antibodies are associated with pulmonary hypertension.