Pulmonary Medicine

Pulmonary Complications of Collagen Vascular Diseases

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What every physician needs to know:

Many collagen vascular diseases (CVD) are associated with pulmonary complications. The CVDs most commonly associated with pulmonary complications are systemic lupus erythematosus (SLE), scleroderma, rheumatoid arthritis (RA), mixed connective tissue disease (MCTD), polymyositis/dermatomyositis (PM/DM), and Sjögren's syndrome.

Classification

Pulmonary complications of the CVD can be classified into six categories (Table 1).

Table 1.

Pulmonary Manifestations of Various Collagen Vascular Diseases

  • Interstitial lung disease (ILD)

  • Airways disease

  • Pleural disease

  • Pulmonary vascular disease

  • Respiratory muscle weakness

  • Miscellaneous

Are you sure your patient has a pulmonary complication of a collagen vascular disease? What should you expect to find?

Interstitial lung disease

Virtually all potential interstitial pathologies have been described in the setting of CVD, although the frequency of the various subtypes varies among individual CVDs (Table 2). With the exception of RA, where usual interstitial pneumonia (UIP) predominates, among the patterns of ILD, non-specific interstitial pneumonia (NSIP) is most commonly seen in CVD. Other patterns, including organizing pneumonia (OP), diffuse alveolar damage, lymphocytic interstitial pneumonia, and honeycomb lung have also been described. In association with CVD, the radiographic and pathologic patterns of these entities are similar to their idiopathic counterparts, although there may be more inflammation.

Table 2.

The Interstitial Lung Disease Patterns Seen in Various Collagen Vascular Diseases

As with all ILD, the signs and symptoms of ILD in the setting of CVD are non-specific. Cough and dyspnea on exertion are the most common, and with more advanced disease, hypoxemia with exertion may be identified. As these symptoms do not help the clinician distinguish among the possible pulmonary complications of the CVD, additional testing is required for a diagnosis. Although ILD typically develops concurrently with or after a diagnosis of CVD, a small subset of patients may present with ILD symptoms years prior to being diagnosed with CVD.

Airways Disease

The most common airway complications include:

  • Small airways obstruction

  • Bronchiolitis obliterans (BO)

  • Follicular bronchiolitis

  • Bronchiectasis

  • Upper airway obstruction

Patients with small airway obstruction, BO, and follicular bronchiolitis usually present with a non-productive cough, wheezing, and dyspnea. These symptoms may be exacerbated by triggers similar to those of a patient with asthma. Patients with small airway obstruction may improve with bronchodilators and/or oral or inhaled corticosteroids.

Failure to respond to usual treatments of small airways disease may be a sign that the patient’s obstructive lung disease is secondary to BO or follicular bronchiolitis. Patients with BO may also present with more rapidly progressive symptoms than are typically seen in small airways disease. In RA, the disease tends to correlate with joint symptoms, but it has been described prior to the onset of articular manifestations.

Bronchiectasis can be seen as a result of recurrent infections from immunosuppression used in any CVD, but is most commonly seen in Sjögren's syndrome due to impaired mucociliary clearance and bronchial desiccation. Patients complain of a productive cough and progressive dyspnea on exertion. These symptoms are exaggerated during an acute infection, at which point patients may present with increasing or changing sputum production and hemoptysis. Crackles are often heard on examination, although a small percentage of patients may present with wheezing due to airway hyperresponsiveness.

RA and SLE patients who present with hoarseness, dysphagia, or pain with speaking or swallowing should be evaluated for an upper airway obstruction caused by cricoarytenoid arthritis. Knowing these early symptoms may prevent the patient from developing stridor, difficulty breathing, and a potentially life-threatening upper airway obstruction requiring emergency tracheostomy.

Pleural disease

Pleural effusions (Table 3) and pleural inflammation or pleurisy are the most common pleural complications associated with CVD. In SLE, the effusions, which are frequently accompanied by pleuritic chest pain, are usually small and bilateral. Fever and tachycardia can accompany the effusion, raising the concern for infection. The effusions typically occur after or during a full disease flare, but they may precede the arthralgias and other symptoms of SLE in 5-10% of patients. Thoracentesis findings in SLE are consistent with inflammation but not very specific. The effusions are typically exudative with elevated white blood cell count with variable leukocyte predominance/differential. The appearance can range from serous to frankly hemorrhagic. They have low pleural fluid complement levels, and LE cells (neutrophils or macrophages that have engulfed nuclear material of other cells) may be seen. Again, these findings are not specific.

Table 3.

Pleural Effusion in RA and SLE

In RA, effusions are often asymptomatic. They are usually small and unilateral, often occur later in the disease course of RA, and occur more often in men and in those with high rheumatoid factor (RF) titers. Up to half of the time, they occur in those with subcutaneous nodules. Findings on thoracentesis more suggestive of RA include high protein levels, significantly reduced glucose levels, elevated lactate dehydrogenase, and a moderately depressed pH. The RF levels of the pleural fluid are often equal to or even greater than those found in the serum.

Pulmonary vascular disease

The most common vascular complication is secondary pulmonary hypertension related to parenchymal disease, primary pulmonary arterial hypertension or pulmonary venoocclusive disease, especially in scleroderma. Patients with pulmonary hypertension may present with generalized fatigue and progressive dyspnea on exertion. They may also complain of exertional chest pain or syncope. Early on, the only physical examination finding may be an augmented second heart sound. Later, the patient may have a systolic ejection murmur or a diastolic regurgitation murmur. Patients may also demonstrate signs of heart failure, including lower extremity edema or abdominal tenderness from hepatic congestion.

Vasculitis, including necrotizing pulmonary capillaritis, is a rare complication of CVD and seen most commonly in SLE. Vasculitis and capillaritis should be considered in patients who present with diffuse alveolar hemorrhage.

Pulmonary embolism occurs with increased frequency in patients with SLE and antiphospholipid antibody syndrome. These patients are at risk for chronic thromboembolic pulmonary hypertension.

Respiratory muscle weakness

Patients with respiratory muscle weakness present with dyspnea on exertion and orthopnea. Orthopnea reflects further impairment in diaphragmatic function in the supine position with the loss of the assistance of gravity and the shifting of the abdominal contents cephalad. Respiratory muscle weakness is often associated with PM/DM. Associated involvement of the proximal striated muscle portion of the esophagus can cause oropharyngeal dysphagia and lead to a risk of aspiration pneumonia.

Shrinking lung syndrome is an ill-defined respiratory muscle disorder associated with SLE. In addition to dyspnea and orthopnea, patients with this disorder often have episodes of pleuritic chest pain. Shrinking lung syndrome is believed to be due to diaphragmatic dysfunction, but whether this is the result of a primary myopathy of the diaphragm or phrenic neuropathy is unclear.

Miscellaneous disorders

Acute reversible hypoxemia syndrome is a rare complication of SLE. While the pathogenesis remains unknown, it is believed to involve upregulation of the complement cascade leading to a leuko-occlusive vasculopathy. It is a diagnosis of exclusion in patients presenting with acute hypoxia without evidence of parenchymal abnormalities on chest imaging or venous thromboembolism. Treatment includes corticosteroids with or without aspirin.

Patients with RA can develop pulmonary nodules that typically correlate with subcutaneous nodules identified in other locations. These nodules tend to be subpleural and subcentimeter in size. A patient may present with a solitary pulmonary nodule or multiple nodules that wax and wane, and central cavitation can occur. These nodules should be followed to ensure there is no underlying malignancy. Many rheumatoid nodules regress spontaneously or with treatment of the underlying CVD without significant symptoms or complications.

In addition to pulmonary toxicity due to underlying CVD, many immunosuppressive and biologic agents used to treat the manifestations of CVD are associated with pulmonary toxicity ranging from infections to pneumonitis and should be considered in the differential of CVD patients with pulmonary symptoms.

Beware: there are other diseases that can mimic pulmonary complications of collagen vascular diseases:

Secondary infections, often related to immunosuppression, can mimic a number of pulmonary complications of CVD and efforts should be made to identify these given the treatment implications. Rarely malignancies can also present similarly to pulmonary complications of CVD and if suspected, biopsies should be pursued.

Lymphocytic interstitial pneumonia (LIP) can present with centrilobular or subpleural nodules. Although LIP represents a benign lymphoproliferative disorder, it is important to document polyclonality with immunohistochemistry to distinguish nodules related to LIP from lymphoma.

How and/or why did the patient develop a pulmonary complication of a collagen vascular disease?

Not applicable

Which individuals are at greatest risk of developing a pulmonary complication of a collagen vascular disease?

Interstitial lung disease

The prevalence of ILD in patients with CVD varies according to the CVD and the screening method used. In some studies, up to 85% of patients with scleroderma had evidence of ILD by high-resolution computed tomography (HRCT), but only 14-67% had clinically significant (i.e., causing morbidity and mortality) disease. ILD has become the leading cause of death in patients with scleroderma, especially diffuse cutaneous scleroderma.

In RA, the prevalence of ILD is lower than in scleroderma (33% by HRCT, 7-14% with clinically significant disease), but as RA is much more common, the overall burden of disease is larger. Risk factors for ILD in RA include male sex and human leukocyte antigen DRB1. The association between tobacco use and ILD is less clear than once reported. The prevalence of ILD in PM/DM is less well established. One prospective study found ILD in 70% of newly diagnosed patients, and of those, about half progressed over the next several years. Despite the relative frequency of SLE, ILD is a less common complication of SLE than of other pulmonary manifestations.

Airways disease

The risk of developing small airways obstruction and BO is greatest for patients with RA and scleroderma. Follicular bronchiolitis is seen most often in patients with RA, scleroderma, or Sjögren's syndrome. Patients with recurrent infection as a direct sequelae of underlying CTD including RA, Sjögren's, or SLE or from immunosuppression/biologic agents are at highest risk for bronchiectasis. Esophageal dysmotility and gastroesophageal reflux disease can increase the risk of recurrent aspiration and subsequent bronchiectasis in scleroderma. Upper airway manifestations of RA, including cricoarytenoiditis and cervical arthritis, are more common in females.

Pleural disease

Older studies suggest that 30-75% of patients with SLE will have pleuritis with or without pleural effusions at some point in their disease course. Patients with RA also frequently have pleural effusions (and, less commonly, pleurisy), with estimates ranging from 20 to 50%. Scleroderma, PM/DM and Sjögren's rarely produce pleural effusions. Because MCTD patients represent an overlap of SLE with scleroderma and PM/DM, pleural effusions are common in these patients as well.

Vascular disease

Pulmonary vascular involvement that is similar in histology to idiopathic pulmonary arterial hypertension is seen most often in patients with scleroderma (particularly the CREST variant), MCTD, and SLE. Patients with SLE and associated antiphospholipid antibody syndrome are at greatest risk for pulmonary embolism or diffuse alveolar hemorrhage from vasculitis.

Respiratory muscle weakness

Respiratory muscle weakness is seen most often in association with PM/DM, but it can complicate any CVD that has an active myositis component. Shrinking lung syndrome is seen only in patients with SLE.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Interstitial lung disease

Some serologies support the presence of an underlying CVD and may also predict the presence of ILD as a complication.

Anti-Jo-1 is anti-histidyl-tRNA synthetase that can be seen in the anti-synthetase syndrome. This syndrome consists of myositis, ILD, arthritis, and fever, although not all components of the syndrome are always present. Anti-Jo-1 is the most common of the anti-synthetases, but others include anti-threonyl (Anti-PL-7), anti-alanyl (anti-PL-12), anti-glycyl (anti-EJ), anti-isoleucyl (anti-OJ), and anti-asparginyl (anti-KS). Of those with anti-Jo-1 in PM/DM, 13-74% will have an associated ILD. The other anti-synthetase antibodies are associated with varying parts of the triad of the syndrome (ILD, arthritis and fever) and some occur in patients with ILD alone and thus a high index of suspicion is necessary to diagnose them. Anti-Ro52 against extractable nuclear antigen Ro52 is associated with more severe ILD. Patients with antibodies against melanoma differentiation-associated gene 5 (anti-MDA-5) can present with rapidly progressive ILD and skin ulceration in the absence of other dermatologic or myopathy symptoms. Anti-155/140, anti-signal recognition particle, and anti-Mi-2 do not appear to confer a higher risk of ILD.

Anti-Scl-70 is a breakdown product of topoisomerase I. Specific for scleroderma, it is more common in diffuse scleroderma than limited disease. In various studies, having a positive Scl-70 increased the risk of having ILD from one to five times over that of those without it. In addition, having a positive Scl-70 is associated with increased mortality. Its counterpart is the anti-centromere antibody that is also specific for scleroderma but is more common in limited disease and is more often associated with pulmonary hypertension.

RF is made up of antibodies against the Fc portion of IgG. These antibodies are fairly non-specific and are most often associated with RA. They can also be seen in Sjögren's syndrome and scleroderma and even in infection, though much less commonly. There is no association between ILD and RF. Overall, anticitrullinated peptide antibodies (ACPA) have been associated with airways disease in RA and less commonly with ILD, but this may be affected by the particular assay and type of ACPA measured.

What imaging studies will be helpful in making or excluding the diagnosis of a pulmonary complication of a collagen vascular disease?

Interstitial lung disease

Plain CXRs may demonstrate alveolar, interstitial, or focal consolidative changes, depending on the underlying pattern of ILD. Honeycombing may be evident in advanced disease. The CXR is relatively insensitive and non-specific. A HRCT with inspiratory and expiratory views is considered the most appropriate test for evaluating the underlying pattern of ILD.

Airways disease

Patients with small airways disease do not usually require further chest imaging unless they do not respond to usual therapies. Patients with CVD may have had chest imaging for other reasons. A CXR can show hyperinflation and mild bronchial wall thickening in the presence of airways disease, while a chest CT may show bronchial wall thickening, air-trapping, and bronchiectasis.

Patients with BO may have normal chest imaging so the diagnosis should be considered in a patient who has not responded to typical therapies for small airways disease and who has air-trapping or other signs of small airways disease on HRCT. Because air-trapping can help narrow the differential of a patient with CVD who presents with a cough or dyspnea, inspiratory and expiratory images should be obtained. Bronchial wall thickening or bronchiectasis may also be seen.

Chest CT images of patients with follicular bronchiolitis will show centrilobular and peribronchial nodules. Bronchiectasis, which should be evident on chest imaging, is defined as thickening and dilation of the airways. Airways are considered dilated if they are larger than their adjacent pulmonary artery.

CT imaging of the neck may demonstrate cricoarytenoid abnormalities in patients with RA and upper airway obstruction.

Pleural disease

Pleural effusions in SLE are typically small and bilateral, but moderate to massive effusions have been described. In RA effusions are also typically small and unilateral, but they can vary widely in size. Very small effusions can easily be missed on plain CXR; chest CT is more sensitive for detecting small effusions. Ultrasound can be useful in diagnosing the presence of an effusion and also in preparing for a thoracentesis by identifying an appropriate site.

Pulmonary vascular disease

Pulmonary hypertension may be suspected if the main and central pulmonary arteries are enlarged on CXR or chest CT. Dilation of the right atrium and ventricle may also be apparent. CT imaging may reveal a mosaic attenuation pattern, with decreased attenuation in areas of vascular dropout. Expiratory images may be helpful in ruling out air-trapping. As CT findings are relatively insensitive for pulmonary vascular disease, a transthoracic echocardiogram should be ordered in patients when diffusing capacity of the lung for carbon monoxide (DLCO) is reduced out of proportion to spirometry, in those with lightheadedness or dizziness, and annually in those with scleroderma to assess for pulmonary hypertension. Patients who present with diffuse alveolar hemorrhage from capillaritis or vasculitis usually have bilateral airspace opacities on CXR. On CT scan, multifocal ground-glass opacities or consolidation are present.

Respiratory muscle weakness

The presence of small lung volumes on CXR and chest CT in the absence of ILD is a clue, albeit a nonspecific one, to the possible presence of respiratory muscle weakness. There may be associated basilar atelectasis that can sometimes be mistaken for ILD. Fluoroscopic inspection of the diaphragm during a rapid inspiratory maneuver ("sniff test") can be helpful in documenting unilateral diaphragmatic weakness, but false negative studies are common when there is bilateral diaphragmatic weakness.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of a pulmonary complication of a collagen vascular disease?

Interstitial lung disease

Pulmonary function testing in ILD typically demonstrates restriction with a reduced DLCO. An isolated reduction in DLCO may be seen, in which case the clinician must do additional testing to ensure that it is not due to vascular disease and/or anemia.

Airways disease

Reversible airway obstruction should be present on pulmonary function testing in patients with small airways disease. The diagnosis may occasionally be made on HRCT which can detect changes consistent with small airways disease prior to detectable obstruction on pulmonary function testing. Patients should improve symptomatically with the typical therapies for small airways disease, such as bronchodilators and inhaled corticosteroid therapy.

On the other hand, patients with BO tend to have irreversible obstruction on pulmonary function testing and do not respond to usual therapies for small airways disease. BO is more likely to develop in patients with RA who have a positive RF than in those who do not. In addition, a diffusion defect may be present in patients with BO or follicular bronchiolitis. Patients with follicular bronchiolitis may present with normal pulmonary function testing or with evidence of obstruction or restriction.

Patients with upper airway obstruction may have flattening of the inspiratory and expiratory flow volume loop on pulmonary function testing.

Pleural disease

Depending on the size of the effusion and whether there is significant pain, there may be restriction on pulmonary function testing. However, unlike ILD, the DLCO should be preserved.

Pulmonary vascular disease

A diffusion defect is usually identified on pulmonary function testing in patients with pulmonary hypertension. The concurrent presence of significant restriction suggests the possibility of underlying ILD or respiratory muscle weakness. The acute presentation of alveolar hemorrhage in patients with vasculitis or capillaritis usually precludes the performance of pulmonary function testing, but if the test can be performed, it can reveal an elevated DLCO.

Respiratory muscle weakness

Pulmonary function testing typically demonstrates a restrictive pattern. The DLCO is often preserved, but it may be reduced if basilar atelectasis is present. A decrease in the forced vital capacity of more than 30% when measured supine (compared to seated) is a clue to the presence of respiratory muscle weakness. Measurement of maximum inspiratory and expiratory pressures can also be helpful.

What diagnostic procedures will be helpful in making or excluding the diagnosis of a pulmonary complication of a collagen vascular disease?

Interstitial lung disease

Varying patterns of ILD have been seen in CVD, but patients with clearly documented CVD typically do not need a lung biopsy to confirm the diagnosis or differentiate the subtypes especially given the low prevalence of UIP in non-RA CVD and the diagnostic yield of HRCT for most inflammatory ILDs including OP or lymphocytic interstitial pneumonia. However, lung biopsy should still be performed if infection or malignancy remains a major possibility. There is debate about whether knowing the pattern is helpful in either prognosis or therapeutic decisions. For example, some older studies suggest that the UIP pattern in CVD has a more indolent progression than the UIP pattern does in IPF.

More recent studies suggest that this conclusion may not be true. A provocative paper from 2010 suggests that the radiographic pattern is actually more predictive of outcome in CVD than the pattern seen on surgical lung biopsy, again arguing that biopsy may not be necessary or helpful.

Airways disease

Small airways disease should be confirmed by symptomatic improvement after bronchodilators or inhaled/systemic steroid therapy in patients who present with cough, wheezing, and reversible obstruction on pulmonary function testing. Additional diagnostic testing is usually not indicated. However, if a patient does not respond to typical therapy, and chest imaging shows air-trapping, a clinician may suspect BO. The patient can either undergo surgical lung biopsy at that point or undergo a trial of high-dose systemic steroids. Only a small percentage of patients with BO will respond to treatment with steroids, but most patients with severe small airways disease will.

A surgical lung biopsy may also be considered when follicular bronchiolitis is suspected. Surgical lung biopsy may be particularly helpful if the pulmonary symptoms precede the onset of articular manifestations of the CVD.

With classic findings of bronchiectasis on imaging and a history of CVD (especially Sjögren's syndrome), no additional diagnostic tests may be necessary. The clinician may obtain a barium swallow study to look for aspiration as a cause, especially if the distribution of the bronchiectasis is bibasilar. Testing should otherwise be aimed at ruling out other causes of bronchiectasis, especially if other manifestations of the CVD are mild. Laryngoscopy can confirm a diagnosis of upper airway obstruction in patients with cricoarytenoid arthritis.

Pleural disease

Thoracentesis should be performed in the presence of pleural effusions primarily to rule out alternative causes, such as infection or malignancy. The effusions associated with SLE and RA are exudative, and those associated with RA characteristically have low glucose levels, but there are otherwise no defining features.

Pulmonary vascular disease

An echocardiogram and right heart catheterization can be helpful in confirming the diagnosis of pulmonary hypertension. If pulmonary hypertension is suspected but the echocardiogram is normal, exercise studies should be considered, especially for patients who present only with mild or exertional symptoms or have evidence of right ventricular dilation. Due to the significant morbidity associated with pulmonary hypertension and the potential for pulmonary vasodilator therapy, patients with scleroderma should be screened annually for pulmonary hypertension with a transthoracic echocardiogram. Other testing, including a ventilation/perfusion scan and/or a sleep study, can rule out other causes of secondary pulmonary hypertension.

Bronchoalveolar lavage, which is helpful in diagnosing diffuse alveolar hemorrhage associated with capillaritis, demonstrates increasingly bloody fluid with successive aliquots.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of a pulmonary complication of a collagen vascular disease?

In patients with known CVD and pulmonary symptoms, the main purpose of histopathology and cytology is to exclude infection, malignancy, and whenever possible drug toxicity.

If you decide the patient has a pulmonary complication of a collagen vascular disease, how should the patient be managed?

Interstitial lung disease

The only rigorously studied treatment of ILD in the setting of CVD is cyclophosphamide. Three large, randomized, controlled trials and several prospective and retrospective non-controlled trials have examined its efficacy.

The scleroderma lung study (SLS1) randomized 158 patients with "active" ILD to either daily oral cyclophosphamide or placebo for one year. At the end of the year, those on treatment had a small but statistically significant benefit in the FVC of 2.5 percent predicted. The FAST (Fibrosing Alveolitis in Scleroderma Trial) was a British multicenter study of six months of IV cyclophosphamide, followed by six months of azathioprine versus placebo. That smaller study demonstrated a trend toward improvement in FVC on drug, but the improvement was not statistically significant. A subsequent study of the SLS1 group found that the benefit was lost within a year of when the drug was stopped. The scleroderma lung study 2 (SLS2) randomized 73 patients to 12 months of cyclophosphamide followed by 12 months placebo and 63 patients to mycophenolate mofetil for 24 months. The improvement in percent predicted FVC was not statistically different between the treatment arms and was similar to that seen in SLS1. However, mycophenolate mofetil was better tolerated than cyclophosphamide.

Other than these studies, all reports of therapy in CVD-ILD have been limited to case series and open-label non-randomized studies. In general, almost regardless of the underlying pathology, patients with progressive disease are given at least a trial of anti-inflammatory therapy, most often with prednisone. Not all patients with ILD changes on imaging will progress, so not all will need therapy. In addition, the use of steroid-sparing agents like azathioprine and mycophenolate is common in the hopes of slowing, if not improving, disease. There are case reports of the use of other agents, such as cyclosporine and tacrolimus, in refractory disease in PM/DM. The role of the TNF-alpha antagonists remains unclear. While there are case reports of ILDs improving on these agents, there are also many case reports showing a temporal association with worsening.

The relatively recent approval of anti-fibrotic agents for IPF including pirfenidone and nintedanib have sparked interest in their use in fibrotic CVD-ILD. In addition to case reports detailing their tolerability in those with CVD-ILD, there are multiple ongoing clinical trials to evaluate their efficacy in specific CVD-ILDs including RA and scleroderma. Interestingly, the available inclusion criteria only require the presence of ILD without specifying the histologic subtype. As many CVD-ILDs are characterized by inflammation and fibrosis as well as extrapulmonary manifestations, the use of anti-fibrotic agents will likely be more complicated than in those with IPF. During study design and analysis of these trials, it will be important to consider whether the proportion of inflammation and fibrosis on chest imaging impacts treatment response. In addition, careful consideration must be made to identify criteria for starting and titrating both anti-fibrotic agents and anti-inflammatory/biologic agents to maximize efficacy and minimize side effects.

Airways disease

Treatment of small airways disease associated with CVD is similar to that of asthma. In mild cases, a short-acting beta-agonist on an as-needed basis may suffice. As symptoms progress, inhaled corticosteroids, long-acting beta-agonists, and even systemic steroids can be employed.

Although most patients with BO do not respond to systemic steroids, a one- to three-month course of high-dose steroids (1 mg/kg) should be considered. If a patient does not respond after one or two months, steroids can be tapered off quickly. Long-term treatment with macrolides may improve symptoms. In progressive disease, lung transplantation should be considered.

Follicular bronchiolitis is treated by treating the underlying cause.

Treatment of bronchiectasis caused by CVD is the same as the treatment of bronchiectasis in other disorders. Treatment of the underlying cause should include addressing any occult aspiration that may be present (especially in Sjögren's syndrome or scleroderma). Therapies for occult aspiration may include speech therapy and gastroesophageal reflux precautions. Inhaled corticosteroids may improve symptoms from bronchiectasis, and airway clearance maneuvers can help manage secretions. Early antimicrobial therapy, as guided by sputum cultures and systemic steroids, are indicated at times of acute infections.

NSAIDs are used in the management of pain related to cricoarytenoid arthritis. In more severe cases, a temporary tracheostomy may be required to bypass an upper-airway obstruction. Surgical options to manage the arthritis should also be considered.

Pleural disease

Pleural effusion in the setting of RA or SLE often spontaneously resolves so it does not always need therapy. There is little data available to help guide management in RA; some reports suggest that steroids are helpful, but not all reports agree. Rarely, patients need recurrent thoracenteses for management, and even more rarely, they develop chronic pleural disease that requires decortication. In SLE, small effusions with mild pain may be treated with non-steroidal therapy. For more significant disease, steroid therapy, which is usually effective, remains the mainstay of treatment. There are case reports of successful pleurodesis for refractory disease.

Pulmonary vascular disease

Treatment of pulmonary hypertension in the setting of CVD should include treatment of the underlying disease. Diuretics and supplemental oxygen should be used if appropriate, and consultation with a pulmonary hypertension specialist for additional treatment options is advised. A number of oral, intravenous, and inhaled vasodilator agents are available for long-term administration; studies have demonstrated the efficacy of these agents in the setting of CVD, particularly scleroderma.

Mortality in association with alveolar hemorrhage is high. Supportive care with mechanical ventilation and blood transfusions can improve mortality rates. Patients should be started on high doses of systemic corticosteroids (500 mg-1g of methylprednisolone), and intravenous cyclophosphamide should be considered.

Respiratory muscle weakness

Treatment of respiratory muscle weakness in patients with PM/DM involves the use of steroids and other anti-inflammatory agents to address active myositis. There is no proven therapy for shrinking lung syndrome, although some case reports suggest a benefit from steroids, theophylline, and beta agonists.

Ventilatory support (ideally non-invasive) may be required for cases of severe respiratory muscle weakness while the underlying connective tissue disorder is treated.

What is the prognosis for patients managed in the recommended ways?

Interstitial lung disease

The presence of ILD increases mortality among those with CVD. The median survival was 2.6 years for those with RA-ILD compared to 9.9 years in those with RA without ILD. In studies grouping all CVD-ILD together, the survival appears to exceed that of IPF. However, the prognosis of those with CVD-ILD may be influenced, in part, by the CVD subtype and the underlying radiographic pattern. In a small case series, survival among those with undifferentiated CVD appeared worse than those with other CVDs. In another case series, survival among those with scleroderma-ILD exceeded that of other CVD-ILDs. Among those with RA-ILD, the presence of a UIP pattern on HRCT was associated with worse survival than other HRCT patterns and was similar to IPF. Understanding the impact of CVD subtype and radiographic pattern on survival will be important for future epidemiologic and therapeutic trial designs since subtyping CTD-ILD will come at the cost of smaller sample sizes.

Airways disease

Respiratory failure from acute subluxation of cricoarytenoid joint or from airway edema in RA is associated with significant mortality especially if difficult airway anatomy is not recognized early. Obliterative bronchiolitis can progress acutely or indolently but is associated with a poor prognosis. While ~30% of bronchiectasis is clinically asymptomatic, when it is severe enough to be associated with symptoms, it is associated with increased mortality.

Pleural disease

Although pleural effusions associated with SLE and RA may require thoracentesis, they generally are not associated with increased mortality.

Pulmonary vascular disease

Compared to other CVDs, scleroderma is associated with both a higher prevalence of and mortality from pulmonary hypertension. In a large registry of patients (n=429) from the U.K., those with combined respiratory disease and pulmonary hypertension had a worse 3-year survival (28%) compared to those with isolated resting pulmonary hypertension (47%). Three-year survival in SLE-associated pulmonary hypertension was higher at 75%.

Respiratory muscle weakness

Concomitant upper pharyngeal and respiratory muscle weakness can lead to aspiration pneumonia, hypoventilation, atelectasis, and mucus plugging and can occur in patients with underlying ILD, making it difficult to quantify the true impact of respiratory muscle weakness on mortality.

What other considerations exist for patients with a pulmonary complication of a collagen vascular disease?

If extrapulmonary manifestations of CVD are well controlled on minimal immunosuppression, consideration of lung transplantation is appropriate for progressive pulmonary manifestations. Recent trials have demonstrated comparable one and five-year survival among patients with scleroderma when compared to non-CVD pulmonary fibrosis.

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