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 that are most commonly associated with pulmonary complications are systemic lupus erythematosis (SLE), scleroderma (Scl), 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 (Figure 1).

  • Interstitial lung disease (ILD)

  • Airways disease

  • Pleural disease

  • Pulmonary vascular disease

  • Respiratory muscle weakness

  • Miscellaneous

Table 1.

Pulmonary Manifestations of Various Collagen Vascular Diseases

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 (Figure 2). With the exception of rheumatoid arthritis, where usual interstitial pneumonitis (UIP) predominates, among the patterns of ILD, non-specific interstitial pneumonitis (NSIP) is most commonly seen in CTD. Other patterns, including bronchiolitis obliterans organizing pneumonia (BOOP), 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 collagen vascular disease 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 don't help the clinician distinguish among the possible pulmonary complications of the CVD, additional testing is required for the diagnosis.

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 is most commonly seen in Sjögren's syndrome. 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.

RA patients who present with hoarseness, dysphagia, or pain with speaking or swallowing should be evaluated for an upper airway obstruction caused by cricoarytenoidarthritis. 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 (Figure 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 percent of patients. The thoracentesis findings in SLE are consistent with inflammation but are not very specific. The effusions are exudates with an elevated white blood count with a non-specific differential. They have low pleural fluid complement levels, and LE cells (PMNs 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, the effusions are likely to be 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 RF titers. Up to half of the time, they occur in those with subcutaneous nodules. Findings on thoracentesis that are more suggestive of RA include high protein levels, low glucose levels, 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 either secondary pulmonary hypertension related to parenchymal disease or primary pulmonary hypertension. Vasculitis, including necrotizing pulmonary capillaritis, is a rare complication of collagen vascular disease, which is seen most commonly in patients with SLE. Pulmonary embolism occurs with increased frequency in patients with SLE and antiphospholipid antibody syndrome.

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 and capillaritis should be considered in patients who present with diffuse alveolar hemorrhage.

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 that is 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 not clear.

Miscellaneous disorders

Acute reversible hypoxemia syndrome is a rare complication of SLE. Patients present with acute hypoxia and the lack of abnormalities on chest imaging includes the absence of thromboembolic disease. Treatment includes corticosteroids with or without aspirin.

Patients with rheumatoid arthritis 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 connective tissue disease without significant symptoms or complications.

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

Not applicable

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 CVSDs varies according to the screening method used. In some studies, up to 85 percent of patients with scleroderma had evidence of ILD by HRCT, but only 14-67 percent had clinically significant (i.e., causing morbidity and mortality) disease. ILD has become the leading cause of disease deaths in patients with scleroderma.

In rheumatoid arthritis, 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 large. The prevalence of ILD in dermatomyositis/polymyositis is less well established. One prospective study found ILD in 70 percent of newly diagnosed patients, and of those, about half progressed over the next several years. Despite the relative frequency of lupus, ILD is a less common complication of that disease than of other pulmonary manifestations.

Airways disease

The risk of developing small airways obstruction and bronchiolitis obliterans is greatest for patients with RA and Scleroderma. Follicular bronchiolitis is seen most often in patients with RA, Scl, or Sjögren's syndrome. Patients with RA, Sjögren's syndrome, and SLE are at greatest risk for developing bronchiectasis. Upper airway obstruction is seen in patients with RA.

Pleural disease

Older studies suggest that 30-75 percent of patients with SLE will have pleuritis with or without pleural effusions at some point in their disease courses. Patients with RA also frequently have pleural effusions (and, less commonly, pleurisy), with estimates ranging from 20 percent to 50 percent. Scl, PM/DM and Sjögren's rarely produce pleural effusions. Because MCTD patients represent an overlap of SLE with Scl and PM, 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 Scl (particularly the CREST variant), MCTD, and SLE. Patients with SLE and associated antiphospholipid antibody syndrome are at greatest risk for pulmonary embolism.

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 collagen vascular disease 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 ant-synthetases, but others include anti-threonyl (Anti-PL-7), anti-alanyl (anti-PL-12), anti-glycyl (anti-EJ), anti0isoleucyl (anti-OJ), and anti-asparginyl (anti-KS). Of those with this antibody in PM/DM, 13-74 percent will have an associated ILD.

Anti-Scl-70 is a breakdown product of topoisomerase I. Specific for scleroderma, it is more common in diffuse scleroderma than in 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.

Rheumatoid factor (RF) is made up of antibodies against the Fc portion of IgG. These antibodies are fairly non-specific and are most often associated with rheumatoid arthritis. They can also be seen in Sjögren's syndrome and scleroderma and even in infection, though much less commonly. There is no association with ILD and RF in the presence of ILD. Cyclic citrullinated peptides (CCP) are considered more specific.

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 chest radiographs may demonstrate alveolar, interstitial, or focal consolidative changes, depending on the underlying pattern of ILD. Honeycombing may be evident in advanced disease. The chest radiograph is relatively insensitive and non-specific. A high-resolution chest CT 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 collagen vascular diseases may have had chest imaging for other reasons. A chest x-ray can show hyperinflation and mild bronchial wall thickening in the presence of airways disease, while a chest CT scan 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 markers of small airways disease on high-resolution chest imaging. Because air-trapping can help narrow the differential of a patient with collagen vascular disease who presents with a cough or shortness of breath, 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 effusion in SLE is typically small and bilateral, but moderate to massive effusions have been described. In RA, effusions are also typically small, but they can vary widely in size. They are usually unilateral. Very small effusions can easily be missed on plain chest x-ray; chest CT is more sensitive for detecting small effusions. Ultrasound can be useful in diagnosing the presence of an effusion, but it may also be helpful 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 chest X-ray or CT scan of the chest. 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. Patients who present with diffuse alveolar hemorrhage from capillaritis or vasculitis usually have bilateral airspace opacities on chest X-ray. On CT scan, multifocal ground-glass opacities or consolidation are present.

Respiratory muscle weakness

The presence of small lung volumes on chest x-ray 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 diffusing capacity. An isolated diffusing capacity 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 high-resolution chest imaging that can detect changes consistent with small airways disease prior to a 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 the usual therapies for small airways disease. BO is more likely in patients with RA who have a positive rheumatoid factor 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 on whether there is significant pain, there may be restriction on pulmonary function testing. However, unlike in 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 interstitial lung disease 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 diffusion capacity.

Respiratory muscle weakness

Pulmonary function testing typically demonstrates a restrictive pattern. The diffusing capacity is often preserved, but it may be reduced if basilar atelectasis is present. A decrease in the forced vital capacity of more than 30 percent when measured in the supine position (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 the CVDs, but patients with clearly documented collagen vascular disease typically do not need a lung biopsy to confirm the diagnosis or differentiate the subtypes. 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 collagen vascular disease 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 or systemic steroid therapy in patients who present with coughing and 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 this time 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 collagen vascular disease.

With classic chest imaging, findings of bronchiectasis, and a history of collagen vascular disease (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 the other manifestations of the collagen vascular disease are mild.

A laryngoscopy can confirm a diagnosis of upper airway obstruction in patients with cricoaretynoid 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. 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?

None

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 rigorous, studied treatment of ILD in the setting of CVD is the use of cyclophosphamide. Two large, randomized, controlled trials and several prospective and retrospective non-controlled trials have examined its efficacy.

The scleroderma lung study (SLS) 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 SLS group found that the benefit was lost within a year of when the drug was stopped. A follow-up study of cyclophosphamide versus mycophenelate is being conducted now.

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 frequent 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 of DM/PM. The role of the TNF-alpha antagonists remain unclear. While there are case reports of ILD's improving on these agents, there are also many of case reports of a temporal association with worsening.

Airways disease

Treatment of small airways disease associated with collagen vascular disease is similar to that of patients with asthma. In mild cases, a short-acting beta-agonist on an as-needed basis may be sufficient. 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 collagen vascular disease is the same as treatment of bronchiectasis as a result of other disorders. Treatment of the underlying cause should include addressing any occult aspiration that may be present (especially in Sjögren's syndrome or scleroderma). Inhaled corticosteroids may improve symptoms, 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 cricoaretynoid arthritis. In more severe cases, a temporary tracheostomy may be required to bypass an upper-airway obstruction. Surgical options to manage the arthritis should be considered.

Pleural disease

Pleural effusion in the setting of RA or SLE often spontaneously resolves so it does not always need treatment. There is little data available to help guide management of RA; some reports suggest that steroids are helpful, but not all reports agree. Rarely, patients need recurrent thoracentesis 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 use of pleurodesis for refractory disease.

Pulmonary vascular disease

Treatment of primary pulmonary hypertension in the setting of pulmonary vascular disease 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 as needed can improve mortality rates. Patients should be started on high doses of systemic corticosteroids(500 mg to 1 g 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?

Not applicable

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

Not applicable

What’s the evidence?

Aubart, F, Crestani, B, Nicaise-Roland, P, Tubach, F, Bollet, C, Dawidowicz, K. "High levels of anti-cyclic citrullinated peptide autoantibodies are associated with co-occurrence of pulmonary diseases with rheumatoid arthritis". J Rheumatol. vol. 38. 2011. pp. 979-82.

A cross sectional study of 252 RA patients screened with HRCT and anti-CCP2 antibodies found that elevated anti-CCP was an independent risk factor for lung disease.

Balbir-Gurman, A, Yigla, M, Nahir, AM, Braun-Moscovici, Y. "Rheumatoid pleural effusion". Semin Arthritis Rheum. vol. 35. 2006. pp. 368-78.

A systematic review of published cases of RA-associated pleural effusions.

Bongartz, T, Nannini, C, Medina-Velasquez, YF, Achenbach, SJ, Crowson, CS, Ryu, JH. "Incidence and mortality of interstitial lung disease in rheumatoid arthritis: a population-based study". Arthritis Rheum. vol. 62. 2010. pp. 1583-91.

A population-based incidence cohort of patient with RA in Minnesota followed over years. This study describes the incidence of and risk factors for ILD and its prognosis.

Kim, EJ, Elicker, BM, Maldonado, F, Webb, WR, Ryu, JH, Van Uden, JH. "Usual interstitial pneumonia in rheumatoid arthritis-associated interstitial lung disease". Eur Respir J. vol. 35. 2010. pp. 1322-8.

A retrospective cohort study of patients with RA-ILD looks at radiographic patterns and their association with outcomes.

Fathi, M, Vikgren, J, Boijsen, M, Tylen, U, Jorfeldt, L, Tornling, G. "Interstitial lung disease in polymyositis and dermatomyositis: longitudinal evaluation by pulmonary function and radiology". Arthritis Rheum. vol. 59. 2008. pp. 677-85.

A prospective cohort study of newly diagnosed patients with DM/PM and screening for ILD with HRCT.

Good, JT, King, TE, Antony, VB, Sahn, SA. "Lupus pleuritis: clinical features and pleural fluid characteristics with special reference to pleural fluid antinuclear antibodies". Chest. vol. 84. 1983. pp. 714-8.

A small, earlier study describing the characteristics of eighteen patients with lupus pleuritis that focuses on the pleural fluid analysis.

Haupt, HM, Moore, GW, Hutchins, GM. "The lung in systemic lupus erythematosus: analysis of the pathologic changes in 120 patients". Am J Med. vol. 71. 1981. pp. 791-8.

One hundred twenty patients with SLE who underwent autopsy at Hopkins were reviewed and their pathologic findings categorized.

Hoyles, RK, Ellis, RW, Wellsbury, J, Lees, B, Newlands, P, Goh, NS. "A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma". Arthritis Rheum. vol. 54. 2006. pp. 3962-70.

The FAST trial compares IV cyclophosphamide followed by azathioprine versus placebo in scleroderma-associated ILD.

Hunninghake, GW, Fauci, AS. "Pulmonary involvement in the collagen vascular diseases". Am Rev Respir Dis.. vol. 119. 1979. pp. 471-503.

An older review of pulmonary involvement in collagen vascular diseases.

Olson, AL, Swigris, JJ, Sprunger, DB, Fischer, A, Fernandez-Perez, ER, Solomon, J. "Rheumatoid arthritis-interstitial lung disease-associated mortalit". Am J Respir Crit Care Med.. vol. 183. 2011. pp. 372-8.

The mortality and incidence of RA-ILD in the United States from 1988 to 2004 was studied using death certificate diagnoses.

Perez, T, Remy-Jardin, M, Cortet, B. "Airways involvement in rheumatoid arthritis: clinical, functional, and HRCT findings". Am J Respir Crit Care Med. vol. 157. 1998. pp. 1658-1665.

Prospective study demonstrating a high incidence of bronchiectasis and small airways disease in patients with RA.

Romero, S, Barroso, E, Gil, J, Aranda, I, Alonso, S, Garcia-Pachon, E. "Follicular bronchiolitis: clinical and pathologic findings in six patients.". Lung. vol. 181. 2003. pp. 309.

Describes a form of small airways disease sometimes seen in patients with RA.

Walker, WC, Wright, V. "Pulmonary lesions and rheumatoid arthritis". Medicine (Baltimore). vol. 47. 1968. pp. 501-20.

An early seminal study of 516 patients with RA seen in a rheumatology clinic were retrospectively studied to describe the patterns of pulmonary disease seen in this population.

Tashkin, DP, Elashoff, R, Clements, PJ, Goldin, J, Roth, MD, Furst, DE. "Scleroderma Lung Study Research Group. Cyclophosphamide versus placebo in scleroderma lung disease". NEngl J Med.. vol. 354. 2006. pp. 2655-66.

The largest RCT of therapy in CTD-related ILD. This study compared a year of oral daily cyclophosphamide to placebo in patients with scleroderma-associated pulmonary fibrosis.

Warrington, KJ, Moder, KG, Brutinel, WM. "The shrinking lungs syndrome in systemic lupus erythematosus.". Mayo Clin Proc. vol. 7. 2000. pp. 467.

Describes the unusual complication of diaphragmatic dysfunction associated with SLE.

Winslow, WA, Ploss, LM, Loitman, B. "Pleuritis in systemic lupus erythematosus: its importance as an early manifestation in diagnosis". Ann Intern Med. vol. 49. 1958. pp. 70-88.

Another early seminal study describing a large series of SLE patients with pleuritis. The study also reviewed all the cases published in the literature to that point.
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