key: cord-0034781-jsbca3xq authors: Butnor, Kelly J.; Khoor, Andras title: Collagen Vascular Diseases and Disorders of Connective Tissue date: 2008 journal: Dail and Hammar’s Pulmonary Pathology DOI: 10.1007/978-0-387-68792-6_20 sha: 5060cbd289b48b4b2005376c2c18070830a80160 doc_id: 34781 cord_uid: jsbca3xq The collagen vascular diseases, also referred to as connective tissue diseases, are a diverse group of systemic inflammatory disorders thought to be immunologically mediated. The concept of collagen vascular disease began to take shape in the 1930s, when it was recognized that rheumatic fever and rheumatoid arthritis can affect connective tissues throughout the body.1,2 During the following decade, as conditions such as systemic lupus erythematosus (SLE) and scleroderma came to be viewed as systemic diseases of connective tissue, the terms diffuse connective disease and diffuse collagen disease were proposed.3,4 During the same period, the designation of diffuse vascular disease was proposed for diseases such as scleroderma, polymyositis, SLE, and polyarteritis nodosa, which featured widespread vascular involvement.5 With the realization that many of these entities can exhibit both systemic connective tissue manifestations and vascular abnormalities, the unifying designation of collagen vascular disease was introduced.6 The collagen vascular diseases, also referred to as connective tissue diseases, are a diverse group of systemic inflammatory disorders thought to be immunologically mediated. The concept of collagen vascular disease began to take shape in the 1930s, when it was recognized that rheumatic fever and rheumatoid arthritis can affect connective tissues throughout the body.l,2 During the following decade, as conditions such as systemic lupus erythematosus (SLE) and scleroderma came to be viewed as systemic diseases of connective tissue, the terms diffuse connective disease and diffuse collagen disease were proposed. 3 ,4 During the same period, the designation of diffuse vascular disease was proposed for diseases such as scleroderma, polymyositis, SLE, and polyarteritis nodosa, which featured widespread vascular involvement. 5 With the realization that many of these entities can exhibit both systemic connective tissue manifestations and vascular abnormalities, the unifying designation of collagen vascular disease was introduced. 6 Pleuropulmonary manifestations are a significant source of morbidity and mortality for patients with collagen vascular disease. An estimated 1600 deaths result from pulmonary manifestations of collagen vascular disease each year in the United States, which accounts for nearly one quarter of all deaths related to interstitial lung disease. 7 The incidence of collagen vascular diseaserelated interstitial lung disease appears to be increasing, likely the result of improved recognition and enhancements in diagnostic imaging. 8 This chapter discusses pulmonary manifestations of collagen vascular diseases, pulmonary involvement by inflammatory bowel disease, primary biliary cirrhosis, and disorders of connective tissue that are not categorized as collagen vascular diseases. 722 General Histopathologic Patterns and Approach to Diagnosis While a few pulmonary lesions, such as rheumatoid nodules, are essentially pathognomonic of collagen vascular disease, the collagen vascular diseases are best considered a group of disorders with protean pulmonary manifestations. Virtually any component of the lungs, from the large airways to the interstitium, can be affected by collagen vascular disease (Table 20 .1). Pulmonary involvement by collagen vascular disease can simulate a variety of primary diseases of the lung, in particular, the idiopathic interstitial pneumonias (see Chapter 19 for a complete description of the idiopathic interstitial pneumonias). The successful recognition of collagen vascular disease-related interstitial lung disease, therefore, requires the careful integration of clinical and radiographic data. Obtaining this information can often prove challenging. While a patient may have an established diagnosis of collagen vascular disease, such information is sometimes not communicated to the pathologist. In other cases, the patient may have rheumatologic symptoms or signs, but has not been fully evaluated for collagen vascular disease prior to lung biopsy. Pulmonary disease can precede other manifestations of collagen vascular disease by months or even years, adding to the diagnostic challenge. 9 -11 It has been known for some time that collagen vascular diseases can mimic the histologic pattern of interstitial lung disease that is seen in idiopathic pulmonary fibrosis (IPF).12 For this reason, it is essential to exclude collagen vascular disease in patients who exhibit a pattern consistent with usual interstitial pneumonia (UIP) on lung biopsy with a thorough rheumatologic evaluation and serologic studies such as antinuclear antibody (ANA) and rheumatoid factor. It is particularly important for the pathologist to suggest the possibility of collagen vascular disease-related interstitial lung disease in cases with a UIP pattern in which the clinical features are not entirely typical of IPF. Such cases include patients younger than 50 years of age, never smokers, females, and those with atypical radiographic findings. Collagen vascular diseaserelated interstitial lung disease with a UIP-like pattern progresses more slowly and exhibits a more favorable prognosis than does idiopathic UIp' 13 -17 The reason for the differences in behavior between these entities is unclear, but it has been noted that the collagen vascular disease-related UIP-like pattern shows fewer fibroblastic foci than idiopathic UIp ' 16 Prior to the recognition of nonspecific interstitial pneumonia (NSIP) (see Chapter 19) , the UIP pattern was the most frequently observed pathologic pattern of collagen vascular disease-related interstitial pneumonia. [18] [19] [20] [21] However, since its introduction, NSIP has come to be recognized as the most common histologic pattern of interstitial lung disease in collagen vascular disease, accounting for 40% to 60% of cases of collagen vascular disease-related chronic interstitial lung disease in recent series. 22 -24 This is in contrast to the idiopathic interstitial pneumonias, in which the most common histologic pattern, UIP, comprises three quarters of all cases. 24 Although data are limited, the prognosis of NSIP in the setting of collagen vascular disease appears to be similar to that for idiopathic NSIp' 15 . 22 ,25-28 As with idiopathic fibrotic NSIP, the fibrotic pattern of NSIP in the setting of collagen vascular disease is associated with poorer survival than the cellular pattern of NSIp ' 22 . 28 It is not uncommon for several histologic patterns, each mimicking one of the categories of idiopathic interstitial pneumonia, to coexist. Alternatively, a mixture of overlapping patterns with histologic features that resemble several of the idiopathic interstitial pneumonias can occur. In addition to resembling the idiopathic interstitial pneumonias, collagen vascular disease may produce a pattern of interstitial lung disease that is difficult to categorize. In such cases, the recognition of subtle features associated with collagen vascular disease, such as follicular bronchiolitis or a bronchiolocentric distribution of interstitial pneumonia, may allow the pathologist to suggest collagen vascular disease as a possible etiology. Patients with collagen vascular disease are often treated with immunosuppressive or cytotoxic drugs that predispose them to opportunistic infections. Both drug toxicity and infection can mimic de novo collagen vascular disease-related interstitial lung disease. Distinguishing between these entities can be difficult if not impossible in some cases (see Chapter 22) . Transbronchial biopsies are of limited utility in the evaluation of collagen vascular disease-related lung disease due to the small amount of tissue they provide. 29 . 3o Bronchoalveolar lavage (BAL) does playa role in the workup of patients with known or suspected collagen vascular disease inasmuch as its aids in the detection of pulmonary infections. 31 ,32 However, the pathologic assessment of interstitial lung disease associated with collagen vascular disease is best accomplished by open or video-assisted thoracoscopic wedge biopsy. In determining the most appropriate site, or preferable sites to biopsy, the same biopsy guidelines as have been established for suspected idiopathic interstitial lung disease apply. 33 The surgeon should be cautioned to avoid sampling the most severely affected areas, as tissue from such sites may show only nonspecific end-stage honeycomb fibrosis. 34 Sampling less severely involved regions, as well as the transition between normal and affected parenchyma is likely to be most diagnostically useful (see Chapter 1). When processing wedge biopsies from patients with an acute or subacute course, fresh tissue should be taken for microbiologic cultures if not already done so intraoperatively. The liberal use of histochemical stains for infectious organisms in biopsies from such patients can be diagnostically rewarding. In patients with known or suspected Sjogren's syndrome, fresh tissue should be set aside for possible flow cytometric or immunohistochemical studies, given the relative frequency of lymphoproliferative disorders in such patients. Rheumatic fever is a disease of presumed autoimmune etiology associated with antecedent throat infection with group A streptococcus. Once common in the Unites States and other Western countries, rheumatic fever has virtually disappeared from developed countries during the last half-century. As a result, little has been published about its pulmonary manifestations. 35 Rheumatic pneumanias have been the subject of sporadic reports describing both lobar and multilobar consolidation. 36 ,37 In 1966, Massumi and Legier 37 described three patients with active rheumatic carditis complicated by adult respiratory distress syndrome (ARDS) with a rapidly fatal course. Autopsies were performed in two of their cases, which disclosed heavy lungs with organizing pneumonia, interstitial edema, and focal vasculitis. Rheumatic heart disease remains a major health care problem in developing countries, where rheumatic mitral stenosis commonly affects juvenile age groups. Lungs from cases of mitral stenosis exhibit pulmonary hypertension and prominent bronchial smooth muscle hypertrophy. 38.39 Pulmonary hypertension in such cases manifests as moderate to marked medial hypertrophy of medium-sized branches of the pulmonary artery and dilatation lesions (see Chapter 28). Rheumatoid arthritis (RA) is a chronic systemic disease characterized by symmetric nonsuppurative arthritis of the small peripheral joints. It affects about 1 % of the general population worldwide. Sir Alfred Garrod 40 first introduced the term rheumatoid arthritis in 1876 to distinguish it from gout. Pulmonary involvement was first described by Ellman and Ball in 1948. 41 In autopsy studies, approximately half of patients with RA have evidence of active or remote pleuropulmonary disease. 42 ,43 Although RA is more common in women than in men, rheumatoid lung disease is more frequently observed in men with long-standing rheumatoid factor-positive RA and subcutaneous nodules. 42 ,44 Rheumatoid lung disease shows ethnic variations in prevalence; it seems to be more common in Anglo-Saxon than in Mediterranean countries. 45 Studies suggest that extraarticular disease is a major predictor of mortality in patients with RA. 46 Rheumatoid arthritis can involve all major compartments of the lung and may lead to (1) airway disease, (2) diffuse alveolar hemorrhage, (3) interstitial lung disease, (4) pulmonary rheumatoid nodules, (5) vascular lesions, and (6) pleural disease. The prevalence of airflow obstruction in patients with RA is remarkably high, suggesting that airway disease may be a common form of lung involvement. 47 Airway complications of RA include constrictive (obliterative) bronchiolitis, follicular bronchiolitis, bronchiectasis, and bronchocentric granulomatosis. 19.22.47-62 Rheumatoid arthritis patients with constrictive bronchiolitis present with rapidly developing breathlessness, rales, and a high-pitched mid-inspiratory squeak.47 Chest radiographs show distended but otherwise normallungs. 47 High-resolution computed tomography (HRCT) reveals small nodular shadows in the centrilobular regions, patchy areas of low attenuation, and peribronchial thickening. 50 Tests of lung function show airflow obstruction with air trapping. 47 In spite of treatment with antibiotics, bronchodilators, or corticosteroids, most patients die of respiratory failure in 5 to 18 months after the onset of pulmonary symptoms. 47 An association between constrictive bronchiolitis and penicillamine in RA patients has been reported. 48 It has been suggested that penicillamine may impair healing of bronchiolitis. The histologic features of constrictive bronchiolitis in RA are similar to those seen in patients without an underlying connective tissue disease ( Fig. 20.1 ) (see also Chapter 25) . Follicular bronchiolitis is a common finding in patients with RA. Tansey et al. 22 reviewed lung biopsies from patients with RA and respiratory symptoms. Follicular bronchiolitis was the major histologic pattern in six patients (16%) and a minor pattern in five others (14%). The RA patients with follicular bronchiolitis have a chronic clinical course with a main complaint of productive cough.50 High-resolution CT reveals small centrilobular nodules variably associated with peribronchial nodules and ground-glass opacities. 5o ,56 Histologically, coalescent reactive germinal centers are seen adjacent to airways.2o Follicular bronchiolitis can be differentiated from lymphoproliferative disorders by the absence of tumefactive growth, rare lymphoepithelial complexes, and benign appearing follicles (see Chapter 32) . 63 Bronchiectasis can be a feature of rheumatoid arthritis and is often found in patients with severe long-standing nodular disease. Productive cough, hemoptysis, and dyspnea are the most common respiratory symptoms. Radiographic abnormalities in RA-associated bronchiectasis include bibasilar, diffusely increased, interstitial markings and focal infiltrates. Recurrent pulmonary infections and respiratory failure are frequent and may be fatal (see Chapter 5) . 60 Bronchocentric granulomatosis has been reported in a few patients with RA. 61 ,62 The differential diagnosis in such cases includes mycobacterial and fungal infections as well as bronchocentric rheumatoid nodules. 64 Obliteration of the airway lumen and epithelium is an important histologic feature of bronchocentric granulomatosis. This feature is helpful in distinguishing bronchocentric granulomatosis from other conditions that present with peribronchial granulomas. Diffuse alveolar hemorrhage is a rare complication of RA. A clinicopathologic study of 34 patients with biopsyconfirmed diffuse pulmonary hemorrhage by Travis Prior to the description of NSIP in 1994, UIP was the most common pattern of interstitial lung disease in patients with RA, occurring in 1 % to 4% of cases. 76 . 77 However, if current American Thoracic Society/European Respiratory Society criteria for the diagnosis of idiopathic interstitial pneumonias are applied, NSIP is more common than UIP in RA (see Chapter 19) .22.33 The relationship of DIP and respiratory bronchiolitis to RA is uncertain, given that most reported patients are also smokers. 22 Rare cases of rapidly fatal pulmonary fibrosis, clinically resembling Hamman-Rich syndrome or accelerated decline of idiopathic pulmonary fibrosis, have been described. 78 .79 Histologically, these cases show a combination of UIP pattern and diffuse alveolar damage. 79 Open lung biopsy is the preferred method for evaluating RA -associated interstitial lung disease. 19 optic bronchoscopy and BAL.32.80-82 The histopathologic patterns of interstitial lung disease in RA are generally considered indistinguishable from corresponding idiopathic interstitial pneumonias (discussed in detail in Chapter 19) .33.83-85 However, there are some subtle features that, although not specific, may suggest a rheumatoid origin in cases with a UIP-like pattern. 86 The reported prevalence of subcutaneous rheumatoid (necrobiotic) nodules varies greatly, ranging from 13.5% to 53%.87-89 Pulmonary rheumatoid nodules, which can occur singly or as multiple nodules, are the most characteristic but least frequent type of lung lesions in RA. 90 - 93 Walker and Wright 90 reported only three cases (0.6%) in a series of 516 patients, while Jurik et a1. 92 found only one case (0.3%) in a series of 309 patients. Pulmonary rheumatoid nodules are most commonly found in men with advanced seropositive RA and subcutaneous nodules. However, pulmonary rheumatoid nodules can occasionally appear before the onset of arthritis.2o.91.93-97 Solitary rheumatoid nodules may be confused with malignant tumors radiographically.98-loo However, pulmonary adenocarcinomas may also be associated with rheumatoid nodules. iOl 106 Pulmonary rheumatoid nodules may cavitate, occasionally leading to pneumothorax, pyopneumothorax, or fungal colonization. 107-1 14 Caplan syndrome, also known as rheumatoid pneumoconiosis, occurs when rheumatoid nodules develop in patients with pneumoconiosis. Originally described in coal workers with RA, the concept of Caplan syndrome has been subsequently broadened to include RA patients with silica-associated or asbestos-associated lung disease. 115 -122 Radiographically, multiple well-defined homogeneous rounded opacities are seen. 119 Histologically, the nodules described by Caplan are similar to rheumatoid pulmonary nodules, with the occasional addition of black coal dust in the centrally necrotic area of the nodules (see Pleural effusion occurs in only 3% to 5% of patients with RA.1II2. 153 It is usually associated with other manifestations of active disease such as arthritis, subcutaneous rheumatoid nodules, and high titers of rheumatoid factor. 42 Pleural effusions in RA are typically exudative with a low pH, low glucose, and high concentrations of protein and lactate dehydrogenase. 102 . 147 .1 5 1.152,154.155 In most rheumatoid effusions, RA cells can be identified. Rheumatoid arthritis cells are cytologically similar to lupus erythematosus (LE) cells and are characterized by basophilic cytoplasmic inclusions that have been shown to represent phagocytosed IgM rheumatoid factor in immune complex form. The RA cells are not specific for RA and can also be found in other connective tissue diseases, tuberculosis, various malignancies, and pleural effusion of unknown etiology.152 In contrast to adult-onset RA, there have been relatively few descriptions of pulmonary involvement in juvenile RA, and only rare cases with histologic documentation. 83 -85 ,90,156-158 However, over 50% of patients with juvenile RA have abnormal pulmonary function tests, indicating lung disease in juvenile RA may be more prevalent than the small number of reported cases would suggest. 157 Pulmonary lesions in juvenile RA are identical to those seen in adult RA and include pleuritis, pleural adhesions, constrictive bronchiolitis, follicular bronchiolitis, lymphoid interstitial pneumonia, pulmonary vasculitis, pulmonary hypertension, and diffuse alveolar hemorrhage ( Fig. 20.2) . 65, 84, 85, [158] [159] [160] [161] [162] [163] [164] Systemic Lupus Erythematosus Systemic lupus erythematosus (SLE) is a multisystemic disease of autoimmune origin, characterized by a variety of autoantibodies, in particular antinuclear antibodies. Acute or insidious in onset, SLE is a chronic, often febrile disease characterized principally by injury to the skin, joints, kidney, and serosal membranes. However, virtually every organ can be affected, Pleuropulmonary involvement is more common in SLE than in any other connective tissue disease and is associated with an increased risk of mortality, 9, 12, 42, [165] [166] [167] [168] Although the reported incidence ranges from as low as 9% to as high as 98%, the overall rate of pulmonary involvement in SLE in most series is between 50% and 70%.9.12,42, 165-167.169,170 The number of patients with histologically documented significant lung lesions is around 20%. 11, 12, 167, [170] [171] [172] [173] [174] [175] [176] [177] [178] Systemic lupus erythematosus is associated with an array of pulmonary manifestations, Because of the common use of immunosuppressive therapy, SLE patients are prone to infectious complications, and infection is the K.J. Butnor and A. Khoor most common cause of pulmonary infiltrates in these pa tients. 9 .1 2 ,165,172,175 Other major complications include (1) diffuse alveolar hemorrhage, (2) acute lupus pneumonitis, (3) pulmonary hypertension, (4) antiphospholipid syndrome, (5) pleural disease, (6) shrinking lung syndrome, and (7) neoplasms. Diffuse alveolar hemorrhage occurs in approximately 2 % of SLE patients. 168 The typical presentation of acute dyspnea and extensive pulmonary infiltrates may mimic acute lupus pneumonitis, especially in the absence of hemoptysis,179,1811 Both diseases are life-threatening and are treated empirically with corticosteroids and immunosuppression.l8l However, the differential diagnosis in such cases includes opportunistic infection. A misdiagnosis may lead to a potentially disastrous increase in immunosuppressive therapy. Therefore, BAL is recommended in SLE patients with unexplained extensive pulmonary infiltrates to exclude opportunistic infection. In up to 20% of patients, diffuse alveolar hemorrhage is the presenting or dominant manifestation of SLE. 179 ,180 In such cases, SLE must be distinguished from other major causes of diffuse alveolar hemorrhage, such as Wegener granulomatosis, Goodpasture syndrome, microscopic polyangiitis, and idiopathic pulmonary hemorrhage. 65 Histopathologic examination reveals capillaritis in most cases of SLE-related diffuse alveolar hemorrhage, but in some patients, bland pulmonary hemorrhage without capillaritis has been reported. 65 ,179,182-184 Capillaritis is manifested by an infiltrate of necrotic neutrophils within the alveolar septa and is often associated with destruction of the alveolar walls ( 185 Although such inclusions are morphologically similar to nucleoprotein strands of myxoviruses, they are considered to be products of nonspecific cellular injury that can be induced by acid-labile a-interferon. Acute lupus pneumonitis is characterized by the sudden development of severe dyspnea, tachypnea, fever, arterial hypoxemia, and diffuse pulmonary infiltrates. 186, 187 The clinical and radiographic findings of lupus pneumonitis are difficult to distinguish from those of infection and diffuse alveolar hemorrhage. 186 ,187 The mortality rate is around 50%. Patients who survive often exhibit residual interstitial infiltrates and persistent pulmonary function test abnormalities. 186 Histologic sections of the lungs reveal diffuse alveolar damage with hyaline membranes, interstitial edema, and arteriolar thrombosis. 186 Pulmonary hypertension was once considered rare in SLE, but now is being reported with increasing frequency. 181 Abnormalities indicative of subclinical pulmonary hypertension are found on echocardiography in 10% of patients, usually in association with Raynaud phenomenon. 18s The most common presenting complaints of SLE patients with pulmonary hypertension are dyspnea on exertion, chest pain, nonproductive cough, edema, and fatigue or weakness.173 Chest x-ray shows cardiomegaly, a prominent pulmonary artery, and clear lung fields. The diagnosis of pulmonary hypertension is established by demonstrating elevated pulmonary artery pressure at cardiac catheterization. Symptoms may be mild with a protracted course. However, in some patients, the course is more rapid, with death resulting in only a few years. Pathologic examination of the lungs in SLE-related pulmonary hypertension reveals pulmonary arteriopathy with plexiform lesions or thromboembolic arteriopathy. [189] [190] [191] [192] [193] [194] Rarely, pulmonary vasculitis is the cause of the pulmonary hypertension. 189 .1 95 Anti-endothelial cell antibodies and immune complexes may stimulate endothelin-l release from endothelial cells. This mediator is thought to play an important role in the initiation and development of pulmonary hypertension in SLE patients (see Chapter 28) . 173, 196, 197 FIGURE 20.10 . Systemic lupus erythematosus. Electron photomicrograph of tubuloreticular inclusion in alveolar endothelial cell of lupus lung. Antiphospholipid antibodies are a family of autoantibodies that recognize various combinations of phospholipids, phospholipid-binding proteins, or both.19R The term antiphospholipid syndrome was first coined to denote the clinical association between antiphospholipid antibodies and a syndrome of hypercoagulability.199 Currently, a patient with the antiphospholipid syndrome must meet at least one of two clinical criteria (vascular thrombosis or complications of pregnancy) and at least one of two laboratory criteria (anticardiolipin antibodies or lupus anticoagulant antibodies ).1 98 The antiphospholipid syndrome may be divided into two categories. 198 "Primary" antiphospholipid syndrome occurs in patients without clinical evidence of another autoimmune disease, whereas "secondary" antiphospholipid syndrome occurs in association with autoimmune or other diseases. Systemic lupus erythematosus is by far the most common disease with which the antiphospholipid syndrome occurs. Pulmonary complications of the antiphospholipid syndrome include pulmonary embolism and infarction, both thromboembolic and perhaps nonthromboembolic pulmonary hypertension, pulmonary arterial thrombosis, pulmonary microthrombosis, adult respiratory distress syndrome, intraalveolar pulmonary hemorrhage, and postpartum syndrome. [s generally ascribed to diaphragmatic weakness?04 Although neuropathy and myopathy can also occur in SLE, the diaphragmatic dysfunction in shrinking lu~g syndrome appears to be unrelated to these disorders. 20 ).207.209 In one study, the characteristic restrictive defect could not be explained by a primary abnormality of the diaphragm and was attributed to an unspecified restriction in chest wall expansion.2iO There are no specific histologic abnormalities in shrinking lung syndrome. 202 However, in rare cases, diaphragmatic fibrosis has been documented at autopsy. 204 Neoplasms There seems to be an association between SLE and non-Hodgkin lymphoma, lung cancer, and Kaposi sarcoma (see also Chapter 34).211-214 Bjornadal et a\.2J3 found a bimodal incidence of malignancy in SLE patients, with an increased incidence of non-Hodgkin lymphoma early in the patients' course and a later increase in the risk of lung cancer. However, another study of SLE patients failed to confirm an overall association between SLE and lung cancer and showed only a borderline statistically significant increased risk of lymphoma.215 Pulmonary vasculitis has been reported rarely in SLE, and chronic interstitial lung disease is much less prevalent in . Systemic sclerosis (scleroderma) is a generalized connective tissue disorder characterized by thickening of the skin (scleroderma) and frequent involvement of internal organs, notably the heart, lungs, kidneys, and the gastrointestinal tract. Traditional classification of systemic sclerosis is based on the extent of skin involvement. The diffuse form can involve any part of the body. The limited form, also known as the CREST syndrome (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectases), typically involves the face, sparing the trunk and the limbs proximal to the elbows and knees. Pulmonary function abnormalities are common in both the limited and diffuse forms.219 The cumulative survival rate for patients with systemic sclerosis is less than 80% at 2 years, 50% at 8.5 years, and 30% at 12 years after diagnosis, with most patients dying of cardiopulmonary disease. 220 .221 Renal, cardiac, pulmonary, and gastrointestinal involvement impacts negatively on surviva1. 220 Major pulmonary complications of systemic sclerosis include (1) interstitial lung disease, and (2) pulmonary hypertension. In recent studies, NSIP has surpassed UIP as the most common histologic pattern of interstitial lung disease associated with systemic sclerosis. 15.26.7 1 Bouros et a1. 15 reviewed surgical lung biopsies from 80 patients with systemic sclerosis and "fibrosing alveolitis." Nonspecific interstitial pneumonia (n = 62, 77.5%), subcategorized as cellular NSIP (n = 15) and fibrotic NSIP (n = 47), was much more prevalent than UIP (n = 6) , end-stage lung disease (n = 6), or other patterns (n = 6). In a similar study by Kim et a1., 26 13 of 19 patients had NSIP and five had UIP. The CT appearance of systemic sclerosis-associated lung disease often resembles that of idiopathic NSIp' 222 In the study by Kim et aI., comparison of the clinical outcome of 12 patients followed for more than 12 months suggested a better prognosis for NSIP than for UIP. In contrast, the 5-year survival differed little between NSIP (91 %) and UIP (82%) in the similar study by Bouros et a1. Grossly, the lungs are firm in consistency (Fig. 20.12 ). In general, honeycombing is relatively infrequent. The histologic patterns of systemic sclerosis-associated interstitial pneumonias are indistinguishable from those of their idiopathic counterparts (Fig. 20.13 ). However, interstitial lung disease is likely to be accompanied by pleural fibrosis in systemic sclerosis.223 Pulmonary hypertension develops in 10% to 33% of patients with diffuse systemic sclerosis and in 40% to 65 % of patients with the limited form of disease. 219 .224-229 In limited systemic sclerosis, pulmonary hypertension is usually not accompanied by interstitial fibrosis.219 Increasing age (~60 years) at diagnosis is a risk factor for pulmonary arterial hypertension. 230 A decreasing carbon monoxide diffusing capacity (DLco) is a good predictor of subsequent development of isolated pulmonary hypertension in limited systemic sclerosis. 23 intimal thickening (Fig. 20.14) .219,232-236 Plexiform lesions are usually not seen, but there are occasional exceptions.235 Rare cases of pulmonary occlusive venopathy (pulmonary veno-occlusive disease) have also been reported. 237 The cause of pulmonary hypertension in systemic sclerosis is unknown, but endothelial injury has been implicated as the inciting event, a concept that is supported by the detection of circulating endothelial cells in some patients. 238 Dermatomyositis and polymyositis (DPM) are idiopathic inflammatory myopathies. Patients with polymyositis manifest with proximal muscle weakness, elevated serum levels of enzymes derived from skeletal muscle, myopathic changes demonstrated by electromyography (EMG), and evidence of inflammation on muscle biopsy. 255 The addition of skin rash suggests the diagnosis of dermatomyositis. 255 Dermatomyositis-polymyositis is a relatively uncommon disease with an incidence of 5 to 5.5 cases per million in the United States.256257It occurs twice as frequently in women as in men in all age groups, with two peaks of onset, one in the first decade and the second in the fifth and sixth decades. 256 In recent studies, the prevalence of lung disease in DPM varies from 23% to 65%.258-260 Lung disease precedes myositis or skin rash in at least one third of cases. 18 ,261-264 The first description of pulmonary involvement in DPM by Mills and Mathews 265 in 1956 was that of a 52year-old woman with "interstitial pneumonitis." Interstitial lung disease remains the most frequent pulmonary problem in DPM. Prior to the recognition of NSIP, usual interstitial pneumonia (UIP) was considered the most common pattern of interstitial lung disease in DPM. 18264 However, if current criteria are applied,NSIP is the most common. Clinically, interstitial lung disease in DPM usually presents in a manner similar to acute or subacute communityacquired pneumonia.27 Chest radiographs and CT scans typically demonstrate bilateral irregular linear opacities involving the lung basesY Jo-1 antibody is present in about 38% of patients. 27 Survival of patients with DPMrelated interstitial lung disease is significantly better than that observed for patients with idiopathic UIP, and is similar to idiopathic NSIp' 27 There is no significant survival difference between Jo-1 positive and Jo-1 negative groupS.27 Histologically, DPM-related NSIP (Fig. 20.15 ), DAD, organizing pneumonia ( Fig. 20.16) , and VIP are similar to their idiopathic counterparts. 22 .27,266 However, most cases of DPM-related interstitial lung disease are also associated with mild to moderate pleural fibrosis (Fig.20.15B) . 27 Aspiration pneumonia can be a problem in patients with DPM, particularly if there is upper airway or respiratory muscle weakness. Pulmonary vasculitis and pulmonary hypertension have been reported rarely in patients with DPM. 264 ,267 As its name implies, mixed connective tissue disease (MCTD) is characterized by overlapping features of other connective tissue diseases. The most common constituents of this disease, which some alternatively refer to as undifferentiated autoimmune rheumatic/connective tissue disease, are SLE, DPM, and progressive systemic sclerosis.268.269 There is a striking female preponderance of 16: 1. 270 High titers of circulating antibodies to ribonucleoprotein (RNP) antigen are typically present. 268 Antibodies to alveolar septal capillary endothelial cells have been found in some patients. 271 • 272 Pulmonary involvement in MCTD has been reported in 20% to 85% of cases. 12 with MCTD show evidence of subclinical pulmonary involvement in the form of lymphocytic alveoli tis by BAL. 283 The most commonly reported form of pulmonary involvement on biopsy is interstitial fibrosis in a pattern resembling UIp'12.42.274.276-278.280-282 On HRCT, interstitial fibrosis manifests as irregular linear and reticular opacities. 284 Initially, such changes affect the lung bases, while in more advanced cases, honeycombing can observed. Other forms of interstitial disease that have been reported include organizing pneumonia, particularly in patients with prominent lupus features. 2lo Diffuse alveolar damage has also been reported. 274 Pulmonary hypertension is relatively frequent, particularly in patients with prominent scleroderma features. 270 Features identical to those observed in primary pulmonary hypertension, including plexiform lesions and fibrinoid necrosis, have been described. 273 .276.285-291 Uncommon pulmonary vascular manifestations include vasculitis and recurrent thromboemboli. 276 • 282 Massive and even fatal pulmonary hemorrhage has been reported, typically in association with glomerulonephritis. 279 .285.292.293 Pulmonary amyloidosis has also been reported?94 Pleural involvement in the form of effusions or pleuritis is seen occasionally, particularly in patients with other lupus-like manifestations.z74. 278.181.282.295 In patients with predominant clinical features of DPM or scleroderma, aspiration pneumonia can result from esophageal dysfunction. 296 .297 Patients with DPM features are also prone to respiratory failure secondary to respiratory muscle dysfunction. 296.297 As might be expected from the heterogeneity of this disease, pulmonary involvement in MCTD has a variable prognosis. 298 Pulmonary disease in MCTD patients with predominant scleroderma manifestations is particularly refractory to corticosteroids. 2 s 1 FIGURE 20.17 . Follicular bronchiolitis. Bronchiole shows an adjacent lymphoid follicle. This finding may be seen in a number of collagen vascular diseases, including Sjogren's syndrome. Sjogren's syndrome (SS) is an autoimmune disease characterized by a triad of manifestations: keratoconjunctivitis sicca, xerostomia, and arthritis?99 Two forms of the disease are recognized. In primary SS, this triad occurs in isolation. In secondary SS, which accounts for one half to two thirds of cases of SS, these manifestations occur in association with another collagen vascular disease, most typically rheumatoid arthritis.12,42 Primary SS typically affects females in the fifth to seventh decades of life, while the patient population affected by secondary SS is somewhat more heterogeneous. Patients with altered immunity, including bone marrow transplant recipients and individuals infected with human immunodeficiency virus (HIV), appear to have a higher rate of SS than the general population.3oo. 301 The occurrence of SS in families and the increased frequency of certain human leukocyte antigen (HLA) subtypes in patients with SS suggests a genetic predisposition?02.303 However, the underlying etiology of SS has yet to be discovered. A number of autoantibodies are detectable in patients with SS, including rheumatoid factor, antinuclear antibody (ANA), and the ribonucleoproteins SS-A(Ro) and SS-B (La) . SS-B(La) is considered to be most specific for SS. [304] [305] [306] The most common clinical manifestations of SS, which include dry eyes, dry mouth, and salivary gland enlargement, reflect exocrine gland involvement by this disease. Nine to 90% of patients, most commonly those with secondary SS, exhibit pulmonary manifestations. 42.304.305.107-31 7 Pulmonary manifestations in SS typically develop late in the course of disease and only rarely are the presenting feature. 30R Lesions affecting the small airways, such as follicular bronchiolitis, are among the most common histologic findings in patients with SS who have pulmonary involvement (Fig. 20.17) . 22,42.304 Large airway abnormalities include obstruction and desiccation of the tracheobronchial tree.30R JII.m The latter condition, which is referred to as xerotrachea, is characterized by lymphocytic inflammation and atrophy of the submucosal glands ( Fig. 20.18 In series published prior to the recognition of NSIP, lymphocytic interstitial pneumonia (LIP) was the most common interstitial lung disease in SS (Fig. 20.19 ). 304 However, in several more recent series, NSIP has been the predominant pattern (Fig. 20.20 ).23 Uncommonly encountered patterns of interstitial lung disease in SS include UIP and bronchiolitis obliterans-organizing pneumonia (BOOP). 1 2.42.299.304.3118.312.314.322-324 Radiographically, interstitial disease in SS typically gives rise to a reticulonodular pattern. 325 Follicular bronchiolitis and LIP are but part of a spectrum of lymphoid lesions that may develop in SS, which also includes nodular lymphoid hyperplasia, lymphocytic alveoli tis, lymphomatoid granulomatosis, and malignant lymphoma. 12 343 Through the use of modern clonality detection methods such as reverse-transcriptase polymerase chain reaction (RT-PCR), many cases previously designated as pseudolymphomas have been reclassified as malignant lymphomas (see Chapter 32) . 344 On high-resolution computed tomography, pulmonary lymphoma in patients with SS may take the form of consolidation, solitary or multiple nodules, or be distributed along the pulmonary interstitium. 328 High-grade pulmonary lymphomas, such as diffuse large cell lymphoma, arising in the setting of SS are generally associated with a poor prognosis. In one series of patients with SS and lymphoma, four of 10 died within 4 years of receiving a malignant diagnosis.328 Angioinvasion is a relatively frequent finding in pulmonary lymphomas associated with SS. However, this finding does not itself appear to directly impact the prognosis. 328 An array of other pulmonary abnormalities has been reported in SS. Parenchymal nonnecrotizing granulomas may simulate hypersensitivity pneumonia, particularly in cases accompanied by peribronchiolar lymphocytic inflammation (Fig. 20.21 ).305 Rare cases of coexisting SS and sarcoidosis have been described, as have cases of coexisting SS and primary biliary cirrhosis, a condition that occasionally features pulmonary granulomas.334.345-347 Perinuclear antineutrophil cytoplasmic antibody (p-ANCA) positivity has been demonstrated in a few patients with SS, most often in the setting of glomerulonephritis. [348] [349] [350] Multiple bullae have been reported in some SS patients and are thought to be related to peribronchiolar lymphocytic inflammation and scarring. 35 1.352 Thin-walled cysts accompanied by ground-glass opacities may be evident radiographically in SS patients with LIP. 353 .354 Histologically, such cysts correspond to dilated bronchioles with marked peri bronchiolar lymphocytic inflammation. Pulmonary amyloidosis has also been reported in SS patients in association with LIP, MALT lymphoma, and bullous disease. 22 20.20 . Nonspecific interstitial pneumonia (NSIP) pattern in Sjogren's syndrome. In this example of fibrotic NSIP from a patient with Sjogren's syndrome, the interstitium is diffusely and homogeneously expanded by mature fibrosis. and as part of a systemic vasculitis, has also been reported. 315 .318 Pleural manifestations of SS include pleuritis and pleural effusions. 307.363 Management of SS is largely influenced by the presence of other coexisting collagen vascular diseases. Morbidity has been dramatically decreased by aggressive antimicrobial treatment of associated pulmonary infec-A K.J. Butnor and A. Khoor tions.312 Small-airway disease in SS is usually steroidresponsive, while in patients with LIP, corticosteroids and other immunosuppressive agents have been used with variable success. 314 . 364 Ankylosing Spondylitis Ankylosing spondylitis (AS), also known as Marie-Striimpell disease, is a seronegative spondyloarthropathy that predominantly involves the axial skeleton. In contrast to other collagen vascular disorders, AS has a distinct male predominance, with a male-to-female ratio as high as 10:1. 299 Ankylosing spondylitis is strongly associated with the HLA-B27 histocompatibility antigen. While only 2% to 20% of HLA-B27-positive individuals develop AS, over 90% of patients with AS are positive for HLA_B27.36s-369 Patients with AS typically present in the third decade of life with symptoms referable to spinal arthritis and sacroiliitis. Extraarticular manifestations include constitutional symptoms, such as fever and weight loss, as well as cardiovascular disorders, such as conduction defects, aortitis, and aortic insufficiency. Pleuropulmonary involvement in AS is rare, affecting only 1 % to 2% of patients. 37o Involvement of the lungs and pleura typically occurs late in the course of disease and often is asymptomatic.344.371-380 The most common thoracic manifestations of AS are upper lobe fibrobullous disease, which may be uni-or bilateral, and chest wall restriction (Fig. 20.22 About 10% to 20% of patients with pleuropulmonary involvement suffer spontaneous pneumothorax, likely related to rupture of apical bullae. 379 The cystic changes in the lung apices of AS patients are similar to those seen in patients with tuberculosis.379.392 While mycobacteria are not thought to playa role in the development of apical fibrocavitary lesions in AS, such lesions may become infected secondarily by mycobacteria or Aspergillus, resulting in either saprophytic mycetomas or invasive infection. 299 . 373 .382.388 Interstitial fibrosis may occur in AS, the pattern of which is nondescript. 376 ,381,383.385 Rare cases of honeycomb fibrosis have been described. 3s1 Accompanying chronic pleuritis, with or without pleural effusion, is not infrequent. 373 Although the cause of pulmonary fibrosis in AS is postulated to be immune-mediated, the exact pathogenesis is not yet known. 379 Several cases of lung carcinoma have been reported in patients with AS. Some of these patients had previously received radiation therapy, a modality formerly used in the treatment of AS. 393 . 394 Survival data indicate that lung cancer mortality in patients previously irradiated for AS has increased. 395 However, the frequency of lung cancer in AS patients with no history of radiation therapy does not appear elevated? 44 Various other pulmonary abnormalities have been reported in AS, including bronchiectasis, organizing pneumonia, pulmonary hemorrhage, amyloidosis, and LIp ' 373 ,389,396 In addition, the recently described pattern of acute lung injury designated as acute fibrinous and organizing pneumonia (AFOP) has been reported in a patient with underlying AS (see Chapter 4).397 Many of these manifestations, such as interstitial fibrosis, apical bullae, and bronchiectasis, are readily detectable by HRCT. 284 Relapsing polychondritis (RP) is a systemic disease characterized by recurrent inflammation of cartilaginous tissue with subsequent degeneration and replacement by fibrosis. [398] [399] [400] [401] [402] [403] Prior to the introduction of the term relapsing polychondritis in 1960, cases with features similar to RP were described under the designations "polychondropathia" and "chondromalacia.,,401,404-407 Affected sites include the external ear, nose, ribs, larynx, trachea, and major bronchi. 401 .406,408,409 Sites rich in glycosaminoglycans, such as the aorta, cornea, and sclera, may also be involved. 41 0--412 Some series have shown a slight female predominance, while in others males and females are equally affected. 344 ,403 Although RP can occur at any age, the peak reported incidence is in the fifth to seventh decades. 403 While the exact pathogenesis of RP is unknown, an autoimmune origin has been postulated. Antibodies to type II collagen are demonstrable in some patients. 413 Granular deposits of immunoglobulin and the C3 component of complement at the chondrofibrous junction have also been reported, as have antibodies to type II pneumocytes and Clara cells.414.41 5 Other coexisting collagen vascular diseases, such as rheumatoid arthritis, SLE, or SS, are found in up to 25% of cases. 401 Involvement of the large airways causes tracheobronchomalacia, which can lead to expiratory obstruction (Fig. 20.23 ). 416 Airway narrowing can sometimes be so severe as to be life threatening. 417 The pathologic findings in RP vary depending on the phase and extent of disease. In the acute phase, RP is characterized histologically by cartilage erosion, which is accompanied by a dense pericartilaginous inflammatory infiltrate comprised of neutrophils, lymphocytes, plasma cells, and, in some cases, giant cells (Fig. 20.24 ). Over time, active inflammation gives way to dissolution of the proteoglycan matrix and destruction of cartilage, which is followed in most cases by the formation of granulation tissue. In the resolving phase, damaged cartilage often appears metachromatic. 419 Areas of complete destruction undergo fibrosis, which may be so exuberant as to result in stricture formation. 421 In addition to airway involvement, rare instances of parenchymal disease, manifesting radiographically as honeycombing, have been reported. 41S , 422 Although laryngotracheal involvement is present in only about half of cases, it is associated with a poor progno-siS. 4111 ,402 Management of such patients is aimed at maintaining patency of collapse-prone airways through ventilatory support or tracheostomy with stent placement. Corticosteroids and immunosuppressive agents are typically employed in the treatment of Rp ' 299 ,370,401,403,423-427 However, the spontaneous remitting and relapsing nature of RP makes it difficult to quantify the therapeutic effect of these agents. Pleuropulmonary manifestations have been reported in 1 % to 8% of patients. 436 ,437 The predominant thoracic manifestations of Beh<;et's syndrome are either directly related to or represent complications of necrotizing vasculitis (see Chapter 29) . Other pleuropulmonary disorders associated with Beh<;et's syndrome include aneurysms, pulmonary thromboemboli, large airway stenosis and ulceration, pleuritis, pleural effusions, chyloptysis, and organizing pneumonia. 42 .430,432,438-448 Acute interstitial pneumonia (AlP) has also been reported, typically in the setting of underlying pulmonary hemorrhage. 439 Hughes-Stovin syndrome, which is characterized by pulmonary artery aneurysms and hemoptysis, most likely represents a limited from of Beh<;et's. 443, 449 Lung involvement in Beh<;et's syndrome is often associated with a poor outcome. One third of Beh<;et's patients with lung involvement die as a result of pulmonary complications, most commonly from intractable pulmonary hemorrhage. 429 Eosinophilic fasciitis (EF), also known as Schulman's syndrome, is a disorder of unknown etiology that predominantly affects patients in their third to sixth decades, which is characterized by painful sclerodermiform induration of the skin.450.451 A variety of extracutaneous manifestations have been reported, including synovitis, and esophageal dysmotility. 450.452.453 Pleural effusions, often rich in eosinophils, have also been reported. 453 Transbronchial biopsies may show infiltration of the bronchial mucosa by eosinophils. 453 Pulmonary parenchymal disease, in the form of interlobular and peribronchial nodular interstitial thickening, has been noted radiographically in rare instances. 453 A case of bronchiolitis obliterans arising in a patient with EF while on penicillamine therapy has been also reported. 48 The features of EF show some overlap with those described in eosinophilic myalgia syndrome (see Chapter 15) . 454.455 Cutis Laxa Cutis laxa is an extremely rare systemic disorder of elastic tissue. Both familial and acquired forms have been recognized. 456 The skin of patients with cutis laxa is devoid of elastic recoil, which manifests histopathologically as a decrease in the overall number of elastic fibers, as well as degenerative elastic fiber changes. 457 Reported pulmonary complications of cutis laxa include emphysema and pulmonary artery stenosis. 45 8-461 Ehlers-Danlos Syndrome Ehlers-Danlos syndrome is a heterogeneous group of inherited disorders of collagen synthesis and structure characterized by skin hyperextensibility and joint hyper-FIGURE 20.25. Ehlers-Danlos syndrome. A,B. Intraparenchymal fibrous pseudotumor characterized by a nodular proliferation of fibrous tissue. Like fibrous scars, these lesions likely mobility. A variety of pulmonary manifestations have been described, including spontaneous or recurrent pneumothorax, bronchial dilation, parenchymal cysts, and arteriovenous anastomoses. 462 ,463 Fibrous parenchymal scars, presumably a sequela of spontaneous tears, have been reported, as have fibrous nodules and pseudotumors, which are believed to be an exuberant fibroproliferative response to injury (Fig. 20.25) . 464 The fragility of vessel walls in Ehlers-Danlos Syndrome predisposes patients to pulmonary hemorrhage, which in rare cases has resulted in fatal hemoptysis. 465 Both Ehlers-Danlos syndrome and cutis laxa have been associated with Mounier-Kuhn syndrome, a rare entity characterized by tracheobronchomegaly and trachiectasis (see Chapter 5) . 466.467 Pseudoxanthoma Elasticum Pseudoxanthoma elasticum, also known as Gronblad-Strandberg syndrome, is a heritable degenerative disease of elastic tissue. The etiology of pseudoxanthoma elasticum is not well understood, but mutations in the transmembrane protein ABCC6, which is thought to play a role in extracellular matrix deposition and turnover of connective tissue, have been identified. 468 In addition to cutaneous manifestations, which usually become apparent in the second decade of life, other organs, such as the eyes, cardiovascular system, and lungs, may be affected. 469 Histologically, the changes observed in the lungs in pseudoxanthoma elasticum are similar to those seen in other sites. 47o On routinely stained sections, elastic tissue within the lungs appears basophilic and disrupted (Fig. 20.26 ). The basophilia of elastic fibers in pseudoxanthoma elasticum is due to dystrophic calcification and can be highlighted by von Kossa or Alizarin red stains.471 Marfan's Syndrome is a disorder caused by mutations in a gene for the elastin-binding protein fibrillin. While the majority of cases are inherited, about 15% are the result of acquired mutations. 299 ,472 Skeletal changes, including thoracic cage deformities such as kyphoscoliosis, ocular lens dislocation, and cardiovascular abnormalities, characterize this disorder. Well-recognized pulmonary complications of Marfan's syndrome include emphysema, often with apical bulla formation, and spontaneous pneumothorax, which is frequently bilateral and recurrent.460.473-484 For a number of patients, pneumothorax is the initial manifestation of Marfan's syndrome. 480 ,482 Other pulmonary abnormalities in Marfan's syndrome include congenital lobar and airway malformations, diffuse thin-walled cysts, airway hyperreactivity, bronchiectasis, saccular aneurysms of the pulmonary arteries, and respiratory infections, particularly mycobacterial infections.48s-49o A spectrum of interstitial changes, ranging from upper lobe fibrosis to honeycombing, have also been reported. 299 Beals-Hecht syndrome is another disorder that results from a defect in fibrillin; it is characterized by congenital contractures and external ear deformities. Similar to Marfan's syndrome, Beals-Hecht is associated with restrictive K.J. Butnor A pattern of interstitial fibrosis similar to UIP has been reported in several patients with PBC, most often in the setting of other coexisting autoimmune diseases. SOU-S02 Other pulmonary disorders that have been described include pulmonary hypertension, AlP, LIP, chronic interstitial pneumonia, BOOP, bronchiolitis, including constrictive bronchiolitis, and pulmonary hemorrhage accompanied by glomerulonephritis.so3-51o As noted previously, SS, which itself is associated with an array of pulmonary manifestations, may occur together with PBc. 34S .511 While ulcerative colitis (UC) and Crohn's disease (CD) have long been recognized as system disorders, the pulmonary manifestations of idiopathic inflammatory bowel disease (IBD) have only recently been characterized. Pulmonary involvement is more common in UC than CD.512 However, in both forms of IBD, the lungs are one of the least frequently affected extraintestinal sites. Intestinal manifestations precede pulmonary abnormalities in 72 % to 84% of cases. 513 The interval between the onset of colitis and pulmonary disease is quite variable, ranging from weeks to decades. 514 Active colitis is not a prerequisite for the development of lung disease. SIS As many as 90% of patients have quiescent bowel disease at the onset of pulmonary symptoms. 513 Roentgenographically, pulmonary disease in IBD most typically manifests as diffuse infiltrates, although bilateral Germinal centers, which are typically prominent in usual bronchiectasis, are often absent in lED-associated chronic bronchitis and bronchiectasis. 513 The overlying mucosa can exhibit squamous metaplasia, and mucous stasis is occasionally prominent. The second most common pattern of pulmonary involvement in lED is interstitial lung disease. Both NSIP and BOOP patterns have been described. Both may be accompanied by interstitial nonnecrotizing granulomas (Fig. 20.28 ).528.538.539 A single case of DIP in a patient with UC receiving sulfasalazine has also been reported. 540 Subtle differences exist between the histologic pattern of BOOP seen in association with lED and cryptogenic organizing pneumonia. 528 ,529,538,541 The former has been reported to show marked septal edema associated with eosinophils, Rare cases of eosinophilic pneumonia have also been reported in association with IED.513 In such cases, drug toxicity due to sulfasalazine should be ruled out (see Chapter 22) . Five percent of lED patients with pulmonary involvement exhibit necrobiotic parenchymal nodules. 513 To date, such lesions have only been reported in patients with Uc. 513 In the early stages, necrobiotic nodules consist of neutrophils admixed with fibrin. As they mature, these nodules undergo necrosis and cavitation (Fig. 20.29) . The histologic appearance of pulmonary necrobiotic nodules in UC is reminiscent of the cutaneous lesions seen in pyoderma gangrenosum. 513 As pulmonary necrobiotic nodules in UC may resemble infectious granulomas, infection should be excluded through histochemical stains and microbiologic cultures. Ulcerative colitis-associated necrobiotic nodules have some similarities with lesions in Wegener's granulomatosis. However, in contrast to Wegener's granulomatosis, giant cells and vasculitis are notably lacking in necrobiotic nodules associated with Uc. 513 In considering the differential diagnosis of pulmonary necrobiotic nodules, it is important to bear in mind that a subset of patients with lED, in particular those with UC, demonstrate antineutrophil cytoplasmic (ANCA) antibodies.542.543 However, the antibodies observed in patients with lED are perinuclear and directed against MPO antigen (p-ANCA) rather than the antiproteinase 3 cytoplasmic antibodies (c-ANCA) associated with Wegener's gran uloma to sis. 544 Along with infections, lED-associated granulomatous inflammation must be distinguished from hypersensitivity pneumonia, sarcoidosis, and drug-induced granulomas. Establishing a history of chronic active colitis is paramount. However, this may be difficult in cases where colitis has been inactive for a long period and essentially impossible in the rare instances in which pulmonary abnormalities precede other features of lED. Obtaining an exposure history is useful to search for an inciting antigen that might suggest hypersensitivity pneumonia. Differentiating lED-associated granulomatous inflammation from sarcoidosis on histology alone can also be difficult. The recognition of cases of coexisting sarcoidosis and lED makes this distinction even more diagnostically challenging. 520 , [545] [546] [547] [548] [549] Distinguishing pulmonary abnormalities related to lED from drug-induced changes can be quite difficult, given that many patients with lED are treated with immunosuppressive agents like sulfasalazine and 5-acetylsalicylic acid (ASA). Such drugs are known to induce a variety of pulmonary abnormalities, including eosinophilic pneumonia, NSIP, BOOP, and vasculitis. [550] [551] [552] [553] [554] [555] [556] [557] [558] Many other thoracic abnormalities have been described in lED, including pleuritis, pleural effusions, amyloidosis, pulmonary thromboemboli, and apical fibrosis resembling the findings seen in ankylosing spondylitis. [559] [560] [561] The prognosis of lED patients with pulmonary manifestations is good. Most patients improve without any specific therapy. Neither nonsteroidal agents typically used to control the intestinal manifestations of lED nor proctocolectomy appears to ameliorate lED-associated respiratory disease. 514 In fact, bowel surgery may exacer-. ' f ' fIBD513517536Ith bate the respIratory mam estatlOns 0 .-" as been suggested that patients who develop pulmonary disease while being treated with sulfasalazine or 5-ASA discontinue these medications to decrease the potential for confounding drug-induced abnormalities. 64 Refractory cases of lED-associated pulmonary disease may d . 'd 513541 respon to corilcosterOl s. 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The antiphospholipid syndrome Antiphospholipid antibodies and the antiphospholipid syndrome in systemic lupus erythematosus. A prospective analysis of 500 consecutive patients Review: antiphospholipid antibodies and the lung The interstitial lung diseases associated with the collagen-vascular disorders Unexplained" dyspnoea and shrinking lungs in systemic lupus erythematosus Pulmonary dysfunction in systemic lupus erythematosus without pulmonary symptoms Shrinking lung syndrome in SLE-a clinical pathologic study Respiratory muscle dysfunction in systemic lupus erythematosus Inspiratory muscle dysfunction and unexplained dyspnea in systemic lupus erythematosus Serial pulmonary function testing in patients with systemic lupus erythematosus Presentation and prognosis of the shrinking lung syndrome in systemic lupus erythematosus Bilateral phrenic paralysis in a patient with systemic lupus erythematosus Diaphragm strength in the shrinking lung syndrome of systemic lupus erythematosus Systemic lupus erythematosus and lymphoma Non-Hodgkin's lymphoma and other cancers among a cohort of patients with systemic lupus erythematosus Increased cancer incidence in a Swedish cohort of patients with systemic lupus erythematosus Kaposi's sarcoma in a patient with SLE Risk of malignancy in an unselected cohort of Icelandic patients with systemic lupus erythematosus Bronchiolitis obliterans organizing pneumonia associated with systemic lupus erythematosus The association of bronchiolitis obliterans organizing pneumonia, systemic lupus erythematosus, and Hunner's cystitis The association of lymphocytic interstitial pneumonia and systemic lupus erythematosus Pulmonary involvement in systemic sclerosis (scleroderma) Predictors of survival in systemic sclerosis (scleroderma) Mortality and causes of death in a Swedish series of systemic sclerosis patients CT features of lung disease in patients with systemic sclerosis: comparison with idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia Pathologic observations in systemic sclerosis (scleroderma). A study of fiftyeight autopsy cases and fifty-eight matched controls Pulmonary hypertension in the CREST syndrome variant of progressive systemic sclerosis (scleroderma) Prevalence and clinical correlates of pulmonary arterial hypertension in progressive systemic sclerosis Pulmonary hypertension in the CREST syndrome variant of systemic sclerosis Pulmonary hypertension in systemic sclerosis Pulmonary arterial hypertension in progressive systemic sclerosis Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach Age and risk of pulmonary arterial hypertension in scleroderma Predictors of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement Pulmonary vascular lesions in systemic scleroderma Pulmonary scleroderma Pulmonary vascular changes in scleroderma Pathogenesis and evolution of plexiform lesions in pulmonary hypertension associated with scleroderma and human immunodeficiency virus infection The pulmonary pathologic manifestations of the CREST syndrome Pulmonary venoocclusive disease and the CREST variant of scleroderma Endothelial injury in scleroderma. A protease mechanism LeRoy EC Endothelial injury in scleroderma Circulating endothelial cells as a marker of ongoing vascular disease in systemic sclerosis A new era in the management of pulmonary arterial hypertension related to scleroderma: endothelin receptor antagonism Progressive systemic sclerosis complicated by diffuse pulmonary haemorrhage Endobronchial telangiectasias and hemoptysis in scleroderma Bronchiolitis obliterans organizing pneumonia and scleroderma Recurrent bronchiolitis obliterans organizing pneumonia in a patient with limited cutaneous systemic sclerosis Bronchioloalveolar carcinoma and generalized amyloidosis complicating progressive systemic sclerosis Recurrent spontaneous pneumothorax in diffuse scleroderma Progressive generalized scleroderma: respiratory failure from primary chest wall involvement Reversible hypercapnic respiratory insufficiency in scleroderma caused by respiratory muscle weakness Carcinoma of the lung in progressive systemic sclerosis: a tabular review of the literature and a detailed report of the roentgenographic changes in two cases Incidence of lung cancer in systemic sclerosis Cancer and systemic sclerosis. An epidemiologic study Bronchioloalveolar carcinoma in progressive systemic sclerosis Incidence of cancer among patients with systemic sclerosis Polymyositis and dermatomyositis (second of two parts) The epidemiology of polymyositis Incidence of polymyositis-dermatomyositis: a 20-year study of hospital diagnosed cases in Allegheny County, PA 1963-1982 Interstitial lung disease in polymyositis and dermatomyositis Interstitial lung disease in polymyositis and dermatomyositis: clinical course and response to treatment Interstitial lung disease, a common manifestation of newly diagnosed polymyositis and dermatomyositis Interstitial lung disease in polymyositis and dermatomyositis: analysis of six cases and review of the literature Polymyositis and interstitial lung disease Fibrosing alveoli tis in polymyositis. A review of histologically confirmed cases Pulmonary disease in polymyositis/dermatomyositis: a clinicopathological analysis of 65 autopsy cases Mathews WHo Interstitial pneumonitis in dermatomyositis Idiopathic inflammatory myopathy with diffuse alveolar damage Pulmonary hypertension in polymyositis Mixed connective tissue disease-an apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA) Symptomatic Sjogren's syndrome in mixed connective tissue disease Maddison PI Overlap syndromes and mixed connective tissue disease Direct and indirect immunofluorescence as a diagnostic adjunct in the interpretation of nonneoplastic medical lung disease Anti-endothelial cell antibodies in the sera of patients with mixed connective tissue disease-the clinical significance Mixed connective tissue disease with pulmonary hypertension: a clinical and pathological study A prospective evaluation emphasizing pulmonary involvement in patients with mixed connective tissue disease Mixed connective tissue disease-clinical and radiological aspects of 20 cases Severe pulmonary involvement in mixed connective tissue disease Pulmonary involvement in mixed connective tissue disease Intrathoracic manifestations in mixed connective tissue disease Massive pulmonary hemorrhage in mixed connective tissue diseases Mixed connective tissue disease: a clinicopathologic study of 20 cases Respiratory complications in mixed connective tissue disease Lungs in mixed connective tissue disease Subclinical pulmonary involvement assessed by bronchoalveolar lavage in patients with early undifferentiated connective tissue disease Interstitial lung diseases associated with collagen vascular diseases: radiologic and histopathologic findings Fatal pulmonary hypertension and resolving immune-complex glomerulonephritis in mixed connective tissue disease. A case report and review of the literature Mixed connective tissue disease with fatal pulmonary hypertension and a review of literature Pulmonary vascular reactivity in severe pulmonary hypertension associated with mixed connective tissue disease Increased serum angiotensin I-converting enzyme activity in patients with mixed connective tissue disease and pulmonary hypertension Pulmonary hypertension in a child with mixed connective tissue disease Pulmonary hypertension complicating mixed connective tissue disease Mixed connective tissue disease with severe pulmonary hypertension and extensive subcutaneous calcification Pulmonary hemorrhage and acute renal failure in a patient with mixed connective tissue disease Fatal alveolar hemorrhage in a patient with mixed connective tissue disease presenting polymyositis features Amyloidosis in mixed connective tissue disease Bilateral exudative pleuritis, an unusual pulmonary onset of mixed connective tissue disease Diaphragm dysfunction in mixed connective tissue disease. A case report Pulmonary and neuromuscular complications of mixed connective tissue disease: a report and review of the literature Pulmonary involvement in mixed connective tissue disease: comparison with other collagen vascular diseases using high resolution CT Pulmonary involvement in collagen vascular disease: a review of the pulmonary manifestations of the Marfan syndrome, ankylosing spondylitis, Sjogren's syndrome, and relapsing polychondritis Sjogren-type syndrome after allogeneic bone-marrow transplantation Diffuse infiltrative lymphocytosis syndrome in children and adults infected with HIV-l: a model of rheumatic illness caused by acquired viral infection Primary Sjogren's syndrome and other autoimmune diseases in families. Prevalence and immunogenetic studies in six kindreds Sjogren's syndrome. A review with emphasis on immunological features Pulmonary manifestations of Sjogren's syndrome Pulmonary disorders associated with Sjogren's syndrome Predictive value of SS-B precipitating antibodies in Sjogren's syndrome Pulmonary involvement in primary Sjogren's syndrome Pulmonary manifestations of Sjogren's syndrome Reappraisal of respiratory abnormalities in primary and secondary Sjogren's syndrome. A controlled study Respiratory manifestations in primary Sjogren's syndrome. A clinical, functional, and histologic study Sjogren's syndrome. A clinical, pathological, and serological study of sixty-two cases Pulmonary and gastrointestinal manifestations of Sjogren's syndrome Alveolitis correlates with clinical pulmonary involvement in primary Sjogren's syndrome Pleuropulmonary abnormalities in primary Sjogren's syndrome Primary Sjogren syndrome: clinical and immunopathologic features Interstitial lung disease and primary Sjogren's syndrome: clinical-pathological evaluation and response to treatment Interstitial lung disease in primary Sjogren's syndrome. Clinicalpathological evaluation and response to treatment Sjogren's syndrome: report of a fatal case with pulmonary and renal lesions Xerotrachea and interstitial lung disease in primary Sjogren's syndrome Pulmonary involvement in Sjogren's syndrome Chronic obstructive airway disease in patients with Sjogren's syndrome Bronchiolitis obliterans organizing pneumonia and Sjogren's syndrome Usual interstitial pneumonia associated with primary Sjogren's syndrome A case of bronchiolitis obliterans organizing pneumonia associated with primary Sjogren's syndrome who died of superimposed diffuse alveolar damage Primary Sjogren's syndrome and associated lung disease: CT findings in 50 patients The spectrum of benign to malignant lymphoproliferation in Sjogren's syndrome Lymphomatoid granulomatosis of the lung, associated with a long history of benign lymphoepithelial lesions of the salivary glands and lymphoid interstitial pneumonitis Pulmonary lymphoma in Sjogren's syndrome Sjogren's syndrome and fibrosing alveolitis complicated by pulmonary lymphoma Lymphoid infiltration and amyloidosis of lung in Sjogren's syndrome Immunologically diagnosed malignancy in Sjogren's pseudolymphoma Primary Sjogren's syndrome with diffuse cerebral vasculitis and lymphocytic interstitial pneumonitis Lymphoid interstitial pneumonia: clinicopathological and immunopathological findings in 18 cases Bronchopulmonary manifestations of Sjogren's syndrome: the findings of the BAL, TBLB, and bronchoscopy Pulmonary pseudolymphoma presented with a mass lesion in a patient with primary Sjogren's syndrome: beneficial effect of intermittent intravenous cyclophosphamide Low-grade lymphoma of immature T-cell phenotype in a case of lymphocytic interstitial pneumonia and Sjogren's syndrome Diffuse pulmonary lymphoreticular infiltrations associated with dysproteinemia Lymphomatoid granulomatosis (Liebow) Pulmonary polymorphic centroblastic type malignant lymphoma in a patient with lymphomatoid granulomatosis, Sjogren syndrome and other manifestations of a dysimmune state Lymphomas in patients with Sjogren's syndrome: review of the literature and physiopathologic hypothesis Increased risk of lymphoma in sicca syndrome Lymphomas in patients with Sjogren's syndrome are marginal zone B-cell neoplasms, arise in diverse extranodal and nodal sites, and are not associated with viruses Pathology and genetics of tumours of haematopoietic and lymphoid tissues Ferrans VI The lung in connective tissue disorders Pulmonary involvement in primary biliary cirrhosis Association of Sjogren's syndrome and sarcoidosis Coexisting Sjogren's syndrome and sarcoidosis in the lung ANCAassociated pauci-immune crescentic glomerulonephritis complicating Sjogren's syndrome Sjogren's syndrome complicated by MPO-ANCA positive crescentic glomerulonephritis Sjogren's syndrome, cavitating lung disease and high sustained levels of antibodies to serine proteinase 3 Sjogren's syndrome with bronchial gland involvement and multiple bullae Sjogren's syndrome with multiple bullae and pulmonary nodular amyloidosis Lung cyst formation in lymphocytic interstitial pneumonia: CT features Lymphocytic interstitial pneumonia: thin-section CT findings in 22 patients Benign pulmonary lymphocytic infiltration and amyloidosis: computed tomographic and pathologic features in three cases Ravin CEo Nodular pulmonary infiltrate in a patient with Sjogren's syndrome Pulmonary nodular amyloidosis presenting as Sjogren's syndrome Nodular amyloidosis of the lungs associated with Sjogren's syndrome Pulmonary MALT lymphoma with amyloid production in a patient with primary Sjogren's syndrome Pulmonary hypertension in primary Sjogren's syndrome Association of Sjogren's syndrome with pulmonary hypertension: report of two cases and review of the literature The association of Sjogren's syndrome and primary pulmonary hypertension Sjogren's syndrome with pleural effusion Pulmonary findings in patients with primary Sjogren's syndrome Clinical history as a screening test for ankylosing spondylitis The immunopathology of ankylosing spondylitis-a review The risk of developing ankylosing spondylitis in HLA-B27 positive individuals. A comparison of relatives of spondylitis patients with the general population The risk of developing ankylosing spondylitis in HLA-B27 positive individuals: a family and population study High association of an HL-A antigen, W27, with ankylosing spondylitis Pulmonary manifestations of ankylosing spondylitis and relapsing polychondritis Spondylarthritis ankylopoietica: a review and report of twenty cases Ankylosing spondylitis lung disease-an under diagnosed entity? Pleuropulmonary manifestations of ankylosing spondylitis Upper lobe fibrosis associated with ankylosing spondylitis Ankylosing spondylitis and upper lobe fibrosis and cavitation Ankylosing spondylitis and lung fibrosis Fibrocavitating pulmonary lesions in ankylosing spondylitis Fibrobullous disease of the upper lobes: an extra skeletal manifestation of ankylosing spondylitis The pleuropulmonary manifestations of ankylosing spondylitis Pulmonary involvement in ankylosing spondylitis Fibrosing interstitial pneumonitis in ankylosing spondylitis Pulmonary fibrosis, pulmonary tuberculosis and ankylosing spondylitis Pulmonary manifestations of ankylosing spondylitis The chest radiograph in ankylosing spondylitis Upper lobe fibrosis in ankylosing spondylitis Pulmonary cystic disease in ankylosing spondylitis: two cases with unusual superinfection Bronchoalveolar lavage and trans bronchial biopsy in spondyloarthropathies Ankylosing spondylitis lung disease and Mycobacterium scrofulaceum Pulmonary diffuse amyloidosis and ankylosing spondylitis. A rare association Johnston WHo Apical pulmonary disease in ankylosing spondylitis Simultaneous presentation of upper lobe fibrobullous disease and spinal pseudarthrosis in a patient with ankylosing spondylitis Pulmonary fibrosis, mimicking tuberculosis, presenting before joint symptoms in a female with ankylosing spondylitis Ankylosing spondylitis with fibrosis and carcinoma of the lung Ankylosing spondylitis and adenocarcinoma of the lung Cancer mortality following X-ray treatment for ankylosing spondylitis Pulmonary hemorrhage associated with ankylosing spondylitis Acute fibrinous and organizing pneumonia: a histological pattern of lung injury and possible variant of diffuse alveolar damage Relapsing polychondritis Respiratory complications of relapsing polychondritis Relapsing polychondritis: prospective study of 23 patients and a review of the literature Relapsing polychondritis. Survival and predictive role of early disease manifestations Airway complications in relapsing polychondritis Uber einen Fall von systematiseirter Chondromalacie Relapsing polychondritis. Three cases with a clinico-pathological study and literature review Relapsing polychondritis. Clinical and pathologic features in fourteen cases Report of two necropsied cases with histochemical investigation of the cartilage lesion Relapsing polychondritis. Analytical literature review and studies on pathogenesis Relapsing polychondritis: review of current status and case report Relapsing polychondritis: an autoimmune disease Autoantibodies to cartilage and type II collagen in relapsing polychondritis and other rheumatic diseases Relapsing polychondritis. Immunomicroscopic findings in cartilage of ear biopsy specimens Relapsing poly(peri)chondritis associated with fibrosing alveolar disease and antibodies to pneumocytes type II and Clara cells Pulmonary function in relapsing polychondritis Bronchial disease in ulcerative colitis Tracheal stenosis due to relapsing polychondritis in rheumatoid arthritis Fatal bronchial stenosis due to isolated relapsing chondritis Relapsing polychondritis. A clinical, pathologic-anatomic and histochemical study of 2 cases Endobronchial stenting for severe airway obstruction in relapsing polychondritis Pulmonary fibrosis with intractable pneumothorax: new pulmonary manifestation of relapsing polychondritis Cyclosporin A treatment in a case of relapsing polychondritis Progressive tracheobronchial polychondritis: need for early diagnosis Relapsing polychondritis Acute airway obstruction in relapsing polychondritis: treatment with pulse methylprednisolone Relapsing polychondritis: new pulmonary manifestations Pulmonary involvement in Behcet's syndrome Pulmonary manifestations in Behcet's syndrome Pulmonary disease in Behcet's syndrome Pulmonary involvement in Behcet disease Behcet's disease. Report of 41 cases and a review of the literature Pulmonary manifestations in Behcet syndrome. Case report and review of the literature HLA-B5 and Behcet's disease A study of familial occurrence of Behcet's disease with and without ocular lesions Pulmonary manifestations of Behcet's disease Pulmonary arterial aneurysms in Behcet's syndrome: a report of 24 cases Pulmonary vasculitis Acute interstitial pneumonia in a patient with Behcet's syndrome and common variable immunodeficiency Behcet's syndrome with haemoptysis and pulmonary lesions Pathology of the lung in Behcet's disease. Case report and review of the literature Vascular involvement in Behcet's disease: arterial and venous and vessels of all sizes Possible Behcet's disease revealed by pulmonary aneurysms Large bilateral pulmonary artery aneurysms in Behcet's disease: rupture of the contralateral lesion after aneurysmorrhaphy Behcet's disease with pulmonary involvement, superior vena cava syndrome, chyloptysis and chylous ascites Organizing pneumonia associated with pulmonary artery aneurysms in Behcet's disease Pulmonary complications of Behcet's disease Behcet's syndrome with pulmonary involvement-combined therapy for endobronchial stenosis using neodymium-YAG laser, balloon dilation and immunosuppression Pulmonary artery aneurysms with recurrent thrombophlebitis. The "Hughes-Stovin syndrome Eosinophilic fasciitis Report of six cases of a newly recognized scleroderma-like syndrome Eosinophilic fasciitis: extracutaneous manifestations and associations Eosinophilic fasciitis with pulmonary and pleural involvement fasciitis, and eosinophilia associated with the ingestion of tryptophan Mixed connective tissue disease, overlap syndromes, and eosinophilic fasciitis Genetic disorders of the elastic fiber system Report of two cases and review of the literature Cutis laxa (generalized elastolysis). A report of four cases with autopsy findings Congenital cutis laxa with a dominant inheritance and early onset emphysema Mottiaz 1. Pulmonary elastic tissue in generalized elastolysis (cutis laxa) and Marfan's syndrome: a light and electron microscopic study Emphysema and cutis laxa Abnormalities of the lungs and thoracic cage in the Ehlers-Danlos syndrome Rare pulmonary manifestation of Ehlers-Danlos syndrome Fibrous pseudotumours and cyst formation in the lungs in Ehlers-Danlos syndrome Fatal hemoptysis in Ehlers-Danlos syndrome. Old malady with a new curse Tracheobronchiomegaly and acquired cutis lax a in a child. Physiologic and immunologic studies Pseudoxanthoma elasticum: a clinical, histopathological, and molecular update Pseudoxanthoma elasticum: an update Pulmonary calcification and elastic tissue damage in pseudoxanthoma elasticum Clinical pathologic observations in pseudoxanthoma elasticum The Marfan syndrome: diagnosis and management Pulmonary emphysema in a neonate with the Marfan syndrome Pulmonary emphysema in a neonate with Marfan syndrome Pulmonary emphysema in a neonate with Marfan syndrome Elastic tissue in pulmonary emphysema in Marfan syndrome Pulmonary bullous disease in Marfan syndrome Fragile lung in the Marfan syndrome Familial multiple bilateral pneumothorax associated with Marfan syndrome Pneumothorax in the Marfan syndrome: prevalence and therapy Marfan's syndrome and spontaneous pneumothorax Marfan's syndrome presenting as bilateral spontaneous pneumothorax Report of a case and review of the pulmonary abnormalities in this disorder Pulmonary disease in patients with Marfan syndrome Cystic lung in Marfan's syndrome Bronchial hyperreactivity in children with Marfan syndrome Bronchiectasis and Marfan's syndrome Pulmonary arterial aneurysms in Marfan's syndrome Pulmonary tuberculosis in Marfan's syndrome Bronchiectasis and spontaneous pneumothorax in Marfan's syndrome Beals-Hecht syndrome Antimitochondrial antibodies in primary biliary cirrhosis Autoimmune associations in primary biliary cirrhosis Primary biliary cirrhosis: lung involvement Quantitation of hepatic granulomas and epithelioid cells in primary biliary cirrhosis Sarcoidosis and primary biliary cirrhosis. Associated disorders? Sarcoidosis and primary biliary cirrhosis. Literature review and illustrative case Primary biliary cirrhosis. Subclinical inflammatory alveolitis in patients with normal chest roentgenograms Immunological features of lung lavage cells from patients with primary biliary cirrhosis may reflect those seen in pulmonary sarcoidosis Pulmonary involvement in primary biliary cirrhosis Multisystem involvement in chronic liver disease. Studies on the incidence and pathogenesis Primary biliary cirrhosis with fibrosing alveolitis Acute interstitial pneumonia (fibrosing alveolitis) in a patient with primary biliary cirrhosis Pulmonary hypertension associated with primary biliary cirrhosis in the absence of portal hypertension: a case report Interstitial lung disease in primary biliary cirrhosis Lymphocytic alveolitis associated with asymptomatic primary biliary cirrhosis Pulmonary hemorrhage and glomerulonephritis in primary biliary cirrhosis Bronchiolitis obliterans organising pneumonia and primary biliary cirrhosislike lung involvement in a patient with primary biliary cirrhosis Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 14-1998. A 49-year-old woman with primary biliary cirrhosis, pulmonary opacities, and a pleural effusion Lymphocytic bronchitis/bronchiolitis in a patient with primary biliary cirrhosis Sjogren's syndrome in patients with primary biliary cirrhosis Pulmonary manifestations of gastrointestinal disease The lung in inflammatory bowel disease The lung in inflammatory bowel disease Pulmonary complications in patients with inflammatory bowel disease Inflammatory airways disease in ulcerative colitis: CT and high-resolution CT features Chronic bronchial suppuration and inflammatory bowel disease Airway involvement in ulcerative colitis Pulmonary involvement in ulcerative colitis Unexplained bronchopulmonary disease with inflammatory bowel disease Severe inflammatory upper airway stenosis in ulcerative colitis Ulcerative tracheobronchitis years after colectomy for ulcerative colitis Crohn's disease with respiratory tract involvement Bronchiectasis with ulcerative colitis and myelopathy Noninfectious lung pathology in patients with Crohn's disease Constrictive bronchiolitis and ulcerative colitis Diffuse panbronchiolit is preceding ulcerative colitis An unusual perilobular pattern of pulmonary interstitial fibrosis associated with Crohn's disease Are there characteristic alterations in lung tissue associated with Crohn's disease? Commentary: bronchiectasis and inflammatory bowel disease Crohn's disease with pulmonary involvement in a 3 year old boy Crohn's disease of the lung White HI Inflammatory bowel disease associated with granulomatous lung disease: report of a case with endoscopic findings Granulomatous bronchiolitis associated with Crohn's disease Severe pulmonary disease in association with Crohn's disease in a 13-year-old girl Bronchopulmonary involvement in ulcerative colitis Early bronchopulmonary involvement in Crohn disease: a case report Nongranulomatous interstitial lung disease in Crohn's disease Cobden 1, et al. Bronchiolitis obliterans organising pneumonia in a patient with ulcerative colitis Desquamative interstitial pneumonitis complicating inflammatory bowel disease of childhood Steroid-responsive alveolitis associated with ulcerative colitis Autoantibodies to neutrophil cytoplasmic (ANCA) and endothelial cell surface antigens (AECA) in chronic inflammatory bowel disease Pulmonary manifestations of ulcerative colitis mimicking Wegener's granulomatosis Are anti-neutrophil cytoplasmic antibodies (ANCA) clinically useful in inflammatory bowel disease (IBD)? Sarcoidosis associated with regional enteritis (Crohn's disease) Familial occurrence of sarcoidosis and Crohn's disease Regional enteritis and sarcoidosis in one patient. A case report Crohn's disease and sarcoidosis: systemic granulomatosis? Association between inflammatory bowel disease and sarcoidosis. Report of two cases and review of the literature Pulmonary infiltrates and skin pigmentation associated with sulfasalazine Pulmonary vasculitis-an uncommon complication of ulcerative colitis Salazopyrininduced eosinophilic pneumonia Fibrosing alveoli tis, bronchiolitis obliterans, and sulfasalazine therapy Mesalamineinduced hypersensitivity pneumonitis. A case report and review of the literature Mesalazineinduced eosinophilic pneumonia Sulfasalazine pulmonary toxicity in ulcerative colitis mimicking clinical features of Wegener's granulomatosis Pulmonary vasculitis and ulcerative colitis Bronchiolitis obliterans in a patient with ulcerative colitis receiving mesal amine Pulmonary nodules due to reactive systemic amyloidosis (AA) in Crohn's disease Meadway 1. Ulcerative colitis, coli tic spondylitis and associated apical pulmonary fibrosis Arterial thromboembolic complications of inflammatory bowel disease