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Pulmonary Pathology in Connective Tissue Disease Kirk D. Jones, MD1

1 Department of Pathology, University of California San Francisco,

San Francisco, California Semin Respir Crit Care Med 2014;35:201–212.

Abstract Keywords

► autoimmune connective tissue disease ► collagen vascular disease ► lung pathology ► pulmonary pathology ► lung biopsy

Address for correspondence Kirk D. Jones, MD, Department of Pathology, University of California San Francisco (UCSF), 505 Parnassus Avenue, Room 565, Box 0102, San Francisco, CA 94143 (e-mail: [email protected]).

A significant proportion of patients with autoimmune connective tissue disease (CTD) show lung involvement that results in clinical interstitial lung disease (ILD). Surgical lung biopsy is helpful for diagnosis of CTD-ILD in many cases. In this review, we discuss the histologic manifestations of different types of CTD-ILD, focusing on patterns of disease and their differential diagnoses. Acquired autoimmune connective tissue diseases will be covered in this review, while lung involvement in vasculitides, heritable connective tissue disorders, and drug-induced CTD-like conditions will not be discussed.

Interpretation of surgical lung biopsies in connective tissue disease (CTD) can be challenging. The source of these challenges arises from both the multiple clinical scenarios that confront the pulmonologist and the variety of histopathologic patterns observed in the biopsy. Many patients with lung involvement by CTD may not need a biopsy. In the first place, radiologic abnormalities are significantly more prevalent than symptomatic lung disease.1–3 In addition, due to the fact that treatment may not be altered, patients with known CTD and radiographic changes consistent with their disease often do not undergo biopsy. Pathologists encounter lung biopsy specimens from patients with CTD most frequently either during initial presentation of the disease, often establishing the diagnosis, or in cases when the clinical and radiologic findings are not specific to CTD-interstitial lung disease (ILD) (e.g., when drug reaction or infection remain in the differential diagnosis). A variety of patterns of lung injury can be observed in the biopsies from patients with CTD (►Table 1), spanning the range from acute to subacute to chronic. Biopsies may show involvement of several compartments of the lung (e.g., alveolar septa, alveolar spaces, small airways, vessels, and pleura), may often show overlapping patterns of injury, and may show chronic and active disease. This “acute on chronic” pattern of

Issue Theme Pulmonary Complications of Connective Tissue Disease; Guest Editor, Danielle Antin-Ozerkis, MD, Jeffrey Swigris, DO, MS

injury often raises the diagnostic dilemma of whether there is a flare of the underlying CTD or an unrelated process such as infectious pneumonia or drug toxicity. While there are several histologic clues that suggest CTD-ILD, with the exception of few cases (e.g., rheumatoid nodule) a specific CTD type typically cannot be inferred from the biopsy findings. Moreover, the great majority of cases may have significant histologic overlap with other etiologies, for example, infection, hypersensitivity pneumonitis (HP), drug reactions, familial and acquired immunodeficiency disorders, and familial ILD. Therefore, a multidisciplinary approach utilizing clinical, radiologic, and pathologic data is essential in rendering a definitive diagnosis.4 Transbronchial biopsy (TBB) is often not helpful in the diagnosis of ILD due to low sensitivity for most types of diffuse parenchymal disease,5–8 with the notable exception of sarcoidosis9 or if used to exclude infection or malignancy. Although, recent experience with transbronchial cryobiopsy suggests that this technique may improve the diagnostic utility of TBB in evaluating ILD in the future,10 at present surgical lung biopsy remains the gold standard for evaluation of CTD-ILD. An optimal surgical biopsy should be obtained from at least two different lobes, with each piece extending approximately 2 to 3 cm from pleura into the lung

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DOI http://dx.doi.org/ 10.1055/s-0034-1371543. ISSN 1069-3424.

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Anatoly Urisman, MD, PhD1

Pulmonary Pathology in CTD

Urisman, Jones

Table 1 Histologic patterns of lung involvement in CTD-ILD RA DAD

6%

SLE

23 23,37

PM/DM

Rare

17–19

Rare

40,41

3–27%

20–22

5–40%

20,21,39

SSc

SjS

Rare

114

Rare26 < 22%43,44

OP

11–15

C-NSIP

12–15%23,39

9%18

7–73%20,21,39

19–68%42,46

3–28%39,43,44

F-NSIP

29–33%37,39

4%18,47

11–54%21,22

59–68%42,46

28–58%43,44

23,37

< 17%43,44

CB

6%37

?

?

?

78%59,60

FB

6–65%37,39,53

?

?

?

11%59,60

OB

Yes66–69

?

?

Rare70

Pleuritis Arterial thickening

>10% Yes

84–86

18–40% Yes

77,82,83

? Yes

15–26%

42,46

13–56%

18,113

5–33%

20–22

UIP

23,115

Rare

18,39,47

1%

15,24,25

67% 87–90

Yes

113

94

Rare59 ? Yes75,79–81

Abbreviations: CB, cellular bronchiolitis; C-NSIP, cellular nonspecific interstitial pneumonia; DAD, diffuse alveolar damage; FB, follicular bronchiolitis; FNSIP, fibrotic nonspecific interstitial pneumonia; OP, organizing pneumonia; OB, obliterative bronchiolitis; PAH, histologic features of pulmonary arterial hypertension; UIP, usual interstitial pneumonia. Notes: Percentages are estimated from available biopsy series and therefore may show bias toward those cases that undergo biopsy. ?, insufficient data; yes, multiple cases—prevalence in biopsies difficult to estimate from available reports and rare, only isolated cases reported.

parenchyma, targeting areas of pathology such as fibrosis or consolidation as well as the interface with adjacent uninvolved or less involved parenchyma.7,11

Patterns of Lung Injury in Connective Tissue Disease Diffuse Alveolar Damage Diffuse alveolar damage (DAD) is a histologic pattern of injury that typically accompanies a clinically recognizable and sometimes acute onset of respiratory symptoms and often correlates with the clinical entity acute respiratory distress syndrome (ARDS).12 Earliest biopsy changes of DAD include alveolar septal edema and fibrin accumulation in the airspaces (►Fig. 1). Within hours to days, these changes are accompanied by alveolar septal fibroplasia, accumulation of alveolar macrophages (frequently including foam cells), and formation of hyaline membranes.13,14 Organizing thrombi are often found in small to medium-sized arteries. Distal airway squamous metaplasia is also frequently present. Within days to weeks, airspace plugs of organizing pneumonia become a prominent feature, and type II pneumocytes proliferate along the alveolar surfaces, a histologic pattern described as organizing DAD. Prominent neutrophilia may be observed in lavage samples; however, there is usually a paucity of inflammation on histologic sections. Prominent acute inflammation, particularly in the airspaces, should raise suspicion of infection. Other clues to specific non-CTD etiologies may be present. Viral cytopathic changes can be observed in some viral pneumonias (e.g., cytomegalovirus, respiratory syncytial virus, adenovirus); food or other foreign material with or without giant cell reaction may point to aspiration, and prominent eosinophilia may suggest a primary eosinophilic disorder such as Churg–Strauss syndrome or acute eosinophilic pneumonia. Seminars in Respiratory and Critical Care Medicine

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CTD as an etiology of DAD is established by first excluding other possible causes. In CTD cases that initially present with DAD, recognition of rheumatologic symptoms and compatible laboratory findings will typically yield the correct diagnosis. In patients with established CTD, particularly those on immunosuppressive therapy, infectious etiology, and drug toxicity should be given careful consideration. Overall, DAD is an uncommon manifestation of CTD, which may occur in patients with pre-existing CTD-ILD or as the initial presentation of the disease.15 In systemic lupus erythematosus (SLE), cases of diffuse alveolar hemorrhage commonly show features of DAD,16 but pure DAD appears to be

Fig. 1 Diffuse alveolar damage in a patient with systemic sclerosis. The biopsy shows diffuse alveolar septal thickening by edema, granulation tissue, lymphohistiocytic inflammation, and type II pneumocyte hyperplasia. Alveolar spaces contain fibrin, hyaline membranes, and alveolar macrophages.

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exceedingly rare in adults17,18 and perhaps slightly more common in childhood SLE.19 In polymyositis/dermatomyositis (PM/DM), an older case series found DAD pattern in 4 of 15 cases (27%), of which 3 did not have a CTD diagnosis at the time of biopsy20; however, a larger more recent series identified DAD in 2 of 70 cases (3%),21 potentially reflecting improvements in diagnosis and treatment of this disease. Of note, a study by Fujisawa et al comparing five cases of PMILD and eight cases of DM-ILD,22 identified DAD as the primary pattern in three cases of DM-ILD and none associated with PM-ILD, suggesting that DAD is more common in DM-ILD than in PM-ILD. In rheumatoid arthritis (RA), primary DAD pattern was found in 2 of 33 cases (6%) in one study.23 In a recent study of CTD-associated DAD, RA accounted for five of nine cases, four of which were in patients with pre-existing RA-ILD, while one was a de novo presentation of the disease.15 Only single cases of DAD in association with systemic sclerosis (SSc),15,24,25 Sjogren syndrome (SjS),26 and mixed connective tissue disease (MCTD)15,27 have been reported.

Other Acute Lung Injury Patterns Acute lung injury (ALI) or organizing ALI is a histologic diagnosis that is typically used in cases that resemble DAD but lack hyaline membranes.28 Clinically, this pattern may be observed in cases of ARDS or cases with a less acute presentation and a milder course of illness than seen in cases of DAD. However, the same differential diagnosis as that for DAD applies to these cases. In our experience, ALI is a common secondary finding in cases with significant established fibrosis, often present only focally as the so-called “acute on chronic” pattern, and clinically may be recognized as an acute or subacute exacerbation. In contrast to acute exacerbations that manifest as a primary ALI pattern in biopsies and are associated with poor prognosis,29 we are not aware of any studies looking at the significance of secondary ALI pattern in CTD-ILD. Acute fibrinous and organizing pneumonia has been relatively recently described as a distinct histologic pattern of ALI.30 Histologically, it is characterized by prominent fibrin accumulation in the airspaces without hyaline membrane formation. Other features include patchy organizing pneumonia, alveolar septal thickening by usually mild lymphoplasmacytic inflammation, type II pneumocyte hyperplasia, and variable alveolar septal fibroplasia. Although, the experience with this newly recognized pattern is limited, it appears that at least some cases are associated with CTD, including ankylosing spondylitis, PM,30 SLE,31 and undifferentiated connective tissue disease.32 Importantly, abundant airspace fibrin should always raise suspicion of possible Pneumocystis jiroveci pneumonia and be evaluated with a fungal Grocott methenamine silver (GMS) stain.33

Organizing Pneumonia Organizing pneumonia (OP) is characterized histologically by consolidation of airspaces by rounded branching polypoid plugs of granulation tissue (►Fig. 2). This airspace organization is usually found in the alveoli as well as terminal airways.

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Fig. 2 Organizing pneumonia (OP) in a patient with systemic lupus erythematosus. Intra-alveolar rounded plugs of granulation tissue are present. In addition to OP, the underlying alveolar septa are thickened by patchy chronic inflammatory infiltrate, type II pneumocyte hyperplasia, and focally collagenous fibrosis.

Pure involvement of airways is rare and should raise suspicion of a primary small airway disease. Alveolar macrophages with foamy cytoplasm are often present; however, this nonspecific finding may also be observed in cases of aspiration or drug toxicity (e.g., amiodarone).34–36 Scattered neutrophils may be present but are usually not prominent; abundant acute inflammation, particularly involving the airspaces, should raise concern for infection. Similarly, scattered eosinophils are often present, but prominent airspace eosinophilia should raise concern for a primary eosinophilic condition (e.g., Churg–Strauss syndrome or eosinophilic pneumonia) or a drug reaction. In general, when a predominant OP pattern is encountered, a broad differential diagnosis should be considered, which in addition to CTD-ILD should include infectious pneumonia (particularly viral or atypical bacterial), aspiration, and drug toxicity; cryptogenic organizing pneumonia is a diagnosis of exclusion. Many cases of CTD-ILD have at least focal findings of OP that are usually superimposed on other patterns of lung injury, most commonly interstitial fibrosis. However, pure OP is a less common finding in CTD-ILD. In RA-ILD, OP was reported as a primary pattern in 2 of 18 cases (11%) in one series37 and in another in 6 of 40 cases (15%); interestingly, in the latter study OP was also documented as a secondary pattern in 3 of the cases (8%).23 OP can occasionally be the presenting manifestation of RA.38 In PM/DM-ILD, OP as the primary pattern was present in 6 of 15 cases (40%) in one study,20 5 of 13 (38%) in another,39 and in 1 of 22 (5%) in third.21 Only single reports of OP in SLE have been documented.40,41 OP is a very rare manifestation of SSc, documented only in 1 of 80 cases (1%) in the largest available series.42 OP has been reported as a rare inaugural manifestation of SjS, and was also found in 4 of 18 biopsies (22%) in a series where 22% of cases were diagnosed with SjS and ILD Seminars in Respiratory and Critical Care Medicine

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within 1 month of the initial presentation43; however, no OP cases were found in another study of 33 patients, most of whom had established SjS-ILD.44

Nonspecific interstitial pneumonia (NSIP)-pattern fibrosis, or fibrotic NSIP,45 is a common pattern of fibrosis associated with CTD-ILD. It is characterized by diffuse although often variable alveolar septal thickening by collagen deposition (►Fig. 3). The amount of associated interstitial inflammation varies (see Interstitial Inflammation below), but in most cases it consists of mild patchy lymphoplasmacytic infiltrate that may or may not show accentuation around airways or peripherally near the pleura. Although common in CTD-ILD, not every case of fibrotic NSIP is a case of CTD-ILD. Histologic clues to support CTD may be present in some cases (see Histologic Clues to Diagnosis of CTD-ILD below); however, the findings are most often nonspecific and other causes of fibrotic NSIP should be considered. In RA-ILD, NSIP-pattern fibrosis was observed in 6 of 18 biopsies (33%), 2 of which were accompanied by significant interstitial inflammation (cellular and fibrotic NSIP) in one study,37 while another found fibrotic NSIP in 5 of 17 cases (29%).39 In PM/DM-ILD, fibrotic NSIP was seen in 2 of 18 (11%) and combined cellular and fibrotic NSIP in 9 of 18 (50%) in one study,21 and NSIP not otherwise specified (NOS) in 7 of 13 cases (54%) in another,22 which also showed a higher proportion of NSIP cases in PM-ILD (4 of 5) compared with DM-ILD (3 of 8). In SSc-ILD, fibrotic NSIP as the major histopathologic pattern was present in 47 of 80 cases (59%) in one study,42 and NSIP NOS in 13 of 19 cases (68%) in another.46 Similarly, in SjS-ILD, fibrotic NSIP was found in 19 of 33 cases (58%),44 and NSIP NOS in 5 of 18 cases (28%).43 Although, difficult to estimate from the available older case series, fibrotic NSIP appears to be less common in SLE but may be present in up to 4% of biopsied cases.18,47

Usual interstitial pneumonia (UIP)-pattern fibrosis is frequently encountered in CTD-ILD. This pattern is more prevalent in advanced cases and correlates with decreased survival compared with NSIP-pattern fibrosis.21,42 UIP is classically identified by its patchy nature (spatial heterogeneity) and chronic active appearance (temporal heterogeneity). The fibrosis is accentuated in the subpleural regions with microscopic honeycombing observed as irregular airspaces surrounded by dense fibrosis (►Fig. 4). The central lung tissue is usually less fibrotic, and there are fibroblast foci (regions of new fibrosis) at the interface between these central and peripheral regions. Although cases of CTD-ILD may show UIP-pattern fibrosis, there are often features that differ from typical cases of idiopathic pulmonary fibrosis (IPF). Fibroblast foci may be less frequent than in cases of UIPIPF.27 Other findings that may suggest CTD-ILD rather than UIP-IPF include airway-centered fibrosis, NSIP-pattern fibrosis instead of normal lung in the central lobular regions, or prominent interstitial inflammation with lymphoid aggregates. In RA-ILD, UIP as the primary pattern was found in 5 of 40 examined cases (13%) in one study23 and in 10 of 18 cases (56%) in another.37 An older study of PM/DM-ILD20 found UIPpattern fibrosis in 5 of 15 cases (33%), while a more recent study identified only 1 case of UIP in 22 biopsies (5%) from patients with PM/DM-ILD.21 Of note, a report comparing PMILD and DM-ILD, described UIP pattern in one of five (20%) and two of eight (25%) of cases, respectively.22 In SSc-ILD, UIP pattern was found in 5 of 19 cases (26%) in one study46 and in 12 of 80 cases (15%) in another.42 UIP pattern was reported in 3 of 18 cases (17%) of SjS-ILD in one study,43 while another found only 1 case of possible UIP (honeycomb changes only) in a total of 33 cases.44 Although, chronic interstitial fibrosis may be present in up to 5% of cases of SLE-ILD, UIP pattern is rare in this disease.3,18,39,47

Fig. 3 Fibrotic nonspecific interstitial pneumonia in a patient with systemic sclerosis. The main finding is the presence of variable but diffuse alveolar septal thickening by fibrosis. Mild interstitial lymphoplasmacytic inflammation is also present.

Fig. 4 Usual interstitial pneumonia pattern fibrosis in a patient with rheumatoid arthritis. The findings include marked subpleural fibrosis with microscopic honeycombing, and rare fibroblast foci. Less affected parenchyma is present more centrally.

Interstitial Fibrosis

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Interstitial Inflammation Cellular interstitial pneumonia (CIP) is a common pattern of inflammation associated with CTD and may occur in isolation (cellular NSIP) or in combination with NSIP-pattern fibrosis. The main histologic finding is the presence of mixed lymphoplasmacytic inflammation within alveolar septa (►Fig. 5), often accentuated around airways. In most cases, the infiltrate is mild and patchy but may be heavy and diffuse in some cases. When the inflammation is accompanied by fibrosis, the descriptors such as cellular and fibrotic (or fibrotic and cellular) NSIP are used (see Interstitial Fibrosis above). In RA-ILD, primary CIP pattern was present in 5 of 40 cases (13%) and as a secondary pattern in 6 of 40 cases (15%) in one study,23 and another study reported cellular NSIP as the primary pattern in 2 of 17 cases (12%).39 In SLE, a study of 120 autopsy cases found “interstitial pneumonia” (distinct from interstitial fibrosis) attributable to SLE-ILD in 11 cases (9%).18 In PM/DM-ILD, CIP was identified in 1 of 15 cases (7%) in one study,20 cellular NSIP or cellular and fibrotic NSIP in 16 of 22 (73%) in another,21 and in 3 of 13 (23%) in a third study.39 In SSc, cellular NSIP primary pattern was present in 15 of 80 cases (19%) in one study,42 and NSIP NOS in 13 of 19 cases (68%) in another.46 In SjS-ILD, cellular NSIP was identified in 1 of 33 cases (3%) in one study,44 in 1 of 5 (20%) in another,39 and NSIP NOS in 5 of 18 cases (28%) in a third study.43 The term lymphocytic interstitial pneumonia (LIP) is reserved for cases with diffuse and marked thickening of alveolar septal interstitium by dense and in most cases predominantly lymphocytic infiltrate.48 The infiltrate is polyclonal and may be admixed with variable numbers of plasma cells and macrophages. Germinal centers are frequently present. Histologically, LIP overlaps with follicular bronchiolitis and nodular lymphoid hyperplasia. When present, LIP

Fig. 5 Cellular nonspecific interstitial pneumonia in a patient with systemic lupus erythematosus. The biopsy shows diffuse alveolar septal thickening by lypmphoplasmacytic inflammation with accentuation around bronchioles. Alveolar spaces are free of significant inflammation.

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pattern may raise concern for a possible lymphoproliferative process, which should be ruled out using appropriate immunohistochemical and flow cytometric analyses. LIP has been associated with some viral infections, particularly human immunodeficiency virus,49,50 and this possibility should be considered when LIP pattern is encountered in a biopsy. LIP was classically observed in SjS-ILD, where it was initially reported in at least 25% of cases based on a series of 12 biopsies,51 and a more recent study identified LIP primary pattern in 3 of 18 SjS-ILD cases (17%).43 A more recent retrospective analysis of 1,167 surgical biopsies from patients with ILD identified only 15 cases of LIP, of which 8 were associated with SjS, and 1 case each with RA, SLE, and PM; importantly, the set also included one patient with monoclonal gammopathy, and one patient with severe combined immunodeficiency syndrome.52

Small Airway Involvement Chronic inflammation involving small airways (bronchiolitis) is observed in several types of CTD-ILD,39,53,54 commonly in combination with other patterns of injury and rarely as an isolated finding. Several patterns of involvement have been recognized.55–57 In cases with moderate diffuse peribronchiolar mononuclear inflammation, the term cellular bronchiolitis (CB) is used (►Fig. 6A). Follicular bronchiolitis (FB) describes cases with prominent peribronchiolar lymphoid follicles (►Fig. 6B), often with germinal centers. Scattered neutrophils may be noted, usually within the epithelium or in the lumen, but significant acute inflammation is uncommon and should raise suspicion of infection. Cases with FB will frequently coexist with CB, suggesting that the two patterns represent a continuum of inflammation rather than distinct etiologies.58 FB and CB are more common in RA and SjS than in other CTD-ILD types. In RA-ILD, 1 case of each (6%) was observed in one study,37 while another found FB as a major pattern in 6 of 17 cases (35%) and as a minor pattern in another 5 cases (29%; 65% total).39 Similarly, in SjS-ILD, FB was identified in one of nine cases (11%) and CB in seven cases (78%).59 Additional cases of FB in RA-ILD and SjS have been reported.53,60 From available series, it is hard to estimate the frequency of FB and CB in other CTD-ILD types, but based on our experience, mild CB is frequently present in most types of CTD-ILD, while FB as a major finding is rare outside of RA, SjS, and possibly MCTD.21,42,60,61 Obliterative bronchiolitis (OB), or constrictive bronchiolitis, is characterized by circumferential subepithelial scarring resulting in narrowing and obliteration of bronchiolar lumens (►Fig. 6C).56 It is important to distinguish OB from the airway involvement in OP. In OP, the fibroblastic plugs are intraluminal, while in OB, the fibrosis is intramural. For this reason, the older name for OP of bronchiolitis obliterans organizing pneumonia is discouraged.62 In many cases, OB may be subtle and focal, occurring as a small region of narrowing within the length of the bronchiole. For this reason, evaluation of multiple level sections and elastic tissue stains is helpful. The presence of air trapping on computed tomography (CT) is a supportive correlate. Seminars in Respiratory and Critical Care Medicine

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Urisman, Jones Although, most frequently seen in lung transplants as a manifestation of chronic rejection,63–65 OB is found in rare cases of CTD-ILD. It has been reported mostly in RA-ILD,66–68 and a recent study of 25 patients with RA-ILD and clinical features of OB found histologic evidence of OB in 8 of 9 available biopsies.69 OB appears to be exceedingly rare in other types of CTD-ILD but has been reported in SjS59 and SSc.70

Vascular Involvement Pulmonary arterial hypertension (PAH) is a well-recognized manifestation of CTD associated with decreased survival.71–73 Although only a small subset of patients will have clinically recognizable PAH, histologic changes of PAH are more common and may be encountered in isolation or in combination with other interstitial changes, particularly fibrosis (►Fig. 7). The findings range in severity from mild arterial myointimal

Fig. 6 Spectrum of small airway involvement in a single patient with rheumatoid arthritis. (A) Cellular bronchiolitis: the bronchiole is surrounded by relatively mild lymphoplasmacytic inflammation. (B) Follicular bronchiolitis: heavy peribronchiolar inflammation with formation of subepithelial lymphoid aggregates resulting in luminal narrowing and mucostasis. (C) Obliterative bronchiolitis: near-complete obliteration of the bronchiole by constrictive fibrosis.

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Fig. 7 Histologic changes of pulmonary arterial hypertension in a patient with systemic sclerosis. (A) Marked medial hypertrophy with intimal fibroplasia in a medium-sized pulmonary artery. (B) Pulmonary atherosclerosis: myointimal fibroplasia with myxoid change and accumulation of foamy macrophages in a larger caliber pulmonary artery. (The images are from the same patient as in ►Fig. 3).

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thickening to more pronounced intimal proliferation, to plexiform lesions, fibromyxoid change and fibrinoid necrosis in the most severe cases.74–77 PAH is most commonly encountered in SSc,71,78 where autopsy series show histologic features of PAH in up to two-thirds of cases. These cases show clinical evidence of PAH, and show vascular changes out of proportion to the background interstitial fibrosis, particularly in rapidly progressive cases.75,79–81 PAH and its histopathologic features have also been reported in SLE,77,82,83 RA,84–86 PM/DM,87–90 MCTD,91–93 and SjS.94 Pulmonary veno-occlusive disease is a distinct pattern of sclerotic vascular changes with primary involvement of pulmonary veins and venules95,96; this rare clinicopathologic entity is associated with a rapidly progressive course, often requiring prompt transplantation, and is being increasingly recognized in association with CTD.96,97

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capillaries.100 Fibrinoid necrosis may occur in the most severe cases. Capillaritis is thought to be a nonspecific finding that correlates with acute hemorrhage and may be a marker of endothelial cell injury101; it is generally not helpful in identifying the etiology of DAH, and its absence does not rule out any specific cause.99,102 However, significant capillaritis with giant cells is suggestive of Wegener granulomatosis (WG), particularly in the presence of other features of WG such as geographic basophilic necrosis and granulomatous inflammation.103 Among different CTD types, DAH is most common in SLE and is associated with significant mortality.104–106 Rare cases of DAH have also been reported in RA,98,107 SSc,108–111 MCTD,107 and PM/DM.112 Evaluation of possible causes of DAH relies heavily on clinical and laboratory findings.

Pleural Involvement

Diffuse alveolar hemorrhage (DAH) may be caused by several disorders, including CTD, systemic vasculitic conditions, acute pulmonary-renal syndromes, such as Goodpasture syndrome, and idiopathic pulmonary hemosiderosis.98,99 The histologic findings typically include a mix of acute and organizing hemorrhage with or without capillaritis (►Fig. 8). Acute hemorrhage is manifested by fresh blood within alveolar spaces with associated fibrin accumulation and interstitial changes of ALI, bordering on DAD in the most severe cases. Old hemorrhage is recognized by accumulation of hemosiderin-filled macrophages in the airspaces with or without OPlike plugs, interstitial deposition of hemosiderin and hematoidin, frequently with encrustation of the elastic fibers (endogenous pneumoconiosis). Patchy alveolar septal fibrosis may also be present. Capillaritis is recognized as linear accumulation of neutrophils along the alveolar septal

Pleural involvement is variable among CTD types and may range from clinically silent mild chronic inflammation to more acute forms of pleuritis that are more likely to be associated with complications such as effusion and pneumothorax.113,114 Acute fibrinous pleuritis is characterized by edematous pleural thickening with prominence of dilated capillaries, surface accumulation of fibrin and associated reactive mesothelial hyperplasia ( ►Fig. 9). Sparse acute inflammation is usually present, but a heavy neutrophilic infiltrate should raise concern for infection. In organizing pleuritis, the pleura is thickened by granulation tissue with variable degrees of fibroplasia and chronic typically mild lymphoplasmacytic inflammation. Surface fibrin and mesothelial hyperplasia are present in many cases, suggesting a temporal continuum with acute fibrinous pleuritis, sometimes described as fibrinous and organizing pleuritis. Pneumothorax is usually associated with this type of pleuritis and also shows large numbers of eosinophils. Chronic

Fig. 8 Diffuse alveolar hemorrhage in a patient with systemic lupus erythematosus. The alveolar spaces are filled by macrophages containing golden-brown hemosiderin pigment. The underlying alveolar septa show reactive thickening by lymphohistiocytic inflammation and type II pneumocyte hyperplasia.

Fig. 9 Chronic pleuritis in a patient with systemic lupus erythematosus. The pleura shows thickening by fibrosis and patchy chronic inflammation with surface granulation tissue formation, focal fibrin accumulation, and adhesion formation (at the tip). Also, note the presence of peribronchiolar fibrosis in the subpleural parenchyma.

Alveolar Hemorrhage

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pleuritis may vary from mild patchy lymphoplasmacytic infiltrate to prominent pleural inflammation with formation of lymphoid aggregates and germinal centers. Mild pleural fibrosis accompanies most cases of chronic pleuritis, but occasional cases have marked pleural thickening by fibrosis, in which case a diagnosis of fibrous pleuritis may be made. Pleural effusions occur most often in SLE (30–50%), MCTD (50%), RA (20%), SSc (7%), and only rarely in other CTD types.113,114 The incidence of pathologic involvement of the pleura in CTD is likely higher. In RA, old autopsy series showed frequent nonspecific pleuritis, pleural adhesions, rheumatoid nodules, and granulomatous pleuritis,115 although some of the cases may have been due to coincidental infection such as tuberculosis.116 In a more recent biopsy series of RA-ILD,23 acute and/or chronic pleuritis as a secondary pattern was present in 4 of 40 cases (10%). Pleural thickening was documented in up to 70% of autopsies of patients with RA.113 In SLE, pleuritis not explained by any other condition was found in 22 of 120 autopsy cases (18%) by one study,18 while another reported acute fibrinous pleuritis in 40% and pleural fibrosis in 30% of autopsy cases.113 The same report described pleural adhesions in SSc in 67% and pleural fibrosis in 86% of autopsy cases. The histologic patterns of pleural involvement and their prevalence in surgical biopsies is not well documented in other CTD types, but in our experience mild chronic pleuritis with patchy pleural fibrosis and associated reactive mesothelial hyperplasia are present in at least half of biopsied cases of CTD-ILD, typically superimposed on other interstitial changes.

Histologic Clues to Diagnosis of CTD-ILD With the exception of rare cases showing rheumatoid nodules (see below), specific diagnosis of CTD-ILD can rarely if ever be made based on lung biopsy findings alone. However, several histologic clues are important to recognize, which when found make the diagnosis of CTD-ILD more likely.

Rheumatoid Nodules Subcutaneous rheumatoid nodules are a classic pathognomonic feature of RA.117 In the lung the most common location is in the pleura and interlobular septa. When present these necrobiotic nodules are thought to be very specific for RA.23 The nodules have central infarct-like necrosis, occasionally with neutrophils, surrounded by a rim of palisading histiocytes (►Fig. 10). The features overlap those of necrotizing granulomas, and careful examination with stains for acid-fast bacilli and fungi is indicated. Elastic stains are helpful in ruling out vascular infarcts, particularly of venous type. In a review of surgical pathology cases, rheumatoid nodules were present in 13 of 40 (33%) biopsies from patients with RAILD.23

Fig. 10 Rheumatoid nodule in a patient with rheumatoid arthritis. This large nodule is pleural-based and shows a central area of brightly eosinophilic infarct-like necrosis surrounded by a zone of dark basophilic necrosis and more peripherally by palisading histiocytes.

important clue to the diagnosis of CTD-ILD. As systemic diseases, CTD often affect multiple organs and tissues, and in the lung they frequently involve several different structures. This can be most helpful in differentiation of CTD-ILD from IPF, which only rarely affects the pleura or small airways, and hypersensitivity pneumonitis, which only rarely affects the pleura.

Interstitial Fibrosis with Overlapping NSIP and UIP Features Interstitial fibrosis in CTD will frequently show a histologic overlap of UIP and NSIP patterns.118,119 This is often manifested by concomitant subpleural and bronchiolocentric fibrosis, or a lack of centrilobular normal-appearing lung as would be observed in UIP-IPF.120,121 Although, this overlap is a helpful diagnostic clue, it is by no means specific for CTD-ILD. Similar findings may be seen in some cases of chronic hypersensitivity pneumonia,122–124 rare chronic drug toxicities (e.g., nitrofurantoin125), and familial ILD.126

Lymphoid Aggregates Formation of prominent lymphoid aggregates, often with germinal centers, is a characteristic feature of CTD-ILD (►Fig. 11). Classically described in RA23 and SjS,127 lymphoid aggregates, or diffuse lymphoid hyperplasia, are also encountered in other types of CTD-ILD. Although, helpful as a diagnostic clue, lymphoid aggregates are not exclusive to CTD-ILD and can be observed in infectious pneumonias, immune deficiency syndromes, bronchiectasis, and in smokers with diffuse lymphoid hyperplasia.

Involvement of Multiple Lung Compartments

Lack of Well-Formed Granulomas

Concurrent involvement of alveolar septal interstitium, airways, vessels, and pleura (in any combination) is an

Prominent well-formed granulomas are not a typical finding in CTD-ILD. If present, infection (particularly if there is central

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Fig. 11 Lymphoid aggregates (diffuse lymphoid hyperplasia) in a patient with rheumatoid arthritis. Numerous interstitial lymphoid follicles are present and are most prominent at the interface of fibrosis and less affected parenchyma. The primary pattern is most consistent with fibrotic and cellular nonspecific interstitial pneumonia.

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necrosis) and sarcoidosis are more likely. Although, granulomas have been reported as a secondary finding in RA-ILD23 and SjS-ILD,39 their histologic features and distribution is not well documented, aside from rare cases where they appear to be small and poorly formed.128 Moreover, given the significant rate of lower respiratory tract infection in RA-ILD patients, including tuberculosis,116 we suspect that some of the granulomatous cases may be infectious in origin. While airspace collections of loosely adherent epithelioid macrophages and occasional multinucleated giant cells, sometimes with cholesterol clefts, can be found in areas of stasis, most commonly in the distal subpleural parenchyma, this is a nonspecific finding associated with interstitial fibrosis, irrespective of the cause.

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Conclusions

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Much like Richard III in Shakespeare’s Henry VI, Part III, who stated, “I can add colors to the chameleon, change shapes with Proteus for advantage, and set the murderous Machiavel to school,”129 CTD forces the practicing pathologist to consider this nefarious mimic in several differential diagnostic settings. Recognition of the numerous possible histologic findings in pulmonary biopsies from patients with CTD-ILD is the first step in pathologic diagnosis. Due to the common overlap of other etiologies including infection and drug reaction, it is vital to obtain clinical and radiologic data to support any final diagnosis.

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Conflict of Interest The authors declare that they have no competing interests.

systemic autoimmune diseases: radiographic and high-resolution CT findings. Radiographics 2000;20(6):1623–1635 Kim EA, Lee KS, Johkoh T, et al. Interstitial lung diseases associated with collagen vascular diseases: radiologic and histopathologic findings. Radiographics 2002;22(Spec No):S151–S165 Cheema GS, Quismorio FP Jr. Interstitial lung disease in systemic lupus erythematosus. Curr Opin Pulm Med 2000;6(5):424–429 Ryerson CJ, Collard HR. Update on the diagnosis and classification of ILD. Curr Opin Pulm Med 2013;19(5):453–459 Fishbein MC. Diagnosis: to biopsy or not to biopsy: assessing the role of surgical lung biopsy in the diagnosis of idiopathic pulmonary fibrosis. Chest 2005;128(5, Suppl 1):520S–525S Ryerson CJ, Urbania TH, Richeldi L, et al. Prevalence and prognosis of unclassifiable interstitial lung disease. Eur Respir J 2013;42(3): 750–757 Kaarteenaho R. The current position of surgical lung biopsy in the diagnosis of idiopathic pulmonary fibrosis. Respir Res 2013; 14(1):43 Myers JL, Katzenstein AL. Beyond a consensus classification for idiopathic interstitial pneumonias: progress and controversies. Histopathology 2009;54(1):90–103 Chapman JT, Mehta AC. Bronchoscopy in sarcoidosis: diagnostic and therapeutic interventions. Curr Opin Pulm Med 2003;9(5): 402–407 Griff S, Ammenwerth W, Schönfeld N, et al. Morphometrical analysis of transbronchial cryobiopsies. Diagn Pathol 2011;6:53 Flaherty KR, Travis WD, Colby TV, et al. Histopathologic variability in usual and nonspecific interstitial pneumonias. Am J Respir Crit Care Med 2001;164(9):1722–1727 Tomashefski JF Jr. Pulmonary pathology of acute respiratory distress syndrome. Clin Chest Med 2000;21(3):435–466 The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000;342(18):1301–1308 Hamilton PP, Onayemi A, Smyth JA, et al. Comparison of conventional and high-frequency ventilation: oxygenation and lung pathology. J Appl Physiol 1983;55(1 Pt 1):131–138 Parambil JG, Myers JL, Ryu JH. Diffuse alveolar damage: uncommon manifestation of pulmonary involvement in patients with connective tissue diseases. Chest 2006;130(2):553–558 Zamora MR, Warner ML, Tuder R, Schwarz MI. Diffuse alveolar hemorrhage and systemic lupus erythematosus. Clinical presentation, histology, survival, and outcome. Medicine (Baltimore) 1997;76(3):192–202 Asherson RA, Ridley M, Fletcher CD, Hughes GR. Systemic lupus erythematosus, pulmonary hypertension and adult respiratory distress syndrome (ARDS). Clin Exp Rheumatol 1988;6(3):301–304 Haupt HM, Moore GW, Hutchins GM. The lung in systemic lupus erythematosus. Analysis of the pathologic changes in 120 patients. Am J Med 1981;71(5):791–798 Nadorra RL, Landing BH. Pulmonary lesions in childhood onset systemic lupus erythematosus: analysis of 26 cases, and summary of literature. Pediatr Pathol 1987;7(1):1–18 Tazelaar HD, Viggiano RW, Pickersgill J, Colby TV. Interstitial lung disease in polymyositis and dermatomyositis. Clinical features and prognosis as correlated with histologic findings. Am Rev Respir Dis 1990;141(3):727–733 Douglas WW, Tazelaar HD, Hartman TE, et al. Polymyositisdermatomyositis-associated interstitial lung disease. Am J Respir Crit Care Med 2001;164(7):1182–1185 Fujisawa T, Suda T, Nakamura Y, et al. Differences in clinical features and prognosis of interstitial lung diseases between polymyositis and dermatomyositis. J Rheumatol 2005;32(1): 58–64

Seminars in Respiratory and Critical Care Medicine

Vol. 35

No. 2/2014

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

1 Mayberry JP, Primack SL, Müller NL. Thoracic manifestations of

Pulmonary Pathology in CTD

Urisman, Jones

23 Yousem SA, Colby TV, Carrington CB. Lung biopsy in rheumatoid

43 Parambil JG, Myers JL, Lindell RM, Matteson EL, Ryu JH. Interstitial

arthritis. Am Rev Respir Dis 1985;131(5):770–777 Muir TE, Tazelaar HD, Colby TV, Myers JL. Organizing diffuse alveolar damage associated with progressive systemic sclerosis. Mayo Clin Proc 1997;72(7):639–642 Phillips K, Byrne-Dugan C, Batterson E, Seibold JR. Rapidly progressive fatal interstitial lung disease in a patient with systemic sclerosis. Nat Rev Rheumatol 2009;5(4):225–228 Usui Y, Kimula Y, Miura H, et al. A case of bronchiolitis obliterans organizing pneumonia associated with primary Sjögren’s syndrome who died of superimposed diffuse alveolar damage. Respiration 1992;59(2):122–124 Watanabe Y, Koyama S, Moriguchi M, et al. Rapidly progressive respiratory failure in mixed connective tissue disease: report of an autopsy case. Intern Med 2012;51(24):3415–3419 Leslie KO. My approach to interstitial lung disease using clinical, radiological and histopathological patterns. J Clin Pathol 2009; 62(5):387–401 Churg A, Wright JL, Tazelaar HD. Acute exacerbations of fibrotic interstitial lung disease. Histopathology 2011;58(4):525–530 Beasley MB, Franks TJ, Galvin JR, Gochuico B, Travis WD. Acute fibrinous and organizing pneumonia: a histological pattern of lung injury and possible variant of diffuse alveolar damage. Arch Pathol Lab Med 2002;126(9):1064–1070 Hariri LP, Unizony S, Stone J, et al. Acute fibrinous and organizing pneumonia in systemic lupus erythematosus: a case report and review of the literature. Pathol Int 2010;60(11):755–759 Valim V, Rocha RH, Couto RB, Paixão TS, Serrano EV. Acute fibrinous and organizing pneumonia and undifferentiated connective tissue disease: a case report. Case Rep Rheumatol 2012; 2012:549298 Ward MM, Donald F. Pneumocystis carinii pneumonia in patients with connective tissue diseases: the role of hospital experience in diagnosis and mortality. Arthritis Rheum 1999;42(4):780–789 Kennedy JI, Myers JL, Plumb VJ, Fulmer JD. Amiodarone pulmonary toxicity. Clinical, radiologic, and pathologic correlations. Arch Intern Med 1987;147(1):50–55 Larsen BT, Vaszar LT, Colby TV, Tazelaar HD. Lymphoid hyperplasia and eosinophilic pneumonia as histologic manifestations of amiodarone-induced lung toxicity. Am J Surg Pathol 2012;36(4): 509–516 Bedrossian CW, Warren CJ, Ohar J, Bhan R. Amiodarone pulmonary toxicity: cytopathology, ultrastructure, and immunocytochemistry. Ann Diagn Pathol 1997;1(1):47–56 Lee HK, Kim DS, Yoo B, et al. Histopathologic pattern and clinical features of rheumatoid arthritis-associated interstitial lung disease. Chest 2005;127(6):2019–2027 Henriet AC, Diot E, Marchand-Adam S, et al. Organising pneumonia can be the inaugural manifestation in connective tissue diseases, including Sjogren’s syndrome. Eur Respir Rev 2010; 19(116):161–163 Tansey D, Wells AU, Colby TV, et al. Variations in histological patterns of interstitial pneumonia between connective tissue disorders and their relationship to prognosis. Histopathology 2004;44(6):585–596 Gammon RB, Bridges TA, al-Nezir H, Alexander CB, Kennedy JI Jr. Bronchiolitis obliterans organizing pneumonia associated with systemic lupus erythematosus. Chest 1992;102(4):1171–1174 Otsuka F, Amano T, Hashimoto N, et al. Bronchiolitis obliterans organizing pneumonia associated with systemic lupus erythematosus with antiphospholipid antibody. Intern Med 1996; 35(4):341–344 Bouros D, Wells AU, Nicholson AG, et al. Histopathologic subsets of fibrosing alveolitis in patients with systemic sclerosis and their relationship to outcome. Am J Respir Crit Care Med 2002;165(12): 1581–1586

lung disease in primary Sjögren syndrome. Chest 2006;130(5): 1489–1495 Ito I, Nagai S, Kitaichi M, et al. Pulmonary manifestations of primary Sjogren’s syndrome: a clinical, radiologic, and pathologic study. Am J Respir Crit Care Med 2005;171(6):632–638 Katzenstein AL, Fiorelli RF. Nonspecific interstitial pneumonia/ fibrosis. Histologic features and clinical significance. Am J Surg Pathol 1994;18(2):136–147 Kim DS, Yoo B, Lee JS, et al. The major histopathologic pattern of pulmonary fibrosis in scleroderma is nonspecific interstitial pneumonia. Sarcoidosis Vasc Diffuse Lung Dis 2002;19(2): 121–127 Eisenberg H, Dubois EL, Sherwin RP, Balchum OJ. Diffuse interstitial lung disease in systemic lupus erythematosus. Ann Intern Med 1973;79(1):37–45 Nicholson AG. Lymphocytic interstitial pneumonia and other lymphoproliferative disorders in the lung. Semin Respir Crit Care Med 2001;22(4):409–422 Morris JC, Rosen MJ, Marchevsky A, Teirstein AS. Lymphocytic interstitial pneumonia in patients at risk for the acquired immune deficiency syndrome. Chest 1987;91(1):63–67 Oldham SA, Castillo M, Jacobson FL, Mones JM, Saldana MJ. HIVassociated lymphocytic interstitial pneumonia: radiologic manifestations and pathologic correlation. Radiology 1989;170(1 Pt 1):83–87 Deheinzelin D, Capelozzi VL, Kairalla RA, Barbas Filho JV, Saldiva PH, de Carvalho CR. Interstitial lung disease in primary Sjögren’s syndrome. Clinical-pathological evaluation and response to treatment. Am J Respir Crit Care Med 1996;154(3 Pt 1): 794–799 Cha SI, Fessler MB, Cool CD, Schwarz MI, Brown KK. Lymphoid interstitial pneumonia: clinical features, associations and prognosis. Eur Respir J 2006;28(2):364–369 Fortoul TI, Cano-Valle F, Oliva E, Barrios R. Follicular bronchiolitis in association with connective tissue diseases. Lung 1985;163(5): 305–314 Epler GR, Snider GL, Gaensler EA, Cathcart ES, FitzGerald MX, Carrington CB. Bronchiolitis and bronchitis in connective tissue disease. A possible relationship to the use of penicillamine. JAMA 1979;242(6):528–532 Colby TV. Pulmonary pathology in patients with systemic autoimmune diseases. Clin Chest Med 1998;19(4):587–612, vii Allen TC. Pathology of small airways disease. Arch Pathol Lab Med 2010;134(5):702–718 Wright JL, Cagle P, Churg A, Colby TV, Myers J. Diseases of the small airways. Am Rev Respir Dis 1992;146(1):240–262 Colby TV. Bronchiolitis. Pathologic considerations. Am J Clin Pathol 1998;109(1):101–109 Nakanishi M, Fukuoka J, Tanaka T, et al. Small airway disease associated with Sjögren’s syndrome: clinico-pathological correlations. Respir Med 2011;105(12):1931–1938 Howling SJ, Hansell DM, Wells AU, Nicholson AG, Flint JD, Müller NL. Follicular bronchiolitis: thin-section CT and histologic findings. Radiology 1999;212(3):637–642 Keane MP, Lynch JP III. Pleuropulmonary manifestations of systemic lupus erythematosus. Thorax 2000;55(2):159–166 Travis WD, Costabel U, Hansell DM, et al; ATS/ERS Committee on Idiopathic Interstitial Pneumonias. An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 2013; 188(6):733–748 Reichenspurner H, Girgis RE, Robbins RC, et al. Obliterative bronchiolitis after lung and heart-lung transplantation. Ann Thorac Surg 1995;60(6):1845–1853

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29 30

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33

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35

36

37

38

39

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55 56 57 58 59

60

61 62

63

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

210

Urisman, Jones

64 Schlesinger C, Meyer CA, Veeraraghavan S, Koss MN. Constrictive

85 Onodera S, Hill JR. Pulmonary Hypertension. Report of a Case in

(obliterative) bronchiolitis: diagnosis, etiology, and a critical review of the literature. Ann Diagn Pathol 1998;2(5):321–334 Lynch JP III, Weigt SS, DerHovanessian A, Fishbein MC, Gutierrez A, Belperio JA. Obliterative (constrictive) bronchiolitis. Semin Respir Crit Care Med 2012;33(5):509–532 Myers JL, Colby TV. Pathologic manifestations of bronchiolitis, constrictive bronchiolitis, cryptogenic organizing pneumonia, and diffuse panbronchiolitis. Clin Chest Med 1993;14(4): 611–622 Geddes DM, Corrin B, Brewerton DA, Davies RJ, Turner-Warwick M. Progressive airway obliteration in adults and its association with rheumatoid disease. Q J Med 1977;46(184):427–444 Bégin R, Massé S, Cantin A, Ménard HA, Bureau MA. Airway disease in a subset of nonsmoking rheumatoid patients. Characterization of the disease and evidence for an autoimmune pathogenesis. Am J Med 1982;72(5):743–750 Devouassoux G, Cottin V, Lioté H, et al; Groupe d’Etudes et de Recherche sur les Maladies “Orphelines” Pulmonaires (GERM”O”P). Characterisation of severe obliterative bronchiolitis in rheumatoid arthritis. Eur Respir J 2009;33(5):1053–1061 Tzeng DZ, Leslie KO, Shelton D, Chan A. Unusual dyspnea in a woman with CREST syndrome. Chest 2008;133(1):286–290 Fagan KA, Badesch DB. Pulmonary hypertension associated with connective tissue disease. Prog Cardiovasc Dis 2002;45(3): 225–234 Galiè N, Manes A, Farahani KV, et al. Pulmonary arterial hypertension associated to connective tissue diseases. Lupus 2005; 14(9):713–717 Shahane A. Pulmonary hypertension in rheumatic diseases: epidemiology and pathogenesis. Rheumatol Int 2013;33(7): 1655–1667 Wagenvoort CA. The pathology of primary pulmonary hypertension. J Pathol 1970;101(4): Young RH, Mark GJ. Pulmonary vascular changes in scleroderma. Am J Med 1978;64(6):998–1004 Pietra GG, Edwards WD, Kay JM, et al. Histopathology of primary pulmonary hypertension. A qualitative and quantitative study of pulmonary blood vessels from 58 patients in the National Heart, Lung, and Blood Institute, Primary Pulmonary Hypertension Registry. Circulation 1989;80(5):1198–1206 Dorfmüller P, Humbert M, Perros F, et al. Fibrous remodeling of the pulmonary venous system in pulmonary arterial hypertension associated with connective tissue diseases. Hum Pathol 2007;38(6):893–902 Koh ET, Lee P, Gladman DD, Abu-Shakra M. Pulmonary hypertension in systemic sclerosis: an analysis of 17 patients. Br J Rheumatol 1996;35(10):989–993 Salerni R, Rodnan GP, Leon DF, Shaver JA. Pulmonary hypertension in the CREST syndrome variant of progressive systemic sclerosis (scleroderma). Ann Intern Med 1977;86(4):394–399 Cool CD, Kennedy D, Voelkel NF, Tuder RM. Pathogenesis and evolution of plexiform lesions in pulmonary hypertension associated with scleroderma and human immunodeficiency virus infection. Hum Pathol 1997;28(4):434–442 Yousem SA. The pulmonary pathologic manifestations of the CREST syndrome. Hum Pathol 1990;21(5):467–474 Fayemi AO. Pulmonary vascular disease in systemic lupus erythematosus. Am J Clin Pathol 1976;65(3):284–290 Quismorio FP Jr, Sharma O, Koss M, et al. Immunopathologic and clinical studies in pulmonary hypertension associated with systemic lupus erythematosus. Semin Arthritis Rheum 1984;13(4): 349–359 Gardner DL, Duthie JJ, MacLeod J, Allan WS. Pulmonary hypertension in rheumatoid arthritis: report of a case with intimal sclerosis of the pulmonary and digital arteries. Scott Med J 1957; 2(5):183–188

Association with Rheumatoid Arthritis. Ohio State Med J 1965; 61:141–144 Castro GW, Appenzeller S, Bertolo MB, Costallat LT. Isolated pulmonary hypertension secondary to rheumatoid arthritis. Clin Rheumatol 2006;25(6):901–903 Caldwell IW, Aitchison JD. Pulmonary hypertension in dermatomyositis. Br Heart J 1956;18(2):273–276 Bunch TW, Tancredi RG, Lie JT. Pulmonary hypertension in polymyositis. Chest 1981;79(1):105–107 Grateau G, Roux ME, Franck N, et al. Pulmonary hypertension in a case of dermatomyositis. J Rheumatol 1993;20(8):1452–1453 Minai OA. Pulmonary hypertension in polymyositis-dermatomyositis: clinical and hemodynamic characteristics and response to vasoactive therapy. Lupus 2009;18(11):1006–1010 Sullivan WD, Hurst DJ, Harmon CE, et al. A prospective evaluation emphasizing pulmonary involvement in patients with mixed connective tissue disease. Medicine (Baltimore) 1984;63(2):92–107 Bull TM, Fagan KA, Badesch DB. Pulmonary vascular manifestations of mixed connective tissue disease. Rheum Dis Clin North Am 2005;31(3):451–464, vi Alpert MA, Goldberg SH, Singsen BH, et al. Cardiovascular manifestations of mixed connective tissue disease in adults. Circulation 1983;68(6):1182–1193 Launay D, Hachulla E, Hatron PY, Jais X, Simonneau G, Humbert M. Pulmonary arterial hypertension: a rare complication of primary Sjögren syndrome: report of 9 new cases and review of the literature. Medicine (Baltimore) 2007;86(5):299–315 Wagenvoort CA, Wagenvoort N. The pathology of pulmonary veno-occlusive disease. Virchows Arch A Pathol Anat Histol 1974; 364(1):69–79 Lantuéjoul S, Sheppard MN, Corrin B, Burke MM, Nicholson AG. Pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis: a clinicopathologic study of 35 cases. Am J Surg Pathol 2006;30(7):850–857 Urisman A, Leard LE, Nathan M, et al. Rapidly progressive pulmonary venoocclusive disease in young women taking oral contraceptives. J Heart Lung Transplant 2012;31(9):1031–1036 Travis WD, Colby TV, Lombard C, Carpenter HA. A clinicopathologic study of 34 cases of diffuse pulmonary hemorrhage with lung biopsy confirmation. Am J Surg Pathol 1990;14(12):1112–1125 Colby TV, Fukuoka J, Ewaskow SP, Helmers R, Leslie KO. Pathologic approach to pulmonary hemorrhage. Ann Diagn Pathol 2001; 5(5):309–319 Mark EJ, Ramirez JF. Pulmonary capillaritis and hemorrhage in patients with systemic vasculitis. Arch Pathol Lab Med 1985; 109(5):413–418 Belmont HM, Abramson SB, Lie JT. Pathology and pathogenesis of vascular injury in systemic lupus erythematosus. Interactions of inflammatory cells and activated endothelium. Arthritis Rheum 1996;39(1):9–22 Franks TJ, Koss MN. Pulmonary capillaritis. Curr Opin Pulm Med 2000;6(5):430–435 Yi ES, Colby TV. Wegener’s granulomatosis. Semin Diagn Pathol 2001;18(1):34–46 Marino CT, Pertschuk LP. Pulmonary hemorrhage in systemic lupus erythematosus. Arch Intern Med 1981;141(2):201–203 Myers JL, Katzenstein AA. Microangiitis in lupus-induced pulmonary hemorrhage. Am J Clin Pathol 1986;85(5):552–556 Churg A, Franklin W, Chan KL, Kopp E, Carrington CB. Pulmonary hemorrhage and immune-complex deposition in the lung. Complications in a patient with systemic lupus erythematosus. Arch Pathol Lab Med 1980;104(7):388–391 Schwarz MI, Zamora MR, Hodges TN, Chan ED, Bowler RP, Tuder RM. Isolated pulmonary capillaritis and diffuse alveolar hemorrhage in rheumatoid arthritis and mixed connective tissue disease. Chest 1998;113(6):1609–1615

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Pulmonary Pathology in CTD

Urisman, Jones

108 Griffin MT, Robb JD, Martin JR. Diffuse alveolar haemorrhage

120 Flaherty KR, Colby TV, Travis WD, et al. Fibroblastic foci in

associated with progressive systemic sclerosis. Thorax 1990; 45(11):903–904 Vázquez-Del Mercado M, Mendoza-Topete A, Best-Aguilera CR, Garcia-De La Torre I. Diffuse alveolar hemorrhage in limited cutaneous systemic sclerosis with positive perinuclear antineutrophil cytoplasmic antibodies. J Rheumatol 1996;23(10):1821–1823 Kallenbach J, Prinsloo I, Zwi S. Progressive systemic sclerosis complicated by diffuse pulmonary haemorrhage. Thorax 1977; 32(6):767–770 Chaer RA, Massad MG, Evans A, Olopade C, Varga J. Systemic sclerosis complicated by diffuse alveolar hemorrhage. Med Sci Monit 2001;7(5):1013–1015 Schwarz MI, Sutarik JM, Nick JA, Leff JA, Emlen JW, Tuder RM. Pulmonary capillaritis and diffuse alveolar hemorrhage. A primary manifestation of polymyositis. Am J Respir Crit Care Med 1995;151(6):2037–2040 Joseph J, Sahn SA. Connective tissue diseases and the pleura. Chest 1993;104(1):262–270 Bouros D, Pneumatikos I, Tzouvelekis A. Pleural involvement in systemic autoimmune disorders. Respiration 2008;75(4):361–371 Walker WC, Wright V. Pulmonary lesions and rheumatoid arthritis. Medicine (Baltimore) 1968;47(6):501–520 Baum J. Infection in rheumatoid arthritis. Arthritis Rheum 1971; 14(1):135–137 Ziff M. The rheumatoid nodule. Arthritis Rheum 1990;33(6): 761–767 Katzenstein AL, Mukhopadhyay S, Myers JL. Diagnosis of usual interstitial pneumonia and distinction from other fibrosing interstitial lung diseases. Hum Pathol 2008;39(9):1275–1294 Smith M, Dalurzo M, Panse P, Parish J, Leslie K. Usual interstitial pneumonia-pattern fibrosis in surgical lung biopsies. Clinical, radiological and histopathological clues to aetiology. J Clin Pathol 2013;66(10):896–903

usual interstitial pneumonia: idiopathic versus collagen vascular disease. Am J Respir Crit Care Med 2003;167(10): 1410–1415 Song JW, Do KH, Kim MY, Jang SJ, Colby TV, Kim DS. Pathologic and radiologic differences between idiopathic and collagen vascular disease-related usual interstitial pneumonia. Chest 2009; 136(1):23–30 Churg A, Sin DD, Everett D, Brown K, Cool C. Pathologic patterns and survival in chronic hypersensitivity pneumonitis. Am J Surg Pathol 2009;33(12):1765–1770 Akashi T, Takemura T, Ando N, et al. Histopathologic analysis of sixteen autopsy cases of chronic hypersensitivity pneumonitis and comparison with idiopathic pulmonary fibrosis/usual interstitial pneumonia. Am J Clin Pathol 2009;131(3): 405–415 Hayakawa H, Shirai M, Sato A, et al. Clinicopathological features of chronic hypersensitivity pneumonitis. Respirology 2002;7(4): 359–364 Rosenow EC III, DeRemee RA, Dines DE. Chronic nitrofurantoin pulmonary reaction. Report of 5 cases. N Engl J Med 1968; 279(23):1258–1262 Leslie KO, Cool CD, Sporn TA, et al. Familial idiopathic interstitial pneumonia: histopathology and survival in 30 patients. Arch Pathol Lab Med 2012;136(11):1366–1376 Anderson LG, Talal N. The spectrum of benign to malignant lymphoproliferation in Sjögren’s syndrome. Clin Exp Immunol 1972;10(2):199–221 Butnor K, Khoor A. Collagen vascular diseases and disorders of connective tissue. In: Tomashefski JF, ed. Dail and Hammar’s Pulmonary Pathology. 3rd ed. New York, NY: Springer; 2008 Shakespeare W, Brooke T. The Third Part of King Henry the Sixth. New Haven, CT: Yale University Press; 1923

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