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Cross-Disciplinary Collaboration in Connective Tissue Disease-Related Lung Disease Aryeh Fischer, MD1

Luca Richeldi, MD, PhD2

1 Division of Rheumatology, National Jewish Health, Denver, Colorado 2 Department of Clinical and Experimental Sciences, University of

Southampton, Southampton, United Kingdom

Address for correspondence Aryeh Fischer, MD, Division of Rheumatology, National Jewish Health, 1400 Jackson Street, Denver, Colorado 80206 (e-mail: fi[email protected]).

Abstract

Keywords

► connective tissue disease ► interstitial lung disease ► collagen vascular disease

Lung disease is a common manifestation of connective tissue disease (CTD) and is associated with significant morbidity and mortality. The evaluation of lung disease, and interstitial lung disease (ILD) in particular, in patients with CTD is complex because of the heterogeneity of the CTDs, the varied types and degrees of severity of ILD encountered, and because ILD can be identified at any point in time in these patients. Cross-disciplinary, thorough evaluations are needed when CTD patients develop ILD or when evaluating ILD patients for the presence of occult CTD. Determining that ILD is associated with an established CTD requires the exclusion of alternative etiologies, and thorough assessments of the clinical features of both the CTD and ILD. The detection of occult CTD in patients with “idiopathic” ILD requires careful attention to the demographic profile, historical clues, subtle physical examination findings, specific autoantibody positivity, radiological and histopathological features, and can be optimized by a multidisciplinary approach that includes rheumatological collaboration. Not all patients with CTD-associated ILD require pharmacological therapy, and management decisions should consider pace and severity of the disease, intra- and extrathoracic features of activity and can be optimized by cross-disciplinary collaboration.

The connective tissue diseases (CTDs) are the systemic rheumatological illnesses characterized by autoimmune phenomena and immune-mediated organ dysfunction or damage. Although grouped together, it is important to recognize that there is significant heterogeneity of clinical features associated with each CTD. The category of CTD includes a variety of diseases: rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), polymyositis/dermatomyositis (PM/DM) (including antisynthetase syndrome), primary Sjögren syndrome, mixed CTD, and undifferentiated CTD. These diseases can potentially impact all organ systems, the lungs are frequent targets and all patients with these disorders are at risk for developing associated lung disease. There are a wide variety of pulmonary manifestations associated with the CTDs and essentially every component of the respiratory tract is at risk of injury. Certain of these diseases are associated with specific types of lung involve-

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

ment (►Table 1).1–4 To illustrate some of the diversity, consider that lung disease is the leading cause of death in SSc5 and is typically manifested by pulmonary hypertension (PH) or interstitial lung disease (ILD).5 However, in SLE, PH and ILD occur far less often—yet, pleural disease is more commonly encountered.6 Patients with RA and primary Sjögren syndrome are at a higher risk for developing airways disease (bronchiolitis and bronchiectasis) as well as ILD, whereas patients with PM/DM commonly develop ILD and yet are much less likely to develop airway complications.1,2 The complex intersections of CTD and their lung manifestations are highlighted by the fact that the lung disease can vary by time of onset, and pattern and severity of disease. The lung manifestations may be the presenting clinical feature of a CTD7 (with extrathoracic findings of the CTD developing months or years later) or may be identified in well-established, long-standing CTD. Furthermore, the finding of lung

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DOI http://dx.doi.org/ 10.1055/s-0034-1371530. ISSN 1069-3424.

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Semin Respir Crit Care Med 2014;35:159–165.

Cross-Disciplinary Collaboration in CTD-Related Lung Disease

Fischer, Richeldi

Table 1 Most common CTD-associated pulmonary manifestations1 SSc

RA

Primary Sjögren

MCTD

PM/DM

SLE

Airways




þþ

þþ

þ




þ

ILD

þþþ

þþ

þþ

þþ

þþþ

þþ

Pleural




þþ

þ

þ




þþþ

Vascular

þþþ




þ

þþ

þ

þ

DAH
















þ

Abbreviations: CTD, connective tissue disease; DAH, diffuse alveolar hemorrhage; ILD, interstitial lung disease; MCTD, mixed connective tissue disease; PM/DM, polymyositis/dermatomyositis; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SSc, systemic sclerosis. Note: The number of þ signs indicates relative prevalence of each manifestation.

abnormalities may be subclinical in nature, chronically progressive, or can be fulminant, and life threatening in nature. In this article, we discuss our cross-disciplinary approach to the evaluation of lung disease in the CTD patient. We focus specifically on the ILD evaluation because this lung manifestation occurs commonly across the spectrum of CTD, is an area in which the importance of a cross-disciplinary approach has been most effectively and consistently demonstrated, is potentially the most devastating of pulmonary manifestations, and finally, because ILD often poses the most significant of challenges to the practicing clinician.

Clinical Landscape ILD Arising within Established CTD ILD is commonly identified in patients with established, wellcharacterized CTD. Recent data suggest radiographic prevalence rates of subclinical ILD as high as 33 to 57% in various cohorts of patients with CTD.8 It is worth emphasizing that although ILD may be routinely identified in patients with CTD, the finding of ILD in patients with established CTD does not mean the two are necessarily related. Cross-disciplinary and thorough collaborative evaluations are needed to explore whether the lung disease is due to other causes (e.g., hypersensitivity pneumonitis). Furthermore, because a high percentage of patients with CTD are on immunosuppressive medications, the finding of new pulmonary infiltrates in these cohorts should raise strong consideration for respiratory infection—with typical or atypical pathogens. Consideration for medication-induced lung toxicity is also warranted because many of the immunomodulatory agents are associated with pneumonitis. In this regard, just as with any other patient that presents with parenchymal lung disease, a comprehensive evaluation is needed to explore all potential etiologies (e.g., infection, medication toxicity, environmental and occupational exposures, familial disease, smoking-related lung disease, and malignancy). Certainly the possibility of CTD-associated ILD (CTD-ILD) warrants due consideration, but determining that the ILD is truly associated with the underlying CTD is usually decided through a process of elimination. In our experience, these evaluations are often enhanced by a cross-disciplinary approach. In general, when considering the evaluation of ILD in patients with established CTD, we consider the following steps. Seminars in Respiratory and Critical Care Medicine

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Confirming the Underlying CTD This may be simple, particularly when the underlying CTD is well characterized, for example, in a patient with longstanding deforming RA associated with positive rheumatoid factor (RF) and cyclic citrullinated peptide autoantibodies. Yet, it is not uncommon to encounter situations whereby the precise rheumatological diagnosis is less certain and the finding of ILD may impact its precise classification and clinical diagnosis. Take for instance the patient with a weakly positive antinuclear antibody (ANA), positive anti-Ro (SS-A) autoantibody, and arthralgia, rash, and fatigue. Such a patient may be considered to have a clinical diagnosis of SLE. If however, that patient develops acute respiratory distress syndrome and is found to have lung injury patterns of nonspecific interstitial pneumonia (NSIP), diffuse alveolar damage (DAD), and organizing pneumonia (OP), along with radiographic features of esophageal dysmotility, and the peripheral digital fissuring of “mechanic’s hands,” one might give more careful consideration for the antisynthetase syndrome; rather than what was suspected—before the development of ILD—to be SLE.

Determining Whether the ILD Pattern “Fits” with the Underlying CTD Nearly all of the lung injury patterns described for idiopathic interstitial pneumonia (IIP) are known to occur across the spectrum of CTD.9 (Notable exceptions are respiratory bronchiolitis ILD and desquamative interstitial pneumonia; both of these patterns are closely linked with cigarette smoking and not typically considered to be CTD-associated patterns.9) As such, the patterns of NSIP, usual interstitial pneumonia (UIP), lymphocytic interstitial pneumonia (LIP), DAD or OP may all occur in patients with CTD; with NSIP being the most common pattern identified across the spectrum of CTD.9,10 RA may be the only exception, as recent data suggest that UIP may be more common in RA than NSIP.11,12 Small series do suggest that certain patterns may be more specific to certain of the CTDs. For example, fibrotic NSIP is the most common pattern in SSc.13,14 LIP may be more often identified in primary Sjögren syndrome, and the combination of NSIP/ OP with extreme bibasilar predominance is more closely linked to the antisynthetase syndrome.15 Also, distribution of the lung injury pattern is helpful as the ILD seen in CTD is usually symmetric, basilar, and peripheral predominant. As such, asymmetric, apical, and upper lobe predominant disease should raise suspicions for an alternative etiology, such

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as sarcoidosis or hypersensitivity pneumonitis. Similarly, unexplained nodules or dense areas of consolidation should prompt strong considerations for alternative etiologies, particularly infection or malignancy.

Excluding Infection, Medication-Induced Pneumonitis, and Hypersensitivity Pneumonitis As mentioned above, just because the patient has a CTD, does not preclude the possibility of alternative etiologies for the ILD. Comprehensive and cross-disciplinary evaluations are needed in patients with CTD found to have ILD. We emphasize that rendering a diagnosis of CTD-ILD requires careful consideration and exclusion of other etiologies for the ILD. Bronchoalveolar lavage (BAL) can be useful in sorting through the initial differential diagnosis, especially to exclude infection. Its usefulness as a baseline predictor of disease progression is less certain. Historically, BAL neutrophilia or eosinophilia in patients with SSc-ILD has been considered useful as a predictor of progressive ILD.16,17 However, two recent well-designed prospective studies in patients with SScILD failed to demonstrate any prognostic significance obtained from BAL.18,19 Taken together, the routine use of BAL to solely predict the likelihood of disease progression in CTD-ILD is not recommended. Transbronchial biopsy may be diagnostic in more airway-centric complications, such as bronchiolitis, or assessing for sarcoidosis or malignancy but is less useful in determining underlying interstitial pneumonia (IP) patterns.

Deciding When to Obtain a Surgical Lung Biopsy Because data have yet to show that determining a specific type of lung injury pattern impacts prognosis in CTDILD,10,13 the role of surgical lung biopsy in patients with these diseases remains controversial.20 The distinction between the specific ILD patterns (e.g., UIP vs. NSIP) is known to have prognostic significance among patients with IIP—but does not appear to be prognostically significant in patients with CTD.10,13 In the largest series of biopsied SSc-ILD subjects (n ¼ 80), Bouros et al showed that changes in diffusing capacity over time—but not histopathological distinction between NSIP and UIP—predicted prognosis.13 Similarly, among a cohort of 93 patients with a diverse spectrum of CTD-ILD, Park et al demonstrated that age, pulmonary function, and degree of dyspnea were of prognostic importance— but differences in IP type did not impact survival.10 The relatively small cohort sizes of existing studies and the impact of selection and referral bias cannot be discounted and therefore the predictive power of different patterns of lung histopathology remains uncertain in CTD-ILD. Furthermore, CTD-ILD patients tend to be treated with immunosuppressive therapies—targeting both progressive ILD and the extrathoracic inflammatory features—irrespective of specific ILD pattern. In this context, because the biopsy finding may not impact treatment decisions, particularly immunosuppression, clinicians frequently forego surgical lung biopsy. However, in those patients with an atypical or unclassifiable radiologic pattern, a surgical lung biopsy may be useful to ensure an alternative diagnosis is not present.

Fischer, Richeldi

In general, we believe a surgical lung biopsy is indicated in patients with preexisting CTD in cases when there are concerns for a coexistent, alternative etiology (e.g., hypersensitivity pneumonitis or sarcoidosis), when the ILD pattern on high-resolution computed tomography (HRCT) is atypical for the underlying CTD (e.g., upper lobe or asymmetric disease), when the HRCT features suggest malignancy or infection (e.g., progressive nodules, cavitation, consolidation, pleural thickening, or effusion), or when a specific pattern cannot be identified by HRCT. Ultimately, the decision of whether to proceed with surgical lung biopsy can be optimized by crossdisciplinary collaboration, and is individualized to each patient, with due consideration for its associated risks, and whether its findings will impact management decisions and prognosis.

ILD as the First Manifestation of a CTD Considering the possibility of underlying CTD is a fundamental component of the evaluation of patients presenting with IIP. Within this scenario, the identification of an occult CTD is common. A recent study, reported that of 114 consecutive ILD patients evaluated at a tertiary referral center, 17 (15%) were confirmed to have a new CTD diagnosis.21 There is no standardized approach to the assessment for underlying CTD. Current practice includes performing a thorough history and physical examination and testing for circulating autoantibodies. Many centers have found that a cross-disciplinary approach that includes rheumatological consultation is a central component of evaluating IIP for the presence of underlying CTD. However, in practice, it is both unrealistic and impractical to have rheumatological evaluation for all cases of IIP, but certain proposed guidelines for deciding when to get rheumatological consultation may be more realistic (►Table 2).2 Because the extrathoracic features of the CTDs can be subtle, confirming the presence of occult CTD can be challenging. As the following select studies demonstrate, a thorough—and cross-disciplinary—evaluation with heightened surveillance for subtle extrathoracic features of CTD, assessing a broader array of more-specific autoantibodies, and consideration of radiographic and histopathological features are all important components of the ILD evaluation and make the detection of occult CTD more likely. Fischer et al identified a cohort of 285 patients with biopsy proven UIP considered to have idiopathic pulmonary fibrosis (IPF).22 A total of 25 subjects (9%) were found to have ANA positivity with a nucleolar-staining pattern, and of these, 13 also had a positive Th/To (a nucleolar antigen highly specific for SSc) antibody. Retrospectively, most of those with nucleolar ANA positivity, and especially those with the SSc-specific Th/To antibody, had subtle extrathoracic features of SSc that included digital edema, Raynaud phenomenon, telangiectasia, and esophageal hypomotility. The authors concluded that because these individuals had autoantibody positivity known to be highly specific for SSc, extrathoracic features suggestive of SSc, and an IP pattern common for SSc, that these patients likely had occult presentation of SSc rather than IPF.22 A small follow-up series from these same investigators from a crossSeminars in Respiratory and Critical Care Medicine

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Cross-Disciplinary Collaboration in CTD-Related Lung Disease

Cross-Disciplinary Collaboration in CTD-Related Lung Disease Table 2 Suggested categories of ILD patients that require further rheumatological evaluation2 1. Women, particularly those younger than 50. 2. Any patient with extrathoracic manifestations is highly suggestive of CTD, that is, Raynaud phenomenon, esophageal hypomotility, inflammatory arthritis of the metacarpal–phalangeal joints or wrists, digital edema, or symptomatic keratoconjuctivitis sicca. 3. All cases of NSIP, LIP, or any ILD pattern with secondary histopathology features that might suggest CTD, that is, extensive pleuritis, dense perivascular collagen, lymphoid aggregates with germinal center formation, prominent plasmacytic infiltration. 4. Patients with a positive ANA or RF in high titer (generally considered to be ANA > 1:320 or RF > 60 IU/mL), a nucleolar-staining ANA at any titer, or any positive autoantibody specific as to a particular CTD, that is, anti-CCP, anti-Scl-70, anti-Ro, anti-La, anti-dsDNA, anti-Smith, anti-RNP, anti-tRNA synthetase. Abbreviations: ANA, antinuclear antibody; CCP, cyclic citrullinated peptide; CTD, connective tissue disease; ILD, interstitial lung disease; LIP, lymphocytic interstitial pneumonia; NSIP, nonspecific interstitial pneumonia; RF, rheumatoid factor.

disciplinary ILD program that incorporated rheumatological evaluation described six patients evaluated within a 12month span for presumed IIP.23 All were found to have a positive nucleolar-pattern ANA, along with either the antiTh/To or anti-Scl-70 antibody, and all had subtle extrathoracic features of SSc that included telangiectasia, Raynaud phenomenon, digital edema, or esophageal hypomotility; but none had skin thickening. This small series reinforced the concept that ILD may be the presenting manifestation of SSc that engaging rheumatology for ILD evaluation can be helpful, and that suspicions for SSc are warranted in patients with a nucleolar-pattern ANA and NSIP or UIP when present with subtle extrathoracic features of the disease, even in the absence of overt skin thickening.23 Mittoo et al described a retrospectively evaluated cohort of 114 consecutive patients referred to a multidisciplinary ILD program.21 A total of 34 subjects (30%) were found to have CTD-ILD and of these, only half had presented with a preexisting CTD. These authors argued that when confronted with an IIP, the presence of younger age, high-titer ANA, and elevated muscle enzymes were associated with underlying CTD. In another study, from a multidisciplinary clinic, a cohort of 50 ILD patients was retrospectively described.24 Of the patients with a final diagnosis of CTD-ILD, 28% were referred with a diagnosis of IPF. Among those referred with CTD-ILD, 36% had their diagnosis changed to an alternate CTD-ILD. In total, the diagnosis was changed in 54% of patients who presented to the ILD clinic. Changes in therapy occurred in 80% of patients with CTD-ILD and in 27% of patients with IPF. The authors concluded that a multidisciplinary ILD clinic offers patients an innovative mode of health care delivery that can enhance diagnosis, affect treatment regimens, and improve quality of care and emphasized that rheumatologists Seminars in Respiratory and Critical Care Medicine

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Fischer, Richeldi

can play a significant role in the clinical care of CTD-ILD patients.24 A recent study highlights the importance of maintaining a heightened suspicion for occult CTD in cases of NSIP—even when the ANA and RF are negative. Fischer et al described 37 patients that presented with clinical features of antisynthetase syndrome, with negative ANA and negative anti-Jo-1 antibodies, and that were assessed for other anti-tRNA synthetase antibodies.15 Nine (24%) were confirmed to have nonanti-Jo-1 positive antisynthetase syndrome based on clinical features and the presence of other antisynthetase antibodies (seven with anti-PL-7, two with anti-PL-12 antibodies). All presented with dyspnea as the initial symptom and with ILD as the first manifestation. Elevated muscle enzymes were identified in three patients but only two had muscle weakness. All had the subtle extrathoracic features of antisynthetase syndrome that included “mechanic’s hands,” Raynaud phenomenon, inflammatory arthritis, myositis, or esophageal hypomotility. Pulmonary physiology revealed restriction (forced vital capacity 60% of predicted) and impaired gas transfer (diffusing capacity for carbon monoxide 40% of predicted). All had similar findings on thoracic HRCT scans, with basilar predominance of abnormalities and patterns suggestive of NSIP and OP. The authors concluded that antiPL-7 and PL-12 antibodies may be more common among patients presenting with IIP than formerly considered and should be checked in patients with features of the antisynthetase syndrome despite a negative screen for ANA or antiJo-1 antibodies.15 Taken together, there are many variables to consider when evaluating a patient with presumed IIP for the presence of occult CTD. We have found that careful attention to the following items can be particularly useful.

Clinical Features Demographic features can help distinguish the patient with an underlying CTD. In comparison to IPF, patients with CTDILD are more likely to be younger in age and commonly females. Furthermore, a detailed review of systems—specifically focused on CTD symptoms such as Raynaud phenomenon, digital edema, and inflammatory arthritis—and thorough physical examination looking for cutaneous and musculoskeletal manifestations of CTD can be particularly helpful. Certain specific clinical features lend more support for underlying CTD than others. Of the CTD symptoms encountered in patients with IIP, perhaps none is as important as Raynaud phenomenon. The presence of Raynaud phenomenon is associated with a pattern of NSIP25 and when identified in a patient with ILD should raise strong suspicions for underlying CTD in general, and SSc (with or without overt skin thickening) in particular. Indeed, Raynaud phenomenon is encountered in nearly all patients with SSc and is a common finding in patients with PM/DM, the antisynthetase syndrome, primary Sjögren syndrome, SLE, mixed CTD, and undifferentiated CTD. Performing nail fold capillary microscopy can be useful when assessing a patient with Raynaud phenomenon. In particular, the presence of dilated or tortuous capillary loops or identifying significant

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areas lacking capillary loops (i.e., capillary dropout) may be suggestive of SSc or PM/DM (►Fig. 1). The reporting of symmetric joint swelling or stiffness, or identifying synovitis on physical examination is also very useful and suggests underlying CTD. Because inflammatory arthritis is encountered in all of the CTDs, autoantibody profiles may be needed to clarify which specific CTD is present. In contrast, more generalized, less-specific symptoms, such as gastroesophageal reflux, pain, fatigue, dry eyes, dry mouth, alopecia, and weight loss, are not nearly as helpful because they are ubiquitous and not nearly as specific for CTD. The cutaneous manifestations of SSc and the antisynthetase syndrome are worthy of particular emphasis because these two disorders are frequently associated with ILD and their extrathoracic features are both specific and yet quite often subtle. It is important to recognize that the “mechanic’s hands” sign of antisynthetase syndrome can manifest with only mild distal digital fissuring (►Fig. 2), and that palmar telangiectasia may be limited to the finding of only few scattered dilated capillaries. These features highlight the need for cross-disciplinary participation in the evaluation of ILD.

Circulating Autoantibodies Because autoantibody positivity is a hallmark of CTD, their assessment is an important part of the evaluation of patients with IIP.26 For patients with ILD in whom there is consideration for underlying CTD, a broad panel of screening autoantibodies (►Table 3) is often recommended.2 It is also important to take note of the pattern of immunofluorescence when the ANA is positive, as the nucleolar-staining ANA pattern in patients with ILD may suggest SSc spectrum of disease.22,23 Importantly, we highlight that the ANA and RF are poor screening tests: they have low specificity—particularly when present at low titer—and can be seen in healthy individuals. In addition, given that a negative ANA and RF may dissuade some clinicians from pursuing further evaluation, cases of occult CTD that may be ANA and RF negative (e.g., antisynthetase syndrome) are missed.

Fischer, Richeldi

Fig. 2 A photograph of the distal digital fissuring characteristic of “mechanic’s hands” in a patient with the antisynthetase syndrome.

Radiologic Features Thoracic HRCT imaging plays a central role in the evaluation of ILD by providing detailed information on pattern, distribution, and extent of the ILD. Furthermore, HRCT offers valuable information regarding the presence of extraparenchymal abnormalities including pleural disease and pericardial and esophageal features. In contrast to IIP, patients with CTD-ILD are more likely to have multicompartment involvement with concomitant airways disease, pleural effusions, pericardial effusions, and pericardial thickening, and esophageal dilatation (►Fig. 3).27–29 Patients with CTD are also more likely to have HRCT patterns suggestive of NSIP when compared with patients without CTD.27–29 HRCT has varying degrees of correlation with histopathological pattern. Among CTD-ILD patients with the typical HRCT pattern for UIP, the histopathology almost always correlates.27–29 Interestingly, the converse does not hold true; CTD patients with histopathological patterns of UIP may have HRCT patterns suggestive of NSIP.27–29 As discussed above, noting unusual lung injury patterns or distribution (e.g., upper lope predominance or marked asymmetry), or dense areas of consolidation, may impact decisions to perform surgical lung biopsy.

Histopathological Features

Fig. 1 A nail fold capillary microscopic image from a patient with systemic sclerosis. Note the presence of marked capillary loop tortuosity, dilation, and areas of vascular dropout.

Several histopathological features may be useful when trying to distinguish an IIP from CTD-ILD. An initial clue to an underlying CTD is the presence of multicompartment involvement on the biopsy; in addition to parenchymal lung injury, there may be components of airways, vascular, or pleural disease.30,31 When compared with IPF, CTD-associated UIP (CTD-UIP) is characterized by fewer fibroblastic foci, less overall fibrosis, and less honeycombing.30–33 Flaherty et al compared the histopathological features of 9 patients with CTD-UIP to that of 99 patients with IPF.33 Those with CTD-UIP were younger, had better lung function, and shorter duration of dyspnea. They found that those with IPF had significantly higher fibroblast focus scores than CTD-UIP and that the fibroblast focus score was the most discriminative feature between these groups. Song et al compared histopathological Seminars in Respiratory and Critical Care Medicine

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Cross-Disciplinary Collaboration in CTD-Related Lung Disease

Cross-Disciplinary Collaboration in CTD-Related Lung Disease Table 3 Useful antibodies for CTD-ILD assessment2 Autoantibody

Commonly associated CTD

High titer ANA ( 1:320 titer)

Many

High titer RF ( 60 IU/mL)

RA, Sjögren disease, SLE

Anti-CCP

RA

Anti-centromere

Systemic sclerosis

Anti-nucleolar-ANA

Systemic sclerosis

Fischer, Richeldi

Additional histopathological features that lend support for the presence of underlying CTD include the presence of lymphoid aggregates, germinal centers, increased perivascular collagen, follicular bronchiolitis, lymphoplasmacytic inflammation, eosinophil infiltration, or pleuritis.30,31

Management Considerations

Anti-Ro (SS-A)

Many

Anti-La (SS-B)

SLE, Sjögren disease

Anti-Smith

SLE

Anti-ribonucleoprotein

SLE, MCTD

Anti-dsDNA

SLE

Anti-topoisomerase (Scl-70)

Systemic sclerosis

Anti-tRNA synthetase antibodies

Polymyositis/ dermatomyositis (antisynthetase syndrome)

Anti-PM-Scl

Systemic sclerosis / myositis overlap

Anti-Th/To

Systemic sclerosis

Anti-U3 ribonucleoprotein

Systemic sclerosis

Anti-MDA-5 (CADM)

Clinical amyopathic dermatomyositis

Abbreviations: ANA, antinuclear antibody; CCP, cyclic citrullinated peptide; CTD, connective tissue disease; ILD, interstitial lung disease; MCTD, mixed connective tissue disease; RF, rheumatoid factor; SLE, systemic lupus erythematosus.

features in 39 patients with CTD-UIP to 61 patients with IPF.32 They found that the biopsies in those with CTD-UIP had fewer fibroblastic foci and less honeycombing but had more germinal center formation and more evidence of inflammation than seen with IPF.32

Not all patients with CTD-ILD require immunosuppressive therapy. Radiographic findings of ILD on HRCT are common, and only a subset of patients will show clinically significant, progressive disease that mandates the need for treatment. The decision to treat CTD-ILD often rests upon whether the patient is clinically impaired by the ILD, whether the ILD is progressive, and what comorbid conditions or mitigating factors exist.34 In our experience, these determinations can be enhanced by effective cross-disciplinary engagement. Therapy for CTD-ILD is generally reserved for those patients with clinically significant, progressive disease, and this determination is based upon a constellation of clinical assessment tools that include both subjective and objective measures of respiratory impairment (e.g., dyspnea assessments, pulmonary physiology, and HRCT and histopathology findings). The evaluation and management of patients with CTD-ILD is optimized by effective cross-disciplinary interactions among pulmonologists and rheumatologists.34 In particular, when considering immunomodulatory therapy options for CTD-ILD, both intrathoracic and extrathoracic disease manifestations and degrees of activity need to be assessed and taken into consideration when designing a therapeutic regimen. Given the heterogeneity in disease presentation, the multiple systems that may be affected and the broad range of disease severity, coordinated care is essential. In all cases of CTD-ILD, disease monitoring, choice of therapy and on-going longitudinal assessment and reassessment of a treatment response is complex and is optimized by effective collaborative care among pulmonologists, rheumatologists, and other health care providers.

Summary

Fig. 3 A high-resolution computed tomographic image in a patient with systemic sclerosis demonstrating evidence of a lower lobepredominant fibrosing interstitial pneumonia with marked esophageal dilation and presence of air-fluid level suggestive of severe esophageal hypomotility. Seminars in Respiratory and Critical Care Medicine

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Lung disease is a common manifestation of CTD and is associated with significant morbidity and mortality. The evaluation of lung disease, and ILD in particular, in patients with CTD is complex because of the heterogeneity of the CTDs, the varied types and degrees of severity of ILD encountered, and because ILD can be identified at any point in time in these patients. Cross-disciplinary, thorough evaluations are needed when CTD patients develop ILD or when evaluating ILD patients for the presence of occult CTD. Determining that ILD is associated with an established CTD requires the exclusion of alternative etiologies, and thorough assessments of the clinical features of both the CTD and ILD. The detection of occult CTD in patients with “idiopathic” ILD, requires careful attention to the demographic profile, historical clues, subtle physical examination findings, specific autoantibody positivity, radiologic and histopathological features and can be

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optimized by a multidisciplinary approach that includes rheumatological collaboration. Not all patients with CTDILD require pharmacologic therapy, and management decisions should consider pace and severity of the disease, intraand extrathoracic features of activity and can be optimized by cross-disciplinary collaboration.

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Disease-Associated Lung Disease. 2nd ed. New York: Springer; 2012 Frankel SK, Brown KK. Collagen vascular diseases of the lung. Clin Pulm Med 2006;13(1):25–36 Olson AL, Brown KK. Connective tissue disease-associated lung disorders. Eur Resp Mon 2009;46:225–250 Steen VD. The lung in systemic sclerosis. J Clin Rheumatol 2005; 11(1):40–46 Swigris JJ, Fischer A, Gillis J, Meehan RT, Brown KK. Pulmonary and thrombotic manifestations of systemic lupus erythematosus. Chest 2008;133(1):271–280 Cottin V. Interstitial lung disease: are we missing formes frustes of connective tissue disease? Eur Respir J 2006;28(5):893–896 Doyle TJ, Hunninghake GM, Rosas IO. Subclinical interstitial lung disease: why you should care. Am J Respir Crit Care Med 2012; 185(11):1147–1153 American Thoracic Society; European Respiratory Society. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med 2002; 165(2):277–304 Park JH, Kim DS, Park IN, et al. Prognosis of fibrotic interstitial pneumonia: idiopathic versus collagen vascular disease-related subtypes. Am J Respir Crit Care Med 2007;175(7):705–711 Kim EJ, Elicker BM, Maldonado F, et al. Usual interstitial pneumonia in rheumatoid arthritis-associated interstitial lung disease. Eur Respir J 2010;35(6):1322–1328 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 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 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 Fischer A, Swigris JJ, du Bois RM, et al. Anti-synthetase syndrome in ANA and anti-Jo-1 negative patients presenting with idiopathic interstitial pneumonia. Respir Med 2009;103(11):1719–1724 Kowal-Bielecka O, Kowal K, Highland KB, Silver RM. Bronchoalveolar lavage fluid in scleroderma interstitial lung disease: tech-

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Cross-Disciplinary Collaboration in CTD-Related Lung Disease

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