Review article
Arthritis Care & Research DOI 10.1002/acr.22394
“Interstitial Lung Disease in Undifferentiated Forms of Connective Tissue Disease” Aryeh Fischer and Kevin K. Brown
Aryeh Fischer, MD Associate Professor of Medicine National Jewish Health 1400 Jackson Street Denver, Colorado, USA 80206 [email protected]
Kevin K. Brown, MD Professor and Vice-Chair, Department of Medicine National Jewish Health
Corresponding author: Aryeh Fischer, MD
Key words: connective tissue disease, interstitial lung disease, collagen vascular disease, undifferentiated connective tissue disease, autoimmune-featured interstitial lung disease, lung-dominant connective tissue disease
No funding was provided for this manuscript.
Neither author has financial relationships that pose any conflict of interest to the contents of this manuscript. This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an ‘Accepted Article’, doi: 10.1002/acr.22394 © 2014 American College of Rheumatology Received: Dec 25, 2013; Revised: Mar 13, 2014; Accepted: Jul 01, 2014
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ABSTRACT
The intersection of interstitial lung disease (ILD) and connective tissue disease (CTD) is complex and commonly includes the scenario whereby ILD is identified in patients with pre-existing CTD, is the presenting manifestation of an occult CTD, or arises within the context of a suggestive form of CTD. Determining that an ILD is CTD-associated is important because this knowledge often impacts management and prognosis. Identifying occult CTD in patients with presumed idiopathic ILD can be challenging and requires a comprehensive, often multidisciplinary, evaluation. There is much uncertainty and controversy surrounding the suggestive forms of CTD-associated ILD (CTD-ILD) and prospective studies are needed to provide a better understanding of the natural history of these cohorts, how to best manage them, and to determine whether they behave similar to classifiable forms of CTD-ILD.
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SIGNIFICANT / INNOVATE FINDINGS
The intersection of ILD and CTD is complex and includes any of the following scenarios: i.) the identification of ILD within pre-existing, classifiable forms of CTD, ii.) ILD that is the first manifestation of a well-characterized and classifiable form of CTD, or iii.) ILD that arises within the context of a clinical scenario that is only suggestive of underlying CTD. In this review, we discuss the clinical aspects of these intersecting conditions and focus especially on the latter two scenarios.
We highlight areas of uncertainty and discuss the controversies surrounding the clinical scenario whereby patients have only suggestive forms of CTD-ILD.
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CLINICAL CASE VIGNETTE
A 37 year-old woman, never smoker, presents with acute onset of dyspnea and cough. She has no relevant past medical history. On symptom review she describes generalized puffiness of the hands that has been present for the past several months. Her rheumatologic review of systems is otherwise negative. On physical examination, she is noted to have mild digital edema but no evidence of Raynaud’s phenomenon, sclerodactyly or telangiectasia. Her musculoskeletal examination is normal; no synovitis or muscle weakness is detected. On respiratory examination she has audible crackles limited to the lower lung zones bilaterally. Her high-resolution computed tomography images reveal evidence of ILD with a bilateral, peripheral predominant distribution of ground glass opacifications suggestive of the lung injury pattern of non-specific interstitial pneumonia (NSIP) (Figure 1). Serologic testing of extensive autoantibodies is only notable for a positive anti-Ro (SS-A) antibody and she has normal inflammatory markers.
Does this patient have a connective tissue disease-associated interstitial lung disease?
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INTRODUCTION
The interstitial lung diseases (ILD) are a heterogeneous group of disorders that diffusely affect the pulmonary parenchyma and are classified together based on specific clinical, radiological, and histopathological features (1, 2). While these diseases often occur without any identifiable etiology, they commonly arise within the context of an environmental exposure or underlying connective tissue disease (CTD) (1-4). Determining if an ILD is CTD-associated is important and can be challenging. A multidisciplinary approach – that includes the rheumatologist – is often useful when assessing for CTD in patients that have presumed IIP (3, 5-10).
As a general rule, the CTDs manifest with autoimmune-mediated organ dysfunction and the lungs are a frequent target. There are multiple pulmonary manifestations; essentially every component of the respiratory tract is at risk of injury, and certain CTDs are associated with specific patterns of lung involvement. All patients with CTD are at risk for developing ILD, and certain CTDs are particularly associated with developing parenchymal disease. Because of differences in cohort composition and differing methods in how the presence of ILD was determined there are variable prevalence rates reported for specific forms of CTD-ILD. For example, 40-90% of individuals with systemic sclerosis (SSc) (11, 12), 30-70% of individuals with poly-/dermatomyositis (PM/DM) (13, 14), and 10-58% of individuals with rheumatoid arthritis (RA) (15-17) have ILD. There is also an expanding appreciation that ILD may be the first or only manifestation of a CTD (6, 7, 18-20). Much less is known – and significant controversies
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exist – regarding the lung manifestations associated with undifferentiated or suggestive forms of CTD (8).
Thus, the intersection of ILD and CTD is complex and includes any of the following scenarios: i.) the identification of ILD within pre-existing, classifiable forms of CTD, ii.) ILD that is the first manifestation of a well-characterized and classifiable form of CTD, or iii.) ILD that arises within the context of a clinical scenario that is only suggestive of underlying CTD. In this review, we discuss the clinical aspects of these intersecting conditions and focus especially on the latter two scenarios.
RELEVANCE OF A DIAGNOSIS OF CTD-ASSOCIATED ILD
There are numerous implications of a diagnosis of CTD-associated ILD (CTD-ILD). Most significantly, the well-characterized, classifiable forms of CTD-ILD (e.g., SSc-ILD) appear to have a more favorable prognosis than that of idiopathic interstitial pneumonia (IIP) (21, 22). Other implications include providing a clinical explanation for otherwise unexplained extra-thoracic manifestations (e.g. Raynaud’s phenomenon or esophageal hypomotility) and highlighting a need for surveillance for other disease features (e.g. pulmonary arterial hypertension screening in SSc or malignancy surveillance in PM/DM), and guiding therapeutic decisions. Another important aspect for considering an associated CTD in those that come to clinical attention due to ILD is the potential for an earlier diagnosis of underlying CTD. For instance, if the lung disease precedes the articular aspects of RA, it is conceivable that such early recognition of underlying RA
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would lead to more prompt implementation of disease modifying anti-rheumatic drug therapies that could favorably impact the clinical and radiographic articular outcomes.
There are also numerous implications from a research perspective; for example, providing precise phenotypes to allow for more effective pathobiology and natural history studies leading to the development of novel, targeted therapeutics. Indeed, among the most significant challenges encountered with CTD-ILD is that few effective therapeutic options exist, these conditions have been the target of few adequately powered and designed placebo-controlled trials, and there remains a poor understanding of the natural history of these diseases (3). The appreciation that ILD may precede the other clinical manifestations of a CTD is in line with recent research studies demonstrating that the lungs may be the initiating site of immune dysregulation in RA (23-27) and it is plausible to consider that immune dysregulation in the lungs may be important in other CTDs as well.
ILD OCCURING IN PATIENTS WITH PRE-EXISTING CTD
ILD can be a devastating manifestation of CTD and is known to be a leading cause of morbidity and mortality in these disorders. The finding of ILD in patients with preexisting CTD is not uncommon. Indeed, recent studies of select CTD cohorts have shown radiographic prevalence rates of “subclinical ILD” ranging from 33 to 57% (16, 28-31). However, just because ILD is identified in a patient with CTD does not mean the
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two are inter-related. For example, having RA does not preclude, and may actually predispose toward, the development of lung injury due to other causes (e.g., infection and medication-associated pneumonitis). Because patients with pre-existing CTD are often immunosuppressed, the finding of new pulmonary infiltrates in these patients should raise strong suspicions for respiratory infection; with either typical or atypical pathogens. Consideration for medication-associated lung toxicity is warranted because many of the immunomodulatory and anti-inflammatory therapies – especially methotrexate – have all been associated with a potential for pneumonitis. In this regard, just as with any other patient with ILD, a comprehensive and multidisciplinary 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). Determining whether the ILD is associated with the pre-existing CTD should be decided through a process of elimination (9).
ILD AS THE FIRST MANIFESTATION OF CLASSIFIABLE CTD
Identifying occult and classifiable CTD when confronted with presumed IIP is common. Indeed, 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 (10). There is no standardized approach to the identification of an underlying CTD in patients with ILD. The current practice in determining whether an underlying CTD is present often includes a thorough history and physical examination and testing for circulating
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autoantibodies (1, 32). Many tertiary centers have also found that a multidisciplinary evaluation that includes rheumatologic consultation is useful. However, because it is both unrealistic and impractical to have rheumatologic specialty evaluation for all cases of IIP, and in the absence of evidence-based guidelines to help determine when to seek rheumatologic expertise, some have proposed that rheumatologic consultation could have more utility in certain clinical scenarios because of a higher index of suspicion for the presence of underlying CTD (Table 1) (9).
Confirming the presence of an underlying CTD in patients with presumed IIP can be challenging.
One group of investigators described 68 patients with IIP that were
followed prospectively over 11 years (33). Thirteen patients (19%) eventually developed a classifiable CTD. The prevalence of a positive rheumatoid factor (RF) or anti-nuclear antibody (ANA) was no different in the group that developed clinically apparent CTD compared with those that did not. The authors concluded that patients defined as having an IIP cannot be distinguished from those that ultimately develop a CTD-ILD before the systematic manifestations appear (33).
A thorough evaluation for subtle extra-thoracic features of CTD, assessing a broader array of specific autoantibodies, as well as consideration of radiographic and histopathologic features are all important components of an evaluation for occult CTD (19). Furthermore, and as the following studies will attest, a multidisciplinary approach – that includes the rheumatologist – can be useful when assessing the patient with presumed IIP for the presence of an underlying CTD.
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One study retrospectively reviewed a cohort of 285 subjects with biopsy proven UIP that were considered to have idiopathic pulmonary fibrosis (IPF) (34). Twenty-five subjects (9%) were found to have ANA positivity with a nucleolar-staining pattern, and of these, 13 also had a positive Th/To antibody. Retrospectively, most of the subjects with nucleolar ANA positivity, and especially those with Th/To antibody positivity, had the subtle extra-thoracic features of SSc spectrum of disease that included digital edema, Raynaud’s phenomenon, telangiectasia, and esophageal hypomotility; but none had evidence of skin thickening. The authors concluded that because these individuals had autoantibody positivity known to be highly specific for SSc, extra-thoracic features consistent with SSc spectrum, and the lung injury pattern of usual interstitial pneumonia (UIP) that is commonly seen in SSc, these individuals likely had SSc spectrum of disease rather than IPF (34). A follow-up study from the same center described 6 individuals evaluated over a 12 month period for presumed idiopathic NSIP or IPF (35). All had nucleolar-pattern ANA positivity along with either Th/To or anti-Scl-70 antibody positivity and all had some extra-thoracic features of SSc including telangiectasia, Raynaud’s phenomenon, digital edema, or esophageal hypomotility. This small cohort further reinforced the notion that ILD may be the presenting manifestation of SSc and that strong suspicions for SSc are warranted – and extra-thoracic features for SSc should be sought – in patients with nucleolar-pattern ANA and NSIP or UIP patterns of lung injury (35).
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Mittoo and colleagues retrospectively evaluated a cohort of 114 consecutive patients referred to a tertiary referral center for ILD evaluation (10). Thirty-four subjects (30%) were found to have CTD-ILD and of these only half had presented with established, preexisting CTD. They found that younger age, high-titer ANA, and elevated muscle enzymes were associated with underlying CTD (10). Further highlighting the importance of a multidisciplinary evaluation, Castelino and colleagues described a cohort of 50 patients with ILD evaluated over a one year period at a tertiary referral center (5). Of the 25 patients with a final diagnosis of CTD-ILD, 28% had been initially referred with a diagnosis of IPF. Among those referred with CTD-ILD, 36% had their diagnosis changed to an alternate CTD. In total, the diagnosis was changed in 54% of the cohort (5). Another study described a cohort of 9 patients evaluated over a 2 year period with idiopathic NSIP that were ANA negative but found to have the anti-synthetase syndrome based on the presence of a tRNA synthetase antibody, NSIP, and subtle extra-thoracic features that included “mechanic’s hands”, Raynaud’s phenomenon, inflammatory arthritis, myositis, or esophageal hypomotility (36). Interestingly, and characteristic of the anti-synthetase syndrome, these individuals were all ANA and RF negative. The authors emphasized the utility of multidisciplinary evaluation of presumed IIP and that heightened suspicion for an underlying CTD is warranted in cases of NSIP – even when the ANA and RF are negative – and that assessing tRNA synthetase antibodies may help identify occult forms of the anti-synthetase syndrome (36). Similarly, Watanabe and colleagues screened 198 consecutive cases of IIP with a panel of anti-tRNA synthetase antibodies and identified positive anti-tRNA synthetase antibodies in 13 cases (7%) (37). They reported that those with positive antibodies were younger and more likely to have
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NSIP or UIP with lymphoid follicules. Among the 13 with a positive tRNA synthetase antibody, extra-thoracic manifestations of anti-synthetase syndrome were retrospectively identified in 7 cases (54%) (37).
ILD IN UNDIFFERENTIATED OR SUGGESTIVE FORMS OF CTD-ILD
There is a growing appreciation that many patients with IIP have subtle features suggestive of an autoimmune etiology and these individuals quite often do not meet classification criteria for a specific CTD (3, 8, 19). It has even been suggested that idiopathic NSIP is itself an autoimmune disease or is the lung manifestation of undifferentiated CTD (UCTD) (38, 39). Because of the better prognosis associated with CTD-ILD, there may be an inherent desire to define these cases as CTD-ILD. Sometimes these subtle symptoms or signs occur in the absence of serologic abnormalities, or a circulating autoantibody known to be highly specific for a certain CTD (such as anti-Jo-1 with the anti-synthetase syndrome) may be present without typical systemic or extra-thoracic features. Other scenarios exist whereby specific radiologic or histopathologic features are suggestive of an underlying CTD and yet the absence of extra-thoracic or serologic findings precludes reliable classification as CTD-ILD (8, 19).
In an area without consensus regarding terminology, the terms “UCTD”, “lungdominant CTD” or “autoimmune-featured ILD” have all been used to describe such patients with suggestive forms of CTD-ILD. Each of these categories has a unique
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set of proposed criteria (Table 2), represent the ideas of investigative teams from distinct ILD referral centers, and have yet to be prospectively validated (8).
UCTD IN RHEUMATOLOGIC LITERATURE
Nearly all of the descriptions of UCTD have been in the rheumatologic literature. The first descriptions of “undifferentiated diseases” date back to the 1960’s (40). In 1980, LeRoy proposed the concept of “undifferentiated connective tissue syndromes” to define early phases of CTDs mainly characterized by the presence of Raynaud’s phenomenon and digital edema (41). Over the subsequent years, UCTD has been generally defined as a condition manifesting with signs and symptoms suggestive of a CTD, along with ANA positivity, but not fulfilling existing rheumatologic classification criteria for any specific CTD (42-45). Mosca and colleagues have reported that about 60% of patients with UCTD will remain undifferentiated, and that when evolution to defined CTD occurs, it usually does so within the first 5 years of disease (42-45). UCTD may evolve into any of the CTDs, but most often evolves into systemic lupus erythematosus. UCTD patients that do not develop a characterizable CTD are considered to have a mild clinical picture – or “stable UCTD” – characterized by the presence of arthralgias or arthritis, Raynaud’s phenomenon, leukopenia, anemia, and dry eyes or dry mouth (45). An important distinguishing characteristic of UCTD is that no major organ involvement (such as lung disease) has been described (45). Because of the mild clinical picture, UCTD patients rarely require immunosuppressive therapies.
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A recent expert review on UCTD distinguishes “monosymptomatic UCTD” comprised of single organ-dominant diseases (such as ILD) that do not fulfill specific CTD criteria from that of stable, mild “oligosymptomatic UCTD” (45). The authors acknowledge that the concept of UCTD includes a wide spectrum of diseases ranging from “organdominant” conditions, to “stable UCTD”, to early CTDs, or mild forms of CTDs. They suggest that only persistently oligosymptomatic conditions – and not “organ dominant” disease – be classified as UCTD. Mosca and colleagues have proposed the following preliminary classification criteria for UCTD: i.) signs and symptoms suggestive of a CTD, but not fulfilling criteria for defined CTDs, ii.) positive ANAs and iii.) a disease duration of at least 3 years (45).
UCTD IN PULMONARY LITERATURE
Recently, the concept of UCTD has been of interest within the pulmonary community as well. In 2007, Kinder and colleagues proposed a broader and less specific set of UCTD criteria and applied these criteria to a cohort of patients with IIP (Table 2) (39). Retrospectively, they identified 28 subjects with an IIP that met their UCTD definition and compared these subjects with a control group of 47 subjects with IIP. Interestingly, those defined as having UCTD were more likely to be female, younger, and non-smokers and were more likely to have radiographic and histopathologic evidence of NSIP. In all, 88% of those with idiopathic NSIP met their definition for UCTD, and led the authors to propose that most patients previously classified as having idiopathic NSIP have
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clinical, serologic, radiographic, and pathologic characteristics of an autoimmune disease and that idiopathic NSIP may be the lung manifestation of UCTD (39).
Corte and colleagues have called into question the clinical relevance of defining ILD patients as having UCTD and specifically called into question the application of the proposed broader, less-specific UCTD criteria (46). They retrospectively studied 45 patients with biopsy-proven NSIP and 56 patients with biopsy-proven UIP. They reported that CTD features are common in patients with IIP, with 31% of NSIP and 13% of IPF patients fulfilling the stricter, more traditional criteria for UCTD (46). When the broader, less specific, UCTD criteria was applied an astounding 71% of NSIP and 36% of IPF patients could be reclassified as having UCTD (39, 46). Because of its lack of specificity, the authors argued against further implementation of the broader set of UCTD criteria in patients with ILD. Furthermore, the identification of UCTD by either set of criteria did not impact survival. Instead, Corte and colleagues devised an algorithm that was predictive of the presence of NSIP and improved survival consisting of the absence of typical HRCT features of IPF, a compatible demographic profile (women < 50 years of age) or the presence of Raynaud’s phenomenon (46).
“AUTOIMMUNE-FEATURED ILD”
Vij and colleagues described a cohort of UIP-predominant ILD patients retrospectively identified as having a suggestive form of CTD-ILD (47). Among 200 patients evaluated in an ILD referral center, 63 were considered to have
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“autoimmune-featured ILD”. A classification of autoimmune-featured ILD required the presence of a sign or symptom suggestive of a CTD and a serologic test reflective of an autoimmune process (Table 2) (47). The cohort that met their case definition of autoimmune-featured ILD had a demographic profile resembling that of IPF: most were older (average age of 66 years) and male. The most common clinical symptoms were dry eyes, dry mouth, or gastroesophageal reflux disease. Seventyfive percent with autoimmune-featured ILD had a lung injury pattern of UIP; overall survival was similar to that of IPF, and worse than in those with classifiable forms of CTD-ILD. Interestingly, on subset analysis, the presence of an ANA at > 1:1280 titer was associated with improved survival (47).
“LUNG-DOMINANT CTD”
A multidisciplinary group of investigators proposed a different set of provisional classification criteria to define the cohort of individuals with suggestive forms of CTDILD as having “lung-dominant CTD” (Table 2) (19). A classification of lung-dominant CTD would be reserved for those cases where the ILD has a “rheumatologic flavor” as supported by specific autoantibodies or histopathologic features and yet does not meet criteria for a defined CTD based on the lack of adequate extra-thoracic features. The authors argued that implicit with the concept of lung-dominant CTD is the recognition that specific autoantibodies and/or histopathologic features alone can be enough to classify a patient as having a suggestive form of CTD-ILD (19). The presence of specific objective extra-thoracic features highly suggestive of CTD (e.g., Raynaud’s phenomenon,
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inflammatory arthritis) are important and will lend further support for an underlying CTD, but their absence should not preclude a classification of lung-dominant CTD. The authors emphasized that their intent was that the concept of lung-dominant CTD and the associated criteria should be viewed as provisional, and that they might serve as a platform for further multidisciplinary, multicenter investigations, including validation via prospective study (19).
A number of potential advantages to the introduction of this novel classification were suggested (19): 1) the criteria offered are objective and measurable, 2) non-specific symptoms (e.g., dry eyes, myalgias, arthralgias, or gastroesophageal reflux disease), nonspecific inflammatory markers (e.g., erythrocyte sedimentation rate or C-reactive protein), and low-titer ANA or RF are not included because of their high prevalence in patients without CTD, 3) surveillance for evolution to classifiable forms of CTD is encouraged, 4) the classification isolates them from the default category of IIP and provides a framework by which questions regarding this subset’s natural history, pathobiology, treatment, and prognosis can be answered and, 5) the classification allows their distinction from the classifiable, well-characterized forms of CTD, without attempting to redefine existing CTD classification schemes and categories (e.g., UCTD) (19).
AREAS OF UNCERTAINTY
Because of the generally improved outcomes associated with CTD-ILD, and because different treatment approaches are often implemented in patients with CTD-ILD,
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determining whether these suggestive forms of CTD-ILD represent a spectrum of CTD-ILD – rather than IIP – is important (8). In essence, it is important to know whether these suggestive forms of CTD-ILD have a similar natural history as the classifiable forms of CTD-ILD and whether the approach to their management should be similar to that of CTD-ILD or to that of IIP. Current strategies for identifying and classifying these patients are controversial and inadequate, there is far too little interdisciplinary dialogue in this arena, and the advancement of this field would be well served by efforts to bridge these divides.
There is also concern that the proposed sets of criteria for suggestive forms of CTDILD are different enough that research studies being implemented in various centers using these unique criteria may not be applicable to cohorts from centers using the other sets of criteria. The criteria proposed for the modified or broader definition of UCTD and the criteria proposed to define autoimmune-featured ILD appear more similar to each other than the criteria proposed to define lung-dominant CTD. In both UCTD and autoimmune-featured ILD, at least one of a variety of extrapulmonary features (with varying specificity) combined with at least one abnormality of a variety of laboratory tests (with varying specificity) is required. Though there is some overlap between the extra-pulmonary features and laboratory tests in these two sets of criteria, they do remain distinct. In contrast, for lungdominant CTD, rather than relying on extra-pulmonary clinical features of varying specificity, the criteria require that the individual with ILD must be have a specific autoantibody and/or specific histopathological features on surgical lung biopsy.
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Given these differences between the sets of criteria, patients that meet the proposed classification according to one set may not meet criteria for either of the others!
The lack of consensus regarding terminology and the different sets of existing proposed classification criteria limits the ability to conduct the multicenter and multidisciplinary prospective studies needed to answer the many fundamental questions about this ILD subgroup (8).
A PATH FORWARD
In an effort to move beyond the current impasses and address these areas of controversy, an American Thoracic Society / European Respiratory Society Task Force – “An International Working Group on Undifferentiated forms of CTD-ILD” – has been recently formed (8). This Task Force is comprised of an international, multidisciplinary panel of CTD-ILD experts, including investigators from the centers that have put forth the differing criteria for UCTD, lung-dominant CTD, and autoimmune-featured ILD. The primary objective of the Task Force is to develop consensus regarding the nomenclature and criteria for the classification of suggestive forms of CTD-ILD. The Task Force will also identify key areas of uncertainty that are worthy of further research in this cohort. Once there is international and multidisciplinary consensus surrounding the nomenclature and classification criteria of these suggestive forms of CTD-ILD, the requisite platform will be in place to enable the much-needed prospective, multicenter, and
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multidisciplinary studies to further our understanding of this important subgroup of ILD (8).
MANAGEMENT CONSIDERATIONS
Without any data to guide specific recommendations on management of undifferentiated or suggestive forms of CTD-ILD, we suggest it would be reasonable to model strategies employed for defined forms of CTD-ILD (48). Within such a context, it is important to recognize that not all patients with CTD-ILD require pharmacologic treatment. Radiographic findings of ILD on HRCT are common, but only a subset of patients will show clinically significant, progressive disease. The decision to treat any form of CTDILD often rests upon whether the patient is clinically impaired by the ILD, whether it is progressive, and what comorbid conditions or mitigating factors exist. Therapy for all forms of 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 (48).
Similar to the definite forms of CTD-ILD, the evaluation and management of patients with suggestive forms of CTD-ILD is likely to be optimized by effective multidisciplinary interactions among pulmonologists and rheumatologists. In particular, when considering immunomodulatory therapy options for CTD-ILD, both intra-thoracic and extra-thoracic disease manifestations and degrees of activity need to be assessed and
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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, disease monitoring, choice of therapy and on-going longitudinal assessment and re-assessment of a treatment response is complex and is optimized by effective collaborative care among pulmonologists, rheumatologists, and other health-care providers (48).
CLINICAL CASE VIGNETTE DISCUSSION
At the outset of this manuscript, we described a case reflective of the subject matter of this review: A patient with a suggestive form of CTD-ILD. The individual could be considered to have an “autoimmune flavor” to her ILD based on her demographic profile (a 37 year-old-woman), a subtle extra-thoracic clinical feature (digital edema), objective autoimmunity (a positive anti-Ro antibody) and radiographic imaging compatible with the lung injury pattern most often identified in those with CTD: non-specific interstitial pneumonia (NSIP). Though the individual described may not meet formal classification criteria of any of the defined forms of CTD, her clinical scenario does represent a suggestive form of CTD-ILD. As highlighted in this review, this type of scenario is not uncommon, and our hope is that the coming years will be witness to the multidisciplinary collaborative approaches to clinical care and research needed to further our understanding of this important cohort.
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SUMMARY
The intersection of ILD and CTD is complex and commonly includes the scenario whereby ILD is identified in patients with pre-existing CTD, is the presenting manifestation of an occult CTD, or arises within the context of a suggestive form of CTD. Determining that an ILD is CTD-associated is important because this knowledge often impacts management and prognosis. Identifying occult CTD in patients with presumed idiopathic ILD can be challenging and requires a comprehensive, often multidisciplinary, evaluation. There is much uncertainty and controversy surrounding the scenarios whereby ILD occurs within scenarios that are suggestive of CTD-ILD. Multicenter and multidisciplinary efforts are underway to achieve consensus regarding the nomenclature and classification criteria of these suggestive forms of CTD-ILD and these efforts should provide the platform for the requisite prospective studies needed to provide a better understanding of the natural history of these cohorts, how to best manage them, and to determine whether they behave similar to the well-characterized, classifiable forms of CTD-ILD.
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Table 1: Suggested categories of ILD patients who require further rheumatologic evaluation (9)
1. Women, particularly those younger than 50 2. Any patient with extra-thoracic manifestations highly suggestive of CTD a. i.e. Raynaud’s 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 pathologic pattern with secondary histopathology features that might suggest CTD a. i.e. 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 to a particular CTD a. i.e. anti-CCP, anti-Scl-70, anti-Ro, anti-La, anti-dsDNA, anti-Smith, antiRNP, anti-tRNA synthetase
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Table 2. Proposed classification criteria for the suggestive forms of CTD-ILD (3, 19, 39, 47) Proposed category Undifferentiated CTD (broader definition) (requires at least one clinical feature and one laboratory finding)
Autoimmunefeatured ILD
(requires at least one clinical feature and one laboratory finding)
Lung-dominant CTD (requires all three listed clinical features and either 4a or 4b)
Clinical features One or more of the following symptoms: Dry eyes or dry mouth Gastro-oesophageal reflux disease Weight loss Recurrent unexplained fever Joint pain or swelling Rash Photosensitivity Dysphagia Nonandrogenic alopecia Mouth ulcers Raynaud’s phenomenon Morning stiffness Proximal muscle weakness One or more of the following symptoms: Dry eyes or dry mouth Gastro-oesophageal reflux disease Weight loss Foot or leg swelling Joint pain or swelling Rash Photosensitivity Dysphagia Hand ulcers Mouth ulcers Raynaud’s phenomenon Morning stiffness Proximal muscle weakness All of the following features: 1.
2. 3.
NSIP, UIP, LIP, OP, DAD, (or DIP if no smoking history), as determined by surgical lung biopsy or suggested by HRCT and Insufficient extra-thoracic features of a definite CTD and No identifiable alternative aetiology for IP and
Laboratory or histopathology findings One or more of these laboratory abnormalities: ANA (any titer) RF Anti-Ro Anti-La Anti-Jo-1 Anti-topoisomerase (Scl-70) Erythrocyte sedimentation rate (2 times normal) C-reactive protein elevation
One or more of these laboratory abnormalities: ANA > 1:160 titer RF Anti-Ro Anti-La Anti-Smith Anti-ribonucleoprotein Anti-dsDNA Anti-topoisomerase (Scl-70) Anti-CCP Anti-Jo-1 Aldolase Creatine phosphokinase 4a. Any one of these autoantibodies ANA > 1:320 titer RF > 60 IU/mL Anti-nucleolar ANA (any titer) Anti-centromere Anti-CCP Anti-Ro Anti-La Anti-dsDNA Anti-ribonucleoprotein Anti-Smith Anti-topoisomerase (Scl-70) Anti-tRNA synthetase Anti-PM-Scl 4b. OR at least two of these histopathology features: Lymphoid aggregates with germinal centres Extensive pleuritis Prominent plasmacytic infiltration Dense perivascular collagen
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FIGURE LEGENDS:
Figure 1: High resolution computed tomographic image demonstrating bilateral, peripheral predominant ground glass opacifications suggestive of non-specific interstitial pneumonia
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REFERENCES:
1. ATS/ERS. 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. 2. Cottin V. Interstitial lung disease. European respiratory review : an official journal of the European Respiratory Society. 2013;22(127):26-32. 3. Fischer A, du Bois R. Interstitial lung disease in connective tissue disorders. Lancet. 2012;380(9842):689-98. 4. Castelino FV, Varga J. Interstitial lung disease in connective tissue diseases: evolving concepts of pathogenesis and management. Arthritis Res Ther. 2010;12(4):213. 5. Castelino FV, Goldberg H, Dellaripa PF. The impact of rheumatological evaluation in the management of patients with interstitial lung disease. Rheumatology (Oxford). 2011;50(3):489-93. 6. Cottin V. Interstitial lung disease: are we missing formes frustes of connective tissue disease? Eur Respir J. 2006;28(5):893-6. 7. Fischer A. Interstitial lung disease: a rheumatologist's perspective. J Clin Rheumatol. 2009;15(2):95-9. 8. Fischer A. Interstitial lung disease in suggestive forms of connective tissue disease. J Bras Pneumol. 2013;39(6):641-3. 9. Fischer A, du Bois RM. A Practical Approach to Connective Tissue DiseaseAssociated Lung Disease. 2nd ed. Baughman RP, du Bois RM, editors. New York: Springer; 2012. pp217-37 10. Mittoo S, Gelber AC, Christopher-Stine L, Horton MR, Lechtzin N, Danoff SK. Ascertainment of collagen vascular disease in patients presenting with interstitial lung disease. Respir Med. 2009;103(8):1152-8. 11. White B. Interstitial lung disease in scleroderma. Rheum Dis Clin North Am. 2003;29(2):371-90. 12. Highland KB, Garin MC, Brown KK. The spectrum of scleroderma lung disease. Semin Respir Crit Care Med. 2007;28(4):418-29. 13. Schnabel A, Hellmich B, Gross WL. Interstitial lung disease in polymyositis and dermatomyositis. Curr Rheumatol Rep. 2005;7(2):99-105. 14. Schwarz MI. The lung in polymyositis. Clin Chest Med. 1998;19(4):701-12, viii. 15. Dawson JK, Fewins HE, Desmond J, Lynch MP, Graham DR. Fibrosing alveolitis in patients with rheumatoid arthritis as assessed by high resolution computed tomography, chest radiography, and pulmonary function tests. Thorax. 2001;56(8):622-7. 16. Gabbay E, Tarala R, Will R, Carroll G, Adler B, Cameron D, et al. Interstitial lung disease in recent onset rheumatoid arthritis. Am J Respir Crit Care Med. 1997;156(2 Pt 1):528-35.
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17. Turesson C, O'Fallon WM, Crowson CS, Gabriel SE, Matteson EL. Extraarticular disease manifestations in rheumatoid arthritis: incidence trends and risk factors over 46 years. Ann Rheum Dis. 2003;62(8):722-7. 18. Antoniou KM, Margaritopoulos G, Economidou F, Siafakas NM. Pivotal clinical dilemmas in collagen vascular diseases associated with interstitial lung involvement. Eur Respir J. 2009;33(4):882-96. 19. Fischer A, West SG, Swigris JJ, Brown KK, du Bois RM. Connective tissue disease-associated interstitial lung disease: a call for clarification. Chest. 2010;138(2):251-6. 20. Tzelepis GE, Toya SP, Moutsopoulos HM. Occult connective tissue diseases mimicking idiopathic interstitial pneumonias. Eur Respir J. 2008;31(1):11-20. 21. Bouros D, Wells AU, Nicholson AG, Colby TV, Polychronopoulos V, Pantelidis P, 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):1581-6. 22. Park JH, Kim DS, Park IN, Jang SJ, Kitaichi M, Nicholson AG, et al. Prognosis of fibrotic interstitial pneumonia: idiopathic versus collagen vascular disease-related subtypes. Am J Respir Crit Care Med. 2007;175(7):705-11. 23. Klareskog L, Malmstrom V, Lundberg K, Padyukov L, Alfredsson L. Smoking, citrullination and genetic variability in the immunopathogenesis of rheumatoid arthritis. Seminars in immunology. 2011;23(2):92-8. 24. Klareskog L, Stolt P, Lundberg K, Kallberg H, Bengtsson C, Grunewald J, et al. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum. 2006;54(1):38-46. 25. Fischer A, Solomon JJ, du Bois RM, Deane KD, Olson AL, Fernandez-Perez ER, et al. Lung disease with anti-CCP antibodies but not rheumatoid arthritis or connective tissue disease. Respir Med. 2012;106(7):1040-7. 26. Demoruelle MK, Deane KD, Holers VM. When and where does inflammation begin in rheumatoid arthritis? Current opinion in rheumatology. 2014;26(1):64-71. 27. Demoruelle MK, Weisman MH, Simonian PL, Lynch DA, Sachs PB, Pedraza IF, et al. Brief report: airways abnormalities and rheumatoid arthritis-related autoantibodies in subjects without arthritis: early injury or initiating site of autoimmunity? Arthritis Rheum. 2012;64(6):1756-61. 28. Doyle TJ, Hunninghake GM, Rosas IO. Subclinical interstitial lung disease: why you should care. Am J Respir Crit Care Med. 2012;185(11):1147-53. 29. Gochuico BR, Avila NA, Chow CK, Novero LJ, Wu HP, Ren P, et al. Progressive preclinical interstitial lung disease in rheumatoid arthritis. Arch Intern Med. 2008;168(2):159-66. 30. Launay D, Remy-Jardin M, Michon-Pasturel U, Mastora I, Hachulla E, Lambert M, et al. High resolution computed tomography in fibrosing alveolitis associated with systemic sclerosis. J Rheumatol. 2006;33(9):1789-801. 31. Uffmann M, Kiener HP, Bankier AA, Baldt MM, Zontsich T, Herold CJ. Lung manifestation in asymptomatic patients with primary Sjogren syndrome: assessment with high resolution CT and pulmonary function tests. J Thorac Imaging. 2001;16(4):282-9. 32. Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based
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guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183(6):788824. 33. Homma Y, Ohtsuka Y, Tanimura K, Kusaka H, Munakata M, Kawakami Y, et al. Can interstitial pneumonia as the sole presentation of collagen vascular diseases be differentiated from idiopathic interstitial pneumonia? Respiration. 1995;62(5):248-51. 34. Fischer A, Pfalzgraf FJ, Feghali-Bostwick CA, Wright TM, Curran-Everett D, West SG, et al. Anti-th/to-positivity in a cohort of patients with idiopathic pulmonary fibrosis. J Rheumatol. 2006;33(8):1600-5. 35. Fischer A, Meehan RT, Feghali-Bostwick CA, West SG, Brown KK. Unique characteristics of systemic sclerosis sine scleroderma-associated interstitial lung disease. Chest. 2006;130(4):976-81. 36. Fischer A, Swigris JJ, du Bois RM, Lynch DA, Downey GP, Cosgrove GP, et al. Anti-synthetase syndrome in ANA and anti-Jo-1 negative patients presenting with idiopathic interstitial pneumonia. Respir Med. 2009;103(11):1719-24. 37. Watanabe K, Handa T, Tanizawa K, Hosono Y, Taguchi Y, Noma S, et al. Detection of antisynthetase syndrome in patients with idiopathic interstitial pneumonias. Respir Med. 2011;105(8):1238-47. 38. Fujita J, Ohtsuki Y, Yoshinouchi T, Yamadori I, Bandoh S, Tokuda M, et al. Idiopathic non-specific interstitial pneumonia: as an "autoimmune interstitial pneumonia". Respir Med. 2005;99(2):234-40. 39. Kinder BW, Collard HR, Koth L, Daikh DI, Wolters PJ, Elicker B, et al. Idiopathic nonspecific interstitial pneumonia: lung manifestation of undifferentiated connective tissue disease? Am J Respir Crit Care Med. 2007;176(7):691-7. 40. Sabo I. The lanthanic or undifferentiated collagen disease. Hiroshima J Med Sci. 1969;18(4):259-64. 41. LeRoy EC, Maricq HR, Kahaleh MB. Undifferentiated connective tissue syndromes. Arthritis Rheum. 1980;23(3):341-3. 42. Mosca M, Neri R, Bencivelli W, Tavoni A, Bombardieri S. Undifferentiated connective tissue disease: analysis of 83 patients with a minimum followup of 5 years. J Rheumatol. 2002;29(11):2345-9. 43. Mosca M, Neri R, Bombardieri S. Undifferentiated connective tissue diseases (UCTD): a review of the literature and a proposal for preliminary classification criteria. Clin Exp Rheumatol. 1999;17(5):615-20. 44. Mosca M, Tani C, Bombardieri S. Undifferentiated connective tissue diseases (UCTD): a new frontier for rheumatology. Best Pract Res Clin Rheumatol. 2007;21(6):1011-23. 45. Mosca M, Tani C, Carli L, Bombardieri S. Undifferentiated CTD: a wide spectrum of autoimmune diseases. Best Pract Res Clin Rheumatol. 2012;26(1):73-7. 46. Corte TJ, Copley SJ, Desai SR, Zappala CJ, Hansell DM, Nicholson AG, et al. Significance of connective tissue disease features in idiopathic interstitial pneumonia. Eur Respir J. 2012;39(3):661-8. 47. Vij R, Noth I, Strek ME. Autoimmune-featured interstitial lung disease: a distinct entity. Chest. 2011;140(5):1292-9. 48. Fischer A, Brown, KK, Frankel, SK. Treatment of connective tissue disease related interstitial lung disease. . Clinical Pulmonary Medicine. 2009;16(2):74-80.
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High resolution computed tomographic image demonstrating bilateral, peripheral predominant ground glass opacifications suggestive of non-specific interstitial pneumonia 254x190mm (72 x 72 DPI)
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Arthritis Care & Research DOI 10.1002/acr.22394
“Interstitial Lung Disease in Undifferentiated Forms of Connective Tissue Disease” Aryeh Fischer and Kevin K. Brown
Aryeh Fischer, MD Associate Professor of Medicine National Jewish Health 1400 Jackson Street Denver, Colorado, USA 80206 [email protected]
Kevin K. Brown, MD Professor and Vice-Chair, Department of Medicine National Jewish Health
Corresponding author: Aryeh Fischer, MD
Key words: connective tissue disease, interstitial lung disease, collagen vascular disease, undifferentiated connective tissue disease, autoimmune-featured interstitial lung disease, lung-dominant connective tissue disease
No funding was provided for this manuscript.
Neither author has financial relationships that pose any conflict of interest to the contents of this manuscript. This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an ‘Accepted Article’, doi: 10.1002/acr.22394 © 2014 American College of Rheumatology Received: Dec 25, 2013; Revised: Mar 13, 2014; Accepted: Jul 01, 2014
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ABSTRACT
The intersection of interstitial lung disease (ILD) and connective tissue disease (CTD) is complex and commonly includes the scenario whereby ILD is identified in patients with pre-existing CTD, is the presenting manifestation of an occult CTD, or arises within the context of a suggestive form of CTD. Determining that an ILD is CTD-associated is important because this knowledge often impacts management and prognosis. Identifying occult CTD in patients with presumed idiopathic ILD can be challenging and requires a comprehensive, often multidisciplinary, evaluation. There is much uncertainty and controversy surrounding the suggestive forms of CTD-associated ILD (CTD-ILD) and prospective studies are needed to provide a better understanding of the natural history of these cohorts, how to best manage them, and to determine whether they behave similar to classifiable forms of CTD-ILD.
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SIGNIFICANT / INNOVATE FINDINGS
The intersection of ILD and CTD is complex and includes any of the following scenarios: i.) the identification of ILD within pre-existing, classifiable forms of CTD, ii.) ILD that is the first manifestation of a well-characterized and classifiable form of CTD, or iii.) ILD that arises within the context of a clinical scenario that is only suggestive of underlying CTD. In this review, we discuss the clinical aspects of these intersecting conditions and focus especially on the latter two scenarios.
We highlight areas of uncertainty and discuss the controversies surrounding the clinical scenario whereby patients have only suggestive forms of CTD-ILD.
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CLINICAL CASE VIGNETTE
A 37 year-old woman, never smoker, presents with acute onset of dyspnea and cough. She has no relevant past medical history. On symptom review she describes generalized puffiness of the hands that has been present for the past several months. Her rheumatologic review of systems is otherwise negative. On physical examination, she is noted to have mild digital edema but no evidence of Raynaud’s phenomenon, sclerodactyly or telangiectasia. Her musculoskeletal examination is normal; no synovitis or muscle weakness is detected. On respiratory examination she has audible crackles limited to the lower lung zones bilaterally. Her high-resolution computed tomography images reveal evidence of ILD with a bilateral, peripheral predominant distribution of ground glass opacifications suggestive of the lung injury pattern of non-specific interstitial pneumonia (NSIP) (Figure 1). Serologic testing of extensive autoantibodies is only notable for a positive anti-Ro (SS-A) antibody and she has normal inflammatory markers.
Does this patient have a connective tissue disease-associated interstitial lung disease?
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INTRODUCTION
The interstitial lung diseases (ILD) are a heterogeneous group of disorders that diffusely affect the pulmonary parenchyma and are classified together based on specific clinical, radiological, and histopathological features (1, 2). While these diseases often occur without any identifiable etiology, they commonly arise within the context of an environmental exposure or underlying connective tissue disease (CTD) (1-4). Determining if an ILD is CTD-associated is important and can be challenging. A multidisciplinary approach – that includes the rheumatologist – is often useful when assessing for CTD in patients that have presumed IIP (3, 5-10).
As a general rule, the CTDs manifest with autoimmune-mediated organ dysfunction and the lungs are a frequent target. There are multiple pulmonary manifestations; essentially every component of the respiratory tract is at risk of injury, and certain CTDs are associated with specific patterns of lung involvement. All patients with CTD are at risk for developing ILD, and certain CTDs are particularly associated with developing parenchymal disease. Because of differences in cohort composition and differing methods in how the presence of ILD was determined there are variable prevalence rates reported for specific forms of CTD-ILD. For example, 40-90% of individuals with systemic sclerosis (SSc) (11, 12), 30-70% of individuals with poly-/dermatomyositis (PM/DM) (13, 14), and 10-58% of individuals with rheumatoid arthritis (RA) (15-17) have ILD. There is also an expanding appreciation that ILD may be the first or only manifestation of a CTD (6, 7, 18-20). Much less is known – and significant controversies
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exist – regarding the lung manifestations associated with undifferentiated or suggestive forms of CTD (8).
Thus, the intersection of ILD and CTD is complex and includes any of the following scenarios: i.) the identification of ILD within pre-existing, classifiable forms of CTD, ii.) ILD that is the first manifestation of a well-characterized and classifiable form of CTD, or iii.) ILD that arises within the context of a clinical scenario that is only suggestive of underlying CTD. In this review, we discuss the clinical aspects of these intersecting conditions and focus especially on the latter two scenarios.
RELEVANCE OF A DIAGNOSIS OF CTD-ASSOCIATED ILD
There are numerous implications of a diagnosis of CTD-associated ILD (CTD-ILD). Most significantly, the well-characterized, classifiable forms of CTD-ILD (e.g., SSc-ILD) appear to have a more favorable prognosis than that of idiopathic interstitial pneumonia (IIP) (21, 22). Other implications include providing a clinical explanation for otherwise unexplained extra-thoracic manifestations (e.g. Raynaud’s phenomenon or esophageal hypomotility) and highlighting a need for surveillance for other disease features (e.g. pulmonary arterial hypertension screening in SSc or malignancy surveillance in PM/DM), and guiding therapeutic decisions. Another important aspect for considering an associated CTD in those that come to clinical attention due to ILD is the potential for an earlier diagnosis of underlying CTD. For instance, if the lung disease precedes the articular aspects of RA, it is conceivable that such early recognition of underlying RA
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would lead to more prompt implementation of disease modifying anti-rheumatic drug therapies that could favorably impact the clinical and radiographic articular outcomes.
There are also numerous implications from a research perspective; for example, providing precise phenotypes to allow for more effective pathobiology and natural history studies leading to the development of novel, targeted therapeutics. Indeed, among the most significant challenges encountered with CTD-ILD is that few effective therapeutic options exist, these conditions have been the target of few adequately powered and designed placebo-controlled trials, and there remains a poor understanding of the natural history of these diseases (3). The appreciation that ILD may precede the other clinical manifestations of a CTD is in line with recent research studies demonstrating that the lungs may be the initiating site of immune dysregulation in RA (23-27) and it is plausible to consider that immune dysregulation in the lungs may be important in other CTDs as well.
ILD OCCURING IN PATIENTS WITH PRE-EXISTING CTD
ILD can be a devastating manifestation of CTD and is known to be a leading cause of morbidity and mortality in these disorders. The finding of ILD in patients with preexisting CTD is not uncommon. Indeed, recent studies of select CTD cohorts have shown radiographic prevalence rates of “subclinical ILD” ranging from 33 to 57% (16, 28-31). However, just because ILD is identified in a patient with CTD does not mean the
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two are inter-related. For example, having RA does not preclude, and may actually predispose toward, the development of lung injury due to other causes (e.g., infection and medication-associated pneumonitis). Because patients with pre-existing CTD are often immunosuppressed, the finding of new pulmonary infiltrates in these patients should raise strong suspicions for respiratory infection; with either typical or atypical pathogens. Consideration for medication-associated lung toxicity is warranted because many of the immunomodulatory and anti-inflammatory therapies – especially methotrexate – have all been associated with a potential for pneumonitis. In this regard, just as with any other patient with ILD, a comprehensive and multidisciplinary 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). Determining whether the ILD is associated with the pre-existing CTD should be decided through a process of elimination (9).
ILD AS THE FIRST MANIFESTATION OF CLASSIFIABLE CTD
Identifying occult and classifiable CTD when confronted with presumed IIP is common. Indeed, 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 (10). There is no standardized approach to the identification of an underlying CTD in patients with ILD. The current practice in determining whether an underlying CTD is present often includes a thorough history and physical examination and testing for circulating
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autoantibodies (1, 32). Many tertiary centers have also found that a multidisciplinary evaluation that includes rheumatologic consultation is useful. However, because it is both unrealistic and impractical to have rheumatologic specialty evaluation for all cases of IIP, and in the absence of evidence-based guidelines to help determine when to seek rheumatologic expertise, some have proposed that rheumatologic consultation could have more utility in certain clinical scenarios because of a higher index of suspicion for the presence of underlying CTD (Table 1) (9).
Confirming the presence of an underlying CTD in patients with presumed IIP can be challenging.
One group of investigators described 68 patients with IIP that were
followed prospectively over 11 years (33). Thirteen patients (19%) eventually developed a classifiable CTD. The prevalence of a positive rheumatoid factor (RF) or anti-nuclear antibody (ANA) was no different in the group that developed clinically apparent CTD compared with those that did not. The authors concluded that patients defined as having an IIP cannot be distinguished from those that ultimately develop a CTD-ILD before the systematic manifestations appear (33).
A thorough evaluation for subtle extra-thoracic features of CTD, assessing a broader array of specific autoantibodies, as well as consideration of radiographic and histopathologic features are all important components of an evaluation for occult CTD (19). Furthermore, and as the following studies will attest, a multidisciplinary approach – that includes the rheumatologist – can be useful when assessing the patient with presumed IIP for the presence of an underlying CTD.
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One study retrospectively reviewed a cohort of 285 subjects with biopsy proven UIP that were considered to have idiopathic pulmonary fibrosis (IPF) (34). Twenty-five subjects (9%) were found to have ANA positivity with a nucleolar-staining pattern, and of these, 13 also had a positive Th/To antibody. Retrospectively, most of the subjects with nucleolar ANA positivity, and especially those with Th/To antibody positivity, had the subtle extra-thoracic features of SSc spectrum of disease that included digital edema, Raynaud’s phenomenon, telangiectasia, and esophageal hypomotility; but none had evidence of skin thickening. The authors concluded that because these individuals had autoantibody positivity known to be highly specific for SSc, extra-thoracic features consistent with SSc spectrum, and the lung injury pattern of usual interstitial pneumonia (UIP) that is commonly seen in SSc, these individuals likely had SSc spectrum of disease rather than IPF (34). A follow-up study from the same center described 6 individuals evaluated over a 12 month period for presumed idiopathic NSIP or IPF (35). All had nucleolar-pattern ANA positivity along with either Th/To or anti-Scl-70 antibody positivity and all had some extra-thoracic features of SSc including telangiectasia, Raynaud’s phenomenon, digital edema, or esophageal hypomotility. This small cohort further reinforced the notion that ILD may be the presenting manifestation of SSc and that strong suspicions for SSc are warranted – and extra-thoracic features for SSc should be sought – in patients with nucleolar-pattern ANA and NSIP or UIP patterns of lung injury (35).
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Mittoo and colleagues retrospectively evaluated a cohort of 114 consecutive patients referred to a tertiary referral center for ILD evaluation (10). Thirty-four subjects (30%) were found to have CTD-ILD and of these only half had presented with established, preexisting CTD. They found that younger age, high-titer ANA, and elevated muscle enzymes were associated with underlying CTD (10). Further highlighting the importance of a multidisciplinary evaluation, Castelino and colleagues described a cohort of 50 patients with ILD evaluated over a one year period at a tertiary referral center (5). Of the 25 patients with a final diagnosis of CTD-ILD, 28% had been initially referred with a diagnosis of IPF. Among those referred with CTD-ILD, 36% had their diagnosis changed to an alternate CTD. In total, the diagnosis was changed in 54% of the cohort (5). Another study described a cohort of 9 patients evaluated over a 2 year period with idiopathic NSIP that were ANA negative but found to have the anti-synthetase syndrome based on the presence of a tRNA synthetase antibody, NSIP, and subtle extra-thoracic features that included “mechanic’s hands”, Raynaud’s phenomenon, inflammatory arthritis, myositis, or esophageal hypomotility (36). Interestingly, and characteristic of the anti-synthetase syndrome, these individuals were all ANA and RF negative. The authors emphasized the utility of multidisciplinary evaluation of presumed IIP and that heightened suspicion for an underlying CTD is warranted in cases of NSIP – even when the ANA and RF are negative – and that assessing tRNA synthetase antibodies may help identify occult forms of the anti-synthetase syndrome (36). Similarly, Watanabe and colleagues screened 198 consecutive cases of IIP with a panel of anti-tRNA synthetase antibodies and identified positive anti-tRNA synthetase antibodies in 13 cases (7%) (37). They reported that those with positive antibodies were younger and more likely to have
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NSIP or UIP with lymphoid follicules. Among the 13 with a positive tRNA synthetase antibody, extra-thoracic manifestations of anti-synthetase syndrome were retrospectively identified in 7 cases (54%) (37).
ILD IN UNDIFFERENTIATED OR SUGGESTIVE FORMS OF CTD-ILD
There is a growing appreciation that many patients with IIP have subtle features suggestive of an autoimmune etiology and these individuals quite often do not meet classification criteria for a specific CTD (3, 8, 19). It has even been suggested that idiopathic NSIP is itself an autoimmune disease or is the lung manifestation of undifferentiated CTD (UCTD) (38, 39). Because of the better prognosis associated with CTD-ILD, there may be an inherent desire to define these cases as CTD-ILD. Sometimes these subtle symptoms or signs occur in the absence of serologic abnormalities, or a circulating autoantibody known to be highly specific for a certain CTD (such as anti-Jo-1 with the anti-synthetase syndrome) may be present without typical systemic or extra-thoracic features. Other scenarios exist whereby specific radiologic or histopathologic features are suggestive of an underlying CTD and yet the absence of extra-thoracic or serologic findings precludes reliable classification as CTD-ILD (8, 19).
In an area without consensus regarding terminology, the terms “UCTD”, “lungdominant CTD” or “autoimmune-featured ILD” have all been used to describe such patients with suggestive forms of CTD-ILD. Each of these categories has a unique
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set of proposed criteria (Table 2), represent the ideas of investigative teams from distinct ILD referral centers, and have yet to be prospectively validated (8).
UCTD IN RHEUMATOLOGIC LITERATURE
Nearly all of the descriptions of UCTD have been in the rheumatologic literature. The first descriptions of “undifferentiated diseases” date back to the 1960’s (40). In 1980, LeRoy proposed the concept of “undifferentiated connective tissue syndromes” to define early phases of CTDs mainly characterized by the presence of Raynaud’s phenomenon and digital edema (41). Over the subsequent years, UCTD has been generally defined as a condition manifesting with signs and symptoms suggestive of a CTD, along with ANA positivity, but not fulfilling existing rheumatologic classification criteria for any specific CTD (42-45). Mosca and colleagues have reported that about 60% of patients with UCTD will remain undifferentiated, and that when evolution to defined CTD occurs, it usually does so within the first 5 years of disease (42-45). UCTD may evolve into any of the CTDs, but most often evolves into systemic lupus erythematosus. UCTD patients that do not develop a characterizable CTD are considered to have a mild clinical picture – or “stable UCTD” – characterized by the presence of arthralgias or arthritis, Raynaud’s phenomenon, leukopenia, anemia, and dry eyes or dry mouth (45). An important distinguishing characteristic of UCTD is that no major organ involvement (such as lung disease) has been described (45). Because of the mild clinical picture, UCTD patients rarely require immunosuppressive therapies.
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A recent expert review on UCTD distinguishes “monosymptomatic UCTD” comprised of single organ-dominant diseases (such as ILD) that do not fulfill specific CTD criteria from that of stable, mild “oligosymptomatic UCTD” (45). The authors acknowledge that the concept of UCTD includes a wide spectrum of diseases ranging from “organdominant” conditions, to “stable UCTD”, to early CTDs, or mild forms of CTDs. They suggest that only persistently oligosymptomatic conditions – and not “organ dominant” disease – be classified as UCTD. Mosca and colleagues have proposed the following preliminary classification criteria for UCTD: i.) signs and symptoms suggestive of a CTD, but not fulfilling criteria for defined CTDs, ii.) positive ANAs and iii.) a disease duration of at least 3 years (45).
UCTD IN PULMONARY LITERATURE
Recently, the concept of UCTD has been of interest within the pulmonary community as well. In 2007, Kinder and colleagues proposed a broader and less specific set of UCTD criteria and applied these criteria to a cohort of patients with IIP (Table 2) (39). Retrospectively, they identified 28 subjects with an IIP that met their UCTD definition and compared these subjects with a control group of 47 subjects with IIP. Interestingly, those defined as having UCTD were more likely to be female, younger, and non-smokers and were more likely to have radiographic and histopathologic evidence of NSIP. In all, 88% of those with idiopathic NSIP met their definition for UCTD, and led the authors to propose that most patients previously classified as having idiopathic NSIP have
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clinical, serologic, radiographic, and pathologic characteristics of an autoimmune disease and that idiopathic NSIP may be the lung manifestation of UCTD (39).
Corte and colleagues have called into question the clinical relevance of defining ILD patients as having UCTD and specifically called into question the application of the proposed broader, less-specific UCTD criteria (46). They retrospectively studied 45 patients with biopsy-proven NSIP and 56 patients with biopsy-proven UIP. They reported that CTD features are common in patients with IIP, with 31% of NSIP and 13% of IPF patients fulfilling the stricter, more traditional criteria for UCTD (46). When the broader, less specific, UCTD criteria was applied an astounding 71% of NSIP and 36% of IPF patients could be reclassified as having UCTD (39, 46). Because of its lack of specificity, the authors argued against further implementation of the broader set of UCTD criteria in patients with ILD. Furthermore, the identification of UCTD by either set of criteria did not impact survival. Instead, Corte and colleagues devised an algorithm that was predictive of the presence of NSIP and improved survival consisting of the absence of typical HRCT features of IPF, a compatible demographic profile (women < 50 years of age) or the presence of Raynaud’s phenomenon (46).
“AUTOIMMUNE-FEATURED ILD”
Vij and colleagues described a cohort of UIP-predominant ILD patients retrospectively identified as having a suggestive form of CTD-ILD (47). Among 200 patients evaluated in an ILD referral center, 63 were considered to have
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“autoimmune-featured ILD”. A classification of autoimmune-featured ILD required the presence of a sign or symptom suggestive of a CTD and a serologic test reflective of an autoimmune process (Table 2) (47). The cohort that met their case definition of autoimmune-featured ILD had a demographic profile resembling that of IPF: most were older (average age of 66 years) and male. The most common clinical symptoms were dry eyes, dry mouth, or gastroesophageal reflux disease. Seventyfive percent with autoimmune-featured ILD had a lung injury pattern of UIP; overall survival was similar to that of IPF, and worse than in those with classifiable forms of CTD-ILD. Interestingly, on subset analysis, the presence of an ANA at > 1:1280 titer was associated with improved survival (47).
“LUNG-DOMINANT CTD”
A multidisciplinary group of investigators proposed a different set of provisional classification criteria to define the cohort of individuals with suggestive forms of CTDILD as having “lung-dominant CTD” (Table 2) (19). A classification of lung-dominant CTD would be reserved for those cases where the ILD has a “rheumatologic flavor” as supported by specific autoantibodies or histopathologic features and yet does not meet criteria for a defined CTD based on the lack of adequate extra-thoracic features. The authors argued that implicit with the concept of lung-dominant CTD is the recognition that specific autoantibodies and/or histopathologic features alone can be enough to classify a patient as having a suggestive form of CTD-ILD (19). The presence of specific objective extra-thoracic features highly suggestive of CTD (e.g., Raynaud’s phenomenon,
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inflammatory arthritis) are important and will lend further support for an underlying CTD, but their absence should not preclude a classification of lung-dominant CTD. The authors emphasized that their intent was that the concept of lung-dominant CTD and the associated criteria should be viewed as provisional, and that they might serve as a platform for further multidisciplinary, multicenter investigations, including validation via prospective study (19).
A number of potential advantages to the introduction of this novel classification were suggested (19): 1) the criteria offered are objective and measurable, 2) non-specific symptoms (e.g., dry eyes, myalgias, arthralgias, or gastroesophageal reflux disease), nonspecific inflammatory markers (e.g., erythrocyte sedimentation rate or C-reactive protein), and low-titer ANA or RF are not included because of their high prevalence in patients without CTD, 3) surveillance for evolution to classifiable forms of CTD is encouraged, 4) the classification isolates them from the default category of IIP and provides a framework by which questions regarding this subset’s natural history, pathobiology, treatment, and prognosis can be answered and, 5) the classification allows their distinction from the classifiable, well-characterized forms of CTD, without attempting to redefine existing CTD classification schemes and categories (e.g., UCTD) (19).
AREAS OF UNCERTAINTY
Because of the generally improved outcomes associated with CTD-ILD, and because different treatment approaches are often implemented in patients with CTD-ILD,
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determining whether these suggestive forms of CTD-ILD represent a spectrum of CTD-ILD – rather than IIP – is important (8). In essence, it is important to know whether these suggestive forms of CTD-ILD have a similar natural history as the classifiable forms of CTD-ILD and whether the approach to their management should be similar to that of CTD-ILD or to that of IIP. Current strategies for identifying and classifying these patients are controversial and inadequate, there is far too little interdisciplinary dialogue in this arena, and the advancement of this field would be well served by efforts to bridge these divides.
There is also concern that the proposed sets of criteria for suggestive forms of CTDILD are different enough that research studies being implemented in various centers using these unique criteria may not be applicable to cohorts from centers using the other sets of criteria. The criteria proposed for the modified or broader definition of UCTD and the criteria proposed to define autoimmune-featured ILD appear more similar to each other than the criteria proposed to define lung-dominant CTD. In both UCTD and autoimmune-featured ILD, at least one of a variety of extrapulmonary features (with varying specificity) combined with at least one abnormality of a variety of laboratory tests (with varying specificity) is required. Though there is some overlap between the extra-pulmonary features and laboratory tests in these two sets of criteria, they do remain distinct. In contrast, for lungdominant CTD, rather than relying on extra-pulmonary clinical features of varying specificity, the criteria require that the individual with ILD must be have a specific autoantibody and/or specific histopathological features on surgical lung biopsy.
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Given these differences between the sets of criteria, patients that meet the proposed classification according to one set may not meet criteria for either of the others!
The lack of consensus regarding terminology and the different sets of existing proposed classification criteria limits the ability to conduct the multicenter and multidisciplinary prospective studies needed to answer the many fundamental questions about this ILD subgroup (8).
A PATH FORWARD
In an effort to move beyond the current impasses and address these areas of controversy, an American Thoracic Society / European Respiratory Society Task Force – “An International Working Group on Undifferentiated forms of CTD-ILD” – has been recently formed (8). This Task Force is comprised of an international, multidisciplinary panel of CTD-ILD experts, including investigators from the centers that have put forth the differing criteria for UCTD, lung-dominant CTD, and autoimmune-featured ILD. The primary objective of the Task Force is to develop consensus regarding the nomenclature and criteria for the classification of suggestive forms of CTD-ILD. The Task Force will also identify key areas of uncertainty that are worthy of further research in this cohort. Once there is international and multidisciplinary consensus surrounding the nomenclature and classification criteria of these suggestive forms of CTD-ILD, the requisite platform will be in place to enable the much-needed prospective, multicenter, and
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multidisciplinary studies to further our understanding of this important subgroup of ILD (8).
MANAGEMENT CONSIDERATIONS
Without any data to guide specific recommendations on management of undifferentiated or suggestive forms of CTD-ILD, we suggest it would be reasonable to model strategies employed for defined forms of CTD-ILD (48). Within such a context, it is important to recognize that not all patients with CTD-ILD require pharmacologic treatment. Radiographic findings of ILD on HRCT are common, but only a subset of patients will show clinically significant, progressive disease. The decision to treat any form of CTDILD often rests upon whether the patient is clinically impaired by the ILD, whether it is progressive, and what comorbid conditions or mitigating factors exist. Therapy for all forms of 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 (48).
Similar to the definite forms of CTD-ILD, the evaluation and management of patients with suggestive forms of CTD-ILD is likely to be optimized by effective multidisciplinary interactions among pulmonologists and rheumatologists. In particular, when considering immunomodulatory therapy options for CTD-ILD, both intra-thoracic and extra-thoracic disease manifestations and degrees of activity need to be assessed and
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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, disease monitoring, choice of therapy and on-going longitudinal assessment and re-assessment of a treatment response is complex and is optimized by effective collaborative care among pulmonologists, rheumatologists, and other health-care providers (48).
CLINICAL CASE VIGNETTE DISCUSSION
At the outset of this manuscript, we described a case reflective of the subject matter of this review: A patient with a suggestive form of CTD-ILD. The individual could be considered to have an “autoimmune flavor” to her ILD based on her demographic profile (a 37 year-old-woman), a subtle extra-thoracic clinical feature (digital edema), objective autoimmunity (a positive anti-Ro antibody) and radiographic imaging compatible with the lung injury pattern most often identified in those with CTD: non-specific interstitial pneumonia (NSIP). Though the individual described may not meet formal classification criteria of any of the defined forms of CTD, her clinical scenario does represent a suggestive form of CTD-ILD. As highlighted in this review, this type of scenario is not uncommon, and our hope is that the coming years will be witness to the multidisciplinary collaborative approaches to clinical care and research needed to further our understanding of this important cohort.
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SUMMARY
The intersection of ILD and CTD is complex and commonly includes the scenario whereby ILD is identified in patients with pre-existing CTD, is the presenting manifestation of an occult CTD, or arises within the context of a suggestive form of CTD. Determining that an ILD is CTD-associated is important because this knowledge often impacts management and prognosis. Identifying occult CTD in patients with presumed idiopathic ILD can be challenging and requires a comprehensive, often multidisciplinary, evaluation. There is much uncertainty and controversy surrounding the scenarios whereby ILD occurs within scenarios that are suggestive of CTD-ILD. Multicenter and multidisciplinary efforts are underway to achieve consensus regarding the nomenclature and classification criteria of these suggestive forms of CTD-ILD and these efforts should provide the platform for the requisite prospective studies needed to provide a better understanding of the natural history of these cohorts, how to best manage them, and to determine whether they behave similar to the well-characterized, classifiable forms of CTD-ILD.
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Table 1: Suggested categories of ILD patients who require further rheumatologic evaluation (9)
1. Women, particularly those younger than 50 2. Any patient with extra-thoracic manifestations highly suggestive of CTD a. i.e. Raynaud’s 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 pathologic pattern with secondary histopathology features that might suggest CTD a. i.e. 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 to a particular CTD a. i.e. anti-CCP, anti-Scl-70, anti-Ro, anti-La, anti-dsDNA, anti-Smith, antiRNP, anti-tRNA synthetase
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Table 2. Proposed classification criteria for the suggestive forms of CTD-ILD (3, 19, 39, 47) Proposed category Undifferentiated CTD (broader definition) (requires at least one clinical feature and one laboratory finding)
Autoimmunefeatured ILD
(requires at least one clinical feature and one laboratory finding)
Lung-dominant CTD (requires all three listed clinical features and either 4a or 4b)
Clinical features One or more of the following symptoms: Dry eyes or dry mouth Gastro-oesophageal reflux disease Weight loss Recurrent unexplained fever Joint pain or swelling Rash Photosensitivity Dysphagia Nonandrogenic alopecia Mouth ulcers Raynaud’s phenomenon Morning stiffness Proximal muscle weakness One or more of the following symptoms: Dry eyes or dry mouth Gastro-oesophageal reflux disease Weight loss Foot or leg swelling Joint pain or swelling Rash Photosensitivity Dysphagia Hand ulcers Mouth ulcers Raynaud’s phenomenon Morning stiffness Proximal muscle weakness All of the following features: 1.
2. 3.
NSIP, UIP, LIP, OP, DAD, (or DIP if no smoking history), as determined by surgical lung biopsy or suggested by HRCT and Insufficient extra-thoracic features of a definite CTD and No identifiable alternative aetiology for IP and
Laboratory or histopathology findings One or more of these laboratory abnormalities: ANA (any titer) RF Anti-Ro Anti-La Anti-Jo-1 Anti-topoisomerase (Scl-70) Erythrocyte sedimentation rate (2 times normal) C-reactive protein elevation
One or more of these laboratory abnormalities: ANA > 1:160 titer RF Anti-Ro Anti-La Anti-Smith Anti-ribonucleoprotein Anti-dsDNA Anti-topoisomerase (Scl-70) Anti-CCP Anti-Jo-1 Aldolase Creatine phosphokinase 4a. Any one of these autoantibodies ANA > 1:320 titer RF > 60 IU/mL Anti-nucleolar ANA (any titer) Anti-centromere Anti-CCP Anti-Ro Anti-La Anti-dsDNA Anti-ribonucleoprotein Anti-Smith Anti-topoisomerase (Scl-70) Anti-tRNA synthetase Anti-PM-Scl 4b. OR at least two of these histopathology features: Lymphoid aggregates with germinal centres Extensive pleuritis Prominent plasmacytic infiltration Dense perivascular collagen
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FIGURE LEGENDS:
Figure 1: High resolution computed tomographic image demonstrating bilateral, peripheral predominant ground glass opacifications suggestive of non-specific interstitial pneumonia
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REFERENCES:
1. ATS/ERS. 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. 2. Cottin V. Interstitial lung disease. European respiratory review : an official journal of the European Respiratory Society. 2013;22(127):26-32. 3. Fischer A, du Bois R. Interstitial lung disease in connective tissue disorders. Lancet. 2012;380(9842):689-98. 4. Castelino FV, Varga J. Interstitial lung disease in connective tissue diseases: evolving concepts of pathogenesis and management. Arthritis Res Ther. 2010;12(4):213. 5. Castelino FV, Goldberg H, Dellaripa PF. The impact of rheumatological evaluation in the management of patients with interstitial lung disease. Rheumatology (Oxford). 2011;50(3):489-93. 6. Cottin V. Interstitial lung disease: are we missing formes frustes of connective tissue disease? Eur Respir J. 2006;28(5):893-6. 7. Fischer A. Interstitial lung disease: a rheumatologist's perspective. J Clin Rheumatol. 2009;15(2):95-9. 8. Fischer A. Interstitial lung disease in suggestive forms of connective tissue disease. J Bras Pneumol. 2013;39(6):641-3. 9. Fischer A, du Bois RM. A Practical Approach to Connective Tissue DiseaseAssociated Lung Disease. 2nd ed. Baughman RP, du Bois RM, editors. New York: Springer; 2012. pp217-37 10. Mittoo S, Gelber AC, Christopher-Stine L, Horton MR, Lechtzin N, Danoff SK. Ascertainment of collagen vascular disease in patients presenting with interstitial lung disease. Respir Med. 2009;103(8):1152-8. 11. White B. Interstitial lung disease in scleroderma. Rheum Dis Clin North Am. 2003;29(2):371-90. 12. Highland KB, Garin MC, Brown KK. The spectrum of scleroderma lung disease. Semin Respir Crit Care Med. 2007;28(4):418-29. 13. Schnabel A, Hellmich B, Gross WL. Interstitial lung disease in polymyositis and dermatomyositis. Curr Rheumatol Rep. 2005;7(2):99-105. 14. Schwarz MI. The lung in polymyositis. Clin Chest Med. 1998;19(4):701-12, viii. 15. Dawson JK, Fewins HE, Desmond J, Lynch MP, Graham DR. Fibrosing alveolitis in patients with rheumatoid arthritis as assessed by high resolution computed tomography, chest radiography, and pulmonary function tests. Thorax. 2001;56(8):622-7. 16. Gabbay E, Tarala R, Will R, Carroll G, Adler B, Cameron D, et al. Interstitial lung disease in recent onset rheumatoid arthritis. Am J Respir Crit Care Med. 1997;156(2 Pt 1):528-35.
John Wiley & Sons, Inc.
26
Page 27 of 29
Arthritis Care & Research
17. Turesson C, O'Fallon WM, Crowson CS, Gabriel SE, Matteson EL. Extraarticular disease manifestations in rheumatoid arthritis: incidence trends and risk factors over 46 years. Ann Rheum Dis. 2003;62(8):722-7. 18. Antoniou KM, Margaritopoulos G, Economidou F, Siafakas NM. Pivotal clinical dilemmas in collagen vascular diseases associated with interstitial lung involvement. Eur Respir J. 2009;33(4):882-96. 19. Fischer A, West SG, Swigris JJ, Brown KK, du Bois RM. Connective tissue disease-associated interstitial lung disease: a call for clarification. Chest. 2010;138(2):251-6. 20. Tzelepis GE, Toya SP, Moutsopoulos HM. Occult connective tissue diseases mimicking idiopathic interstitial pneumonias. Eur Respir J. 2008;31(1):11-20. 21. Bouros D, Wells AU, Nicholson AG, Colby TV, Polychronopoulos V, Pantelidis P, 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):1581-6. 22. Park JH, Kim DS, Park IN, Jang SJ, Kitaichi M, Nicholson AG, et al. Prognosis of fibrotic interstitial pneumonia: idiopathic versus collagen vascular disease-related subtypes. Am J Respir Crit Care Med. 2007;175(7):705-11. 23. Klareskog L, Malmstrom V, Lundberg K, Padyukov L, Alfredsson L. Smoking, citrullination and genetic variability in the immunopathogenesis of rheumatoid arthritis. Seminars in immunology. 2011;23(2):92-8. 24. Klareskog L, Stolt P, Lundberg K, Kallberg H, Bengtsson C, Grunewald J, et al. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum. 2006;54(1):38-46. 25. Fischer A, Solomon JJ, du Bois RM, Deane KD, Olson AL, Fernandez-Perez ER, et al. Lung disease with anti-CCP antibodies but not rheumatoid arthritis or connective tissue disease. Respir Med. 2012;106(7):1040-7. 26. Demoruelle MK, Deane KD, Holers VM. When and where does inflammation begin in rheumatoid arthritis? Current opinion in rheumatology. 2014;26(1):64-71. 27. Demoruelle MK, Weisman MH, Simonian PL, Lynch DA, Sachs PB, Pedraza IF, et al. Brief report: airways abnormalities and rheumatoid arthritis-related autoantibodies in subjects without arthritis: early injury or initiating site of autoimmunity? Arthritis Rheum. 2012;64(6):1756-61. 28. Doyle TJ, Hunninghake GM, Rosas IO. Subclinical interstitial lung disease: why you should care. Am J Respir Crit Care Med. 2012;185(11):1147-53. 29. Gochuico BR, Avila NA, Chow CK, Novero LJ, Wu HP, Ren P, et al. Progressive preclinical interstitial lung disease in rheumatoid arthritis. Arch Intern Med. 2008;168(2):159-66. 30. Launay D, Remy-Jardin M, Michon-Pasturel U, Mastora I, Hachulla E, Lambert M, et al. High resolution computed tomography in fibrosing alveolitis associated with systemic sclerosis. J Rheumatol. 2006;33(9):1789-801. 31. Uffmann M, Kiener HP, Bankier AA, Baldt MM, Zontsich T, Herold CJ. Lung manifestation in asymptomatic patients with primary Sjogren syndrome: assessment with high resolution CT and pulmonary function tests. J Thorac Imaging. 2001;16(4):282-9. 32. Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based
John Wiley & Sons, Inc.
27
Arthritis Care & Research
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guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183(6):788824. 33. Homma Y, Ohtsuka Y, Tanimura K, Kusaka H, Munakata M, Kawakami Y, et al. Can interstitial pneumonia as the sole presentation of collagen vascular diseases be differentiated from idiopathic interstitial pneumonia? Respiration. 1995;62(5):248-51. 34. Fischer A, Pfalzgraf FJ, Feghali-Bostwick CA, Wright TM, Curran-Everett D, West SG, et al. Anti-th/to-positivity in a cohort of patients with idiopathic pulmonary fibrosis. J Rheumatol. 2006;33(8):1600-5. 35. Fischer A, Meehan RT, Feghali-Bostwick CA, West SG, Brown KK. Unique characteristics of systemic sclerosis sine scleroderma-associated interstitial lung disease. Chest. 2006;130(4):976-81. 36. Fischer A, Swigris JJ, du Bois RM, Lynch DA, Downey GP, Cosgrove GP, et al. Anti-synthetase syndrome in ANA and anti-Jo-1 negative patients presenting with idiopathic interstitial pneumonia. Respir Med. 2009;103(11):1719-24. 37. Watanabe K, Handa T, Tanizawa K, Hosono Y, Taguchi Y, Noma S, et al. Detection of antisynthetase syndrome in patients with idiopathic interstitial pneumonias. Respir Med. 2011;105(8):1238-47. 38. Fujita J, Ohtsuki Y, Yoshinouchi T, Yamadori I, Bandoh S, Tokuda M, et al. Idiopathic non-specific interstitial pneumonia: as an "autoimmune interstitial pneumonia". Respir Med. 2005;99(2):234-40. 39. Kinder BW, Collard HR, Koth L, Daikh DI, Wolters PJ, Elicker B, et al. Idiopathic nonspecific interstitial pneumonia: lung manifestation of undifferentiated connective tissue disease? Am J Respir Crit Care Med. 2007;176(7):691-7. 40. Sabo I. The lanthanic or undifferentiated collagen disease. Hiroshima J Med Sci. 1969;18(4):259-64. 41. LeRoy EC, Maricq HR, Kahaleh MB. Undifferentiated connective tissue syndromes. Arthritis Rheum. 1980;23(3):341-3. 42. Mosca M, Neri R, Bencivelli W, Tavoni A, Bombardieri S. Undifferentiated connective tissue disease: analysis of 83 patients with a minimum followup of 5 years. J Rheumatol. 2002;29(11):2345-9. 43. Mosca M, Neri R, Bombardieri S. Undifferentiated connective tissue diseases (UCTD): a review of the literature and a proposal for preliminary classification criteria. Clin Exp Rheumatol. 1999;17(5):615-20. 44. Mosca M, Tani C, Bombardieri S. Undifferentiated connective tissue diseases (UCTD): a new frontier for rheumatology. Best Pract Res Clin Rheumatol. 2007;21(6):1011-23. 45. Mosca M, Tani C, Carli L, Bombardieri S. Undifferentiated CTD: a wide spectrum of autoimmune diseases. Best Pract Res Clin Rheumatol. 2012;26(1):73-7. 46. Corte TJ, Copley SJ, Desai SR, Zappala CJ, Hansell DM, Nicholson AG, et al. Significance of connective tissue disease features in idiopathic interstitial pneumonia. Eur Respir J. 2012;39(3):661-8. 47. Vij R, Noth I, Strek ME. Autoimmune-featured interstitial lung disease: a distinct entity. Chest. 2011;140(5):1292-9. 48. Fischer A, Brown, KK, Frankel, SK. Treatment of connective tissue disease related interstitial lung disease. . Clinical Pulmonary Medicine. 2009;16(2):74-80.
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High resolution computed tomographic image demonstrating bilateral, peripheral predominant ground glass opacifications suggestive of non-specific interstitial pneumonia 254x190mm (72 x 72 DPI)
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