Interstitial Lung Disease in Undifferentiated Forms of Connective Tissue Disease



Fig. 27.1
High resolution computed tomographic image demonstrating bilateral, peripheral predominant ground glass opacifications suggestive of non-specific interstitial pneumonia



Does this patient have connective tissue disease-associated interstitial lung disease?



Introduction


The interstitial lung diseases 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]. While these diseases often occur as clinically isolated, they commonly arise within the context of an underlying connective tissue disease (CTD) [2]. Excluding an associated CTD is probably the most important and challenging step in diagnosing idiopathic pulmonary fibrosis (IPF) and a multidisciplinary approach – that includes the rheumatologist – is often useful when assessing for CTD in patients with suspected IPF.

The designations “connective tissue disease” or “collagen vascular disease” are used interchangeably and refer to the spectrum of systemic autoimmune diseases that are characterized by autoimmune phenomena (e.g. circulating autoantibodies) and autoimmune-mediated organ damage (Table 27.1). Although these disorders are grouped together, there is significant heterogeneity of clinical features associated with each of the specific CTDs. In addition to well-characterized forms of CTD, it is not uncommon for individuals to have incomplete or partial forms with clinical features that fall short of fulfilling existing classification criteria for a specific disease – resulting in a clinical diagnosis of “undifferentiated CTD” [3].


Table 27.1
Connective tissue diseases and other rheumatologic diseases associated with lung disease







































Connective tissue diseases

Rheumatoid arthritis

Systemic lupus erythematosus

Systemic sclerosis

Primary Sjögren’s syndrome

Polymyositis/dermatomyositis/anti-synthetase syndrome

Mixed connective tissue disease

Undifferentiated connective tissue disease

Otherrheumatologicdisorders

Systemic vasculitis

 Polyangiitis with granulomatosis (Wegener’s)

 Microscopic polyangiitis

 Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)

Spondyloarthropathy

Relapsing polychondritis

Behçet’s disease

Anti-phospholipid syndrome

As a general rule, CTD manifests with autoimmune-mediated organ dysfunction with the lungs as a frequent target. There are multiple pulmonary manifestations; essentially every component of the respiratory tract is at risk of injury (Table 27.2). Furthermore, specific CTDs are often associated with specific patterns of lung involvement (Table 27.3). Certain CTDs are more likely to be associated with parenchymal disease, (e.g. systemic sclerosis [SSc] and poly-/dermatomyositis [PM/DM]), but all patients with CTD are at risk, and there is an expanding appreciation that ILD may be the first or only manifestation of a CTD [59]. Much less is known, and significant controversy exists, regarding the lung manifestations associated with partial or undifferentiated forms of CTD.


Table 27.2
Primary and secondary pulmonary manifestations of connective tissue diseases





















































Primary manifestations

Pleural

 Pleurisy

 Effusion/thickening

Airways

 Upper

  Cricoarytenoid disease

  Ttracheal disease

 Lower

  Bronchiectasis

  Bronchiolitis

Vascular

 Pulmonary arterial hypertension

 Vasculitis

Parenchymal

 Interstitial lung disease

 Diffuse alveolar hemorrhage

 Acute pneumonitis

Rheumatoid nodules

Secondary manifestations

Infections

Drug-toxicity

Malignancy

Thromboembolism



Table 27.3
Most common CTD-associated pulmonary manifestations [4]



























































 
SSc

RA

Primary Sjögren’s

MCTD

PM/DM

SLE

Airways


++

++

+


+

ILD

+++

++

++

++

+++

+

Pleural


++

+

+


+++

Vascular

+++


+

++

+

+

DAH






++


The number of + signs indicates relative prevalence of each manifestation

SSc systemic sclerosis, RA rheumatoid arthritis, CTD connective tissue disease, MCTD mixed connective tissue disease, PM/DM polymyositis/dermatomyositis, SLE systemic lupus erythematosus, ILD interstitial lung disease, DAH diffuse alveolar hemorrhage

Thus, the intersection of ILD and CTD is complex and includes any of the following scenarios: (i) the identification of ILD within established, well-characterized forms of CTD, (ii) ILD as the presenting manifestation of a well-characterized form of CTD, or (iii) ILD that arises within the context of a suggestive, or undifferentiated, form of CTD. In this chapter, we review the clinical aspects of these intersecting conditions and focus especially on the latter two with ILD as the presenting manifestation of either well-characterized or undifferentiated forms of CTD.


Implications of a Diagnosis of CTD-ILD


There are numerous implications of a diagnosis of CTD-associated ILD (CTD-ILD). Most significantly, well-characterized forms of CTD-ILD, such as SSc-associated ILD, appear to have a more favorable prognosis than the idiopathic interstitial pneumonias (IIP) [10, 11]. (Far less is known about whether a similar survival benefit is seen in undifferentiated forms of CTD-ILD and this will be discussed in subsequent sections.) Other implications include providing a clinical explanation for otherwise unexplained extra-thoracic manifestations (e.g. Raynaud’s phenomenon, esophageal hypomotility, myositis) 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. Research implications include providing a precise phenotype to allow more effective pathobiology and natural history studies hopefully 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 the disease.


ILD Within Pre-existing CTD


It is common to detect ILD in patients with pre-existing, well-characterized forms of CTD. Indeed, recent studies of CTD cohorts have shown radiographic prevalence rates of subclinical ILD ranging from 33 to 57 % [1216]. ILD is particularly common in patients that have SSc, PM/DM, RA, primary Sjögren’s syndrome, and mixed CTD (MCTD). However, just because parenchymal lung disease is identified in a patient with CTD does not mean the two are inter-related. For example, the presence of pre-existing RA does not preclude, and may predispose toward, the development of lung injury due to other causes (e.g., infection and drug-induced pneumonitis). Because patients with pre-existing CTD are often treated with immunosuppressive agents, the finding of new pulmonary infiltrates in an immunocompromised host should raise strong suspicions for respiratory infection – with either typical or atypical pathogens. Consideration for drug-induced lung toxicity is warranted because many of the immunomodulatory and anti-inflammatory therapies – especially methotrexate, but also aspirin, non-steroidal anti-inflammatory drugs, sulfasalazine, leflunomide, and the anti-tumor necrosis factor alpha (TNFα) agents – are all associated with drug-induced pneumonitis [1734]. In this regard, just as with any other patient that presents with parenchymal lung disease, a comprehensive evaluation is needed to explore all potential etiologies (e.g., infection, drug-toxicity, environmental and occupational exposures, familial disease, smoking-related lung disease, and malignancy). Determining whether the ILD is associated with the pre-existing CTD is decided through a process of elimination [4].


ILD as the First Manifestation of a CTD


Identifying occult CTD when confronted with a so-called “idiopathic” interstitial pneumonia 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 [35].

There is no standardized approach to the identification of CTD. Current practice for assessing its assessment includes a thorough history and physical examination and testing for circulating autoantibodies [1, 36]. Many tertiary centers have also found that a multi-disciplinary evaluation that includes rheumatologic consultation is useful. In practice, it is both unrealistic and impractical to have rheumatologic specialty evaluation for all cases of IIP, and certain guidelines for deciding when to obtain rheumatologic consultation have been suggested (Table 27.4) [4].


Table 27.4
Suggested categories of ILD patients who require further rheumatologic evaluation [4]



















1. Women, particularly those younger than 50

2. Any patient with extra-thoracic manifestations highly suggestive of CTD

 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

 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

 i.e. anti-CCP, anti-Scl-70, anti-Ro, anti-La, anti-dsDNA, anti-Smith, anti-RNP, anti-tRNA synthetase

Confirming the presence of a specific CTD in the absence of characteristic clinical findings is challenging [37]. Homma and colleagues evaluated whether interstitial pneumonia as the sole presentation of CTD can be differentiated from an IIP [38]. They described 68 patients who had presented with an IIP and were followed prospectively over 11 years. Thirteen patients (19 %) eventually developed 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 with CTD-ILD before the systematic manifestations appear [38].

Although we recognize that detecting occult CTD is challenging and that ANA and RF positivity alone are not very useful, a thorough evaluation for subtle extra-pulmonary features of CTD, assessing a broader array of specific autoantibodies (Table 27.5) (and incorporating ANA titer and pattern of immunofluorescence), as well as consideration of radiographic and histopathologic features are all important components of an evaluation and make it more likely that occult CTD will be detected [8]. Moreover, and as the following studies will attest, a multidisciplinary approach – that includes the rheumatologist – can be useful when assessing the ILD patient for underlying CTD.


Table 27.5
Useful antibodies for CTD-ILD assessment


























































Autoantibody

Commonly associated CTD

High titer ANA (>1:320 titer)

Many

High titer RF (>60 IU/mL)

RA, Sjögren’s disease, SLE

Anti-CCP

RA

Anti-centromere

Systemic sclerosis

Anti-nucleolar-ANA

Systemic sclerosis

Anti-Ro (SS-A)

Many

Anti-La (SS-B)

SLE, Sjögren’s disease

Anti-Smith

SLE

Anti-ribonucleoprotein

SLE, MCTD

Anti-dsDNA

SLE

Anti-topoisomerase (Scl-70)

Systemic sclerosis

Anti-tRNA synthetase antibodies

Poly-/dermatomyositis (anti-synthetase syndrome)

Anti-PM-Scl

Systemic sclerosis/myositis overlap

Anti-Th/To

Systemic sclerosis

Anti-U3 ribonucleoprotein

Systemic sclerosis

ANCA

Systemic vasculitis

Fischer and colleagues retrospectively reviewed a cohort of 285 subjects with biopsy proven UIP that were considered to have IPF [39]. 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 (nucleolar antibody highly specific for SSc) [40] antibody. Retrospectively, most of the subjects with nucleolar antibody positivity, and especially those with Th/To antibody positivity, had subtle extra-pulmonary features of SSc that included digital edema, Raynaud’s phenomenon, telangiectasia, and esophageal hypomotility. The authors concluded that because these individuals had autoantibody positivity known to be highly specific for SSc, extra-pulmonary features suggestive of SSc, and a parenchymal injury pattern seen in SSc, these individuals likely had SSc rather than IPF [39]. This same group also described six individuals evaluated over a 12 month period for idiopathic NSIP or UIP [41]. All had nucleolar-pattern ANA positivity along with either Th/To or Scl-70 positivity and all had some extra-pulmonary 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-pulmonary features for SSc should be sought – in patients with nucleolar-pattern ANA and NSIP or UIP patterns of lung injury.

Mittoo and colleagues retrospectively evaluated a cohort of 114 consecutive patients referred to a tertiary referral center for ILD evaluation [35]. Thirty-four subjects (30 %) were found to have CTD-ILD and of these only half had presented with established, pre-existing CTD. Of the 17 identified to have an underlying CTD, 10 had PM/DM, 3 had systemic lupus erythematosus (SLE), 1 each with SSc and polyangiitis with granulomatosis (Wegener’s) and 2 with undifferentiated forms of CTD. They found that younger age, high-titer ANA, and elevated muscle enzymes were associated with underlying CTD [35].

Further highlighting the importance of a multi-disciplinary evaluation, Castelino and colleagues described a cohort of 50 patients with ILD evaluated over a 1 year period at a tertiary referral center [42]. 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 [42]. Fischer and colleagues described a cohort of nine 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-pulmonary features that included “mechanic’s hands”, Raynaud’s phenomenon, inflammatory arthritis, myositis, or esophageal hypomotility [43]. Interestingly, and characteristic of the anti-synthetase syndrome, these individuals were all ANA and RF negative. The authors emphasized the utility of cross-specialty evaluation of otherwise idiopathic ILD 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 presentations of anti-synthetase syndrome [43]. Similarly, Watanabe and colleagues screened 198 consecutive cases of IIP with a panel of anti-tRNA synthetase antibodies and identified positive anti-synthetase antibodies in 13 cases (7 %) [44]. They reported that those with positive antibodies were younger and more likely to have NSIP or UIP with lymphoid follicules. Furthermore, among the 13 with a positive tRNA synthetase antibody, extra-pulmonary manifestations of anti-synthetase syndrome were retrospectively identified in seven cases (54 %) [44].

Finally, two recent series have shown that ILD may also be the presenting manifestation of RA and that assessing for RA-specific autoantibodies in patients with IIP may identify an at-risk phenotype for later RA development [45, 46]. Gizinski and colleagues described a series of four patients with ILD, RF, and anti-cyclic-citrullinated peptide (CCP) positivity and no articular findings of RA [46]. All were male, former smokers, and the average age at time of diagnosis of ILD was 70 years. Three patients died within 2 years of diagnosis of progressive lung fibrosis and never developed articular symptoms consistent with RA; but one case met full criteria for the articular aspects of RA several months after stopping immunosuppressive treatment for ILD. In a more recent series, Fischer and colleagues described 74 subjects evaluated over a 2 year period with anti-CCP antibody positivity, lung disease, and no evidence of RA or other CTD [45]. Most were women and former cigarette smokers. Four distinct radiographic phenotypes were identified: isolated airways disease (54 %), isolated parenchymal lung disease (14 %), mixed airways and parenchymal lung disease (26 %), and combined pulmonary fibrosis with emphysema (7 %). Among subjects with high-titer anti-CCP positivity (45 %), 3 developed the articular manifestations of RA within 2 years of surveillance: only 1 of the 3 ever smoked, 2 had isolated inflammatory airways disease, and 1 had combined airways and parenchymal lung disease. The authors highlighted that the lung disease in this cohort resembled that seen in established RA, lung disease may be the presenting manifestation of RA, and anti-CCP positivity in inflammatory airways or parenchymal lung disease may be a pre-RA phenotype [45].


Undifferentiated Forms of CTD-ILD (Table 27.6)





Table 27.6
Proposed criteria for categories of suggestive forms of CTD-ILD [2]







































































































































































Proposed category

Clinical features

Laboratory or histopathology findings

Undifferentiated CTD (stricter definition)

One or more of the following symptoms:

One or more of these autoantibodies:

(requires at least one clinical feature and one laboratory finding)

Dry eyes or dry mouth, Joint pain or swelling

ANA (high titer)

Raynaud’s phenomenon

RF (high titer)

Proximal muscle weakness

Anti-Smith

Morning stiffness

Anti-ribonucleoprotein

Anti-dsDNA

Anti-Ro

Anti-La

Anti-Jo-1

Anti-topoisomerase (Scl-70)

Anti-centromere

Undifferentiated CTD (broader definition)

One or more of the following symptoms:

One or more of these laboratory abnormalities:

(requires at least one clinical feature and one laboratory finding)

Dry eyes or dry mouth

ANA (any titer)

Gastro-oesophageal reflux disease

RF

Weight loss

Anti-Ro

Recurrent unexplained fever

Anti-La

Joint pain or swelling

Anti-Jo-1

Rash

Anti-topoisomerase (Scl-70)

Photosensitivity

Erythrocyte sedimentation rate (two times normal)

Dysphagia

C-reactive protein elevation

Nonandrogenic alopecia

Mouth ulcers

Raynaud’s phenomenon

Morning stiffness

Proximal muscle weakness

Lung-dominant CTD

A ll of the following features:

4a. Any one of these autoantibodies

(requires all three listed clinical features and either 4a or 4b)

1. NSIP, UIP, LIP, OP, DAD, (or DIP if no smoking history), as determined by surgical lung biopsy or suggested by HRCT and

ANA > 1:320 titer

2. Insufficient extra-thoracic features of a definite CTD and

RF > 60 IU/mL

3. No identifiable alternative aetiology for IP and

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

Autoimmune-featured ILD

One or more of the following symptoms:

One or more of these laboratory abnormalities:

(requires at least one clinical feature and one laboratory finding)

Dry eyes or dry mouth

ANA ≥ 1:160 titer

Gastro-oesophageal reflux disease

RF

Weight loss

Anti-Ro

Foot or leg swelling

Anti-La

Joint pain or swelling

Anti-Smith

Rash

Anti-ribonucleoprotein

Photosensitivity

Anti-dsDNA

Dysphagia

Anti-topoisomerase (Scl-70)

Hand ulcers

Anti-CCP

Mouth ulcers

Anti-Jo-1

Raynaud’s phenomenon

Aldolase

Morning stiffness

Creatine phosphokinase

Proximal muscle weakness

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 established classification criteria for existing CTDs [2, 8]. It has even been suggested that idiopathic NSIP is itself an autoimmune disease or is the lung manifestation of undifferentiated CTD (UCTD) [47, 48]. Because of the otherwise generally better survival associated with CTD-ILD, there may be an inherent desire to find reasons to define disease as CTD-ILD. In some of these individuals a serum autoantibody known to be highly specific for a certain CTD (such as anti-CCP with RA) may be present despite the absence of overt systemic features and this poses challenges to diagnostic precision. In contrast to the improved survival experience associated with well-characterized forms of CTD-ILD, it remains to be determined whether undifferentiated forms of CTD-ILD are associated with a better outcome.

Also controversial is when there is a “rheumatologic flavor” to the ILD, but one which falls short of fulfilling the requisite features to allow a specific rheumatological diagnosis to be made using currently accepted criteria. These patients, in whom it appears that the lung is either the lone, or most clinically-significant manifestation of an occult CTD, are suspected of having a systemic autoimmune disease based on the presence of circulating autoantibodies, specific histopathological features on surgical lung biopsy, or extra-thoracic manifestations and could be classified as having “lung dominant CTD” rather than “idiopathic” disease [8]. Furthermore, despite recognition that ILD may be the first manifestation of CTD, current rheumatologic classification criteria do not allow a specific CTD designation for isolated ILD.

Current strategies for identifying and classifying these types of patients are both controversial and inadequate. Proposed terminology to describe and classify such patients includes “lung-dominant CTD” [8], “UCTD” [48], and “auto-immune featured ILD” [49].


UCTD in the Rheumatology Literature


In addition to well-characterized forms of CTD, it is common to encounter patients that have partial or incomplete forms of CTD and these cases are often considered to have UCTD [3, 5052]. The first descriptions of “undifferentiated diseases” were made in 1969 by Sabo [53]. 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 [54]. 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 [3, 5052]. 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 [3, 5052]. UCTD may evolve into any of the CTDs, but most often evolves into systemic lupus erythematosus (SLE). 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 [3]. An important distinguishing characteristic of UCTD is that no major organ involvement (such as lung disease) has been described [3]. Because of the mild clinical picture, UCTD patients rarely require immunosuppressive therapies.

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” [3]. The authors acknowledge that the concept of UCTD includes a wide spectrum of diseases ranging from ‘organ-dominant’ 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 [3].


UCTD in the Pulmonary Literature (Table 27.6)


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 [48]. Retrospectively, they identified 28 subjects with an IIP that met their proposed criteria for UCTD and compared these subjects with a control group of 47 subjects with an IIP that did not meet their criteria. Interestingly, those that they defined as having UCTD were more likely to be female, younger, and non-smokers and were more likely to have ground-glass opacities on HRCT and NSIP on surgical lung biopsy. In all, 88 % of those with idiopathic NSIP met their definition for UCTD, and led the authors to conclude that most patients previously classified as having idiopathic NSIP have clinical, serologic, radiographic, and pathologic characteristics of autoimmune disease and they proposed that idiopathic NSIP is the lung manifestation of UCTD [48]. Of note, the accompanying editorial by Kim and Nagai pointed out several limitations of this study and argued against accepting the conclusion that idiopathic NSIP is UCTD [55]. In particular, they emphasized that there was uncertainty in the diagnosis of UCTD and a concern for more false-positive cases because the authors modified the more traditional UCTD criteria – that requires autoantibody positivity – to include nonspecific inflammatory markers (C-reactive protein, creatine phosphokinase, aldolase, or erythrocyte sedimentation rate) [55].

More recently, 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 broader, less-specific UCTD criteria proposed by Kinder and colleagues [56]. 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 [56]. However, when the broader, less specific, criteria of Kinder for UCTD was applied, an astounding 71 % of NSIP and 36 % of IPF patients could be reclassified as having UCTD [48, 56]. Because of its lack of specificity, the authors argued against further implementation of the Kinder set of criteria to define UCTD in patients with ILD. Furthermore, the identification of UCTD by either 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) or the presence of Raynaud’s phenomenon [56].

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