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.

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 % [12–16]. 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 [17–34]. 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].

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].

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.

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].

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].