Clinical Vignette

A 45-year-old woman, never smoker, presents with a slowly progressive dyspnea and also reports a dry cough that is worse with exertion. On symptom review, she reports several months of puf ness of the hands but denies any other features to suggest an autoimmune disease. On physical examination, she is noted to have digital edema and mild distal digital ssuring but no evidence of Raynaud phenomenon, sclerodactyly, or telangiectasia. Her musculoskeletal examination is otherwise normal; no synovitis or muscle weakness is detected. She has audible crackles on respiratory examination bilaterally. Her high-resolution computed tomography images reveal evidence of diffuse lung disease suggestive of nonspeci c interstitial pneumonia (NSIP) pattern (Fig. 15.1). Laboratory testing is notable only for a positive anti-nuclear antibody at high titer (1:1280). All other serologies and lab tests are normal.

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

A. Sergew (*)

Division of Pulmonary Sciences and Critical Care Medicine, National Jewish Health, Denver, CO, USA

e-mail: sergewa@njhealth.org

A. Fischer

Bristol Myers Squibb, Denver, CO, USA e-mail: Aryeh.Fischer@bms.com

K. Brown

National Jewish Health, Denver, CO, USA

e-mail: brownk@njhealth.org; brownk@NJC.ORG

Fig. 15.1  High-resolution computed tomographic image demonstrating a pattern suggestive of nonspeci c interstitial pneumonia

Introduction

The interstitial lung diseases (ILD) (also called interstitial pneumonias) are a heterogeneous group of pulmonary disorders that affect the pulmonary parenchyma and are classi ed together based on common clinical, radiological, and histopathological features [1]. Some occur in the absence of any known cause or association, the idiopathic interstitial pneumonias (IIP). Known causes and associations include environmental/occupational exposures, medications, speci c genetic defects, and underlying connective tissue disease (discussed elsewhere). Connective tissue disease (CTD) refers to the spectrum of systemic diseases characterized by circulating autoantibodies and autoimmune-mediated organ damage. ILD in this setting is termed connective tissue disease-­associated interstitial lung disease (CTD-ILD) [2], and accounts for 15–30% of new ILD diagnoses [3, 4]. In addition to characterized forms of CTD, it is not uncommon for individuals to have a variety of clinical features that suggest, but fall short of ful lling existing classi cation criteria for a speci c disease. When ILD occurs in a patient with

autoimmune signs, symptoms, and/or serologies, one of the following scenarios may exist: (1) ILD is the presenting problem and further clinical evaluation reveals an underlying CTD, (2) ILD develops in a patient with a previously diagnosed CTD, (3) the ILD may occur within a clinical context suggestive, but not diagnostic of CTD, a scenario coined “interstitial pneumonia with autoimmune features” (IPAF). In this chapter, we review the third scenario, the clinical aspects of IPAF.

Diagnostic Criteria

An IIP is a diagnosis of exclusion, all other potential explanations for the presence of ILD have been considered and ruled out. However, within this group there is population of patients that have signs, symptoms and/or serologies suggestive of a CTD, but do not t current CTD diagnostic criteria. Multiple de nitions have been proposed for these patients, including “undifferentiated CTD associated ILD” (UCTD-­ILD) [5], “lung-dominant CTD” [6] or “autoimmune-­featured ILD” [7]. Each of these de nitions differ slightly from each other and community acceptance has been variable. The European Respiratory Society/American Thoracic Society convened an international Task Force on Undifferentiated Forms of Connective Tissue Disease-­associated Interstitial Lung Disease and in 2015 published a consensus statement that coined the term “interstitial pneumonia with autoimmune features” (IPAF) to describe patients who otherwise met criteria for an IIP, but also had ndings suggestive, but not diagnostic of a CTD [8]. IPAF was established as a research classi cation to allow for a way to categorize­ and phenotype these patients and not as a clinical classi cation, though it has achieved wide-spread community acceptance.

The de nition of IPAF requires the presence of an interstitial pneumonia based on chest imaging, with or without surgical histopathology, the exclusion of other causes of interstitial pneumonia, and ndings suggestive but not diagnostic of an underlying CTD. More speci cally, IPAF requires a combination of features from 2 or more domains: clinical, serologic, and morphologic (Table 15.1). The clinical domain includes Raynaud phenomenon, palmar telangiectasia, distal digital tip ulceration, and digital edema. These are ndings are associated with (but not diagnostic of) systemic sclerosis (SSc) [9, 10]. When Raynaud phenomenon is present in a patient with an IIP, a chest imaging or histopathologic pattern of nonspeci c interstitial pneumonia (NSIP) [11] is often seen. Besides SSc, the presence of Raynaud should raise one’s suspicion for other underlying CTDs such as polymyositis/dermatomyositis (PM/DM), anti-synthetase syndrome, primary Sjögren syndrome, mixed connective tissue disease (MCTD), and systemic lupus ery-

thematosus (SLE). Both “mechanic’s hands” (cracking roughening of skin at the tips and sides of ngers) and Gottron sign (exanthem on the extensor surface of the digits) are associated with anti-synthetase syndrome or SScmyositis overlap [12]. As more general clinical features such as alopecia, myalgias, dry eyes, weight loss, and photosensitivity are nonspeci c, they are not included in the clinical domain, nor is the presence of joint pain alone, as it is nonspeci c. However, symmetric joint swelling, morning stiffness, or synovitis on physical examination is more speci c for an underlying CTD, and is part of the clinical domain. A patient with an IIP patient and any of these ndings should be evaluated by a rheumatologist [8].

The serology domain includes: anti-nuclear antibodies (ANA), rheumatoid factor (RF), myositis panel, and anti-­ citrullinated peptide (CCP) antibodies [13]. Importantly, ANA and RF are poor screening tests: they have low speci-city–particularly when present at low titer, and can be seen in otherwise healthy individuals [14, 15]. The IPAF criteria address this by requiring a high titer ANA and RF. An exception exists for low titer ANA if a nucleolar or centromere-­ staining pattern is present. Both of these suggest the SSc spectrum of disease [15].

The morphologic domain includes ndings from both chest imaging and lung histopathology. Thoracic high-­ resolution computed tomography (HRCT) imaging plays a central role in the evaluation of ILD by providing detailed information on the presence of abnormal features and their distribution, as well as the pattern and extent of disease. The most common chest imaging patterns seen in CTDILD are NSIP, organizing pneumonia (OP), NSIP with OP, and lymphocytic interstitial pneumonia (LIP) [16–19]. Although usual interstitial pneumonia (UIP) and diffuse alveolar damage (DAD) patterns can be seen in CTD-ILD, they are not included in the IPAF morphologic domain as their presence alone does not suggest CTD. HRCT also allows for the identi cation of extra-parenchymal abnormalities, ndings that include pleural disease, lymphadenopathy [16, 17], pleural effusions, and pericardial thickening/effusion [18].

When histopathology is available, it may also provide clues to the presence of an underlying CTD [20]. Suggestive histologic patterns include NSIP or LIP, as well as the presence of speci c pathologic features including dense perivascular collagen, extensive pleuritis, lymphoid aggregates with germinal center formation, and prominent plasmacytic in ltration [20]. Furthermore, the presence of abnormalities in multiple anatomic compartments is common. In addition to parenchymal disease, small airway, pleural, pericardial, and pulmonary vascular involvement are frequently seen [20]. The presence of any of these histologic ndings should raise the possibility of an underlying CTD.

The de nition of IPAF was an effort to establish globally accepted criteria for those patients with clinical features that lie between CTD-ILD and IIP. These criteria have not been validated and reassessment of the three domains, as enlightened by further clinical expertise and practice, is needed. As with any new criteria generated by committee, time and further experience have led to calls to update them.

Modi cations to each of the diagnostic domains have been proposed. In the clinical domain, the addition of esophageal hypomotility has been suggested [21]. In the serologic domain, concern has been raised about the inclusion of the anti-tRNA synthetase antibodies, as they are commonly seen in the setting of anti-synthetase syndrome [22–28]. In one study that followed 684 patients with anti-synthetase ­antibodies, 146 (21%) ful lled IPAF criteria [26]. Within a median follow-up of 12 months, 42% had a de nitive diagnosis of CTD suggesting IPAF as more transient in this population. Another study compared patients who met IPAF criteria with and without anti-tRNA synthetase antibodies; the former had an improved survival [28]. These two studies highlight that patients with IPAF and with anti-tRNA synthetase antibodies may have a different disease trajectories and prognoses. Additionally, in the serologic domain, the exclusion of anti-neutrophil cytoplasmic antibody (ANCA), myeloperoxidase (MPO), and proteinase-3 (PR-3) has been questioned. Patients with a brosing ILD and ANCA positivity, although rare, are regularly reported [29–31]. It is not uncommon for MPO ANCA positive patients and/or patients with microscopic polyangiitis to develop ILD [32, 33]. Within a few years of follow-up, one quarter of the patients with MPO ANCA serologies and IIP can develop vasculitis [32]. The clinical features and prognosis of PR-3 positive IIP patients appears to differ from IIP patients without these antibodies [32, 34] suggesting these patients, like those who met IPAF criteria, may bene t from further phenotyping.

In the morphologic domain, the exclusion of UIP has been questioned. IPAF with a UIP chest imaging or histologic pattern may represent a subset of patients with a uniquely poor prognosis [28, 35–37] as well as in those with leukocyte telomere length < tenth percentile [38]. Identifying IPAF with a UIP chest imaging or histologic pattern is important given its impact on prognosis and needs further study. A separate issue is the absence of a speci c de nition for the multi-compartment histopathologic involvement. Stricter de nitions may lead to more uniformity of diagnosis.

The de nition of IPAF will continue evolve, as we continue to study its longitudinal behavior, prognosis, and response to therapy.

Several studies from various countries have published on the common patterns and features seen. These characteristics are summarized on Table 15.1. Signi cant heterogeneity is seen, likely due to some combination of the inclusion criteria, referral bias, the small study size, and their retrospective study design. Overall, female predominance is common, with few studies showing a male predominance [35, 37, 39– 53]. Age at the time of diagnosis is generally in the sixth or seventh decade. There is a higher prevalence of non-­smokers. Most patients met IPAF criteria based on the serologic and morphologic domains. The most common clinical domainnding is Raynaud phenomenon, and the most common serologic domain nding is a positive ANA, with anti-SSA the next most common. The most common morphologic domain nding is the presence of an NSIP pattern on chest imaging. A UIP pattern, although not part of the criteria, was also present in a signi cant number of the patients, by both chest imaging and histology. Overall, multiple studies have demonstrated that a certain portion of patients who met IPAF criteria evolve into CTD-ILD [39, 40, 51, 54, 55]—and this highlights that in some cases, an IPAF “diagnosis” should remain provisional, and that longitudinal surveillance of evolution is a fundamental principle in the care of these patients.

Disease Progression and Prognosis

Recent studies have explored the question of whether patients who meet the IPAF criteria have outcomes more similar to well-characterized CTD-ILD or to non-IPAF IIP patients. Hernandez-Gonzalez et al. showed no difference in 1-year survival between CTD-ILD, IPAF and other forms of ILD [53]. This study also showed no signi cant differences in functional progression after 1 year as de ned by ≥10% change in FVC and/or ≥ 15% decline in DLCO. Kim and colleagues followed 109 patients who met IPAF criteria for a mean period of 45 months [37]. Compared to those with non-­IPAF IIP, patients who met IPAF criteria had a slower rate of decline in lung function and an increased propensity to develop a characterized CTD. Prognosis was comparable to CTD-ILD and better than an equivalent IIP. Those with UIP pattern, older age and lower DLCO had higher shortterm mortality [37]. Kelly et al. studied 101 patients who met IPAF criteria. Compared to IPF, patients with IPAF and a UIP chest imaging or histologic pattern had similar survival; however, those with IPAF with a pattern other than UIP had longer survival [47]. Collins et al. studied 15 patients with IPAF, 36 patients with CTD-ILD, and 53

patients with IPF as well as 124 patients who were antibody positive that did not t into one of these categories (non-IPF IIP subjects). After a year, there was no signi cant difference in FVC or DLCO between the groups [46]. Lim et al. followed 54 patients who met IPAF criteria, 175 IPF patients, and 76 patients with CTD-ILD [50]. Acute exacerbations were observed in 26% of the IPAF group, 35.4% of the IPF group, and 33% of the CTD-ILD (p < 0.001. Mean survival time was 73 months in IPAF, 104 months in CTDILD and was signi cantly worse in the IPF group as compared to both (p < 0.001) at 52 months in IPF. A multivariate analysis showed those with IPAF had a signi cantly better survival as compared to those with IPF [50].

Dai et al. recently reviewed 1429 IIP patients and found that 177 met the IPAF criteria [41]. Those who met the IPAF criteria survived longer than those with IPF (n = 235) (p < 0.001) but not as long as the non-IPAF, non-IPF cohort (n = 996) (p < 0.001). The mean survival time was 295.0 weeks in the IPAF group and 128 weeks in the IPF group [41]. Oldham et al. retrospectively studied 144 who met the IPAF criteria and were able to report on longitudinal behavior. Overall mortality was 40% during the follow-up period and 11% went on to lung transplantation [35]. There was a trend towards longer survival in patients who met IPAF criteria when compared to those with IPF (p = 0.07) but worse when patients who met IPAF were compared to those with CTD-ILD (p < 0.001). Similar to other studies, patients who met IPAF criteria with UIP on chest imaging or histologic patterns showed survival similar to IPF, while those categorized as IPAF without UIP had similar survival to CTD-ILD [35]. Sebastiani et al. prospectively enrolled 52 patients with IPAF and 104 IPF patients and followed them for 45 ± 32 months [48]. Over the follow-up period, seven patients who had previously met IPAF criteria evolved to a de nite CTD. The 5-year survival in the IPAF group was estimated to be 69.5 ± 7.8%, higher than IPF. On univariate analysis, FVC and DLCO were the only factors found to be associated with mortality [48].

Markers of prognosis have been explored in many of these trials. As noted earlier, Kelly et al. ndings suggest thending of UIP on chest imaging or histology was associated with worse prognosis [47]. In Dai’s study, univariate analysis showed age, history of tobacco use, presence of ANA ≥1:320, anti-RNP antibodies, as well as imaging ndings of OP, pleural effusion or thickening were signi cantly associated with higher mortality. On multivariate analysis, age, history of tobacco, OP on chest imaging and presence of anti-RNP antibody predicted worsened survival [41]. Chung et al. followed 136 patients who met IPAF criteria and found that a signi cant majority of patients had a UIP pattern (57.4%), which was associated with smoking, male gender and older age. An NSIP pattern was noted in a quarter of patients. On multivariate analysis, the patients who met IPAF

criteria with honeycombing and pulmonary artery enlargement on chest CT had a worse prognosis [55]. Oldham et al. noted worse prognosis on univariate analysis with older age, UIP pattern and hypothyroidism. A higher DLCO and the presence of the clinical domain were associated with better survival. IPAF that included features in the clinical domain had a signi cantly increased survival (p = 0.03) while those serological and morphological domains had worse survival. There was a signi cant risk of increased mortality especially in those with multi-compartment features. On multivariate analysis, age and DLCO were predictive of survival [35].

Ito et al. followed 98 patients who met IPAF criteria and reported a 5-year survival of 71% and a median survival of 12.5 years [40]. The 5-year survival rates were reported to be 100% in the OP pattern group, 87% in the NSIP + OP pattern group, and 59% in the NSIP pattern group. Markers of poor prognosis included NSIP pattern and SSc speci c antibodies (ANA nucleolar pattern, ANA centromere pattern, anti-­ ribonucleoprotein, and anti-Scl-70). The presence of bronchoalveolar lavage fuid with lymphocytes >15% was associated with longer survival on univariate analysis. A total of 12 patients progressed to a characterized CTD (7 RA, 2 SSc, 1 SLE, 1 Sjögren and systemic sclerosis, and 1 dermatomyositis and systemic sclerosis) [40]. In a retrospective analysis of 156 IPF, 167 CTD-ILD, and 57 patients who met IPAF criteria, there was no statistically signi cant difference in the overall survival (median duration 16 months) between the IPF and IPAF group (probability of overall survival at 1 year was 95% and 84%, respectively, p = 0.05). In the IPAF group, the presence of a UIP pattern as compared to NSIP did not impact survival [44]. In a univariate analysis, history of smoking was associated with worsened survival.

Yoshimura et al. studied 194 patients with chronic brosing interstitial pneumonia out of which 32 were categorized as meeting criteria for IPAF [45]. The overall survival and incidence of acute exacerbations were better in the those who met the IPAF criteria as compared to those who did not meet IPAF criteria. IPAF with an NSIP pattern also resulted in improved survival when compared to those with NSIP without IPAF.

Yamakawa et al. compared brotic NSIP patients who met IPAF criteria (n = 58) with non-IPAF, idiopathic brotic NSIP (n = 35), and CTD-ILD with brotic NSIP (n = 64) [52]. The median follow-up ranged from 3.8 to 6.5 years and survival was better in IPAF than for idiopathic brotic NSIP (p < 0.001) but similar to CTD-ILD (p = 0.920). The cumulative 5-year survival rate was 65% and the 10-year survival rate was 37% in the idiopathic brotic NSIP group (nonIPAF), 95.4% and 70% in IPAF group, and 88.5% and 82% in the CT-ILD group. Univariate analysis suggested a worse prognosis with male gender, older age, history of smoking, diagnosis of idiopathic brotic NSIP, dyspnea on exertion, absence of ndings in the clinical domain, lower FVC or

DLCO, and emphysema on HRCT. Bif et al. showed no signi cant 3-year mortality difference between IPAF and idiopathic NSIP [43]. More patients with IPAF required oxygen compared with patients with idiopathic NSIP (22% versus 7%, p = 0.034). Patients who met IPAF criteria with and without anti-synthetase antibodies were compared and there was no signi cant difference in 3-year survival although there was a trend towards worse survival in the IPAF group with those antibodies.

In the only prospective study to date, 45 patients who met IPAF criteria were compared to 143 IPF patients [51]. At baseline, the IPAF group had higher FVC and DLCO values. The IPF group was older, more male, with more patients on oxygen. Of the 19 patients who met IPAF criteria who were followed for at least 1 year, two developed a UIP pattern on chest imaging and one developed PM. Several patients went on to develop additional antibodies and clinical features suggestive of a CTD but never met diagnostic criteria, although the authors note that a longer period of follow-up may result in more CTD diagnoses.

Taken together, our current knowledge is clearly incomplete, and does not allow de nitive conclusions to be drawn from these cohorts. The above studies show us the variability of patients who meet IPAF criteria and this heterogeneity impacts our understanding of prognosis and longitudinal behavior. The available data do not allow de nitive conclusions regarding prognosis when comparing IPAF with IIPs or CTD-ILD, however, the subset of patients who met IPAF criteria with UIP on chest imaging or histologic pattern likely has a survival time similar to IPF. The frequency of evolution to CTD-ILD is still uncertain, but clearly occurs. The available data do not provide speci c guidance to help the practitioner predict prognosis or decide on treatment.

Management Considerations and Future

Studies

Unfortunately, there are few studies to guide therapeutic decisions in IPAF. As such, in practice, we borrow from our knowledge of therapies utilized in CTD-ILD and IIP summarized elsewhere. This section focuses on published reports speci cally in IPAF.

Cyclophosphamide (CYC) Wiertz et al. conducted a case series of 38 patients with IIP who were refractory to oral glucocorticoids, and were subsequently treated with intravenous CYC pulse therapy [56]. Of the 38 patients, 7 died during treatment, 4 had to discontinue due to drug toxicities, and 4 patients had missing data. Of the remaining patients, 13 met the criteria for IPAF and 10 had non-IPAF IIP. Before CYC, there was a mean decline of FVC of 15% in the total population and after treatment a mean increase of FVC by

3%. Compared to the patients with non-IPAF IIP, those who met IPAF criteria had more bene t with an FVC change of −12% before therapy and an improvement of +9% when evaluated after 6 months of therapy. In the IIP group, an FVC change of −18% prior to CYC therapy and −6% when evaluated 6 months after therapy.

Mycophenolate Mofetil (MMF) In a recent cohort study of 52 patients who met IPAF criteria, half received MMF and the other half did not receive MMF. After 22 months there was no difference in the FVC and DLCO between the treated and untreated group. However, in comparing the FVC and DLCO before and after MMF in the treated group, there was a trend towards a slowing of FVC and DLCO decline after treatment [54].

Anti-fbrotics Nintedanib is an intracellular tyrosine kinase inhibitor that has been shown to slow the decline in FVC and potentially prolong the time to acute exacerbation in IPF [57–60]. Nintedanib has also been shown to slow the adjusted annual rate of change in FVC in SSc-ILD, both alone and when combined with MMF [61]. The subsequent INBUILD trial studied the use of nintedanib in non-IPF progressing brotic ILDs over 52 weeks [62]. In this heterogeneous population of patients with a variety of brosing ILD who had shown clinical evidence of disease progression over the previous 24 months, despite appropriate therapy, the annual rate of decline in FVC was signi - cantly reduced in the nintedanib group when compared to placebo. Studies are underway to further understand the role of nintedanib on progressive brosing ILD [62, 63]. Pirfenidone has shown a bene t in reducing the decline in FVC in patients with IPF [64, 65]. Pooled studies of pirfenidone in IPF show a signi cant reduction in mortality risk and progression-free survival [66, 67]. Pirfenidone was also studied in a Phase 2 multi-­centered, double-blind study involving patients with progressive brosing unclassi able interstitial pneumonia randomized to oral pirfenidone (n = 127) or placebo (n = 126) for 24 weeks [68]. There were 15 patients who met IPAF criteria in the pirfenidone group and 18 in the placebo group. The primary endpoint evaluated the mean change in FVC using a home spirometer, however, variability in the values made this assessment dif cult. The median change in FVC using home spirometry after 24 weeks was −88 mL in the pirfenidone group and −157 mL in the placebo group. The placebo group was more likely to have a >10% (p = 0.011) decline in FVC than the pirfenidone group. The mean change in DLCO from baseline, mean change in 6MWD from baseline, cough and quality of life scores was also not statistically signi cant between the two groups.

Pirfenidone is also currently being evaluated in other brosing ILDs including CTD-ILD and IPAF in current trials in combination or in place of with immunosuppressants [63, 69–73].