Idiopathic inflammatory myopathies include clinical subtypes represented by dermatomyositis (DM), polymyositis (PM), immune necrotizing myositis, antisynthetase syndrome (ASSD), and inclusion-body myopathy. This is a spectrum of chronic inflammatory and autoimmune conditions characterized by variable clinical and immunological features (1), such as the prominent skin involvement or the vasculitis in DM (2), the coexistence of Raynaud phenomenon, arthritis, muscle damage, and interstitial lung disease (ILD) in ASSD (3), features that are generally absent in the immune necrotizing or inclusion-body myopathies (4, 5). Whether patients diagnosed with PM should be regarded as a separate group or rather included in the others remains a topic for debate (6).

There have been reports of a growing number of myositis-specific (MSA) and myositis-associated (MAA) autoantibodies in different conditions to predict organ involvement and comorbidities. While MSA are found almost uniquely in patients with idiopathic inflammatory myopathies, MAA are also observed in other connective tissue diseases such as systemic sclerosis, systemic lupus erythematosus, or Sjögren’s syndrome (7). Based on their specific nature and the observation that their coexistence is virtually exceptional, MSA have been proposed to become major determinants for the taxonomy of idiopathic inflammatory myopathies (8) and different specificities can help stratifying patients into groups with homogenous phenotypes (6, 9). As an example, DM with positive anti-Mi-2 antibodies is associated with severe muscle involvement (10), whereas anti-MDA5 antibodies positivity is associated with clinically amyopathic DM, peculiar skin features, and rapidly-progressive ILD (11).

While idiopathic inflammatory myopathies represent less than 5% cases of ILD observed by pulmonologists (12), the prevalence of ILD has been estimated as 40% in idiopathic inflammatory myopathies, reaching highest prevalence rates in ASSD and in clinically amyopathic DM (13, 14) where it is associated with significant morbidity and mortality (15, 16). As we are going to describe in the present review, the risk of developing ILD, its phenotype and progression vary significantly in different idiopathic inflammatory myopathies (17) and an adequate identification of MSA and MAA is expected to predict ILD onset and outcome.

The concept of progressive pulmonary fibrosis (PPF) has been introduced to indicate every fibrosing ILD other than idiopathic pulmonary fibrosis which demonstrates clinical and/or radiological and/or functional signs of progression with no primitive explanation (18). It has been estimated that up to 40% of ILD cases other than idiopathic pulmonary fibrosis evolve into a PPF phenotype (19). While the incidence of progressive fibrosis in patients with idiopathic inflammatory myopathy-ILD remains unclear (20), there are reports suggesting that a considerable proportion of subjects may evolve to PPF during the disease course in the presence of established risk factors (15, 21) such as older age, extensive fibrosis at high-resolution computed tomography (HRCT) (i.e., traction bronchiectasis, usual interstitial pneumonia – UIP pattern), progression or non-stabilization with initial therapy, and short telomere syndromes (22). Fibrotic HRCT pattern at baseline, diabetes mellitus and steroid-use have been identified as risk factors for PPF in patients with connective tissue disease-ILD (23). Short disease course, African American ethnicity, and gastro-esophageal reflux are considered specific risk factors for PPF in patients with systemic sclerosis-ILD, whereas the smoking status is associated with PPF in rheumatoid arthritis-associated ILD, and the extension of lung involvement at HRCT is a risk factor in both systemic sclerosis-ILD and rheumatoid arthritis-ILD (22). The results of the SENSCIS and INBUILD trials have shown that nintedanib is an antifibrotic treatment that leads to significant reduction in forced vital capacity 1-year decline in patients with systemic sclerosis-ILD and progressive fibrosing ILD (24, 25).

Older age, reduced forced vital capacity, ground-glass opacities, acute and subacute onset, and extent of abnormalities at HRCT represent unfavorable prognostic factors for idiopathic inflammatory myopathy-associated ILD in a meta-analysis by Kamiya and Colleagues; in the same report, anti-Jo-1 antibody was associated with favorable outcomes (26) but the authors admitted the low quality of supporting data. When considering only ASSD, features such as signs of fibrosis at HRCT, smoking status, and lung damage biomarkers (such as surfactant protein D) have been associated with worse outcomes (21, 27). However, these studies evaluated the prognosis of idiopathic inflammatory myopathy-ILD without distinguishing specific clinical, functional, and radiological trajectories. Taken altogether, the lines of evidence demonstrate no established risk factors for PPF in patients with idiopathic inflammatory myopathy-ILD, and the proportion of these patients undergoing PPF remains largely unknown.

Myositis autoantibodies are ideal candidates for precision medicine, being associated with clinical features and prognosis with one of the highest degrees of specificity among serum autoantibodies, as also demonstrated in ILD patients (28). Table 1 summarizes the major elements of the association between myositis autoantibodies and ILD (11, 28–50). Chronic, insidious, non-specific interstitial pneumonia (NSIP) with extensive ground glass opacity is the most common manifestation of ILD in patients with ASSD (29), especially when combined with organizing pneumonia; however, a UIP pattern can be observed in up to 10% cases and is associated with PPF (3, 30). The risk of ILD in patients with ASSD is highest with anti-PL-7, anti-PL-12, and anti-EJ antibodies (31). However, ILD is the leading cause of mortality in ASSD, independent of the serologic status (28), as for the anti-MDA5 syndrome characterized by aggressive, rapidly evolving ILD as recently confirmed (11, 50). Organizing pneumonia pattern with extensive, bilateral and consolidations at HRCT are typical of this subset, whereas signs of fibrosis are poorly represented (32), and pulmonary histology can show features of diffuse alveolar damage (33). Additional MSA are less frequently associated with the ILD onset, as in the case of anti-TIF1-gamma antibodies, which may be detected when malignancy coexists (34). A reduced risk of ILD has been reported with anti-NXP2 antibodies (28), but recent evidence has shown some inconsistency with this hypothesis (35). Indeed, a significant prevalence of NSIP and organizing pneumonia was reported in a cohort of anti-NXP2 positive patients, even if ILD tended to be clinically indolent (35). Anti-Mi-2 positivity is associated with a lower incidence of ILD, with good response to immunosuppressants, and favorable outcomes when compared to other forms of idiopathic inflammatory myopathies (36). The spectrum of immune-mediated necrotizing myopathies has been traditionally considered at low risk for extra-muscular manifestations, especially in anti-HMGCR positive cases associated with statin exposure (37). Nonetheless, recent data have suggested a significant prevalence of NSIP in patients with anti-SRP myositis, showing good treatment response and clinical stability throughout disease course (38). Antibodies directed at the nucleolar antigens PM/Scl-75 and PM/Scl-100 are frequently associated with late-onset, chronic NSIP in patients with PM/systemic sclerosis overlap (28, 39), and cases of isolated ILD have been reported in patients testing positive for such specificities (39). Anti-PM/Scl antibodies are found more often in patients with favorable outcomes (40), and no difference in survival was observed in a cohort of patients with anti-PM/Scl syndrome, irrespective of ILD (41). The PM/Scl-75 component is more frequently detected than the PM/Scl-100 (42) autoantigen, reported more frequently in association with a more active, inflammatory phenotype of myositis and ILD (39). Further evidence is required to demonstrate whether antibodies directed toward the two subunits are associated with different disease manifestations and might benefit from different therapies. Anti-Ku autoantibodies are rarely detected in patients with connective tissue diseases, and they can be associated with various clinical manifestations (43), including ILD especially when associated with myopathy (44) and in the absence of other detectable autoantibodies (45). While rare, the anti-Ku antibody is of outstanding importance when managing idiopathic inflammatory myopathy-ILD, since cases of resistance to corticosteroids and immunosuppressants have been reported (46).

Anti-Ro52 antibodies still represent one of the most common autoantibodies in patients with connective tissue diseases (51, 52), with high prevalence of ILD with unfavorable outcomes (47–49). In particular cases, the coexistence of anti-Ro52 and anti-MDA5 antibodies has been associated with aggressive and rapidly progressive ILD in anti-MDA5 syndrome (53, 54) but there are conflicting data on the prognostic role of anti-Ro52 antibodies when associated with other MSA (55, 56). Of note, signs of lung fibrosis at HRCT were described in patients with ILD in mixed connective tissue disease and anti-Ro52 positivity (57), while lower prevalence of fibrosing ILD was found in a cohort of anti-Ro52 positive subjects with Sjogren’s syndrome compared to Ro52-negative patients (58). Remarkably, no autoantibody is currently able to predict PPF development in patients with idiopathic inflammatory myopathy-ILD. Given their prevalence and current clinical significance, elucidating the role of anti-Ro52 antibodies in this sense represents a major clinical unmet need.

We retrospectively analyzed a cohort of patients with idiopathic inflammatory myopathies, and described the main demographic, clinical, and serological features, focusing on the anti-Ro52 status. We also analyzed on patients with idiopathic inflammatory myopathy-ILD, comparing clinical, functional, radiological (HRCT), and serological characteristics. Serum immunoprecipiation for MSA/MAA was performed according to established methods (72) while anti-Ro52 antibodies were tested by ELISA.

Supplementary Table 1 illustrates the characteristics of the cohort of 55 patients with a diagnosis of idiopathic inflammatory myopathy included in the study. ANA at titer ≥1:160 were detected in 42/55 (76%) patients, and anti-Ro52 ELISA tested positive in 14/55 (25%) sera. Median ages at diagnosis were 52.5 years (range 38.5–60.5 years) in the anti-Ro52 negative group, and 48.5 years (range 45–62 years) in the anti-Ro52 positive group. No significant differences in the gender ratio, prevalence of malignancy and coexisting autoimmune disorders were observed between the two groups. ILD was significantly more prevalent in the anti-Ro52 positive group (79%) than in the anti-Ro52-negative group (37%; p = 0.007), while no difference was observed for other clinical manifestations such as myositis, skin rash, Raynaud phenomenon, arthritis, dysphagia, and cardiomyopathy. As for autoimmune serological results, antisynthetase antibodies occurred much more frequently in the Ro52-positive group, but no significant differences were reported for anti-MDA5, anti-PM/Scl, and other MSA/MAA status between the two groups.

Table 2 summarizes the main features of patients with idiopathic inflammatory myopathy-ILD based on their anti-Ro52 status. The Ro52-positive group was younger (median age 49 versus 55 years in Ro52-negative subjects), but no significant differences were retrieved in terms of demographic and clinical features (including baseline creatine kinase values), except for a predominance of Raynaud phenomenon in the Ro52-negative group. The two groups did not differ in terms of pulmonary function tests, as baseline values of forced vital capacity and diffusing capacity for carbon monoxide were similar and the proportion of patients with worsening pulmonary function was comparable. Imaging findings from baseline HRCT were analyzed for the detection of ground glass opacities, consolidations, and signs of fibrosis (defined as the presence of subpleural reticulation, traction bronchiectasis, and/or honeycombing) (18), and no differences were observed in terms of consolidations between the two groups. Remarkably, ground glass opacity was significantly more frequent in patients testing negative for anti-Ro52 antibodies and signs of fibrosis were more prevalent in patients with anti-Ro52 positivity (82%) than in negative subjects (30%, p = 0.0189). As for serological results, a higher prevalence of antisynthetase antibodies was confirmed in the Ro52-positive group, also when considering the ILD subgroup, while no differences were found for ANA, anti-MDA5, anti-PM/Scl, and other MSA/MAA.

It is crucial to screen for idiopathic inflammatory myopathies in patients with ILD and a cluster of myositis autoantibodies is significantly associated with ILD onset in these patients. Currently, there is no established risk factor for PPF in patients with idiopathic inflammatory myopathy, and serum autoantibodies are ideal candidates in this sense. We report and discuss the implications of the association between anti-Ro52 antibodies and lung fibrosis in a cohort of patients with idiopathic inflammatory myopathies, and we speculate that anti-Ro52 may represent a risk factor for PPF in these patients. Data from larger cohorts and longer follow-up periods are required to corroborate this hypothesis. Other myositis autoantibodies should be also tested.

The data that support the findings of this study are available from the corresponding author, CS, upon reasonable request.

The studies involving human participants were reviewed and approved by Humanitas Research Hospital. The patients/participants provided their written informed consent to participate in this study.

All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

This work was partially supported by “Ricerca Corrente” funding from Italian Ministry of Health to IRCCS Humanitas Research Hospital.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The reviewer GDL declared a past co-authorship with the author(s) MDS to the handling editor.

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