MSA is detected in 45%-85% of adult IIM patients, most commonly anti-aminoacyl-tRNA synthetase (ARS) antibody (20%-40%), followed by anti-melanoma differentiation-associated gene 5 (MDA5) antibody (8%-20%), and others [12]. As shown in Table 1, the MSA profile correlates significantly with the phenotype of IIM: anti-MDA5, Mi2, transcriptional intermediary factor 1-γ (TIF1-γ), nuclear matrix protein-2 (NXP2), and small ubiquitin-like modifier 1 activating enzyme (SAE) antibodies are associated with the DM phenotype [1,12,13]. In particular, anti-MDA5 antibody are highly associated with the CADM phenotype, while anti-TIF1-γ and NXP2 antibodies are associated with malignancy [1,12,13]. Anti-ARS antibodies, including histidyl (Jo-1), threonyl (PL-7), alanyl (PL-12), glycyl (EJ), isoleucyl (OJ), asparaginyl (KS), phenylalanyl (Zo), tyrosyl (Ha), valyl (VRS), and cysteinyl (CRS) antibodies, are associated with an anti-synthetase syndrome (ASyS) characterized by ILD, myositis, inflammatory polyarthritis, fever, Raynaud’s phenomenon, and mechanic’s hands [1,12,13]. Anti-signal recognition particle (SRP) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies are associated with IMNM, which is characterized by predominant muscle fiber necrosis with little or no lymphocytic infiltrate [1,11-13]. Additionally, each antibody was correlated with distinct features of extramuscular manifestations, including ILD [1,12,13,15]. It is worth noting that some relationships between the MSA profiles and clinical features were significantly affected by racial differences, as discussed in the subsequent sections.

Despite the clinical significance of MSA in IIM, there is no standardized universal MSA detection assay [13]. While immunoprecipitation (IP) assays using radioisotope-labeled cell lysates have traditionally served as the gold standard for MSA detection, the complexity of this procedure has significantly restricted the number of facilities capable of performing it [7]. Several commercially available comprehensive autoantibody detection assays have been developed to overcome these disadvantages. However, no assay has been validated for its sensitivity and specificity. For example, line blotting, which can simultaneously measure multiple autoantibodies, is extensively used in clinical practice. However, its sensitivity and specificity for detecting MSA vary widely depending on the type of MSA, which often leads to false-positive or false-negative results [16]. Therefore, clinicians should consider the accuracy of these tests in various ways. Anti-nucleolar antibody (ANA) indirect immunofluorescence (IIF), which is widely used to screen for autoantibodies in the CTD, often helps to increase the reliability of MSA results when concordance between the ANA IIF staining pattern and detected MSA is observed [17]. As a caution, when analyzing ANA IIF, it is essential to examine not only the nuclear staining pattern but also the cytoplasmic staining pattern. This is because certain MSA, particularly those associated with ILD, such as anti-MDA5 and ARS antibodies, are anti-cytoplasmic antibodies [1,17]. Regarding monospecific immunoassays, commercial enzyme-linked immunosorbent assays are available for anti-TIF1-γ, Mi2, MDA5, and ARS-antibodies (only measuring Jo-1, PL-7, PL-12, EJ, and KS) with almost 100% sensitivity and specificity compared with their gold standard assay, IP [18,19].

Between 53% and 66% of individuals with ARS-ILD experience a chronic onset lasting over 3 months (>3 months), with some being asymptomatic (15%). Additionally, 18%-47% of individuals with ARS-ILD exhibit significant progression within 3 months (<3 months), termed as rapidly progressive ILD (RP-ILD) [15,25]. Regardless of presentation, they generally respond well to initial treatment with 64%-95% response rates and have a comparatively favorable prognosis, with a 5-year survival rate of approximately 90% [25,28,34-37]. However, ARS-ILD often relapses during glucocorticoid tapering, leading to a subsequent decline in lung function and fatal long-term outcome [36-38]. In two studies with a median follow-up of more than 5 years, the recurrence rate of ARS-ILD was as high as 38%-56%, with a median time from treatment initiation to the first recurrence of 2 to 3 years [36,38].

ASyS frequently manifests with distinct extrapulmonary symptoms, serving as significant indicators for suspecting ARS-ILD. These symptoms include myositis, polyarthritis, fever, Raynaud’s phenomenon, and mechanic’s hands [33]. These findings may be present inconsistently or absent altogether (33%) during the initial work-up but could develop throughout the disease [23,25,32]. Additionally, the prevalence of extrapulmonary manifestations is associated with individual anti-ARS antibodies. Myositis is one of the most common extrapulmonary manifestations, occurring in 40%-55% of cases at disease onset and rising to 50%-80% during the course of the disease. However, it is uncommon in cases with anti-PL-12 antibodies (17%-38%) and anti-KS antibodies (0%) [23,25]. Similar to that in IIM without anti-ARS antibodies, myositis in ASyS predominantly affects the symmetric proximal muscles, causing muscle weakness, muscle pain, or fatigue, with elevated serum muscle enzyme levels [1]. Polyarthritis is also a common manifestation of ASyS, with a higher prevalence in patients with Jo-1 antibody (58%-61.1%) than in those with other anti-ARS antibodies (20%-35%) [23,25]. Only 32%-40% of patients with ASyS have typical skin manifestations of DM, such as heliotrope rash, Gottron’s papules, or Gottron’s sign at diagnosis [23,33]. Thus, a significant number of ASyS, especially anti-non-Jo1 ARS-antibodies, do not meet the criteria for IIM [2,3,23]. Another characteristic cutaneous manifestation of ASyS is the mechanic’s hands, a fissure with hyperkeratotic papules and scales along the sides of the fingers. Although once considered a pathognomonic feature of ASyS, mechanic’s hands occur in only 28%-40% of patients with ASyS and can be seen in patients with other MSAs [23,33,39]. Fever and Raynaud’s phenomenon occur in 20%-45% of patients with ASyS [23,33].

MDA5-ILD often presents as a RP-ILD (69%) with a poor prognosis, whereas chronic forms of ILD are less common (7%) [15,34,35]. However, there are racial differences in MDA5-ILD, with RP-ILD as low as 18%-21% in non-Asian populations [24,40]. MDA5-ILD, especially RP-ILD, shows a poor treatment response, and approximately one-third of patients die of respiratory failure within 1 year despite intensive treatment [34,35].

Between 80% and 90% of patients with MDA5-ILD have typical cutaneous manifestations at initial presentation, allowing the diagnosis of DM, especially CADM [24,40]. In particular, patients with MDA5-ILD present unique mucocutaneous manifestations reflecting the underlying vasculopathy, which is an important clue for the early diagnosis of MDA5-ILD. Skin ulcers are the most distinctive cutaneous manifestation in patients with MDA5-antibody with a 40%-82% prevalence and are less common in IIM with other MSAs [39]. Skin ulcers are often associated with severe pain and occur at specific sites, such as the proximal interphalangeal and metacarpophalangeal joints of the fingers, elbows, shoulders, knees, ankles, digital pulp, and nail folds [39]. More importantly, the presence of skin ulcers can be a prognostic factor of MDA5-ILD [41]. Therefore, clinicians should look for skin ulcers at these predilection sites when evaluating patients with ILD, especially RP-ILD. Palmar papules, also known as the inverted Gottron’s sign, are another unique cutaneous manifestation in patients with anti-MDA5 antibodies, with a prevalence of 20%-60% [39]. They occur on the palms and palmar aspects of the fingers, with the predicted involvement of the metacarpophalangeal or interphalangeal joint creases [39]. Additionally, they are often associated with pain and ulceration. Other characteristic skin manifestations in patients with anti-MDA5 antibodies include nonscarring alopecia (78%), oral ulcers (50%), and panniculitis (20%) [39]. The mechanic’s hands were also often seen [39]. In addition to skin lesions, arthritis/arthralgia was common (72.2%) [40]. Although rare, patients with anti-MDA5 antibodies may present with ILD without skin or muscle manifestations [27].

SAE-ILD is usually a mild ILD with no or mild respiratory symptoms and responds well to treatment without relapse and progression [42]. Anti-SAE antibodies correlate well with typical DM skin manifestations, often preceding muscle involvement [31,42].

SRP-ILD is usually a mild ILD with no or mild respiratory symptoms and does not show RP-ILD [30]. SRP-ILD responds well to treatment and rarely develops into a progressive course [30]. Patients with anti-SRP antibodies present severe myopathy and elevated serum creatine kinase [11]. Approximately 40% of the patients with anti-SRP antibodies develop dysphagia, which may lead to aspiration pneumonia or may even be associated with the development of ILD [30,43].

The most common chest CT findings in ARS-ILD are ground-glass opacities (GGO) (98%-100%), followed by reticular opacities (67%-87%) and consolidations (43%-48%) [45-47]. Subpleural curved linear shadows are seen in 26%-38% [46,47]. Honeycombing is rare (3%-9%) or, if present, limited at presentation but increases or occurs in approximately one-third of patients over time [45-47]. The axial distribution of the abnormality is frequently peripherally predominant (70%-95%), often along with a peribronchovascular distribution (73%) [47]. The craniocaudal distribution is almost always lower lobe predominant, and reticular opacities with traction bronchiectasis in the lower lobes are suggestive of ARS-ILD [45,47]. According to the radiological IIPs classification [22], nonspecific interstitial pneumonia (NSIP) pattern is the most common (44%-55%), followed by NSIP+organizing pneumonia (OP) pattern (19%-34%) and OP pattern (6%-28%) (Figure 2) [21,45-47]. The usual interstitial pneumonia (UIP) pattern has also been reported (1%-4%), but this probably represents an advanced stage of NSIP or NSIP+OP pattern [44-47].

The chest CT findings of MDA5-ILD are mainly made up of GGO (83%-100%) and consolidations (58.3%-75%), while reticular opacities are less common (0%-15%) and honeycombing is extremely rare [48,49]. Nonseptal linear opacities, such as subpleural curvilinear shadows or perilobular opacities, were frequently observed (83.3%-90%) (Figure 3) [48-50]. The axial distribution of the abnormality was almost always peripheral, occasionally with peribronchovascular distribution (25%) [49]. The craniocaudal distribution is almost always lower lobe predominance [49]. Particularly, consolidation with volume loss in the lower lobes suggests RP-ILD with a poor prognosis [51,52]. However, even subtle subpleural linear opacities or GGOs at initial evaluation may rapidly progress to widespread GGOs, indicating diffuse alveolar damage (DAD) (Figure 4). According to the radiological IIPs classification [22], most cases are classified as OP or OP+NSIP patterns, which are sometimes considered unclassifiable. In contrast, minor cases are classified as NSIP patterns, and UIP patterns are extremely rare in the Japanese cohort [49,50]. In a recent cluster analysis that divided IIM-ILD into three clusters based on CT findings, more subpleural consolidation, fewer reticular opacities, and no honeycombing were considered characteristic features in a cluster composed mainly of MDA5-ILD [44]. Thus, these CT features help to differentiate MDA5-ILD from other IIM-ILD subtypes, although there is considerable overlap. Of note, a recent study of non-Asian patients with MDA5-ILD showed that the NSIP pattern was the most common (51%) and the UIP pattern was present in 13%, suggesting that, as in clinical features, there may be substantial racial differences in the CT findings of MDA5-ILD [24].

SAE-ILD shows limited subpleural GGO predominantly in the bilateral basal lungs, which is compatible with NSIP pattern [53]. SRP-ILD showed GGO (37%), reticulation (63%), and consolidation (33.3%), with lower lobe and peribrochovascular predominance [30]. Traction bronchiectasis (7.4%) and cysts (3.7%) were less common [30]. According to the radiological IIPs classification [22], the NSIP pattern was the most common (37%), followed by the OP pattern (33%) [30].

When treating IIM-ILD, it is essential to initially consider the manner of onset of ILD. As mentioned above, IIM-ILD can present with RP-ILD, a majority of which corresponds to MDA5-RP-ILD with a poor prognosis. Several recommendations have suggested triple combination therapy, including high-dose corticosteroids, calcineurin inhibitors, and intravenous cyclophosphamide for MDA5-RP-ILD [6,60-62]. Given the potential superiority of initial triple combination therapy over a stepwise approach in treating MDA5-RP-ILD, early diagnosis and initiation of triple combination therapy are desirable to improve the prognosis of MDA5-RP-ILD [64]. In contrast, triple combination therapy may result in overtreatment for certain patients, particularly those with MDA-5-negative RP-ILD, as it raises the risk of opportunistic infections [64]. Therefore, early detection of anti-MDA5 antibodies in patients with RP-ILD is critical. However, as the measurement of anti-MDA5 antibodies typically takes several days or weeks, in the case of fulminant ILD, we should speculate on the presence of anti-MDA5 antibodies from the aforementioned characteristic skin manifestations, such as skin ulcers, CADM presentation, and/or CT findings. However, given that minor patients with MDA5-ILD show a lung-dominant presentation, the possibility of MDA5-ILD should not be ruled out even in the absence of overt skin or muscle manifestations [24,27]. Despite the intensive treatments, a significant number of patients with MDA5-RP-ILD show progression with a fatal outcome. In refractory cases, the potential use of tofacitinib, rituximab, and plasma exchange as rescue therapies has been suggested [65-67]. Previous studies have identified predictive factors for poor prognosis in patients with MDA5-ILD. They include older age, higher C-reactive protein and ferritin levels, low oxygenation, higher serum titer of the anti-MDA5 antibody, and the coexistence of anti-Ro52 antibody [68-70]. Higher serum levels of Krebs von den Lungen-6, a useful biomarker reflecting disease activity in various ILDs, have also been reported to be associated with a poor prognosis in MDA5-ILD [68]. Therefore, clinicians should consider early initiation of rescue therapy in addition to triple combination therapy in patients with these risk factors. Conversely, patients with MDA5-ILD without these poor prognostic factors might be treated with corticosteroids and single immunosuppressive agent [71]. MDA5-negative RP-ILD, predominantly comprising ARS-ILD cases, typically show favorable responses to corticosteroids combined with immunosuppressants [34,35]. Nonetheless, due to the potential for fatal outcomes associated with MDA5-negative RP-ILD, additional immunosuppressive medications should be considered for cases of progressive ILD despite initial treatment, regardless of the presence or absence of anti-MDA5 antibodies [6,35]. Following the acute phase, the maintenance therapy for RP-ILD mirrors that of the chronic form of ILD, as elaborated below.

For patients with the chronic IIM-ILD, clinicians should aim to improve prognosis not only in the short term, but also in the long term. Although there is no consensus regarding the initiation of therapy, treatment initiation is determined based on a comprehensive assessment of the severity and progression of the patient’s symptoms, radiographic findings, and/or lung function impairment, as well as the patient’s age and comorbidities. Some patients with chronic ILD have a stable course without progression and can be managed with caution, adopting a watch-and-wait approach [6].

Similar to RP-ILD, the MSA profile is a useful guide for an appropriate treatment strategy in the chronic form of IIM-ILD. In ARS-ILD, initial combination therapy with corticosteroids and a single immunosuppressant is recommended to prevent relapse and subsequent decline in lung function [6,36,38]. If there is no relapse, a dose reduction of corticosteroids and immunosuppressants should be considered to minimize side effects. Notably, a recent study suggested an association between obesity and relapse in patients with ARS-ILD, likely due to the influence of adipokines and cytokines released from the adipose tissue [72]. As corticosteroids may induce obesity, weight control may be important in ARS-ILD to prevent recurrence. Despite careful management, many patients experience recurrence of ILD. If recurrence occurs, clinicians should consider redosing the current treatment, switching, or adding other immunosuppressants (tacrolimus, cyclosporine A, azathioprine, cyclophosphamide, mycophenolate mofetil, and rituximab) or intravenous immunoglobulin. However, the current evidence of their usefulness is limited [73-75]. In addition to pharmacotherapy, supplemental oxygen therapy and pulmonary rehabilitation are recommended. Lung transplantation should be considered in patients who develop severe lung impairment despite treatment.

Chronic IIM-ILD without anti-ARS antibodies is less likely to recur than ARS-ILD [38]. Therefore, corticosteroid monotherapy may be permitted in patients with chronic IIM-ILD without anti-ARS antibodies [6]. Notably, a significant number of patients with MDA5-ILD, especially non-Asian patients, have a chronic form of ILD [24,40]. In French cohorts, clusters composed mainly of chronic MDA5-ILD showed good long-term prognosis [40]. In addition, another large study that included 76 patients with chronic MDA5-ILD showed that only one patient died from ILD progression, although most patients received immunosuppressants during the follow-up [24]. While no study has specifically explored the recurrence rate and detailed clinical course of the chronic form of MDA5-ILD, it’s plausible that recurrence and progression of ILD may be less frequent in patients with chronic MDA5-ILD. The management approach for recurrence and progression of ILD in non-ARS chronic IIM-ILD remains consistent with that for ARS-ILD.

Given the current evidence supporting the efficacy of antifibrotic agents across a broad spectrum of ILDs, their use is appealing for patients with chronic progressive ILD [76]. However, the INBUILD trial, which evaluated the efficacy and safety of nintedanib in various ILDs with progressive phenotypes, included only two patients with ARS-ILD and one with PM-related ILD, resulting in weaker evidence for antifibrotic therapy in IIM-ILD than in other ILDs [77]. Although other studies demonstrating the efficacy in chronic progressive IIM-ILD are also lacking, interestingly, recent retrospective studies have demonstrated the potential efficacy of antifibrotic therapy for RP-ILD in patients with IIM along with its tolerability [78,79]. As mentioned above, although the efficacy of antifibrotic agents in IIM-ILD is under investigation, a recent guideline recommends antifibrotic agents for patients with progression of ILD on initial therapy, considering the pace of progression and the amount or pattern of fibrotic change on CT [63].