Introduction

The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of immune-mediated conditions that affect the muscles and various other target organs including the skin, lung, and joints. The manifestations are varied but inflammation of the target organs leading to organ dysfunction is seen. On the basis of differences in clinical presentation, histopathology, serology, and response to treatment, four distinct subgroups are generally recognized: dermatomyositis (DM), polymyositis (PM), immune-mediated necrotizing myopathy (IMNM), and sporadic inclusion body myositis (IBM) [1].

Dermatomyositis is characterized by microvascular injury affecting both the skin and muscle, resulting in the development of proximal muscle weakness and a polymorphous rash [1]. It can manifest with a skin rash and muscle weakness, skin rash alone (amyopathic), or only muscle weakness (DM sine dermatitis). Organ involvement can span the setting of mild skin disease to severe cases of profound weakness, lung disease, and calcinosis.

Diagnosing dermatomyositis

Patients can be categorized as DM on the basis of clinical presentation and presence of a rash, muscle or skin biopsy findings, and/or serology. The diagnostic criteria proposed by Bohan and Peter remain the most widely used to date [2, 3]. However, in this classification scheme published in 1975, only two forms of IIMs were recognized—PM and DM. Criteria used to define PM and DM included the presence of symmetrical proximal muscle weakness, muscle histopathology showing evidence of inflammation, elevation of serum muscle enzymes, electromyographic changes of an irritable myopathy, and characteristic dermatologic changes in DM. The point of differentiation for these two entities was the presence of a rash, leading to a diagnosis of DM. Muscle biopsy findings were not used to differentiate between the two groups.

With further understanding of these diseases and better characterization of histopathology, distinct differences on muscle biopsy were noted between PM and DM and also led to the recognition of two other distinct groups, IBM and IMNM [4]. In patients with DM, inflammatory infiltrates are mainly composed of CD4+ T cells, macrophages, and B cells and are found in the perimysium and perivascular areas. Perifascicular muscle fiber atrophy as well as deposition of the C5b-9 complement membrane attack complex (MAC) on small blood vessels is also seen and noted to be characteristic [5]. Therefore, by the European Neuromuscular Centre (ENMC) 2003 criteria, a diagnosis of definite DM was proposed as the fulfillment of all clinical criteria (subacute onset of weakness, proximal > distal/neck flexor > neck extensor weakness, presence of typical rashes of DM) with muscle biopsy findings which included the presence of perifascicular atrophy [4]. Probable DM could be diagnosed when all clinical criteria were seen, with other muscle biopsy features or alternative laboratory criteria. Laboratory criteria included elevated muscle enzymes, compatible EMG changes, MRI findings of muscle edema, or the presence of myositis-specific antibodies. Muscle biopsy changes for this category included that of MAC deposition on small blood vessels, MHC-class I expression on perifascicular fibers, or perivascular/perimysial inflammatory cell infiltrates. As pathognomonic features on muscle biopsy were noted for DM, the ENMC criteria also made provision for cases of dermatomyositis sine dermatitis where a typical rash was not seen but muscle changes were noted. It also allowed for the distinction of amyopathic dermatomyositis where skin changes were noted, but without discernable muscle involvement.

The discovery of several myositis-specific and myositis-associated antibodies (MAA) has been an important advancement in the study of IIMs, where autoimmunity plays a key role. Myositis-specific autoantibodies occur in approximately 70% of DM patients and are remarkably specific for DM and IMNM while myositis-associated autoantibodies (MAA) are generally detected in overlap syndromes (OS) and other connective tissue diseases (Table 1) [6, 7•, 8, 9]. These MSAs and MAAs target diverse intracellular components. In dermatomyositis, the MSAs have been found to be tightly linked to specific phenotypes which can be very useful in aiding diagnosis, treatment, and prognosis [7•, 10••, 11]. Although most of the widely accepted classification criteria for myositis do not specifically incorporate antibody data, it is clear that the presence of these antibodies is very useful to create more homogenous patient subgroups within DM and the rest of the IIMs. Further, while the MSAs can coexist, they are usually mutually exclusive, allowing for even better delineation of clinical phenotypes [12, 13].

Table 1 Dermatomyositis-specific and myositis-associated autoantibodies
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Therefore, when considering DM, we see an evolution of diagnostic criteria initially based on clinical presentation and the demonstration of a rash, to a heavy reliance on histopathology, to the current era where antibody testing is not only diagnostic, but also useful to define the disease syndrome (Table 1).

Treatment

Dermatomyositis-specific autoantibodies and clinical phenotypes

Anti-Mi-2

The anti-Mi-2 antibody targeting DNA helicase was first detected in 1984 [14]. Phenotypically, it is associated with the development of the classic cutaneous features of DM. Patients can present with the heliotrope rash, Gottron’s papules (Fig. 1), V-sign (Fig. 2), arm erythema (Fig. 3), shawl sign, photosensitive poikiloderma, and periungual and cuticular overgrowth (Fig. 1). Additional cutaneous manifestations recently described include facial dermatosis and flagellate erythema [15•]. The pattern of muscle involvement follows the typical DM distribution with proximal muscle weakness and notably elevated muscle enzymes. There is usually sparing of the lung and joints and a remarkable response to steroids, resulting in a good overall prognosis with a 5-year survival rate of > 90% [16]. On muscle histopathology, anti-Mi-2 patients have been reported to have more primary inflammation compared to those with other DM-specific antibodies [17]. In terms of cancer risk, anti-Mi-2 is not typically associated with a paraneoplastic syndrome; however, a European cohort reported an elevated malignancy risk, but only in anti-Mi-2 Ab-positive patients possessing the N-terminal fragment of the Mi-2 antigen [18,19,20].

Fig. 1
figure 1

Multiple erythematous to pinkish, slightly hyperkeratotic papules on the skin overlying the distal interphalangeal and proximal interphalangeal joints on the hand known as “Gottron’s papules” associated with periungual erythema and cuticular overgrowth.

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Fig. 2
figure 2

Deep red, coalescent macules, and patches on the neck and chest, known as the “V-sign”.

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Fig. 3
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Erythematous to violaceous patches spanning the lateral aspect of the upper extremity.

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Anti-p140 or anti-NXP-2

First described in juvenile DM in 1997, anti-NXP-2 autoantibodies target a protein involved in various nuclear processes known as nuclear matrix protein 2. As with other MSAs, there has been significant ethnogeographic variation in prevalence, ranging from < 2% in a Japanese cohort to > 15% in their Italian counterparts [21, 22]. In juvenile DM, a more severe phenotype has been described which includes severe weakness, muscle atrophy, polyarthritis, contractures, and intestinal vasculitis [23, 24]. Calcinosis cutis is a feature of both the juvenile and adult form [22,23,24,25,26]. In adults, more severe systemic disease can be seen with myalgia and dysphagia but relatively milder skin disease [27]. Distal weakness as well as subcutaneous edema has also been described [28]. In contrast to anti-Mi-2 antibodies, biopsy of affected muscle of patients with anti-NXP-2 has shown less primary inflammation than those without the antibody [17]. The relationship with malignancy is conflicting using different cohorts, but possible malignancy has been described only in adults [22,23,24,25,26, 29]. In a study of patients at our institution, we noted a 3.68-fold increased risk of malignancy compared to the general population.

Anti-MDA5 or anti-CADM-140

The anti-clinically amyopathic DM (CADM) 140 antibody was noted by Sato et al. in 2005 to be expressed in over half of Japanese patients with amyopathic DM but none in classic DM or PM [30]. It targets a type of RNA helicase integral to the innate immune system response to RNA viruses called the melanoma differentiation-associated gene 5 protein. Clinically, it is associated with skin-limited disease, minimal muscle involvement, and varying severities of interstitial lung disease (ILD). The cutaneous manifestations transcend those of classic DM and include characteristic skin ulcerations (Fig. 4), palmar papules, and diffuse hair thinning [15•, 31]. Asian patients appear to express anti-CADM-140 at a higher frequency and are particularly prone to the rapidly progressive form of ILD (RPILD), a finding that was not duplicated in earlier studies on Europeans and Americans [32]. However, a recent study on a cohort in the USA showed equal frequency of anti-MDA5 in both CADM and classic DM. This suggests not only that the occurrence of either CADM or classic DM in patients with anti-MDA5 may vary among ethnic groups, but also that in certain populations, anti-MDA5 may not be specific to CADM, but rather to ILD and RPILD [33]. Compared to classic DM, patients with MDA5-positive CADM have a relatively lower risk of associated malignancy [29, 30, 34].

Fig. 4
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Distinct ulcers surrounding and overlying Gottron’s papules characteristic of MDA5-associated DM.

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Anti-p155/140 or anti-TIF1 antibodies

Initially discovered in 2006, anti-TIF1 antibodies were found to target nuclear transcription factors in the human transcriptional intermediatory factor family [35]. Across various ethnogeographic subsets, anti-p155/140 or anti-TIF1 antibodies have been strongly linked to malignancy in DM and have been found in up to 100% of adult patients with cancer-associated myositis in several cohorts [35,36,37]. In juvenile DM, however, it phenotypically manifests as calcinosis [38]. While it carries a reduced risk of ILD, the skin manifestations are typically severe and present as diffuse photoerythema and facial dermatitis often described as a “dusky red” face [15•, 31]. Muscle involvement occurs in the majority of patients. In a report by Fujimoto on Japanese patients, 68% had classic DM while the rest had clinically amyopathic DM [28]. On biopsies of affected muscle, patients who were TIF1-positive appeared to have more mitochondrial dysfunction than their TIF1-negative counterparts [17]. The lung is relatively spared, with only 4% developing ILD in a Japanese cohort [28, 39].

Anti-SAE

Discovered in the sera of DM patients in 2007, anti-SAE antibodies seek out the small ubiquitin-like modifier (SUMO)-activating enzyme involved in post-translational modification [40]. Clinically, anti-SAE positivity has been linked to a CADM-like phenotype featuring prominent cutaneous disease that can precede onset of myositis [7•, 12]. While dysphagia and other systemic features are typical, a high prevalence of ILD was found to be unique to Asian patients only [7•, 12, 41]. The risk of cancer is not clearly established and has ranged from 0 to 57% in various cohorts [40,41,42,43,44,45]. Overall, the prognosis of patients with anti-SAE positivity is considered good [44].

Anti-synthethase antibodies

First discovered in the 1980s, the anti-synthetase antibodies form a group of autoantibodies that target various forms of the aminoacyl-tRNA synthetase enzyme. Clinically, they can present as either dermatomyositis or polymyositis and are therefore not DM-specific but constitute a discrete subgroup. They occur in varying frequencies (approximately 20% for anti-Jo-1 and < 5% for all the rest) and are likewise associated with the development of distinct phenotypes collectively referred to as the anti-synthetase syndrome (ASyS) [37, 46, 47]. In general, ASyS is characterized by the classic triad of myositis, ILD, and polyarthritis occurring alongside other findings such as mechanic’s hands, Raynaud’s phenomenon, or fever [48,49,50]. The classic triad is eventually noted in the majority of ASyS patients especially those expressing anti-Jo-1 positivity but the component symptoms may initially manifest at different points in time [51]. The presence of anti-Jo-1 antibodies, which are detected most frequently in ASyS, portend more severe muscle involvement, whereas anti-PL-7 and anti-PL-12 denote more severe interstitial lung disease as well as increased frequency of gastroesophageal reflux [48, 50, 52]. Incidentally, the Black race has been reported to be an independent predictor of severity of pulmonary involvement [50].

Myositis-associated autoantibodies

DM and PM can occur together with various autoimmune and connective tissue diseases such as systemic sclerosis (SSc), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjogren’s syndrome, or mixed connective tissue disease. These overlap syndromes are also characterized by the presence of autoantibodies, namely, anti-Ro/SSA, anti-PM/Scl, anti-Ku, and anti-U1-RNP that also have considerable diagnostic and prognostic value. The most common OS involving myositis is PM-Scl, also known as scleromyositis, which makes up 40% of myositis-related overlap syndromes [53].

Anti-Ro/SSA (Anti-Ro52 in particular) is frequently seen in patients with anti-Jo-1-positive ASyS and is associated with earlier onset of arthritis, mechanic’s hands, and similarly appearing, hyperkeratotic, fissured lesions on the feet dubbed “Hiker’s feet” [50, 54, 55]. It has also been linked to more severe myositis and arthritis with worse prognosis [56]. Several studies showed that anti-Ro positivity in the context of ASyS was associated with a higher risk of malignancy whereas others did not yield similar findings [50, 56, 57].

Anti-PM/Scl, also referred to as anti-exosome, is seen in up to 40% of patients with scleromyositis but can also occur in isolated SSc, DM, or PM. It clinically manifests as myositis, arthritis, and Raynaud’s phenomenon with or without concomitant esophageal dysmotility, ILD, pulmonary hypertension, or renal dysfunction [58]. It can mimic the anti-synthetase syndrome. Some reports have found an association with mechanic’s hands and plantar hyperkeratosis [59, 60]. In general, anti-PM/Scl antibodies portend a good prognosis in that skin involvement tends to be limited and responsive to steroids [61].

Anti-Ku antibodies directed against the subunit of a protein kinase involved in DNA repair and recombination were first detected in the sera of Japanese patients with scleromyositis in the 1980s and have been linked to a wide array of clinical findings including arthralgias, myositis, Raynaud’s phenomenon, skin thickening, GERD, and even primary pulmonary hypertension [62,63,64]. As with other autoantibodies, significant differences have been noted across ethnogeographic groups not just in terms of presentation but also with regard to prevalence and disease associations [63,64,65,66].

Anti-U1-RNP occurs in high titers in mixed connective tissue disease but can also be seen in lower titers in SLE and SSc. It has been reported to occur with anti-Jo-1 in severe forms of myositis and with anti-CCP in erosive arthritis [67, 68].

Serologic testing for autoantibodies

Although knowledge of antibody status is very useful for myositis, clinical testing is not as widely available, with a variety of methodologies leading to issues of standardization and validation. Immunoprecipitation (IP) or double immunodiffusion (DID) assays have historically been used to detect autoantibodies in the sera of myositis patients; however, they are cumbersome to perform and are not widely available [69]. To fill the need for improved access to testing by clinicians and researchers alike, commercial kits utilizing enzyme-linked immunosorbent assays (ELISA) or immunoblot assays have been developed and show good performance [32, 37, 70, 71•]. The advent of these high-precision commercial kits that allow for more accessible testing will further enhance the clinical utility of autoantibodies in evaluating DM and other IIMs.

Whether or not MSA and/or MAA titers can be used to monitor disease activity or progression remains to be fully investigated. Two recent studies revealed a correlation between anti-Jo-1 titers and various measures of myositis disease activity including creatinine kinase (CK) levels, while two others found that levels of anti-CADM-140 were either significantly lower or virtually undetectable in patients who were considered treatment-responsive or in clinical remission [30, 72,73,74]. Additionally, anti-TIF1-γ and anti-Mi-2 titers were also shown to correlate with improvement in myositis disease activity indices [74]. Thus, the possibility that certain autoantibodies can serve as biomarkers for monitoring disease activity and treatment response further expands its clinical utility in the management of IIMs.

Caveats to the clinical utility of autoantibodies in DM and other IIMs

Since the first myositis-specific autoantibodies were discovered in the 1980s, there has been a surge in interest in elucidating their prevalence and disease associations. Cohort studies of different sizes involving subjects of varying ethnicities from a wide range of countries have contributed meaningfully to the wealth of information that is now available. As was evident throughout this review, the findings are not always consistent and may even vary considerably across populations. Whether this is attributed to (1) inherent immunogenetic differences partly determined by race, (2) degree or nature of exposure to different exogenous (e.g., viral or ultraviolet [UV]) stimuli depending on geographic location, or (3) non-standardized methods of measuring antibodies and the lack of a uniform set of cut-offs is still uncertain [47]. However, as more and more studies are performed and as testing becomes more accessible, it is reasonable to expect that more definitive trends and patterns will become apparent.

It is also important to keep in mind that other factors independent of autoantibody profile can influence the severity and specific symptomatology of the different DM and IIM subsets. For instance, a recent cohort study in the USA that looked at both Black and Caucasian patients found that the Black race was an independent predictor of interstitial lung disease severity in anti-synthetase syndrome (ASyS) that was unrelated to increased anti-PL-12 expression in Black patients. Further, while amyopathic DM has been traditionally ascribed to the presence of anti-CADM-140 antibodies based on large studies on Asian populations, results gleaned from a US-based cohort found anti-CADM positivity to occur just as frequently in patients with classic DM as those with CADM [33, 75, 76]. Thus, while there may be a mechanistic link between race and autoantibody expression, other racially determined immunogenetic factors independent of autoantibody status may contribute to the observed phenotypic differences.

Finally, the exact nature of the relationship between expression of these autoantibodies and their disease associations remains unclear. Whether or not they play a direct role in pathogenesis or merely represent an epiphenomenon is yet to be elucidated [7•, 77,78,79,80]. Some evidence to support a pathogenetic role in genetically susceptible individuals lies in the discovery that myotoxic proteins induced by type 1 interferons (IFN) are upregulated in large numbers in the muscle tissue of patients with DM and that certain autoantibodies such as anti-Jo-1 are capable of inducing type 1 IFN production, leading to a sustained inflammatory response [79, 81, 82]. As further proof, animal studies have shown that the anti-Mi-2 antibody associated with the classic cutaneous manifestations of DM targets a keratinocyte-derived protein whose production is stimulated by UV exposure [83]. The inhibition of this UV-protective response by anti-Mi-2 autoantibodies may thus contribute to development of the photosensitive, polymorphous rashes of DM. As such, a deeper understanding of the function of not just the autoantibodies themselves but of their target antigens is crucial to determining their precise roles, if any, in disease pathogenesis.

Conclusions

Myositis-specific and myositis-associated autoantibodies play an ever-increasing role in the diagnosis, management, and prognostication of DM and the other idiopathic inflammatory myopathies. With the introduction of more easily performable quantification methods such as ELISA and the push to establish standardized cut-offs, their usefulness may eventually extend to disease activity and treatment response monitoring. However, variations in the frequency of autoantibody positivity and their corresponding phenotypes across different cohorts that are likely driven by a complex interplay of racially, genetically, and environmentally determined factors independent of autoantibody status serve as limitations to its usefulness. As more and more data from studies on diverse ethnogeographic groups becomes available, it is likely that more definitive and reliable population-specific correlations in autoantibody and phenotypic expression will emerge. Regardless, it falls on the clinician to adopt an individualized approach to each patient and incorporate all the other available clinical, histopathologic, serologic, and radiographic tools to arrive at the correct diagnosis and determine the appropriate treatment strategy.