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MUSCULAR DISEASE: Edited by John Vissing

Where are we moving in the classification of idiopathic inflammatory myopathies?

Tanboon, Jantimaa,b; Uruha, Akinoric; Stenzel, Wernerc; Nishino, Ichizoa,b

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doi: 10.1097/WCO.0000000000000855
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Idiopathic inflammatory myopathies (IIM), also known as autoimmune myositis, are a rare group of auto-immune-associated muscle disorders with a heterogenous yet highly specific spectrum of muscular and extramuscular involvement. Historically, IIM was classified into three major subgroups including polymyositis, dermatomyositis, and inclusion body myositis (IBM) mainly by their clinical or pathological features or both in combination [1–13]. The discovery of myositis-specific antibodies (MSA) and mounting evidence of their association with a relatively specific clinicopathological features together with transcriptomics findings gradually change the trend of IIM classification over the past four decades to clinicoseropathological criteria [14,15,16▪▪,17,18▪,19–21,22▪,23▪] (Fig. 1), which classifies IIM into four major subgroups: dermatomyositis, IBM, immune-mediated necrotizing myopathy (IMNM) and recently proposed as a separate entity – antisynthetase syndrome (ASS), whereas the existence of polymyositis as a distinct entity has been questioned [16▪▪,24–26]. This review summarizes and comments on recent knowledge regarding IIM major subgroup classification. 

Development of classifications for idiopathic inflammatory myopathy and discovery of myositis-specific antibodies by chronological order. ADM, amyopathic dermatomyositis; ASS, antisynthetase syndrome; CAM, cancer associated myositis; cN1A, cytosolic 5’-nucleotidase 1A; DM, dermatomyositis; HMGCR, 3-hydroxy-3-methylglutaryl-coenzyme A reductase; IBM, inclusion body myositis; IIM, idiopathic inflammatory myopathy; IMNM, immune-mediated necrotizing myopathy; JDM, juvenile dermatomyositis; MDA5, melanoma differentiation-associated gene 5; Mi-2, nucleosome remodeling deacetylase complex; MSA, myositis-specific antibody; NXP-2, nuclear matrix protein 2; OM, overlap myositis; PM, polymyositis; SAE, small ubiquitin-like modifier-activating enzyme; SRP, signal recognition particle; TIF1-γ, transcription intermediary factor 1γ. Note: the scale represent the year that relevant literature was published.
Box 1
Box 1:
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In the 1975 Bohan and Peter classification, myositis patients were clinically divided into dermatomyositis and polymyositis by the presence of typical skin rash, which included description compatible with heliotrope rash, periorbital edema, Gottron papules, Gottron sign, V-sign, and shawl sign only in dermatomyositis [1]. Interestingly, its pathological criteria did not separate dermatomyositis from polymyositis as it allowed perifascicular atrophy (PFA) to be present in both entities. Some of the later classifications were also clinically oriented with criteria variations based on expert opinion [5,6]. The clinicopathological classification for dermatomyositis was introduced by Dalakas in 1991, and later by the 119th European Neuromuscular Centre (ENMC) international workshop classification of idiopathic inflammatory myopathies in 2003 (2003 ENMC-IIM) [3,7,8]. The 2003 ENMC-IIM criteria for dermatomyositis included subacute or insidious onset symmetrical limb-girdle type muscle weakness and typical dermatomyositis skin rash and requires PFA as the specific criterion for the diagnosis of ‘definite’ dermatomyositis [8] (Table 1).

Table 1
Table 1:
Major changes in the new 2018 European Neuromuscular Centre classification for dermatomyositis

In our opinion, the discovery of prominent type 1 interferon (IFN1) signature and the recognition of dermatomyositis-specific antibodies (DMSA) initiated the transformation of current understanding of dermatomyositis classification [21,27▪▪]. Surrogate immunohistochemical markers for IFN1 signature including sarcoplasmic expression of myxovirus resistance protein A (MxA), interferon-stimulated gene 15 (ISG15), and retinoic acid inducible gene I (RIG-I) are consistently present in dermatomyositis [28–31,32▪]. Among these surrogate markers, MxA is the most studied and is probably the most diagnostically useful marker on muscle histology [29,31,32▪,33▪]. To date, five DMSAs are identified: anticomplex nucleosome remodeling histone deacetylase (Mi-2), antitranscription intermediary factor 1 γ (TIF1-γ), antinuclear matrix protein 2 (NXP-2), antimelanoma differentiation-associated gene 5 (MDA5), and antismall ubiquitin-like modifier-activating enzyme (SAE). Amounting evidences suggest that each DMSA is associated with distinct clinicopathological features [18▪,34] (Table 2). Clinically, anti-TIF1-γ and anti-NXP-2 dermatomyositis are highly associated with malignancy [35–37]; anti-TIF1-γ with dysphagia [38,39]; anti-Mi-2 with prominent muscle involvement but less evidences of association with malignancy [37,40,41]; anti-NXP-2 with skin edema, muscle ischemia, and subcutaneous calcinosis [42,43]; and anti-MDA5 with clinically amyopathic dermatomyositis, atypical skin lesions, rapidly progressive and eventually fatal interstitial lung disease (RP-ILD), and arthritis [44]. A recent unsupervised data analysis in a Caucasian and African cohort identified three subgroups of MDA5-positive patients: RP-ILD cluster frequently associated with mechanic's hands and poor prognosis; rheumatoid cluster associated with joint involvements with less frequent skin lesion, less muscle involvement, less RP-ILD (this cluster has very good prognosis); and vasculopathic cluster associated with skin vasculopathy, skin ulcers, digital necrosis, calcinosis, and muscle weakness with intermediate prognosis [45▪▪]. Anti-SAE seems to be differently associated with malignancy in different ethnic groups; the risk is increased in a Chinese but not in a European cohort [36,37]. Although anti-TIF1-γ anti-Mi-2 and anti-SAE are associated with typical dermatomyositis skin rash, anti-MDA5 is associated with mucocutaneous ulceration, palmar papules, nonscarring alopecia, and panniculitis [44]. Anti-NXP-2 is the least associated with skin lesion [46▪▪].

Table 2
Table 2:
Clinicoseropathological characteristics in major subgroups of idiopathic inflammatory myopathies

Associations between human leukocyte antigen (HLA) regions and different DMSAs have been reported in some antibody subtypes in different ethnic groups (Table 2). In anti-Mi-2 dermatomyositis, HLA-DRB107:01 has been reported in Korean populations and adult Caucasian population and HLA-DRB103:02 in the African American population. In anti-MDA5 dermatomyositis, HLA-DRB101:01/04:05 has been reported in the Japanese population and HLA-DRB112:02 in the Korean populations. In Caucasian population with anti-TIF1-γ dermatomyositis, HLA-DQB102:01 has been reported in juvenile-onset disease and HLA-DQB102:02 in adult-onset disease, suggestive of possible different pathogenesis in different age groups in anti-TIF1-γ dermatomyositis. There was no significant classical HLA or amino acid associations in the Caucasian population with anti-NXP-2, anti-MDA5, or anti-SAE dermatomyositis [20,47–49].

Pathologically, in addition to PFA and decreased cytochrome C oxidase (COX) activity at the perifascicular area, each DMSA is frequently associated with characteristic findings (Tanboon et al., in preparation), for example: anti-TIF1-γ is associated with punched out fibers; anti-MDA5 with relatively normal histology or only mild nonspecific myopathic changes on hematoxylin and eosin staining but some diffuse human leukocyte antigen-ABC [HLA-ABC, major histocompatibility complex (MHC) class I] and MxA staining; anti-NXP-2 with microinfarction; anti-Mi-2 with marked necrotic and regeneration, perifascicular necrosis, perimysial fragmentation, and perimysial alkaline phosphatase activity (Tanboon et al. 2020, in revision) (Fig. 2). Because of the small number of patients, information is limited for anti-SAE-associated dermatomyositis.

Muscle biopsy findings generally suggestive of dermatomyositis (a--d) and characteristic findings in dermatomyositis according to antibody subtypes (e--l): (a) Perifascicular atrophy and perivascular lymphocytic infiltration; (b) decreased COX activity (brown) showing only SDH staining (blue) on perifascicular myofibers by double staining for COX/SDH; (c) sarcoplasmic MxA positivity in perifascicular area; (d) MHCn positivity in perifasicular area; anti-TIF1-γ DM (e and i) with perifascicular atrophy and vacuolated punched-out fibers (e); higher magnification shows punched out fibers (green arrowhead) (i); anti-MDA5 DM (f and j) with nonspecific muscle biopsy finding and absence of perifascicular atrophy (f); MxA staining in anti-MDA5 DM shows sarcoplasmic positivity in scattered fibers (j); anti-NXP-2 DM (g and k) with microinfarction characterized by clusters of pale/hyalinized eosinophilic fibers in the upper right corner (g); decreased to absence of NADH-TR enzyme histochemical activity in the area corresponding to infarction. Remaining outline of some infarcted fibers are observed (k); anti-Mi-2 DM (h and l) with perifascicular fiber necrosis (highlighted in one fascicle with green arrowhead) (h). Perimysial connective tissue fragmentation is observed; anti-Mi-2 DM with increased ALP enzymatic activity in perimysium (l). (a--h, j--l 200× bar = 50 μm; i 600× bar = 20 μm. ALP, alkaline phosphatase; COX/SDH, double staining cytochrome C oxidase and succinic dehydrogenase; H&E, hematoxylin and eosin; MHCn, neonatal myosin; MxA, myxovirus resistance protein A; NADH-TR, nicotinamide adenine dinucleotide dehydrogenase-tetrazolium reductase).

Until the recent 239th ENMC international workshop classification of dermatomyositis in 2018 (2018 ENMC-DM), DMSA has never been officially incorporated into dermatomyositis classification. This may be because of the relatively recent discovery of the majority of DMSA as compared with the discovery anti-Mi-2 (Fig. 1). In fact, a subset of MSAs that are currently held to be specific to other IIM subtypes were included as inclusion criteria for IIM but not for further subgroup categorization as in the classification proposed by Tanimoto et al. in 1995 (anti-Jo-1), by Targoff et al. in 1997 (antisynthetase, anti-SRP, and anti-Mi-2), and by the 2017 European League Against Rheumatism/American College of Rheumatology Classification Criteria for adult and juvenile IIM (anti-Jo-1, 2017 EULAR-ACR) [5,6,11,12]. The diagnosis of dermatomyositis in these classifications was based on the presence of dermatomyositis skin lesion(s). Notably, in a longitudinal cohort study of ASS, these skin lesions can be present in 14, 17, and 19% at the onset and cumulatively present in 58, 70, and 56% along the average of 4.1 years of follow-up in patients with anti-Jo-1, anti-PL-12, and anti-PL-7, respectively [50]. Hence, it is arguable that dermatomyositis diagnosed by these skin features will probably at least partly result in a mixture of IIM especially with respect to ASS-associated myositis.


In 2018, the 239th ENMC workshop reached an international consensus for a modernized dermatomyositis classification -- 2018 ENMC-DM [18▪]. The major changes in 2018 ENMC-DM are summarized in Table 1. According to the 2018 ENMC-DM, a dermatomyositis classification can be made when presence of clinical cutaneous exam findings of at least two of the following: Gottron sign, Gottron papules and/or heliotrope rash, and skin biopsy consistent with interface dermatitis; presence of at least one of clinical exam findings and dermatomyositis muscle features that is fulfilled with one of the following: presence of proximal muscle weakness and elevated muscle enzyme (creatine kinase, CK); presence of proximal muscle weakness and suggestive dermatomyositis muscle biopsy, that is, lymphocytic infiltration (often in perivascular area), pale staining of COX on perifascicular fibers (Fig. 2), and/or positive neuronal cell adhesion molecule (NCAM) staining on perifascicular fibers; presence of elevated muscle enzyme and suggestive dermatomyositis muscle biopsy (as described above) or presence of definitive dermatomyositis muscle biopsy, that is, PFA and/or perifascicular MxA overexpression with rarity or absence of perifascicular necrosis; or presence of clinical exam findings (as previously described) and positivity of one of the following DMSA: anti-TIF1-γ, anti-Mi-2, anti-MDA5, anti NXP-2, and anti-SAE [18▪]. Notably, ulcerative skin lesions on the extensor surface of the metacarpophalangeal, proximal interphalangeal, and/or distal interphalangeal joints as could be present in anti-MDA5 dermatomyositis are considered equivalent to Gottron papules by the criteria. The diagnosis of clinically ADM is rendered if at least two clinical findings and skin biopsy finding criteria are fulfilled in the absence of muscle features. The 2018 ENMC-DM criteria are clinicoseropathologically oriented and include antibody-defined subgroups in the classification. Dermatomyositis patients with DMSA will be subclassified according to antibody subtype whereas dermatomyositis patients without DMSA will be subclassified as seronegative dermatomyositis. Other antibody-defined IIM (i.e. IMNM and ASS) with or without dermatomyositis-like rash will not be classified as dermatomyositis by this classification [18▪]. Although the 2018 ENMC-DM expands the criteria for definitive dermatomyositis muscle biopsy by including presence of sarcoplasmic MxA expression, the criteria only limit to perifascicular pattern positivity. In a previous study, however, 43% of MxA positivity can be present beyond the perifascicular area [32▪]. In our Japanese cohort of 202 antibody-defined dermatomyositis, scattered and diffuse sarcoplasmic MxA staining pattern are observed in 59.9% of the patients. Pure scattered and diffuse MxA staining pattern (without perifascicular pattern) was most commonly observed in anti-MDA5 dermatomyositis, 68.0% (Tanboon et al., in preparation). In our opinion, presence of any sarcoplasmic MxA positivity should be regarded as a muscle biopsy criterion for definitive dermatomyositis. Notably, absence of overt PFA and presence of necrotic fibers in the perifascicular region should not preclude the diagnosis of dermatomyositis. In our cohort, absence of PFA is most commonly observed in anti-MDA5 dermatomyositis (76%) and anti-NXP-2 dermatomyositis (62.9%) whereas perifascicular necrosis (PFN) is present in a 50% of anti-Mi-2 dermatomyositis (Tanboon et al., 2020 manuscript in revision). In addition, immunohistochemistry used to identify perifascicular disease should not be limited to NCAM but may also include neonatal myosin or utrophin as alternatives (Fig. 2). The 2018 ENMC-DM only allows the diagnosis of dermatomyositis in patients with clinical dermatomyositis skin lesions, the diagnosis of ‘dematomyositis sine dermatitis’ (DMSD)-DM without skin manifestation, cannot be made with this classification. Dermatomyositis is characterized by prominent IFN1 signature [21,22▪,23▪] and categorized by DMSA, thus, sarcoplasmic expression of IFN1 surrogate marker together with DMSA positivity even in the absence of dermatomyositis skin lesion should suffice to make the diagnosis of dermatomyositis. We believe that DMSD should be recognized as a subtype of dermatomyositis. The concept of DMSD is not well accepted and there is no definite criteria for the duration of the adermopathic period to qualify the diagnosis; our definition for being adermopathic is absence of skin lesion at the time of muscle biopsy [46▪▪]. In our recently published data, 8% (14/182) of antibody-defined dermatomyositis patients with sarcoplasmic MxA expression did not have skin lesions at the time of muscle biopsy and 86% (12/14) of these patients were anti-NXP2 positive [46▪▪]. As there are ongoing developments of dermatomyositis-specific therapy targeting IFN1 pathway, such as Janus kinase inhibitor, having DMSD categorize as an entity of dermatomyositis spectrum will guide access to future clinical trials and treatments that could be beneficial for these patients [27▪▪,51▪]. Needless to say, serology and muscle biopsy play crucial roles to recognize this condition.


ASS is a serologically based entity defined by presence of one of the following autoantibodies directed against aminoacyl transfer RNA synthetase (antisynthetase): anti-Jo-1 (histidyl), anti-PL-7 (threonyl), anti-PL-12 (alanyl), anti-EJ (glycyl), anti-OJ (isoleucyl), anti-KS (asparaginyl), anti-Ha (tyrosyl), and anti-Zo (phenylalanyl) clinically accompanied by various combination of myositis, interstitial lung disease (ILD), arthritis/arthralgia, mechanic's hands, Raynaud phenomenon, and fever [50]. ASS is rarely associated with cancer and rarely present in children [50,52▪]. Clinical findings and the clinical courses of ASS are various among reports. Anti-Jo-1 was reported to have a trend toward exclusive and more severe muscle involvement whereas anti-PL-7 and anti-PL-12 were reported to have a trend toward exclusive and more severe lung involvement [50]. However, a recent large retrospective study of 828 patients in American and European Network of Antisynthetase Syndrome (AENEAS) collaborative cohort showed broad similarity of clinical findings and clinical course in these antibodies although muscle involvement was less common in anti-PL-12 [52▪]. Of note, anti-OJ detection can be technically challenging by line/blot immunoassays and ELISA as isoleucyl-tRNA synthetase is a component of multienzyme synthetase complex. As the structural complex confirmation is essential for anti-OJ recognition, the current preferred method to detect anti-OJ is immunoprecipitation [53▪]. As a result, the clinicopathologic description and prevalence of anti-OJ ASS described in the literature may not be reliable unless the immunoprecipitation method is used for antibody detection. In a recent study in the Caucasian population, anti-Jo-1 ASS was associated with HLA-B08:01 and HLA-DRB103:01 [47]. Absence of significant HLA region association in other ASS subtypes in this study was likely because of small sample size [47]. Pathological description in ASS is limited to anti-Jo-1, anti-OJ, and anti-PL-7 with presence of perifascicular necrosis, perifascicular fragmentation, and perimysial alkaline phosphatase positivity [54,55] (Fig. 3 a--e), which may be at least partly because of scarce muscle involvement in some subtypes including anti-PL-12. Although there was an attempt to categorize ASS as a clinicoserological subgroup by Love et al.[14] back in 1991, ASS has never been officially categorized as a separate entity of IIM. Without serological test, ASS may well be misclassified either as polymyositis or, if skin lesion or PFA present, as dermatomyositis. This speculation is supported by the recent unsupervised multivariate analysis by Mariampillai et al.[16▪▪] that a population of IIM reclassified as a clinically and serologically representative of ASS are composed of patients historically diagnosed as polymyositis and rarely dermatomyositis by Bohan and Peter classification. It is noteworthy that the ASS cluster is separate from other reclassified clusters of dermatomyositis, IMNM, and IBM; the finding support ASS as a separate entity. Transcriptomic studies suggested that, in ASS, activation of type 2 interferon (IFN2) pathway is higher than of IFN1 pathway resulting in higher expression of IFN2-inducible genes [22▪,23▪]. The findings correlate well with expression level of IFN2-inducible genes on muscle biopsy sample including expression of HLA-DR on myofibers [22▪]. In our study of 954 muscle biopsies (212 ASS, 101 IBM, 501 other IIM, and 140 muscular dystrophy potentially mimic IIM), HLA-DR expression of any pattern is present in 60.4 and 98% of ASS and IBM, respectively; HLA-DR expression is uncommon in any other major IIM groups. Among all IIM, perifascicular HLA-DR expression is most commonly observed in ASS esp. in anti-Jo-1 ASS (60.0%) (Tanboon et al., in preparation). HLA-DR expression and its perifascicular predominance can be used as a surrogate marker for IFN2 activation in ASS. In addition, in the absence of rimmed vacuoles -- the finding favors IBM, perifascicular HLA-DR expression (36.8% in ASS) could be useful to aid identification of ASS with no detectable antibodies as a future entity after exclusion possibility of other IIM (Tanboon et al., preparation). Finally, nuclear actin inclusions have been found exclusively in ASS muscle biopsies [56]

Characteristic findings in major subtypes of idiopathic inflammatory myopathy. Antisynthetase syndrome (a--e): (a) perifasicular necrosis and perimysial connective tissue fragmentation (green star); (b) increased ALP enzymatic activity in perimysium; (c) diffuse HLA-ABC positivity; (d) HLA-DR positivity in perifascicular fibers; (e) sarcolemmal C5b-9 deposition on perifascicular fibers. Immune mediated necrotizing myopathy (f--k): (f) scattered multistage necrotic and regenerating fibers; (g) no obvious increased ALP activity in perimysium; (h) diffuse HLA-ABC positivity (can be faint); (i) HLA-DR staining is usually negative in myofibers. Normal capillary staining is noted; (j) sarcolemmal C5b-9 positivity is noted; (k) p62 positivity with diffuse tiny-dot pattern. Inclusion body myositis (l--q): (l) lymphocytic invasion in endomysium and nonnecrotic fibers. A fiber suspicious of containing rimmed vacuoles is observed in H&E; (m) rimmed vacuoles are highlighted in mGT; (n) diffuse HLA-ABC positivity; (o) HLA-DR positivity in scattered fibers; (p) CD8 highlights lymphocytes invading endomysium and nonnecrotic fibers; (q) p62 positivity in large coarse dot-like pattern in subsarcolemma and perivacuolar areas. (a--d, f--i, n--o 200× bar = 50 μm; e, k, l, m, p, q 400× bar = 20 μm; j 600× bar = 20 μm. ALP, alkaline phosphatase; ASS, antisynthetase syndrome; C5b-9, membrane attack complex; H&E, hematoxylin and eosin; IBM, inclusion body myositis; IMNM, immune mediated necrotizing myopathy; mGT, modified Gömöri trichrome; HLA, human leukocyte antigen; HLA-ABC= MHC class I; HLA-DR = MHC class II; p62 = sequestosome-1).


The current classification of IMNM established by the 224th ENMC international workshop in 2016 (2016 ENMC-IMNM), is a revision of clinicopathologic description of IMNM in 2003 ENMC-IIM with integration of serological studies. The 2016 ENMC-IMNM categorizes IMNM into three subgroups according to positive antibodies: antisignal recognition particle (SRP) IMNM, anti3-hydroxy-3-methylgluaryl-coenzyme A reductase (HMGCR), and seronegative IMNM [17]; IMNM can affect people of wide age range [57–59]. In children, the disease can be slowly progressed and mimic muscular dystrophy [60]; the youngest age of onset in IMNM is 10 months old in a patient with anti-HMGCR positivity [58]. Among the three subgroups, anti-SRP IMNM is associated with more severe muscle involvement and may associate with increased risk of cardiac involvement and ILD [37,61]. Extramuscular involvement in anti-HMGCR IMNM is rare. Although anti-HMGCR autoantibodies were initially found in IMNM patients who were taking statins, a significant number of patients are statin-naïve. Statin-naïve patients are younger and tend to have poorer outcome than statin-exposed anti-HMGCR and anti-SRP IMNM patients [57]. Seronegative IMNM show frequent association with extramuscular involvement and increased risk of malignancy [57]; anti-HMGCR IMNM association with malignancy is controversial whereas there is no association in anti-SRP IMNM [62]. Unlike the other major subgroups of IIM, IMNM does not show strong correlation with either IFN1 or IFN2 signature pathway [22▪,23▪]. HLA-DRB111:01 and HLA-DRB107:01 reported to be associated with adult and juvenile anti-HMGCR IMNM, respectively [20,47,63,64]. There is no significant association with classical HLA alleles and anti-SRP IMNM in a large cohort of Caucasian population [47]. In Japanese population, HLA-DRB108:03 is associated with statin associated IMNM and anti-SRP IMNM but not anti-HMGCR, which may implicate statin treatment on pathogenesis of IMNM through both HLA-DRB108:03 anti-SRP and HLA-DRB111:01 anti-HMGCR pathway [63]. Pathologically, IMNM is characterized by scattered different necrotic and regenerating fibers. The majority of infiltrating inflammatory cells are macrophages; in most cases, only a small number of lymphocytes are present [17] (Fig. 3 f--k). On immunohistochemistry, in addition to mild HLA-ABC expression, C5b-9 is deposited on the sarcolemma, which suggests that myofiber necrosis is mediated by antibody-mediated classical complement activation. This hypothesis is supported by presence of patients’ autoantibodies, IgG, and C1q depositions on the sarcolemma; C1q is the initiator of classical pathway [65▪▪]. Furthermore, passive transfer of patients’ sera recapitulates IMNM in mice [66▪▪]. In a recent study, sarcolemmal p62 positivity with a pattern of diffuse tiny dots in IMNM was shown to be colocalized with key molecules in chaperon-assisted selective autophagy (CASA), for example, BAG3, HSP70, HSPB5 [67▪]. HLA-ABC expression was also present on the same fibers. In the same study, increased mRNA levels of endoplasmic reticulum (ER)-stress response genes, EDEM and XBP1 is shown in IMNM. As SRP and HMGCR are present on ER, the authors of the study linked IMNM with CASA and proposed that diffuse tiny dot-like p62 positive pattern might be useful to distinguish seronegative IMNM from other entities [67▪]. However, its sensitivity and specificity in IMNM and in potentially IMNM-mimic neuromuscular diseases should be further evaluated.


The first classification of IBM classification by Griggs et al. in 1995 was principally pathology-based; it allowed IBM to be diagnosed without any clinical or laboratory data required, if the muscle biopsy already met all requirements for pathological criteria [4]. The clinicopathological classification of IBM was later formulated during the 188th ENMC international workshop-‘ENMC IBM Research Diagnostic Criteria’ (2011 ENMC-IBM) and classified IBM into three categories: clinicopathologically defined IBM (CPD-IBM), clinically defined IBM, and probable IBM, allowing some diagnostic flexibilities as compare to classification by Griggs et al.[10]. Clinically, the basic criteria for all three categories include slowly progressive muscle weakness more than 12 months in individuals over 45 years of age with CK level less than 15 times of upper normal limits. A combination of muscle weakness level involving (a) knee extension muscle equal or more than hip flexion muscle and (b) finger flexion muscle over shoulder abduction muscle is evaluated in each category as follows: (a) and/or (b) in CPD-IBM; (a) and (b) in clinically defined IBM; and (a) or (b) in probable IBM. Pathological criteria for CPD-IBM require the presence of all of the following: endomysial inflammatory cell infiltration, rimmed vacuoles, and presence of protein accumulation (by histochemical methods for amyloid or immunohistochemistry for p62, SMI-31, or TDP-43) (Fig. 3 l--q) or presence of 15–18 nm tubulofilaments by electron microscopy. Presence of at least one of the above pathological criteria or expression of MHC class I is required for clinically defined IBM and probable IBM [10]. Both ‘definite’ IBM by Griggs et al. and CPD-IBM 2011 ENMC-IBM criteria are highly specific (98–100%) but the sensitivity of these criteria are low: 11 and 29% for ‘definite’ and ‘possible’ IBM by Griggs et al., respectively and 15, 57, and 84% for CPD-IBM, clinically defined IBM, and probable IBM by 2011 ENMC-IBM, respectively [9]. To invent higher performing criteria, Lloyd et al. used machine-learning to construct data-derived IBM classification and proposed criteria that requires all of the following to be present: finger flexor or quadriceps weakness; endomysial inflammation; and either invasion of nonnecrotic muscle fibers or presence of rimmed vacuoles [9]. The criteria by Lloyd et al. have 90% sensitivity and 96% specificity. This criteria are user-friendly but some severe inflammatory myopathies or other myopathy with rimmed vacuoles may meet the criteria as well [9]. Thus, additional pathological, immunohistochemical, or even genetic studies should be performed to rule out any possibility of ‘non-IBM’ vacuolar myopathy. Additional pathological/immunohistochemical findings characteristic for IBM included: presence of mitochondrial abnormality demonstrated by COX-negative fibers or ragged red fibers, CD8-positive cell infiltration in endomysium and nonnecrotic fibers, presence of degenerative biomarkers, for example, discrete subsarcolemmal or perivacuolar p62 positivity, and HLA-DR positivity [68]. Similar to ASS, IFN2 pathway activation is high in IBM but HLA-DR positivity, a surrogate marker for IFN2 activation, is always very strong and is more diffuse in IBM whereas the perifascicular pattern is more common in ASS [22▪,23▪,69,70] (Tanboon et al., in preparation). A recent study showed increased number of highly differentiated cytotoxic (CD8+CD57+) T cells that express killer cell lectin-like receptor G1 (KLRG1), a lymphocyte-co-inhibitory or immune checkpoint receptor [71▪▪]. Markers associate with T-cell cytotoxicity, differentiation/exhaustion/senescent signature are increased in IBM in comparison with other IIM and other nonimmune muscle diseases [71▪▪,72]. The findings provided possible explanation for refractoriness of IBM to broad nonselective T-cell depletion – alemtuzumab that cause increased blood CD8+ terminally differentiated effector memory T cells (TEMRA) and treatment targeting proliferating cells [71▪▪]. In addition, using immunohistochemical staining to identify CD8+CD57+ T cells or CD8+CD57+KLRG1+T cells in muscle biopsy may help strengthen the diagnosis of IBM in clinically suggestive patients. Anticytosolic-5’ nucleotidase 1A (cN1A, NT5C1A) is the only known antibody to be present but not exclusive to IBM [68]. It is also present in a substantial portion of heterogenous neuromuscular and nonneuromuscular conditions including but not limit to Sjögren syndrome, dermatomyositis, juvenile myositis, and healthy children, although at lower frequency than IBM [68,73]. Presence of anticN1A antibody has been suggested to be associated with more severe clinical phenotype in IBM: more severe muscle weakness, bulbar, and respiratory involvement, increased mortality risk, excess of COX-deficient fibers on muscle biopsy and likelihood of having facial weakness and death because of respiratory cause in IBM [74–76]. Thus, its utility as a prognostic marker in IBM may be considered only in relevant clinicopathological context. Of note, HLA-DRB103:01 and HLA08:01 are reported to be associated with IBM [68].


Overlap syndrome was mentioned in Bohan and Peter [1] classification as a myositis in the course of connective tissue disorder that the independent criteria should be met for each disorder. The concept of overlap myositis was proposed by Troyanov et al. in 2005 as a clinicoserological classification defined by presence of myositis and at least one clinical overlap feature with those present in connective tissue disease and/or an overlap antibody [15]. Many antibodies that were originally or later categorized as antibody for overlap myositis including antisynthetase, anti-SRP, anti-MDA5 are now re-classified to ASS, IMNM, and dermatomyositis, respectively. The remaining antibody in overlap myositis classification include antisystemic sclerosis (SSc)-specific antibodies and antibodies associated with SSc in the overlap, which include but not limit to anti-Ku, antipolymyositis (polymyositis)/scleroderma (Scl), and anti-U1-ribonucleoprotein (RNP) antibodies [15,19,77,78]. Comprehensive list of clinical overlap features and overlap antibodies can be found elsewhere [15,77]. The antibodies’ list mentioned above has been reported in a wide spectrum of connective tissue/autoimmune disease. In this review, we will limit discussion on relatively well characterized antibodies associated with overlap myositis. Anti-Ku has been reported in myositis mainly in association with SSc, and in a smaller proportion of Sjögren syndrome and systemic lupus erythematosus (SLE). Anti-Ku-positive patient with myositis/elevated CK are associated with higher risk of ILD [79]. Presence of anti-Ku is associated with corticosteroid-sensitive myositis and corticosteroid-resistant ILD [80]. Anti-PM/Scl-positive patients may show a peculiar distribution of weakness with deltoid muscle being more affected than hip flexors [81]. In comparison with other IIM, muscle weakness in anti-U1-RNP is less prevalent at the onset but will later appear during the course of disease. Anti-U1-RNP is moderately associated with ILD (second to ASS) and usually associates with glomerulonephritis and pericarditis [82]. Muscle biopsy in anti-Ku and anti-U1-RNP is often similar to necrotizing myopathy whereas common histological feature found in anti-PM/Scl muscle biopsy often features perivascular inflammation [80–82].


Antimitochondrial M2 antibody (AMA), a signature for primary biliary cholangitis (PBC), can be present in various conditions mainly in autoimmune disease spectrum including but not limiting to SSc, Sjögren syndrome, and autoimmune hepatitis; it can also be present in nonautoimmune liver disease. AMA has been increasingly recognized to be associated with myositis with an incidence of 11.3% in a 212 Japanese cohort and 0.006% in an 1180 American cohort of inflammatory myopathy [3,84]. In these cohorts, 12.5 and 14.3% had preceding PBC. Myopathy with AMA positivity tended to be associated with chronic disease course, muscle atrophy, frequent cardiac involvement (especially arrythmia), and pathologically necrotizing myopathy [83,84]. Notably, granulomatous inflammation was observed in 25% of the Japanese cohort [83]. High-intensity signal in the adductor magnus observed with short tau inversion recovery (STIR) MRI, so-called ‘cuneiform sign’ was suggestive to be characteristic for the disease [85].


Cytotoxic T-lymphocyte-associate protein 4 (CTLA-4), program cell death 1 (PD-1)/and PD-1 ligand (PD-L1) are immune checkpoints with inhibitory function on T-cell immune response. Activation of these pathways allows tumor cells to escape from the host immune system [86▪]. Blockades of these pathways by immune checkpoint inhibitors (ICIs) in tumor immunotherapy, thus enhance T-cell activity and may increase immune response to self-antigen that may lead to a large variety of immune-related adverse events (irAE). Anti-PD-1/PD-L1 inhibitor-associated myositis is not a typical IIM but a recently recognized emergence condition because of high rate of patients needing intensive care treatment and a high rate of fatal disease. Notably, myositis associated with anti-PD1/PD-L1 inhibitor monotherapy is more common than anti-CTLA4 and PD-1/PD-L1 inhibitor treatment in combination and much more common than anti-CTLA4 monotherapy; the frequency related to each regimen is 83, 15, and 2%, respectively [87]. Theoretically, anti-PD-1/PD-L1 inhibitor-associated myositis needs to be distinguished from paraneoplastic myopathy. Unlike paraneoplastic myositis that could occur any time during clinical course, anti PD-1/PDL-1-associated myositis has acute or subacute onset within 1 month after initial ICIs exposure [87–90]. In addition, anti PD-1/PD-L1-associated myositis usually accompany with ocular involvement similar to myasthenia gravis-type features and myocarditis and associate with higher mortality rate as compared with IIM. So far, none of the reported cases have associated MSAs except one patient who was positive for anti-NXP-2/Mi-2, although likely to be a false-positive according to the authors [90]. Of note, antistriational antibodies (antititin, anti-Kv1.4, or both) were detected in 68% of the patients [89]. The common muscle biopsy findings are multifocal confluent area of necrosis and with prominent cluster of CD68 infiltration [88–90]. Although the anti-PD-1/PD-L1-associated myositis is relatively rare, it can be potentially fatal especially in patient with combination therapy and in patient with concomitant myocarditis [87]. However, most patients generally improved after immunosuppressive treatment and discontinuation of the check point inhibitors [88–90]. Assessment of serum CK and muscle biopsy is essential to make the diagnosis in the patient as the myositis symptoms can be overlooked in severely ill patient [87]. Thorough clinical and laboratory assessments including neurophysiology, antibody workup, muscle enzymes, and muscle biopsy are essential for the recognition of potentially fatal condition, characterization, and further explanation on its pathogenesis.


IIM is suggestively classified into four major subgroups: dermatomyositis, ASS, IMNM, and IBM. Most of the classifications are clinicoseropathologically oriented that clinical and serological criteria play major parts. Transcriptomics and haplotype studies will probably tailor subclassification. Nevertheless, pathomorphological evaluation is indispensable for classification of IBM, categorization of seronegative IIM, and in-depth characterization of IIM with known antibodies. In addition, pathological findings may provide clues to improve our understanding on underlying pathomechanisms and their diagnostic and therapeutic implications. The 2018 ENMC-DM, for the first time, included a surrogate marker for signature pathway activation (MxA) and DMSA in the classification criteria. With serological information, 2018 ENMC-DM emphasizes different boxes of classification for non-DMSA-antibody-positive IIM with dermatomyositis-like skin lesions. For the next dermatomyositis classification revision, scattered and diffuse MxA-positive pattern should be included in dermatomyositis muscle feature criteria. In addition, DMSD should be considered as spectrum of dermatomyositis as the condition may have therapeutic implication.


We thank Dr. Michio Inoue for clinical information of studies mentioned in this review. We also thank Ms. Kaoru Tatezawa, Ms. Kazu Iwasawa, Ms. Naho Fushimi, and Mr. Hisayoshi Nakamura for technical assistance.

Financial support and sponsorship

The work was supported partly by Intramural Research Grant (2–5 and 29-4) for Neurological and Psychiatric Disorders of NCNP.

Conflicts of interest

There are no conflicts of interest.


Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest


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antisynthetase syndrome; dermatomyositis; immune checkpoint inhibitor; immune-mediated necrotizing myopathy; inclusion body myositis; myositis-specific antibody

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