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Year : 2022  |  Volume : 65  |  Issue : 5  |  Page : 241-251
Evolving classification and role of muscle biopsy in diagnosis of inflammatory myopathies

1 Department of Pathology, Apollo Hospitals, Hyderabad, Telangana, India
2 Department of Pathology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India

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Date of Submission22-Oct-2021
Date of Decision26-Jan-2022
Date of Acceptance27-Jan-2022
Date of Web Publication11-May-2022


Idiopathic inflammatory myopathy (IIM) is a broad term that includes dermatomyositis, polymyositis, overlap myositis, sporadic inclusion body myositis, and immune-mediated necrotizing myopathy. The understanding of the pathogenesis of IIM is ever-evolving with regular updates in the classification schema. With the recognition of autoantibodies and their detection, the diagnostic algorithms are changing in favor of non-invasive diagnoses. However, muscle biopsy has immensely contributed to our understanding of the pathogenesis of inflammatory myopathies, and the pathologic features of different subtypes are well established. The biopsy also aids in distinguishing myopathies with overlapping clinical features, particularly dystrophies, which can show inflammation on biopsy in some cases. In this article, the various classification schemes of the IIM are reviewed. Also, the pathogenesis and pathology of each type of IIM have been highlighted. This article emphasizes the role of muscle biopsy in the diagnosis of inflammatory myopathies.

Keywords: Classification, inflammatory myopathies, muscle biopsy

How to cite this article:
Swain M, Uppin M. Evolving classification and role of muscle biopsy in diagnosis of inflammatory myopathies. Indian J Pathol Microbiol 2022;65, Suppl S1:241-51

How to cite this URL:
Swain M, Uppin M. Evolving classification and role of muscle biopsy in diagnosis of inflammatory myopathies. Indian J Pathol Microbiol [serial online] 2022 [cited 2022 May 28];65, Suppl S1:241-51. Available from: https://www.ijpmonline.org/text.asp?2022/65/5/241/345030

   Introduction Top

Idiopathic inflammatory myopathy (IIM) is a broad term that includes dermatomyositis (DM), polymyositis (PM), overlap myositis (OM), sporadic inclusion body myositis (IBM), and immune-mediated necrotizing myopathy (IMNM). The understanding of the pathogenesis and pathology of these diseases is being periodically reviewed and updated. With advances in autoantibodies, the diagnostic algorithm is shifting away from invasive biopsy policies. However, muscle biopsy remains the gold standard for overlapping clinical features and negative autoantibody profiles. The classifications of IIM have changed from being clinical to clinicopathological to the current clinico-sero-pathological classification.[1] In their review, Tanboon et al.[2] have highlighted a diagrammatic representation of classifications in chronologic order and the time of discovery for autoantibodies. Some of the landmark classifications including the approach and entities have been enlisted in [Table 1]. The purpose of this review article is to highlight the changes in these classifications concerning biopsy pathology and their relevance to the diagnosis of IIM. Relevant articles, which have exclusively studied myopathologic aspects of IIM, have also been reviewed.
Table 1: List of landmark classifications of IIM along with their approach and the entities included in each classification

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   Dermatomyositis Top

The fundamental classification by Bohan and Peter highlighted biopsy features like necrosis, phagocytosis, regeneration, perifascicular atrophy (PFA), and perivascular inflammatory exudates.[3] These features were common to DM and PM. Dermatomyositis is a complement-mediated vasculopathy that begins with the deposition of a membrane attack complex (MAC) on the endothelial cells, resulting in capillaritis, ischemia, and microinfarcts.[4] The PFA is also attributed to perifascicular ischemia. The inflammatory cells comprise CD4+ T cells, macrophages, B cells, and CD123+ plasmacytoid dendritic cells (PDCs). This formed the basis for the definite pathologic criteria of DM introduced by the 119th European Neuromuscular Centre (ENMC-2003) international workshop classification of IIM.[5]

A landmark study by Salajegheh et al.[6] further refined the pathogenesis of DM. They studied 54 biopsies of IIM, including 14 dermatomyositis, using computational methods, microarrays, immunohistochemistry (IHC), and electron microscopy (EM).[6] It was observed that genes induced by interferon-1 (IFN1) were highly over-expressed in biopsies of DM in comparison to antisynthetase syndrome (ASS) and other myositis. Immunohistochemistry for interferon inducible protein and myxovirus resistance protein A (MxA) showed dense staining of perifascicular and sometimes all myofibers in 8/14 patients and on capillaries in 13/14 patients. They also observed a greater number of PDCs and fewer CD4 cells in comparison to those reported previously. The IFN1 signature in the muscle can be studied with the help of surrogate IHC markers like MxA, interferon stimulated gene 15 (ISG15), and retinoic acid-inducible gene I (RIG-I). All these have shown consistent expression in DM.[7],[8],[9],[10],[11] Of these, MxA expression was found to be the most reliable with consistent staining pattern. The staining pattern can be perifascicular, diffuse, or focal sarcoplasmic expression. It has been proposed that any staining for MxA in muscle fibers should be taken as a definite criterion for DM. The same has also been observed in patients with SLE, suggesting similarities in their patho-mechanism and treatment for DM and SLE.

This has been incorporated into the 2018 ENMC meeting with a modernized clinico-sero-pathological classification of DM.[12] At the classification meeting, Dr. Nishino proposed that IFN 1 signature is specific to DM and should be redefined as a type I interferonopathy, whereas ASS is a separate disease.[12]

Other diseases that show perifascicular atrophy or necrosis in the absence of MxA expression or autoantibodies will not be classified as DM as per this classification.

Pathologic features

According to ENMC 2003 criteria, PFA is a specific feature for the diagnosis of “definite” DM. The criteria for “possible” DM include perivascular, perimysial inflammatory infiltrate or MAC deposition on small blood vessels or reduced capillary density or tubuloreticular inclusions in endothelial cells on EM or MHC-1 expression of perifascicular fibers [Figure 1].[5]
Figure 1: Biopsy features of dermatomyositis showing (a) perifascicular atrophy, (b) intense perivascular lymphomononuclear infiltrate, (c) the infiltrate showing positivity for CD4 T cells (d) CD20 positive B cells, and (e) CD123 positive PDCs. (f) MHC class I antigen shows classic perifascicular distribution

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The ENMC 2018 criteria for DM are:[12]

Definitive DM muscle biopsy findings: perifascicular atrophy and/or perifascicular MxA over-expression with rare or absent perifascicular necrosis.

Suggestive DM muscle biopsy findings: lymphocytic infiltrates (often perivascular), evidence of perifascicular disease (perifascicular predominant fibers that are pale on COX staining and/or positive on NCAM staining).

The diagnosis of DM can be made with classic clinical features including skin lesions and proximal muscle weakness along with DM specific muscle features and autoantibodies (DMSA), which include TIF-1, NXP2, Mi2, MDA-5, and SAE. These antibodies are used for sub-classification of DM and those without DMSA are classified as seronegative DM.

Comparison of DMSA and pathologic features

Tanboon and Nishino highlighted the clinicopathologic differences between the various forms of DM associated with autoantibodies.[1] The clinical features, pathology, and prognosis are different among the five subgroups of DM defined by the type of autoantibody. A detailed list of antibodies along with clinical features, biopsy findings, and prognosis has been enlisted in [Table 2].
Table 2: Details of antibodies in DM and IMNM highlighting the clinical features, biopsy findings, and prognosis

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mi-2: This shows typical DM skin lesions with a benign course. The biopsies show a prevalence of primary inflammation (i.e., focal lymphocytic invasion of myofibers).[13] JDM in mi-2 has relatively severe pathological findings based on a validated juvenile DM biopsy scoring system.[14],[15],[16] These biopsies show diffuse CD68+ dominant inflammatory infiltrates, regenerative fibers, and increased sarcolemmal C5b-9 deposition on non-necrotic fibers compared to anti-Mi2-negative DM controls (n = 32).

TIF1-g (anti-transcription intermediary factor 1 g): This has a higher association with malignancy, particularly ovarian cancer.[17] The biopsies show PFA and punched-out vacuoles. These vacuoles do not show rimming like in IBM and also appear as “ghost fibers” on ATP-ase pH 9.4 and prominent cytochrome oxidase (COX)-paleness, and greyish to pale-bluish discoloration in combined COX-SDH at (succinate dehydrogenase) stains.

MDA-5 (anti-melanoma differentiation associated gene) is associated with amyopathic DM, mucocutaneous lesions, and interstitial lung disease.[12] The biopsy shows non-PFA histology with non-specific myopathic changes. Vasculopathy is not obvious.[18],[19] As muscle involvement is frequently patchy, selection of the most affected muscle tissue is warranted.

Anti-NXP-2 (anti-nuclear matrix protein-2): This is most common in juvenile patients with severe disease and muscle ischemia. Subcutaneous calcinosis is seen in adult and juvenile patients.[20] Microinfarctions are a common pathologic finding.

Immunohistochemistry: The markers contributing to the pathogenesis of DM can be demonstrated on muscle biopsies with the help of surrogate IHC markers, which helps in confirming the diagnosis. Expression of MHC-1 has been widely studied and is also a criterion for diagnosis of “possible DM” according to the ENMC workshop, 2003. However, there is no consensus on its specificity since its expression has also been noted in dystrophies.[21],[22],[23],[24]

Sarcolemmal expression of MAC is an indicator of immune-mediated muscle injury. This is a criterion for “possible DM” as per ENMC 2003. The expression can be seen both in the capillaries as well as in the sarcolemma. Sarcolemmal expression is more pronounced in mi-2 DM, whereas capillary expression is seen in anti-TIF gamma DM. HLA DR expression is not consistent in DM.

   Immune-mediated necrotizing myopathy Top

Immune-mediated necrotizing myopathy (IMNM), also known as necrotizing autoimmune myopathy (NAM), is an emerging entity in the group of IIM. It is defined by the presence of myofiber necrosis, degeneration, and regeneration along with a lack of significant inflammatory infiltrate.[25]

Necrotizing myopathies without inflammation have been reported since 1947, but were possibly reported as either PM or DM as per the Bohan and Peter classification.[3],[26],[27] Smith[28] in 1969 and Urich and Wilkinson[29] in 1970 described cases of paraneoplastic necrotizing myopathies as showing necrotic muscle fibers with regenerating fibers and histiocytes, differentiating them from classical PM and DM. Vosskämper et al. in 1989 considered necrotizing myopathy in association with malignancy to be a distinct histological subtype.[26],[30]

Emslie-Smith and Engel in 1991 reported three cases of necrotizing myopathy with microangiopathy causing thickened capillaries, microvascular MAC deposition, capillary depletion, and minimal inflammation, associated with connective tissue disease and transitional cell carcinoma, responding to immunotherapy.[31]

Increasing recognition of this entity led to the proposal by Anthony Amato of the “Muscle Study Group” for a separate classification in 2004.[5] The term “immune-mediated necrotizing myopathy,” was introduced in this classification. The muscle biopsy criteria included many necrotic muscle fibers as the predominant histological feature, sparse inflammatory cells, absence of perimysial infiltrate, MAC deposition on small blood vessels, or pipestem capillaries on EM, but without tubuloreticular inclusions in endothelial cells.[5],[32],[33]

The current classification based on the 224th ENMC workshop of 2016 is clinico-sero-pathological, incorporating autoantibody detection.[25]

Three serologically defined subtypes are now recognized.

1) Anti-Signal Recognition Particle (SRP) IMNM; 2) Anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) IMNM; 3) Seronegative IMNM.[25],[27],[33] Details of antibodies along with clinical features, biopsy findings, and prognosis have been enlisted in [Table 2].


SRP, signal recognition particle, is a cytosolic ribonucleotide protein with an RNA molecule to which are bound six polypeptides. This is responsible for guiding newly synthesized polypeptides emerging from the ribosomes to the rough endoplasmic reticulum for post-translational modifications.[26],[27]

First identified in 1986 in a patient with PM, this antibody is established as specific for this subtype, being seen 22%–39% of these patients in various series.[34],[35] These can also be seen in patients with limb-girdle muscular dystrophy type 2A and other diseases.[36] SRP myopathy is more severe and has a poor recovery.[26],[37]


The use of statins as lipid-lowering agents unmasked a distinct form of autoimmune myopathy associated with their use.[38] In 2010, antibodies to HMGCR were identified in patients with IMNM, 63% of whom were on statins.[39] This seminal finding was closely followed by several studies supporting the association of anti-HMGCR autoantibodies with IMNM and statin use.[40],[41] HMGCR is the rate-limiting enzyme in cholesterol synthesis and the pharmacologic target of statins.[39],[42] A significant number of IMNMs are also seen in statin-naive patients.[2],[43] These are younger, have higher CK levels, and have poorer outcomes. Exposure to dietary sources of statins like mushrooms and yeast extracts could be responsible for these cases.[44]

The class II human leukocyte antigen (HLA) allele D related B (DRB) 1* 11: 01 is known to have a strong association with HMGCR IMNM in adults, whereas HLA-DRB1* 07: 01 is associated with pediatric cases.[28],[45]

The association of anti-HMGCR antibodies with statin intake and/or specific class II HLA alleles implicates the processing of HMGCR by the host immune system. Certain epitopes of HMGCR, when processed by antigen-presenting cells, can potentially trigger an immune response.[45]

The proposed mechanisms include altered HMGCR expression levels, immunogenicity of HMGCR-derived peptides due to conformational changes caused by the binding of statin to HMGCR, and immunogenic HLA alleles.

Anti-HMGCR antibodies thus formed by binding to the HMGCR protein on the myofiber surface may facilitate immune-mediated injury by complement fixation.[46]

Seronegative IMNM

Defined by absent MSAs and a necrotizing myopathy in which drug/toxic myopathy has been excluded; connective tissue disease, malignancy, and extra-muscular features are more frequent in this type.[2],[27]

Pathologic features

The key histologic features are myonecrosis, myophagocytosis, regeneration, and a relative paucity of lymphocytic infiltrate as defined in the 119th ENMC workshop.[5] The pathologic features are shown in [Figure 2]. The necrosis is scattered rather than diffuse, with the various stages of regeneration indicating a temporal evolution.[5],[27] The percentage of necrotic fibers is low, at 3.2% in SRP IMNM and 1.8% in HMGCR IMNM.[47] This contrasts it from other causes of widespread necrosis, as seen in toxic myopathies and rhabdomyolysis.[47] Some do not exhibit necrotizing myopathy and may be completely normal histologically, indicating a sampling error.[34],[47] Myonecrosis is not specific to this entity and can be seen in 16% of DM and in 79% of anti-Jo1 positive IIM.[12],[48] Other features include many regenerating fibres along with nuclear abnormalities, variation in size of muscle fibres, atrophic fibres and connective tissue damage and proliferation.[25],[26],[27],[32],[42],[45]
Figure 2: Biopsy features of immune-mediated necrotizing myopathy. (a) Biopsy shows many necrotic fibers without any evidence of inflammation. (b) Multiple necrotic fibers surrounded by regenerating fibers. (c) Necrotic fibers are seen as moth-eaten fibers on SDH stain. (d) Staining for MHC class I antigen is faint and is seen only in non-necrotic fibers

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Since the initial criterion of a pauci lymphocytic IIM of the 119th ENMC, there is evidence now that lymphocytic inflammation can be present. Around 25% of patients exhibit lymphocytic infiltrates similar to that seen in biopsies from anti-Jo1+ and DM patients.[25],[46],[47] Lymphocytic invasion of non-necrotic myofibers is extremely rare.[27],[34],[39],[46],[47],[48] and, if present, is indicative of a different subset of IIM. HMGCR+ IMNM has been shown to have plasmacytoid dendritic cells similar to DM.[49] CD 163 positive M2 macrophages were reported in 100% of the biopsies.[49]


ENMC 2004 criteria mentioned lack of MHC I positivity in IMNM, but now there is evidence of MHC I staining, though maybe fainter than in other IIMs.[25],[26],[27],[39],[42],[50]

MAC is demonstrable on the sarcolemma of non-necrotic myofibers but lacks specificity as it is seen in other IIMs and some dystrophies. MAC deposition may also be seen on capillaries though the intensity of staining may be faint as compared to DM.[2],[25],[26],[27],[32],[39],[42],[50],[51] This supports an antibody-driven complement-mediated pathogenesis.[24]

Necrotic and regenerating myofibers of IMNM have shown an abnormal expression of autophagic proteins, a feature peculiar to IMNM and not seen in IBM,DM or PM. The latter appears to be a peculiar feature of IMNM and was not noted in IBM, DM, or PM patients. IHC for p62 can be used for the diagnosis of seronegative IMNM.[2],[27]

   Antisynthetase Syndrome Top

Antisynthetase syndrome (ASS) was not recognized as a separate form of inflammatory or autoimmune myopathy and was misdiagnosed as PM or DM by the criteria of Bohan and Peter.[3] This syndrome is defined by the presence of antibodies against aminoacyl transfer RNA synthetase (ARS) and has varied clinical manifestations, including myositis, ILD, mechanic hands, arthritis, Raynaud's phenomenon, and fever.[52] Eight different antibodies have been implicated, of which the most common is Anti-Jo-1, which shows muscle involvement.

Pathologic features

The biopsy shows perimysial pathology with the presence of perifascicular atrophy and necrosis, which can be mistaken for DM. However, it is important to know that, pathogenetically, ASS and DM are separate entities. Unlike the recently diagnosed IFN1 signature in DM, ASS shows activation of type 2 interferon (IFN2); this was identified by transcriptomic studies.[53],[54]

Unlike DM, the biopsy features of ASS associated with Jo-1, OJ, and PL-7 are uniform. The comparison of other antibodies and biopsy features is not available.

It is important to remember that clinico-serologic criteria are mandatory for the proper characterization of ASS. Muscle biopsy taken in isolation, without knowledge of MSA antibodies, can be misinterpreted as DM. ASS has been proposed to be characterized as a separate and specific form of inflammatory myopathy owing to its association with a distinctive clinical and autoantibody profile.[12]


The surrogate IHC marker for the IFN 2 signature is HLA-DR, which has shown consistent sarcolemmal expression in biopsies of ASS. It has been proposed that perifascicular HLA-DR expression could be useful in the identification of ASS with no detectable antibodies after excluding other types of IIM. Aouizerate et al.[55] demonstrated myofiber MHC-II expression in 81.8% of ASS and 23.5% of DM, which was statistically significant. Moreover, the perifascicular expression pattern was specifically seen only in ASS but not in DM.[55] The absence of MxA expression is a good way of differentiating DM. MAC also shows sarcolemmal expression along with MHC-1.

   Inclusion Body Myositis Top

This is considered the most frequent myopathy in patients over 40 years of age. IBM was introduced as a myopathologic rather than a clinical entity.[56] It was not recognized as a separate entity by Bohan and Peter.[3] The majority of IBM recognized in the literature comes under the category of “polymyositis not responding to steroids.”[56]

IBM results from interplay of multiple etiologies that lead to chronic inflammation as well as degeneration in muscle tissue.[4] Viruses, muscle aging, protein misregulation (such as abnormal proteostasis), impaired autophagy, and HLA genotypes may play a role, either alone or in combination. The muscle fibers are invaded mostly by cytotoxic CD8+ T cells with some macrophages and are surrounded by CD4+ T cells and macrophages. Congophilic amyloid deposits in the muscle fiber similar to those seen in Alzheimer's disease reflect the neurodegenerative aspect of IBM.[57] Whether the primary event is inflammation or degeneration is a matter of debate.

The pathologic criteria were first proposed in a consensus meeting of expert clinicians and pathologists in 1995.[56] The criteria are summarized in [Table 3]. A diagnosis of “Definite IBM” [Figure 3] can only be made if all the pathologic criteria are satisfied. In the presence of classic clinical features, if only muscle invasion is seen and rimmed vacuoles are absent, then the diagnosis made is “possible IBM.”
Table 3: Griggs criteria for IBM

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Figure 3: Biopsy features of inclusion body myositis. (a) Biopsy demonstrating inflammation around non-necrotic fibers (b) with focal invasion of the fiber by inflammatory cells and (c) rimmed vacuoles; inset showing red rimming on MGT stain. (d) Mitochondrial abnormalities in the form of blue ragged fibers on SDH (asterisk). (e) The same fiber is COX negative (asterisk). (f) MHC class I antigen shows diffuse over-expression along the sarcolemma

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Many studies, however, have found that the classic pathologic features may be absent in biopsies. It was observed that following strict pathologic criteria brings in bias, and hence the 2011 ENMC classification incorporated a combined “clinicopathologic” approach for the classification of IBM [Table 4].[58]
Table 4: ENMC 2011 Criteria for diagnosis of inclusion body myositis

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The criteria put forth by Griggs et al. as well as the ENMC 2011 criteria are highly specific (98%–100%) but have low sensitivity. The sensitivity is only 11% and 29% for “definite” and “possible” IBM.[56],[58]

Lloyd et al.[59] used a machine-learning derived IBM classification and proposed criteria that require all of the following to be present: finger flexor or quadriceps weakness, endomysial inflammation, and either invasion of non-necrotic muscle fibers or the presence of rimmed vacuoles. These criteria have 90% sensitivity and 96% specificity. They suspended the criteria given by Griggs et al.[56]

Pathologic features

Endomysial inflammation around non-necrotic fibers with partial invasion is a prerequisite for the diagnosis of IBM. However, all biopsies need not show partial invasion.[60] Rimmed vacuoles are a marker of autophagy but can be seen in various other myopathies like myofibrillar myopathies and Nonaka myopathy. Congophilic deposits are seen, particularly if rimmed vacuoles are present. The amyloid stains and electron microscopy are not routinely done in all labs owing to technical problems and inconvenience.[61] The pathologic features are depicted in [Figure 3].

Mitochondrial abnormalities are almost always seen in the biopsies of IBM. Studies have identified these in the majority of IBMs, even in the absence of rimmed vacuoles.[60]

The mitochondrial abnormalities can be seen as COX-negative fibers that appear blue with a combined COX-SDH staining. Because IBM is a disorder of the elderly, there is no consensus about the percentage of the COX-negative fibers. More than 2% of fibers have been considered significant.


MHC Class I expression helps, particularly in biopsies that do not show inflammation, however lacks specificity for the diagnosis of IBM.

The amyloid deposits cross-react with amyloid β-42, apolipoprotein E, α-synuclein, presenilin, ubiquitin, and phosphorylated tau. Deposits of TDP43, a DNA-binding protein aberrantly translocated from the nuclei to the cytoplasm, and p62, a shuttle protein that transports polyubiquitinated proteins, detected within the muscle fibers with the use of immunostaining, have been advocated as diagnostic markers.[57],[62]

A combination of rimmed vacuoles, a characteristic pattern of p62 staining, and increased sarcolemmal and sarcoplasmic MHC I expression had a sensitivity of 93% and a specificity of 100% for IBM. p62 staining in the absence of rimmed vacuoles had a specificity of 91% for IBM, but a sensitivity of only 44%.[63]

IBM has shown activation of IFN2 pathway which can be demonstrated by immunohistochemical expression of HLA-DR, a surrogate marker for IFN2. The pattern of expression in biopsy is more diffuse rather than perifascicular as seen in DM.

Anticytosolic-5' nucleotidase 1A (cN1A, NT5C1A) is the only known antibody to be present but is not exclusive to IBM.[64],[65] The presence of anticN1A antibody is associated with clinical severity of muscle weakness, facial weakness, bulbar and respiratory involvement leading to death. Thus, its utility as a prognostic marker in IBM is mentioned to be considered only in the relevant clinico-pathological context.[66]

   Polymyositis Top

Polymyositis (PM) is a definite type of IIM. However, it often overlaps with other types due to similar clinical and biopsy features. As per Bohan and Peter, it is a subacute proximal myopathy without skin rash.[3]

Myositis is mediated by cytotoxic CD8+ T cells. These cells are presented to the muscle fibers via aberrantly expressed class I MHC molecules through T cell receptors. MHC Class I is normally absent in muscle fibers. This forms the MHC-CD8 complex. Other co stimulatory molecules, such as BB1 and ICOSL, as well as their ligands (CD28, CTLA-4, and ICOS), as well as ICAM-1 or LFA-1, help to stabilize the synaptic interaction between CD8+ cells and MHC class I on muscle fibers. Perforin granules released by the auto-aggressive T cells mediate muscle-fiber necrosis. Cytokines, such as interferon-γ, interleukin-1, and tumor necrosis factor (TNF) released by the activated T cells, may enhance MHC class I up-regulation and T-cell cytotoxicity. Activated B cells or PDCs are clonally expanded in the endomysium and may participate in the process in a still-undefined role, either as antigen-presenting cells or through cytokines and autoantibody production.[4]

These mechanisms have been incorporated into the ENMC 2003 criteria for defining PM. They define PM as subacute or insidious onset muscle weakness with elevated serum creatine kinase and endomysial CD8+ T-cell infiltration, surrounding and invading muscle fibers without skin rash.[5]

Pathologic features

The classic features include the presence of T cells surrounding and invading muscle fibers. This is associated with myopathic features like fiber atrophy and hypertrophy, degeneration, and regeneration. Vacuoles are absent. The biopsy criteria for “definite PM” were endomysial inflammatory cell infiltrate (T-cells) surrounding and invading non-necrotic muscle fibers, and for “possible PM,” endomysial CD8+ T-cells surrounding but not invading non-necrotic muscle fibers, or ubiquitous MHC-1 expression [Figure 4].[5]
Figure 4: Biopsy features of polymyositis. (a and b) Presence of lymphomononuclear infiltrate around non-necrotic fibers (c) with focal fiber invasion. (d and e) the infiltrate is positive for CD8 T cells. (f) MHC class I antigen is expressed diffusely along the sarcolemma

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Figure 5: Flow chart explaining the biopsy features to arrive at an appropriate subtype diagnosis of IIM

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The consistent immunohistochemical expression is diffuse sarcolemmal expression of MHC class I. However, with advances in detection and implication of autoantibodies, the majority of cases earlier diagnosed as PM are now reclassified into other types, including IMNM, ASS, dermatomyositis, and IBM.[67] This questions the existence of PM as a stand-alone entity!

   Overlap myositis Top

Many studies define overlap myositis (OM) as patients who fulfill both IIM and connective tissue disease (CTD) criteria. The recent definition of OM is myositis plus one or more overlap features or certain myositis associated antibodies (MAA) without meeting the criteria for CTD.[68] The main CTDs associated with IIM are systemic sclerosis (SSc) in 5%–43% of cases, systemic lupus erythematosus (SLE) in 4%–16%, and rheumatoid arthritis (RA) in 3%–5%, while Sjögren syndrome (SjS) is rare in IIM.[68],[69]

The common MAAs included are for antipoly-myositis/scleroderma (PM/Scl), anti-Ku, anti-U1-ribonucleoprotein (RNP), and anti-U3-RNP antibodies.[70],[71],[72] The biopsies of patients with anti-PM/Scl antibodies have shown intense perivascular infiltration.[73]

Necrotizing myopathy tends to show anti-Ku and anti-U1-RNP.[74],[75] Study of biopsies in patients with systemic sclerosis has shown a mild form of myositis with sparse endomysial T-lymphocytic infiltrates and the absence of any muscle fiber invasion.[76] This was termed “MMCP,” i.e., minimal myositis with capillary pathology. IHC for interferon signatures was negative with diffuse MHC class I expression.[77]

   Additional studies with a focus on the myopathology of IIM Top

It has been observed that all inflammatory myopathies cannot be reliably classified into definite subgroups of DM, PM, and IBM, particularly when biopsy lacks inflammatory foci. Alan Pestronk has given a focused and pure myopathologic approach to the classification of IIM.[78],[79] This was based on the examination of several sets of features, including immune characteristics, type of muscle fiber damage, and tissues involved. The groups in this classification were immune myopathies with perimysial pathology associated with antisynthetase antibodies (IMPP); myovasculopathies including childhood DM; immune polymyopathies with little inflammation associated with SRP; immune myopathies with endomysial pathology (IM-EP), which includes brachio-cervical inflammatory myopathy; histiocytic inflammatory sarcoid like myopathy; and inflammatory myopathies with vacuoles, aggregates, and mitochondrial pathology that resembles IBM (IM-VAMP).

Sampling errors, the focal nature of the disease, and inter-observer variability due to lack of clarity of pathologic parameters are some of the pitfalls of the ENMC 2003 criteria.

Hou et al.[80] in their study tried to quantify the so-called undefined criteria in ENMC classification by taking sections at multiple levels and using IHC markers with MHC-1, MHC-2, MAC, CD4, and CD8. This resulted in the reclassification of the Non-DM/s-IBM group in 21.57% of the cases. Furthermore, there are no clinical or therapeutic differences between non-DM and s-IBM. Thus, strict differentiation may not be necessary.

Attempts have also been made to score the four domains of the biopsy, including inflammation, vasculitis, fiber changes, and endomysial fibrosis.[81],[82] However, these scores were not found to be reliable to differentiate the subtypes of IIM, and the correlation between muscle power and CK levels was modest.

The EULAR/ACR published a new practical tool to subtype the IIM and also differentiate the IIM from its mimics.[83] The results were based on the clinical and pathologic findings in 976 IIM patients. A total of 16 variables were included from six categories, including the age of onset, muscle weakness, skin manifestation, other clinical manifestations, laboratory measurements, and muscle biopsy, and each was assigned a weight (score). The total probability of 90%, corresponding to having a total aggregate score of ≥7.5 without muscle biopsy and ≥8.7 with muscle biopsy, was defined as “definite IIM” and 55% and 90% were defined as “probable IIM,” whereas the range of 50% and 55% were classified as “possible IIM.” These probability ranges were calculated by a web calculator.

These criteria demonstrated sensitivity and specificity of 87% and 82%, respectively, with higher accuracy when muscle biopsies were included (93% and 88%). The best performance was seen for JDM. The advantages of these criteria are that they are data-driven and use a limited number of accessible, defined clinical and laboratory parameters.

However, these criteria included only five autoantibodies, and muscle biopsy was optional. They are more clinically oriented and incorrect typing can occur in the absence of cutaneous lesions or the presence of other specific MSAs. It is important to note that muscle biopsy is essential in seronegative cases along with IHC to differentiate DM, IMNM, and ASS.

   Conclusion Top

Muscle biopsy and ancillary techniques have helped in understanding the pathogenetic mechanisms of these myopathies. The discovery of autoantibodies has changed the strategy of evaluation. However, one-third of IIMs are seronegative, and techniques for the detection of the antibodies are not uniform. Muscle biopsy remains an essential tool in such cases. The pathologic criteria defining the majority of IIM are now well established. Diagnosis of IBM is not possible without a biopsy. Hence, pathology is an important parameter in the classification criteria, and a clinic-sero-pathological classification is an appropriate way ahead.

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Conflicts of interest

There are no conflicts of interest.

   References Top

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Tanboon J, Uruha A, Stenzel W, Nishino I. Where are we moving in the classification of idiopathic inflammatory myopathies? Curr Opin Neurol 2020;33:590-3.  Back to cited text no. 2
Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med 1975;292:344-7.  Back to cited text no. 3
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Correspondence Address:
Megha Uppin
Department of Pathology, Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad - 500 082, Telangana
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpm.ijpm_1033_21

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