|Ahead of print publication
Idiopathic inflammatory myopathy: From muscle biopsy to serology
Ritu Verma1, Vimal Kumar Paliwal2
1 Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
2 Department of Neurology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
|Date of Submission||10-May-2020|
|Date of Acceptance||29-Aug-2020|
Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow - 226 014, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Idiopathic inflammatory myopathies (IIMs) are heterogeneous group of muscle disorders characterized by variable degree of muscle weakness and muscle inflammation. Various classification systems have been proposed for myositis. However, there remains a diagnostic uncertainty due to the presence of overlapping clinical and pathological features. Similar treatment outcomes to immunosuppressant drugs further add to diagnostic confusion. Introduction of myositis-specific and myositis-associated autoantibodies has widened the disease spectrum of IIMs. Despite being very crucial for the diagnosis and classification of myositis, these autoantibodies are not always present. Therefore, histopathological features and immunohistochemical markers are considered gold standard for the diagnosis of myositis. A correct diagnosis has important clinical and therapeutic implications. In this review, we have focused on salient clinicopathological features and newly developed serological markers in major subtypes of IIMs.
Keywords: Autoantibody, classification, diagnostic criteria, inflammatory myopathy, muscle biopsy
| Introduction|| |
Idiopathic inflammatory myopathies (IIMs) are immune-mediated diseases of skeletal muscles and other organs systems. Conventionally, IIMs have been classified based on clinical phenotype and muscle histopathology. Recently, the introduction of myositis-specific autoantibodies and myositis-associated autoantibodies (MAA) has widened the disease spectrum of IIMs that was previously limited to dermatomyosits (DM), polymyositis (PM), and inclusion body myositis (IBM) [Table 1]. Nearly two-third of patients with IIMs may have one or more detectable autoantibody. However, due to variable sensitivity and specificity of autoantibodies for the diagnosis of myositis, histological and immunohistochemical evaluation of muscle biopsy still play a pivotal role in the diagnosis of various subtypes of IIMs. In this review, we focused on the salient clinicopathological features of different IIMs and discussed their role in classification in view of newly available serological markers for the diagnosis of IIMs.
| Diagnosis of Idiopathic Inflammatory Myopathies|| |
For the diagnosis of IIMs, clinicians rely on symptoms, signs, electromyography (EMG), and elevated serum levels of muscle enzymes. EMG recognizes myositis by the presence of small polyphasic motor-unit action potentials, increased insertional activity, and spontaneous muscle fiber activity. However, these myopathic changes on EMG are also seen in many patients with muscular dystrophy and other noninflammatory muscle diseases. Due to overlap with other muscle disease, muscle biopsy is the key element for diagnostic workup. Inflammatory changes are the pertinent feature on muscle histology. However, it is to note that inflammatory cell infiltrates are not specific to IIMs and can be seen in muscular dystrophies and metabolic myopathies. Simultaneous immunohistochemical assessment of MHC-1 expression and presence of T-cells and macrophages is also helpful for diagnosis. It is also to be noted that the surface expression of MHC-1 is not specific to IIMs and can be seen in few muscular dystrophies as well. Staining for MHC-II or applying a cutoff value of ≥50% for the fraction of fibers staining internally with MHC-1 appears to be 100% specific for IIMs.
Autoantibody testing has now become an important tool for the diagnosis of IIMs. The presence of MAA is helpful in distinguishing inflammatory from noninflammatory myopathy. Myositis-specific autoantibodies are almost exclusively present in IIMs. The most common anti-aminoacyl-tRNA synthetase autoantibody is anti-Jo1 antibody seen in 20%–25% patients of PM or dermatomyositis. The correlation between the presence of specific antibody and muscle histology is not very clearly elucidated and needs further experiments.
| Pathogenesis of Idiopathic Inflammatory Myopathies|| |
Several mechanisms have been proposed for the pathogenesis of myositis, and the important ones are:
- Direct effect of inflammatory cell infiltrate including CD4+ and CD8+ T-cells, B cells, macrophages, and dendritic cells
- Indirect effect of cytokines including interleukins (ILs), tumor necrosis factor, and interferon
- Involvement of microvasculature (capillaries and venules) showing thickening of endothelial cells and increased expression of adhesion molecules and also decrease in the number of capillaries in muscle tissue
- Humoral mechanism as suggested by the presence of autoantibodies in serum and expression of complements and immunoglobulin in muscle biopsy
- Genetic polymorphism as seen by clinical differences in various subtypes.
Capillaries are considered primary antigenic targets in DM. Humoral-mediated autoimmunity leads to complement system activation and membrane attack complex (MAC) deposition on endothelial cells of endomysial capillaries. MAC, C3b, and C4b are detected early in patient's serum. These may be detected in the capillaries even before the appearance of inflammatory or structural changes on muscle histology. Some authors refute the famous perifascicular atrophy theory whereby the ischemia caused by focal microvascular depletion produces the perifascicular atrophy of muscle fibers. Hypoxia has also been suggested as a postulated mechanism. Hypoxia-inducible factor 1α and its downstream gene products are overexpressed in DM. The role of CD4+ T cells has also been proposed in the pathogenesis. Role of cytokines as IL-1, IL-6, IL-15, and IFN is also postulated.
Endomysial CD8+ T cells play a central role in the immune pathogenesis of PM. Though rare, a clonal expansion of B cells has also been identified in PM. Microvasculature is intact in PM. These CD8+ T cells and macrophages interact with MHC1 in muscle fibers, releasing cytotoxic granules, and cause the morphological changes (myonecrosis). Muscle fibers normally do not express detectable amount of MHC Class I or II antigens. In PM and IBM, widespread overexpression of MHC is an early event seen even in areas devoid of inflammation. It is postulated that upregulation of MHC1 is related to overexpression of cytokines and chemokines seen in these patients.
There are no T cell infiltrate or MHC1 expression in immune-mediated necrotizing myopathy (IMNM)/NAM as opposed to PM and IBM. Some patients have deposition of complement on blood vessels. It is likely that NAM is an antibody-mediated disease.
There is strong evidence for the inflammatory component including clonally restricted, antigen-driven, infiltrating CD8 + T cells in IBM. A strong association with HLA genes and with cN1A antibodies has also been found. It is now known that inflammation can cause secondary degenerative features. Inflammatory cytokines induce the expression of the immunoproteasome in muscle, which strongly co-localizes with fibers expressing MHC1. Overexpression of MHC1 can induce ER stress and protein unfolding. Among immune and neurodegenerative-related genes, HLA region has the strongest association with IBM, especially HLA-DRB1.
| Muscle Biopsy Features|| |
A muscle biopsy is essential not only to confirm IIMs but also to identify the subset of IIMs and distinguish it from other noninflammatory muscle diseases. The common histological parameter to all IIMs is the presence of inflammatory infiltrate in muscle tissue. Though muscle biopsy is gold standard for the diagnosis of myositis, there are some overlapping and some distinct features, which are used to classify different IIMs and to differentiate them from other muscular diseases [Table 2].
|Table 2: Summary of histopathological features and important autoantibodies in major subtypes of idiopathic inflammatory myopathies|
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Muscle fiber component
Muscle biopsy shows features of active myopathic changes and inflammatory infiltrate in inflammatory myopathy. However, immune-mediated myopathy may lack distinctive inflammatory infiltrate. Morphological features to consider in the diagnosis are distribution of fiber damage, presence or absence of chronic remodeling, and rimmed vacuoles. Immunohistochemical staining for MHC1, MAC, and labeling of COX is also helpful. dermatomyositis.
The characteristic histopathological features of PM and dermatomyositis are the presence of mononuclear inflammatory cell infiltrates and degeneration and regeneration of muscle fibers [Figure 1]. Atrophy of the muscle fibers in perifascicular location is considered the hallmark of Perifascicular atrophy involves both Type 1 and Type 2 muscle fibers. Internalized nuclei, muscle fiber necrosis, vacuolar changes, and endomysial fibrosis may also be seen in dermatomyositis. Sometimes, perifascicular atrophy and skin lesions characteristic of dermatomyositis are often seen in anti-synthetase syndrome (ASS), especially anti-Jo1 myositis.
|Figure 1: Muscle biopsy in a patient with Dermatomyositis showing perifasicular atrophy (arrow) (a), perivascular inflammatory infiltrate (b) and moderate endomysial and perimysial fibrosis (c). Muscle biopsy in a patient with Polymyositis showing scattered endomysial inflammatory foci invading non-necrotic muscle fiber (d), focal degenerative muscle fiber (e) and minimal fibrosis (f). (a,b,d,e- hematoxylin and eosin stain, x40 & c,f- modified gomori trichrome, x40)|
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PM shows nonspecific biopsy features such as mild fiber size variations, scattered necrotic and regenerating fibers, and increase in perimysial and/or endomysial connective tissue [Figure 1].
In IMNM/NAM, muscle biopsy shows no or minimal inflammation, however there is prominent, randomly distributed muscle fiber necrosis and regenerating fibers in various stages. Similar features are also seen in muscular dystrophy and toxic myopathies.
Muscle biopsy in IBM reveals distinct features as nonnecrotic muscle fibers with one or more, irregular and various sized vacuoles, most with basophilic granular deposits around the edges (rimmed vacuoles), eosinophilic cytoplasmic inclusions, usually near the vacuoles and single or multiple intracellular amyloid depositions, usually in nonvacuolated area. However, in the early stage of disease, all features may not be seen in muscle biopsy. The rimmed vacuoles contain debris that is red and granular on modified Gomori trichrome stain. They often show the presence of prominent chronic myopathic changes as frequent pyknotic nuclear clumps and hypertrophic fibers resembling chronic neurogenic atrophy.
Myositis is often absent or subclinical in ASS, with intersitial lung disease being the primary clinical manifestation, therefore muscle biopsy is not performed. While muscle biopsy is useful in the diagnosis of other IIMs, there is no evidence of role of muscle biopsy in the diagnosis of ASS. The muscle biopsy shows perifascicular muscle fiber necrosis and an increase in sarcolemmal MHC1 expression predominantly in the perifascicular region.
In DM, the inflammatory component is usually perivascular and perimysial [Figure 1]. It predominantly consists of CD4+ T cells, macrophages, dendritic cells, and B cells.
Endomysial inflammatory infiltrate is usually seen at multiple foci in PM [Figure 1]. It is mainly composed of CD8+ T cells and to a lesser extent CD4+ T cells, macrophages, and dendritic cells. This inflammatory infiltrate usually surrounds or invades viable myofiber. This difference in the inflammatory component and location of inflammation within the muscles suggests different pathogenic mechanisms of PM and DM. T-cell-mediated myofiber damage is a predominant mechanism in PM, whereas microvascular inflammation produces dermatomyositis.
In IMNM, the inflammation is predominantly endomysial and perivascular, however in comparison to other inflammatory myopathies, macrophages are the predominant cells.
In IBM, there are endomysial CD8+ T cells as seen in PM. However, mitochondrial myopathic changes such as cytochrome-C-oxidase negative fibers help to differentiate IBM from DM and PM even in the absence of rimmed vacuoles.
Deposition of MAC around small blood vessels in perifascicular location is the earliest abnormality detected in dermatomyositis. The atrophic fibers in DM often show loss of COX reactivity. This is in contrast to atrophic fibers in ASS where COX reactivity is typically retained. In IBM, COX-negative and ragged red fibers are often encountered. Sarcoplasmic immunohistochemical expression of myxovirus resistance protein (MxA), a surrogate marker for IFN1 pathway activation, has been recognized as highly sensitive (71%–77%) and specific (98%–100%) for the diagnosis of dermatomyositis.
Increased expression of MHC Class II and I is present in regenerating and normal muscle fibers in myositis. The MHC Class I expression is more frequently observed. Upregulation of MHC1 is usually seen in perifascicular fibers in DM whereas diffuse expression is seen in PM.. These dual CD8 + and MHC1-positive muscle fiber is an important feature of PM. This helps in differentiating PM from muscular dystrophies such as Duchene muscular dystrophy that may sometimes show muscle inflammation.,,
Upregulation of MHC1 antigen in nonnecrotic muscle fibers can help to diagnose IMNM/NAM. Complement deposition on capillaries and sarcolemma of non-necrotic fibers is more characteristic of an immune-mediated process.
MHC1 is diffusely upregulated in IBM. In the MRC 2010 criteria for the diagnosis of IBM, increased expression of MHC1 on intact muscle fibers was added as one of the pathologic features. The European Neuromuscular Centre (ENMC) 2011 criteria later on included the presence of protein accumulation demonstrated by either intracellular amyloid deposit, or other protein detected with antibodies to p62, SMI31, or TDP43 to the pathologic criteria. There is also increase in the number of COX-negative muscle fibers in IBM.
In OM, biopsy reveals perifascicular necrosis and perifascicular sarcolemmal binding of complements and MHC1 and MHCII antibodies.
Comparing MHC1 expression with the type of MSAs, it has been found that MHC1 staining is higher in anti-EJ and anti-NXP2 groups and is lowest in anti-SRP group, though this difference was not statistically significant.
Electron microscopic studies are not routinely required. However, in difficult situations and for research purposes, it may be useful. In DM, the presence of tubuloreticular inclusions within the endothelial cytoplasm of arterioles and capillaries is the unique ultrastructural alteration. In IBM, tubulofilamentous inclusions of 15–21 nm in the cytoplasm and/or in the nucleus of the muscle fibers known as paired helical filaments are seen. In addition, cytoplasmic 6-01 nm amyloid-like filaments and deposits of flocculomembranous and amorphous material are seen. Actin aggregates in myocyte nuclei may be identified in ASS.
| Autoantibodies|| |
More than 80% of patients with inflammatory myositis may have the presence of autoantibodies. They have been classified as myositis-specific autoantibodies (MSAs) and MAAs. MSAs have a specificity of 90% and are associated with distinct phenotypes. MAAs are not disease specific and are seen in patients with overlap syndrome. Twenty percent of the patients with DM have anti-Mi2 antibody and 10%–30% have MDA5 antibody. TIF-1γ is the most common antibody in JDM, without malignancy. Recently, anti-SAE antibody has been found in ~8% of patients of DM.
IMNM/NAM is usually associated with anti-HMGCR and anti-SRP antibodies, seen in 60%–80% of patients. Anti-SRP antibody is usually associated with a severe disease course. Anti-HMGCR antibody is considered quite specific for NAM. The autoimmune mechanism of NAM is unclear as anti-SRP and anti-HMGCR antibodies have not been convincingly shown to be pathogenic. As SRP and HMGCR are involved in protein synthesis, their co-localization with neural cell adhesion molecule-positive regenerating fibers suggests that these proteins might be enhancing regeneration rather than initiating myofiber destruction.
The only antibody associated with IBM is anti-cN1A. Elevated levels are reported to be 33%–76% sensitive and 92%–96% specific for IBM. However, this antibody has been detected in other autoimmune disorders such as Sjögren's syndrome, systemic lupus erythematosus, and DM. Antibodies associated with overlap myositis excluding the ASS antibodies are anti-Ku, anti-PM/Scl, anti-Ro/Sjögren's syndrome, anti-U1 RNP, and anti-PUF60 antibodies. Anti-Jo1 antibody is the most common of the eight anti-synthetase antibodies seen in OM and is seen in ~30% of patients. Other antibodies associated with connective tissue disorders are also seen in OM patients. Anti-PM/Scl is the most common of these antibodies.
It has been proposed that for diagnosis of ASS, patients must have the presence of tRNA synthetase antibody and one other clinical feature. However, later, stricter criteria were framed and it included the presence of an aminoacyl tRNA synthetase autoantibody plus two major or one major and two minor criteria. Most of these criterion are clinical with no emphasis on histology features. However, it has been emphasized that ASS should not be excluded if there is high suspicion as antibody titers fluctuate during the course of disease.
Few studies have correlated histopathological features of muscle biopsy with the type of MSA in serum. Severe muscle involvement was seen in anti-SRP group and mild in anti-MDA5 and anti-TIF1γ groups. Unlike other ASAs, anti-Jo1 group had distinct perifascicular necrosis. Punched-out fibers and perifascicular atrophy were most frequent in anti-NXP2 patients. Connective tissue proliferation is more severe in anti-EJ group and anti-Jo1 group. The present criteria for the diagnosis of idiopathic pulmonary fibrosis with autoimmune features include features in clinical, histological, and serological domains. In serology, antibodies associated with connective tissue diseases such as rheumatoid factor, anti-citrullinated peptide, anti-nuclear antibody, and several MSAs are seen. Autoantibodies associated with it are predominantly antisynthetase antibody (anti-tRNA synthetase) and dermatomyositis-specific antibodies (Mi2, NXP2, MDA5, and TIF1-γ auto-antibodies) and sometimes anti-SRP, anti-SAE, and anti-HMGCR. Therefore, there should be a high suspicion for inflammatory myopathy in MSA-positive patients with interstitial lung disease.
| Diagnostic Challenges|| |
The main goal of differential diagnosis is to accurately specify the IIM subtype and rule out the mimics with secondary inflammatory pathology as muscular dystrophies, metabolic myopathy, infectious myopathy, toxic myopathy, or drug-induced myopathy. Though several guidelines for a diagnostic muscle biopsy features for IIMs have been proposed, none has been standardized. The use of different terminologies and criteria has made the diagnosis of inflammatory myopathy a difficult task. Focal invasion by CD8+ T cells of nonnecrotic muscle fibers expressing MHC1 is the main diagnostic feature because the CD8/MHC1 complex is distinctive of IIMs, and is different from degenerative, toxic, necrotizing myopathies with secondary macrophagic infiltration.
The 205th ENMC has recommended a list of basic stains to be used in muscle biopsy, assessment of myopathic features, and a score sheet describing these features. Muscle biopsy sections (snap freeze) should be stained with hematoxylin and eosin, modified Gomori trichrome, ATPase at 4.3 pH, nicotinamide adenine dinucleotide tetrazolium reductase, Cytochrome-C oxidase/succinate dehydrogenase (COX), acid phosphatase, alkaline phosphatase, and nonspecific esterase. Immunohistochemistry consists of detection of MAC, MHC1, CD4, CD8, CD31 (endothelial cells), CD68, and p62.
Despite well-established prototypical features in DM, PM, and IBM, none are truly pathognomonic. As the histopathological features on muscle biopsy may be unspecific or minimal or overlapping, the choice of muscle to be biopsied, proper processing, and careful interpretation are important. Determining the location and nature of cell infiltrate is important to avoid misinterpretation of the biopsy.
The main errors in the interpretation of morphological features are as follows:
- Forgetting that pathological involvement may be patchy
- Missing fiber necrosis due to overwhelming inflammation (cytotoxic T cells in PM, IBM, and macrophages in IMNM/NAM and few muscular dystrophies)
- Not recognizing the exact location of MHC1 expression-uniform expression of MHC1 in most muscle fibers as seen in PM and IBM and only in perifascicular location in DM. Ubiquitous expression of MHC1 is not seen in limb-girdle dystrophy, degenerative diseases, or metabolic myopathies
- Labeling perifascicular atrophy in the absence of inflammation as nonspecific feature
- Microvasculature involvement may be overlooked in the muscle biopsy
- Typical histological features of IBM may be absent in up to 15% of cases.
The combination of endomysial inflammation with rimmed vacuoles, ubiquitous MHC1 expression, and CD8+ T cells along with the presence of COX-negative fibers and congophilic deposits is diagnostic of IBM. Diagnostic confusion occurs when muscle biopsy shows only inflammation characterized by MHC1 expression and CD8+ T cells, and these patients may be labeled as PM. In such cases, presence of COX-negative fibers and fibers with chronic changes in the form of occasional large fibers, splitting or increase connective tissue will favor the diagnosis of IBM.
Clinical phenotypes, autoantibodies, and biopsy features have been used by several different classification criteria that have been proposed both for the diagnosis and subtyping of IIMs. However, there is no universally accepted criterion. The most widely used classification of Bohan and Peter utilizes clinical and histological features, but this criterion may diagnose certain muscular dystrophies as PM. It also fails to differentiate PM from NAM and IBM. Overdiagnosis of PM has been illustrated in a study where 50% of patients were diagnosed with PM using Bohan and Peter criteria.
ENMC criteria in 2003 used radiological features (magnetic resonance imaging of muscle) and the presence of autoantibodies to segregate patients into different specific subtypes. This classification criterion also included a list of inclusion and exclusion variables to be used in clinical, laboratory, and pathological features. These criteria were later shown to have a sensitivity of 51%–71% and a specificity of 82%–97%.
In 2011, another classification based solely on histopathology was proposed. It defined six new classes such as (1) immune myopathies with perimysial pathology; (2) myovasculopathies; (3) immune polymyopathies; (4) immune myopathies with endomysial pathology; (5) histiocytic inflammatory myopathy; and (6) inflammatory myopathy with vacuoles, aggregates, and mitochondrial pathology. However, further validation studies are needed to find its clinical usefulness.
In 2016, muscle biopsy features in all the four domains (inflammation, vascular, muscle fiber, and connective tissue) were extensively studied and scored and were then compared with clinical variables. For subtyping of IIMs, they had applied Bohan and Peter criteria. It was concluded that there is only modest correlation of muscle biopsy score with muscle power and CK levels.
In 2018, histological features of muscle biopsy were compared with clinical features and treatment outcomes in IIM subtypes. They had utilized ENMC classification for subtyping of IIMs. It was concluded that pathological changes used in ENMC criteria are dependent on muscle biopsy sampling and are thus biased. They also highlighted that results are less reproducible in the subtyping of IIMs when there is change in the cutoff levels of certain histological parameters such as number of T cells in perivascular location.
The International Myositis Classification Criteria Project (IMCCP) published a new classification criterion based on scores given to the different variables (12 clinical and 4 pathological parameters) to diagnose IIMs. Here, IIM was considered when the sum of all variables gave a probability of >55%. This scoring system helped to distinguish IIMs from other muscle diseases and also distinguishes the major subtypes of IIMs. The sensitivity and specificity of this new criterion was compared with that of previous important criteria, and it was found to have an overall sensitivity of 93% and specificity of 87%. However, the authors later on communicated that this provisional criterion also needs revision as more autoantibodies have been discovered and more specific biopsy features should be included. Absence of a universally accepted criteria for classification of myositis produces difficulties in the diagnosis and management of these patients.
Different MSA have been related to different clinical manifestations. Anti-Mi2, anti-TIF1γ, and anti-NXP2 are associated with skin involvement; ASA is associated with myositis and Gottron's papule; and anti-SRP is associated with dysphagia and severe necrotizing myositis. All these clinical manifestations lead to higher diagnostic scores bases on 2017 standard. Thus, MSA-positive patients are more likely to have probable or definite IIM, making diagnosis more reliable., Patients with ASS syndrome may have dermatomyositis-like skin lesions. As both these entities are distinct from each other, though may share some histological features on muscle biopsy (myofiber necrosis particularly perifascicular in location and perimysial (predominantly perivascular) mononuclear cell infiltrate and MHC1 and 2 expression on the cytoplasm and sarcolemma of non-necrtoic fibers), myxovirus resistance A expression in the cytoplasm of myofibers can help in distinguishing both entities. [Table 3] highlights some of the overlapping features in muscle biopsy of important IIMs among themselves and other muscular diseases and their differentiating features.
|Table 3: Overlapping histological features in idiopathic inflammatory myopathies and their differential|
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| Conclusion|| |
Numerous diagnostic and classification criteria have been proposed over six decades using the clinical, radiological, serological, and detailed histological features of muscle biopsy. Though the advancement in the detection of more and new autoantibodies has helped in understanding the pathogenesis of IIMs, it has resulted in difficulty in the subtyping of IIMs. Histopathology and immunohistochemistry remain gold standard for the diagnosis of myositis. However, using pathological criterion for subtyping myositis suffers from interobserver variability. Therefore, there is a need for well-defined parameters to diagnose and classify myositis.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]