New Myositis Classification Criteria—What We Have Learned Since Bohan and Peter

In 1975, the original Bohan and Peter classification proposal for both diagnosis and classification was published and remains to this day the most widely used classification criteria in the field of IIM (Table 1). For the first time, DM and PM were differentiated by the presence of classical DM skin rashes, definitions for “definite,” “probable,” and “possible” diagnosis for each subset were proposed and importantly certain exclusion criteria to eliminate IIM mimickers were provided. Despite these novelties, the Bohan and Peter criteria were criticized for including several non-specific myositis features (i.e., myopathic electromyography), vague exclusion criteria, unclear definitions of the classical DM skin rashes, and for not specifying the exact number of features necessary to fulfill certain specific criteria (i.e., muscle biopsy). In 1977, the criteria were applied to a case series of 153 IIM subjects, but the absence of a control group precluded the authors to comment on the ability of their criteria to discriminate DM/PM from mimickers such as neuromuscular conditions [8]. Subsequent studies reported that the Bohan and Peter criteria could adequately distinguish DM/PM from systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) [9]. Their combined sensitivity for definite and probable DM/PM diagnosis in 885 patients in studies published from 1977 to 1993 ranged between 74 and 100% [10].

At the time the Bohan and Peter criteria were published, a new subset of myositis resistant to corticosteroid treatment with specific tubulofilament and amyloid deposition on histopathology was described and named inclusion body myositis (IBM) [11, 12]. This subset showed distinctive clinical and laboratory features including a slowly progressive course, a specific pattern of muscle involvement, and the aforementioned typical histologic findings. This new entity was incorporated in the IIM diagnostic criteria formulated by Dalakas in 1991 [13]. These criteria, based on expert opinion, provided more detailed descriptions of each criterion of the Bohan and Peter criteria, including the histopathologic features expected to be found in DM, PM, or sporadic IBM (sIBM). Accordingly, perifascicular atrophy was considered diagnostic of DM especially if coupled with perivascular inflammatory infiltrates. Endomysial inflammation surrounding or invading non-necrotic muscle fibers without rimmed vacuoles and eosinophilic cytoplasmic inclusions was characteristic of PM.

While some investigators focused their efforts on linking histopathologic changes associated with each IIM subset to underlying pathologic mechanisms, others were discovering and describing myositis-specific autoantibodies (MSA). By 1990, seven MSA targeting different cytoplasmic ribonucleoproteins including helicase protein (Mi2), signal recognition particle (SRP), and five anti-aminoacyl-tRNA synthetases (histidyl (Jo1), threonyl (PL-7), alanyl (PL-12), glycyl (EJ), and isoleucyl (OJ)) were discovered and each one was found to be associated with unique clinical features [14, 15••]. In 1991, Love et al. proposed a novel classification of IIM based on these MSA, subsequent to a cross-sectional analysis of 212 IIM patients [16]. For each MSA subgroup, they detailed different disease profiles in terms of clinical features, human leucocyte antigen (HLA) associations, and prognosis. The “anti-synthetase syndrome” which refers to the association of interstitial lung disease (ILD), fever, arthritis, mechanic’s hand, myositis, and anti-synthetase autoantibody positivity was well-described, along with the anti-Mi2 phenotype of DM with classical rashes and good response to steroids.

In 1995, Tanimoto et al. published a new set of nine criteria to classify patients as either DM or PM based on a multicenter retrospective study with questionnaires and chart review [17]. Four of these criteria were not included in the original Bohan and Peter criteria: (1) muscle pain on grasping or spontaneous muscle pain; (2) non-destructive arthritis or arthralgias; (3) signs of systemic inflammation—fever, elevated C-reactive protein, or erythocyte sedimentation rate; and (4) the presence of anti-Jo1 antibody. Except for the latter, these new criteria were non-specific for IIM and several subsets such as juvenile IIM, cancer-associated myositis, and sIBM were not included in the analysis. A few years later, Targoff et al. proposed new modifications to the Bohan and Peter criteria with the goal of increasing the specificity of the original criteria which incorporated all the known MSAs at the time and muscle magnetic resonance imaging (MRI) [10]. sIBM was included in their IIM subsets as defined by the diagnostic criteria published by Griggs et al. that require specific clinical features and the presence on muscle biopsy of (1) inflammation, (2) vacuoles, and (3) amyloid deposits or tubulofilament by electron microscopy [18].

For decades, clinicians, especially dermatologists, recognized an entity called DM sine myositis or amyopathic DM [19] that refers to subjects with DM rashes without evidence of muscle involvement. In 2002, Sontheimer wrote an editorial proposing the expansion of the DM spectrum to include hypomyopathic and amyopathic dermatomyositis (ADM) [20]. ADM was integrated in the 2003 revised Dalakas diagnostic criteria but since it allowed “subclinical myopathy” on investigations, ADM more closely met the definition of hypomyopathic DM introduced by Sontheimer [21]. Van der Meulen et al. emphasized the importance of histopathologic assessment in identifying IIM subsets and raised the risk of misclassification of sIBM cases as PM by previous classification criteria [22]. Their paper fueled discussions among IIM experts who questioned the currently accepted definition of PM [22‐26].

The European Neuromuscular Center (ENMC) criteria designed on behalf of the Muscle Study Group and published in 2004 also required histopathologic confirmation in conjunction with clinical and laboratory criteria for IIM classification. These detailed criteria include MRI findings, some MSA, and specific immunohistochemical stainings that help differentiate DM and PM such as major histocompatibility complex class 1 (MHC-1) and membrane attack complex (MAC) [27‐29]. They delineate seven IIM subsets: IBM, PM, DM, ADM, possible DM sine dermatitis, non-specific myositis, and immune-mediated necrotizing myopathy (IMNM). The IMNM subset is differentiated by histopathologic features where muscle necrosis predominates with only sparse or mild perivascular inflammatory cells and possible vascular MAC deposition. The “non-specific myositis” refers to a subset of IIM that lacks the characteristic histopathologic changes of DM, PM, or IMNM, but still presents with perivascular or perimysial inflammatory cell infiltrates or scattered endomysial CD8+ T cells not clearly surrounding or invading muscle fibers. The authors believe that these different histopathology-oriented approaches to classification better reflect the underlying pathogenic insults, suggesting DM to be a B cell-mediated microangiopathy and PM a result of a MHC-1 restricted cytotoxic T cell response. In 2011, Pestronk challenged this hypothesis and introduced a very detailed classification of myopathology for IIM based on expert opinion, setting aside the previous DM, PM, and sIBM nomenclature [30]. The six patterns constituting Pestronk’s classification are immune myopathy with perimysial pathology (IMPP), myovasculopathy, immune polymyopathy, IIM with endomysial pathology (IIM-EP), histiocytic inflammatory myopathy, and inflammatory myopathy with vacuoles, aggregates, and mitochondrial pathology (IM-VAMP). Under that classification model, a DM patient could be classified either in the IMPP or myovasculopathy group, depending on the morphological features on muscle biopsy. This proposed classification was not validated and, although histopathological features are specific for different subtypes of IIM, some IIM patients will not be classified as such because they present with limited, unspecific, or overlapping histopathological features, giving histopathology-based criteria a low sensitivity. Furthermore, histopathological features may change over time and could reflect disease duration more than clinical phenotypes in some cases.

In the first decade of the twenty-first century, several new MSAs were described including three new anti-aminoacyl-tRNA synthetases (asparaginyl (KS), tyrosyl (HA), phenylalanyl (Zo)), the anti-melanoma differentiation antigen 5 (anti-MDA5), the anti-small ubiquitin-like modifier activating enzyme (anti-SAE), the anti-transcriptional intermediary factor 1 (anti-TIF1), the anti-antinuclear matrix protein (anti-NXP-2), and the anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (anti-HMGCR). Some of those autoantibodies have been linked to specific phenotypes and clinical courses such as the anti-TIF1γ, strongly associated with cancer-associated DM, or anti-HMGCR, a marker of IMNM associated with statin use [31‐33]. MSAs and their role in IIM are ever-evolving topic and have been previously reviewed extensively elsewhere [14, 34‐36].

In 2005, Troyanov et al. approached IIM classification from a different perspective, merging IIM clinical features with MSAs and myositis-associated autoantibodies profiles [37]. They considered overlap features, such as arthritis, ILD, or Raynaud phenomenon, as central components of their classification scheme. Their initial clinico-serological classification included four subsets: overlap myositis (OM), pure DM, pure PM, and cancer-associated myositis. The OM subset is characterized by the presence of autoantibodies such as anti-synthetases, SSc-associated autoantibodies, anti-SRP, and/or overlap features. Pure DM refers to the presence of a DM rash and/or positivity for anti-Mi2, and pure PM includes patients without overlap features or autoantibodies. Using this purely clinical approach, OM was the most frequent subset in the 100 IIM subjects included in their study. This subgroup also showed good response to corticosteroids. This clinico-serological classification was correlated with the muscle biopsies of 178 IIM patients based on the ENMC histopathologic criteria, and both approaches were found to be complementary [38••]. This classification was later updated by the authors to integrate newly described MSAs such as anti-MDA5, and more subsets namely overlap myositis with DM features (OMDM), necrotizing autoimmune myositis (NAM), and sIBM. Nailfold capillaroscopy abnormalities were also introduced as a characteristic feature of DM and OM [39••, 40]. In 2016, Benveniste et al. outlined a classification scheme integrating clinical and pathological features with four IIM subsets (IBM, OM, IMNM, and DM) and subdivision by MSA status [15••]. This interesting classification that bears similarities with the clinico-serological approach proposed by Troyanov et al. is however based on expert opinions and requires further validation.

IIM classification has been a matter of debate for decades, and myositis experts agree on the importance of reaching a consensus to improve future clinical trials. The previous classification criteria were mainly empirically derived and not properly validated. When studies were based on patient’s data, patient cohorts were often small, single-center, and did not include controls. To palliate for this, a group of international IIM experts including adult and pediatric rheumatologists, neurologists, dermatologists, epidemiologists, and biostatisticians was assembled in 2004 to develop new IIM classification criteria following the recommendations published by the EULAR/ACR [3, 4]. The goal was the development of classification criteria that would distinguish IIMs from mimickers and categorize IIMs in major subgroups with a minimum of clinical and readily available laboratory features. A consensus method was used for study design, definition of possible criteria candidates, and selection of IIM subgroups and comparators. Ninety-three variables were identified, selected from both previous criteria and suggestions of experts, and applied to 976 IIM cases and 624 non-IIM cases from 47 centers across the world. Two models, with or without muscle biopsy results, were developed to better reflect some clinical settings such as pediatrics, where performing muscle biopsy is not standard of care. Based on a complex but robust method, 16 variables deemed to provide better discrimination for IIM cases were weighted and included in a final criteria set presented in Table 2 and Fig. 1. A web-based calculator provides a score that represents the probability of a particular individual to have an IIM. Thus, researchers using this classification retain the capability to tailor the inclusion criteria to a certain level of sensitivity or specificity depending on the type of study considered. It provides detailed definition for each criteria and showed a sensitivity and specificity for a probable IIM diagnosis of 93 and 88%, respectively, when biopsy results are included (Table 3) [7, 41]. As with any classification schema, the EULAR/ACR model presents limitations. IIM being a heterogeneous group of diseases, not enough patients from rare subgroups (e.g., IMNM, hypomyopathic DM, and juvenile PM) could be recruited and only one MSA, anti-Jo1, was documented in enough subjects to be included in the final variables. It is plausible that with wider use of myositis antibodies, anti-Jo1 could be replaced by any MSA. Muscle MRI, only available in 38% of cases, was also excluded from the analysis. Thus, these criteria will soon require revision using a cohort with further data on MSAs and MRI, as well as validation in an external cohort with IIM cases and comparators.