Adult Inflammatory Myopathies: Updates on Classification and Management

Inflammatory myopathies (IM), commonly referred to as myositis, constitute a group of rare autoimmune diseases mostly affecting skeletal muscle. Additional extramuscular manifestations may include skin rash, arthritis, interstitial lung disease (ILD), and cardiac involvement.¹ The classification of IM comprises dermatomyositis, overlap myositis, antisynthetase syndrome (ASyS), immune-mediated necrotizing myopathy (IMNM), and sporadic inclusion body myositis (sIBM). The diagnosis of polymyositis is controversial and should only be made when the other types of myositis have been excluded. ASyS often presents with multisystem involvement, including ILD, arthritis, and (peri)myocarditis, whereas overlap myositis is frequently associated with connective tissue disorders.² IMNM and sIBM are identified as muscle-predominant phenotypes within the IM spectrum.

The identification of myositis-specific autoantibodies, which are present in up to 60% of individuals with IM, and myositis-associated autoantibodies has been linked to specific clinical phenotypes, and can be used to classify individuals with IMs into homogeneous phenotypic subtypes.¹

Diagnosing IM and its subgroups involves evaluating a combination of clinical symptoms and signs, as well as muscle biopsy features, muscle MRI patterns, serologic assessments, electroneuromyography features, and serum levels of muscle enzymes (Table). In this article, we review the diagnosis, classification, and evaluation of IMs.

Classification

Dermatomyositis

People diagnosed with dermatomyositis typically experience proximal muscle weakness over several weeks to months. Common symptoms include difficulty walking, getting up from a chair, climbing stairs, and lifting arms above the head. Around one-third of individuals may also experience dysphagia and neck weakness. Muscle pain is not a frequent complaint in individuals with dermatomyositis, but may be present, especially with fascial involvement.³ While assessing the individual, it is crucial to search for signs and symptoms of other organ involvement, particularly skin lesions characteristic of dermatomyositis. These include periorbital blue–purple rash (heliotrope rash); erythematous rash on the face, anterior chest (V sign), shoulders (shawl sign), and lateral hips (Holster sign); and a violaceous eruption on the knuckles (Gottron papules).³

Creatine kinase (CK) levels may be markedly elevated in individuals with dermatomyositis. However, in some cases, CK levels may be normal or only mildly elevated. Aldolase may also be elevated, especially in cases where the perimysium is involved.³ EMG is not necessary for diagnosis but is often performed when there are uncertainties in the differential diagnosis (eg, to exclude neurogenic causes of weakness and disorders of the neuromuscular junction). In IM, EMG reveals myopathic characteristics, including short-duration, small-amplitude motor unit action potentials (MUAPs) with early MUAP recruitment. Spontaneous activity, such as fibrillation potentials and positive sharp waves (also termed “irritative”), can be present when there is active degeneration of muscle fibers, but this is not a universal or specific feature of IM.³ Muscle imaging with ultrasound or MRI has become increasingly used as a diagnostic tool. MRI reveals T2- and short tau inversion recovery–weighted heterogeneous hyperintensities in the muscles, suggestive of muscle edema or inflammation. Gadolinium enhancement is also present, but frequently is not necessary for diagnosis, depending on the context. On ultrasound, a slight increase in echogenicity occurs in the setting of inflammation, with possible changes in muscle architecture. However, these findings can be mild. In chronic inflammation, there is a more marked increase in echogenicity. In active dermatomyositis,⁴ ultrasound shows an increase in echogenicity focally in muscle and in the overlying subcutaneous tissue, and MRI demonstrates T2/short tau inversion recovery hyperintensities in the fascial region of individual muscles, a characteristic less frequently seen in other IM subtypes.^3,5 The hallmark feature of dermatomyositis muscle biopsy is perifascicular atrophy. However, only ~50% of individuals with dermatomyositis have this histopathologic feature. Although a muscle biopsy may be helpful to confirm a diagnosis of dermatomyositis when perifascicular atrophy is present, individuals with typical skin manifestations or a known dermatomyositis-specific autoantibody (ie, anti–Mi-2, anti–nuclear matrix protein 2 [NXP2], anti–transcription intermediary factor 1 [TIF1], or anti–melanoma differentiation-associated protein 5 [MDA5]) usually do not require a muscle biopsy to confirm the diagnosis.⁶

Each dermatomyositis-specific autoantibody recognizes one of several different proteins or collections of proteins, including the Mi-2/nucleosome remodeling and deacetylase (NuRD) complex, NXP2, TIF1, and MDA5. Each of these autoantibodies is associated with a distinct clinical phenotype.

Anti–Mi-2. Anti–Mi-2 autoantigens are part of the NuRD complex, and anti–Mi-2 antibodies were initially recognized as myositis-specific in dermatomyositis in 1985.^7,8 Recently, it was recognized that muscle biopsies from people with anti–Mi-2 antibodies display a distinctive transcriptomic profile of more than 100 genes, and their expression levels correlate with both disease severity markers and titers of anti–Mi-2 autoantibodies.⁹ The unique gene set associated with anti–Mi-2 is notably enriched for genes regulated by the chromodomain helicase DNA binding protein 4 (CHD4)/NuRD complex. Immunoglobulin is evident within the nuclei and cytoplasm of muscle fibers in individuals with anti–Mi-2–positive dermatomyositis, and the proteins encoded by the Mi-2–specific genes are actively expressed within the muscle fibers of these individuals.⁹ The autoantigens targeted by anti–Mi-2 autoantibodies are components of the transcriptional repressor CHD4/NuRD.⁹ Consequently, it is postulated that anti–Mi-2 autoantibodies may infiltrate the sarcolemma of previously damaged muscle fibers, binding to CHD proteins and disrupting the CHD4/NuRD complex. Given the role of the CHD4/NuRD complex in inhibiting gene expression, this disruption could lead to derepression of the set of more than 100 genes. This cascade of events might exert a detrimental effect on muscle fibers, potentially contributing to the underlying pathology of the disease.⁹

The prevalence of anti–Mi-2 autoantibodies in adult dermatomyositis populations spans from 2% to 38%.⁷ These individuals present with “classic dermatomyositis,” characterized by the development of pathognomonic cutaneous manifestations.¹⁰ The cutaneous manifestations disproportionately associated with Mi-2 dermatomyositis in adults include Gottron papules (ie, violaceous erythematous patches, and thin, scaly plaques over the knee and elbow extensor surfaces), heliotrope rash, V-neck sign, shawl sign, cuticular overgrowth, poikiloderma, and flagellate erythema.^7,10 Other, more severe cutaneous features of dermatomyositis, such as calcinosis and ulcerative vasculopathy, are not commonly seen in this clinical subset.¹⁰

The highest CK and lactate dehydrogenase levels were observed in both juvenile and adult dermatomyositis with anti–Mi-2 compared with other dermatomyositis autoantibodies,^7,10 which is consistent with these individuals having exceptional weakness. Muscle biopsies in anti–Mi-2–positive dermatomyositis showed more necrosis compared with other autoantibody subgroups.¹¹ Despite the severity of presenting signs and symptoms, individuals typically have a favorable prognosis, with a good response to treatment; however, a risk of recurrence remains.⁷ Anti–Mi-2–positive individuals have a significantly diminished risk of ILD and lower malignancy rates compared with anti–Mi-2–negative individuals.⁷

Anti-NXP2. Individuals with anti-NXP2 antibodies also have substantial muscle weakness. They are more likely to have myalgia, subcutaneous edema, or dysphagia. Although anti–NXP2-positive and anti–NXP2-negative individuals have a similar prevalence of proximal weakness, a higher proportion of individuals with anti-NXP2 antibodies also have distal weakness, such as in finger extensors.¹² Calcinosis is also associated with anti-NXP2 autoantibodies. However, there is no association between muscle disease severity and the presence of calcinosis.¹³ Progressive calcinosis can develop long after the muscle disease has been well controlled.

MRI scans show increased muscle atrophy in anti–NXP2-positive compared with anti–NXP2-negative individuals. Anti–NXP2-positive individuals with dermatomyositis have a slightly increased risk for malignancy within 3 years of diagnosis.¹²

Anti-TIF1γ. TIF1 proteins, formerly known as p155/140, are pivotal tumor suppressor proteins serving as a transcriptional corepressor and a negative regulator of interferon-Β.^14-16 Each of the 3 subunits (α, Β, and γ) is associated with distinct autoantibodies.¹⁶

Anti-TIF1γ autoantibodies are prevalent in both juvenile and adult dermatomyositis, particularly in White populations, with a prevalence ranging from 38% to 41%.¹³ These individuals tend to have more severe and chronic dermatomyositis skin rashes. Anti-TIF1γ dermatomyositis presents with classic skin rashes, including photosensitive cutaneous disease featuring heliotrope rash, V sign, and Gottron papules.¹⁰ Distinctive dermatologic manifestations include ovoid erythematous palatal patches, palmar hyperkeratosis, psoriasis-like lesions, purpuric patches, and hypopigmented patches mixed with telangiectatic macules. The ovoid palatal patch demonstrates interface dermatitis, and is associated with an increased risk of malignancy.¹⁷ Despite the severity of cutaneous disease activity in these individuals, there is a decreased risk of calcinosis cutis, at least in adults.⁷ Both clinical dermatomyositis and clinically amyopathic dermatomyositis are observed in this subgroup, and individuals with muscle involvement tend to have relatively lower mean CK levels.¹³ Gastrointestinal involvement, including dysphagia, abdominal pain, vomiting, diarrhea, gastrointestinal bleeding, and bowel perforation, has been described. These individuals generally lack ILD, arthritis, and Raynaud phenomenon (RP).¹³

The primary clinical significance of anti-TIF1γ dermatomyositis is its strong association with underlying malignancy.¹³ Autoantibodies targeting TIF1 are implicated in the development of both solid and hematologic malignancies, with reported tumor rates ranging from 20% to 65% in the literature.¹⁰ The prevailing hypothesis suggests that anti-TIF1γ antibodies are generated as part of the immune response against tumors.¹⁰ Recently, it has been found that other autoantibodies, such as anti-Sp4, accompany anti-TIF1γ in individuals who do not develop cancer. This observation has led to the hypothesis that a more intense immune reaction against the tumor may effectively eliminate cancer cells.¹⁸

Anti-MDA5. MDA5, previously known as CADM140, is an RNA-specific helicase involved in the antiviral immune response, notably contributing to the production of type I interferon.¹⁰ Autoantibodies against MDA5 are prevalent in most adults with clinically amyopathic dermatomyositis and in 10% to 30% of individuals with dermatomyositis overall.¹⁰

Anti-MDA5 dermatomyositis is linked to an increased risk of developing ILD, which, in certain cases, may progress rapidly,¹⁰ which is often refractory to immunosuppression and carries a high mortality rate.¹⁹ These individuals may have ground-glass opacity on CT and worsening arterial oxygen pressure (PaO2).¹⁰ The presence of skin ulcers is associated with an increased risk for ILD.²⁰ Concomitant anti-Ro52 with anti-MDA5 autoantibodies increases the risk of ILD and cutaneous ulcerations.²¹ In addition to its pulmonary implications, anti-MDA5 dermatomyositis presents with distinctive cutaneous findings believed to be attributable to the development of cutaneous vasculopathy of small and medium-sized vessels found in biopsies.¹³ These include cutaneous ulceration, often occurring at the site of Gottron papules and the lateral nail folds, as well as painful palmar papules (referred to as “inverse Gottron papules”), panniculitis, severe nonscarring alopecia, cutaneous ulcers, livedoid lesions on pulps, mechanic hands, calcinosis cutis, and a higher prevalence of oral erosions compared with anti–MDA5 autoantibody–negative dermatomyositis.^7,10,13

Anti-SAE. Anti–small ubiquitin-like modifier activating enzyme (SAE) dermatomyositis is a relatively infrequent subset of dermatomyositis, accounting for 8% of cases in adults, with variations in frequency across different races and ethnicities.¹⁰ This particular dermatomyositis subtype exhibits a strong association with human leukocyte antigen (HLA)-DQB1*03; HLA-DRB1*04 and 03-DQB1*03 are also identified risk factors.^21a

Individuals with anti-SAE dermatomyositis typically present with pronounced cutaneous manifestations and minimal myopathy.¹⁰ Over time, progressive muscle involvement becomes evident, often accompanied by severe dysphagia.¹⁰ Anti–SAE1/2-positive individuals have a typical dermatomyositis rash. Cutaneous ulcers are also observed.^21b Other dermatologic findings include dark red or violaceous rash and “angel wings,” consisting of widespread erythema sparing the inferior scapula.¹³ Some case series note frequent systemic symptoms, such as fever and weight loss.¹⁰ In anti–SAE1/2-positive individuals, ILD tends to be mild, with a low prevalence of respiratory symptoms despite ILD evident on imaging. Recent studies in China and Japan have identified a subset of these individuals also presenting with pulmonary arterial hypertension.⁷ The etiology of this hypertension in relation to the severity of ILD remains under investigation.⁷

The presence of anti-SAE antibodies has been identified as a predictive factor for hydroxychloroquine drug eruptions.¹⁰ SAE-related dermatomyositis generally has a good prognosis, although skin disease can be difficult to control, requiring multiple medication changes.¹⁹

Overlap Myositis

Overlap myositis refers to the coexistence of IM in the context of another defined connective tissue disorder, such as systemic lupus erythematosus (SLE), systemic sclerosis (SS), rheumatoid arthritis, or Sjögren syndrome.³ In contrast to myositis-specific autoantibodies, which are only found in individuals with IM, these individuals often have myositis-associated autoantibodies, with the most prevalent ones being anti–polymyositis/scleroderma (PM/Scl) and anti–U1-RNP (ribonucleoprotein) antibodies.³ These antibodies have been identified in up to 20% of people with myositis.³ Anti-PM/Scl is associated with predominant upper limb weakness, whereas anti–U1-RNP is linked to ILD.³ Muscle biopsy of individuals with overlap myositis may reveal perivascular inflammation or myofiber necrosis along with an increase in MHC-I staining.³

Anti-PM/Scl autoantibodies may be found in people with a dermatomyositis/scleroderma overlap syndrome.¹⁹ In people with anti-PM/Scl, anti–U1–small nuclear RNP (snRNP), or anti-Ku autoantibodies, there is an elevated risk of developing ILD, pulmonary hypertension, arthritis, mechanic hands, and RP.¹⁹ Individuals may have only RP or small telangiectasias on the chest or face, without evident sclerodactyly or tight skin on the face or extremities.¹⁹ Thus, a high level of diagnostic suspicion is crucial to diagnose these overlap syndromes.¹⁹ Unlike other types of IM, anti-PM/Scl-positive individuals often have a greater degree of weakness in the arm abductors compared with the hip flexors.²²

Anti–U1-snRNP is conventionally identified in mixed connective tissue disease, where people have at least 2 of either SS, myositis, or SLE.¹⁹ In contrast to anti-PM/Scl, anti–U1-snRNP positivity has been associated with a more robust response to steroids.¹⁹ Pericarditis and glomerulonephritis are more common clinical problems in people with these autoantibodies.²³

Anti-Ku antibodies are detected in people with myositis with overlap syndromes of SLE, scleroderma, and Sjögren syndrome. The prognosis varies based on clinical manifestations, with musculoskeletal features responding well to high-dose steroids, whereas ILD often proves resistant to steroid treatment.¹⁹

Antisynthetase Syndrome

Several distinct subtypes of ASyS have been described based on the presence of autoantibodies recognizing different tRNA synthetases (eg, anti–histidyl tRNA synthetase [Jo-1], anti–threonyl tRNA synthetase [PL7], anti–alanyl tRNA synthetase [PL12], anti-Zo, anti-Ha, anti-KS, anti-OJ, anti-EJ).¹⁹ A new anti–aminoacyl tRNA synthetase (ARS) antibody directed against valyl tRNA synthetase (VRS) in a person with typical features of ASyS has been described.²⁴ The presence of one of these ASyS-specific autoantibodies is considered a prerequisite for classifying an individual as having ASyS.³

ASyS is identified by the presence of ASyS autoantibodies in the context of IM, ILD, or joint involvement.²⁵ Additional symptoms, such as fever, mechanic hands, or RP, may also manifest.³ Mechanic hands represents the traditional cutaneous presentation characterized by scaliness, hyperkeratosis, fissures, or hyperpigmentation, primarily affecting the ulnar surface of the thumb and the radial aspect of the fingers.¹³ The presence of mechanic hands is correlated with an increased risk of ILD.¹³ A parallel manifestation on the feet, called “hiker feet,” involves bilateral dryness, cracking, and hyperkeratosis, frequently observed concurrently with mechanic hands.²⁶ Not all people with ASyS have muscle weakness. Muscle involvement is more prevalent in people with the anti–Jo-1 subtype, and pulmonary issues are more common in people with the anti-PL12 or anti-PL7 subtypes, with some individuals displaying no clinical weakness.³ Morbidity and mortality rates in ASyS are often associated with rapidly progressive pulmonary involvement.³ The characteristics of muscle involvement in ASyS are the same as those of dermatomyositis, including proximal muscle weakness, elevated muscle enzymes, and myopathic changes on EMG.

Individuals with ASyS have hyperintensities on intramuscular T2-weighted MRI scans, but a specific distribution has not been described. Muscle biopsies may reveal perifascicular atrophy, such as dermatomyositis.²⁷ However, in comparison to dermatomyositis, muscle biopsies in ASyS may display more perifascicular necrotic fibers.²⁷

A better 5- and 10-year survival rate was described in individuals with ASyS with anti–Jo-1 antibodies versus those without anti–Jo-1 antibodies.¹⁹ The presence of anti-PL12 is linked to features that overlap with SS, such as skin sclerosis, esophageal involvement, and pulmonary hypertension.¹⁹ Cutaneous manifestations are more frequently observed in individuals with anti-EJ, anti-PL12, or anti-PL7 antibodies.¹⁹

Immune-Mediated Necrotizing Myopathy

Three subtypes of IMNM have been defined based on the presence or absence of autoantibodies recognizing the signal recognition protein (SRP) or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR). People with a necrotizing muscle biopsy in the absence of any known myositis-specific autoantibody are said to have seronegative IMNM.²⁸

Anti-HMGCR Autoantibody-Positive Myopathy (Statin-Associated IMNM). Autoantibodies recognizing HMGCR are associated with IMNM and statin use.^29,30 Anti–HMGCR antibody–positive myopathy accounts for approximately 6% of all idiopathic IMs³⁰ and 40% of all IMNMs.²⁹ This does not resolve after statin withdrawal and requires immunosuppression. Individuals develop subacute or insidious proximal muscle weakness, markedly elevated CK levels, irritative myopathy on EMG, and muscle edema on MRI. CK level on presentation ranges from 3,000 to 24,000 U/L (average 10,000 U/L),²⁹ with an elevated aldolase level in 75% of individuals.³¹ Dysphagia occurs in 25% to 60% of individuals and 20% experience weight loss, but extramuscular features such as ILD, rash, and arthritis are notably rare. HMGCR-IMNM with a disease duration longer than 3 years may resemble limb-girdle muscular dystrophy on skeletal muscle pathology and presentation.³²

Anti–SRP Autoantibody–Positive Myopathy. Approximately 3% to 6% of all individuals with idiopathic IMs³³ and 15% to 20% of people with IMNM²⁹ have antibodies that recognize SRP.

Clinically, anti–SRP-IMNM is characterized by acute or subacute, moderately severe, symmetric proximal weakness, often accompanied by myalgia, dyspnea, dysphagia, or muscle atrophy. Involvement of distal leg, bulbar, and axial muscles may also be observed in severe cases of SRP-IMNM.³⁴ People with rapidly progressive SRP-IMNM may be bedridden on presentation, which is less common in anti–HMGCR-positive IMNM. In comparison with SRP autoantibody–negative individuals, those with SRP-IMNM have a younger age at symptom onset. Younger age at onset is associated with more severe clinical symptoms in both SRP-IMNM and HMGCR-IMNM. SRP-IMNM also presents with neck weakness, dysphagia, respiratory insufficiency, and muscle atrophy more frequently than does HMGCR-IMNM.³⁴ Cardiac involvement may occur in SRP-IMNM and is associated with a worse prognosis.³⁴ Cardiac MRI is commonly recommended to screen for myocardial damage. Other extramuscular manifestations may be present in those with SRP-IMNM, including chest pain, arthritis, Sicca syndrome, mechanic hand, and carpal tunnel syndrome. Approximately 20% of people with SRP-IMNM have ILD,³⁴ although this is rarely clinically relevant.

Compared with HMGCR-IMNM and antibody-negative IMNM, SRP-IMNM has a lower risk of underlying malignancy.³⁴ A highly elevated CK level, usually exceeding 1,000 IU/L, is prominent in SRP-IMNM, with a positive correlation between serum CK levels and myofiber necrosis. Human leukocyte antigens DRB108:03, B5001, and DQA10104 are risk factors for developing SRP-IMNM, whereas DRB111:01 is more prevalent in HMGCR-IMNM.³⁴ Muscle MRI in SRP-IMNM reveals focal or diffuse muscle edema, atrophy, and fatty infiltration predominantly in proximal lower extremities. Fascial edema is less frequently observed in SRP-IMNM compared with dermatomyositis, and rapid fat infiltration (revealed on an MRI scan) may be a risk factor associated with refractory SRP-IMNM.³⁴ Atypical pathologic manifestations, including substantial mitochondrial abnormality, myofibrillary pathologic changes, and granulomatous inflammation, occasionally occur in SRP-IMNM. EMG is characterized by typical myogenic damage with positive sharp waves and fibrillation potentials in proximal limbs along with early recruitment of MUAPs. Myotonic discharges can sometimes be observed in SRP-IMNM.³⁴

Autoantibody-Negative IMNM. Studies in this group are limited by the heterogeneity of the disease. Seronegative individuals generally have clinical presentation and biopsy features similar to those of people with necrotizing myopathy with anti-HMGCR and anti-SRP autoantibodies. One notable difference is that preliminary reports show a higher rate of cancer-associated myositis, with a frequency of approximately 25%, necessitating vigilant cancer screening, especially within 3 years of the onset of myositis and in people older than 50 years.³⁵ Compared with seropositive IMNM, seronegative IMNM is characterized by female predominance (1:3), frequent occurrence of associated connective tissue disorders (22% vs 9%), and significantly higher rates of extramuscular disease activity (50% vs 16%), also after excluding people with an associated connective tissue disease (35% vs 7%).³⁶

Conclusion

Five primary types of IMs are recognized: dermatomyositis, including amyopathic dermatomyositis; overlap myositis; ASyS; IMNM; and sIBM. Within each type, specific autoantibodies separate cases into homogeneous subtypes. This broad classification is likely to change as more is learned about IMs, and the number of cases classified as antibody-negative dermatomyositis, antibody-negative IMNM, and polymyositis will decrease. A detailed understanding of disease mechanisms is needed to unveil new therapeutic targets.