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Diagnosis and Management of Immune-Mediated Myopathies

  • Margherita Milone
    Correspondence
    Correspondence: Address to Margherita Milone, MD, PhD, Neuromuscular Medicine Division, Department of Neurology, Mayo Clinic, 200 First St SW, Rochester, MN 55905.
    Affiliations
    Neuromuscular Medicine Division, Department of Neurology, Mayo Clinic, Rochester, MN
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      Abstract

      Immune-mediated myopathies (IMMs) are a heterogeneous group of acquired muscle disorders characterized by muscle weakness, elevated creatine kinase levels, and myopathic electromyographic findings. Most IMMs feature the presence of inflammatory infiltrates in muscle. However, the inflammatory exudate may be absent. Indeed, necrotizing autoimmune myopathy (NAM), also called immune-mediated necrotizing myopathy, is characterized by a necrotizing pathologic process with no or minimal inflammation in muscle. The recent discovery of antibodies associated with specific subtypes of autoimmune myopathies has played a major role in characterizing these diseases. Although diagnostic criteria and classification of IMMs currently are under revision, on the basis of the clinical and muscle histopathologic findings, IMMs can be differentiated as NAM, inclusion body myositis (IBM), dermatomyositis, polymyositis, and nonspecific myositis. Because of recent developments in the field of NAM and IBM and the controversies around polymyositis, this review will focus on NAM, IBM, and dermatomyositis.

      Abbreviations and Acronyms:

      CK (creatine kinase), cN1A (cytosolic 5′-nucleotidase 1A), DM (dermatomyositis), HMGCR (3-hydroxy-3-methylglutaryl coenzyme A reductase), IBM (inclusion body myositis), IIM (idiopathic inflammatory myopathy), IMM (immune-mediated myopathy), IVIG (intravenous immunoglobulin), MHC (major histocompatibility complex), MRI (magnetic resonance imaging), NAM (necrotizing autoimmune myopathy), PM (polymyositis), SRP (signal recognition particle)
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      Learning Objectives: On completion of this article, you should be able to (1) diagnose the most common immune-mediated myopathies, (2) associate antibodies with specific immune-mediated myopathies, and (3) differentiate muscle pathologic features of common immune-mediated myopathies.
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      Dr Milone received funding from the Center for Individualized Medicine and Department of Neurology, Mayo Clinic.
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      Immune-mediated myopathies (IMMs) are a heterogeneous group of acquired muscle disorders characterized by muscle weakness, elevated creatine kinase (CK) levels, and myopathic electromyographic findings. Because of the frequent presence of inflammatory infiltrates on muscle biopsy, IMMs are often referred to as idiopathic inflammatory myopathies (IIMs). However, the inflammatory exudate may be absent in the muscle in some IMMs. Indeed, muscle biopsy of necrotizing autoimmune myopathy (NAM), also called immune-mediated necrotizing myopathy, often reveals prominent muscle fiber necrosis and regeneration with minimal or no inflammation.
      • Liang C.
      • Needham M.
      Necrotizing autoimmune myopathy.
      • De Bleecker J.L.
      • De Paepe B.
      • Aronica E.
      • de Visser M.
      ENMC Myositis Muscle Biopsy Study Group
      205th ENMC International Workshop: pathology diagnosis of idiopathic inflammatory myopathies part II 28-30 March 2014, Naarden, The Netherlands.
      Since the 1975 classification of polymyositis (PM) and dermatomyositis (DM) by Bohan and Peter,
      • Bohan A.
      • Peter J.B.
      Polymyositis and dermatomyositis (first of two parts).
      there has been a constant effort to define diagnostic criteria and reclassify the IMMs, but to date, no diagnostic criteria or classification has found unanimous consensus.
      On the basis of the clinical and muscle histopathologic findings, IMMs can be distinguished as DM, PM, inclusion body myositis (IBM), NAM, and nonspecific myositis.
      • De Bleecker J.L.
      • De Paepe B.
      • Aronica E.
      • de Visser M.
      ENMC Myositis Muscle Biopsy Study Group
      205th ENMC International Workshop: pathology diagnosis of idiopathic inflammatory myopathies part II 28-30 March 2014, Naarden, The Netherlands.
      The entity PM is controversial, and although still recognized as a specific IIM, it seems to be overdiagnosed.
      • van der Meulen M.F.
      • Bronner I.M.
      • Hoogendijk J.E.
      • et al.
      Polymyositis: an overdiagnosed entity.
      • Amato A.A.
      • Griggs R.C.
      Unicorns, dragons, polymyositis, and other mythological beasts.
      Many patients with PM have been later diagnosed as having IBM or overlapping myositis.
      • van de Vlekkert J.
      • Hoogendijk J.E.
      • de Visser M.
      Myositis with endomysial cell invasion indicates inclusion body myositis even if other criteria are not fulfilled.
      • Troyanov Y.
      • Targoff I.N.
      • Tremblay J.L.
      • Goulet J.R.
      • Raymond Y.
      • Senécal J.L.
      Novel classification of idiopathic inflammatory myopathies based on overlap syndrome features and autoantibodies: analysis of 100 French Canadian patients.
      The distinction of DM, PM, IBM, NAM, and nonspecific myositis does not entirely reflect the true spectrum of IMMs. Indeed, a subset of IIM can have extramuscular involvement consisting of lung, skin, or joint involvement (overlap myositis). In addition, the recently discovered myositis-associated antibodies link to specific clinical and pathologic phenotypes and may even guide treatment.
      • Benveniste O.
      • Stenzel W.
      • Allenbach Y.
      Advances in serological diagnostics of inflammatory myopathies.
      These antibodies complement the clinical and myopathologic findings and contribute to the characterization of the IMMs. Therefore, these antibodies could be of tremendous value in the reclassification of IMMs.
      This article will discuss NAM, IBM, and DM as defined by clinical and myopathologic features.

      Needs in the Field

      In light of the knowledge on noninflammatory IMMs, the rarity of PM, and the discovery of myositis-associated antibodies, it has become evident that the old Bohan and Peter classification,
      • Bohan A.
      • Peter J.B.
      Polymyositis and dermatomyositis (first of two parts).
      as well as the more recently proposed classifications of IMMs, are in need of verification and revision.
      • De Bleecker J.L.
      • De Paepe B.
      • Aronica E.
      • de Visser M.
      ENMC Myositis Muscle Biopsy Study Group
      205th ENMC International Workshop: pathology diagnosis of idiopathic inflammatory myopathies part II 28-30 March 2014, Naarden, The Netherlands.
      • Hoogendijk J.E.
      • Amato A.A.
      • Lecky B.R.
      • et al.
      119th ENMC international workshop: trial design in adult idiopathic inflammatory myopathies, with the exception of inclusion body myositis, 10-12 October 2003, Naarden, The Netherlands.
      • Pestronk A.
      Acquired immune and inflammatory myopathies: pathologic classification.
      Diagnostic criteria for each subtype require definition and consensus.

      Necrotizing Autoimmune Myopathy

      Clinical Features

      Necrotizing autoimmune myopathy manifests with subacute proximal limb muscle weakness and persistently elevated CK levels. In contrast to immune-mediated inflammatory myopathies, NAM muscle biopsies often reveal no or minimal inflammation but prominent muscle fiber necrosis and regeneration (Figure 1, Table 1).
      • Liang C.
      • Needham M.
      Necrotizing autoimmune myopathy.
      • Kassardjian C.D.
      • Lennon V.A.
      • Alfugham N.B.
      • Mahler M.
      • Milone M.
      Clinical features and treatment outcomes of necrotizing autoimmune myopathy.
      Necrotizing autoimmune myopathy most frequently affects adults but can also occur in children.
      • Suzuki S.
      • Ohta M.
      • Shimizu Y.
      • Hayashi Y.K.
      • Nishino I.
      Anti-signal recognition particle myopathy in the first decade of life.
      • Allenbach Y.
      • Drouot L.
      • Rigolet A.
      • et al.
      French Myositis Network
      Anti-HMGCR autoantibodies in European patients with autoimmune necrotizing myopathies: inconstant exposure to statin.
      The weakness is predominantly proximal and more prominent in the lower limbs. In a recent Mayo Clinic study, coexisting distal weakness involving foot dorsiflexors and finger extensors was documented in more than 40% of patients.
      • Kassardjian C.D.
      • Lennon V.A.
      • Alfugham N.B.
      • Mahler M.
      • Milone M.
      Clinical features and treatment outcomes of necrotizing autoimmune myopathy.
      Neck muscle weakness and dysphagia are common. Occasionally, head drop and camptocormia are the predominant clinical features.
      • Kassardjian C.D.
      • Lennon V.A.
      • Alfugham N.B.
      • Mahler M.
      • Milone M.
      Clinical features and treatment outcomes of necrotizing autoimmune myopathy.
      • Ghosh P.S.
      • Milone M.
      Camptocormia as presenting manifestation of a spectrum of myopathic disorders.
      Myalgia may or may not be present. Respiratory muscle weakness is common as suggested by dyspnea, a restrictive pattern on pulmonary function tests, and abnormal findings on overnight oximetry. The respiratory muscle weakness can result in hypercapnic respiratory failure and the need for mechanical ventilation,
      • Kassardjian C.D.
      • Lennon V.A.
      • Alfugham N.B.
      • Mahler M.
      • Milone M.
      Clinical features and treatment outcomes of necrotizing autoimmune myopathy.
      • Apiwattanakul M.
      • Milone M.
      • Pittock S.J.
      • et al.
      Signal recognition particle immunoglobulin G detected incidentally associates with autoimmune myopathy.
      not only in the setting of generalized weakness but also at disease onset.
      • Jaeger B.
      • de Visser M.
      • Aronica E.
      • van der Kooi A.J.
      Respiratory failure as presenting symptom of necrotizing autoimmune myopathy with anti-melanoma differentiation-associated gene 5 antibodies.
      Cardiac involvement is infrequent and occurs in the form of left ventricular wall motion abnormalities or takotsubo cardiomyopathy.
      • Kassardjian C.D.
      • Lennon V.A.
      • Alfugham N.B.
      • Mahler M.
      • Milone M.
      Clinical features and treatment outcomes of necrotizing autoimmune myopathy.
      • Bangert E.
      • Afanasyeva M.
      • Lach B.
      • et al.
      Takotsubo cardiomyopathy in the setting of necrotizing myopathy.
      Necrotizing autoimmune myopathy can be associated with cancer; therefore, cancer screening is needed.
      • Kassardjian C.D.
      • Lennon V.A.
      • Alfugham N.B.
      • Mahler M.
      • Milone M.
      Clinical features and treatment outcomes of necrotizing autoimmune myopathy.
      • Alshehri A.
      • Choksi R.
      • Bucelli R.
      • Pestronk A.
      Myopathy with anti-HMGCR antibodies: perimysium and myofiber pathology.
      • Kadoya M.
      • Hida A.
      • Hashimoto Maeda M.
      • et al.
      Cancer association as a risk factor for anti-HMGCR antibody-positive myopathy.
      Although NAM is commonly a subacute myopathy, it can also manifest with slowly progressive weakness mimicking muscular dystrophies, clinically and pathologically.
      • Benveniste O.
      • Romero N.B.
      Myositis or dystrophy? traps and pitfalls.
      Figure thumbnail gr1
      Figure 1Muscle biopsy specimens from a patient with necrotizing autoimmune myopathy and anti–3-hydroxy-3-methylglutaryl coenzyme A reductase antibodies. A, There are numerous scattered necrotic muscle fibers (asterisks), fewer regenerating fibers (arrow), and no inflammatory exudate; few fibers have internalized nuclei (arrowhead) (hematoxylin-eosin). B, Macrophages invading necrotic fibers appear red (acid phosphatase stain).
      Table 1Pathologic Hallmarks of Immune-Mediated Myopathies
      MyopathyMuscle histologic featuresInflammatory cells
      NAMNecrotic and regenerating muscle fibersOnly about 20% of patients have an inflammatory exudate on muscle biopsy
      IBMInflammatory infiltrate invading nonnecrotic muscle fibers

      Rimmed vacuoles

      Congophilic inclusions
      CD 8+ T cells

      Macrophages
      DMPerifascicular muscle fiber atrophy

      Focal capillary depletion
      CD4+ T cells

      Plasmacytoid dendritic cells
      DM = dermatomyositis; IBM = inclusion body myositis; NAM = necrotizing autoimmune myopathy.

      Diagnosis

      The diagnosis of NAM relies on the combination of clinical and pathologic features and the exclusion of other etiologies that can result in a similar muscle histopathologic pattern. The histologic features of NAM (necrotizing myopathy with minimal or no inflammation) are nonspecific and also compatible with early muscular dystrophy or toxic myopathies.
      • Allenbach Y.
      • Benveniste O.
      Acquired necrotizing myopathies.
      The subacute onset of the weakness makes hereditary myopathy unlikely. The presence of serologic markers (see “Necrotizing Autoimmune Myopathy,” “Serologic Markers” section) and clinical response to immunotherapy support the autoimmune nature of the disease. Often, biopsy specimens from patients with NAM exhibit C5b9 deposits on the sarcolemma of nonnecrotic muscle fibers and diffuse major histocompatibility complex (MHC) class 1 up-regulation.
      • De Bleecker J.L.
      • De Paepe B.
      • Aronica E.
      • de Visser M.
      ENMC Myositis Muscle Biopsy Study Group
      205th ENMC International Workshop: pathology diagnosis of idiopathic inflammatory myopathies part II 28-30 March 2014, Naarden, The Netherlands.
      • Allenbach Y.
      • Benveniste O.
      Acquired necrotizing myopathies.
      • Chung T.
      • Christopher-Stine L.
      • Paik J.J.
      • Corse A.
      • Mammen A.L.
      The composition of cellular infiltrates in anti-HMG-CoA reductase-associated myopathy.
      However, the latter finding is nonspecific because it can be observed in muscular dystrophies, especially in those frequently associated with an inflammatory exudate in muscle.
      • Fanin M.
      • Angelini C.
      Muscle pathology in dysferlin deficiency.
      • Confalonieri P.
      • Oliva L.
      • Andreetta F.
      • et al.
      Muscle inflammation and MHC class I up-regulation in muscular dystrophy with lack of dysferlin: an immunopathological study.
      • Darin N.
      • Kroksmark A.K.
      • Ahlander A.C.
      • Moslemi A.R.
      • Oldfors A.
      • Tulinius M.
      Inflammation and response to steroid treatment in limb-girdle muscular dystrophy 2I.
      Although muscle fiber necrosis and regeneration are the main histologic features of NAM, approximatly 20% of patients with anti–3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) antibody have minor inflammatory infiltrates.
      • Pinal-Fernandez I.
      • Mammen A.L.
      Spectrum of immune-mediated necrotizing myopathies and their treatments.
      When present, the inflammatory cells are located in the endomysium and perivascular sites (CD8+ T cells invading nonnecrotic muscle fibers, as observed in PM, are not a feature of NAM) and consist predominantly of macrophages. These macrophages are likely involved in tissue repair and not destruction, as suggested by their M2 polarization.
      • Chung T.
      • Christopher-Stine L.
      • Paik J.J.
      • Corse A.
      • Mammen A.L.
      The composition of cellular infiltrates in anti-HMG-CoA reductase-associated myopathy.
      More conspicuous T-cell infiltrates have been described in anti–signal recognition particle (SRP) antibody–positive NAM.
      • Benveniste O.
      • Stenzel W.
      • Allenbach Y.
      Advances in serological diagnostics of inflammatory myopathies.

      Serologic Markers

      Levels of CK are always elevated in NAM, to the order of several thousands.
      The 2 main antibodies associated with NAM are the anti-HMGCR and anti-SRP antibodies (Table 2). Approximately a third of patients with NAM have no detectable HMGCR or SRP antibodies.
      Table 2Antibodies and Clinical Associations
      cN1A = cytosolic 5′-nucleotidase 1A; DM = dermatomyositis; Jo1 = histidyl–transfer RNA synthetase; IBM = inclusion body myositis; ILD = interstitial lung disease; MDA5 = melanoma differentiation–associated gene 5; NAM = necrotizing autoimmune myopathy; NA = not available; NXP2 = nuclear matrix protein 2; SAE = small ubiquitinlike modifier activating enzyme; SRP = signal recognition particle; TIF-1γ = transcriptional intermediary factor 1-γ.
      ,
      Dermatomyositis and NAM are associated with an increased risk of cancer compared with age- and sex-matched controls. Risk of cancer is higher in the presence of certain antibodies.
      AntibodyPhenotypeAdditional clinical features
      Anti–Mi-2DMNA
      Anti–TIF-1γDM↑ Risk of cancer

      ILD

      Severe skin disease
      Anti-MDA5DM

      Amyopathic DM
      ILD
      Anti-SAEDM
      Anti-NXP2DM↑ Risk of cancer (in adults)

      Calcinosis (in juvenile DM)
      Anti-Jo1Antisynthetase syndrome, myositis-predominantILD
      Anti-HMGCRNAM↑ Risk of cancer
      Anti-SRPNAM↑ vs unchanged risk of cancer
      Anti-cN1AIBMNA
      a cN1A = cytosolic 5′-nucleotidase 1A; DM = dermatomyositis; Jo1 = histidyl–transfer RNA synthetase; IBM = inclusion body myositis; ILD = interstitial lung disease; MDA5 = melanoma differentiation–associated gene 5; NAM = necrotizing autoimmune myopathy; NA = not available; NXP2 = nuclear matrix protein 2; SAE = small ubiquitinlike modifier activating enzyme; SRP = signal recognition particle; TIF-1γ = transcriptional intermediary factor 1-γ.
      b Dermatomyositis and NAM are associated with an increased risk of cancer compared with age- and sex-matched controls. Risk of cancer is higher in the presence of certain antibodies.
      3-Hydroxy-3-methylglutaryl coenzyme A reductase is the enzyme that catalyzes the rate-limiting step of cholesterol synthesis. Antibodies directed against HMGCR are present in patients with NAM who have been exposed to statins but also in statin-naive patients.
      • Kassardjian C.D.
      • Lennon V.A.
      • Alfugham N.B.
      • Mahler M.
      • Milone M.
      Clinical features and treatment outcomes of necrotizing autoimmune myopathy.
      • Pinal-Fernandez I.
      • Mammen A.L.
      Spectrum of immune-mediated necrotizing myopathies and their treatments.
      • Mammen A.L.
      Statin-associated autoimmune myopathy.
      Up to one-third of anti-HMGCR antibody–positive patients with NAM are statin naive and tend to have myopathy that is more resistant to treatment.
      • Mammen A.L.
      Statin-associated autoimmune myopathy.
      However, statins are also contained in dietary constituents, and therefore, individuals may not actually be statin naive. This factor has created confusion about the possible role of statins as a trigger for NAM. The duration of exposure to statins does not seem to affect the development of NAM, and in some patients, the myopathy has developed after discontinuation of the statins. In addition, statin discontinuation does not arrest the progression of the anti-HMGCR–associated myopathy.
      • Pinal-Fernandez I.
      • Mammen A.L.
      Spectrum of immune-mediated necrotizing myopathies and their treatments.
      In general, anti-HMGCR antibody titers correlate with CK levels and disease activity.
      • Allenbach Y.
      • Drouot L.
      • Rigolet A.
      • et al.
      French Myositis Network
      Anti-HMGCR autoantibodies in European patients with autoimmune necrotizing myopathies: inconstant exposure to statin.
      • Pinal-Fernandez I.
      • Mammen A.L.
      Spectrum of immune-mediated necrotizing myopathies and their treatments.
      • Werner J.L.
      • Christopher-Stine L.
      • Ghazarian S.R.
      • et al.
      Antibody levels correlate with creatine kinase levels and strength in anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase-associated autoimmune myopathy.
      However, in a large cohort of Chinese patients with low prevalence of statin exposure, serum levels of anti-HMGCR antibody did not match disease activity.
      • Ge Y.
      • Lu X.
      • Peng Q.
      • Shu X.
      • Wang G.
      Clinical characteristics of anti-3-hydroxy-3-methylglutaryl coenzyme A reductase antibodies in Chinese patients with idiopathic inflammatory myopathies.
      Atorvastatin and simvastatin were the most common statins in the Mayo Clinic NAM cohort.
      • Kassardjian C.D.
      • Lennon V.A.
      • Alfugham N.B.
      • Mahler M.
      • Milone M.
      Clinical features and treatment outcomes of necrotizing autoimmune myopathy.
      Atorvastatin was the statin most frequently associated with anti-HMGCR antibodies in a more recent study.
      • Basharat P.
      • Lahouti A.H.
      • Paik J.J.
      • et al.
      Statin-induced anti-HMGCR-associated myopathy.
      The anti-HMGCR antibodies are quite specific for NAM. A large international study of approximately 1900 sera detected anti-HMGCR antibodies in NAM and in only a few cases of inflammatory myopathies associated with muscle fiber necrosis (PM and DM) but not in the serum of patients with muscular dystrophy.
      • Musset L.
      • Allenbach Y.
      • Benveniste O.
      • et al.
      Anti-HMGCR antibodies as a biomarker for immune-mediated necrotizing myopathies: a history of statins and experience from a large international multi-center study.
      Patients with self-limiting statin intolerance and self-limiting cerivastatin-related rhabdomyolysis had no anti-HMGGCR antibodies, suggesting that the early detection of the anti-HMGCR antibodies could distinguish statin-associated NAM from the statin self-limiting myopathy.
      • Pinal-Fernandez I.
      • Mammen A.L.
      Spectrum of immune-mediated necrotizing myopathies and their treatments.
      • Floyd J.S.
      • Brody J.A.
      • Tiniakou E.
      • Psaty B.M.
      • Mammen A.
      Absence of anti-HMG-CoA reductase autoantibodies in severe self-limited statin-related myopathy.
      Essentially, the detection of anti-HMGCR antibodies would allow the early diagnosis and treatment of NAM. However, the measurement of anti-HMGCR antibodies in the cohort of patients with self-limiting cerivastatin-related rhabdomyolysis was performed years after the diagnosis of rhabdomyolysis. Therefore, the possibility that these patients had circulating antibodies at the time of the myopathy or “seronegative” NAM cannot be excluded. In addition, cerivastatin was removed from the market in early 2000 because of renal failure secondary to rhabdomyolysis.
      • Furberg C.D.
      • Pitt B.
      Withdrawal of cerivastatin from the world market.
      Therefore, the observation that cerivastatin-related rhabdomyolysis is not associated with anti-HMGCR antibodies cannot be generalized to all the statins.
      Signal recognition particle is a complex consisting of 6 polypetides and a 7S RNA molecule that is important for the translocation of newly formed proteins to the endoplasmic reticulum. Similar to anti-HMGCR, anti-SRP antibody titers also correlate with CK levels and degree of muscle weakness, raising the possibility of a pathogenic role for such antibodies in NAM.
      • Benveniste O.
      • Drouot L.
      • Jouen F.
      • et al.
      Correlation of anti-signal recognition particle autoantibody levels with creatine kinase activity in patients with necrotizing myopathy.
      The specificity of anti-SRP antibodies is controversial because these antibodies have also been reported in other autoimmune disorders.
      • Brouwer R.
      • Hengstman G.J.
      • Vree Egberts W.
      • et al.
      Autoantibody profiles in the sera of European patients with myositis.
      • Kao A.H.
      • Lacomis D.
      • Lucas M.
      • Fertig N.
      • Oddis C.V.
      Anti-signal recognition particle autoantibody in patients with and patients without idiopathic inflammatory myopathy.
      Moreover, the use of the terms NAM, PM, and myositis interchangeably in some studies limits the assessment of the diagnostic specificity of anti-SRP antibodies.
      Comparing anti-HMGCR antibody–positive and anti-SRP antibody–positive patients with NAM, the latter seem to have more severe weakness and susceptibility to development of interstitial lung disease.
      • Pinal-Fernandez I.
      • Parks C.
      • Werner J.L.
      • et al.
      Longitudinal course of disease in a large cohort of myositis patients with autoantibodies recognizing the signal recognition particle.
      • Watanabe Y.
      • Uruha A.
      • Suzuki S.
      • et al.
      Clinical features and prognosis in anti-SRP and anti-HMGCR necrotising myopathy.
      In comparison with the general population, patients who have NAM with anti-HMGCR antibodies, as well as those without anti-HMGCR or anti-SRP antibodies, have a higher incidence of malignant disease, which was not observed in a cohort of anti-SRP antibody–positive patients with NAM.
      • Allenbach Y.
      • Keraen J.
      • Bouvier A.M.
      • et al.
      High risk of cancer in autoimmune necrotizing myopathies: usefulness of myositis specific antibody.
      Cancers of various types seem to occur mainly within 3 years of NAM diagnosis and in patients older than 50 years.
      • Allenbach Y.
      • Keraen J.
      • Bouvier A.M.
      • et al.
      High risk of cancer in autoimmune necrotizing myopathies: usefulness of myositis specific antibody.
      However, malignant disorders have also been documented in anti-SRP antibody–positive NAM.
      • Apiwattanakul M.
      • Milone M.
      • Pittock S.J.
      • et al.
      Signal recognition particle immunoglobulin G detected incidentally associates with autoimmune myopathy.
      Therefore, independent from the coexisting serologic markers, broad screening for cancer is appropriate.

      Pathogenesis

      The role of anti-HMGCR and anti-SRP antibodies and their pathogenicity in NAM remain unknown. It has been suggested that the HMGCR up-regulation induced by statins may contribute to the development of the disease in immunogenetically predisposed individuals (only 2-3 per 100,000 statin-treated patients per year have development of NAM
      • Mammen A.L.
      Statin-associated autoimmune myopathy.
      ). The HMGCR overexpression in regenerating muscle tissue could perpetuate the muscle insult by driving the autoimmune response.
      • Pinal-Fernandez I.
      • Mammen A.L.
      Spectrum of immune-mediated necrotizing myopathies and their treatments.
      A similar mechanism may apply to NAM-associated cancer, as HMGCR is up-regulated in some malignant cells.
      • Chushi L.
      • Wei W.
      • Kangkang X.
      • Yongzeng F.
      • Ning X.
      • Xiaolei C.
      HMGCR is up-regulated in gastric cancer and promotes the growth and migration of the cancer cells.
      In regard to anti-SRP antibodies, their potential pathogenicity in NAM is indirectly suggested by the correlation of the antibody titer with the CK values
      • Benveniste O.
      • Drouot L.
      • Jouen F.
      • et al.
      Correlation of anti-signal recognition particle autoantibody levels with creatine kinase activity in patients with necrotizing myopathy.
      and demonstration of anti-SRP antibody–dependent complement-mediated muscle cell lysis in culture.
      • Rojana-udomsart A.
      • Mitrpant C.
      • Bundell C.
      • et al.
      Complement-mediated muscle cell lysis: a possible mechanism of myonecrosis in anti-SRP associated necrotizing myopathy (ASANM).

      Treatment

      No randomized clinical trials have been performed in patients with NAM, and treatment is based on expert opinion and data from case series. Although therapy should be individualized, it appears that corticosteroids alone are often not sufficient to treat the disease, and most patients require at least 2 immunosuppressant drugs. In the Mayo Clinic cohort, patients who received 2 or more immunotherapeutic agents (corticosteroids, intravenous immunoglobulin [IVIG], and a steroid-sparing immunosuppressant agent) in the first 3 months of treatment were more likely to experience significant improvement.
      • Kassardjian C.D.
      • Lennon V.A.
      • Alfugham N.B.
      • Mahler M.
      • Milone M.
      Clinical features and treatment outcomes of necrotizing autoimmune myopathy.
      In addition, early treatment with IVIG seems to be associated with a more significant improvement in strength.
      • Benveniste O.
      • Stenzel W.
      • Allenbach Y.
      Advances in serological diagnostics of inflammatory myopathies.
      • Kassardjian C.D.
      • Lennon V.A.
      • Alfugham N.B.
      • Mahler M.
      • Milone M.
      Clinical features and treatment outcomes of necrotizing autoimmune myopathy.
      • Allenbach Y.
      • Drouot L.
      • Rigolet A.
      • et al.
      French Myositis Network
      Anti-HMGCR autoantibodies in European patients with autoimmune necrotizing myopathies: inconstant exposure to statin.
      • Suzuki S.
      • Hayashi Y.K.
      • Kuwana M.
      • Tsuburaya R.
      • Suzuki N.
      • Nishino I.
      Myopathy associated with antibodies to signal recognition particle: disease progression and neurological outcome.
      • Garcia-Rosell M.
      • Moore S.
      • Pattanaik D.
      • Menon Y.
      • Bertorini T.
      • Carbone L.
      Signal recognition antibody-positive myopathy and response to intravenous immunoglobulin G (IVIG).
      • Ramanathan S.
      • Langguth D.
      • Hardy T.A.
      • et al.
      Clinical course and treatment of anti-HMGCR antibody-associated necrotizing autoimmune myopathy.
      Intravenous immunoglobulin as monotherapy has also been successful in treating rare cases of anti-HMGCR antibody–positive NAM.
      • Mammen A.L.
      Statin-associated autoimmune myopathy.
      Rituximab may be especially beneficial in anti-SRP antibody–positive NAM.
      • Pinal-Fernandez I.
      • Parks C.
      • Werner J.L.
      • et al.
      Longitudinal course of disease in a large cohort of myositis patients with autoantibodies recognizing the signal recognition particle.
      • Ashton C.
      • Junckerstorff R.
      • Bundell C.
      • Hollingsworth P.
      • Needham M.
      Treatment and outcomes in necrotising autoimmune myopathy: an Australian perspective.
      Corticosteroid weaning or discontinuation of immunotherapy is associated with a high relapse rate.
      • Kassardjian C.D.
      • Lennon V.A.
      • Alfugham N.B.
      • Mahler M.
      • Milone M.
      Clinical features and treatment outcomes of necrotizing autoimmune myopathy.
      • Ashton C.
      • Junckerstorff R.
      • Bundell C.
      • Hollingsworth P.
      • Needham M.
      Treatment and outcomes in necrotising autoimmune myopathy: an Australian perspective.

      Inclusion Body Myositis

      Clinical Features

      Inclusion body myositis is often indicated as sporadic IBM to distinguish it from hereditary IBM, which has a genetic etiology. The term IBM will be used here to indicate the acquired form. Inclusion body myositis is the most common acquired muscle disease in patients older than 50 years.
      • Hilton-Jones D.
      • Brady S.
      Diagnostic criteria for inclusion body myositis.
      It has a mild male predominance and is characterized by early development of quadriceps and finger flexor weakness and atrophy (Figure 2, A and B). The weakness is frequently asymmetric. When present, quadriceps weakness greater than that in the hip flexors favors the diagnosis of IBM over other inflammatory myopathies. Dysphagia and weakness of the foot dorsiflexors are also common. Facial weakness occurs in up to 55% of cases (Figure 2, C), and axial weakness may occur in the advanced stage of the disease.
      • Dimachkie M.M.
      • Barohn R.J.
      Inclusion body myositis.
      • Needham M.
      • Mastaglia F.L.
      Sporadic inclusion body myositis: a review of recent clinical advances and current approaches to diagnosis and treatment.
      Occasionally, facial weakness, dysphagia, and camptocormia secondary to paraspinal muscle weakness can be the manifesting feature of IBM.
      • Ghosh P.S.
      • Laughlin R.S.
      • Engel A.G.
      Inclusion-body myositis presenting with facial diplegia.
      • Ma H.
      • McEvoy K.M.
      • Milone M.
      Sporadic inclusion body myositis presenting with severe camptocormia.
      Asymptomatic impairment of respiratory function is common in IBM, as well as sleep-disordered breathing, independent from daytime respiratory function.
      • Della Marca G.
      • Sancricca C.
      • Losurdo A.
      • et al.
      Sleep disordered breathing in a cohort of patients with sporadic inclusion body myositis.
      • Rodríguez Cruz P.M.
      • Needham M.
      • Hollingsworth P.
      • Mastaglia F.L.
      • Hillman D.R.
      Sleep disordered breathing and subclinical impairment of respiratory function are common in sporadic inclusion body myositis.
      Diaphragmatic weakness has been described occasionally.
      • Martin S.E.
      • Gondim D.D.
      • Hattab E.M.
      Inclusion body myositis involving the diaphragm: report of a pathologically confirmed case.
      Although muscle weakness slowly progresses and may result in severe disability, life expectancy is not affected, although death can be related to aspiration pneumonia secondary to dysphagia.
      • Benveniste O.
      • Guiguet M.
      • Freebody J.
      • et al.
      Long-term observational study of sporadic inclusion body myositis.
      There is no evidence that IBM affects cardiac tissue, and the prevalence of cardiac abnormalities in IBM seems similar to that observed in the general population with similar age distribution.
      • Cox F.M.
      • Delgado V.
      • Verschuuren J.J.
      • et al.
      The heart in sporadic inclusion body myositis: a study in 51 patients.
      Figure thumbnail gr2
      Figure 2Features of inclusion body myositis. Note weakness of the finger flexors (A) but spared strength of finger extensors (B) in the same patient and weakness of the orbicularis oculi (C), as suggested by inability to close the eyes, in another patient.

      Diagnosis

      Muscle biopsy remains the criterion standard for the diagnosis of IBM. Patients with the classic pathologic features of IBM (Figure 3, Table 1)—autoaggressive CD8+ T cells invading nonnecrotic muscle fibers, rimmed vacuoles, congophilic inclusions, protein aggregates, and histologic signs of mitochondrial dysfunction—are diagnosed with definite IBM.
      • Griggs R.C.
      • Askanas V.
      • DiMauro S.
      • et al.
      Inclusion body myositis and myopathies.
      However, all the pathologic features of IBM may not be present in the muscle biopsy specimen, especially in the early stage of the disease. Therefore, researchers and clinicians have emphasized the relevance of clinical findings (eg, quadriceps weakness and flexor digitorum profundus weakness) in the diagnosis of IBM.
      • De Bleecker J.L.
      • De Paepe B.
      • Aronica E.
      • de Visser M.
      ENMC Myositis Muscle Biopsy Study Group
      205th ENMC International Workshop: pathology diagnosis of idiopathic inflammatory myopathies part II 28-30 March 2014, Naarden, The Netherlands.
      • Rose M.R.
      ENMC IBM Working Group
      188th ENMC International Workshop: inclusion body myositis, 2-4 December 2011, Naarden, The Netherlands.
      Figure thumbnail gr3
      Figure 3Muscle biopsy specimens from a patient with inclusion body myositis. A, Autoaggressive inflammatory infiltrates invading a nonnecrotic muscle fiber (arrow) (hematoxylin-eosin, original magnification ×40). B, Rimmed vacuoles (arrow) (trichrome stain, original magnification ×40). C, Congophilic inclusions within a muscle fiber appear bright red (arrow) (Congo red–stained section viewed under rhodamine optics, original magnification ×40).
      A recent study identified T-cell large granular lymphocytic leukemia in more than half of a cohort of 38 patients with IBM and muscle invasion by large granular lymphocytes.
      • Greenberg S.A.
      • Pinkus J.L.
      • Amato A.A.
      • Kristensen T.
      • Dorfman D.M.
      Association of inclusion body myositis with T cell large granular lymphocytic leukaemia.
      These findings led to the hypothesis that transformation of T-cell expansion into a neoplastic disorder might contribute to IBM refractoriness to immunotherapy. This study was criticized because of the unknown chronology of the IBM and T-cell large granular lymphocytic leukemia (which of the 2 diseases manifested first?) and lack of coexisting hematologic abnormalities (anemia or neutropenia) in IBM.
      • Hohlfeld R.
      • Schulze-Koops H.
      Cytotoxic T cells go awry in inclusion body myositis.

      Serologic Markers

      In IBM, the CK value is normal or increased less than 10-fold above the upper limit of normal.
      Anti–cytosolic 5′-nucleotidase 1A (cN1A) autoantibodies are a serologic marker of IBM (Table 2).
      • Larman H.B.
      • Salajegheh M.
      • Nazareno R.
      • et al.
      Cytosolic 5′-nucleotidase 1A autoimmunity in sporadic inclusion body myositis.
      • Pluk H.
      • van Hoeve B.J.
      • van Dooren S.H.
      • et al.
      Autoantibodies to cytosolic 5′-nucleotidase 1A in inclusion body myositis.
      Cytosolic 5′-nucleotidase 1A catalyzes the conversion of adenosine monophosphate into adenosine and phosphate. Moderate and high reactivity of anti-cN1A antibodies has been reported to be 92% and 98% specific for the diagnosis of IBM, respectively.
      • Pluk H.
      • van Hoeve B.J.
      • van Dooren S.H.
      • et al.
      Autoantibodies to cytosolic 5′-nucleotidase 1A in inclusion body myositis.
      In a small group of patients with IBM, the anti-cN1A antibody seropositivity was associated with more severe motor disability and respiratory involvement.
      • Goyal N.A.
      • Cash T.M.
      • Alam U.
      • et al.
      Seropositivity for NT5c1A antibody in sporadic inclusion body myositis predicts more severe motor, bulbar and respiratory involvement.
      However, anti-cN1A antibodies have also been detected in other autoimmune diseases, mainly systemic lupus erythematosus and Sjögren syndrome, and occasionally in nonautoimmune neuromuscular diseases.
      • De Bleecker J.L.
      • De Paepe B.
      • Aronica E.
      • de Visser M.
      ENMC Myositis Muscle Biopsy Study Group
      205th ENMC International Workshop: pathology diagnosis of idiopathic inflammatory myopathies part II 28-30 March 2014, Naarden, The Netherlands.
      • Herbert M.K.
      • Stammen-Vogelzangs J.
      • Verbeek M.M.
      • et al.
      Disease specificity of autoantibodies to cytosolic 5′-nucleotidase 1A in sporadic inclusion body myositis versus known autoimmune diseases.
      Therefore, anti-cN1A positivity should be interpreted in relationship to the patient's clinical and myopathologic findings. Anti-cN1A antibodies can be supportive of the diagnosis of IBM when the canonical myopathologic features of IBM are missing.
      Because amyloidogenic proteins accumulate in IBM muscle, investigators have studied amyloidogenic molecules as possible biomarkers of IBM. An increase of amyloid precursor protein β, β-secretase-1 (β-site amyloid precursor protein–cleaving enzyme 1) and γ-secretase (both enzymes process amyloid precursor protein), was demonstrated in the plasma from patients with IBM when compared with controls and other inflammatory myopathies.
      • Catalán-García M.
      • Garrabou G.
      • Morén C.
      • et al.
      BACE-1, PS-1 and sAPPβ levels are increased in plasma from sporadic inclusion body myositis patients: surrogate biomarkers among inflammatory myopathies [published online ahead of print November 3, 2015].
      However, the low sensitivity of these amyloidogenic biomarkers (despite the high specificity of ∼90%) limits their use in clinical practice.
      • Gallay L.
      • Petiot P.
      Sporadic inclusion-body myositis: recent advances and the state of the art in 2016.

      Pathogenesis

      The pathogenesis of IBM remains unclear. The disease is thought to be the result of a combined inflammatory and degenerative process. The autoaggressive inflammatory infiltrates mainly consisting of CD8+ T cells, sarcolemmal overexpression of MHC-1 and II,
      • Mastaglia F.L.
      • Needham M.
      Inclusion body myositis: a review of clinical and genetic aspects, diagnostic criteria and therapeutic approaches.
      regulatory T-cell down-regulation in blood,
      • Allenbach Y.
      • Chaara W.
      • Rosenzwajg M.
      • et al.
      Th1 response and systemic treg deficiency in inclusion body myositis.
      association with other autoimmune diseases,
      • Rojana-udomsart A.
      • Needham M.
      • Luo Y.B.
      • et al.
      The association of sporadic inclusion body myositis and Sjögren's syndrome in carriers of HLA-DR3 and the 8.1 MHC ancestral haplotype.
      and the recently discovered anti-cN1A antibodies suggest an autoimmune etiology.
      • Larman H.B.
      • Salajegheh M.
      • Nazareno R.
      • et al.
      Cytosolic 5′-nucleotidase 1A autoimmunity in sporadic inclusion body myositis.
      • Pluk H.
      • van Hoeve B.J.
      • van Dooren S.H.
      • et al.
      Autoantibodies to cytosolic 5′-nucleotidase 1A in inclusion body myositis.
      The rimmed vacuoles, abnormal protein aggregates, and lack of response to immunosuppressant therapy have pointed to a defect in protein degradation and a degenerative process as mechanisms contributing to the disease. Recently, a genetic contribution to the pathogenesis of IBM has emerged. Rare cases of sporadic IBM fulfilling diagnostic criteria for IBM were found to have sequence variants in genes causing hereditary IBM (eg, valosin containing protein, VCP; sequestosome 1, SQSTM1; slow/β cardiac myosin heavy chain 7, MYH7).
      • Gang Q.
      • Bettencourt C.
      • Houlden H.
      • Hanna M.G.
      • Machado P.M.
      Genetic advances in sporadic inclusion body myositis.
      • Weihl C.C.
      • Baloh R.H.
      • Lee Y.
      • et al.
      Targeted sequencing and identification of genetic variants in sporadic inclusion body myositis.
      Moreover, association studies have suggested a genetic susceptibility to IBM (eg, strong association with HLA-DRB*03:01 or disease-modifying effect of a specific polymorphism in translocase of outer mitochondrial membrane 40, TOMM40).
      • Needham M.
      • Mastaglia F.L.
      Sporadic inclusion body myositis: a review of recent clinical advances and current approaches to diagnosis and treatment.
      • Gang Q.
      • Bettencourt C.
      • Houlden H.
      • Hanna M.G.
      • Machado P.M.
      Genetic advances in sporadic inclusion body myositis.

      Treatment

      To date, there is no evidence that immunosuppressant drugs are beneficial in IBM. A long-term observational study found that immunosuppressive treatment did not improve the disease course and may have exacerbated the progression of the disability.
      • Benveniste O.
      • Guiguet M.
      • Freebody J.
      • et al.
      Long-term observational study of sporadic inclusion body myositis.
      A recent clinical trial with placebo vs bimagrumab, an activin receptor II inhibitor antibody, provided class I evidence that bimagrumab increases thigh muscle volume measured by magnetic resonance imaging (MRI).
      • Amato A.A.
      • Sivakumar K.
      • Goyal N.
      • et al.
      Treatment of sporadic inclusion body myositis with bimagrumab.
      However, a phase 2b/3 study found no evidence for beneficial effect of bimagrumab, leading to discontinuation of the study. Nevertheless, some physicians would consider a trial of treatment with corticosteroids and a steroid-sparing agent in patients with IBM who have rapidly progressive disease or associated autoimmune disease.
      • Needham M.
      • Mastaglia F.L.
      Sporadic inclusion body myositis: a review of recent clinical advances and current approaches to diagnosis and treatment.
      At the present time, treatment of IBM is largely supportive.

      Dermatomyositis

      Clinical Features

      Dermatomyositis is an inflammatory disease with prominent muscle and skin involvement. It causes subacute or insidiously progressive proximal muscle weakness, sometimes accompanied by myalgia. Dysphagia occurs and is more frequent in patients with severe weakness of sternomastoid muscles.
      • Mugii N.
      • Hasegawa M.
      • Matsushita T.
      • et al.
      Oropharyngeal dysphagia in dermatomyositis: associations with clinical and laboratory features including autoantibodies.
      Skin manifestations in DM include heliotrope rash, malar rash, Gottron papules, erythematous dermatitis, and photosensitivity. Nail beds can have dilated capillary loops. Oral features of DM are well characterized, such as lichen planus, gingival telangiectasia, desquamative gingivitis, and ovoid palatal patch.
      • Bernet L.L.
      • Lewis M.A.
      • Rieger K.E.
      • Casciola-Rosen L.
      • Fiorentino D.F.
      Ovoid palatal patch in dermatomyositis: a novel finding associated with anti-TIF1γ (p155) antibodies.
      The rash precedes or occurs at the same time as the weakness. Interstitial lung disease can be a facet of the multisystem inflammatory disease that causes DM. Older age at diagnosis, fever, heliotrope rash, and arthritis increase the risk of interstitial lung disease,
      • Zhang L.
      • Wu G.
      • Gao D.
      • et al.
      Factors associated with interstitial lung disease in patients with polymyositis and dermatomyositis: a systematic review and meta-analysis.
      which results in increased morbidity and mortality.
      • Johnson C.
      • Pinal-Fernandez I.
      • Parikh R.
      • et al.
      Assessment of mortality in autoimmune myositis with and without associated interstitial lung disease.
      Juvenile DM frequently follows a febrile episode and rash. It often has multisystem involvement and much more frequent subcutaneous calcinosis compared with adult DM.
      • Dimachkie M.M.
      • Barohn R.J.
      Idiopathic inflammatory myopathies.
      Severe juvenile DM can also affect the gastrointestinal tract, leading to severe abdominal pain, ulceration, or perforation.
      • Gitiaux C.
      • De Antonio M.
      • Aouizerate J.
      • et al.
      Vasculopathy-related clinical and pathological features are associated with severe juvenile dermatomyositis.
      Dermatomyositis is associated with an increased risk of malignant disease compared with age- and sex-matched controls, especially in males and in patients older than 45 years.
      • Antiochos B.B.
      • Brown L.A.
      • Li Z.
      • Tosteson T.D.
      • Wortmann R.L.
      • Rigby W.F.
      Malignancy is associated with dermatomyositis but not polymyositis in Northern New England, USA.
      The risk of cancer is higher in the 5 years surrounding the diagnosis of DM (2 years before and 3 years after) and also over the lifetime following the diagnosis of DM. The most frequent malignant disorders affect the breast, lung, pancreas, and colon. Patients with cancer seem less likely to have interstitial lung disease.
      A form of amyopathic DM manifests with the hallmark skin findings and no clinical or laboratory evidence of myositis but preserved susceptibility to the development of interstitial lung disease.
      • Udkoff J.
      • Cohen P.R.
      Amyopathic dermatomyositis: a concise review of clinical manifestations and associated malignancies.
      In regard to the risk of malignancy in amyopathic DM, there is conflicting information. Therefore, cancer screening is advised in patients with amyopathic DM.
      • Udkoff J.
      • Cohen P.R.
      Amyopathic dermatomyositis: a concise review of clinical manifestations and associated malignancies.
      • Bailey E.E.
      • Fiorentino D.F.
      Amyopathic dermatomyositis: definitions, diagnosis, and management.

      Diagnosis

      The diagnosis of DM relies on clinical manifestations and muscle pathologic findings. The hallmark pathologic feature of DM is the perifascicular muscle fiber atrophy, often accompanied by one or more of the following perifascicular structural abnormalities: internalized nuclei, muscle fiber necrosis, regeneration, focal basophilia, vacuolar changes, increased oxidative enzyme reactivity, and endomysial fibrosis (Figure 4, Table 1). The perifascicular atrophy is invariably associated with capillary depletion, often accompanied by membrane attack complex deposition on the muscle microvasculature.
      • Lahoria R.
      • Selcen D.
      • Engel A.G.
      Microvascular alterations and the role of complement in dermatomyositis.
      The inflammation is predominantly perimysial and perivascular and consists of CD4+ T cells and plasmacytoid dendritic cells. Autoaggressive inflammatory CD8+ T cells invading nonnecrotic muscle fibers are not a feature of DM.
      Figure thumbnail gr4
      Figure 4Muscle biopsy specimens from a patient with dermatomyositis. A and B, Note perifascicular muscle atrophy (arrows), a hallmark of dermatomyositis (A, hematoxylin-eosin; B, ATPase stain, pH 4.3). C, The inflammatory exudate concentrates in the perimysium at perivascular sites (arrow) (hematoxylin-eosin). D, Additional structural abnormalities are present in perifascicular regions: internalized nuclei (blue arrow), necrotic (asterisk) and regenerating (arrowheads) muscle fibers, vacuolar changes (black arrow) (hematoxylin-eosin).

      Serologic Markers

      In DM, CK values are often but not always elevated. Therefore, CK measurement may not be helpful in measuring disease activity. Various antibodies can be associated with DM (Table 2).
      The presence of anti–transcriptional intermediary factor 1-γ antibodies in adult patients with DM has a particularly high risk of cancer (48%-75%),
      • Targoff I.N.
      • Mamyrova G.
      • Trieu E.P.
      • et al.
      Childhood Myositis Heterogeneity Study GroupInternational Myositis Collaborative Study Group
      A novel autoantibody to a 155-kd protein is associated with dermatomyositis.
      • Fiorentino D.F.
      • Chung L.S.
      • Christopher-Stine L.
      • et al.
      Most patients with cancer-associated dermatomyositis have antibodies to nuclear matrix protein NXP-2 or transcription intermediary factor 1γ.
      • Hida A.
      • Yamashita T.
      • Hosono Y.
      • et al.
      Anti-TIF1-γ antibody and cancer-associated myositis: a clinicohistopathologic study.
      which, according to the most recent study, is detected within a year of the diagnosis of myopathy.
      • Hida A.
      • Yamashita T.
      • Hosono Y.
      • et al.
      Anti-TIF1-γ antibody and cancer-associated myositis: a clinicohistopathologic study.
      Dysphagia may also be more frequent in patients with DM who have anti–transcriptional intermediary factor 1-γ antibodies.
      • Mugii N.
      • Hasegawa M.
      • Matsushita T.
      • et al.
      Oropharyngeal dysphagia in dermatomyositis: associations with clinical and laboratory features including autoantibodies.
      Antibodies directed against the nuclear matrix protein NXP2 also carry an increased risk of cancer.
      • Fiorentino D.F.
      • Chung L.S.
      • Christopher-Stine L.
      • et al.
      Most patients with cancer-associated dermatomyositis have antibodies to nuclear matrix protein NXP-2 or transcription intermediary factor 1γ.
      In addition, anti-NXP2 antibodies predict the presence of calcinosis, especially in juvenile DM.
      • Gunawardena H.
      • Wedderburn L.R.
      • Chinoy H.
      • et al.
      Juvenile Dermatomyositis Research Group, UK and Ireland
      Autoantibodies to a 140-kd protein in juvenile dermatomyositis are associated with calcinosis.
      Antibodies directed against Mi2, a component of the nucleosome remodeling–deacetylase chromatin remodeling complex, have been associated with DM without lung involvement. Anti-Mi2 antibody–positive patients respond well to corticosteroids and rituximab.
      • Benveniste O.
      • Stenzel W.
      • Allenbach Y.
      Advances in serological diagnostics of inflammatory myopathies.
      Anti–melanoma differentiation–associated gene 5 antibodies predict rapidly progressive interstitial lung disease.
      • Zhang L.
      • Wu G.
      • Gao D.
      • et al.
      Factors associated with interstitial lung disease in patients with polymyositis and dermatomyositis: a systematic review and meta-analysis.
      They are associated with minimal or no perifascicular atrophy, despite the MHC-1 up-regulation in perifascicular regions, and their titer correlates with disease activity.
      • Benveniste O.
      • Stenzel W.
      • Allenbach Y.
      Advances in serological diagnostics of inflammatory myopathies.
      • Sato S.
      • Kuwana M.
      • Fujita T.
      • Suzuki Y.
      Anti-CADM-140/MDA5 autoantibody titer correlates with disease activity and predicts disease outcome in patients with dermatomyositis and rapidly progressive interstitial lung disease.
      Anti-Jo1 (or anti–histidyl-tRNA synthetase) antibodies have long been known to predict interstitial lung disease with an incidence as high as 90%. The combination of inflammatory myopathy, interstitial lung disease, arthritis, Reynaud phenomenon, and mechanic's hand and antisynthetase antibodies characterize the antisynthetase syndrome.
      • Benveniste O.
      • Stenzel W.
      • Allenbach Y.
      Advances in serological diagnostics of inflammatory myopathies.
      In addition to anti-Jo1 antibodies, there are other less common antisynthetase antibodies, such as anti-PL-7, PL-12, OJ, KS, EJ, Zo, and Ha antibodies. Severe skin involvement and systemic features have also been linked to the anti–small ubiquitinlike modifier activating enzyme.
      • Fujimoto M.
      • Watanabe R.
      • Ishitsuka Y.
      • Okiyama N.
      Recent advances in dermatomyositis-specific autoantibodies.

      Pathogenesis

      The pathogenesis of DM is still poorly understood. Several studies have focused on dissecting the mechanism leading to the myopathologic hallmark of perifascicular muscle atrophy. Results have been controversial, spanning from ischemia secondary to microvascular insult to increased expression of type 1 interferon–induced gene transcripts and proteins in the perifascicular muscle fibers and capillaries.
      • Emslie-Smith A.M.
      • Engel A.G.
      Microvascular changes in early and advanced dermatomyositis: a quantitative study.
      • Greenberg S.A.
      A gene expression approach to study perturbed pathways in myositis.
      The mechanism driving the overproduction of type 1 interferon and how this process results in capillary damage remains to be elucidated. A recent study confirmed that the perifascicular muscle atrophy is associated with focal microvascular depletion and that ischemia contributes to the perifascicular atrophy.
      • Lahoria R.
      • Selcen D.
      • Engel A.G.
      Microvascular alterations and the role of complement in dermatomyositis.
      The same study found that the observed microvascular membrane attack complex deposits in DM result from activation of the classic complement pathway, triggered by direct binding of C1q to injured endothelial cells. However, these observations did not explain the primary cause of the microangiopathy. An inflammatory vasculopathy has also been recognized as cause of the gastrointestinal ulceration and perforation in severe juvenile DM.
      • Gitiaux C.
      • De Antonio M.
      • Aouizerate J.
      • et al.
      Vasculopathy-related clinical and pathological features are associated with severe juvenile dermatomyositis.

      Treatment

      Corticosteroids at various dosages are the first-line treatment.
      • Johnson N.E.
      • Arnold W.D.
      • Hebert D.
      • et al.
      Disease course and therapeutic approach in dermatomyositis: a four-center retrospective study of 100 patients.
      • Tieu J.
      • Lundberg I.E.
      • Limaye V.
      Idiopathic inflammatory myositis.
      Higher dosages of prednisone may provide more immunosuppression but carry a risk of corticosteroid-induced myopathy. The greatest improvement in strength seems to occur in the first 6 to 12 months after treatment initiation.
      • Johnson N.E.
      • Arnold W.D.
      • Hebert D.
      • et al.
      Disease course and therapeutic approach in dermatomyositis: a four-center retrospective study of 100 patients.
      Various immunotherapeutic agents (methotrexate, azathioprine, IVIG, cyclosporine, mycophenolate mofetil) can be used as second-line agents or first-line agents combined with corticosteroids, but none is superior to others.
      • Johnson N.E.
      • Arnold W.D.
      • Hebert D.
      • et al.
      Disease course and therapeutic approach in dermatomyositis: a four-center retrospective study of 100 patients.
      • Tieu J.
      • Lundberg I.E.
      • Limaye V.
      Idiopathic inflammatory myositis.
      A retrospective study found that methotrexate combined with corticosteroids is superior to prednisolone alone.
      • Joffe M.M.
      • Love L.A.
      • Leff R.L.
      • et al.
      Drug therapy of the idiopathic inflammatory myopathies: predictors of response to prednisone, azathioprine, and methotrexate and a comparison of their efficacy.
      However, methotrexate carries the risk of pulmonary fibrosis. Therefore, methotrexate should be avoided in patients with interstitial lung disease or antibodies predicting interstitial lung disease. Rituximab has been used successfully in adult and pediatric patients with refractory myositis.
      • Oddis C.V.
      • Reed A.M.
      • Aggarwal R.
      • et al.
      RIM Study Group
      Rituximab in the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis: a randomized, placebo-phase trial.
      Other drugs, such as tacrolimus or etanercept, and plasmapheresis have also been utilized for management of refractory DM.
      • Tieu J.
      • Lundberg I.E.
      • Limaye V.
      Idiopathic inflammatory myositis.
      Muscle Study Group
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      It is important to treat infections, which are partially due to immunosuppression, because of the associated 5% mortality rate.
      • Johnson N.E.
      • Arnold W.D.
      • Hebert D.
      • et al.
      Disease course and therapeutic approach in dermatomyositis: a four-center retrospective study of 100 patients.
      Consensus-based recommendations were recently published for treatment of juvenile DM.
      • Enders F.B.
      • Bader-Meunier B.
      • Baildam E.
      • et al.
      Consensus-based recommendations for the management of juvenile dermatomyositis.
      Recommended therapy includes combined use of corticosteroids and methotrexate. Intravenous immunoglobulin, mycophenolate mofetil, cyclophosphamide, rituximab, infliximab, and cyclosporine should be used only to treat more severe DM or a disease partially responsive to corticosteroids and methotrexate. Skin disease requires aggressive therapy because of the associated high morbidity. Calcinosis may respond to bisphosphonates. It has been suggested that discontinuation of the methotrexate or other disease-modifying drug be considered once the patient is in remission and has not taken corticosteroids for at least 1 year.

      Additional Investigations

      Needle electromyography is useful in confirming the myopathic nature of the weakness in IMMs but does not differentiate the various subtypes. Motor unit potentials have myopathic features (reduced amplitude and duration) in most autoimmune myopathies but in sporadic IBM exhibit mixed myopathic and neurogenic changes. Abnormal spontaneous muscle activity includes fibrillation potentials, sharp waves, and complex repetitive discharges. Myotonic discharges are often recorded in statin-associated NAM.
      • Kassardjian C.D.
      • Lennon V.A.
      • Alfugham N.B.
      • Mahler M.
      • Milone M.
      Clinical features and treatment outcomes of necrotizing autoimmune myopathy.
      The lack of abnormal spontaneous muscle activity in a patient with IMM who has worsening weakness while taking corticosteroids often suggests a corticosteroid-induced myopathy.
      T2-weighted muscle MRI may reveal signal abnormality in muscle and fascia due to inflammation, edema, or muscle replacement by connective tissue. In addition, MRI can be a useful tool to monitor disease activity.
      • Gitiaux C.
      • De Antonio M.
      • Aouizerate J.
      • et al.
      Vasculopathy-related clinical and pathological features are associated with severe juvenile dermatomyositis.

      Challenges and Pitfalls

      Diagnostic criteria and classification of IMMs remain challenging. Some diagnostic criteria are based on clinical and muscle pathologic criteria, while others are more clinically and serologically oriented. Additional correlation between pathologic findings, specific antibodies, and extramuscular features would be valuable in better characterizing these diseases. The lack of universally accepted diagnostic criteria continues to be an obstacle to clinical trials, which are already hampered by the rarity of these myopathies. The variability of diagnostic criteria may lead to the enrollment of patients with different IMMs into a clinical trial and the exclusion of others. The crucial role of physical therapy and occupational therapy is not emphasized enough in clinical practice and should be part of the treatment plan.

      Unsolved Clinical Questions

      The role of myositis-associated antibodies remains poorly understood and requires further investigations. Their pathogenicity has not been proved. The correlation between the presence of a specific antibody and muscle pathologic findings should be better defined and validated. The value of anti-cN1A autoantibodies as a diagnostic and prognostic tool in IBM requires further investigation. Similarly, the role played by statins as a trigger for the anti-HMGCR antibody formation and development of NAM warrants further elucidation, especially in light of the presence of anti-HMGCR antibodies in statin-naive (or presumably naive) patients. Understanding what leads to microangiopathy in DM or whether IBM is a primary inflammatory or degenerative muscle disease would be fundamental to opening avenues to treatment. There is a need for randomized clinical trials to standardize and optimize evidence-based patient care. Longitudinal studies to learn more about the disease progression and markers of disease activity would enhance our understanding of these myopathies and would provide more solid guidance for timing of immunotherapy withdrawal.

      Conclusion

      Immune-mediated myopathies are clinically, serologically, and pathologically heterogeneous. The lack of inflammation on muscle biopsy does not exclude an IMM. The presence of certain antibodies may predict specific complications and a higher risk of cancer.

      Acknowledgments

      Special thanks to my patients who agreed to have photographs taken and reproduced to enhance our understanding of immune-mediated myopathy.

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