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Idiopathic Inflammatory Myopathies: Current Trends in Pathogenesis, Clinical Features, and Up-to-Date Treatment Recommendations

      Abstract

      Recently, there have been important advances in the understanding of the pathophysiologic features, assessment, and management of patients with a newly diagnosed idiopathic inflammatory myopathy (IIM). Myositis-specific autoantibodies have been identified to define patient subgroups and offer prognostic implications. Similarly, proinflammatory cytokines, such as interleukin 6 and type 1 interferon–dependent genes, may serve as potential biomarkers of disease activity in adult and juvenile patients with dermatomyositis (DM). Moreover, magnetic resonance imaging has become an important modality for the assessment of muscle inflammation in adult IIM and juvenile DM. Immune-mediated necrotizing myopathies also are being recognized as a subset of IIM triggered by medications such as statins. However, confusion exists regarding effective management strategies for patients with IIM because of the lack of large-scale, randomized, controlled studies. This review focuses primarily on our current management and treatment algorithms for IIM including the care of pediatric patients with juvenile DM. For this review, we conducted a search of PubMed and MEDLINE for articles published from January 1, 1970, to December 1, 2011, using the following search terms: idiopathic inflammatory myopathies, dermatomyositis, polymyositis, juvenile dermatomyositis, sporadic inclusion body myositis, inclusion body myositis, inflammatory myositis, myositis, myopathies, pathogenesis, therapy, and treatment. Studies published in English were selected for inclusion in our review as well as additional articles identified from bibliographies.

      Abbreviations and Acronyms:

      ADL (activities of daily living), βINF1a (interferon-β-1a), CK (creatine kinase), CSA (cyclosporine A), CT (computed tomography), CYC (cyclophosphamide), DM (dermatomyositis), EMG (electromyography), HAQ (Health Assessment Questionnaire), HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase), IIM (idiopathic inflammatory myopathy), IL (interleukin), ILD (interstitial lung disease), IMNM (immune-mediated necrotizing myopathy), IVIG (intravenous immunoglobulin), IVMP (intravenous methylprednisolone), JDM (juvenile dermatomyositis), MHC (major histocompatibility complex), MMF (mycophenolate mofetil), MMT (manual muscle test), MRI (magnetic resonance imaging), MSA (myositis-specific autoantibody), MTX (methotrexate), pDC (plasmacytoid dendritic cell), PM (polymyositis), sIBM (sporadic inclusion body myositis), TNF-α (tumor necrosis factor α), tRNA (transfer RNA)
      • Myositis-specific autoantibodies may define subgroups of patients with idiopathic inflammatory myositis, suggest specific extramuscular organ involvement such as the pulmonary and cardiac systems, and may offer a long-term prognosis.
      • Magnetic resonance imaging, T1-weighted, T2-weighted, and sequences using fat suppression techniques and short tau inversion recovery, provides useful information to identify a muscle site for biopsy, diagnose myositis, and monitor treatment response.
      • For adult patients with idiopathic inflammatory myositis, we suggest an initial drug regimen of high-dose corticosteroids concurrent with a steroid-sparing agent, such as methotrexate, azathioprine, or mycophenolate mofetil, followed by a tapering course of corticosteroids.
      • For juvenile dermatomyositis uncomplicated by severe disease, we begin corticosteroids at 2 mg/kg up to a maximum of 60 mg/d with a taper after 2 to 4 weeks, depending on patient response. Subcutaneous methotrexate is added at the onset of treatment at a dosage of 15 mg/m2 once weekly.
      • For adult or juvenile patients with severe myositis, extensive extramuscular organ involvement, or refractory disease, we use high-dose methylprednisolone in addition to intravenous immunoglobulin, cyclophosphamide, rituximab, or cyclosporine.
      • Novel biomarkers of disease activity such as interleukin 6 and type 1 interferon–regulated genes may serve as indicators of disease activity in adult and juvenile myositis.
      The idiopathic inflammatory myopathies (IIMs) are a group of rare, systemic diseases that affect the muscles and result in proximal muscle weakness, muscle enzyme elevations, and extramuscular manifestations such as fever, weight loss, and rash. The IIMs are classified on the basis of patterns of presentation, age at onset, and immunohistopathologic features in skin and muscle biopsy specimens.
      • Bohan A.
      • Peter J.B.
      Polymyositis and dermatomyositis (first of two parts).
      • Bohan A.
      • Peter J.B.
      Polymyositis and dermatomyositis (second of two parts).
      • Emslie-Smith A.M.
      • Arahata K.
      • Engel A.G.
      Major histocompatibility complex class I antigen expression, immunolocalization of interferon subtypes, and T cell-mediated cytotoxicity in myopathies.
      • Dalakas M.C.
      • Sivakumar K.
      The immunopathologic and inflammatory differences between dermatomyositis, polymyositis and sporadic inclusion body myositis.
      Dermatomyositis (DM) is characterized by an erythematous rash and symmetric proximal muscle weakness. Muscle biopsy reveals a mononuclear, inflammatory cell exudate arranged in a perivascular and perifascicular distribution with degenerating and regenerating muscle fibers and perifascicular atrophy.
      • Emslie-Smith A.M.
      • Arahata K.
      • Engel A.G.
      Major histocompatibility complex class I antigen expression, immunolocalization of interferon subtypes, and T cell-mediated cytotoxicity in myopathies.
      • Dalakas M.C.
      • Sivakumar K.
      The immunopathologic and inflammatory differences between dermatomyositis, polymyositis and sporadic inclusion body myositis.
      • Engel A.G.
      • Arahata K.
      • Emslie-Smith A.
      Immune effector mechanisms in inflammatory myopathies.
      • Engel A.G.
      • Arahata K.
      Mononuclear cells in myopathies: quantitation of functionally distinct subsets, recognition of antigen-specific cell-mediated cytotoxicity in some diseases, and implications for the pathogenesis of the different inflammatory myopathies.
      • Arahata K.
      • Engel A.G.
      Monoclonal antibody analysis of mononuclear cells in myopathies, IV: cell-mediated cytotoxicity and muscle fiber necrosis.
      • Arahata K.
      • Engel A.G.
      Monoclonal antibody analysis of mononuclear cells in myopathies, III: immunoelectron microscopy aspects of cell-mediated muscle fiber injury.
      • Greenberg S.A.
      Proposed immunologic models of the inflammatory myopathies and potential therapeutic implications.
      • Kissel J.T.
      • Mendell J.R.
      • Rammohan K.W.
      Microvascular deposition of complement membrane attack complex in dermatomyositis.
      • Emslie-Smith A.M.
      • Engel A.G.
      Microvascular changes in early and advanced dermatomyositis: a quantitative study.
      Juvenile DM (JDM) affects children younger than 18 years and is characterized by proximal muscle weakness, calcinosis cutis, cutaneous vasculitis, ulcerations, and vasculopathy affecting the gastrointestinal tract.
      • Crowe W.E.
      • Bove K.E.
      • Levinson J.E.
      • Hilton P.K.
      Clinical and pathogenetic implications of histopathology in childhood polydermatomyositis.
      • Rider L.G.
      • Miller F.W.
      Classification and treatment of the juvenile idiopathic inflammatory myopathies.
      • Lorenzoni P.J.
      • Scola R.H.
      • Kay C.S.
      • Prevedello P.G.
      • Espíndola G.
      • Werneck L.C.
      Idiopathic inflammatory myopathies in childhood: a brief review of 27 cases.
      • Feldman B.M.
      • Rider L.G.
      • Reed A.M.
      • Pachman L.M.
      Juvenile dermatomyositis and other idiopathic inflammatory myopathies of childhood.
      Juvenile DM has similar histopathologic findings as adult DM, with perifascicular and perivascular inflammatory infiltrates, muscle degeneration and regeneration, and type I and type II fiber atrophy.
      • Lorenzoni P.J.
      • Scola R.H.
      • Kay C.S.
      • Prevedello P.G.
      • Espíndola G.
      • Werneck L.C.
      Idiopathic inflammatory myopathies in childhood: a brief review of 27 cases.
      Polymyositis (PM) is characterized by symmetric proximal muscle weakness, and it has a distinct immunohistopathologic phenotype involving CD8+ cytotoxic T cells invading nonnecrotic muscle fibers.
      • Emslie-Smith A.M.
      • Arahata K.
      • Engel A.G.
      Major histocompatibility complex class I antigen expression, immunolocalization of interferon subtypes, and T cell-mediated cytotoxicity in myopathies.
      • Dalakas M.C.
      • Sivakumar K.
      The immunopathologic and inflammatory differences between dermatomyositis, polymyositis and sporadic inclusion body myositis.
      • Engel A.G.
      • Arahata K.
      • Emslie-Smith A.
      Immune effector mechanisms in inflammatory myopathies.
      • Engel A.G.
      • Arahata K.
      Mononuclear cells in myopathies: quantitation of functionally distinct subsets, recognition of antigen-specific cell-mediated cytotoxicity in some diseases, and implications for the pathogenesis of the different inflammatory myopathies.
      • Arahata K.
      • Engel A.G.
      Monoclonal antibody analysis of mononuclear cells in myopathies, IV: cell-mediated cytotoxicity and muscle fiber necrosis.
      • Arahata K.
      • Engel A.G.
      Monoclonal antibody analysis of mononuclear cells in myopathies, III: immunoelectron microscopy aspects of cell-mediated muscle fiber injury.
      • Greenberg S.A.
      Proposed immunologic models of the inflammatory myopathies and potential therapeutic implications.
      • Kissel J.T.
      • Mendell J.R.
      • Rammohan K.W.
      Microvascular deposition of complement membrane attack complex in dermatomyositis.
      • Emslie-Smith A.M.
      • Engel A.G.
      Microvascular changes in early and advanced dermatomyositis: a quantitative study.
      Immune-mediated necrotizing myopathy (IMNM) is a severe myopathy with minimal inflammatory infiltrate on muscle biopsy; it may be triggered by viral infections, medications such as statins, and malignant neoplasms.
      • Emslie-Smith A.M.
      • Engel A.G.
      Necrotizing myopathy with pipestem capillaries, microvascular deposition of the complement membrane attack complex (MAC), and minimal cellular infiltration.
      • Bronner I.M.
      • Hoogendijk J.E.
      • Wintzen A.R.
      • et al.
      Necrotising myopathy, an unusual presentation of a steroid-responsive myopathy.
      • Liang C.
      • Needham M.
      Necrotizing autoimmune myopathy.
      • Grable-Esposito P.
      • Katzberg H.D.
      • Greenberg S.A.
      • Srinivasan J.
      • Katz J.
      • Amato A.A.
      Immune-mediated necrotizing myopathy associated with statins.
      • Christopher-Stine L.
      • Casciola-Rosen L.A.
      • Hong G.
      • Chung T.
      • Corse A.M.
      • Mammen A.L.
      A novel autoantibody recognizing 200-kd and 100-kd proteins is associated with an immune-mediated necrotizing myopathy.

      Werner JL, Christopher-Stine L, Ghazarian SR, et al. Antibody levels correlate with creatine kinase levels and strength in anti-HMG-CoA reductase-associated autoimmune myopathy [published online ahead of print August 29, 2012]. Arthritis Rheum. http://dx.doi.org/10.1002/art.34673.

      Finally, sporadic inclusion body myositis (sIBM) has pathologic features that suggest a degenerative neuromuscular disease with muscle fiber vacuolization and an abnormal accumulation of amyloid-β and phosphorylated tau proteins thought to be analogous to Alzheimer disease.
      • Lotz B.P.
      • Engel A.G.
      • Nishino H.
      • Stevens J.C.
      • Litchy W.J.
      Inclusion body myositis: observations in 40 patients.
      • Weihl C.C.
      • Pestronk A.
      Sporadic inclusion body myositis: possible pathogenesis inferred from biomarkers.
      • Karpati G.
      • O’Ferrall E.K.
      Sporadic inclusion body myositis: pathogenic considerations.
      • Salajegheh M.
      • Pinkus J.L.
      • Nazareno R.
      • Amato A.A.
      • Parker K.C.
      • Greenberg S.A.
      Nature of “tau” immunoreactivity in normal myonuclei and inclusion body myositis.
      • Griggs R.C.
      • Askanas V.
      • DiMauro S.
      • et al.
      Inclusion body myositis and myopathies.
      Emerging data suggest that the autoantibody status of patients with IIM defines phenotypes and predicts outcomes such as treatment response and extramuscular organ involvement. Myositis-specific autoantibodies (MSAs) may be found in the serum of approximately 50% to 60% of patients with IIM, and they are directed against proteins in the cell nucleus and cytoplasm. The common MSAs are the aminoacyl transfer RNA (tRNA), synthetases anti-p155/140 antibody (a 155-kDa reactive nuclear protein), anti-Mi2, anti-SRP, and anti-CADM-140, although there are many others used as markers to define subsets of IIM.
      • Love L.A.
      • Leff R.L.
      • Fraser D.D.
      • et al.
      A new approach to the classification of idiopathic inflammatory myopathy: myositis-specific autoantibodies define useful homogeneous patient groups.
      • Gunawardena H.
      • Betteridge Z.E.
      • McHugh N.J.
      Myositis-specific autoantibodies: their clinical and pathogenic significance in disease expression.
      • Hengstman G.J.
      • van Brenk L.
      • Vree Egberts W.T.
      • et al.
      High specificity of myositis specific autoantibodies for myositis compared with other neuromuscular disorders.
      • Targoff I.N.
      Myositis specific autoantibodies.
      • Hoshino K.
      • Muro Y.
      • Sugiura K.
      • Tomita Y.
      • Nakashima R.
      • Mimori T.
      Anti-MDA5 and anti-TIF1-γ antibodies have clinical significance for patients with dermatomyositis.
      • Sato S.
      • Hoshino K.
      • Satoh T.
      • et al.
      RNA helicase encoded by melanoma differentiation-associated gene 5 is a major autoantigen in patients with clinically amyopathic dermatomyositis: association with rapidly progressive interstitial lung disease.
      • 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.
      • Betteridge Z.E.
      • Gunawardena H.
      • McHugh N.J.
      Novel autoantibodies and clinical phenotypes in adult and juvenile myositis.
      Moreover, novel biomarkers have been identified to potentially serve as serologic evidence of increased disease activity and to monitor treatment response. In particular, interleukin (IL) 6 and type 1 interferon genes and proteins may serve as markers for disease activity in DM.
      • Bilgic H.
      • Ytterberg S.R.
      • Amin S.
      • et al.
      Interleukin-6 and type 1 interferon-regulated genes and chemokines mark disease activity in dermatomyositis.
      • Baechler E.C.
      • Bauer J.W.
      • Slattery C.A.
      • et al.
      An interferon signature in the peripheral blood of dermatomyositis patients is associated with disease activity.
      • Greenberg S.A.
      • Pinkus J.L.
      • Pinkus G.S.
      • et al.
      Interferon-α/β–mediated innate immune mechanisms in dermatomyositis.
      • Raju R.
      • Dalakas M.C.
      Gene expression profile in the muscles of patients with inflammatory myopathies: effect of therapy with IVIg and biological validation of clinically relevant genes.

      Reed AM, Peterson E, Bilgic H, et al. Changes in novel biomarkers of disease activity in juvenile and adult dermatomyositis are sensitive biomarkers of disease course [published online ahead of print August 8, 2012]. Arthritis Rheum. http://dx.doi.org/10.1002/art.34659.

      This review focuses on our current treatment recommendations. The approach to treatment of IIM has not been standardized because of the rarity of the disease and the lack of controlled treatment trials. Hence, universal agreement does not exist among myositis experts regarding treatment decisions and management strategies. Our institution has a standard protocol for the treatment of IIM that we will review. In addition, current literature regarding MSAs as predictors of clinical phenotypes and disease outcomes and novel biomarkers of disease activity will be discussed. We conducted a search of PubMed and MEDLINE for articles published from January 1, 1970, to December 1, 2011, using the following search terms: idiopathic inflammatory myopathies, dermatomyositis, polymyositis, juvenile dermatomyositis, sporadic inclusion body myositis, inclusion body myositis, inflammatory myositis, myositis, myopathies, pathogenesis, therapy, and treatment. Studies published in English were selected for inclusion in our review. Additional articles were obtained from retrieved article bibliographies.

      Clinical and Laboratory Features of IIM

      Dermatomyositis

      Dermatomyositis presents with an erythematous, photosensitive rash with poikiloderma, Gottron papules, periorbital edema, heliotrope rash, and periungual telangiectasias. Rashes may involve the face, neck, torso, fingers, and extensor surfaces of the extremities. Infrequently, patients with DM have cutaneous vasculitis, ulcerations, and calcinosis, but these features are seen more often in JDM.
      • Rider L.G.
      • Miller F.W.
      Classification and treatment of the juvenile idiopathic inflammatory myopathies.
      • Lorenzoni P.J.
      • Scola R.H.
      • Kay C.S.
      • Prevedello P.G.
      • Espíndola G.
      • Werneck L.C.
      Idiopathic inflammatory myopathies in childhood: a brief review of 27 cases.
      • Feldman B.M.
      • Rider L.G.
      • Reed A.M.
      • Pachman L.M.
      Juvenile dermatomyositis and other idiopathic inflammatory myopathies of childhood.
      Symmetric proximal muscle weakness develops over weeks to months coupled with elevated muscle enzyme levels. Electromyographic (EMG) abnormalities include polyphasic motor unit action potentials of short duration and low amplitude and increased insertional and spontaneous activity with fibrillation potentials, sharp waves, and/or repetitive discharges. Other organ systems may be involved, such as vascular, pulmonary, gastrointestinal, and cardiac systems.
      • Dalakas M.C.
      • Sivakumar K.
      The immunopathologic and inflammatory differences between dermatomyositis, polymyositis and sporadic inclusion body myositis.
      • Feldman B.M.
      • Rider L.G.
      • Reed A.M.
      • Pachman L.M.
      Juvenile dermatomyositis and other idiopathic inflammatory myopathies of childhood.
      Pulmonary manifestations range from aspiration pneumonia due to weakness of the ventilatory muscles to interstitial lung disease (ILD). The most common ILD pattern is a nonspecific interstitial pneumonitis that has the appearance of ground-glass opacities without honeycombing on high-resolution computed tomography (CT) of the lungs; it can be seen in up to one-third of patients with DM or PM.
      • Marie I.
      • Hachulla E.
      • Chérin P.
      • et al.
      Interstitial lung disease in polymyositis and dermatomyositis.
      Interstitial lung disease may lead to complications such as pulmonary hypertension or cor pulmonale. Rarely, the ILD can be rapidly progressive and fatal.
      • Marie I.
      • Hachulla E.
      • Chérin P.
      • et al.
      Interstitial lung disease in polymyositis and dermatomyositis.
      • Selva-O’Callaghan A.
      • Labrador-Horillo M.
      • Muñoz-Gall X.
      • et al.
      Polymyositis/dermatomyositis-associated lung disease: analysis of a series of 81 patients.
      Dysphagia related to proximal muscle dysfunction due to cricopharyngeal weakness or spasm may be evident on videofluoroscopy.
      • Oh T.H.
      • Brumfield K.A.
      • Hoskin T.L.
      • Stolp K.A.
      • Murray J.A.
      • Bassford J.R.
      Dysphagia in inflammatory myopathy: clinical characteristics, treatment strategies, and outcome in 62 patients.
      Cardiac manifestations may not be as symptomatic as other organ manifestations of DM. For example, an asymptomatic arrhythmia such as sinus tachycardia may be detected by electrocardiography, and diastolic dysfunction may be seen on echocardiography. Although severe cardiac manifestations are not typical in DM, myocarditis has been found on autopsy studies.
      • Yazici Y.
      • Kagen L.J.
      Cardiac involvement in myositis.
      • Gupta R.
      • Wayangankar S.A.
      • Targoff I.N.
      • Hennebry T.A.
      Clinical cardiac involvement in idiopathic inflammatory myopathies: a systematic review.
      A common set of criteria for the diagnosis of DM (also used for PM) is that proposed by Bohan and Peter
      • Bohan A.
      • Peter J.B.
      Polymyositis and dermatomyositis (first of two parts).
      • Bohan A.
      • Peter J.B.
      Polymyositis and dermatomyositis (second of two parts).
      : (1) characteristic skin findings, (2) proximal muscle weakness, (3) elevated muscle enzyme levels, (4) a myopathic pattern on EMG, and (5) evidence of an endomysial, mononuclear inflammatory infiltrate on muscle biopsy. (Four of the 5 criteria must be present for a definite diagnosis of PM.
      • Bohan A.
      • Peter J.B.
      Polymyositis and dermatomyositis (first of two parts).
      • Bohan A.
      • Peter J.B.
      Polymyositis and dermatomyositis (second of two parts).
      )

      Polymyositis

      Polymyositis presents with symmetric, proximal muscle weakness without a rash, elevated muscle enzyme levels, and extramuscular organ involvement similar to that in DM, such ILD and myocarditis.
      • Dalakas M.C.
      • Sivakumar K.
      The immunopathologic and inflammatory differences between dermatomyositis, polymyositis and sporadic inclusion body myositis.
      • Marie I.
      • Hachulla E.
      • Chérin P.
      • et al.
      Interstitial lung disease in polymyositis and dermatomyositis.
      • Yazici Y.
      • Kagen L.J.
      Cardiac involvement in myositis.
      Polymyositis is a rarer entity. Some experts believe that patients may be misdiagnosed as having PM given its nonunique clinical features shared with other myopathies.
      • Dalakas M.C.
      Pathophysiology of inflammatory and autoimmune myopathies.

      Immune-Mediated Necrotizing Myopathy

      Immune-mediated necrotizing myopathy is now being recognized as part of the group of IIMs and is best characterized as a necrotizing myopathy with minimal or no inflammatory infiltrate on muscle biopsy. Pathogenesis is hypothesized to be immune mediated with a trigger such as a drug, and it may be responsive to immunosuppressive treatment.
      • Emslie-Smith A.M.
      • Engel A.G.
      Necrotizing myopathy with pipestem capillaries, microvascular deposition of the complement membrane attack complex (MAC), and minimal cellular infiltration.
      • Bronner I.M.
      • Hoogendijk J.E.
      • Wintzen A.R.
      • et al.
      Necrotising myopathy, an unusual presentation of a steroid-responsive myopathy.
      • Liang C.
      • Needham M.
      Necrotizing autoimmune myopathy.
      • Grable-Esposito P.
      • Katzberg H.D.
      • Greenberg S.A.
      • Srinivasan J.
      • Katz J.
      • Amato A.A.
      Immune-mediated necrotizing myopathy associated with statins.
      There are clinical distinctions between IMNM and a toxic or necrotizing myopathy: the course of a necrotizing myopathy may be self-limited, and recovery may occur after the offending agent is discontinued, occasionally over weeks to months.
      • Bronner I.M.
      • Hoogendijk J.E.
      • Wintzen A.R.
      • et al.
      Necrotising myopathy, an unusual presentation of a steroid-responsive myopathy.
      • Liang C.
      • Needham M.
      Necrotizing autoimmune myopathy.
      Similarly, patients with IMNM may have high elevations of creatine kinase (CK) levels, greater than 10 times the upper limits of normal, with acute or subacute onset of proximal muscle weakness that may be severe. However, patients with IMNM may also have a chronic disease course. Management, in general, is similar to that for patients with DM or PM with respect to use of corticosteroids and other immunosuppressants as indicated for control of disease.
      • Bronner I.M.
      • Hoogendijk J.E.
      • Wintzen A.R.
      • et al.
      Necrotising myopathy, an unusual presentation of a steroid-responsive myopathy.
      • Liang C.
      • Needham M.
      Necrotizing autoimmune myopathy.
      • Grable-Esposito P.
      • Katzberg H.D.
      • Greenberg S.A.
      • Srinivasan J.
      • Katz J.
      • Amato A.A.
      Immune-mediated necrotizing myopathy associated with statins.
      Triggers that have been identified include viruses, cancer, connective tissue diseases, and certain medications such as statins. Statin-induced necrotizing myopathy has been associated with an antibody against the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) protein that is up-regulated in regenerating muscle fibers.
      • Grable-Esposito P.
      • Katzberg H.D.
      • Greenberg S.A.
      • Srinivasan J.
      • Katz J.
      • Amato A.A.
      Immune-mediated necrotizing myopathy associated with statins.
      • Christopher-Stine L.
      • Casciola-Rosen L.A.
      • Hong G.
      • Chung T.
      • Corse A.M.
      • Mammen A.L.
      A novel autoantibody recognizing 200-kd and 100-kd proteins is associated with an immune-mediated necrotizing myopathy.

      Werner JL, Christopher-Stine L, Ghazarian SR, et al. Antibody levels correlate with creatine kinase levels and strength in anti-HMG-CoA reductase-associated autoimmune myopathy [published online ahead of print August 29, 2012]. Arthritis Rheum. http://dx.doi.org/10.1002/art.34673.

      Anti-HMGCR antibodies may become clinically useful for monitoring disease activity. Recently, Werner et al

      Werner JL, Christopher-Stine L, Ghazarian SR, et al. Antibody levels correlate with creatine kinase levels and strength in anti-HMG-CoA reductase-associated autoimmune myopathy [published online ahead of print August 29, 2012]. Arthritis Rheum. http://dx.doi.org/10.1002/art.34673.

      found that anti-HMGCR correlated with CK levels and extremity strength; treatment was associated with decreased antibody levels and improved arm strength.

      Sporadic Inclusion Body Myositis

      Sporadic inclusion body myositis is distinctive among the IIMs because it is characterized by symmetric or asymmetric weakness of insidious onset involving the proximal and/or distal muscles occurring after age 50 years with a male to female ratio of 3:1.
      • Lotz B.P.
      • Engel A.G.
      • Nishino H.
      • Stevens J.C.
      • Litchy W.J.
      Inclusion body myositis: observations in 40 patients.
      Classically, atrophy of the forearm flexors, finger flexors, and quadriceps muscles is observed. Dysphagia may be a prominent feature leading to poor outcomes such as feeding tube placement or recurrent aspiration pneumonia. Muscle enzyme levels, such as the CK level, may be minimally elevated. A muscle biopsy reveals an inflammatory mononuclear cell infiltrate with rimmed vacuoles and congophilic deposits.
      • Lotz B.P.
      • Engel A.G.
      • Nishino H.
      • Stevens J.C.
      • Litchy W.J.
      Inclusion body myositis: observations in 40 patients.
      • Weihl C.C.
      • Pestronk A.
      Sporadic inclusion body myositis: possible pathogenesis inferred from biomarkers.
      • Karpati G.
      • O’Ferrall E.K.
      Sporadic inclusion body myositis: pathogenic considerations.
      • Salajegheh M.
      • Pinkus J.L.
      • Nazareno R.
      • Amato A.A.
      • Parker K.C.
      • Greenberg S.A.
      Nature of “tau” immunoreactivity in normal myonuclei and inclusion body myositis.
      The Griggs criteria
      • Griggs R.C.
      • Askanas V.
      • DiMauro S.
      • et al.
      Inclusion body myositis and myopathies.
      that are frequently used for diagnosis address several clinical, laboratory, and histopathologic features: duration of illness longer than 6 months; age at onset older than 30 years; weakness of proximal and distal muscles of upper and lower extremities and either finger flexor weakness, wrist flexor greater than wrist extensor weakness, or quadriceps weakness; serum CK level less than 12 times normal; and muscle biopsy evidence of invasion of nonnecrotic fibers by mononuclear cells, vacuolated muscle fibers, and intracellular amyloid deposits or 15- to 18-nm tubulofilaments on muscle biopsy. Patients have a definite diagnosis of sIBM if they satisfy the vacuolated muscle fibers criteria in addition to all the other criteria.
      • Griggs R.C.
      • Askanas V.
      • DiMauro S.
      • et al.
      Inclusion body myositis and myopathies.

      Juvenile Dermatomyositis

      Juvenile DM presents in patients less than 18 years of age with skin and muscle features similar to those in adult DM.
      • Crowe W.E.
      • Bove K.E.
      • Levinson J.E.
      • Hilton P.K.
      Clinical and pathogenetic implications of histopathology in childhood polydermatomyositis.
      • Rider L.G.
      • Miller F.W.
      Classification and treatment of the juvenile idiopathic inflammatory myopathies.
      Traditionally, the Bohan and Peter criteria are employed for diagnosis.
      • Bohan A.
      • Peter J.B.
      Polymyositis and dermatomyositis (first of two parts).
      • Bohan A.
      • Peter J.B.
      Polymyositis and dermatomyositis (second of two parts).
      However, on the basis of a 2006 international consensus survey of members of the Network for Juvenile Dermatomyositis and the Paediatric Rheumatology International Trials Organisation, criteria have been proposed to include features of muscle inflammation seen on magnetic resonance imaging (MRI) and/or ultrasonography, nailfold capillaroscopy, calcinosis cutis (soft tissue calcification), and dysphonia.
      • Ruperto N.
      • Ravelli A.
      • Pistorio A.
      • et al.
      Paediatric Rheumatology International Trials Organisation (PRINTO); Pediatric Rheumatology Collaborative Study Group (PRCSG)
      The provisional Paediatric Rheumatology International Trials Organisation/American College of Rheumatology/European League Against Rheumatism disease activity core set for the evaluation of response to therapy in juvenile dermatomyositis: a prospective validation study.
      • Brown V.E.
      • Pilkington C.A.
      • Feldman B.M.
      • Davidson J.E.
      Network for Juvenile Dermatomyositis, Paediatric Rheumatology European Society (PReS)
      An international consensus survey of the diagnostic criteria for juvenile dermatomyositis (JDM).
      Nailfold capillaroscopy is particularly useful in predicting severity of disease and monitoring the clinical course in patients with JDM.
      • Dolezalova P.
      • Young S.P.
      • Bacon P.A.
      • Southwood T.R.
      Nailfold capillary microscopy in healthy children and in childhood rheumatic diseases: a prospective single blind observational study.
      Extramuscular manifestations include Raynaud phenomenon, inflammatory arthritis, pneumonitis, vasculopathy of the gastrointestinal tract leading to bowel ischemia and/or infarction, and cardiomyopathy. Dysphagia is also a prominent clinical feature of JDM, with features of cricopharyngeal muscle dysfunction similar to adult DM.
      • Rider L.G.
      • Miller F.W.
      Classification and treatment of the juvenile idiopathic inflammatory myopathies.
      • Lorenzoni P.J.
      • Scola R.H.
      • Kay C.S.
      • Prevedello P.G.
      • Espíndola G.
      • Werneck L.C.
      Idiopathic inflammatory myopathies in childhood: a brief review of 27 cases.
      • Feldman B.M.
      • Rider L.G.
      • Reed A.M.
      • Pachman L.M.
      Juvenile dermatomyositis and other idiopathic inflammatory myopathies of childhood.
      • Constantin T.
      • Ponyi A.
      • Orbán I.
      • et al.
      National registry of patients with juvenile idiopathic inflammatory myopathies in Hungary—clinical characteristics and disease course of 44 patients with juvenile dermatomyositis.
      Juvenile DM can be further classified on the basis of disease course, including monocyclic, polycyclic, chronic, and ulcerative disease. Monocyclic refers to a disease course characterized by remission within 2 to 3 years, while a polycyclic course is marked by periods of relapse.
      • Rider L.G.
      • Miller F.W.
      Classification and treatment of the juvenile idiopathic inflammatory myopathies.
      • Spencer C.H.
      • Hanson V.
      • Singsen B.H.
      • Bernstein B.H.
      • Kornreich H.K.
      • King K.K.
      Course of treated juvenile dermatomyositis.
      Although usually associated with systemic-onset juvenile idiopathic arthritis, macrophage activation syndrome may be present in children with JDM.
      • Sterba G.
      • Rodriguez C.
      • Sifontes S.
      • Vigilanza P.
      Macrophage activation syndrome due to methotrexate in a 12-year-old boy with dermatomyositis.
      • Shulman A.I.
      • Punaro M.
      Critical care of the pediatric patient with rheumatic disease.
      Macrophage activation syndrome is a severe, life-threatening, systemic inflammatory condition characterized by the presence of activated macrophages that phagocytose erythroid precursors in the marrow, leading to progressive cytopenias, fever, hepatosplenomegaly, and coagulopathy. Affected patients should be managed in a critical care setting, and treatment involves high-dose corticosteroids, cyclosporine, and anakinra, a recombinant IL-1 receptor antagonist.
      • Shulman A.I.
      • Punaro M.
      Critical care of the pediatric patient with rheumatic disease.
      • Gattorno M.
      • Piccini A.
      • Lasigliè D.
      • et al.
      The pattern of response to anti-interleukin-1 treatment distinguishes two subsets of patients with systemic-onset juvenile idiopathic arthritis.

      Amyopathic and Hypomyopathic Dermatomyositis

      Two subsets of DM have been described, amyopathic DM and hypomyopathic DM. Criteria have been developed to classify these subsets. Patients with amyopathic DM have the classic rash seen in DM without evidence of muscle inflammation, as determined by normal muscle enzyme levels within 2 years after diagnosis and normal EMG findings.
      • Euwer R.L.
      • Sontheimer R.D.
      Amyopathic dermatomyositis: a review.
      Hypomyopathic DM refers to patients who do not have muscle weakness, but there may be evidence of muscle inflammation such as a mild elevation in CK level, abnormalities on EMG, inflammation detected by MRI of proximal muscles, and abnormalities in muscle biopsy specimens.
      • Gerami P.
      • Schope J.M.
      • McDonald L.
      • Walling H.W.
      • Sontheimer R.D.
      A systematic review of adult-onset clinically amyopathic dermatomyositis (dermatomyositis siné myositis): a missing link within the spectrum of the idiopathic inflammatory myopathies.
      Interstitial lung disease has been described in patients with amyopathic DM.
      • Suda T.
      • Fujisawa T.
      • Enomoto N.
      • et al.
      Interstitial lung diseases associated with amyopathic dermatomyositis.
      Malignancy has also been reported in patients with amyopathic DM, although the incidence is lower than that found in classic DM.
      • Gerami P.
      • Schope J.M.
      • McDonald L.
      • Walling H.W.
      • Sontheimer R.D.
      A systematic review of adult-onset clinically amyopathic dermatomyositis (dermatomyositis siné myositis): a missing link within the spectrum of the idiopathic inflammatory myopathies.
      • Bendewald M.J.
      • Wetter D.A.
      • Li X.
      • Davis M.P.
      Incidence of dermatomyositis and clinically amyopathic dermatomyositis: a population-based study in Olmsted County, Minnesota.

      Pathogenesis

      Our current understanding of the pathogenesis of IIM is that there is a combination of genetic and environmental factors that determine susceptibility to IIM.
      • Reed A.M.
      • Ytterberg S.R.
      Genetic and environmental risk factors for idiopathic inflammatory myopathies.
      Certain HLA alleles on chromosome 6, in particular HLA-DQA1*0501 and HLA-DRB1*0301, have been associated with IIM.
      • Reed A.M.
      • Stirling J.D.
      Association of the HLA-DQA1*0501 allele in multiple racial groups with juvenile dermatomyositis.
      • Shamim E.A.
      • Rider L.G.
      • Miller F.W.
      Update on the genetics of the idiopathic inflammatory myopathies.
      Polymorphisms in the tumor necrosis factor α (TNF-α) (TNFα-308A) allele have been associated with a longer disease course, increased disease severity, and calcinosis in JDM.
      • Shamim E.A.
      • Rider L.G.
      • Miller F.W.
      Update on the genetics of the idiopathic inflammatory myopathies.
      • Pachman L.M.
      • Liotta-Davis M.R.
      • Hong D.K.
      • et al.
      TNFalpha-308A allele in juvenile dermatomyositis: association with increased production of tumor necrosis factor alpha, disease duration, and pathologic calcifications.
      Viral infections, such as with Coxsackie B virus, may trigger the onset of immune dysregulation in the genetically susceptible host.
      • Christensen M.L.
      • Pachman L.M.
      • Schneiderman R.
      • Patel D.C.
      • Friedman J.M.
      Prevalence of Coxsackie B virus antibodies in patients with juvenile dermatomyositis.
      There are several important histologic differences among the inflammatory myopathies that suggest different pathogenic mechanisms.

      Dermatomyositis and Juvenile Dermatomyositis

      Dermatomyositis is a complement-mediated vasculopathy of the small vessels in muscle tissue resulting in ischemia and vessel damage. There is deposition of the C5b-9 membrane attack complex around the microvasculature.
      • Kissel J.T.
      • Mendell J.R.
      • Rammohan K.W.
      Microvascular deposition of complement membrane attack complex in dermatomyositis.
      Classic histopathologic findings are mononuclear cell infiltrates in muscle fibers, necrotic fibers, and degenerating and regenerating fibers. Perifasicular atrophy of the myofibrils may be seen, possibly related to tissue hypoperfusion from ischemic microangiopathy in later stages of the muscle disease.
      • Bohan A.
      • Peter J.B.
      Polymyositis and dermatomyositis (first of two parts).
      • Bohan A.
      • Peter J.B.
      Polymyositis and dermatomyositis (second of two parts).
      • Emslie-Smith A.M.
      • Arahata K.
      • Engel A.G.
      Major histocompatibility complex class I antigen expression, immunolocalization of interferon subtypes, and T cell-mediated cytotoxicity in myopathies.
      • Dalakas M.C.
      • Sivakumar K.
      The immunopathologic and inflammatory differences between dermatomyositis, polymyositis and sporadic inclusion body myositis.
      • Engel A.G.
      • Arahata K.
      • Emslie-Smith A.
      Immune effector mechanisms in inflammatory myopathies.
      • Engel A.G.
      • Arahata K.
      Mononuclear cells in myopathies: quantitation of functionally distinct subsets, recognition of antigen-specific cell-mediated cytotoxicity in some diseases, and implications for the pathogenesis of the different inflammatory myopathies.
      • Arahata K.
      • Engel A.G.
      Monoclonal antibody analysis of mononuclear cells in myopathies, IV: cell-mediated cytotoxicity and muscle fiber necrosis.
      • Arahata K.
      • Engel A.G.
      Monoclonal antibody analysis of mononuclear cells in myopathies, III: immunoelectron microscopy aspects of cell-mediated muscle fiber injury.
      • Greenberg S.A.
      Proposed immunologic models of the inflammatory myopathies and potential therapeutic implications.
      • Kissel J.T.
      • Mendell J.R.
      • Rammohan K.W.
      Microvascular deposition of complement membrane attack complex in dermatomyositis.
      • Emslie-Smith A.M.
      • Engel A.G.
      Microvascular changes in early and advanced dermatomyositis: a quantitative study.
      The mononuclear cell infiltrates consist of B cells and CD4+ T cells in the perimysial and perivascular area and plasmacytoid dendritic cells (pDCs) in perifascicular areas, which supports a humorally mediated mechanism of pathogenesis.
      • Emslie-Smith A.M.
      • Arahata K.
      • Engel A.G.
      Major histocompatibility complex class I antigen expression, immunolocalization of interferon subtypes, and T cell-mediated cytotoxicity in myopathies.
      • Dalakas M.C.
      • Sivakumar K.
      The immunopathologic and inflammatory differences between dermatomyositis, polymyositis and sporadic inclusion body myositis.
      • Engel A.G.
      • Arahata K.
      • Emslie-Smith A.
      Immune effector mechanisms in inflammatory myopathies.
      • Engel A.G.
      • Arahata K.
      Mononuclear cells in myopathies: quantitation of functionally distinct subsets, recognition of antigen-specific cell-mediated cytotoxicity in some diseases, and implications for the pathogenesis of the different inflammatory myopathies.
      • Arahata K.
      • Engel A.G.
      Monoclonal antibody analysis of mononuclear cells in myopathies, IV: cell-mediated cytotoxicity and muscle fiber necrosis.
      • Arahata K.
      • Engel A.G.
      Monoclonal antibody analysis of mononuclear cells in myopathies, III: immunoelectron microscopy aspects of cell-mediated muscle fiber injury.
      • Greenberg S.A.
      Proposed immunologic models of the inflammatory myopathies and potential therapeutic implications.
      • Kissel J.T.
      • Mendell J.R.
      • Rammohan K.W.
      Microvascular deposition of complement membrane attack complex in dermatomyositis.
      Similarly, JDM has histopathologic features supporting a small-vessel vasculopathy or vasculitis as a pathogenic mechanism. Typical muscle biopsy findings of JDM include atrophy in the perifasicular areas from tissue hypoperfusion.
      • Crowe W.E.
      • Bove K.E.
      • Levinson J.E.
      • Hilton P.K.
      Clinical and pathogenetic implications of histopathology in childhood polydermatomyositis.
      • Rider L.G.
      • Miller F.W.
      Classification and treatment of the juvenile idiopathic inflammatory myopathies.
      • Lorenzoni P.J.
      • Scola R.H.
      • Kay C.S.
      • Prevedello P.G.
      • Espíndola G.
      • Werneck L.C.
      Idiopathic inflammatory myopathies in childhood: a brief review of 27 cases.
      • Feldman B.M.
      • Rider L.G.
      • Reed A.M.
      • Pachman L.M.
      Juvenile dermatomyositis and other idiopathic inflammatory myopathies of childhood.
      Common proinflammatory cytokines described in DM and JDM include type 1 interferons (α/β) and TNF-α. These cytokines may be present in muscle tissue and endothelial cells and may induce major histocompatibility complex (MHC) class I expression in normal and regenerating muscle cells.
      • Emslie-Smith A.M.
      • Arahata K.
      • Engel A.G.
      Major histocompatibility complex class I antigen expression, immunolocalization of interferon subtypes, and T cell-mediated cytotoxicity in myopathies.
      • Dalakas M.C.
      • Sivakumar K.
      The immunopathologic and inflammatory differences between dermatomyositis, polymyositis and sporadic inclusion body myositis.
      • Greenberg S.A.
      Proposed immunologic models of the inflammatory myopathies and potential therapeutic implications.
      • Li C.K.
      • Varsani H.
      • Holton J.L.
      • Gao B.
      • Woo P.
      • Wedderburn L.R.
      Juvenile Dermatomyositis Research Group (UK and Ireland)
      MHC Class I overexpression on muscles in early juvenile dermatomyositis.
      Other cytokines that have been observed are IL-4, IL-6, IL-15, and IL-17. The proinflammatory cytokines predominate in muscle tissue, leading to migration of CD4+ T cells such as Th1 and Th17, B cells, CD8+ T cells, macrophages, and pDCs.
      • Emslie-Smith A.M.
      • Arahata K.
      • Engel A.G.
      Major histocompatibility complex class I antigen expression, immunolocalization of interferon subtypes, and T cell-mediated cytotoxicity in myopathies.
      • Dalakas M.C.
      • Sivakumar K.
      The immunopathologic and inflammatory differences between dermatomyositis, polymyositis and sporadic inclusion body myositis.
      • Engel A.G.
      • Arahata K.
      • Emslie-Smith A.
      Immune effector mechanisms in inflammatory myopathies.
      • Engel A.G.
      • Arahata K.
      Mononuclear cells in myopathies: quantitation of functionally distinct subsets, recognition of antigen-specific cell-mediated cytotoxicity in some diseases, and implications for the pathogenesis of the different inflammatory myopathies.
      • Arahata K.
      • Engel A.G.
      Monoclonal antibody analysis of mononuclear cells in myopathies, IV: cell-mediated cytotoxicity and muscle fiber necrosis.
      • Arahata K.
      • Engel A.G.
      Monoclonal antibody analysis of mononuclear cells in myopathies, III: immunoelectron microscopy aspects of cell-mediated muscle fiber injury.
      • Greenberg S.A.
      Proposed immunologic models of the inflammatory myopathies and potential therapeutic implications.
      • Greenberg S.A.
      • Pinkus J.L.
      • Pinkus G.S.
      • et al.
      Interferon-α/β–mediated innate immune mechanisms in dermatomyositis.
      • Li C.K.
      • Varsani H.
      • Holton J.L.
      • Gao B.
      • Woo P.
      • Wedderburn L.R.
      Juvenile Dermatomyositis Research Group (UK and Ireland)
      MHC Class I overexpression on muscles in early juvenile dermatomyositis.
      • López de Padilla C.M.
      • Vallejo A.N.
      • McNallan K.T.
      • et al.
      Plasmacytoid dendritic cells in inflamed muscle of patients with juvenile dermatomyositis.
      • Liu Y.J.
      IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors.
      Dendritic cells are antigen-presenting cells that are now recognized as important mediators in the inflammatory response in DM and JDM. A type of dendritic cell, pDCs, have been found in the skin and muscle tissue of patients with DM and JDM.
      • López de Padilla C.M.
      • Vallejo A.N.
      • McNallan K.T.
      • et al.
      Plasmacytoid dendritic cells in inflamed muscle of patients with juvenile dermatomyositis.
      • López de Padilla C.M.
      • Vallejo A.N.
      • Lacomis D.
      • McNallen K.
      • Reed A.M.
      Extranodal lymphoid microstructures in inflamed muscle and disease severity of new-onset juvenile dermatomyositis.
      They are known for producing type 1 interferon in response to viral nucleic acids.
      • Swiecki M.
      • Colonna M.
      Accumulation of plasmacytoid DC: roles in disease pathogenesis and targets for immunotherapy.
      Transforming growth factor β has been observed in muscle tissue, which may promote anti-inflammatory effects and fibrosis.
      • Lundberg I.
      • Ulfgren A.K.
      • Nyberg P.
      • Andersson U.
      • Klareskog L.
      Cytokine production in muscle tissue of patients with idiopathic inflammatory myopathies.
      Chemokines are chemoattractants that promote development of inflammatory changes due to migration of leukocytes to muscle tissue; commonly described chemokines include the macrophage inflammatory proteins 1α (chemokine ligand 3) and 1β (chemokine ligand 4), which attract T and B cells, and B-cell chemokine CXCL13, which is prominent in perimysial infiltrates and is a B-cell activator.
      • Liprandi A.
      • Bartoli C.
      • Figarella-Branger D.
      • Pellissier J.F.
      • Lepidi H.
      Local expression of monocyte chemoattractant protein-1 (MCP-1) in idiopathic inflammatory myopathies.
      • De Paepe B.
      • Creus K.K.
      • De Bleecker J.L.
      Role of cytokines and chemokines in idiopathic inflammatory myopathies.

      Polymyositis

      In PM, an endomysial mononuclear cell infiltrate surrounds and invades nonnecrotic muscle fiber cells, causing muscle fiber necrosis and regeneration.
      • Emslie-Smith A.M.
      • Arahata K.
      • Engel A.G.
      Major histocompatibility complex class I antigen expression, immunolocalization of interferon subtypes, and T cell-mediated cytotoxicity in myopathies.
      • Dalakas M.C.
      • Sivakumar K.
      The immunopathologic and inflammatory differences between dermatomyositis, polymyositis and sporadic inclusion body myositis.
      • Engel A.G.
      • Arahata K.
      • Emslie-Smith A.
      Immune effector mechanisms in inflammatory myopathies.
      • Engel A.G.
      • Arahata K.
      Mononuclear cells in myopathies: quantitation of functionally distinct subsets, recognition of antigen-specific cell-mediated cytotoxicity in some diseases, and implications for the pathogenesis of the different inflammatory myopathies.
      • Arahata K.
      • Engel A.G.
      Monoclonal antibody analysis of mononuclear cells in myopathies, IV: cell-mediated cytotoxicity and muscle fiber necrosis.
      • Arahata K.
      • Engel A.G.
      Monoclonal antibody analysis of mononuclear cells in myopathies, III: immunoelectron microscopy aspects of cell-mediated muscle fiber injury.
      Unlike DM, the microvasculture of muscle tissue does not appear to be involved in its pathogenesis, and B cells are rarely seen. It is believed that a cellular-mediated cytotoxic mechanism accounts for its pathogenesis.
      • Emslie-Smith A.M.
      • Arahata K.
      • Engel A.G.
      Major histocompatibility complex class I antigen expression, immunolocalization of interferon subtypes, and T cell-mediated cytotoxicity in myopathies.
      • Greenberg S.A.
      Proposed immunologic models of the inflammatory myopathies and potential therapeutic implications.
      CD8+ cytotoxic T cells and macrophages clonally expand and interact with muscle fibers expressing MHC class I, resulting in muscle fiber changes in the endomysium.
      • Emslie-Smith A.M.
      • Arahata K.
      • Engel A.G.
      Major histocompatibility complex class I antigen expression, immunolocalization of interferon subtypes, and T cell-mediated cytotoxicity in myopathies.
      • Dalakas M.C.
      • Sivakumar K.
      The immunopathologic and inflammatory differences between dermatomyositis, polymyositis and sporadic inclusion body myositis.
      • Engel A.G.
      • Arahata K.
      • Emslie-Smith A.
      Immune effector mechanisms in inflammatory myopathies.
      • Engel A.G.
      • Arahata K.
      Mononuclear cells in myopathies: quantitation of functionally distinct subsets, recognition of antigen-specific cell-mediated cytotoxicity in some diseases, and implications for the pathogenesis of the different inflammatory myopathies.
      • Arahata K.
      • Engel A.G.
      Monoclonal antibody analysis of mononuclear cells in myopathies, IV: cell-mediated cytotoxicity and muscle fiber necrosis.
      • Arahata K.
      • Engel A.G.
      Monoclonal antibody analysis of mononuclear cells in myopathies, III: immunoelectron microscopy aspects of cell-mediated muscle fiber injury.
      • Greenberg S.A.
      Proposed immunologic models of the inflammatory myopathies and potential therapeutic implications.
      Polymyositis has the same proinflammatory cytokines and chemokines that are seen in DM, including type 1 interferons (α/β) and TNF-α.
      • Dalakas M.C.
      • Sivakumar K.
      The immunopathologic and inflammatory differences between dermatomyositis, polymyositis and sporadic inclusion body myositis.
      • Greenberg S.A.
      Proposed immunologic models of the inflammatory myopathies and potential therapeutic implications.
      • Li C.K.
      • Varsani H.
      • Holton J.L.
      • Gao B.
      • Woo P.
      • Wedderburn L.R.
      Juvenile Dermatomyositis Research Group (UK and Ireland)
      MHC Class I overexpression on muscles in early juvenile dermatomyositis.

      Sporadic Inclusion Body Myositis

      As in PM, patients with sIBM have CD8+ cytotoxic T cells and macrophages in the endomysium that surround and invade nonnecrotic muscle fiber cells, leading to muscle fiber necrosis in fibers expressing MHC class I.
      • Emslie-Smith A.M.
      • Arahata K.
      • Engel A.G.
      Major histocompatibility complex class I antigen expression, immunolocalization of interferon subtypes, and T cell-mediated cytotoxicity in myopathies.
      • Dalakas M.C.
      • Sivakumar K.
      The immunopathologic and inflammatory differences between dermatomyositis, polymyositis and sporadic inclusion body myositis.
      • Engel A.G.
      • Arahata K.
      • Emslie-Smith A.
      Immune effector mechanisms in inflammatory myopathies.
      • Engel A.G.
      • Arahata K.
      Mononuclear cells in myopathies: quantitation of functionally distinct subsets, recognition of antigen-specific cell-mediated cytotoxicity in some diseases, and implications for the pathogenesis of the different inflammatory myopathies.
      • Arahata K.
      • Engel A.G.
      Monoclonal antibody analysis of mononuclear cells in myopathies, IV: cell-mediated cytotoxicity and muscle fiber necrosis.
      • Arahata K.
      • Engel A.G.
      Monoclonal antibody analysis of mononuclear cells in myopathies, III: immunoelectron microscopy aspects of cell-mediated muscle fiber injury.
      Also similar to PM, a cellular-mediated cytotoxic mechanism is believed to be the primary feature of pathogenesis in sIBM.
      • Emslie-Smith A.M.
      • Arahata K.
      • Engel A.G.
      Major histocompatibility complex class I antigen expression, immunolocalization of interferon subtypes, and T cell-mediated cytotoxicity in myopathies.
      • Greenberg S.A.
      Proposed immunologic models of the inflammatory myopathies and potential therapeutic implications.
      Muscle degeneration in sIBM is characterized by rimmed vacuoles seen on light microscopy, nuclear and cytoplasmic inclusions detected on electron microscopy, congophilic amyloid deposits, and phosphorylated tau proteins.
      • Dalakas M.C.
      • Sivakumar K.
      The immunopathologic and inflammatory differences between dermatomyositis, polymyositis and sporadic inclusion body myositis.
      • Lotz B.P.
      • Engel A.G.
      • Nishino H.
      • Stevens J.C.
      • Litchy W.J.
      Inclusion body myositis: observations in 40 patients.
      • Karpati G.
      • O’Ferrall E.K.
      Sporadic inclusion body myositis: pathogenic considerations.
      • Salajegheh M.
      • Pinkus J.L.
      • Nazareno R.
      • Amato A.A.
      • Parker K.C.
      • Greenberg S.A.
      Nature of “tau” immunoreactivity in normal myonuclei and inclusion body myositis.
      • Griggs R.C.
      • Askanas V.
      • DiMauro S.
      • et al.
      Inclusion body myositis and myopathies.
      Due to the degeneration seen on muscle histopathologic studies, sIBM has become increasingly considered a degenerative myopathy with inflammatory features.
      • Weihl C.C.
      • Pestronk A.
      Sporadic inclusion body myositis: possible pathogenesis inferred from biomarkers.
      • Karpati G.
      • O’Ferrall E.K.
      Sporadic inclusion body myositis: pathogenic considerations.
      As in DM and PM, proinflammatory cytokines circulate in sIBM, including type 1 interferons (α/β) and TNF-α.
      • Dalakas M.C.
      • Sivakumar K.
      The immunopathologic and inflammatory differences between dermatomyositis, polymyositis and sporadic inclusion body myositis.
      • Greenberg S.A.
      Proposed immunologic models of the inflammatory myopathies and potential therapeutic implications.
      • Li C.K.
      • Varsani H.
      • Holton J.L.
      • Gao B.
      • Woo P.
      • Wedderburn L.R.
      Juvenile Dermatomyositis Research Group (UK and Ireland)
      MHC Class I overexpression on muscles in early juvenile dermatomyositis.

      Immune-Mediated Necrotizing Myopathy

      In IMNM, macrophages surround necrotic muscle fibers, and atrophic and regenerating fibers are present. Immunostaining reveals T lymphocytes (CD3) and macrophages (CD68) around necrotic and regenerating muscle fibers. The pathogenesis of IMNN is incompletely understood at this time, but macrophages may be the primary effector cell.
      • Emslie-Smith A.M.
      • Engel A.G.
      Necrotizing myopathy with pipestem capillaries, microvascular deposition of the complement membrane attack complex (MAC), and minimal cellular infiltration.
      • Bronner I.M.
      • Hoogendijk J.E.
      • Wintzen A.R.
      • et al.
      Necrotising myopathy, an unusual presentation of a steroid-responsive myopathy.
      • Liang C.
      • Needham M.
      Necrotizing autoimmune myopathy.
      • Grable-Esposito P.
      • Katzberg H.D.
      • Greenberg S.A.
      • Srinivasan J.
      • Katz J.
      • Amato A.A.
      Immune-mediated necrotizing myopathy associated with statins.
      In addition, anti-SRP and the anti-HMGCR (200 and 100 kDa) proteins have been found in patients with IMNN, suggesting an antibody-mediated autoimmune mechanism of pathogenesis.
      • Grable-Esposito P.
      • Katzberg H.D.
      • Greenberg S.A.
      • Srinivasan J.
      • Katz J.
      • Amato A.A.
      Immune-mediated necrotizing myopathy associated with statins.
      • Christopher-Stine L.
      • Casciola-Rosen L.A.
      • Hong G.
      • Chung T.
      • Corse A.M.
      • Mammen A.L.
      A novel autoantibody recognizing 200-kd and 100-kd proteins is associated with an immune-mediated necrotizing myopathy.

      Werner JL, Christopher-Stine L, Ghazarian SR, et al. Antibody levels correlate with creatine kinase levels and strength in anti-HMG-CoA reductase-associated autoimmune myopathy [published online ahead of print August 29, 2012]. Arthritis Rheum. http://dx.doi.org/10.1002/art.34673.

      Myositis-Specific Autoantibodies

      Immune dysregulation in IIM may result in antibodies against specific nuclear and cytoplasmic antigens (Table 1). Characteristic phenotypes may be associated with certain MSAs.
      • Love L.A.
      • Leff R.L.
      • Fraser D.D.
      • et al.
      A new approach to the classification of idiopathic inflammatory myopathy: myositis-specific autoantibodies define useful homogeneous patient groups.
      Common MSAs are the aminoacyl tRNA synthetases. These enzymes catalyze binding of amino acids to specific tRNAs. These autoantigens include the following: Jo-1, PL-7, PL-12, OJ, EJ, KS, Ha, and Zo.
      • Love L.A.
      • Leff R.L.
      • Fraser D.D.
      • et al.
      A new approach to the classification of idiopathic inflammatory myopathy: myositis-specific autoantibodies define useful homogeneous patient groups.
      • Gunawardena H.
      • Betteridge Z.E.
      • McHugh N.J.
      Myositis-specific autoantibodies: their clinical and pathogenic significance in disease expression.
      • Hengstman G.J.
      • van Brenk L.
      • Vree Egberts W.T.
      • et al.
      High specificity of myositis specific autoantibodies for myositis compared with other neuromuscular disorders.
      • Targoff I.N.
      Myositis specific autoantibodies.
      The anti-Jo-1 antibody is the most common. It is found in approximately 20% of adult patients with IIM. Anti-Jo-1 is the hallmark antibody for the antisynthetase syndrome, which consists of fever, mechanic’s hands, Raynaud phenomenon, myositis, ILD, and arthritis. The frequencies of the other anti-tRNA synthetases range from 1% to 5%.
      • Love L.A.
      • Leff R.L.
      • Fraser D.D.
      • et al.
      A new approach to the classification of idiopathic inflammatory myopathy: myositis-specific autoantibodies define useful homogeneous patient groups.
      • Gunawardena H.
      • Betteridge Z.E.
      • McHugh N.J.
      Myositis-specific autoantibodies: their clinical and pathogenic significance in disease expression.
      • Betteridge Z.E.
      • Gunawardena H.
      • McHugh N.J.
      Novel autoantibodies and clinical phenotypes in adult and juvenile myositis.
      Table 1Myositis-Specific Autoantibodies, Clinical Associations, and Frequencies in Adult and Juvenile Idiopathic Inflammatory Myopathies
      Adapted from Arthritis Res Ther,
      • Betteridge Z.E.
      • Gunawardena H.
      • McHugh N.J.
      Novel autoantibodies and clinical phenotypes in adult and juvenile myositis.
      with permission.
      AutoantibodyTarget autoantigenClinical featuresFrequency (%)
      IIMJDM
      Anti-synthetaseAminoacyl-tRNA synthetaseMechanic’s hands, arthritis, Raynaud phenomenon, ILD, myositis, fever30-401-5
       Jo-1Histidyl-tRNA synthetase20
       PL-7Theronyl-tRNA synthetase<5
       PL-12Alanyl-tRNA synthetase<5
       OJIsoleucyl-tRNA synthetase<5
       EJGlycyl-tRNA synthetase<5
       KSAsparaginyl-tRNA synthetase<5
       HaTyrosyl-tRNA synthetase<1
       ZoPhenylalanyl-tRNA synthetase<1
      Anti-CADM-140MDA5Aggressive ILD in Asians50-73 (Asians)Unknown
      Anti-p155/140TIF1-γMalignancy13-2122-29
      Anti-SRPSignal recognition particleNecrotizing myopathy5-101-3
      Anti-Mi2Nuclear helicaseClassic DM skin features<104-10
      Anti-200/100HMG-CoA reductaseNecrotizing myopathy<10Unknown
      DM = dermatomyositis; HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A; IIM = idiopathic inflammatory myopathy; ILD = interstitial lung disease; MDA5 = melanoma differentiation-associated gene 5; TIF1-γ = transcriptional intermediary factor 1 γ; tRNA = transfer RNA; ellipses = not applicable.
      The anti-Mi2 antibody acts against a nuclear helicase involved in transcriptional activation. Patients have classic cutaneous features including Gottron papules, shawl sign, cuticle overgrowth, V-sign, and a heliotrope rash.
      • Gunawardena H.
      • Betteridge Z.E.
      • McHugh N.J.
      Myositis-specific autoantibodies: their clinical and pathogenic significance in disease expression.
      • Hengstman G.J.
      • van Brenk L.
      • Vree Egberts W.T.
      • et al.
      High specificity of myositis specific autoantibodies for myositis compared with other neuromuscular disorders.
      • Targoff I.N.
      Myositis specific autoantibodies.
      Ultraviolet light has been implicated, suggesting an environmental trigger in adult DM.
      • Love L.A.
      • Weinberg C.R.
      • McConnaughey D.R.
      • et al.
      Ultraviolet radiation intensity predicts the relative distribution of dermatomyositis and anti-Mi-2 autoantibodies in women.
      The anti-SRP antibody is directed against the signal recognition particle. It is a 6-polypeptide complex that escorts newly synthesized proteins from the cytoplasm to the endoplasmic reticulum.
      • Gunawardena H.
      • Betteridge Z.E.
      • McHugh N.J.
      Myositis-specific autoantibodies: their clinical and pathogenic significance in disease expression.
      • Hengstman G.J.
      • van Brenk L.
      • Vree Egberts W.T.
      • et al.
      High specificity of myositis specific autoantibodies for myositis compared with other neuromuscular disorders.
      • Targoff I.N.
      Myositis specific autoantibodies.
      Patients with anti-SRP antibody have necrotizing myopathy, acute in onset, with dilated cardiomyopathy and a poor response to standard immunosuppression.
      • 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.
      • Valiyil R.
      • Casciola-Rosen L.
      • Hong G.
      • Mammen A.
      • Christopher-Stine L.
      Rituximab therapy for myopathy associated with anti-signal recognition particle antibodies: a case series.
      Other MSAs are the p155/140 doublet kDa proteins and antimelanoma differentiation-association gene 5 (anti-MDA5) autoantibodies.
      • Gunawardena H.
      • Betteridge Z.E.
      • McHugh N.J.
      Myositis-specific autoantibodies: their clinical and pathogenic significance in disease expression.
      • Hengstman G.J.
      • van Brenk L.
      • Vree Egberts W.T.
      • et al.
      High specificity of myositis specific autoantibodies for myositis compared with other neuromuscular disorders.
      • Targoff I.N.
      Myositis specific autoantibodies.
      • Targoff I.N.
      • Mamyrova G.
      • Trieu E.P.
      • et al.
      Childhood Myositis Heterogeneity Study Group; International Myositis Collaborative Study Group
      A novel autoantibody to a 155-kd protein is associated with dermatomyositis.
      • Chinoy H.
      • Fertig N.
      • Oddis C.V.
      • Ollier W.E.
      • Cooper R.G.
      The diagnostic utility of myositis autoantibody testing for predicting the risk of cancer-associated myositis.
      Autoantibodies to p155/140 doublet protein are associated with cancer with an 89% specificity and 70% sensitivity.
      • Targoff I.N.
      • Mamyrova G.
      • Trieu E.P.
      • et al.
      Childhood Myositis Heterogeneity Study Group; International Myositis Collaborative Study Group
      A novel autoantibody to a 155-kd protein is associated with dermatomyositis.
      • Chinoy H.
      • Fertig N.
      • Oddis C.V.
      • Ollier W.E.
      • Cooper R.G.
      The diagnostic utility of myositis autoantibody testing for predicting the risk of cancer-associated myositis.
      The anti-MDA5 antibody acts against the retinoic acid–inducible gene receptors involved in recognizing viral proteins. It has been described in Asians with amyopathic DM, although it can occur in non-Asian patients as well. The anti-MDA5 antibody has been associated with rapid onset of ILD and death.
      • Targoff I.N.
      Myositis specific autoantibodies.
      • Hoshino K.
      • Muro Y.
      • Sugiura K.
      • Tomita Y.
      • Nakashima R.
      • Mimori T.
      Anti-MDA5 and anti-TIF1-γ antibodies have clinical significance for patients with dermatomyositis.
      • Sato S.
      • Hoshino K.
      • Satoh T.
      • et al.
      RNA helicase encoded by melanoma differentiation-associated gene 5 is a major autoantigen in patients with clinically amyopathic dermatomyositis: association with rapidly progressive interstitial lung disease.
      The MSAs may be markers of disease, but recent studies suggest that certain MSAs, such as anti-Jo-1, trigger or help propagate immune dysregulation by becoming endogenous type 1 interferon inducers by peripheral blood mononuclear cells in vitro.
      • Gunawardena H.
      • Betteridge Z.E.
      • McHugh N.J.
      Myositis-specific autoantibodies: their clinical and pathogenic significance in disease expression.
      • Eloranta M.L.
      • Barbasso Helmers S.
      • Ulfgren A.K.
      • Rönnblom L.
      • Alm G.V.
      • Lundberg I.E.
      A possible mechanism for endogenous activation of the type I interferon system in myositis patients with anti-Jo-1 or anti-Ro 52/anti-Ro 60 autoantibodies.
      In children, the frequency of MSAs is less than adults with myositis. Rarely, anti-synthetases are detected. Rider et al
      • Rider L.G.
      • Miller F.W.
      • Targoff I.N.
      • et al.
      A broadened spectrum of juvenile myositis: myositis-specific autoantibodies in children.
      found MSAs in only 2 of 52 children tested; only one had anti-Jo-1 antibody, and the other had anti-PL-12 antibody. Similarly, Wedderburn et al
      • Wedderburn L.R.
      • McHugh N.J.
      • Chinoy H.
      • et al.
      Juvenile Dermatomyositis Research Group (JDRG)
      HLA class II haplotype and autoantibody associations in children with juvenile dermatomyositis and juvenile dermatomyositis-scleroderma overlap.
      studied 99 children with JDM and overlap connective tissue disease; only 2 of 24 children with JDM and scleroderma overlap had anti-Jo-1 antibodies. Clinical features in children with anti-Jo-1 antibodies are similar to those in adults with arthritis and ILD.
      • Rider L.G.
      • Miller F.W.
      • Targoff I.N.
      • et al.
      A broadened spectrum of juvenile myositis: myositis-specific autoantibodies in children.
      • Feldman B.M.
      • Reichlin M.
      • Laxer R.M.
      • Targoff I.N.
      • Stein L.D.
      • Silverman E.D.
      Clinical significance of specific autoantibodies in juvenile dermatomyositis.
      Other autoantibodies described in children are anti-MJ, anti-Mi2, and the p155/140 kDa protein. Curiously, although autoantibodies to the p155/140 kDa protein have been found in 29% of patients with JDM, their presence is not associated with cancer.
      • Gunawardena H.
      • Betteridge Z.E.
      • McHugh N.J.
      Myositis-specific autoantibodies: their clinical and pathogenic significance in disease expression.
      • 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.
      Rather, autoantibodies to the p140 kDa protein have been associated with calcinosis in JDM, with an odds ratio of 7.0.
      • 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.
      The anti-SRP antibody is rarely seen in children, although it has been described in African American girls with juvenile PM.
      • Rouster-Stevens K.A.
      • Pachman L.M.
      Autoantibody to signal recognition particle in African American girls with juvenile polymyositis.

      Initial Disease Investigations

      The differential diagnosis of noninflammatory myopathies includes muscular dystrophy of late onset, limb-girdle dystrophy (ie, dysferlinopathies) with onset during adult years, adult-onset nemaline myopathy associated with monoclonal gammopathy, or myotonic dystrophy type 2.
      • Benveniste O.
      • Romero N.B.
      Myositis or dystrophy? Traps and pitfalls.
      It is important to remember that muscular dystrophy and mitochondrial myopathies should be included in the differential diagnosis in a patient presenting with proximal muscle weakness and elevated muscle enzyme levels. A muscle biopsy can help to distinguish among these neuromuscular diseases and genetic testing. Typical histopathologic features of muscular dystrophy include a reduction or absence of dystrophin with degenerating and regenerating muscle fibers and replacement of muscle with fat or connective tissue; there may be invasion of muscle fibers by mononuclear cells, leading to diagnostic confusion with PM.
      • Emery A.E.
      The muscular dystrophies.
      Genetic testing for muscular dystrophy should include testing for the dystrophin gene.
      • Ray P.N.
      • Belfall B.
      • Duff C.
      • et al.
      Cloning of the breakpoint of an X; 21 translocation associated with Duchenne muscular dystrophy.
      Mitochondrial myopathies have the classic histopathologic abnormalities of subsarcolemmal and interfibrillar accumulation of mitochondria visualized on Gomori trichrome stain and “ragged red fibers” of glycogen and neutral lipids against a blue background of muscle fibers with reduction or absence of cytochrome c oxydase.
      • Reichmann H.
      • Vogler L.
      • Seibel P.
      Ragged red or ragged blue fibers.
      The differential list for noninflammatory myopathies also includes drug-induced myopathy, endocrine myopathy such as thyroid disorder or hyperparathyroidism, and metabolic and infectious myopathies. In children, the differential diagnosis should include Duchenne or Becker muscular dystrophy and an infectious myopathy related to acute viral illness such as coxsackievirus or influenza virus.
      • Zampieri S.
      • Ghirardellow A.
      • Iaccarino L.
      • et al.
      Polymyositis-dermatomyositis and infections.
      Relevant laboratory studies are a complete blood cell count, erythrocyte sedimentation rate, C-reactive protein, thyroid-stimulating hormone, sodium, potassium, bicarbonate, serum urea nitrogen, creatinine, magnesium, fasting calcium, phosphorus, magnesium, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, CK, and aldolase levels. In addition, a fasting glucose and lipid panel should be obtained to determine risk for diabetes or hyperlipidemia. It is important to measure the connective tissue disease autoantibodies as well because an antinuclear antibody and antibodies to the extractable nuclear antigens such as anti-SS-A, anti-SS-B, anti-Smith, anti-RNP, anti-Scl 70, and anti-centromere antibodies suggest that the myopathy may be secondary to a connective tissue disease, although a positive autoantibody result does not necessarily establish a connective tissue disease diagnosis. Occasionally, a panel for MSAs may define the clinical phenotype, which may help to confirm the diagnosis, especially in patients with atypical clinical presentations. Myositis-specific autoantibodies may also offer a prognosis for subsets of patients, such as those with tRNA synthetase antibodies. Myositis-specific autoantibody tests are typically sent to a large reference laboratory, and results may not be available for several weeks.
      Additional tests should include an EMG and a muscle biopsy. Electromyography should be performed for 2 major reasons: (1) to confirm a myopathic process characterized by polyphasic motor unit action potentials of short duration and low amplitude with increased insertional and spontaneous activity with fibrillation potentials, sharp waves, or repetitive discharges and (2) to target a muscle for biopsy. A muscle biopsy is one of the most important investigative tools for differentiating an inflammatory from a noninflammatory myopathy and for subclassification purposes. It is also the gold criterion for confirming a diagnosis of IIM. To maximize the diagnostic yield and reduce sampling error, a weak muscle should be chosen for biopsy. Often this weakness is demonstrated by EMG abnormalities of the affected muscle; the same muscle on the opposite side should be chosen for biopsy. If a muscle biopsy cannot be done or the results are inconclusive, a skin biopsy may help to confirm the diagnosis of DM, coupled with other supporting evidence. The typical histopathologic findings on skin biopsy examination are a vacuolar interface dermatitis with vacuolar changes of the epidermal basal layer, apoptosis, necrotic keratinocytes, and perivascular lymphocytic infiltrate and mucin deposition in the dermis.
      • Santmyire-Rosenberger B.
      • Dugan E.M.
      Skin involvement in dermatomyositis.
      • Callen J.P.
      Cutaneous manifestations of dermatomyositis and their management.
      This vacuolar interface pattern may be seen in lupus erythematosus as well; however, direct immunofluorescence should yield negative results in patients with DM and positive results in lupus.
      • Callen J.P.
      Cutaneous manifestations of dermatomyositis and their management.
      In IIM, although the muscle is the primary target, other organ systems may be affected. We recommend performing chest radiography and baseline pulmonary function testing including determination of maximal inspiratory and expiratory pressures. Reduced inspiratory pressures or poor effort from respiratory muscle weakness could potentially lead to poor outcomes such as aspiration pneumonia. A reduced diffusing capacity for carbon monoxide may suggest an ILD process. Chest radiographs may be insensitive to detecting subtle pulmonary changes from ILD; hence, high-resolution CT of the lungs should be performed. We also recommend echocardiography if the suspicion for cardiac involvement is high.

      Malignancy in Adults With IIM

      Malignancy occurs in 25% of adult patients with DM within 0 to 5 years of disease onset. In PM, the association is approximately 10% to 15%.
      • Buchbinder R.
      • Forbes A.
      • Hall S.
      • Dennett X.
      • Giles G.
      Incidence of malignant disease in biopsy-proven inflammatory myopathy: a population-based cohort study.
      • Zantos D.
      • Zhang Y.
      • Felson D.
      The overall and temporal association of cancer with polymyositis and dermatomyositis.
      • Sigurgeirsson B.
      • Lindelöf B.
      • Edhag O.
      • Allander E.
      Risk of cancer in patients with dermatomyositis or polymyositis: a population-based study.
      • Hill C.L.
      • Zhang Y.
      • Sigurgeirsson B.
      • et al.
      Frequency of specific cancer types in dermatomyositis and polymyositis: a population-based study.
      Malignancy has also been associated with amyopathic dermatomyositis.
      • Gerami P.
      • Schope J.M.
      • McDonald L.
      • Walling H.W.
      • Sontheimer R.D.
      A systematic review of adult-onset clinically amyopathic dermatomyositis (dermatomyositis siné myositis): a missing link within the spectrum of the idiopathic inflammatory myopathies.
      • Bendewald M.J.
      • Wetter D.A.
      • Li X.
      • Davis M.P.
      Incidence of dermatomyositis and clinically amyopathic dermatomyositis: a population-based study in Olmsted County, Minnesota.
      Breast and ovarian cancers are common in women, whereas lung and prostate cancers predominate in men. Other cancers associated with myositis include pancreatic, gastric, colorectal, and bladder cancer and non-Hodgkin lymphoma.
      • Buchbinder R.
      • Forbes A.
      • Hall S.
      • Dennett X.
      • Giles G.
      Incidence of malignant disease in biopsy-proven inflammatory myopathy: a population-based cohort study.
      • Zantos D.
      • Zhang Y.
      • Felson D.
      The overall and temporal association of cancer with polymyositis and dermatomyositis.
      • Sigurgeirsson B.
      • Lindelöf B.
      • Edhag O.
      • Allander E.
      Risk of cancer in patients with dermatomyositis or polymyositis: a population-based study.
      • Hill C.L.
      • Zhang Y.
      • Sigurgeirsson B.
      • et al.
      Frequency of specific cancer types in dermatomyositis and polymyositis: a population-based study.
      Practices differ among clinicians when evaluating for malignancy. Our practice is to perform age-appropriate cancer screening tests, including mammography, colonoscopy, prostate-specific antigen measurement, and prostate and pelvic examinations. An elevated CA-125 level at DM diagnosis in women may be predictive of increased risk for ovarian or primary peritoneal malignancy.
      • Whitmore S.E.
      • Anhalt G.J.
      • Provost T.T.
      • et al.
      Serum CA-125 screening for ovarian cancer in patients with dermatomyositis.
      Computed tomography of the abdomen/pelvis or pelvic ultrasonography facilitates identification of a malignancy of ovarian, endometrial, or primary peritoneal origin. If resources allow, positron emission tomography may be useful if findings on initial studies are unremarkable but the suspicion for cancer remains high; however, there are no guidelines, to our knowledge, that recommend performing positron emission tomography as part of the malignancy evaluation.

      Malignancy in Children With IIM

      Malignancy is rare in children with JDM. In 1993, Sherry et al
      • Sherry D.D.
      • Haas J.E.
      • Milstein J.M.
      Childhood polymyositis as a paraneoplastic phenomenon.
      described 6 children who had a paraneoplastic phenomenon involving PM and cancer. A recent literature review from 1963 to 2008 identified 12 children with JDM or PM and malignancy occurring within a range of 0 to 44 months from myositis diagnosis; these children were commonly diagnosed as having lymphoma or leukemia and had unexpected examination findings such as hepatosplenomegaly and extensive lymphadenopathy.
      • Morris P.
      • Dare J.
      Juvenile dermatomyositis as a paraneoplastic phenomenon: an update.
      In general, in the absence of suggestive examination findings, an exhaustive evaluation for an underlying malignancy is not warranted in children with newly diagnosed myositis.

      Imaging

      Magnetic resonance imaging has become a diagnostic modality routinely used to confirm myositis. Indeed, evolving guidelines for diagnosing JDM have resulted in increased use of muscle MRIs.
      • Ruperto N.
      • Ravelli A.
      • Pistorio A.
      • et al.
      Paediatric Rheumatology International Trials Organisation (PRINTO); Pediatric Rheumatology Collaborative Study Group (PRCSG)
      The provisional Paediatric Rheumatology International Trials Organisation/American College of Rheumatology/European League Against Rheumatism disease activity core set for the evaluation of response to therapy in juvenile dermatomyositis: a prospective validation study.
      • Brown V.E.
      • Pilkington C.A.
      • Feldman B.M.
      • Davidson J.E.
      Network for Juvenile Dermatomyositis, Paediatric Rheumatology European Society (PReS)
      An international consensus survey of the diagnostic criteria for juvenile dermatomyositis (JDM).
      We obtain MRIs of the proximal muscle groups in children with JDM to avoid invasive testing such as an EMG or muscle biopsy. Magnetic resonance imaging, T1-weighted, T2-weighted, and sequences using fat suppression techniques and short tau inversion recovery, provides useful information to diagnose myositis, monitor treatment response, and identify a muscle site for biopsy.
      • Adams E.M.
      • Chow C.K.
      • Premkumar A.
      • Plotz P.H.
      The idiopathic inflammatory myopathies: spectrum of MR imaging findings.
      • Schulze M.
      • Kötter I.
      • Ernemann U.
      • et al.
      MRI findings in inflammatory muscle diseases and their noninflammatory mimics.
      • Maillard S.M.
      • Jones R.
      • Owens C.
      • et al.
      Quantitative assessment of MRI T2 relaxation time of thigh muscles in juvenile dermatomyositis.
      • Park J.H.
      • Vansant J.P.
      • Kumar N.G.
      • et al.
      Dermatomyositis: correlative MR imaging and P-31 MR spectroscopy for quantitative characterization of inflammatory disease.
      • Hernandez R.J.
      • Sullivan D.B.
      • Chenevert T.L.
      • Keim D.R.
      MR imaging in children with dermatomyositis: musculoskeletal findings and correlation with clinical and laboratory findings.
      • Kimball A.B.
      • Summers R.M.
      • Turner M.
      • et al.
      Magnetic resonance imaging detection of occult skin and subcutaneous abnormalities in juvenile dermatomyositis: implications for diagnosis and therapy.
      T1-weighted images may show muscle atrophy and chronic muscle damage.
      • Schulze M.
      • Kötter I.
      • Ernemann U.
      • et al.
      MRI findings in inflammatory muscle diseases and their noninflammatory mimics.
      T2-weighted images are used in active JDM because increased signal in muscle tissues suggests muscle edema, and T2-weighted relaxation times are a quantitative measure of muscle inflammation and correlate with disease activity.
      • Maillard S.M.
      • Jones R.
      • Owens C.
      • et al.
      Quantitative assessment of MRI T2 relaxation time of thigh muscles in juvenile dermatomyositis.
      • Park J.H.
      • Vansant J.P.
      • Kumar N.G.
      • et al.
      Dermatomyositis: correlative MR imaging and P-31 MR spectroscopy for quantitative characterization of inflammatory disease.
      • Kimball A.B.
      • Summers R.M.
      • Turner M.
      • et al.
      Magnetic resonance imaging detection of occult skin and subcutaneous abnormalities in juvenile dermatomyositis: implications for diagnosis and therapy.
      Magnetic resonance imaging also may document fat atrophy on T2-weighted images. In DM, the connective tissue septa and muscle fascia may be involved.
      • Schulze M.
      • Kötter I.
      • Ernemann U.
      • et al.
      MRI findings in inflammatory muscle diseases and their noninflammatory mimics.
      • Hernandez R.J.
      • Sullivan D.B.
      • Chenevert T.L.
      • Keim D.R.
      MR imaging in children with dermatomyositis: musculoskeletal findings and correlation with clinical and laboratory findings.
      Recently, a novel MRI-based scoring system using a 4-point scale indicating degree of muscle inflammation has been developed for objective assessment of active JDM using short tau inversion recovery–weighted axial images of the thighs, with a focus on 4 muscle groups—gluteal, hamstrings, quadriceps, and adductors.
      • Davis W.R.
      • Halls J.E.
      • Offiah A.C.
      • Pilkington C.
      • Owens C.M.
      • Rosendahl K.
      Assessment of active inflammation in juvenile dermatomyositis: a novel magnetic resonance imaging-based scoring system.
      Magnetic resonance elastography is an experimental imaging method used to quantify mechanical elasticity of muscle and tissue. The method involves shear waves that are generated and propagated on MRI with postprocessing performed to produce a quantitative map of tissue elasticity.
      • Amarteifio E.
      • Nagel A.M.
      • Kauczor H.U.
      • Weber M.A.
      Functional imaging in muscular diseases.
      • McCullough M.B.
      • Domire Z.J.
      • Reed A.M.
      • et al.
      Evaluation of muscles affected by myositis using magnetic resonance elastrography.
      McCollough et al
      • McCullough M.B.
      • Domire Z.J.
      • Reed A.M.
      • et al.
      Evaluation of muscles affected by myositis using magnetic resonance elastrography.
      evaluated 9 patients with active myositis (DM, PM, JDM) and found reduced stiffness of the vastus medialis in the relaxed state in these patients compared to healthy controls. The usefulness of magnetic resonance elastography has not been established in clinical practice to date.

      Treatment Guidelines

      The major goals of treatment are to eliminate inflammation, restore muscle performance, and prevent chronic muscle disease and other organ system damage to reduce morbidity and regain quality of life. Therapy for newly diagnosed IIM involves a multidisciplinary approach with specialists depending on disease manifestations, including rheumatologists, neurologists, dermatologists, pulmonologists, physical therapists, speech therapists, occupational therapists, and orthopedic surgeons.

      Initial Treatment Approach to Adult Patients With IIM

      At diagnosis of IIM in adults, we initiate treatment with high-dose corticosteroids and a steroid-sparing agent (Figure 1). The rationale for corticosteroid use stems from early studies documenting improvement in muscle inflammation.
      • Winkelman R.K.
      • Mulder D.W.
      • Lambert E.H.
      • Howard Jr., F.M.
      • Diessner G.R.
      Course of dermatomyositis-polymyositis: comparison of untreated and cortisone-treated patients.
      • Lundberg I.
      • Kratz A.K.
      • Alexanderson H.
      • Patarroyo M.
      Decreased expression of interleukin-1alpha, interleukin-1 beta, and cell adhesion molecules in muscle tissue following corticosteroid treatment in patients with polymyositis and dermatomyositis.
      Lundberg et al
      • Lundberg I.
      • Kratz A.K.
      • Alexanderson H.
      • Patarroyo M.
      Decreased expression of interleukin-1alpha, interleukin-1 beta, and cell adhesion molecules in muscle tissue following corticosteroid treatment in patients with polymyositis and dermatomyositis.
      found decreased expression of class I MHC antigens including IL-1α, IL-1β, and cell adhesion molecules and improved muscle strength in adult patients treated with prednisolone for 3 to 6 months. We initiate prednisone at a dosage of 0.5 to 1 mg/kg per day, which typically is 60 to 80 mg/d as a single daily dose, with a taper after 2 to 4 weeks depending on patient response. We taper the dosage by 10 mg every 2 weeks to a dosage of 30 mg/d. At that time, the taper is slowed by 5 mg every 2 weeks until the dosage reaches 20 mg/d. Once the 20-mg/d dosage is achieved, the taper is slowed by 2.5 mg every 2 weeks until the taper is completed. Occasionally, at 10 mg/d the taper may be slowed by 1 mg every 2 to 4 weeks until completed.
      Figure thumbnail gr1
      Figure 1Initial management of uncomplicated, newly diagnosed idiopathic inflammatory myopathy in adult patients. IBW = ideal body weight; MTX = methotrexate.
      Concurrent with corticosteroids, we administer an immunosuppressive drug to function as a steroid-sparing agent. Typically, these medications are slow acting and may take up to 3 to 6 months to reach full efficacy. The usual choices are methotrexate (MTX), azathioprine, and mycophenolate mofetil (MMF) (Figure 1). No trials have shown the superiority of one of these agents over the others. Bunch et al
      • Bunch T.W.
      • Worthington J.W.
      • Combs J.J.
      • Ilstrup D.M.
      • Engel A.G.
      Azathioprine with prednisone for polymyositis: a controlled, clinical trial.
      showed that patients treated with azathioprine at a dosage of 2 mg/kg for 3 months in a controlled, double-blind trial improved muscle strength, but there was no significant difference compared with controls. A long-term follow-up trial demonstrated improvement in functional disability at 3 years in patients treated with prednisone and azathioprine.
      • Bunch T.W.
      Prednisone and azathioprine for polymyositis: long-term followup.
      If azathioprine is chosen, we check the patient’s thiopurine methyltransferase level to screen for enzyme deficiency. Myelosuppression can occur in patients with a thiopurine methyltransferase deficiency who are treated with standard dosages of azathioprine. The goal dosage should be 2 mg/kg of ideal body weight in divided doses. Typically, we begin at 25 to 50 mg/wk with increments of 25 to 50 mg/wk until the goal dosage is reached. Common adverse effects include nausea and loose stools; less common adverse effects include fever and liver toxicity.
      Methotrexate has been used since the 1970s to treat IIM. Metzger et al
      • Metzger A.L.
      • Bohan A.
      • Goldberg L.S.
      • Bluestone R.
      • Pearson C.M.
      Polymyositis and dermatomyositis: combined methotrexate and corticosteroid therapy.
      demonstrated improvement in 17 of 22 patients with DM or PM treated with intravenous MTX, with normalization of the CK level and improvement in strength. If MTX is chosen, we begin with an initial dosage of 15 mg orally once weekly with 1 mg/d of folic acid supplementation because MTX is an antagonist of folate metabolism. We initiate MTX at a lower dosage in an effort to avoid potential intolerance or adverse effects. We aim for an MTX target dosage of 25 mg once weekly within 3 to 6 months. As with azathioprine use, transaminitis and gastrointestinal adverse effects are common in patients taking MTX. To avoid the potential for MTX-induced liver toxicity, we counsel patients to avoid excessive alcohol use. Screening for preexisting liver disease with baseline liver function tests and measurement of antibodies for hepatitis B and hepatitis C should be done before initiating MTX. Screening for lung disease is also advised; MTX-induced pneumonitis is a rare adverse effect that may be indistinguishable from ILD associated with a connective tissue disease. However, the presence of ILD is not an absolute contraindication for MTX use. Painful stomatitis can be a complication among adult patients with myositis. Higher doses of folic acid and leucovorin may be used as rescue therapy for MTX toxicities. Women of childbearing potential should be counseled to use a reliable form of birth control while taking MTX because it is teratogenic.
      Certain follow-up studies are done to ensure toleration of treatment. Within 2 to 4 weeks of starting MTX or azathioprine, a complete blood cell count, liver enzyme function tests, and creatinine measurement should be obtained once a month for 3 consecutive months. Once a stable dosage is achieved, laboratory follow-up every 2 to 3 months thereafter is appropriate.
      • Saag K.G.
      • Teng G.G.
      • Patkar N.J.
      • et al.
      American College of Rheumatology
      American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis.
      Mycophenolate mofetil has emerged as an efficacious drug to treat IIM. It is an inhibitor of inosine monophosphate dehydrogenase, which affects de novo purine synthesis and T- and B-cell proliferation. Several retrospective case series have shown its efficacy in the treatment of severe DM and PM. Gelber et al
      • Gelber A.C.
      • Nousari H.C.
      • Wigley F.M.
      Mycophenolate mofetil in the treatment of severe skin manifestations of dermatomyositis: a series of 4 cases.
      reported a case series of 4 patients who had DM with severe skin disease who benefitted from MMF therapy. Edge et al
      • Edge J.C.
      • Outland J.D.
      • Dempsey J.R.
      • Callen J.P.
      Mycophenolate mofetil as an effective corticosteroid-sparing therapy for recalcitrant dermatomyositis.
      found that 10 of 12 patients who had myositis with severe skin disease had improvement after 4 to 8 weeks of MMF. Patients with IIM who have pulmonary complications (eg, anti-synthetase syndrome) may respond favorably to MMF. In a small series, Morganroth et al
      • Morganroth P.A.
      • Kreider M.E.
      • Werth V.P.
      Mycophenolate mofetil for interstitial lung disease in dermatomyositis.
      retrospectively studied 4 of 16 patients who had DM with ILD and found that 3 of the 4 had complete normalization of pulmonary function at 1-year follow-up. However, although ILD may affect up to 20% of adult patients with IIM, large-scale, controlled treatment trials are lacking to date. In adult patients with IIM, we initiate MMF at a dosage of 500 mg twice daily and increase the dosage by 500 mg every week, sometimes every 2 weeks depending on drug tolerability, up to a goal dosage of 2 g/d (1000 mg twice daily). Infrequently, the dosage may be increased to 3 g/d (1500 mg twice daily) if tolerated. Some physicians may monitor the MMF level (glucuronide) to ensure that the drug is within the therapeutic range. Compliance may become an issue in the higher dosage ranges because of adverse effects, commonly nausea and loose stools. Laboratory evaluation is essential to monitor for leukopenia or transaminitis. Women of childbearing potential should be counseled to use 2 reliable forms of birth control because MMF is also teratogenic.
      For adult patients with IIM who have dysphagia, notable weight loss, severe rash, or weakness, we use intravenous immunoglobulin (IVIG) at a dosage of 1 to 2 g/kg of ideal body weight, usually given over 2 consecutive days (1 g/kg each on day 1 and day 2) once a month for 1 to 6 months. The serum IgA level should be checked before administering IVIG because IgA deficiency may lead to fever, infusion reactions, and/or severe anaphylaxis that is believed to be caused by macromolecular complexes formed between the infused IgA and anti-IgA antibodies.
      • Dalakas M.C.
      Mechanism of action of intravenous immunoglobulin and therapeutic considerations in the treatment of autoimmune neurologic diseases.
      If IgA deficiency is detected, the patient should receive an IVIG preparation with reduced IgA levels. If the dose of IVIG is higher than 80 g, we occasionally administer the dose over 3 to 5 days at 0.4 g/kg. The rationale for IVIG use comes from a placebo-controlled trial of 15 patients with DM who received IVIG every month for 3 months with option for crossover. Twelve patients had improvement in muscle strength, rash, and activities of daily living (ADL). Repeated muscle biopsies in 5 patients who received IVIG treatment showed an increase in muscle fiber diameter, resolution of complement deposits in capillaries, and a reduction in MHC class I antigens.
      • Dalakas M.C.
      • Illa I.
      • Dambrosia J.M.
      • et al.
      A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis.
      Several mechanisms of action may account for its effects: blocking of Fc receptors, inhibition of complement activation, influencing antigen recognition by sensitized T cells, and modulation of Fc-receptor mediated activity leading to downregulation of phagocytosis.
      • Dalakas M.C.
      Mechanism of action of intravenous immunoglobulin and therapeutic considerations in the treatment of autoimmune neurologic diseases.
      • Dalakas M.C.
      Intravenous immunoglobulin in autoimmune neuromuscular diseases.
      However, the favorable effect of IVIG on muscle inflammation observed in muscle tissue biopsy specimens could not be repeated in a later study that included 13 treatment-resistant patients with DM, JDM, PM, and inclusion body myositis.
      • Barbasso Helmers S.
      • Dastmalchi M.
      • Alexanderson H.
      • et al.
      Limited effects of high-dose intravenous immunoglobulin (IVIG) treatment on molecular expression in muscle tissue of patients with inflammatory myopathies.

      Treatment Approach for Adult Patients With Severe IIM or Disease Refractory to Conventional Therapy

      Patients with IIM that are refractory to standard therapy or who present with severe cutaneous disease, severe muscle weakness, and/or dysphagia with notable weight loss are treated with intravenous methylprednisolone (IVMP) at dosages of 500 mg to 1000 mg daily for 1-3 consecutive days followed by high-dose oral corticosteroids with taper (Figure 2). A case series reported by Bolosiu et al
      • Bolosiu H.D.
      • Man L.
      • Rednic S.
      The effect of methylprednisolone pulse therapy in polymyositis/dermatomyositis.
      involving 7 patients with IIM treated with IVMP daily for 3 days once monthly for 3 months demonstrated improvement in CK levels. Common adverse effects of high-dose corticosteroids include sleep disturbances, exacerbation of mood disorders such as anxiety or depression, psychosis, hypertension, and hyperglycemia.
      Figure thumbnail gr2
      Figure 2Treatment of idiopathic inflammatory myopathy refractory to conventional therapy or with severe organ-threatening manifestations such as interstitial lung disease, severe dysphagia with weight loss, severe weakness, or cardiomyopathy. CYC = cyclophosphamide; CSA = cyclosporine A; IV = intravenous; IVIG = intravenous immunoglobulin; JDM = juvenile dermatomyositis.
      We reserve the use of cyclophosphamide (CYC), either oral or intravenous, for severe organ manifestations. There are limited studies regarding the use of CYC in IIM with pulmonary complications. Yamasaki et al
      • Yamasaki Y.
      • Yamada H.
      • Yamasaki M.
      • et al.
      Intravenous cyclophosphamide therapy for progressive interstitial pneumonia in patients with polymyositis/dermatomyositis.
      conducted an open-label study of 17 patients with DM/PM or amyopathic DM treated with CYC and prednisolone. They found that 11 of the 17 patients had improvement in dyspnea, and 8 of the 17 patients had a 10% improvement in vital capacity and regression of lung fibrosis on high-resolution lung CT. Unfortunately, CYC is associated with cytopenias, hemorrhagic cystitis, premature ovarian failure, sterility, severe infections, nausea, and vomiting. The typical intravenous dosage of 0.6 to 1.0 g/m2 is given after adequate oral hydration (2-3 L within 24 hours) and intravenous hydration with normal saline, antiemetics, and mesna (40% of CYC dose). Oral mesna is given 4 and 8 hours after CYC infusion for 2 doses (20% of CYC infusion) to reduce the complication of hemorrhagic cystitis. Cyclophosphamide infusions are given every 4 weeks for 3 to 6 months. Infrequently, the duration is extended to 12 months. It is our practice to monitor the white blood cell count for the nadir that occurs 8 to 14 days after CYC infusion to avoid a nadir of less than 3.0 × 10(9)/L.3 If CYC is given orally, we administer 1 to 2 mg/kg, but we do not exceed a 200-mg daily dosage. Patients are advised about maintaining adequate hydration to avoid hemorrhagic cystitis. We recommend that patients urinate frequently, especially first thing in the morning on waking, to prevent the acrolein metabolite from inducing hemorrhagic cystitis.
      Rituximab is becoming the alternative to CYC in patients who have refractory IIM or severe disease complications. Rituximab is a human monoclonal antibody to CD20 that is expressed on B cells and depletes circulating B cells. Levine
      • Levine T.D.
      Rituximab in the treatment of dermatomyositis: an open-label pilot study.
      performed an open-label trial of 6 patients with DM who received 4 weekly infusions at 375 mg/m2 and found improvement in muscle strength, reduction of CK levels, and improved cutaneous and pulmonary disease after 12 weeks. Myositis seemed to recur when circulating B cells returned. Mahler et al
      • Mahler E.A.
      • Blom M.
      • Voermans N.C.
      • van Engelen B.G.
      • van Riel P.L.
      • Vonk M.C.
      Rituximab treatment in patients with refractory inflammatory myopathies.
      conducted a prospective trial in 13 patients with refractory IIM to assess the efficacy of rituximab dosed at 1000 mg in a 2-week interval and found a significant reduction in muscle enzyme levels and improvements in strength, disease activity, and quality of life scores at 27.1 months of follow-up. The Rituximab in Myositis study,

      Oddis CV, Reed AM, Aggarwal R, et al; Rituximab in Myositis (RIM) Study Group. Rituximab in the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis: a randomized, placebo-phase trial [published online ahead of print November 2, 2012]. Arthritis Rheum. http://dx.doi.org/10.1002/art.37754.

      the first prospective, double-blind, randomized, multicenter trial of rituximab in myositis, involved 200 pediatric and adult patients who received rituximab for refractory disease. A favorable response and improvement was seen in 83% of patients throughout the 44-week trial. We administer two 1000-mg doses of rituximab 2 weeks apart for adults. We obtain baseline immunoglobulin levels (IgG, IgM, IgA), determine hepatitis B and C antibody levels, and screen for latent tuberculosis prior to administering rituximab. Severe infectious complications are a concern. Progressive multifocal leukoencephalopathy has been reported in rheumatic patients treated with rituximab; caution should be used in patients who are severely immunosuppressed.
      • Vulliemoz S.
      • Lurati-Ruiz F.
      • Borruat F.X.
      • et al.
      Favourable outcome of progressive multifocal leucoencephalopathy in two patients with dermatomyositis.
      Progressive multifocal leukoencephalopathy also has been reported in patients with myositis who have not been treated with rituximab; therefore, a high index of suspicion for JC virus reactivation should be reserved for any patient presenting with central nervous system abnormalities.
      • Molloy E.S.
      • Calabrese L.H.
      Progressive multifocal leukoencephalopathy associated with immunosuppressive therapy in rheumatic diseases: evolving role of biologic therapies.
      Cyclosporine A (CSA) and tacrolimus are agents that inhibit T-cell–mediated immune functions such as suppression of IL-2 gene transcription. They have been used for the treatment of IIM with severe ILD. In one open-label, randomized study,
      • Vencovský J.
      • Jarosová K.
      • Machácek S.
      • et al.
      Cyclosporine A versus methotrexate in the treatment of polymyositis and dermatomyositis.
      36 patients with active DM or PM were randomized to either MTX at dosages of 7.5 mg to 15 mg once weekly or CSA at dosages of 3.0 to 3.5 mg/kg daily. The 2 groups had equal improvement in outcomes such as strength, endurance, and patient global assessments. Additionally, a few retrospective trials of CSA have demonstrated improvement in ILD and partial regression of calcinosis; however, because of serious adverse effects including hypertension and renal insufficiency, the use of CSA is limited.
      • Maeda K.
      • Kimura R.
      • Komuta K.
      • Igarashi T.
      Cyclosporine treatment for polymyositis/dermatomyositis: is it possible to rescue the deteriorating cases with interstitial pneumonitis?.
      • Qushmaq K.A.
      • Chalmers A.
      • Esdaile J.M.
      Cyclosporine A in the treatment of refractory adult polymyositis/dermatomyositis: population based experience in 6 patients and literature review.
      Serum CSA trough levels are monitored routinely to avoid renal toxicity. Oddis et al
      • Oddis C.V.
      • Sciurba F.C.
      • Elmagd K.A.
      • Starzl T.E.
      Tacrolimus in refractory polymyositis with interstitial lung disease.
      described pulmonary improvement in 8 patients with IIM treated with tacrolimus who had anti-Jo-1 or anti-SRP antibodies. Due to concern about serious adverse effects, our practice is to reserve the use of CSA and tacrolimus for severe, refractory IIM.

      Initial Treatment Approach to Patients With JDM

      For children with JDM, we begin prednisone at 2 mg/kg up to a maximum of 60 mg/d with a taper after 2 to 4 weeks depending on patient response, similar to the corticosteroid taper for adult patients with myositis. A suggested corticosteroid taper schedule was recently published by Huber et al
      • Huber A.M.
      • Giannini E.H.
      • Bowyer S.L.
      • et al.
      Protocols for the initial treatment of moderately severe juvenile dermatomyositis: results of a Children’s Arthritis and Rheumatology Research Alliance consensus conference.
      based on consensus-driven treatments: reduce corticosteroid dosages of 2 mg/kg every 2 weeks until the dosage reaches 0.5 mg/kg and then taper the dosage by 10% to 20% of the current dosage for 4 weeks until completion. Subcutaneous MTX is added at the onset at a dose of 15 mg/m2 once weekly and is a key component of the Childhood Arthritis and Rheumatology Research Alliance consensus treatments.
      • Huber A.M.
      • Robinson A.B.
      • Reed A.M.
      • et al.
      Juvenile Dermatomyositis Subcommittee of the Childhood Arthritis and Rheumatology Research Alliance
      Consensus treatments for moderate juvenile dermatomyositis: beyond the first two months: results of the second Childhood Arthritis and Rheumatology Research Alliance consensus conference.

      Treatment Approach to Patients With JDM Refractory to Standard Treatment

      For patients with JDM who present with severe muscular and/or extramuscular disease or disease refractory to standard treatment, we administer IVMP at 30 mg/kg to a maximum of 1 g/d for 3 days. Several small trials have described improvement in outcomes with IVMP, usually in conjunction with MTX and/or hydroxychloroquine. Huang
      • Huang J.L.
      Long-term prognosis of patients with juvenile dermatomyositis initially treated with intravenous methylprednisolone pulse therapy.
      conducted a retrospective study of 24 patients with JDM and found that 13 of 24 patients treated with IVMP initially had a shorter time to achieve normal strength and improvement of rash. Al-Mayouf et al
      • Al-Mayouf S.
      • Al-Mazyed A.
      • Bahabri S.
      Efficacy of early treatment of severe juvenile dermatomyositis with intravenous methylprednisolone and methotrexate.
      studied 12 patients with severe JDM with dysphagia and/or cutaneous vasculitis treated with MTX and IVMP early in the disease course or 5 to 72 months after diagnosis. All 6 patients treated early with MTX improved and achieved discontinuation of corticosteroids and remission without development of calcinosis. Riley et al
      • Riley P.
      • Maillard S.M.
      • Wedderburn L.R.
      • Woo P.
      • Murray K.J.
      • Pilkington C.A.
      Intravenous cyclophosphamide pulse therapy in juvenile dermatomyositis: a review of efficacy and safety.
      used intravenous CYC at dosages of 0.5 to 1.0 mg/m2 to treat JDM, and 10 of 12 patients had disease improvement. Intravenous immunoglobulin is also efficacious (and safe) in JDM, as proven in 38 children treated with 1056 infusions; adverse events were reported in preparations containing high IgA levels.
      • Manlhiot C.
      • Tyrrell P.N.
      • Liang L.
      • Atkinson A.R.
      • Lau W.
      • Feldman B.M.
      Safety of intravenous immunoglobulin in the treatment of juvenile dermatomyositis: adverse reactions are associated with immunoglobulin A content.
      Other immunosuppressive drugs have been used such as azathioprine, CSA, and systemic tacrolimus.
      • Miller L.C.
      • Michael A.F.
      • Kim Y.
      Childhood dermatomyositis: clinical course and long-term follow-up.
      • Zeller V.
      • Cohen P.
      • Prieur A.M.
      • Guillevin L.
      Cyclosporin A therapy in refractory juvenile dermatomyositis: experience and longterm followup of 6 cases.
      • Yamada A.
      • Ohshima Y.
      • Omata N.
      • Yasutomi M.
      • Mayumi M.
      Steroid-sparing effect of tacrolimus in a patient with juvenile dermatomyositis presenting poor bioavailability of cyclosporine A.
      Mycophenolate mofetil is not routinely used as a conventional immunosuppressant in children with JDM, although one report described a case series of MMF use at a dosage range from 800 to 1350 mg/m2 per day in 8 children with JDM that resulted in improved muscle strength and ability to taper corticosteroids by at least 18% after 3 months of therapy.
      • Dagher R.
      • Desjonquères M.
      • Duquesne A.
      • et al.
      Mycophenolate mofetil in juvenile dermatomyositis: a case series.
      Finally, rituximab is gaining acceptance for treating severe or refractory JDM. Bader-Meunier et al
      • Bader-Meunier B.
      • Decaluwe H.
      • Barnerias C.
      • et al.
      Club Rhumatismes et Inflammation
      Safety and efficacy of rituximab in severe juvenile dermatomyositis: results from 9 patients from the French Autoimmunity and Rituximab registry.
      conducted a multicenter trial of 9 patients with refractory JDM and found that 3 of 6 children treated with rituximab for severe muscle disease had complete clinical remission; they were able to taper the corticosteroids to less than 15% of the child’s baseline dosage or stop corticosteroids completely after a follow-up of 1.3 to 3 years. If rituximab is chosen to treat JDM, we use the following doses: children with a body surface area of 1.5 m2 or less receive 575 mg/m2 at each infusion, and children with a body surface area greater than 1.5 m2 receive 750 mg/m2 up to 1 g per infusion.

      Therapy for Skin Disease in DM and JDM

      Avoidance of UV rays is paramount to preventing skin flares in patients with DM and JDM; judicious use of sunscreens with a sun protection factor of 50 or higher in addition to appropriate coverage with wide-brimmed hats and long-sleeved shirts should be advised. Topical corticosteroids at varying strengths as well as topical tacrolimus (0.1%) has been used in JDM and DM.
      • Yoshimasu T.
      • Ohtani T.
      • Sakamoto T.
      • Oshima A.
      • Furukawa F.
      Topical FK506 (tacrolimus) therapy for facial erythematous lesions of cutaneous lupus erythematosus and dermatomyositis.
      Hydroxychloroquine is an antimalarial drug administered at 200 mg twice daily (5 mg/kg). It is primarily used for cutaneous manifestations of DM or JDM. For nonresponders, chloroquine can be used at dosages of 250 to 500 mg/d. A baseline electrocardiogram should be obtained to screen for QT prolongation. Quinacrine is another treatment option.
      • Callen J.P.
      Cutaneous manifestations of dermatomyositis and their management.
      Ophthalmologic monitoring for retinal toxicity using newer testing modalities such as multifocal electroretinography and spectral domain optical coherence tomography is important before drug initiation as a baseline screening to rule out macular disease; subsequent annual screening should begin 5 years or less after initiation of the drug if the patient is still taking hydroxychloroquine and there are underlying risk factors for retinal toxicity.
      • Marmor M.
      • Kellner U.
      • Lai T.Y.
      • Lyons J.S.
      • Mieler W.F.
      American Academy of Ophthalmology
      Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy.
      For refractory skin disease, MMF has been reported to be effective.
      • Gelber A.C.
      • Nousari H.C.
      • Wigley F.M.
      Mycophenolate mofetil in the treatment of severe skin manifestations of dermatomyositis: a series of 4 cases.
      • Edge J.C.
      • Outland J.D.
      • Dempsey J.R.
      • Callen J.P.
      Mycophenolate mofetil as an effective corticosteroid-sparing therapy for recalcitrant dermatomyositis.
      Intravenous immunoglobulin may be helpful as an additional medication for treatment of refractory skin disease.
      • Callen J.P.
      Cutaneous manifestations of dermatomyositis and their management.
      • Dalakas M.C.
      • Illa I.
      • Dambrosia J.M.
      • et al.
      A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis.

      Treatment of Calcinosis in DM and JDM

      Calcinosis cutis is a common complication of JDM, and its presence suggests active disease in JDM and a delay to diagnosis and treatment.
      • Pachman L.M.
      • Hayford J.R.
      • Chung A.
      • et al.
      Juvenile dermatomyositis at diagnosis: clinical characteristics of 79 children.
      Classically, calcinosis is found at the subcutaneous level, but it may be seen intramuscularly, in fascial planes, and in areas at risk for trauma such as the elbows and knees. Calcinosis may also be present in adult patients with DM and those with DM/scleroderma overlap, although it is less common than in JDM. Calcinosis is discouraging to treat because of the lack of meaningful response with most treatments. Several agents have been used with minimal or no improvement, including diltiazem, colchicine, bisphosphonates, probenecid, warfarin, and intralesional corticosteroids. Of these agents, diltiazem may produce a partial response.
      • Balin S.J.
      • Wetter D.A.
      • Andersen L.K.
      • Davis M.D.
      Calcinosis cutis occurring in association with autoimmune connective tissue disease: the Mayo Clinic experience with 78 patients, 1996-2009.
      However, a recent case report noted improvement of severe ulcerative skin disease and calcinosis with abatacept and sodium thiosulfate, a vasodilator that chelates calcium, in a 14-year-old girl with recalcitrant JDM, although use of these medications would be off label in this context.
      • Arabshahi B.
      • Silverman R.A.
      • Jones O.Y.
      • Rider L.G.
      Abatacept and sodium thiosulfate for treatment of recalcitrant juvenile dermatomyositis complicated by ulceration and calcinosis.
      Eventually, the calcinosis may regress, although joint contractures and secondary infections may be complications. If there is considerable pain associated with an area of calcinosis, surgical excision may be an option.

      Treatment of sIBM

      In general, we treat patients with newly diagnosed sIBM with immunosuppression using the same treatment algorithms used for DM and PM with the goal of suppressing muscle inflammation, although the disease typically is resistant to standard immunotherapy. The rationale for immunotherapy is that early suppression of the inflammatory cascade may prevent downstream effects leading to muscle degeneration by interfering with protein misfolding.
      • Dalakas M.C.
      Immunotherapy of inflammatory myopathies: practical approach and future prospects.
      However, the degenerative process may predominate over time, leading to loss of efficacy with conventional immunosuppression. If the patient has severe dysphagia, IVIG may be efficacious, although there may be loss of therapeutic benefit over time.
      • Dalakas M.C.
      • Sonies B.
      • Dambrosia J.
      • Sekul E.
      • Cupler E.
      • Sivakumar K.
      Treatment of inclusion body myositis with IVIg: a double-blind, placebo-controlled study.
      • Walter M.C.
      • Lochmüller H.
      • Toepfer M.
      • et al.
      High-dose immunoglobulin therapy in sporadic inclusion body myositis: a double-blind, placebo-controlled study.
      • Cherin P.
      • Pelletier S.
      • Teixeira A.
      • et al.
      Intravenous immunoglobulin for dysphagia of inclusion body myositis.
      Unfortunately, most treatment trials involving patients with sIBM have been small and yielded little with respect to improved outcomes in strength and muscle mass. A randomized, placebo-controlled trial using anti–T-lymphocyte globulin therapy demonstrated improvement in mean muscle strength (1.4%) in 6 patients treated for 12 months compared with patients treated with MTX.
      • Lindberg C.
      • Trysberg E.
      • Tarkowski A.
      • Oldfors A.
      Anti-T-lymphocyte globulin treatment in inclusion body myositis: a randomized pilot study.
      Another small pilot trial using oxandrolone showed borderline significant improvement in upper extremity muscle strength in patients with sIBM.
      • Rutkove S.B.
      • Parker R.A.
      • Nardin R.A.
      • Connolly C.E.
      • Felice K.J.
      • Raynor E.M.
      A pilot randomized trial of oxandrolone in inclusion body myositis.
      Two small randomized, placebo-controlled trials used interferon-β-1a (βINF1a) as treatment.
      Muscle Study Group
      Randomized pilot trial of βINF1a (Avonex) in patients with inclusion body myositis.
      Muscle Study Group
      Randomized pilot trial of high-dose βINF-1a in patients with inclusion body myositis.
      One study was a 24-week multicenter trial assessing the safety and tolerability of βINF1a with a secondary goal of measuring improvements in strength and muscle mass; however, no differences were found between placebo and treated groups at 6 months, and 2 patients experienced severe adverse events including death.
      Muscle Study Group
      Randomized pilot trial of βINF1a (Avonex) in patients with inclusion body myositis.
      The second study investigated the tolerability of a higher dose of βINF1a and found no difference in strength and mass compared with placebo.
      Muscle Study Group
      Randomized pilot trial of high-dose βINF-1a in patients with inclusion body myositis.
      Dalakas et al
      • Dalakas M.C.
      • Rakocevic G.
      • Schmidt J.
      • et al.
      Effect of Alemtuzumab (CAMPATH 1-H) in patients with inclusion-body myositis.
      examined the effect of the monoclonal antibody alemtuzumab (Campath-1H), a medication that depletes peripheral lymphocytes, in 13 patients with sIBM treated for 4 days and found that the decline in strength had lessened 6 months after therapy along with some improvement in ADLs.

      Treatment Response

      Patient response to treatment depends on several factors including tolerance to therapy, the severity of the muscle disease, and the extent and severity of extramuscular organ involvement, if present. In general, we measure improvement of disease by muscle strength based on the manual muscle test (MMT), serum muscle enzyme level normalization at successive clinic visits, the patient’s physical function as determined by validated questionnaires, patient and physician global assessment of disease activity, and physician assessment of improvement of extramuscular organ involvement (Table 2).
      • Rider L.G.
      • Werth V.P.
      • Huber A.M.
      • et al.
      Measures of adult and juvenile dermatomyositis, polymyositis, and inclusion body myositis: Physician and Patient/Parent Global Activity, Manual Muscle Testing (MMT), Health Assessment Questionnaire (HAQ)/Childhood Health Assessment Questionnaire (C-HAQ), Childhood Myositis Assessment Scale (CMAS), Myositis Disease Activity Assessment Tool (MDAAT), Disease Activity Score (DAS), Short Form 36 (SF-36), Child Health Questionnaire (CHQ), physician global damage, Myositis Damage Index (MDI), Quantitative Muscle Testing (QMT), Myositis Functional Index-2 (FI-2), Myositis Activities Profile (MAP), Inclusion Body Myositis Functional Rating Scale (IBMFRS), Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), Cutaneous Assessment Tool (CAT), Dermatomyositis Skin Severity Index (DSSI), Skindex, and Dermatology Life Quality Index (DLQI).
      • Miller F.W.
      • Rider L.G.
      • Chung Y.L.
      • et al.
      International Myositis Outcome Assessment Collaborative Study Group
      Proposed preliminary core set measures for disease outcome assessment in adult and juvenile idiopathic inflammatory myopathies.
      Table 2Core Measures for Assessment of Disease Activity in Inflammatory Myositis (Adult and Juvenile)
      Adapted from Rheumatology (Oxford),
      • Miller F.W.
      • Rider L.G.
      • Chung Y.L.
      • et al.
      International Myositis Outcome Assessment Collaborative Study Group
      Proposed preliminary core set measures for disease outcome assessment in adult and juvenile idiopathic inflammatory myopathies.
      with permission from Oxford University Press.
      DomainCore set measures
      Global activityPhysician global disease activity assessed by Likert or VAS;

      patient/parent global disease activity assessed by Likert or VAS
      Muscle strengthManual muscle strength testing to include proximal, distal, and axial muscles
      Physical functionFor adults, validated ADL questionnaire (HAQ, MAP)

      For children ≥4 y, validated ADL questionnaire (CHAQ)

      For children <4 y, validated ADL questionnaire (CHAQ) and observational tool of function, strength, and endurance (CMAS)
      Laboratory assessmentAt least 2 serum muscle enzyme measurements from the following: CK, aldolase, LDH, AST, or ALT
      Extramuscular diseaseValidated approach assessing cutaneous, gastrointestinal, joint, cardiac, and pulmonary activity
      ADL = activities of daily living; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CHAQ = Childhood Assessment Health Questionnaire; CK = creatine kinase; CMAS = Childhood Myositis Assessment Scale; HAQ = Health Assessment Questionnaire; LDH = lactate dehydrogenase; MAP = Myositis Activities Profile; VAS = visual analog scale.

      Disease Assessments

      There are several instruments, mostly organ-specific but also involving quality of life and function, that are used to assess disease status and response to therapy. Two international collaborative groups, the International Myositis Assessment and Clinical Studies Group and the Paediatric Rheumatology International Trials Organisation, have recommended a core set of measures to assess disease activity, disease damage, and quality of life in adults and children.
      • Ruperto N.
      • Ravelli A.
      • Pistorio A.
      • et al.
      Paediatric Rheumatology International Trials Organisation (PRINTO); Pediatric Rheumatology Collaborative Study Group (PRCSG)
      The provisional Paediatric Rheumatology International Trials Organisation/American College of Rheumatology/European League Against Rheumatism disease activity core set for the evaluation of response to therapy in juvenile dermatomyositis: a prospective validation study.
      • Rider L.G.
      • Werth V.P.
      • Huber A.M.
      • et al.
      Measures of adult and juvenile dermatomyositis, polymyositis, and inclusion body myositis: Physician and Patient/Parent Global Activity, Manual Muscle Testing (MMT), Health Assessment Questionnaire (HAQ)/Childhood Health Assessment Questionnaire (C-HAQ), Childhood Myositis Assessment Scale (CMAS), Myositis Disease Activity Assessment Tool (MDAAT), Disease Activity Score (DAS), Short Form 36 (SF-36), Child Health Questionnaire (CHQ), physician global damage, Myositis Damage Index (MDI), Quantitative Muscle Testing (QMT), Myositis Functional Index-2 (FI-2), Myositis Activities Profile (MAP), Inclusion Body Myositis Functional Rating Scale (IBMFRS), Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), Cutaneous Assessment Tool (CAT), Dermatomyositis Skin Severity Index (DSSI), Skindex, and Dermatology Life Quality Index (DLQI).
      • Miller F.W.
      • Rider L.G.
      • Chung Y.L.
      • et al.
      International Myositis Outcome Assessment Collaborative Study Group
      Proposed preliminary core set measures for disease outcome assessment in adult and juvenile idiopathic inflammatory myopathies.

      Global Activity

      Overall disease activity based on the patient’s history, physical examination findings, laboratory results, and medical therapy is rated on a 10-cm visual analog scale, although a 5-point Likert scale may be used at the time of a patient visit. Patients or parents of patients record the extent of disease activity involving all affected organs that can improve with treatment. The Likert scale is scored with 0 indicating no disease activity and 4 indicating severe disease activity. On the visual analog scale, a score of 0 to 10 decimal places is used with higher score indicating severe disease activity
      • Rider L.G.
      • Werth V.P.
      • Huber A.M.
      • et al.
      Measures of adult and juvenile dermatomyositis, polymyositis, and inclusion body myositis: Physician and Patient/Parent Global Activity, Manual Muscle Testing (MMT), Health Assessment Questionnaire (HAQ)/Childhood Health Assessment Questionnaire (C-HAQ), Childhood Myositis Assessment Scale (CMAS), Myositis Disease Activity Assessment Tool (MDAAT), Disease Activity Score (DAS), Short Form 36 (SF-36), Child Health Questionnaire (CHQ), physician global damage, Myositis Damage Index (MDI), Quantitative Muscle Testing (QMT), Myositis Functional Index-2 (FI-2), Myositis Activities Profile (MAP), Inclusion Body Myositis Functional Rating Scale (IBMFRS), Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), Cutaneous Assessment Tool (CAT), Dermatomyositis Skin Severity Index (DSSI), Skindex, and Dermatology Life Quality Index (DLQI).
      • Miller F.W.
      • Rider L.G.
      • Chung Y.L.
      • et al.
      International Myositis Outcome Assessment Collaborative Study Group
      Proposed preliminary core set measures for disease outcome assessment in adult and juvenile idiopathic inflammatory myopathies.
      (Table 2).

      Skin

      Skin disease may correlate with disease activity, disease damage, and physical function in patients with JDM and DM; hence, assessment of cutaneous activity is important to disease management.
      • Santmyire-Rosenberger B.
      • Dugan E.M.
      Skin involvement in dermatomyositis.
      The Cutaneous Assessment Tool is a comprehensive tool assessing skin disease in JDM and adult DM that involves “activity lesions” such as Gottron papules, shawl sign, and ulcerations and “damage lesions” such as atrophy and/or hypopigmentation/hyperpigmentation in the distribution of a previous Gottron papule, heliotrope rash, or lipoatrophy using a weighted scale to determine severity.
      • Huber A.M.
      • Dugan E.M.
      • Lachenbruch P.A.
      • et al.
      Juvenile Dermatomyositis Disease Activity Collaborative Study Group
      The Cutaneous Assessment Tool: development and reliability in juvenile idiopathic inflammatory myopathy.
      • Huber A.M.
      • Dugan E.M.
      • Lachenbruch P.A.
      • et al.
      Juvenile Dermatomyositis Disease Activity Collaborative Study Group
      Preliminary validation and clinical meaning of the Cutaneous Assessment Tool in juvenile dermatomyositis.
      Other tools used to assess skin disease in adults include the Dermatomyositis Skin Severity Index and the Cutaneous Dermatomyositis Disease Area and Severity Index.
      • Carroll C.L.
      • Lang W.
      • Snively B.
      • Feldman S.R.
      • Callen J.
      • Jorizzo J.L.
      Development and validation of the Dermatomyositis Skin Severity Index.
      • Klein R.Q.
      • Bangert C.A.
      • Costner M.
      • et al.
      Comparison of the reliability and validity of outcome instruments for cutaneous dermatomyositis.

      Muscle

      The manual muscle test is used to measure muscle strength, reported as a score of the number of proximal, distal, and axial muscle groups tested on both sides (26 muscle groups).
      • Rider L.G.
      • Werth V.P.
      • Huber A.M.
      • et al.
      Measures of adult and juvenile dermatomyositis, polymyositis, and inclusion body myositis: Physician and Patient/Parent Global Activity, Manual Muscle Testing (MMT), Health Assessment Questionnaire (HAQ)/Childhood Health Assessment Questionnaire (C-HAQ), Childhood Myositis Assessment Scale (CMAS), Myositis Disease Activity Assessment Tool (MDAAT), Disease Activity Score (DAS), Short Form 36 (SF-36), Child Health Questionnaire (CHQ), physician global damage, Myositis Damage Index (MDI), Quantitative Muscle Testing (QMT), Myositis Functional Index-2 (FI-2), Myositis Activities Profile (MAP), Inclusion Body Myositis Functional Rating Scale (IBMFRS), Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), Cutaneous Assessment Tool (CAT), Dermatomyositis Skin Severity Index (DSSI), Skindex, and Dermatology Life Quality Index (DLQI).
      • Miller F.W.
      • Rider L.G.
      • Chung Y.L.
      • et al.
      International Myositis Outcome Assessment Collaborative Study Group
      Proposed preliminary core set measures for disease outcome assessment in adult and juvenile idiopathic inflammatory myopathies.
      • Harris-Love M.O.
      • Shrader J.A.
      • Koziol D.
      • et al.
      Distribution and severity of weakness among patients with polymyositis, dermatomyositis and juvenile dermatomyositis.
      The MMT has been shortened to MMT8 that scores the 8 proximal, distal, and axial muscle groups on one side.
      • Rider L.G.
      • Werth V.P.
      • Huber A.M.
      • et al.
      Measures of adult and juvenile dermatomyositis, polymyositis, and inclusion body myositis: Physician and Patient/Parent Global Activity, Manual Muscle Testing (MMT), Health Assessment Questionnaire (HAQ)/Childhood Health Assessment Questionnaire (C-HAQ), Childhood Myositis Assessment Scale (CMAS), Myositis Disease Activity Assessment Tool (MDAAT), Disease Activity Score (DAS), Short Form 36 (SF-36), Child Health Questionnaire (CHQ), physician global damage, Myositis Damage Index (MDI), Quantitative Muscle Testing (QMT), Myositis Functional Index-2 (FI-2), Myositis Activities Profile (MAP), Inclusion Body Myositis Functional Rating Scale (IBMFRS), Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), Cutaneous Assessment Tool (CAT), Dermatomyositis Skin Severity Index (DSSI), Skindex, and Dermatology Life Quality Index (DLQI).
      • Harris-Love M.O.
      • Shrader J.A.
      • Koziol D.
      • et al.
      Distribution and severity of weakness among patients with polymyositis, dermatomyositis and juvenile dermatomyositis.
      The United Kingdom Medical Research Council System scale (0-5) is commonly used to gauge muscle strength: 0 indicates the lowest strength and 5 the highest.
      Medical Research Council (Great Britain)
      Aids to the Examination of the Peripheral Nervous System.
      We commonly test muscle groups bilaterally: neck flexion/extension, shoulder abduction, elbow flexion/extension, wrist flexion/extension, hip flexion/extension, hip abduction/adduction, knee flexion/extension, ankle dorsiflexion, and plantar flexion.

      Physical and Occupational Function

      There are several outcome measures to assess ADLs in patients with IIM. The International Myositis Assessment and Clinical Studies group has established a core set of measures for assessment of IIM
      • Rider L.G.
      • Werth V.P.
      • Huber A.M.
      • et al.
      Measures of adult and juvenile dermatomyositis, polymyositis, and inclusion body myositis: Physician and Patient/Parent Global Activity, Manual Muscle Testing (MMT), Health Assessment Questionnaire (HAQ)/Childhood Health Assessment Questionnaire (C-HAQ), Childhood Myositis Assessment Scale (CMAS), Myositis Disease Activity Assessment Tool (MDAAT), Disease Activity Score (DAS), Short Form 36 (SF-36), Child Health Questionnaire (CHQ), physician global damage, Myositis Damage Index (MDI), Quantitative Muscle Testing (QMT), Myositis Functional Index-2 (FI-2), Myositis Activities Profile (MAP), Inclusion Body Myositis Functional Rating Scale (IBMFRS), Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), Cutaneous Assessment Tool (CAT), Dermatomyositis Skin Severity Index (DSSI), Skindex, and Dermatology Life Quality Index (DLQI).
      • Miller F.W.
      • Rider L.G.
      • Chung Y.L.
      • et al.
      International M