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The n e w e ng l a n d j o u r na l of m e dic i n e

Review Article

Dan L. Longo, M.D., Editor

Inflammatory Muscle Diseases
Marinos C. Dalakas, M.D.

I
From the Department of Neurology, nflammatory myopathies are the largest group of potentially
Neuromuscular Division, Thomas Jeffer- treatable myopathies in children and adults. They constitute a heterogeneous
son University, Philadelphia; and Neuro-
immunology Unit, University of Athens group of disorders that are best classified, on the basis of distinct clinicopatho-
Medical School, Athens. Address reprint logic features, in four subtypes: dermatomyositis, polymyositis, necrotizing auto-
requests to Dr. Dalakas at the Depart- immune myositis, and inclusion-body myositis (throughout this review, I use this
ment of Neurology, Neuromuscular Divi-
sion, Thomas Jefferson University, 901 term to refer specifically to sporadic inclusion-body myositis).1-6 A fifth subtype,
Walnut St., Philadelphia, PA 19107, or at termed overlap myositis, is also beginning to be recognized. The identification of
­marinos​.­dalakas@​­jefferson​.­edu. the correct subtype and the distinction of these conditions from other diseases
N Engl J Med 2015;372:1734-47. that have characteristics that mimic these conditions is fundamental, because each
DOI: 10.1056/NEJMra1402225 subtype has a different prognosis and response to therapies. This review reflects
Copyright © 2015 Massachusetts Medical Society.
the current knowledge of these conditions, highlights how best to avoid erroneous
diagnoses, describes the main clinicopathologic and immunologic features, and pro-
vides practical guidelines regarding therapies.

Gener a l Cl inic a l Fe at ur e s
Patients with inflammatory myopathies have increasing difficulty with tasks re-
quiring the use of proximal muscles, such as getting up from a chair, climbing steps,
or lifting objects.1-6 Tasks requiring distal muscles, such as buttoning or holding
objects, are affected early in inclusion-body myositis but only in advanced cases of
polymyositis, dermatomyositis, and necrotizing autoimmune myositis. The ocular
muscles are spared in all subtypes, but facial muscles are commonly affected in
inclusion-body myositis.3 In all disease subtypes, neck-extensor and pharyngeal
muscles can be involved, which results in difficulty holding up the head (head drop)
or in dysphagia. In advanced and rare acute cases, the respiratory muscles can be
affected. Muscle atrophy is detected early in inclusion-body myositis, with selective
atrophy of the quadriceps and forearm muscles, but it develops in all subtypes if
the weakness is severe and chronic. Myalgia and muscle tenderness may occur,
especially in patients with the antisynthetase syndrome (see the Glossary),6,7 but if
pain is severe and the weakness follows a “breakaway” pattern, in which the pa-
tient has difficulty sustaining effort, fasciitis or fibromyalgia should be ruled out.
Extramuscular manifestations may occur in all inflammatory myopathies, al-
though they occur in inclusion-body myositis only in rare cases; these manifesta-
tions include systemic symptoms, such as fever, arthralgia, and Raynaud’s phe-
nomenon, as seen in the antisynthetase syndrome4,6,7; cardiac arrhythmias or
ventricular dysfunction, in relatively uncommon cases in which the affected car-
diac muscle is clinically symptomatic; and pulmonary complications, due primar-
ily to interstitial lung disease, which are reported in 10 to 40% of patients.8 The
prevalence of interstitial lung disease, a condition that is best detected with high-
resolution computed tomography, is as high as 70% among patients with anti–his-
tidyl–transfer RNA (tRNA) synthetase (anti-Jo-1) or anti–melanoma differentiation–

1734 n engl j med 372;18 nejm.org  April 30, 2015

The New England Journal of Medicine
Downloaded from nejm.org on April 27, 2017. For personal use only. No other uses without permission.
Copyright © 2015 Massachusetts Medical Society. All rights reserved.

6.2.1-7.12 The on the face. associated protein (MDA)–5 antibodies (see the bined with a red flush on the face. specific for necrotizing autoimmune myositis. For personal use only. Raynaud’s phenomenon. in- symptom is “misery.volvement of facial and extraocular muscles. irregular and thickened cuti.” Anti–3-hydroxy-3-methylglutaryl–coenzyme A reductase (anti-HMGCR): Autoantibody directed against HMGCR.13 Polymyo- cially common among children. (blue–purple) rash with edema.1-3 In children. the pharmacologic target of statins. neck.9 The lesions are photo. All rights reserved. If the patient’s sitis remains a diagnosis of exclusion and is best strength appears to be normal.9 although subclinical muscle in.7. 2017.11. Copyright © 2015 Massachusetts Medical Society.inclusion-body myositis.org on April 27. and is frequently associ- symptoms include distinct skin manifestations ated with antisynthetase antibodies. breast chest (in a V-sign). associated with amyopathic dermatomyositis or rapidly progressive interstitial lung disease. is seen in both children and adults. and the early and perimysial regions. and zidovudine). the the risk of cancer is increased during the first skin manifestations include periorbital heliotrope 3 to 5 years after the onset of dermatomyositis. or inflammatory dystrophy. statins. associated with typical skin lesions of dermatomyositis.12 radiation. melanoma.defined as a subacute proximal myopathy in adults sitis may be limited to the skin (amyopathic der. and non-Hodgkin’s lymphoma. accompanying or preceding muscle weakness.10 In adults. which consists of myopathy. and back and shoulders (in a cancer. sometimes extrud. Inflammatory Muscle Diseases Glossary Anti–cytosolic 5′-nucleotidase 1A (anti-cN1A. available with the full typical of dermatomyositis. the dermatomyo. or anti-NT5C1A): Autoantibody directed against the cN1A nuclear protein involved in RNA processing. seen in cancer-associated dermatomyositis. Anti–histidyl–transfer RNA synthetase (anti-Jo-1): The most common autoantibody associated with the antisynthetase syndrome. and “me- chanic’s hands. interstitial lung disease. with prominent patho- text of this article at NEJM.org  April 30. Anti–transcriptional intermediary factor 1 γ (anti-TIF-1γ): Autoantibody involved in cell growth and differentiation. elbows.” defined as irritability com. may occur and are espe. . Overlap myo- The specific clinical features of inflammatory sitis is now starting to be recognized as a dis- myopathies are described in Table 1 and in the tinct entity. Anti–signal recognition particle (anti-SRP): Autoantibody directed against a polypeptide complex involved in protein transport to endoplasmic reticulum.18 nejm. fatigue. necrotizing autoimmune ations and infections. penicillamine.myositis. which may evolve into a the risk of these cancers necessitates a thorough scaling discoloration. specific for necrotizing autoimmune myositis. and cracked palmar fingertips (“mechanic’s Polymyositis is rare as a stand-alone entity and hands”) are characteristic of dermatomyositis. Anti–melanoma differentiation–associated protein-5 (anti-MDA-5): Autoantibody directed against a cytoplasmic RNA- specific helicase. malleoli. arthritis.3.11.. a family history of neuro- matomyositis). anterior most common cancers are ovarian cancer.9 Dilated capillary loops at the base of the fingernails. it manifests without the rash that is Supplementary Appendix. and a violaceous eruption (Gottron’s cancer (in Asians). knees. interfascicular.who do not have rash.6-8 a reluctance to socialize. associated with inclusion-body myositis.g. along with anti–nuclear matrix protein 2 (anti-NXP-2).org.Polymyositis cles. 2015 1735 The New England Journal of Medicine Downloaded from nejm. the typi- Dermatomyositis cal skin rash is transient or faint. rash) on the knuckles. colon cancer. No other uses without permission.1-3 is often misdiagnosed. en- n engl j med 372.annual workup in the first 3 years after disease sensitive and may be aggravated by ultraviolet onset. fever. Anti-Mi-2: Autoantibody directed against a nuclear DNA helicase involved in transcriptional activation. erythematous rash with reported a frequency of 9 to 32%. in such cases. nasopharyngeal shawl sign). an early (e. Dermatomyositis logic changes in the perifascicular.muscular disease.3 The symptoms of dermatomyositis may over- lap with those of systemic sclerosis and mixed Specific Cl inic a l Fe at ur e s connective-tissue disease1-7. most patients whose con- Subcutaneous calcifications. exposure to myotoxic drugs volvement is frequent.dition has been diagnosed as polymyositis have ing to the surface of the skin and causing ulcer. and Glossary).

No other uses without permission. ¶ TDP43 and p62 deposits. and interfascicular areas (to a lesser degree of severity) can be seen in overlap myositis (without skin lesions) or the antisyn- thetase syndrome. myositis of fever. no vacuoles. inflammatory dystrophies (such as those due to mutations in the genes encoding dysferlin. For personal use only. up to 50 times the upper limit of Very high. may upper limit of normal in early mal. vacuoles are absent.Anti-cN1A (of uncertain pathologic sig- anti-NXP-2 (implicated in cancer. † Similar pathologic changes in the perifascicular. statins. mild facial ruled out)* muscle weakness in people older than 50 years of age Creatine kinase level High. perifascicular antigen. perimysial. Becker’s muscular dystrophy. 1736 Table 1. necrotizing autoimmune myositis. 2015 atrophy from chronic inflammation Copyright © 2015 Massachusetts Medical Society. more than 50 times the Up to 10 times the upper limit of nor- normal. or myofibrillar myopathies). Slow onset of proximal and distal weak- weakness weakness with characteristic skin weakness in adults (diagnosis is mal.org on April 27. necrotic fibers in spread expression of MHC class I rophages. . calpain. widespread expression of MHC “wedge-like” infarcts.Scattered necrotic fibers with mac. and fasciitis or fibromyalgia need to be ruled out. and perifascic. anti-TIF-1 and Antisynthetase antibodies (often seen in Anti-SRP and anti-HMGCR. can be normal or slightly linger at up to 10 times the upper active disease elevated The limit of normal Electromyography Myopathic units (active and chronic) Myopathic units (active and chronic) Active myopathic units Myopathic units (active and chronic) with some mixed large-size poten- tials Muscle biopsy Perivascular. wide. could May show active inflammation. or anocta- min. or antiretrovirals). facioscapulohumeral muscular dystrophy. ragged-red fibers or cytochrome oxidase–negative fibers are frequently present and are helpful in diagnosis. congophilic amyloid depos- its¶ Autoantibodies Anti-MDA-5.g. ‡ Metabolic muscle diseases presenting as myoglobinuria and toxic or drug-induced myopathies need to be ruled out. imaging guide biopsy site could guide biopsy site but might be difficult to distinguish n engl j med 372. detected with the use of immunostaining.CD8+ cells invading healthy fibers. deposits of complement class I antigen. Shows selective muscle involvement. perimysial. All rights reserved. specif.. arthritis. often severe weakness in ness. 2017. m e dic i n e * Drug-induced myopathies (e. ic for necrotizing autoimmune nificance) n e w e ng l a n d j o u r na l The New England Journal of Medicine associated dermatomyositis) terstitial lung disease. inclusion-body myositis. can at times be normal normal in early active disease. autophagic vacu- atrophy. Downloaded from nejm. overlap myositis) associated with in. no CD8+ cells or vac. frequent falls. have been proposed as tissue biomarkers. anti-Mi-2. § In clinical inclusion-body myositis. ruling out of uoles. reduced capillaries† inflammatory dystrophies on capillaries‡ oles. when patients have the typical inclusion-body myositis phenotype.18 nejm. atrophy of quadriceps and rash in patients of any age made when other causes have been adults forearms. Criteria Supporting the Diagnosis of Inflammatory Myopathies. up to 50 times the upper limit of High.CD8+ cells invading healthy fibers.§ ragged-red or ragged-blue fibers.org  April 30. penicillamine. ular inflammation. and “mechanic’s hands” Magnetic resonance May show active inflammation May show active inflammation. metabolic myopa- thies. Criterion Dermatomyositis Polymyositis Necrotizing Autoimmune Myositis Inclusion-Body Myositis Pattern of muscle Subacute onset of proximal symmetric Subacute onset of proximal symmetric Acute or subacute onset of proxi. such patients are erroneously thought to have polymyositis because of polymyositis-like inflammation.

org  April 30. the presence patients taking statins. a subacute onset of proxi- discontinuation of statins.14-16 ditions and assess disease activity.3 to 70 cases myositis. electromyographic findings. which is elevated in pa- clusion-body myositis is commonly suspected tients with active disease. the age.for ruling out disease mimics such as dystrophies ducted in one U.1-5. Dysphagia occurs in more than 50% ly than polymyositis. county. Assessment dence of inclusion-body myositis was 7.13 It can occur at any age but is seen primarily in adults. overlap myositis. such start or be more severe in one extremity or on one as interstitial lung disease.14. in pattern of muscle involvement. reaching its peak over a period of days or weeks. in patients with connec.6. Typical skin continues to worsen after statin withdrawal (if changes.or necrotizing autoimmune myositis.19 The dis.necrotizing autoimmune myositis and for the ease starts insidiously and develops over a peri.org on April 27. myositis occurs alone or after viral infections. is present or myofasciitis is suspected. Magnetic resonance imaging disabling inflammatory myopathy among persons (MRI) is helpful for diagnosis when muscle edema 50 years of age or older. For personal use only. respond to therapy. it was probably caused mal myopathic weakness points to polymyositis by toxic effects of the drug rather than by im. and progresses steadily. indi- the myopathy improves within 4 to 6 weeks after cate dermatomyositis. the estimated inci.athy is creatine kinase.1-3 riceps muscle weakness causing buckling of the knees.14-16 Most patients with nec. or the clinical phenotype of inclu. and the lowest (less than 10 times the ment of distal muscles. side of the body).17-23 Its prevalence. Muscle higher when adjusted for age. it may sociations with systemic organ involvement. in whom the myopathy of certain autoantibodies (Table 1).head drop.The diagnosis of the exact subtype of inflamma- ly and causing severe weakness and very high tory myopathy is based on the combination of creatine kinase levels. at times asymmetrically (i. accounting for up to 19% of the patients. simu. in two later stud. The highest levels. Among muscle-derived enzymes in serum.18 is much by atrophy in inclusion-body myositis.9 cases of autoantibodies is helpful for the diagnosis of per million in the 1980s and 1990s. as well as per million. it starts Di agnosis either acutely.3 features that can lead to an are seen in patients with necrotizing autoimmune early clinical diagnosis include the early involve.sitis.23 of all inflammatory myopathies. 2015 1737 The New England Journal of Medicine Downloaded from nejm. and for some conditions.15 Necrotizing autoimmune clinical history.4.progressive proximal and distal weakness with rotizing autoimmune myositis have antibodies selective atrophy points to inclusion-body myosi- against signal recognition particle (SRP) or against tis. Inflammatory Muscle Diseases docrinopathy.19. Although serum levels n engl j med 372. All rights reserved. Copyright © 2015 Massachusetts Medical Society.biopsy is essential for the diagnosis of polymyo- ies in Australia and the United States.S.classification of distinct subtypes and their as- od of years. the lating a late-life muscular dystrophy or slowly most sensitive indicator of inflammatory myop- progressive motor-neuron disease.e. muscle enzyme association with cancer. and slowly mune myopathy).9 cases per million population.22 In a small chart-review study con. Electromyography is diagnostically useful in 3-hydroxy-3-methylglutaryl–coenzyme A reductase all disease subtypes to rule out neurogenic con- (HMGCR) (see the Glossary).levels. with or without muscle weakness. progressing steadi. 2017.quadriceps muscles. tempo of disease progression.. frequent falls due to quad- sion-body myositis. and mild facial-muscle weakness. or subacutely. muscle-biopsy tive-tissue disorders such as scleroderma. and inclusion-body myositis. but very high Inclusion-Body Myositis levels from the outset point to necrotizing auto- Inclusion-body myositis is the most common and immune myositis.myositis. which results in Necrotizing autoimmune myositis is a distinct camptocormia (bending forward of the spine) or clinicopathologic entity that occurs more frequent.1-5 Although in.18 nejm.20-23 The Necrotizing Autoimmune Myositis axial muscles may be affected.3.or metabolic or vacuolar myopathies. or in analysis. as well as which was initially estimated in the Netherlands for identification of the particular muscles affected as 4. atrophy of the forearms and inclusion-body myositis. up to when a patient’s presumed polymyositis does not more than 50 times the upper limit of normal. especially foot extensors upper limit of normal) are seen in patients with and finger flexors. No other uses without permission. Serum creatine kinase is elevated in all subtypes.1-5. . necrotizing autoimmune adjusted prevalence ranged from 51.

they can be normal or only slightly elevated ment-Mediated Microangiopathy.4.18 nejm. Consequently. No other uses without permission. especially if the fascia is involved. preted in the context of the clinical picture. on the endothelial cell wall of the endomysial capillar- mation in muscle or fascia.24. The n e w e ng l a n d j o u r na l of m e dic i n e of creatine kinase usually parallel disease activ. in patients with active dermatomyositis. or active inclusion-body myositis. Copyright © 2015 Massachusetts Medical Society. ing major histocompatibility complex [MHC] class I an- fected). B cells. aspartate aminotransferase matomyositis perifascicular atrophy (layers of atrophic and alanine aminotransferase levels are also el. it remains the most important diagnos. fascicles. 2A. In dermatomyositis. often ity complex (MHC) class I antigen (normal mus- with perivascular and interfascicular infiltrates. or microinfarcts. . and facilitate lym- features distinct to each disease subtype. duced. enhance the expression of vascular-cell adhesion of inflammation to biopsy. isch- brosis. Activation of com- ruling out neurogenic disorders.1-5 leading to the formation of C3b. and the findings are inter.3. as well as molecules as- enced laboratory. low-amplitude compared with a myopathic control (Panel D). For personal use only. and mem- brane attack complexes (MACs). 2017. is diagnostic of dermatomyositis (or of overlap 2C. the periphery of the fascicles. sociated with innate immunity (such as MxA. in the muscles of pa- Electromyography can show myopathic motor. and STAT1). it consists predominantly of CD8+ sion and perifascicular atrophy. as unit potentials (short-duration. Serum aldolase levels may be lectin). fibers at the periphery of the fascicle [arrows]) and some inflammatory infiltrates. NCAM. that does not have clinical signs of advanced or and Mi-2). (LFA)–1. and immune activation (express- end-stage disease but is also not minimally af.24. es.org on April 27. muscle fibers expressing major histocompatibil- phic fibers at the periphery of the fascicles. the den- polyphasic units on voluntary activation) and in. 1A). inflam.6.25 and retinoic acid–inducible gene 1 [RIG-1]). and positive sharp the lumen of the remaining capillaries dilated in an ef- fort to compensate for the ischemic process. macro- identifying disease activity.1-5 Perifascicular T cells invading healthy-appearing. phagocytosis — often in a portion of a muscle the inflammation is perivascular and is most fasciculus or the periphery of the fascicle — typically concentrated in multiple foci within the owing to microinfarcts that lead to hypoperfu. Panel B shows the de- evated.7 molecules (VCAMs) and intercellular adhesion molecule Examination of muscle-biopsy samples reveals (ICAM) on the endothelial cell wall. when the skin changes are absent or interfascicular septae or the periphery of the transient)1-5. the inflammation is peri- vascular and is most prominently located in the myositis.10. for lar atrophy. It is useful for assessing the emia.1-3. Figure 1 (facing page). which is characterized by layers of atro. fi. The muscle fibers undergo necrosis and In polymyositis and inclusion-body myositis.25 (Fig. chemokines. but they cannot plement component 3 (C3) (probably triggered by anti- be used for differentiating inflammatory myopa. which bind VCAM-1 and ICAM-1. and lymphocyte function–associated antigen specific. endomysium.org  April 30. or atrophy. cle fibers do not express this antigen) (Fig. and CD123+ plasmacytoid dendritic selection of the muscle with the greatest degree cells. late activation antigen although the results are not always typical or (VLA)–4. as well as in perifascicu- pecially in cases of inclusion-body myositis. this results in the destruction of capillaries. which are most prominent in extent and selectivity of muscle involvement. and phoid cell transmigration to endomysial tissue through the action of their integrins. tients with dermatomyositis (shown in Panel C). nonnecrotic atrophy..1. especially at the periphery of the fascicle. bodies against endothelial cells) is an early event thies from toxic or dystrophic myopathies. position of complement (membranolytic attack com- terpreted as indicating liver disease and that leads plex. in green) on the endothelial cell wall of endo- to an investigation with a liver biopsy instead of mysial vessels (stained in red with Ulex europaeus a muscle biopsy. ies. a sign that is sometimes erroneously in. Dermatomyositis: A Comple- ity. Cytokines released by activated comple- ment lead to the activation of CD4+ T cells.e. and for guiding the phages. and 2D). These findings are useful in determining shows a schematic diagram of a proposed immuno- whether the myopathy is active or chronic and in pathogenesis of dermatomyositis. cell stress (expressing heat shock protein 70 [HSP70] and HSP90). the specimen is processed at an experi. sity of the endomysial capillaries (in yellow–red) is re- creased spontaneous activity with fibrillations. The finding of MHC expression and 1738 n engl j med 372. with complex repetitive discharges. (shown in orange. in a muscle modeling and regeneration (expressing TGF-β. ISG15. Along eosin–stained muscle-biopsy sample with classic der- with creatine kinase. indicating the superimposition of red and green). fatty infiltration. overlap Panel A shows a cross-section of a hematoxylin and myositis. which leads to destruction of endothelial cells also elevated. tigen. Muscle biopsy is most useful when the cicular regions contain fibers that are in a state of re- biopsy site is properly chosen (i.2 Panel E waves. 2015 The New England Journal of Medicine Downloaded from nejm. The perifas- tic tool. All rights reserved. which are deposited MRI can be used to identify edema. C3bNEO.

NXP-2) Chemokines CD8+ T cells (termed the MHC–CD8 complex) is In necrotizing autoimmune myositis. 2015 1739 The New England Journal of Medicine Downloaded from nejm.18 nejm.org on April 27. ISG15 B CE LL HSP70.by macrophages (Fig.17. there are useful for confirming the diagnosis and for rul. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. as seen in some muscular dystrophies. For personal use only. C4 C3 necrotic. 2017. Inflammatory Muscle Diseases A B C D E Possible NO R M A L F A S CICLE D A M A GE D F A S CICLE S antibodies against C1 D endothelial cells Degenerating.25 infiltrates are sparse. MDA-5.abundant necrotic fibers invaded or surrounded ing out disorders with nonimmune inflamma.2. All rights reserved. and MHC class I up-regu- n engl j med 372.3.5. and C2 B Myocyte Capillary Perifascicular Lumen atrophic myocytes ? destruction atrophy enlargement E ND OT HE LIUM Capillary C3 C3bNEO C3a C3b Capillary MAC MAC damage Cytokines MAC ROP HAG E NO TNF-α Mac-1 Molecules Overexpressed MAC RO P HA GE Cytokines VLA-4 in the Perifascicular Region VCAM-1 STAT1 NCAM T C E LL MHC class I Mi-2 Chemokines MxA. 90 RIG-1 LFA-1 TGF-β VESSEL T C E LL ICAM-1 L UMEN Antibody production CD 1 2 3 + (Mi-2. Lymphocytic tion. .org April 30. TIF-1. 2E and 2F).

Although the pathogenic role of vated B cells or plasmacytoid dendritic cells are clonal- the antibodies is unclear. stained in green with an anti-CD8+ monoclonal antibody (Panel oles.20-23 Electron microscopy I. Inclusion-Body Myositis. stabi- lizes the synaptic interaction between CD8+ cells and vacuoles.30 es associated with the antisynthetase syndrome. regardless of statin use. clusion-body myositis (Panel B).14.6. are specific for the diagnosis of clini- MHC class I on muscle fibers. Panel G shows a proposed mechanism of T-cell–medi- flammation is seen. even in fibers not invad- shows tubulofilaments 12 to 16 nm in diameter ed by T cells. and Necrotiz- most often mediated by specific antibodies against ing Autoimmune Myositis and a Proposed Immuno- SRP or HMGCR (see the Glossary).29 interferon-γ.3-5.org  April 30.27. often with pathogenic Scheme for Polymyositis and Inclusion- complement deposits on capillaries.3. Rayn. 2017. Cytokines. vacuoles or amyloid deposits are not sualized with an acid phosphatase reaction (in red). found in the muscle-biopsy sample and only in. In contrast. Copyright © 2015 Massachusetts Medical Society. For personal use only. autophagic surrounding healthy-appearing muscle fibers are visi- vacuoles that have walls lined internally with ble. may enhance depending on the case series and the method of MHC class I up-regulation and T-cell cytotoxicity.26 Such patients have body myositis. which are best vi- phenotype. fibers through their T-cell receptors. Inclusion-body myositis has all the inflamma. Acti- detection used.18 nejm. Up-regulation of costimulatory crotic fibers with MHC class I expression. not invaded by T cells (arrow). oles with bluish-red material. the most widely commercially available nize ARS.7. fever. cross the endothelial cell wall and bind directly to aber- the basis of clinicopathologic correlation. which provided the first pathogenic link antibody.16 Anti-HMGCR.27. No other uses without permission. invading healthy fibers are CD8+ T cells. inflammation around nonne. . even without CTLA-4.15. γδ T cells were found to recog- anti-Jo-1.28 play a fundamental role in T-cell activation. most prominent in fibers “ragged-red” or cytochrome oxidase–negative fi. Antigen-specific CD8+ cells. Necrotizing autoimmune myositis–specific This syndrome is characterized by myositis with anti­bodies are directed against the translational prominent pathologic changes at the periphery transport protein SRP or against HMGCR. there are scattered necrotic fibers invaded by macrophages (Panel F).6.28 Data- rantly expressed MHC class I on the surface of muscle driven criteria confirm that finger-flexor or quad. aminoacyl tRNA synthetases (ARSs). cytochrome oxidase–negative fibers. in which scattered in- pathic changes with increases in connective tissue flammatory foci with lymphocytes invading or and in the variability in fiber size. between ARS and T-cell–mediated immunity.7. there are also chronic myopathic features (increases in connective tissue and material that stains bluish-red with hematoxylin atrophic and hypertrophic fibers) and autophagic vacu- and eosin or modified Gomori trichrome (Fig.7 mune myositis. either as antigen- genotypes. Regulatory Th17 cells cal inclusion-body myositis. and mechanic’s hands. expanded “clinical inclusion-body myositis” diagnosed on in the periphery and subsequently in the endomysium. and and inclusion-body myositis. but in addition has chronic myo. In one rare case.15. including the CD8– tient with polymyositis (Panel A) and a patient with in- MHC complex. interleukin-1. seen in 22% of persons with necrotizing autoim- aud’s phenomenon.4.10 interstitial lung disease. arthritis. In inclusion-body myositis. Perforin Autoantibodies directed against nuclear RNAs granules released by the autoaggressive T cells medi- or cytoplasmic antigens are detected in up to 60% ate muscle-fiber necrosis. Main Inflammatory Features bers. forming the riceps weakness.org on April 27. the cells surrounding or congophilic amyloid deposits next to the vacu.25 Necrotizing autoimmune myositis is of Polymyositis. in necrotizing autoimmune next to the vacuoles. shown in green in Panel D. Panels A and B show cross-sections of hematoxylin and eosin–stained muscle-biopsy samples from a pa- tory features of polymyositis. and ICOS).20 In up to 30% of patients myositis (a cross-section stained with trichrome is with the typical clinical inclusion-body myositis shown in Panel E). These antibodies include those against presenting cells or through the release of cytokines and antibody production. the of the fascicles and the perimysial connective pharmacologic target of statins. correlates 1740 n engl j med 372.16 Among the eight different ARSs that have been identified. In both polymyositis bers representing abnormal mitochondria. also visible is widespread expression of MHC class or fluorescent optics. ly expanded in the endomysium and may participate in cific for distinct clinical phenotypes and HLA-DR the process in a still-undefined role. The n e w e ng l a n d j o u r na l of m e dic i n e lation is often prominent beyond the necrotic fi- Figure 2 (facing page). All rights reserved. accounts for 75% of all antisynthetas. 2B). which leads to an erroneous ated muscle damage in polymyositis and inclusion- diagnosis of polymyositis. which are best visualized with crystal violet C). as well as ICAM-1 or LFA-1. which are detected in 20 to 30% of patients. 2015 The New England Journal of Medicine Downloaded from nejm. some appear to be spe.16. tissue.16 Body Myositis. and tumor necrosis factor (TNF) released by the activated T cells. such as of patients with inflammatory myopathies. MHC–CD8 complex. and molecules (BB1 and ICOSL) and their ligands (CD28.

. detected in 60 to 70% of patients with inclusion- ary factor 1γ (anti-TIF-1γ) and anti–nuclear matrix body myositis.18 nejm.org April 30. tomyositis. 2017. 2015 1741 The New England Journal of Medicine Downloaded from nejm.31 Derma. Copyright © 2015 Massachusetts Medical Society.6. For personal use only. which is associated primarily with enced by geographic.32.16. and anti–transcriptional intermedi.org on April 27.29 although their presence is influ- anti-MDA-5. No other uses without permission. racial. protein 2 (anti-NXP-2). which are usually present tomyositis-associated antibodies include anti-Mi-2.33 although the degree of sensi- n engl j med 372. amyopathic dermatomyositis or interstitial lung Anti–cytosolic 5′-nucleotidase 1A (anti-cN1A) is disease4. in patients with cancer-associated adult derma- which is associated with the typical skin lesions. Inflammatory Muscle Diseases A B C D E F G B cells may serve as antigen-presenting cells B CE LL VESSEL B C E LL and secrete antibodies L UMEN and cytokines Endothelium MACR OPHAGE T H1 7 R E GU LA T O R Y M Y O CYTE CE LLS CD 8 + T CE LL Cytokines and CD28 MHC chemokines CD40 class I CTLA-4 VCAM-1 ICOS complex Cytokines CD 8 + T CEL L ICAM-1 CD80 ICOSL T CE LL BB1 ICOSL CD40L MHC Chemokine class I Perforin ICAM-1 receptor complex Necrosis E ND OT HE LIUM MHC class I complex VLA-4 VCAM VCAM-1 T C E LL ICAM-1 ICAM LFA-1 with creatine kinase levels and strength. and genetic factors. All rights reserved.

it remains to be determined whether the ing mumps virus). and its detection aids in confirm. attempts to amplify viruses — including coxsacki- or regenerative molecules are also overexpressed eviruses.34.up-regulation of adhesion molecules. 2A through ositis should be distinguished from a toxic mi- 2D).T cells participate in the immune process. The residual perifascicular atrophy reflects center formations).42 Analysis of T-cell–receptor molecules expressed by the infiltrating CD8+ T cells reveals clonal expansion of T-cell–recep- Pathol o gic Mech a nisms tor chains and conserved sequences in the anti- Immunopathology gen-binding region. which suggests an antigen- The causes of inflammatory myopathies are un.18 nejm. nonnecrotic muscle fibers that myositis and HIV-associated inclusion-body my- aberrantly express MHC class I (Fig. 1E). and facili. which is absent tochondrial myopathy induced by antiretroviral from the sarcolemma of normal muscle fibers. 2G).38. and (Fig.54 vated T cells. chemokines.25 The CD8+ T cells Inclusion-body myositis is a complex disorder be- contain perforin granules directed toward the cause.2-5. which stress- of endomysial capillaries.es the endoplasmic reticulum of the myofibers.24. be- B cells. in which anti-cN1A autoan- the endofascicular hypoperfusion. In juvenile dermatomyositis.1-5 acid–inducible gene 1 signaling in response to The best evidence for a viral connection involves local signals from the damaged fibers.3. No other uses without permission. prominent at the periphery of the fascicles.Genetic interactions are supported by the associa- tates migration of activated lymphocytes. reduction of the density also cause glycoprotein misfolding.37 macrophages and not within the muscle fibers.and cytokines45-47 (Fig.52. most prominently the remaining capillaries have dilated lumens to in inclusion-body myositis50 (although it is un- compensate for the ischemia2. which improves when the drugs are dis- probably induced by cytokines secreted by acti.driven T-cell response. leading to necrosis.40. Genetic risk factors presumably by antibodies.53 However. ment C5b-9 membranolytic attack complex is acti.org on April 27. 1E). 2015 The New England Journal of Medicine Downloaded from nejm. to the perimysial and endomysial spaces itive necrotizing autoimmune myositis. and Epstein- effect of innate immunity is caused by retinoic Barr virus — from the muscles have failed.org  April 30. 1A through clear whether the muscle can sustain germinal 1D).7 sion molecules on endothelial cells. Copyright © 2015 Massachusetts Medical Society.43. but an area where other inflammatory. because polymyositis or inclusion- leads to autoamplification of perifascicular in.41 The CD8–MHC class I complex is characteristic of polymyositis and inclusion.44 This is further supported known. B-cell activation also occurs. triggers the release of regulating immune responses against undefined proinflammatory cytokines. degenerative.25 The factors that trigger inflammatory muscle The activation of membrane attack complex.35 responsible for disrupting immune tolerance. Th17 and regulatory vated early (before the destruction of muscle fi. and muscle.39 MHC class I expression. T-cell lymphotropic virus I. In polymyositis and inclusion-body myositis. For personal use only.body myositis develops in people infected with flammation by activating interferon-β and MHC human immunodeficiency virus (HIV) or human class I36 (Fig.environmental agents have been proposed. In dermatomyositis. 1E).Myositis ing the histologic diagnosis. 2017.2. CD4+ T cells. and plasmacytoid dendritic tween HLA-DRB1*11:01 and anti-HMGCR–pos- cells. which cause myo- od of detection used.51 Viruses may be inducible proteins in the perifascicular region.continued. including tions between HLA-DRB1*03 and anti-Jo-1. is drugs. influenza virus. . but an autoimmune pathogenesis is by the expression of costimulatory molecules and strongly implicated.49 fiber destruction resembling microinfarcts1-6. which is most tibodies are also detected (see the Glossary). and indicates B-cell activation. and CD8+ cytotoxic T cells surround and invade some are retroviral-specific.24.3. which retroviruses.25 (Fig. cytomegalovirus. paramyxoviruses (includ- (Fig. Innate immunity also plays a role that is between HLA-DRB1*03:01 and HLA-DRB1*01:01 based on increased expression of type I interferon– and inclusion-body myositis.Degenerative Component of Inclusion-Body body myositis. retrovi- maternal chimeric cells may contribute to the ral antigens are detected only in endomysial pathogenesis of the disease. comple. up-regulates adhe. The autoinvasive T cells are clonally driven. The n e w e ng l a n d j o u r na l of m e dic i n e tivity and specificity varies according to the meth. ischemia.48 The bers is evident) and deposited on the endothelial up-regulation and overload of MHC class I may cells. in addition to the autoimmunity compo- 1742 n engl j med 372. necrosis on release.surface of the muscle fibers.52 HIV-associated poly- healthy-appearing.25. diseases remain unknown. All rights reserved.

Proposed Mechanisms in Inclusion-Body Myositis. there is an important degenerative compo. impaired autophagy. The factors that trigger the disease are un- clear.20 Deposits of TDP43. detected within ed fibers has revealed differential up-regulation n engl j med 372. highlighting the interaction between the long-standing chronic inflammatory process and degeneration. 2017. nent. and p62. but viruses. muscle aging.org April 30. highlighted by the presence of congophilic ing. protein misregulation (such as abnormal proteostasis).18 nejm. For personal use only. amyloid-β42.org on April 27.20 but it remains unclear how protein. induce an in- which indicates the presence of protein aggrega. triggers disease. amyloid-β amyloid-β42. these its oligomers are involved in the pathway of in- deposits immunoreact against amyloid precursor tracellular toxicity. DA MA G E D and chemokines F A SC IC LE Accumulation of D AMAG ED misfolded proteins. have been advocated as diagnostic markers. . seen in other vacuolar myopathies. which are also presenilin.21 Laser microdissection of T-cell–invaded cytoplasm. a shuttle protein that trans. and HLA genotypes may play a role.g. and misfolded proteins similar to the ones seen in neuroinflammatory disorders such as Alzheimer’s disease. FASCICLE p-tau. All rights reserved. Copyright © 2015 Massachusetts Medical Society. Shown is a hypothetical schematic diagram of the pathogenesis of inclusion-body myositis. fibers in comparison with noninvaded or vacuolat- ports polyubiquitinated proteins. these proteinaceous aggregates. which leads to cell stress and deposits of β-amyloid precursor protein. amyloid-β42. the muscle fibers with the use of immunostain- nent. amyloid- Capillary F A SC IC LE and related proteins Degenerating CD8+ T Cell Autophagic myocytes vacuole Figure 3. and phosphorylated tau. flammatory and degenerative myopathy and what tion. Therefore. apolipoprotein E. Inflammatory Muscle Diseases Possible triggers: Viruses Muscle aging Chronic inflammation Abnormal proteostasis HLA genotypes MYOCYTE Impaired autophagy Other MHC class I CYTOTOX IC Degeneration CD8+ T CELL complex Cytokines (e. a DNA-binding pro. either alone or in combination.20. ubiquitin HE A LT HY FA S C I C LE Cell stress and fiber damage Autophagic vacuole β-amyloid -amyloid precursor Healthy myocytes DA MA MAGED protein. α-synuclein. or protein aggre- tein aberrantly translocated from the nuclei to the gation.20-22 Similar In vitro evidence suggests that amyloid-β42 and to what is seen in Alzheimer’s disease. interleukin-1β interleukin-1 Perforin and interferon-γ) interferon.. inclusion-body myositis can be considered to be a peripheral model of neuroinflammation. Whether the primary event is inflammatory or degenerative is highly debated and remains unclear. inflammation. 2015 1743 The New England Journal of Medicine Downloaded from nejm. No other uses without permission. ubiquitin.55 amyloid deposits within some fibers.

but a decrease in creatine kinase alone is a dose of 1 mg per kilogram of body weight. and a response. taper to alternate in research trial days When weakness at onset is Intravenous glucocorticoids (1000 mg per day) Not applicable severe or rapidly worsening for 3 to 5 days.57 before starting treatment with oral glucocorti- long-standing inflammation. Not applicable† patient’s condition cyclosporine* responds to glucocorticoids If response to glucocorticoids is Intravenous immune globulin (2 g per kilogram Not applicable‡ insufficient in divided doses over a period of 2 to 5 con- secutive days) If response to glucocorticoids and Reevaluate and reconsider diagnosis. the serum creatine kinase level nisone administered once daily after breakfast at drops.1-6. 1744 n engl j med 372. especially in patients who report a sense of feeling better but Strategies for the treatment of the inflammatory not necessarily of feeling stronger. Copyright © 2015 Massachusetts Medical Society. A tactical T r e atmen t of Der m at om yosi t is. a nd Necro t i zing error is the practice of “chasing” the creatine Au t oim mune M yosi t is kinase level as a sign of response. and anti– interleukin-1β.18 nejm. Treatment of Inflammatory Myopathies: A Step-by-Step Approach. prednisone is tapered. however. tocilizumab (anti–interleukin-6).61 When trials. 2015 The New England Journal of Medicine Downloaded from nejm.8 to 1 g per square meter of body surface area) and oral tacrolimus (4–8 mg per day) may help patients with interstitial lung disease. ‡ In some patients. perform activities in daily living are absent at that time. such as interferon-γ– munosuppressant agent from the outset. therapy. ¶ Candidate agents include eculizumab. 3). is the first-line drug for the For patients in whom glucocorticoids produce treatment of dermatomyositis. cell olone at a dose of 1000 mg per day for 3 to 5 days stress induced by MHC class I or nitric oxide. if the Azathioprine. When the myopathies are described in Table 2. then switch to oral regimen For glucocorticoid sparing. of inflammatory signaling. All rights reserved. Treatment for Inclusion-Body Scenario and Necrotizing Autoimmune Myositis Myositis Initiation of therapy New-onset disease Prednisone (1 mg per kilogram. initiate Participation in research trial intravenous immune globu. alemtuzumab. P olym yosi t is. mycophenolate. but the evidence of efficacy is compelling. participation per day) for 4–6 weeks.org  April 30. polymyositis. it is pref- that aging. recommend participation in a re- search trial¶ if disease does not respond to rituximab * The use of these agents is based on experience but not on controlled studies. preferably by a switch from a daily dose hance degeneration. After 3 to 4 weeks. methotrexate at a dose of up to 20 mg per week.21. Azathioprine can be given at a dose of up to 3 mg per kilogram. and proinflam.20 impaired autophagy. azathioprine. leading to further accumu. up not a sign of improvement.2-4. strength improves. if the ob- lation of stressor molecules and misfolded pro. Intravenous cyclophosphamide (0. For personal use only. matory cytokines such as interferon-γ and as dictated by the response of the disease to interleukin-1β57. Polymyositis.60.60 to 100 mg per day. . up to 100 mg Physical therapy.6.60.org on April 27. Treatment for Dermatomyositis. tapering is accelerated so that treat- ment with a next agent can be started. the dysphagia responds to intravenous immune globulin. coids. Oral pred. to doses on alternate days60. anti–interleukin-17.56 Compelling evidence suggests patients with rapidly worsening disease. necrotizing autoimmune myositis. § Efficacy has not been established with a controlled study.6. The n e w e ng l a n d j o u r na l of m e dic i n e Table 2. either alone or in combination. and cyclosporine at a dose of up to 300 mg daily. this choice of methotrexate.61 Some clinicians prefer to add an im. No other uses without permission. or cyclosporine can be used em- drug is based on experience but not on controlled pirically for glucocorticoid sparing. abnormal proteostasis (the network erable to administer intravenous methylprednis- controlling proteins). mycophenolate at a dose of 2000 to 3000 mg per day. methotrexate. † All glucocorticoid-sparing agents are ineffective. mycophenolate mofetil.61 In receptor signaling. jective signs of increased strength and ability to teins59 (Fig.58 may cumulatively trigger or en. treatment with rituximab§ if diagnosis is re- lin is insufficient confirmed. interstitial lung disease is a coexisting condition. 2017.

was group and the rituximab group. Copyright © 2015 Massachusetts Medical Society. and prevent joint contractures. Overall.77 Trials targeting muscle-inhibiting TGF-β necrotizing autoimmune myositis. and if there are some patients may initially have mild subjective diagnostic uncertainties.60 Glucocorti- If the disease has not responded to glucocor. at week 44.gov num- had received rituximab. 2015 1745 The New England Journal of Medicine Downloaded from nejm. ful.org  April 30. anti.21. when all the patients ongoing controlled study (ClinicalTrials. 2012-005772-34). is not responding to intravenous immune globu- fective for the treatment of dermatomyositis and lin. As with all inflammatory myopa- kin-6 (tocilizumab)70 and anti–interleukin-1 re.62 In patients with dermatomyositis. or anti-SRP antibodies seem more likely to number.60.61 no long-term benefit is achieved. an antibody that inhibits the 8 there was no difference between the placebo signaling of a TGF-β superfamily receptor.73 In- firmed. biologic agents that have been approved travenous immune globulin has been found to be for the treatment of other immune diseases may ineffective in controlled trials but may transiently be considered as experimental treatment options.58 immu- intravenous immune globulin has also appeared nosuppressive agents have been tried as treatment to be effective in the treatment of polymyositis for this disease subtype. a repeat muscle biopsy improvements when treated with one of these should be considered.60 Subcuta.2-4. when the degen- remission in small-scale.75 Alemtuzumab may provide short-term sta- which at a dose of 2 g (divided into two infu. an agent that up-regu- have a response. intravenous im- mune globulin therapy (2 g per kilogram in di. azathioprine. adalimumab. proof-of- of improvement. All rights reserved.6.6. has been completed. the long-term outcome cal glucocorticoids or calcineurin inhibitors and of inflammatory myopathies has substantially sunlight avoidance are recommended. monthly infusions may be required gregates by proinflammatory cytokines in pa- to maintain remission. probably because the disease starts long before neous immune globulin has appeared to sustain patients seek medical advice. but whether there Other biologics that may be considered as experi.80 n engl j med 372. especially those with dyspha- These include rituximab (an anti-CD20 antibody). the enhancement of amyloid-related protein ag- tomyositis63. cricopharyngeal dilation or myotomy may be necrotizing autoimmune myositis. anti-com. and necrotizing autoimmune myositis. tients with inclusion-body myositis. considered. gia. and anti– ful to improve ambulation. agents.79 is reportedly effective in polymyositis69. which is being disuse atrophy. but all have failed. or cessful. If the diagnosis is recon. 2017. anti–interleukin-17. For personal use only.61 In a double-blind study. and on the basis shown in a small-scale study to increase muscle of the study design. however. controlled. lates heat shock protein response and attenuates tors (infliximab.gov Mi-2. nonfatiguing resistance exercises and oc- ceptor (anakinra). Inflammatory Muscle Diseases cyclophosphamide or tacrolimus may be help.60 help some patients. polymyositis. 83% met the definition ber.78 which has prompted an cant.60. . volume after 8 weeks. NCT00769860).18 nejm.67 Tumor necrosis factor inhibi. concept study of arimoclomol (ClinicalTrials. A small. prevent falling. molecules or muscle growth factors are in prog- controlled study involving 200 patients. bilization. improved.76 but a controlled study is needed. the drug had an ineffective and may worsen or trigger disease.64 erative cascade is already advanced. Bimagrumab.org on April 27.57. and although patient should be reevaluated.65 Patients with anti-Jo-1. cyclosporine. and etanercept) are cell stress. When glu. which is effective in best option.66. T r e atmen t of Inclusion-Body vided doses over a period of 2 to 5 consecutive M yosi t is days) is appropriate. At present. In a placebo. For life-threatening dysphagia that complement-mediated diseases and may be ef. intravenous immune globulin was found to Because of T-cell–mediated cytotoxic effects and be effective in the treatment of refractory derma. uncontrolled studies. sions 2 weeks apart) seems effective in some Treatment with anakinra has also not been suc- patients with dermatomyositis. topi.6. anti–interleu. No other uses without permission. with a 10-year survival rate of more cocorticoids fail to induce remission or in severe than 90%. coids. ticoids and intravenous immune globulin. NCT01925209). thies.68 acceptable adverse-event profile. methotrexate.60.63 In open-label trials. were clinically meaningful benefits is still un- mental treatment include alemtuzumab.60. the and mycophenolate are ineffective. which clear.74. at week ress.72 and rapidly progressive cases. the results were not signifi. evaluated in an ongoing trial (EudraCT number.71 which have been effective in cupational and rehabilitation therapies are use- anecdotal cases. symptomatic therapies are the plement C3 (eculizumab). avoid interleukin-1β (gevokizumab).

Engel AG. Bronner IM. Titulaer MJ. most patients Disclosure forms provided by the author are available with the with end-stage disease require assistive devices full text of this article at NEJM. Sigurgeirsson B.​55:​ al. the numerous clinicians and toring board for Baxter. Biophys Acta 2015. Hohlfeld R. Chua F. associated dermatomyositis have anti- tis. Mastaglia FL. 14:​291-313. 34. van Dooren SH. Biochim Biophys flammatory myopathies. J Rheumatol et al. Greenberg SA. Curr Opin Rheuma. of anti synthetase syndrome-induced my. clinical presentations. CSL Behring.​15:​359. 7. 36. Engel WK. and Olmsted County. Autoantibodies to cytosolic 5′-nucle- treatment of the idiopathic inflammatory 2008. Duinen SG. et al. Hohlfeld R. J Biol Chem 2012. Brady S. Emslie-Smith AM. Chen Y-J. eds. criteria for inclusion body myositis. 2017. Pluk H. The polymyositis October 2003. Arahata K. Acquired immune and in. 33. Evaluation and construction of diagnostic 3. Dalakas MC. 37. and Gen. J Pathol 2014.​65:​2954-62. Open 2014. et al. Anti-HMGCR autoantibodies in Euro- in pathogenesis. Medicine (Baltimore) 2014.​2:​437-47. Lancet 2003. 356:​2156-7. opathy Neurology 2015.​83:​426-33. Miller FW. Deciphering the clusion body myositis and polymyositis in 32. Nat Clin Pract Neurol 1990.​70:​418-24.​287:​20986-95. and T cell-mediated overdiagnosed entity. 18. 23.​73:​408-18. Polymyositis: an flammatory and autoimmune myopa. 3-hydroxy-3-methylglutaryl-coenzyme A re. Reed AM. Lancet Neurol 2007. Kredich DW. walker. Engel AG. Salajegheh M. Needham M. Altered RIG-I/DDX58- Frequency of specific cancer types in der.​305:​183-90. Ar- Acta 2015. sion body myositis in the Netherlands: 31. van der Meulen MF. 15.​40(4):​e237-e247. Neuropathol Appl Neurobiol 2012. in my studies over many years. Cox FM. Emslie-Smith AM.​134:​3167-75. or wheelchair. 10. 82. 26. immunolocalization Hoogendijk JE. Femia AN. Minnesota. 8. Neuropathol Appl Neurobiol 2011. Greenberg SA. Inclusion et al.​357:​96-100. tion-based study. Christopher- 37:​226-42. pathogenesis. antigen-specific cell-mediated cytotoxici- tures. of interferon subtypes. Verschuuren JJ. inclusion-body myositis is normal. cohort study identifying the principal the pathogenesis of the different inflam- 1746 n engl j med 372. JAMA 2011.org. 35.​24:​602-8. Major histocompatibility complex class 13. Luo Y-B Mastaglia FL. Mononuclear view: immune-mediated necrotizing my. For personal use only. Fiorentino DF. Drouot L. Callen JP.​233:​258-68. Badrising UA. 2008:​1335-83. dermato.​ therapeutic strategies. Copyright © 2015 Massachusetts Medical Society. Reed AM. Allenbach Y. Wintzen Gadea G. 5. Chung LS. polymyositis and immune-mediated shop: trial design in adult idiopathic in. 2015 The New England Journal of Medicine Downloaded from nejm. Reed AM.​1852:​633-43. Gallardo E. Neurol 2006. Pestronk A.​35:​445-7. and dermatomyositis. Squier W.​1852:​622-32. Arthritis Rheum Weiss MD. et al. No other potential conflict of interest relevant to this article was reported. In:​Engel Neuromuscul Disord 2004. and implications for 38:​632-46. Christopher. Sont JK. Engel tis Res Ther 2010. and all Grifols/Talecris.​12:​R70. recognition of diseases with specific myopathological fea. . sitis autoantibodies.​57:​664-78. Engel AG. Therapath Laboratory. Wang Brain 2011. Arahata K. Badrising UA. Dalakas reports having served on a data and safety moni. Askanas V. 9. Mammen AL. Siewert K. Engel AG. et al. Chang Y-T. aging. Rigolet A.18 nejm. Curr Rheuma. Pathophysiology of in. and 1385-7. serving on steering committees for scientists for their enormous contributions to the field. Epidemiology of inclu. transcription intermediary factor 1γ. Needham M. 39. Huang Y-L. 2011. Lancet 2000. Interferon-α/β-mediated innate im- Nuclear actin aggregation is a hallmark body myositis: current pathogenetic con. Ann Neurol 2013. tionwide cohort study in Taiwan. 20. Interstitial lung dis. Cytosolic 5′-nucleotidase 1A auto- phenotypes and prognosis. myositis. AR. stasis and abnormal mitophagy. rology 2014. et al. with the excep.​93:​150-7. The n e w e ng l a n d j o u r na l of m e dic i n e Although the life expectancy of patients with zyme and lecture fees from Baxter and Octapharma. Chahin N. Arthri. Franzini-Armstrong C. Idiopathic in. Picornell YJ. Mammen AL. et al. otidase 1A in inclusion body myositis. 17. Sporadic inclusion-body myositis: a de. Vleugels RA. Holton JL. Ann Neurol 2013. Neurology cells in myopathies: quantitation of func- opathies — a heterogeneous group of 2008. Ernste FC. Cancer risks of 24. 25.​88:​83-105. Novartis. 6. Amato AA. Review: an update on 16. Ytterberg SR. Biochim ositis. 2. muscle biopsy. et and dermatomyositis complex.​6:​620-31.org  April 30. Mammen AL. Larman HB.​63:​713-21. et al. immunity in sporadic inclusion body my- tol Rep 2013. Rider LG.​ Hilton-Jones D. 10-12 thritis Rheum 2013. Dalakas MC. and out.​73:​397-407. sification.​14:​337-45. Goebel HH. Hum Pathol 316-21. Nazareno ease in inflammatory myopathies: clinical generative muscle disease associated with R. 14.​ dermatomyositis and polymyositis: a na. clinical course. Presse Med 2011. Micro- taneous dermatomyositis: an updated re. Kiely PD. juvenile dermatomyositis. such as a cane. Amato AA. Suárez-Calvet X. 12. Neurology 2000. 21. A 12-year mediated innate immunity in dermato- matomyositis and polymyositis: a popula. Target specificity of an autoreactive AG. Stenzel W. Most patients with cancer- 4. ing myopathies: inconstant exposure to Mayo Clin Proc 2013. thies. clinical features.​362:​971. Shen J-L. Hill CL. myositis. Polymyositis. Dalakas MC. BMJ N Engl J Med 1991. al. myopathies. teach me about these diseases.​20:​224-31. autoimmune myopathy. Nogalska A. cepts and diagnostic and therapeutic ap. Aronica E. sitis: an end stage with major disabilities. Lancet 2001. Am J Clin Dermatol 2013. Sewry C. Chimerism in children with C-B. Wu C-Y. Pinkus GS. et al.​ tol 2012. Cu. Maat-Schieman M. Hanna M.​61:​ thies. AG. Ann Neurol 2005. Dalakas MC. A retrospective ty in some diseases. Zhang Y. Re.23 I thank all the clinical and research fellows who participated Dr.org on April 27. Correlation of 1989. Casciola-Rosen L. van pathogenic human γδ-T cell receptor in New York:​McGraw-Hill. Obermeier B. Stine L. pathological features useful in the diag- myositis and inclusion-body myositis. 595-604. Neu- inflammatory and autoimmune myopa. Hoogendijk JE. Wilson FC. the Netherlands. Naarden. Allenbach Y. All rights reserved. Harwood A. et al.​4(4):​e004552. statin. follow-up in sporadic inclusion body myo. 22.​27:​343-56. Curr Opin Rheumatol 2011. flammatory myopathies: pathologic clas. Nogales- 11. impaired muscle protein homeo.​84:​1-9. and Servier. et flammatory myopathies: current trends a nationwide study. Dalakas MC. 30. and receiving consulting the patients who participated in my research and continue to fees from Baxter. cytotoxicity in myopathies. Stine L. 19. Pinkus JL. tionally distinct subsets. Stenzel W. bodies to nuclear matrix protein NXP-2 or necrotising myopathies.​325:​1487-98. Chung T. St Sauver JL. Dermatomyosi. Autoantibodies against nosis of inclusion body myositis. Lloyd TE. Polymyositis ductase in patients with statin-associated 28. Myology. proaches. Epidemiology of sporadic in. I antigen expression. Myo. Preusse C. pean patients with autoimmune necrotiz- up-to-date treatment recommendations. come in PM and sporadic IBM. Sporadic inclusion body vascular changes in early and advanced view of treatment options and internal myositis — diagnosis. Ann associations. 29. 119th ENMC international work. No other uses without permission. Lecky BR. Neurology 2003. 27.​23:​ 38. tion of inclusion body myositis. 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