Inflammatory Myopathies

AUTHOR: Lydia Sharp, MD

Definition

Inflammatory myopathies are idiopathic diseases of muscle characterized clinically by muscle weakness and pathologically by inflammation and muscle fiber breakdown. They may be further classified as dermatomyositis (DM), immune-mediated necrotizing myopathy, polymyositis (PM), antisynthetase syndrome, and inclusion body myositis (IBM).¹ See separate topics on “Inclusion Body Myositis” and “Necrotizing Autoimmune Myopathy” for details regarding these topics.

Synonyms

Immune-mediated myopathies

Idiopathic inflammatory myopathies

Myositis syndromes

Polymyositis

Dermatomyositis

IMM

ICD-10CM CODES
M33.02		Juvenile dermatopolymyositis with myopathy
M33.12		Other dermatopolymyositis with myopathy
M33.20		Polymyositis, organ involvement unspecified
M33.22		Polymyositis with myopathy
M33.90		Dermatopolymyositis, unspecified, organ involvement unspecified
M33.92		Dermatopolymyositis, unspecified with myopathy

Epidemiology & Demographics

Inflammatory myopathies are the largest group of potentially treatable myopathies in children and adults.

DM:

Occurs in children and in adults (bimodal age peak)
Average age at diagnosis is 40 to 60 yr in adults, 4 to 14 yr in children ²
More common in females than in males (2:1)²
Incidence: 9.54 to 32.74:100,000 ²
Dermatomyositis is associated with a higher risk of cancer, especially in those older than age 50 yr ³

PM:

Occurs mostly in adults, very rare in children ⁴
Average age at diagnosis is over 20 yr⁴
More common in females ⁴
Least common inflammatory myopathy ⁴
Exact incidence unknown

Antisynthetase syndrome:

Associated with antibodies against aminoacyl transfer RNA synthetases ⁵
More common in women ⁵
Average age at diagnosis is 48 yr⁵

Physical Findings & Clinical Presentation

Most patients have a subacute onset over weeks to months.
Pattern is typically symmetric proximal muscle weakness involving the proximal limbs (shoulder and pelvic girdles).
Weakness of neck flexion and extension is common.
Difficulty getting up from a chair, climbing stairs, reaching for objects above head, or combing hair.
Distal muscle involvement and ocular involvement are uncommon.
Sensation is preserved.
Reflexes may be preserved or diminished.
Dysphagia and dysphonia result from involvement of striated muscle of the pharynx and proximal esophagus.
Esophageal dysmotility is common in DM.
Respiratory failure from associated pulmonary fibrosis.
Cardiac conduction abnormalities can be seen with DM.
Systemic autoimmune disease occurs frequently in PM and rarely in DM.
Skin findings in DM:
1. Heliotrope rash on the upper eyelids
2. Erythematous rash on the face
3. May also involve the back and shoulders (shawl sign), neck and chest (V-shape), knees (Fig. E1), and elbows
4. Photosensitivity
5. Gottron papules (violaceous papules overlying dorsal interphalangeal or metacarpophalangeal areas, elbow or knee joints)
6. Nail cracking, thickening, and irregularity (Fig. E2) with periungual telangiectasia
7. Associated with increased risk of interstitial lung disease
Antisynthetase syndrome is associated with:
1. Interstitial lung disease ⁵
2. Arthritis ⁵
3. Raynaud phenomenon ⁵
4. Mechanic’s hands (dry, cracked skin on hands)⁵

Figure E1 Violaceous Plaques on the Knees in a Patient with Dermatomyositis (Gottron Sign)

From Hochberg MC et al: Rheumatology, ed 5, St Louis, 2011, Mosby.

Figure E2 Enlarged nail fold capillaries in a patient with dermatomyositis.

From Hochberg MC et al: Rheumatology, ed 5, St Louis, 2011, Mosby.

Etiology

Mechanisms of muscle fiber damage in myositis are illustrated in Fig. E3.

DM: Complex, immune-mediated microangiopathy. Adaptive immune response via humorally mediated complement attack

Figure E3 Mechanisms of Muscle Fiber Damage in Myositis

ER, Endoplasmic Reticulum; MHC, Major Histocompatibility Complex.

From Firestein GS et al: Firestein & Kelley’s textbook of rheumatology, ed 11, Philadelphia 2021, Elsevier.

PM: Unknown:

Cell-mediated immune major histocompatibility-I (MHC-1) process directed against muscle fibers is likely, given biopsy features.

Diagnosis ⬆ ⬇

The diagnosis of each subtype of inflammatory myopathy is based on clinical history, pattern of muscle involvement, electromyographic findings, muscle biopsy (Table E1), and presence of certain antibodies.
1. Myopathic pattern of muscle weakness.
2. Characteristic rash in DM.
3. Electromyography (EMG) shows myopathic (small-amplitude, short-duration, polyphasic) motor potentials with early recruitment.
4. Majority of patients have “irritable” features (fibrillations and positive sharp waves) on EMG.
5. See “Laboratory Tests.”
6. Biopsy is required for diagnosis and should confirm inflammation before treatment is started. Table 2 describes histologic features of idiopathic inflammatory myopathies. In idiopathic inflammatory myopathies, myopathic features (variation in fiber size, fiber splitting, fatty replacement of muscle tissue, and increased endomysial connective tissue) should be seen in addition to:
  1. DM: Perifascicular atrophy, membrane attack complex (MAC) deposition along capillaries
  2. PM: Endomysial infiltrates composed of CD8+ T cells and macrophages invading nonnecrotic muscle fibers that express MHC-I antigen

TABLE 2 Histologic Features of Idiopathic Inflammatory Myopathies

Feature	Dermatomyositis	Polymyositis	Inclusion Body Myositis
Necrosis of muscle fibers	+	+	+
Variation in fiber diameter	+	+	+
Regeneration of muscle fibers	+	+	+
Proliferation of connective tissue	+	+	+
Infiltration of mononuclear cells ∗	+	+	+
Perivascular and perimysial inflammation	+	–/+	–/+
Endomysial inflammation	–/+	+	+
Perifascicular atrophy	+	–	–
Abnormally dilated capillaries	+	–/+	–
Reduced capillary density	+	–/+	–
Deposition of complement on vessel walls	+	–/+	–
Microinfarcts	+	–	–
Invasion of nonnecrotic fibers by cytotoxic T lymphocytes and macrophages	–	+	+
Expression of major histocompatibility complex class I on muscle fibers	–/+	+	+
Rimmed vacuoles with amyloid deposits and tubulofilaments ^†	–	–	+
Angulated or atrophic and hypertrophic fibers	–	–	+
Ragged red or cytochrome oxidase-negative fibers	–	–	+

^∗Inflammation is absent in a small proportion of polymyositis and dermatomyositis biopsies.

^†Also seen in chronic neurogenic conditions and distal myopathies.

From Firestein GS et al: Kelley’s textbook of rheumatology, ed 9, Philadelphia, 2013, Saunders, Elsevier.

TABLE E1 Classification of Inflammatory Myopathies

Disorder	Age Range	Clinical Features	Muscle Pathology
Dermatomyositis	Juvenile and adult forms	Proximal weakness plus skin	Perimysial and perivascular inflammation, perifascicular atrophy
Antisynthetase syndrome	Children and adults	Proximal weakness	Perifascicular necrosis and macrophagocytosis
Polymyositis	Adult (rare in childhood)	Proximal weakness	Endomysial inflammation with invasion of nonnecrotic muscle fibers
Immune-mediated necrotizing myopathy	Adult	Proximal weakness	Multifocal necrotic muscle fibers
Inclusion body myositis	Adult >40 yr old	Prominent quadriceps and finger flexor weakness; treatment refractory	Endomysial inflammation with invasion of nonnecrotic muscle fibers plus rimmed vacuoles
Overlap syndromes	Adult	Myositis plus defined connective tissue disease	Nonspecific inflammation
Other (granulomatous myositis, eosinophilic myositis)	All ages	Proximal or distal weakness	Specific to type (e.g., granulomas present with granulomatous myositis)

From Goldman L, Schafer AI: Goldman-Cecil medicine, ed 26, Philadelphia, 2019, Elsevier.

Differential Diagnosis (TABLE E3

IBM
Muscular dystrophies
Amyloid myoneuropathy
Amyotrophic lateral sclerosis
Myasthenia gravis
Eaton-Lambert syndrome
Drug-induced myopathies (e.g., quinidine, NSAIDs, penicillamine, HMG-CoA-reductase inhibitors)
Diabetic amyotrophy
Guillain-Barré syndrome
Hyperthyroidism or hypothyroidism
Lichen planus
Amyopathic DM (rash without weakness)
DM sine rash (weakness with characteristic biopsy, but no rash)
Systemic lupus erythematosus (SLE)
Contact atopic or seborrheic dermatitis
Psoriasis

TABLE E3 Differential Diagnosis of Inflammatory Myopathies

Disease		Key Diagnostic Features
Dystrophic Myopathies
Dysferlinopathy (Miyoshi myopathy and LGMD2B)		Mutations in dysferlin gene Progressive proximal (LGMD2B) and distal (Miyoshi myopathy) muscle weakness Onset in late teens to early 20s Increased creatine kinase (CK) levels Inflammation in muscle biopsy Nonresponsiveness to steroids
Facioscapulohumeral muscular dystrophy		Partial deletion in D4Z4 repeats near chromosome 4q telomere at 4q35 Initial facial and shoulder girdle weakness progresses to pelvic girdle and extremities Normal serum CK levels or modest elevation
Becker dystrophy		Mutations in dystrophin gene X-linked recessive disorders Limb-girdle weakness and cardiomyopathy High serum CK levels
Proximal myotonic myopathy		CCTG expansion in intron 1 of ZNF9 gene Autosomal dominant Proximal muscle weakness
Limb-girdle muscular dystrophy (LGMD2D, LGMD2E, LGMD2C, and LGMD2F)		Mutations in sarcoglycans (α, β, γ, and Δ) Limb-girdle weakness and cardiomyopathy High serum CK levels
Metabolic Myopathies
Acid maltase deficiency		Mutations in acid α-glucosidase Proximal muscle weakness Respiratory muscle involvement Abnormal irritability on electromyography (EMG) Increased serum CK levels
McArdle disease		Mutations in myophosphorylase gene Exercise intolerance Fixed proximal muscle weakness Increased serum CK levels
Mitochondrial Myopathies		Mutations in complex I-IV, complex V, and coenzyme Q10 genes Myopathy with limb-girdle weakness Exercise intolerance and fatigue Increased serum CK levels
Endocrine Myopathies
Cushing syndrome		Insidious onset Proximal muscle weakness Normal serum CK, aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) levels
Thyrotoxic myopathy		Subacute onset of proximal muscle weakness Normal serum CK levels or modest elevation Respiratory muscle weakness
Infectious Myopathies
HIV myopathy		Progressive myopathy Proximal symmetric muscle weakness Endomysial inflammation Increased serum CK levels
Parasitic Myopathies
Protozoal myopathy		Clinical features of idiopathic inflammatory myopathies Focal or diffuse inflammation Myocarditis Increased serum CK levels
Drug-Induced Myopathies
Zidovudine myopathy		Proximal muscle weakness Increased serum lactate levels Ragged red fibers and abnormal mitochondria in muscle Improves with drug discontinuation
Statin myopathy		Necrotizing myopathy Acute or subacute painful proximal myopathy Increased serum CK levels
Corticosteroid myopathy		Proximal and distal weakness Type 2 atrophy and vacuolar changes in muscle Increased serum CK levels
d-Penicillamine, interferon-α, and procainamide-induced myopathy		Proximal muscle weakness and pain Inflammation and necrosis in muscle Skin changes Increased serum CK levels
Neuromuscular Diseases
Motoneuron disease		Upper and lower motoneuron signs Asymmetric weakness with denervation atrophy Fasciculations and fatigability Fibrillations and enlarged motor unit potentials on EMG Modest elevation in serum CK levels
Spinal muscular atrophy		Symmetric muscle weakness and atrophy Neurogenic changes on EMG and biopsy Normal serum CK levels
Myasthenia gravis		Abnormal weakness and fatigability Decremental EMG response Antiacetylcholine receptor antibodies Positive anticholinesterase drug test

From Firestein GS et al: Firestein & Kelley’s textbook of rheumatology, ed 11, Philadelphia, 2021, Elsevier.

Laboratory Tests

Creatine kinase (CK) is the most sensitive muscle enzyme test for muscle breakdown.
CK is typically elevated (5 to 50× normal) in active PM.
CK may be normal or only slightly elevated in DM.
Aldolase, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and lactate dehydrogenase (LDH) may be elevated.
Anti-Jo-1 antibodies are seen in myositis with associated interstitial lung disease but are not specific for either DM or PM.
Myositis-specific and myositis-associated autoantibodies in adult polymyositis and dermatomyositis and juvenile dermatomyositis are summarized in Table E4.
DM: Anti-MDA-5, anti-Mi-2, anti-TIF-1, and anti-NXP2 (implicated in cancer-associated dermatomyositis).
PM: Antisynthetase antibodies associated with interstitial lung disease, arthritis, fever, and “mechanic’s hands.”
Electrolytes, thyroid-stimulating hormone, Ca, and Mg should be evaluated to exclude other causes of weakness.
Check ECG for cardiac involvement.

TABLE E4 Myositis-Specific and Myositis-Associated Autoantibodies in Adult Polymyositis and Dermatomyositis and Juvenile Dermatomyositis

Autoantibody	Autoantigen	Clinical Features
Jo-1, non-Jo-1 (PL7, PL12, EJ, OJ, KS, Tyr, Zo)	Amino-acyl-tRNA synthetase	Fever, Raynaud phenomenon, mechanic’s hands, myositis, polyarthritis, ILD
SRP	Signal recognition particle (cytoplasmic protein translocation)	Severe necrotizing myopathy; predominantly PM
Mi-2	Helicase	DM (adult >children); “shawl” sign and other DM rashes
PM-Scl	Nucleolar macromolecular complex	Overlap features of myositis and SSc (or either disease alone); mechanic’s hands
U1RNP	Small nuclear ribonucleoprotein	Overlap syndromes (MCTD)
SUMO-1 (small ubiquitin-like modifier 1)	Small ubiquitin-like modifier enzyme (posttranslational modification)	Adult DM, ILD
TIF1-γ (p155/140)	Transcriptional intermediary factor 1-γ (TIF1-γ)	Cancer-associated myositis in adults; >20% frequency in JDM cohorts; severe cutaneous disease in adult DM and JDM
NXP2/MJ (p140)	NXP-2 (SUMO target; possible role in SUMO-mediated transcriptional repression)	20%-25% frequency in JDM cohorts; calcinosis; severe disease (atrophy or contractures)
MDA-5 (cADM-140)	RNA helicase	ADM, ILD; palmar papules and cutaneous ulcerations
PMS1	PMS1 (DNA mismatch repair enzyme)	Myositis (specifics not known)
Ku ¹	70- and 80-kDa nuclear/nucleolar protein complex (DNA break repair and recombination)	UCTD and overlap syndromes (Raynaud phenomenon, ILD, myositis, arthritis)
HMGCR (200/100 kDa)^2,3	HMG CoA reductase	Necrotizing myopathy

ADM, Amyopathic dermatomyositis; DM, dermatomyositis; DNA, deoxyribonucleic acid; HMG CoA, hydroxymethylglutaryl-coenzyme A; ILD, interstitial lung disease; JDM, juvenile DM; MCTD, mixed connective tissue disease; PM, polymyositis; RNA, ribonucleic acid; SSc, systemic sclerosis; tRNA, transfer ribonucleic acid; UCTD, undifferentiated connective tissue disease.

¹Rozelle A et al: Malignancy in the setting of the anti-synthetase syndrome, J Clin Rheumatol 14:285-288, 2008.

²Zhang L et al: Cardiac involvement in adult polymyositis or dermatomyositis: a systematic review, Clin Cardiol 35(11):686-691, 2012.

³Oddis CV et al: International consensus guidelines for trials of therapies in the idiopathic inflammatory myopathies, Arthritis Rheum 52(9):2607-2615, 2005.

From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.

Imaging Studies

Chest x-ray is used to rule out pulmonary involvement. If suspicious for pulmonary interstitial disease, a high-resolution computed tomography scan of the chest may be helpful.
Radiography is an efficient means of identifying and characterizing soft-tissue calcinosis (Fig. E4).
Although MRI arguably has greater diagnostic value than electromyography or serum enzyme measurements in cases of suspected idiopathic inflammatory myopathy, MRI findings have not been formalized as a diagnostic criterion for idiopathic inflammatory myopathy. The acceptance of MRI as a diagnostic tool in myositis may be inhibited by the high cost and the need for more reliable and validated methods of summarizing the findings of MRI. MRI evaluation before biopsy, however, has become routine at many tertiary care centers. Fascial disease is manifested on MRI by fascial or perifascial hyperintensity on fluid-sensitive sequences. The edema-like signal in the deep subcutis may accompany fasciitis and can indicate associated panniculitis.
Video fluoroscopy or barium swallow study to look for upper esophageal dysfunction in patients with dysphagia and DM.
Table E5 summarizes affected organs and their evaluation in inflammatory muscle disease.

Figure E4 Advanced Calcinosis

Radiograph of the Arm in a Girl with Juvenile Dermatomyositis, Showing Extensive Amorphous and Wispy Calcification Corresponding to Subcutaneous Calcinosis. Sheetlike Calcification Outlining Muscles Corresponds to Deep Fascial Calcification.

From Pope TL et al: Musculoskeletal imaging, ed 2, Philadelphia, 2015, Saunders.

TABLE E5 Affected Organs and Their Evaluation in Inflammatory Muscle Disease

Organ or System	Modalities of Evaluation	Pathologic Processes	Findings
Muscle	Biopsy	Myofiber degeneration and regeneration	Myofiber size variation; vacuolated, necrotic fibers Large central nuclei, basophilic sarcoplasm
		Inflammation	Mononuclear cell infiltration
		Fibrosis	Increased interstitium and fatty replacement of muscle
	EMG	Myofiber destruction	Low-amplitude, short, polyphasic potential; spontaneous fibrillations; irritability
	MRI
	T1 image	Fibrosis	Atrophy of muscle, scarring
	STIR image	Inflammation	Bright signal in inflamed muscle
Heart	ECG, echo	Myocarditis, fibrosis	Arrhythmias, left ventricular hypertrophy
	Biopsy	Myocarditis, fibrosis	Myofiber size variation, mononuclear cell infiltrates, fibrosis
Lungs	CXR, HRCT	Inflammation, fibrosis	Interstitial markings
	PFTs	Inflammation, fibrosis, restrictive lung disease	Decreased TLV, FVC, and DLCO
	Radionuclide scan	Inflammation, fibrosis	Ventilation-perfusion mismatches
	BAL	Inflammation, fibrosis	Abnormal leukocyte numbers and differentials
	Biopsy	Inflammation, fibrosis	Mononuclear cell infiltration, destruction of alveolar space and fibrosis
Skin	Biopsy	Inflammation	Vacuolization of the basal layer; mononuclear cell infiltration
GI system	Radiographic studies	Inflammation, fibrosis	Reflux and uncoordinated peristalsis

BAL, Bronchoalveolar lavage; CXR, chest x-ray examination; echo, echocardiography; DLCO, diffusion capacity for carbon monoxide; ECG, electrocardiography; EMG, electromyography; FVC, forced vital capacity; GI, gastrointestinal; HRCT, high-resolution computed tomography; MRI, magnetic resonance imaging; PFT, pulmonary function tests; STIR, short tau inversion recovery; TLV, total lung volume.

From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.

Treatment ⬆ ⬇

Goal: Maintain function, minimize disease/iatrogenic sequelae

Nonpharmacologic Therapy

Sun-blocking agents with SPF 15 or greater for skin protection in patients with DM
Physical therapy beneficial for gait training and increasing muscle tone and strength
Occupational therapy assists with activities of daily living
Speech therapy to monitor patients with swallowing dysfunction

Acute General Rx

Corticosteroids are the mainstay of therapy. Start prednisone 0.7 to 1 mg/kg per day, up to a maximum dose of 60 mg/day. If severe disease, can give methylprednisolone 1 g intravenous (IV) daily for 3 to 5 days before starting prednisone. Continue until muscle strength improves. Begin tapering by 5 to 10 mg/mo. Consider every-other-day prednisone treatment at same dose (may decrease side effects).⁶
Consider IV immunoglobulin (IVIG) if patient fails to improve on prednisone, or muscle enzymes begin rising when tapering off prednisone. See “Chronic Rx” for specific dosage.
Hydroxychloroquine can be used to treat the cutaneous lesions of DM.
A treatment algorithm for adult patients with inflammatory myopathies is illustrated in Fig. 5.

Figure 5 Treatment Algorithm for Adult Patients with Polymyositis (PM) or Dermatomyositis (DM)

Aza, Azathioprine; Cyc, Cyclophosphamide; ILD, Interstitial Lung Disease; Mmf, Mycophenolate Mofetil; Mtx, Methotrexate; Pft, Pulmonary Function Test; SC, Subcutaneous.

From Firestein GS et al: Firestein & Kelley’s textbook of rheumatology, ed 11, Philadelphia, 2021, Elsevier.

Chronic Rx

Chronic prednisone therapy may be needed for years, but other immunosuppressive (“steroid-sparing”) agents may be added early to decrease long-term steroid side effects.
Azathioprine starting with 50 g daily, titrating to 100 mg/day after 1 week to goal of 2 mg/kg/day.⁶
Methotrexate 5 to 7.5 mg weekly, increased by 2.5 mg/wk to total of 25 mg/wk; consider intramuscular dosing if PO is ineffective. Use cautiously in patients with interstitial lung disease due to possible pulmonary fibrosis.
IV immunoglobulin 2 g/kg total dose over 2 to 5 days.
IV cyclophosphamide 0.5 to 1 g/m² monthly for 6 mo is preferred to oral dosing for refractory cases. However, oral dosing of cyclophosphamide is 1 to 2 mg/kg per day PO or 2 to 4 mg/kg per day in conjunction with prednisone.⁶
Cyclosporine A: Initial dose 2.0 to 2.5 mg/kg bid; long-term maintenance is lowest effective dose.
Mycophenolate mofetil 500 mg PO bid, titrate to 1500 mg PO bid over 1 to 2 mo.⁶

Disposition

20% to 30% of patients achieve clinical remission with treatment.⁶
In patients with residual weakness, deficits typically remain stable over long-term follow-up.
10% experience recurrent disease.
Serum CK often returns to normal before symptoms improve.
During exacerbations, enzymes may rise before clinical symptoms appear.
Poor prognostic indicators include delay in diagnosis, older age, recalcitrant disease, malignancy, interstitial pulmonary fibrosis, dysphagia, leukocytosis, fever, and anorexia.
Infection, malignancy, and cardiac and pulmonary dysfunction are the most common causes of death.

Referral

Neurology or rheumatology referral should be made to help establish the diagnosis and implement treatment.

section name header

Basic Information ⬇

Diagnosis ⬆ ⬇

Treatment ⬆ ⬇

Pearls & Considerations ⬆ ⬇

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