Inflammatory Myopathies

Idiopathic inflammatory myopathies (IIM) are a group of chronic autoimmune disorders characterized by inflammation and degeneration of skeletal muscles. The original Bohan and Peter criteria classify inflammatory myopathies into dermatomyositis (DM), polymyositis (PM), and inclusion body myositis (IBM). Newer subtypes include autoimmune necrotizing myositis and overlap myositis (Dalakas, 2015).

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Diagnosis

Indications for Testing

  • Progressive muscle weakness (usually proximal) 
  • Symmetrical or asymmetrical proximal muscle weakness after more common etiologies have been ruled out

Criteria for Diagnosis

  • See Background for inflammatory myopathies and definitions
Bohan and Peter Criteria for the Diagnosis of Polymyositis (PM) and Dermatomyositis (DM)a
  • Proximal muscle weakness, usually symmetrical
  • Elevated serum muscle enzymes – CK, aldolase
  • Electromyographic abnormalities
    • Common – myopathic potential (low amplitude, short duration, and polyphasic action potentials)
    • Characteristic triad – myopathic potentials, fibrillations, positive sharp waves, increased insertional activity, complex repetitive discharges
  • Muscle biopsy findings typical of PM or DM – necrosis, phagocytosis, regeneration, inflammation
  • Dermatological features of DM, Gottron sign or papules, or heliotrope rash

aDefinite diagnosis requires 4 criteria with rash for DM and without rash for PM; probable diagnosis requires 3 criteria with rash for DM and without rash for PM

CK, creatine kinase; DM, dermatomyositis; PM, polymyositis,

Source: Adapted from Khan, 2011,

Criteria Supporting Inflammatory Myopathy Subtypes
  DM PM Necrotizing Autoimmune IBM

Pattern of muscle weakness

Symmetrical

Proximal

Subacute

Rash present

Symmetrical

Proximal

Subacute

Rash present

Symmetrical

Proximal with severe weakness

Acute or subacute

Rash absent

Asymmetrical

Distal>proximal with atrophy

Slow onset

Rash absent

Age

Adult

Children

Adult

Children (rare)

Adult (elderly common)

Adult (usually >50 yrs)

CK levels

High

High, may remain elevated in spite of treatment

Very high

Lower levels

Normal level not uncommon

EMG

Active and chronic myopathic units

Active and chronic myopathic units

Active myopathic units

Active and chronic myopathic units

Some mixed large-size potentials

Antibodies

Anti-Mi-2

Anti-p155/140

Anti-MDA-5

Anti-NXP2

Antisynthetase antibodies

Anti-SRP

Anti-HMGCR

Anti-CN1A (uncertain pathologic significance)

CK, creatine kinase; DM, dermatomyositis; EMG, electromyography; IBM, inclusion body myositis; PM, polymyositis

Source: Adapted from Dalakas, 2015

Laboratory Testing

  • Initial screening tests
    • Creatine kinase (CK) – elevated in most idiopathic inflammatory myopathies (IIM)
      • Most sensitive muscle-derived enzyme test
      • Consider other causes for elevations >100-fold
    • Thyroid stimulating hormone (TSH) – evaluate for thyroid disease as etiology of muscle weakness
    • Antinuclear antibodies (ANA) with HEp-2 substrate, IgG by immunofluorescent antibody (IFA)
      • Use to rule out underlying connective tissue disease (CTD) or overlap diseases
      • Staining pattern may be useful in determining the type of confirmatory test(s) to perform
      • Positive in 50-80% of patients with inflammatory myopathies
    • Aldolase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LD), serum myoglobin
      • Not usually recommended
      • Variably elevated
      • Highly nonspecific
  • Myositis antibody testing
    • Myositis-specific antibodies (MSA) may be useful in confirming a diagnosis of polymyositis (PM), dermatomyositis (DM), or necrotizing autoimmune myopathies
    • Myositis-associated antibodies (MAA) are present in patients with inflammatory myopathies (IM) and/or other CTD or overlap syndromes
    •  
      Antisynthetase Antibodies
      Autoantibody Target Autoantigen Clinical Associations Frequency (%)

      Jo-1a

      Histidyl-tRNA synthetase

      ​Moderate to severe disease

      Arthritis common

      Low rate of mechanic’s hand

      Adults – 15-20

      PL-7

      Threonyl-tRNA synthetase

      Higher incidence of ILD

      Severe arthritis

      Raynaud phenomenon

      Infrequent myositis

      <5

      PL-12

      Alanyl-tRNA synthetase

      Raynaud phenomenon

      More common to have myositis-associated antibodies present concurrently

      Less incidence of myositis

      Mechanic’s hands rare

      <5

      EJ

      Glycyl-tRNA synthetase

      Mechanic’s hands

      DM

      <5

      OJ

      Isoleucyl-tRNA synthetase

      Arthritis

      High incidence of ILD

      Rare myositis or Raynaud phenomenon

      <5

      KSb

      Asparaginyl -tRNA synthetase

      High incidence of ILD

      Fever

      <5

      Hab

      Tyrosyl-tRNA synthetase

      Arthritis

      Skin rash

      <1

      Zob

      Phenylalanyl-tRNA synthetase

      Case reports

      Arthritis

      Severe, nonspecific interstitial pneumonia

      <1

      aMost common antisynthetase antibody; more common in PM; relationship between Jo-1 antibody titer and disease activity reported but not confirmed

      bLess common antisynthetase antibodies (not currently available for testing); presence of antibodies are highly associated with ILD and with varying degree of myositis

      DM, dermatomyositis; ILD, interstitial lung disease; PM, polymyositis

      Source: Adapted from Solomon, 2011; Ancuta, 2011

    •  

      Other Myositis-Specific Antibodies
      Autoantibody Target Autoantigen Clinical Associations Frequency (%)

      SRP

      SRP

      Acute, severe necrotizing myopathy

      Severe cardiac involvement

      5-10

      Mi-2

      Nucleosome remodeling-histone deacetylase complex (NuRD), gene transcription

      Classic DM, low cancer risk

      Steroid responsiveness

      Favorable prognosis

      <10

      p155/140 (TIF1-gamma)

      Transcriptional intermediary factor 1 (TIF1) γ/α (155 and 140 kDa)

      Aggressive skin lesions in DM

      Cancer in adults >50 years

      13-21

      MDA5 (CADM-140)

      Melanoma differentiation-associated protein 5 (140 kDa)

      Rapidly progressive ILD

      Poor prognosis

      CADM

      50-73 CADM (not in Caucasians)

      NXP-2

      Nuclear matrix protein 2 (140 kDa), transcriptional regulation

      DM

      Increased malignancy risk

      ILD

      <5

      SAE1

      Small ubiquitin-like modifier activating enzyme (90 and 40 kDa)

      Prognosis is favorable

      Initial amyopathic DM, DM

      Severe skin disease, dysphagia, and systemic features

      <5

      HMGCR

      Anti-200/100

      Necrotizing autoimmune myopathy

      May be associated with statin therapy

      Often improves with withdrawal

      <10 necrotizing myopathy

      Mup44

      Anti-Mup44

      sIBM

      Also seen in different autoimmune systemic diseases

      sIBM – 52-63%

      CADM, clinically amyopathic dermatomyositis; DM, dermatomyositis; ILD, interstitial lung disease; sIBM, sporadic inclusion-body myositis; SRP, signal recognition particle

      Source: Adapted from Gunawardena, 2009; Lloyd, 2016

  •  

    Myositis-Associated Antibodies – Target Autoantigen, Overlap Syndromes, and Frequency
    Myositis-Associated Antibodies Target Autoantigen Overlap Syndromes Frequency (%)

    PM/Scl (scleroderma-polymyositis)

    Nucleolar protein complex of 11-16 proteins

    Overlap myositis, MCTD

    10

    Smith/RNP

    U1 small nuclear RNP

    MCTD, overlap myositis

    10

    Ku

    DNA-PK regulatory subunit

    PM-SSc overlap

    20-30

    SS-A/Ro

    Ro-52/TRIM21 and Ro-60 proteins

    ILD in IM patients

    ≥35%

    ILD, interstitial lung disease; IM, inflammatory myopathy; MCTD, mixed connective tissue disease; PM, polymyositis; SSc, systemic sclerosis

Histology

  • Muscle biopsy – gold standard for diagnosis
    • Usually performed on proximal leg muscles but should not be performed in end-stage muscles; magnetic resonance imaging (MRI) may be helpful in choosing muscle
    • Open biopsy preferred – larger sample
    • Findings on muscle biopsy are usually diagnostic for specific subtypes

Other Testing

  • Electromyogram (EMG) – changes consistent with myopathy, including increased spontaneous and insertional activity with fibrillation potential, complex repetitive discharges, positive repetitive discharges, positive sharp waves, early recruitment, and small polyphasic motor unit potentials
    • Abnormal in 70-90% of patients
    • Not specific for IIM
    • Amyopathic DM may have subtle myopathy on EMG

Imaging Studies

  • Ultrasound
    • Muscle edema with alteration of normal architecture
    • May visualize subcutaneous calcifications
  • Computed tomography (CT) – fatty infiltration suggests chronic disease
  • MRI – very sensitive for detection of muscle edema; often used to guide biopsy site

Differential Diagnosis

Isolated muscle weakness
Muscle weakness (with or without rash)
Rash without muscle weakness
  • Psoriasis
  • Eczema
  • Seborrheic dermatitis
  • Polymorphous light eruption

Screening

  • All adult patients with dermatomyositis (DM) should be evaluated for malignancy due to increased risk

Monitoring

  • Creatine kinase myoglobin, and lactate dehydrogenase (LD) levels are most useful in monitoring therapeutic response
  • Necrotizing autoimmune myopathy – decline in anti-HMGCR antibodies associated with treatment response

Background

Epidemiology

  • Incidence – 4-10/million (overall, all subtypes)
  • Age
    • Dermatomyositis (DM) – bimodal peaks
      • Childhood
      • 50-70 years
    • Polymyositis (PM) – age of onset typically >20 years
    • Inclusion body myositis (IBM) – >50 years
    • Autoimmune necrotizing myositis – primarily adults, often older
  • Sex
    • DM and PM – M<F; 1:2
    • IBM – M>F; 2:1
  • Ethnicity
    • DM – unknown
    • PM – some studies suggest higher prevalence in African Americans compared to general U.S. population
    • IBM – higher prevalence in Caucasians

Pathophysiology

  • DM – microangiopathy affecting skin and muscle with deposition of complement-causing lysis of endomysial capillaries and muscle ischemia
  • PM and IBM – T cells invade muscle fibers, leading to necrosis
  • Autoimmune necrotizing myositis – scattered necrotic myofiber with myophagocytosis, absence or paucity of T cells

Clinical Presentation

General features of idiopathic inflammatory myopathies (IIM)
  • Musculoskeletal – progressive muscle weakness (usually symmetrical and proximal)
    • Pharyngeal and neck flexion muscles frequently involved, leading to dysphagia and/or myalgia
    • Sparing of ocular muscles
  • Arthralgias/arthritis – wrists, knees, small joints of hands
  • Constitutional – fever, weight loss
  • Pulmonary – fibrosing alveolitis, aspiration pneumonia
  • Gastrointestinal – esophageal dysfunction, dysphagia
  • Cardiovascular – myocarditis, pericarditis, valvular disease, rhythm disturbances
  • Renal – glomerulonephritis, myoglobinuria (rare)
  • Dermatologic – Raynaud phenomenon, rashes, calcinosis over bony prominences​
Antisynthetase syndrome
  • Found almost exclusively in middle-aged women with polymyositis (PM) or dermatomyositis (DM)
  • Characterized by
    • Low-grade fevers
    • Interstitial pneumonitis – major determinant of morbidity and mortality
    • Hyperkeratosis, cracking of lateral and palmar aspects of the fingers (mechanic’s hands)
    • Raynaud phenomena
    • Inflammatory polyarthritis, myalgias
  • Presence of antinuclear antibodies known as antisynthetases
DM
  • Characteristic photosensitive rash often accompanied by symmetrical, subacute, proximal muscle weakness
    • Rash usually precedes muscle symptoms
    • Blue-purple rash – symmetrical distribution
    • Violaceous discoloration of upper eyelids with periorbital edema (heliotrope rash)
    • Erythema of metacarpophalangeal proximal and distal joints
      • Raised violaceous rash (Gottron sign) or scaly erythematous plaques over dorsal surface of bony prominences (Gottron papules) – considered pathognomonic for DM
    • Macular erythema over the lower neck and upper chest in a V-distribution (V-sign), over upper back (Shawl sign), or over upper thighs (Holster sign)
    • Telangiectasias at base of fingernails, cuticular overgrowth and periungual erythema
    • Vasculitic skin changes– subcutaneous nodules, periungual infarcts, digital ulcerations
  • Cancer-associated myositis
    • Most commonly associated with DM, but can be found in polymyositis (PM)
    • May be diagnosed prior to, simultaneous with, or after myopathy
    • Increased risk of malignancy (20-25%) in adults for the following types (highest risk in first 3-5 years after diagnosis)
  • Amyopathic DM
    • Characteristic cutaneous findings of DM >6 months without muscle involvement
    • May progress to DM
    • Some risk for lung disease, malignancy
    • Electromyography (EMG) may demonstrate subtle myopathy
PM
  • Dominated by muscular presentation – no rash
  • Usually subacute presentation
  • May be associated with other autoimmune diseases
  • Diagnosis of exclusion –  must rule out
    • Neuromuscular disease
    • Endocrinopathy
    • Muscular dystrophy
    • Known biochemical muscle disorder or familial biochemical disorder
    • Drug-induced myopathy
IBM
  • 2 types – sporadic, hereditary
  • Muscle involvement
    • Small muscles in hand frequently involved
    • Distal weakness is most common – deep finger flexors and foot extensors common
      • Proximal muscles less frequently involved
      • Quadriceps involvement common – associated with frequent falls
      • Muscle atrophy early in disease
    • Facial muscles frequently involved
    • Asymmetric distribution common
  • Extramuscular disease rare – dysphagia is the exception (>50% of patients)
  • May be misdiagnosed as polymyositis (PM), adult-onset muscular dystrophy, or motor neuron disease
  • Associated with other autoimmune diseases
Necrotizing autoimmune myositis
  • Acute or subacute presentation
  • Severe proximal muscle weakness – clinically indistinguishable from polymyositis (PM)
  • May occur in association with cancer, other connective tissue disease (CTD), or drug use (eg, statins)
  • Diagnosis of exclusion
Overlap syndromes

Pediatrics

Epidemiology

  • Incidence – 2-3/million (rare)
  • Age
    • Dermatomyositis (DM) – more common in children
      • Mean onset is 7 years
      • 25% present at <4 years
    • Polymyositis (PM) – rare in children
    • Juvenile myositis (JM) – children 2-18 years
  • Sex – M<F, 1:2.3
  • Ethnicity
    • Juvenile dermatomyositis (JDM) – Caucasians
    • Juvenile polymyositis (JPM) – African Americans

Classification

  • JDM
  • JPM
  • Juvenile connective tissue disease myositis (JCTM)

Clinical Presentation

  • JDM
    • ~85% of juvenile idiopathic inflammatory myopathy (JIIM)
    • Symmetrical and proximal muscle weakness
    • Gottron papules
    • Heliotrope rash
    • Periungual telangiectasia
    • Vasculitis – more common than in adults
    • Other organs
      • Cardiac
      • Joints
      • Gastrointestinal
      • Pulmonary
    • May have family history of other autoimmune diseases
    • Amyopathic (hypomyopathic form)
      • Inflammatory rashes without muscle weakness
      • ~25% develop full blown dermatomyositis (Ernste, 2014)
  • JPM
    • 4-8% 
    • Proximal and distal muscle weakness
    • Frequent falling episodes
    • Cardiac damage
  • JCTM
    • 6-11% of juvenile idiopathic inflammatory myopathy (JIIM)
    • Occurs in conjunction with another connective tissue disease (CTD)
    • Raynaud phenomenon
    • Arthritis
    • Malar rash
    • Intestinal lung disease (ILD)

Indications for Testing

Symmetrical and proximal muscle weakness.

Laboratory Testing

  • Initial screening tests – see adult laboratory testing
  • Muscle biopsy – less frequent in children so antibodies are important
JIIM Subsets of Myositis-Associated and Myositis-Specific Antibodies
Antibody JIIM Subgroup Clinical Appearance Frequency (%)

p155/140 (TIF1-gamma)

  • JDM
  • JCTM
  • Cutaneous ulcers
  • Severe DM rashes
  • No malignancy risk
  • Low CK levels
  • Chronic course

23-35

NXP-2 (MJ)

  • JDM
  • Muscle cramps
  • Calcinosis
  • Dysphonia
  • Monocyclic course

23-25

Sm/RNP

  • JCTM (more common)
  • JPM
  • Raynaud phenomenon
  • Sclerodactyly
  • Arthritis

5-10

Mi-2

  • JDM
  • JCTM
  • Classic DM rash
  • Mild disease
  • More common in Hispanic patients

2-13

Antisynthetases (eg, anti-Jo-1)

  • JPM (more common)
  • JDM
  • JCTM
  • Fever
  • Raynaud phenomenon
  • Arthritis
  • Mechanic's hands
  • ILD

2-4

PM/ScL

  • JPM
  • JCTM
  • Raynaud phenomenon
  • Arthritis
  • ILD
  • Dysphagia

1-4

SRP

  • JPM
  • Severe muscle weakness
  • Chronic falls
  • High CK levels
  • More common in African American populations

1

CK, creatine kinase; DM, dermatomyositis; ILD, interstitial lung disease; JCTM, juvenile connective tissue myositis; JDM, juvenile dermatomyositis; JIIM, juvenile idiopathic inflammatory myopathy; JPM, juvenile polymyositis; SRP, signal recognition particle

Adapted from Ernste, 2014

Differential Diagnosis

ARUP Lab Tests

Preferred ANA screening test for connective tissue diseases

If positive, patterns reported include homogeneous, speckled, centromere, nucleolar, nuclear dots, or cytoplasmic; all positive results are reported with endpoint titers

A negative test does not rule out the presence of connective tissue disease 

Aid in initial diagnosis of connective tissue disease

ANA ELISA screen is designed to detect antibodies against dsDNA, histone, SS-A (Ro), SS-B (La), Smith, Smith/RNP, Scl-70, Jo-1, centromere, and an extract of lysed HEp-2 cells

ANA ELISA assays have been reported to have lower sensitivities than ANA IFA for systemic autoimmune rheumatic diseases

Reflex pattern: if ANA are detected by ELISA, then ANA, HEp-2, IgG by IFA will be added

Initial screen for autoimmune connective tissue diseases

One or more reflexive tests may be added, depending on the ANA pattern detected

Only cytoplasmic, nuclear mitotic apparatus (NuMA), and/or nuclear dot pattern will be reported if observed; titers are not performed

Dual or mixed patterns will not be reflexed; additional testing for dual or mixed patterns should be determined by the ordering physician

A negative test does not rule out the presence of connective tissue disease

May be useful for evaluation of patients with progressive proximal muscle weakness and/or cutaneous manifestations suggestive of dermatomyositis and/or associated connective tissue disease

Components include Jo-1, PL-7, PL-12, EJ, SRP, OJ, Mi-2, P155/140, SAE1, MDA5, NXP-2, and TIF1-γ antibodies

Results by themselves are not diagnostic; strong clinical correlation is recommended

Negative results do not rule out a diagnosis of inflammatory myopathy or overlap syndrome

May be useful for evaluation of patients with progressive proximal muscle weakness and antisynthetase syndrome

Components include Jo-1, PL-7, PL-12, EJ, SRP, and OJ antibodies

May be useful for evaluation of patients with characteristic cutaneous manifestations of dermatomyositis with or without muscle weakness

Components include Mi-2, P155/140, SAE1, MDA5, NXP-2, and TIF1-gamma antibodies

May be useful for evaluation of interstitial lung disease in the context of connective tissue disease

Components include SSA 52 and 60 (Ro), Scl-70, Jo-1, PL-7, PL-12, EJ, Ku, SRP, OJ, PM/Scl-100, MDA5, NXP-2, rheumatoid factor, cyclic citrullinated peptide (CCP), ANA antibodies, and RNA polymerase III antibody, IgG

May be useful in the differential evaluation of polymyositis, dermatomyositis, necrotizing autoimmune myopathy, or overlap syndromes associated with connective tissue disease

Results by themselves are not diagnostic; strong clinical correlation is recommended

Negative results do not rule out a diagnosis of inflammatory myopathy or overlap syndromes

Components include SSA 52 and 60 (Ro), SM/RNP (U1) (ENA), Jo-1, Mi-2, PL-7, PL-12, P155/140, EJ, Ku, SRP, OJ, SAE1, MDA5, NXP-2, TIF1-gamma (TIF1-γ), fibrillarin (U3 RNP), and PM/Scl-100 antibodies

Differential diagnosis of myositis in patients with or without statin exposure

Monitor response to treatment

Clinical evaluation for muscle strength and serum creatine kinase (CK)

Detect IgG autoantibodies against HMGCR

Diagnostic relevance in a minor subset of patients with inflammatory myopathy

Results should be used in conjunction with clinical findings, muscle biopsy, and other relevant laboratory tests for disease evaluation

Negative results do not rule out inflammatory myopathies (IM), necrotizing autoimmune myopathy, or statin-associated myopathy

Related Tests

Nonspecific indicator of muscle inflammation or damage

Monitor therapeutic response

Assess thyroid function

Identify risk in patients with palpable thyroid nodules

Reflex pattern – if the thyroid stimulating hormone (TSH) is outside the reference interval, then free T4 testing will be added

Preferred test for screening and monitoring of thyroid function

Do not use as a standalone test; this nonspecific test has been replaced by more specific markers for muscle or liver damage (eg, creatine kinase [CK], alanine aminotransferase [ALT], and aspartate aminotransferase [AST])

Evaluate liver function

Monitor therapeutic response

Preferred test to detect acute phase inflammation (eg, autoimmune diseases, connective tissue disease, rheumatoid arthritis, infection, or sepsis)

Nonspecific test used to detect inflammation associated with infections, cancers, and autoimmune diseases

Rule out hypercalcemia as etiology of muscle weakness

If elevated, indicator of active disease

Not a standalone test

May be useful in monitoring therapy

Recommended first-line test for the evaluation of polymyositis, inflammatory myopathies, or connective tissue disease associated with muscle weakness

Use in the differential diagnosis of connective tissue disease with or without myopathy

Primarily associated with a diagnosis of mixed connective tissue disease (MCTD), but may be seen with patients with systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and inflammatory myopathies

Order as secondary screen based on results of antinuclear antibodies (ANA) testing

Evaluate for SSc or connective tissue disease associated with overlapping features of SSc and/or myositis

Presence of PM/Scl-100 antibodies is associated with features of SSc and/or myositis and is strongly associated with presence of ANA by indirect fluorescent antibody (IFA) nucleolar pattern

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References

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