Inflammatory Myopathies

Diagnosis

Indications for Testing

  • Symmetrical proximal muscle weakness

Criteria for Diagnosis

  • Bohan and Peter criteria for the diagnosis of polymyositis (PM) and dermatomyositis (DM)

    Bohan and Peter Criteria for the Diagnosis of Polymyositis (PM) and Dermatomyositis (DM)

    • Proximal muscle weakness, usually symmetrical
    • Elevated serum muscle enzymes – creatine kinase (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’s sign or papules, or heliotrope rash

    Definite 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

Laboratory Testing

  • Initial screening tests
    • Creatine kinase (CK) – elevated in most inflammatory myopathies
      • Consider other causes for elevations >100-fold
    • Erythrocyte sedimentation rate/C-reactive protein (ESR/CRP) – elevated during active phases of disease
    • Thyroid stimulating hormone (TSH) – use to evaluate for thyroid disease as etiology of muscle weakness
    • Antinuclear antibodies (ANA) – positive in 50-80% of patients
    • Aldolase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LD), serum myoglobin – variably elevated; highly nonspecific
  • Myositis antibody testing
    • Myositis-specific antibodies
      • Antisynthetase antibodies – predictive of lung involvement; not usually found in inclusion body myositis (IBM) 
        • Anti-Jo-1 (histidyl-tRNA synthetase)
          • Most common antisynthetase antibody
          • More common in polymyositis (PM)
          • Most Jo-1-positive patients have lung involvement (antisynthetase syndrome) and moderate to severe disease
          • Relationship between Jo-1 antibody titer and disease activity reported but not confirmed
        • Anti-PL7 (threonyl-tRNA synthetase) – severe arthritis
        • Anti-PL-12 antibodies (anti-alanyl-tRNA synthetase) – pulmonary hypertension
        • Anti-EJ (glycyl-ts RNA synthetase) – DM
        • Anti-OJ (anti-isoleucyl-tRNA synthetase) – interstitial lung disease
        • Anti-KS (asparaginyl tRNA synthetase) – usually interstitial pneumonitis
        • Anti-HA (tyrosyl tRNA synthetase)
        • Anti-Zo (phenylalanyl tRNA synthetase)
      • Nonsynthetase antibodies
        • Anti-signal recognition particle (anti-SRP)
          • Myocardial involvement frequent
          • Severe, rapidly progressive, often necrotizing myositis with high CK
        • Anti-p155/140
          • May be found in juvenile DM
          • Frequent in cancer – associated with DM
        • Anti-Mi-2
          • Almost exclusively in DM
          • Associated with treatment responsiveness
        • Anti-HMGCR – necrotizing myopathy
        • Anti-MDA5 – amyopathic DM
        • Anti-140
        • Anti-SAE
        • Anti-MJ (NXP-2) – juvenile DM, severe calcinosis
        • Anti-200/100 – recently discovered; necrotizing myopathy
  • Myositis-associated antibodies – usually associated with connective tissue diseases
    • Anti-PM-Scl – scleroderma-polymyositis
    • Anti-U1-RNP/anti-U3-RNP
    • Anti-Ku
    • Anti-pLA
    • Anti-topo
    • Anti-Ro (SSA)
    • Anti-5bKDa
    • Anti-PMS1

Histology

  • Muscle biopsy – gold standard for diagnosis
    • Usually performed on proximal muscles of the leg but not in end-stage muscles
      • MRI may be helpful in choosing muscle
    • Open biopsy preferred – larger sample

Other Testing

  • 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 inflammatory myopathies
    • Amyopathic DM may have subtle myopathy on EMG

Imaging Studies

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

Differential Diagnosis

Screening

  • All adult patients with dermatomyositis (DM) should be evaluated for malignancy due to increased risk of malignancy
    • Breast/pelvic exam in females; testicular exam in males
    • Tests to consider
    • American Academy of Dermatology recommends reevaluation for malignancy every 6-12 months for first 2 years following diagnosis

Monitoring

  • Creatine kinase myoglobin, and lactate dehydrogenase (LD) levels are most useful in monitoring therapeutic response

Clinical Background

Inflammatory myopathies 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).

Epidemiology

  • Adults
    • Incidence – 4-10/1,000,000
    • Age
      • DM – bimodal peaks
        • Childhood
        • 50-70 years
      • PM – age of onset typically >20 years
        • Rare in childhood
      • IBM – >45 years
    • 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
  • Children
    • Incidence – 2-3/1,000,000 (rare)
    • Age
      • DM – more common in children; mean onset is 7 years (25% present at <4 years)
      • PM – rare in children
      • Juvenile myositis (JM) – children 2-18 years
    • Sex – M<F, 1:2.3

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

Clinical Presentation

  • General features
    • Musculoskeletal – progressive muscle weakness (usually symmetrical and proximal)
      • Pharyngeal and neck flexion muscles frequently involved, leading to dysphagia and/or myalgia
    • 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
  • DM
    • Characteristic photosensitive rash 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
        • More common in children
        • Subcutaneous nodules, periungual infarcts, digital ulcerations
    • Antisynthetase syndrome
      • Found almost exclusively in middle-aged women
      • 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
      • Presence of antinuclear antibodies known as antisynthetases
    • Cancer-associated myositis
      • Most commonly associated with DM
      • Increased risk of malignancy (20-25%) in the following types (most risk in first 2-3 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
    • Usually subacute presentation
    • May be associated with other autoimmune diseases
    • Diagnosis of exclusion – rule out the following
      • Rash
      • Neuromuscular disease
      • Endocrinopathy
      • Muscular dystrophy
      • Known biochemical muscle disorder
      • Drug-induced myopathy
  • IBM
    • Small muscles in hand frequently involved
      • Distal weakness is more common – deep finger flexors common
        • Proximal muscles less frequently involved
      • Quadriceps involvement common
      • Asymmetric distribution common
    • Extramuscular disease less common; dysphagia is the exception (~60% of patients)
    • May be misdiagnosed as PM
    • Associated with other autoimmune diseases (~20% of the time)
  • JM
    • Skin rash – usually first symptom (no skin rash found in PM)
    • Dermatomyositis – most common symptom; polymyositis extremely rare
    • Other symptoms are similar to adult DM & PM
    • Cutaneous calcinosis more common in juvenile DM when compared to adults

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
Creatine Kinase, Total, Serum or Plasma 0020010
Method: Quantitative Enzymatic

Nonspecific test to evaluate for presence of muscle disease

Monitor therapeutic response

   
Anti-Nuclear Antibodies (ANA), IgG by ELISA with Reflex to ANA, IgG by IFA 0050080
Method: Qualitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody

Aids in evaluation of connective tissue disease

Reflex pattern – if ANA are detected by ELISA, then ANA by IFA titer is added

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

ANA ELISA assays have been reported to have lower sensitivities for antibodies associated with nucleolar and speckled ANA-IFA patterns

Recommend cutaneous direct immunofluorescence testing of active edge of new lesion (lesional biopsy) if dermatologic manifestations are present

Myositis-Specific Antibody Panel 2010862
Method: Qualitative Immunoprecipitation/Semi-Quantitative Multiplex Bead Assay

Aid in differential diagnosis of inflammatory myopathies in conjunction with muscle biopsy and clinical presentation

Components include Jo-1 antibody, IgG; myositis-specific antibody, Mi-2; myositis-specific antibody, PL-7; myositis-specific antibody, PL-12; myositis-specific antibody, P155/140; myositis-specific antibody, EJ; myositis-specific antibody, SRP; myositis-specific antibody, OJ

Results are not diagnostic; clinical correlation is recommended

 
Myositis Antibody Comprehensive Panel 2010851
Method: Qualitative Immunoprecipitation/Semi-Quantitative Multiplex Bead Assay

Most useful if general suspicion for inflammatory myopathy exists, including overlap syndromes

Components include PM/Scl-100 antibody, IgG; SSA (Ro) (ENA) antibody, IgG; RNP (U1) (ribonucleic protein) (ENA) antibody, IgG; Jo-1 antibody, IgG; myositis-specific antibody, Mi-2; myositis-specific antibody, PL-7; myositis-specific antibody, PL-12; myositis-specific antibody, P155/140; myositis-specific antibody, EJ; myositis-specific antibody, SRP; myositis-specific antibody, OJ

Results are not diagnostic; clinical correlation is recommended

 
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Thyroid Stimulating Hormone with reflex to Free Thyroxine 2006108
Method: Quantitative Electrochemiluminescent Immunoassay

Evaluate for thyroid disease

Thyroid Stimulating Hormone 0070145
Method: Quantitative Chemiluminescent Immunoassay

Evaluate for thyroid disease

Aldolase, Serum 0020012
Method: Quantitative Enzymatic

Nonspecific testing for myopathy

Alanine Aminotransferase, Serum or Plasma 0020008
Method: Quantitative Enzymatic

Evaluate liver function

Aspartate Aminotransferase, Serum or Plasma 0020007
Method: Quantitative Enzymatic

Evaluate liver function

Lactate Dehydrogenase, Serum or Plasma 0020006
Method: Quantitative Enzymatic

Monitor therapeutic response

Sedimentation Rate, Westergren (ESR) 0040325
Method: Visual Identification

Evaluate for inflammation

C-Reactive Protein 0050180
Method: Quantitative Immunoturbidimetry

Evaluate for inflammation

Calcium, Serum or Plasma 0020027
Method: Quantitative Spectrophotometry

Rule out hypercalcemia as etiology of muscle weakness

If elevated, indicator of active disease

Myoglobin, Serum 0020224
Method: Quantitative Electrochemiluminescent Immunoassay

May be useful in monitoring therapy

Jo-1 Antibody, IgG 0099592
Method: Semi-Quantitative Multiplex Bead Assay

Screen for inflammatory myopathies

RNP (U1) (Ribonucleic Protein) (ENA) Antibody, IgG 0050470
Method: Semi-Quantitative Multiplex Bead Assay
Signal Recognition Particle (SRP) Antibody 2002098
Method: Immunoprecipitation
PM/Scl-100 Antibody, IgG, by Immunoblot with Reflex to ANA IFA 2003040
Method: Semi-Quantitative Immunoblot/Semi-Quantitative Indirect Fluorescent Antibody