Inflammatory Myopathies

Diagnosis

Indications for Testing

  • Symmetrical proximal muscle weakness

Criteria for Diagnosis

  • Bohan and Peter criteria for diagnosis of PM and DM

    Bohan and Peter Criteria for Diagnosis of PM and DM

    • 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’s sign or papules, or heliotrope rash

    Definite diagnosis requires four criteria with rash for DM and without rash for PM

    Probable diagnosis requires three criteria with rash for DM and without rash for PM

Laboratory Testing

  • Initial screening tests
    • Creatine kinase (CK) – elevated, but consider other causes for elevations >100-fold
    • ESR or CRP – elevated during active phases of disease
    • Calcium – should be normal
    • TSH – rule out thyroid disease
  • Antibody testing
    • ANA – positive in 50-80% of patients
    • Anti-histidyl-tRNA synthetase (Jo-1) testing
      • Found in 18-36% of patients satisfying myositis criteria – not useful in confirming diagnosis; more common in PM
      • Nearly all 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
      • Jo-1 antibodies rarely found in any other disease states
  • Overlap syndromes
    • Other myositis-specific antibodies
      • Anti-synthetase antibodies – predictive of lung involvement, not usually found in IBM 
        • In addition to Jo-1, less common markers include the following
          • Anti-PL7 (threonyl-tRNA synthetase)
          • Anti-PL-12 antibodies (anti-alanyl-tRNA synthetase)
          • Anti-EJ (glycyl-ts RNA)
          • Anti-OJ (anti-isoleucyl-tRNA synthetase)
          • Anti-KS (asparaginyl tRNA synthetase)
          • Anti-HA (tyrosyl tRNA synthetase)
          • Anti-Zo (phenylalanyl tRNA synthetase)
      • Non-synthetase antibodies
        • Anti-signal recognition particle (anti-SRP) – myocardial involvement frequent; severe, rapidly progressive myositis with high CK
        • Anti-p155/140 – may be found in juvenile DM
          • Other myositis-associated autoantibodies rare in juvenile disease
        • Anti-HMGCR
        • Anti-MDA5
        • Anti-Mi-2
        • Anti-140
        • Anti-SA5
        • Anti-MJ (NXP-2)
    • Myositis-associated antibodies
      • Anti-PM-Scl – scleroderma-polymyositis
      • Anti-U1 RNP/anti-U3 RNP
      • Anti-Ku
      • Anti-pLA
      • Anti-topo
      • Anti-RO (SSA)
      • Anti-5bKDa
      • Anti-hPMS1
  • Nonspecific tests
    • Aldolase, AST, ALT, LD, serum myoglobin – variably elevated

Histology

  • Muscle biopsy is 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
  • DM 
    • Demonstrate perivascular and perimysial inflammation (B-cells, macrophages and CD4+ cells)
      • T-cells usually absent
    • Distinct muscle pathology
  • PM
    • Demonstrates CD8+ T-cell invasion of non-necrotic muscle; uniform expression of MHC-1 at surface of muscle
  • IBM 
    • Rimmed vacuoles with amyloid and filamentous masses; cytochrome oxidase negative fibers
    • Uniform expression of MHC-1 at surface of muscle
    • Immunohistochemistry – SM1-31 antibody best detected antibody but not specific for IBM

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 only 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

Differential Diagnosis

Screening

  • All adult patients with DM should be evaluated for 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

  • CK myoglobin, and 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 – >50 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 – rarely present; myoglobinuria, glomerulonephritis
    • Dermatologic – Raynaud phenomenon; common 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
    • Cancer-associated myositis
    • Vasculitic skin changes
      • More common in children
      • Subcutaneous nodules, periungual infarcts, digital ulcerations
    • Amyopathic DM is a subgroup
      • Characteristic cutaneous findings of DM >6 months without muscle involvement
      • May progress to DM
      • No evidence of muscle disease
      • Some risk for lung disease, malignancy
      • May have fatigue – 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
    • Associated with other autoimmune diseases 20% of the time
    • Small muscles in hand frequently involved
      • May involve proximal muscles, but distal weakness is more common
      • Quadriceps also heavily involved
      • Asymmetric distribution common
    • Extramuscular disease less common; dysphagia is the exception
    • May be misdiagnosed as PM
  • Antisynthetase syndrome – association of PM and DM; found almost exclusively in middle-aged women and characterized by the following
    • 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 anti-synthetases
  • JM
    • Skin rash – usually first sign (no skin symptoms in PM)
    • Dermatomyositis form – most common symptom; polymyositis extremely rare
    • Other symptoms are similar to adult DM & PM
    • Cutaneous calcinosis more common in 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

Initial testing

Evaluate for presence of muscle disease

Monitor therapeutic response

   
Lactate Dehydrogenase, Serum or Plasma 0020006
Method: Quantitative Enzymatic
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

Screening test for inflammatory myopathies to rule out connective tissue disease

Pattern may be helpful in distinguishing from other connective tissue diseases

All ELISA results reported as "Detected" are further tested by IFA

ANA ELISA screen is designed to detect antibodies against dsDNA, histone, SS-A (Ro), SS-B (La), Smith, snRNP/Sm, Scl

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

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

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

Screen for inflammatory myopathies

   
Myositis-Specific Panel (15 Antibodies) 2005176
Method: Qualitative Enzyme Immunoassay/Immunoprecipitation

Assist in diagnosis of polymyositis and dermatomyositis

Profile includes anti-PM-Scl, anti-Ku, anti-U1RNP, anti-U2RNP, anti-SRP, anti-Jo-1, anti-PL-7, anti-PL-12, anti-EJ, anti-OJ, SSA-52 kd, P140, P155/140, U3 RNP Fibrillarin

   
Thyroid Stimulating Hormone with reflex to Free Thyroxine 2006108
Method: Quantitative Electrochemiluminescent Immunoassay
Rule out thyroid disease as etiology of muscle weakness    
Sedimentation Rate, Westergren (ESR) 0040325
Method: Visual Identification

Nonspecific test for inflammation

   
C-Reactive Protein 0050180
Method: Quantitative Immunoturbidimetry
Nonspecific test 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

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Thyroid Stimulating Hormone 0070145
Method: Quantitative Chemiluminescent Immunoassay
Aldolase, Serum 0020012
Method: Quantitative Enzymatic

Non-specific testing

Alanine Aminotransferase, Serum or Plasma 0020008
Method: Quantitative Enzymatic

Non-specific testing

Aspartate Aminotransferase, Serum or Plasma 0020007
Method: Quantitative Enzymatic

Non-specific testing

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
Urinalysis, Complete 0020350
Method: Reflectance Spectrophotometry/Microscopy
Cancer Antigen 125 0080462
Method: Quantitative Electrochemiluminescent Immunoassay