Inflammatory Myopathies

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

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

Weakness alone
- Endocrine myopathies
  - Thyroid disease (hyper- and hypo-)
  - Cushing syndrome
- Drug-related myopathies
  - Statins
  - Steroids
  - Diuretics
  - Colchicine
  - Hydroxychloroquine
  - Alcohol
  - Growth hormone
- Amyloidosis
- Sarcoidosis
- Neuropathies
- Polymyalgia rheumatica
- Metabolic myopathies
  - Lipid storage disorders
  - Mitochondrial diseases
- Neuromuscular transmission disorders
  - Myasthenia gravis
- Spinal stenosis
- Paraneoplastic syndromes
  - Eaton-Lambert syndrome
- Muscular dystrophies
  - Limb-girdle dystrophy
  - Facioscapulohumeral dystrophy
  - Duchenne muscular dystrophy
- Motor neuron disorders
  - Spinal muscular atrophy
  - Amyotrophic lateral sclerosis – Lou Gehrig disease
- Vasculitis/polyarteritis nodosa
Weakness (with or without rash)
- Viral
  - Enterovirus (eg, polio)
  - Influenza
  - Parvovirus B19
  - Human T-lymphotropic virus type 1
  - Hepatitis B virus – HBV
- Bacterial/parasitic
  - Toxoplasmosis
  - Trichinella spiralis (trichinosis)
  - Borrelia burgdorferi – Lyme disease
- Other connective tissue diseases
  - Systemic lupus erythematosus
  - Systemic sclerosis – scleroderma
  - Mixed connective tissue disease
- Other inflammatory disease
  - Inflammatory bowel disease
  - Celiac disease
Rash without weakness
- Psoriasis
- Eczema

Screening

All adult patients with DM should be evaluated for malignancy
- Breast/pelvic exam in females; testicular exam in males
- Tests to consider
  - Urinalysis (utero/renal cancer)
  - CA-125 (ovarian cancer)
  - Stool for occult blood (colorectal cancer)
  - Chest x-ray (lung cancer)
  - Mammography (breast cancer)
  - CT of abdomen and pelvis
- 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

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
  - Most commonly associated with DM
  - Increased risk of malignancy (20-25%) in the following types (most risk in first 2-3 years after diagnosis)
- 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

Tests

Tests generally appear in the order most useful for common clinical situations

Test name: Creatine Kinase, Total, Serum or Plasma

ARUP #: 0020010

Methodology: Quantitative Enzymatic

Use:

Initial testing

Evaluate for presence of muscle disease

Monitor therapeutic response

Test name: Lactate Dehydrogenase, Serum or Plasma

ARUP #: 0020006

Methodology: Quantitative Enzymatic

Use: Monitor therapeutic response

Test name: Anti-Nuclear Antibodies (ANA), IgG by ELISA with Reflex to ANA, IgG by IFA

ARUP #: 0050080

Methodology: Qualitative Enzyme-Linked Immunosorbent Assay (ELISA)/Semi-Quantitative Indirect Fluorescent Antibody (IFA)

Use:

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

Limitations:

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

Follow-up:

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

Test name: Jo-1 Antibody, IgG

ARUP #: 0099592

Methodology: Semi-Quantitative Multi-Analyte Fluorescent Detection

Use:

Screen for inflammatory myopathies

Test name: Myositis-Specific Panel (15 Antibodies)

ARUP #: 2005176

Methodology: Qualitative Enzyme Immunoassay/Immunoprecipitation

Use:

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

Test name: Thyroid Stimulating Hormone

ARUP #: 0070145

Methodology: Quantitative Electrochemiluminescent Immunoassay

Use: Rule out thyroid disease as etiology of muscle weakness

Test name: Sedimentation Rate, Westergren (ESR)

ARUP #: 0040325

Methodology: Westergren

Use:

Nonspecific test for inflammation

Test name: C-Reactive Protein

ARUP #: 0050180

Methodology: Quantitative Immunoturbidimetric

Use: Nonspecific test for inflammation

Test name: Calcium, Serum or Plasma

ARUP #: 0020027

Methodology: Quantitative Spectrophotometry

Use:

Rule out hypercalcemia as etiology of muscle weakness

If elevated, indicator of active disease

Test name: Myoglobin, Serum

ARUP #: 0020224

Methodology: Quantitative Electrochemiluminescent Immunoassay

Use:

May be useful in monitoring therapy

Additional Tests Available

Test name: Aldolase, Serum

ARUP #: 0020012

Methodology: Quantitative Enzymatic

Comments:

Non-specific testing

Test name: Alanine Aminotransferase, Serum or Plasma

ARUP #: 0020008

Methodology: Quantitative Enzymatic

Comments:

Non-specific testing

Test name: Aspartate Aminotransferase, Serum or Plasma

ARUP #: 0020007

Methodology: Quantitative Enzymatic

Comments:

Non-specific testing

Test name: RNP (U1) (Ribonucleic Protein) (ENA) Antibody, IgG

ARUP #: 0050470

Methodology: Semi-Quantitative Multi-Analyte Fluorescent Detection

Comments:

Test name: Signal Recognition Particle (SRP) Antibody

ARUP #: 2002098

Methodology: Immunoprecipitation

Comments:

Test name: PM/Scl-100 Antibody, IgG, by Immunoblot with Reflex to ANA IFA

ARUP #: 2003040

Methodology: Semi-Quantitative Immunoblot/Semi-Quantitative Immunofluorescence Antibody

Comments:

Test name: Urinalysis, Complete

ARUP #: 0020350

Methodology: Reflective Photometry/Microscopic by Yellow IRIS

Comments:

Test name: Cancer Antigen 125

ARUP #: 0080462

Methodology: Quantitative Electrochemiluminescent Immunoassay

Comments:

References

General

ARUP Institute for Clinical and Experimental Pathology®

Jaskowski TD, Schroder C, Martins TB, Mouritsen L, Hill HR. Comparison of three commercially available enzyme immunoassays for the screening of autoantibodies to extractable nuclear antigens. J Clin Lab Anal. 1995; 9 (3) :166-172.PubMed

Medical Reviewers

Tebo, Anne E., PhD. Assistant Medical Director, Immunology at ARUP Laboratories; Assistant Professor of Pathology (Clinical), University of Utah

Comprehensive Review: November 2011
Last Update: November 2011