Inflammatory Myopathy

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Inflammatory and Immune Myopathies: Acquired

GENERAL FEATURES

Signs & Lab findings
Antibodies
CK: Serum
Electrodiagnostic
HLA types
Neoplasm associations
Other systemic
Pain
Pathology
Skin lesions
Treatment
Weakness

Pathology
Anti-Decorin (BJ) myopathy
Calcinosis: X-rays
Chondroitin sulfate C deficient
Dermatomyositis
Fasciitis
Focal myositis
Inclusion Body Myositis
Inflammation: Muscle
Inflammation: Cell patterns
Myasthenia gravis
Necrosis: Muscle fibers
Neonatal perifascicular
Nodular granulomatous myositis
Signal recognition particle
Vasculitis: Small & Large vessel

SPECIFIC IMMUNE OR INFLAMMATORY MYOPATHIES
Immune myopathies (Polymyositis +...) General aspects Clinical Laboratory Subtypes & Comparative features Brachio-Cervical Inflammatory Myopathy Collagen vascular disease Complement: C2 deficiency Drug-induced Graft-vs-host disease Idiopathic t-RNA synthetase antibodies Jo-1 OJ Malignancy-associated MAS antibody PM + Mitochondrial disorder (PM/COX-) Sarcoidosis Signal recognition particle antibodies Systemic disorders & Myositis U1-snRNP antibodies Dermatomyositis Childhood Adult: Mi-2 antibody - Adult: Malignancy-associated Adult: EJ antibody + Adult: PM-Scl antibody + Adult: Amyopathic Mi-2 antibody + Inclusion body myositis Animal Models Experimental autoimmune myositis MHC class I upregulation		Other "Myopathies" Anti-Decorin (BJ) myopathy Benign acute childhood myositis Celiac disease Chondroitin sulfate C deficient Eosinophilia myalgia syndrome Fasciitis Focal myositis Quadriceps; Other TRAPS Granulomatous Hemophagocytic lymphohistiocytosis Hereditary IM + abundant Macrophages Infection Lyme myositis Macrophagic myofasciitis Masticator myopathy Multinodular polymyositis Myasthenia gravis Brachiocervial inflammatory myopathies Myositis Lymphorrhages Necrotizing with Encephalopathy Paraneoplastic with Pipestem capillaries SRP antibodies Neonatal perifascicular myopathy Orbital Perimyositis Polymyalgia Rheumatica Pyomyositis Sarcocystis Sarcoidosis Trichinosis

From: M Al-Lozi

Skin lesions

Erythema

Gottron's papules

Nailfold lesions

From: Chinju, South Korea

Immune or Inflammatory Myopathies

General Features^³⁴

Antibodies
CK: Serum
Electrodiagnostic
Neoplasm associations
Other systemic
Pain
Pathology
Prognosis
Skin lesions
Treatment
Weakness

Skin lesions

Disease associations
- Dermatomyositis, Childhood type
- Skin disorders with other immune myopathy syndromes
Heliotrope rash
- Red-purple edematous ± erythema
- Distribution
  - Face & Upper eyelids
  - Exensor surfaces of joints
  - Symmetric
  - Sun exposed regiona
- External links
  - Facial rash
  - Face & Upper eyelids
Gottron's sign
- Red-purple keratotic, atrophic erythema, or macules
- On extensor surfaces of joints: Especially MCP, PIP & Distal IP
- Disease association: Dermatomyositis
- External link: Gottron's sign
Erythema
- Red-purple slightly raised
- On extensor surfaces of hands, elbows or knees
Mechanic's hands
- Raised scaly dry
- On extensor surfaces of finger joints
- Disease association: Anti-Jo1 & Anti-t-rna synthetase antibody syndromes
Nailfold lesions
- Petechiae & Erythema
- Disease association: Dermatomyositis - Anti-Mi-2 antibody positive
Other features
- Rash more commonly pruritic than rash with lupus erythematosis
- Skin lesions often photoaggravated
- Skin lesions may precede myopathy & continue even when improved strength

Weakness

Proximal: Most Dermatomyositis & Polymyositis
Distal: Inclusion body myositis
Brachio-Cervical: BCIM
Asymmetric: Inclusion body myositis
Quadriceps: Inclusion body myositis; Polymyositis with cytochrome oxidase negative muscle fibers
Extraocular: Orbital myositis
Swallowing: Inclusion body myositis; Granulomatous myositis; Scleroderma-associated
Episodic: Necrotizing myopathy with pipestem capillaries
Acute: Infectious; Anti-signal recognition particle antibodies

Pain

Muscle
- Pain on movement, palpation or spontaneous
- Polymyositis or dermatomyositis with collagen vascular disease
- Rhabdomyolysis: Anti-MAS syndrome
- Rule out: Polymyalgia rheumatica
Joint
- Nondestructive arthritis or arthralgias
- Anti-Jo1 & Anti-t-rna synthetase antibody syndromes

Other systemic features

Immune disorders common: BCIM
Lung
- Ventilatory failure: Due to muscle weakness
- Interstitial lung disease³²
  - Frequency in PM/DM: 23%
  - Timing: Relation to myositis
    - Before myopathy 20%
    - With myopathy 41%
    - After myopathy 39%
  - Clinical associations
    - Anti-synthetase syndrome
    - Neoplasm: Unusual
    - Treatment response: More often refractory to corticosteroids
    - Poor prognosis: High morbidity & mortality (14%) associations
      - Hamman-Rich–like pattern: Acute lung disease
      - Initial diffusing capacity of CO less than 45%
      - Neutrophil alveolitis
      - Interstitial pneumonia, usual
  - Antibodies
    - Anti-Jo-1 & Anti-t-RNA synthetase antibody syndromes: 31%
      - Lower frequency: Associated skin changes without myositis
    - Also occurs without myositis-specific antibodies
  - Other laboratory: Higher values of
    - Erythrocyte sedimentation rate
    - C-reactive protein
  - Evaluation at onset & folow-up
    - Pulmonary function tests
    - High resolution chest CT
  - Course
    - Rapidly progressive group: High mortality over months; Poor treatment response
    - Slowly progressive: Long survival
- Aspiration pneumonia
Cardiac: May be associated with poor prognosis
- Myocarditis (PM)
- Small vessel disease (DM)
- Abnormal vasoconstriction (DM): Prinzmetal's angina ? associated with Raynaud's
GI
- Esophageal
  - Frequency: 37%
  - Skeletal or smooth muscle involvement
  - Treatment: IVIg may be effective in refractory cases
- Bowel ischemia: Childhood DM
Arthralgia/Arthritis: 40%
Inflammatory signs
- Fever; High C-reactive protein; High sedimentation rate
- Polymyositis or dermatomyositis with collagen vascular disease
Calcinosis
- Location: Muscle & Subcutaneous
- Dermatomyositis: Childhood - Late
- External links
  - Dermis, images
  - Pediatric Rheumatology, Review

Prognosis worse

Cardiac involvenment
Acute onset
Fever
Arthritis
Hypergammaglobulinemia
Lung fibrosis: Interstitial lung disease

Serum Creatine Kinase (CK)

Very high
Normal or mildly elevated
- Inclusion body myositis; Polymyositis with cytochrome oxidase negative muscle fibers
- Dermatomyositis: Adults with selective fascial pathology; Some childhood DM

Immune myopathies: HLA associations⁴⁶

Adult onset myositis: Associations with Class II haplotype
- Interstitial lung disease: HLA-DRB1*03-DQA1*05-DQB1*02 haplotype
- PM versus controls
  - Increased DQA1*05 > HLA-DRB1*03 & DQB1*02
  - Reduced HLA-DRB1*07
- DM vs controls: Increased DQB1*02 > HLA-DRB1*03 and DQA1*05
Interstitial lung disease
- Increased HLA-DRB1*03-DQA1*05-DQB1*02 haplotype
Jo-1 myositis
- HLA-DRw52; DR3 (90%); DQ2 (80%)
- Anti-synthetase & Anti-PM-Scl
  - General: DRB1*0301; DQA1*0501; & DQB1*02
Anti-SRP myopathy
- HLA DRw52; DR5 (57%)
- Increased vs controls: DRB1*02-DQA1*01-DQB1*06 & DRB1*11-DQA1*05-DQB1*03
PM-Scl
- DRB1*03-DQA1*05-DQB1*02
U1-RNP

DRB1*04-DQA1*03-DQB1*03

Anti-MAS myopathy
- DRw53; DR4
Anti-PL-12
- HLA: DR2 (45%); DR8 (27%); DQ1 (70%)
D-penicillamine
- HLA type DR4
GVH myositis
- No association with B8/DR3
Familial inflammatory myopathy
- Homozygosity at HLA-DQA1 locus
Dermatomyositis, childhood
- Increased frequency: B8, DR3 & A1 + B8 + DR3
- Class II HLA: DQα1*0501 antigen (88%)
- DM: DMA*0103 & DMB*0102
Dermatomyositis: Mi-2 antibody positive: Associations vary with ethnicity²⁷
- DR7 (75%), Tryptophan at position 9 of DRβ chain; DRB1*0701
- Caucasian (Mi-2): DRB1*07; DQA1*0201; DQB1*02
- Mestizo adults (Mi-2): DRB1*04; DQA1*03
Inclusion body myositis
- HLA types: DRβ1*0301, DRβ3*0101 (or DRβ3*0202) & DQβ1*0201
Sarcoidosis: Class II HLA allelic variation³⁹
- DRB1*1101: Associated with sarccoid in blacks & whites (2x to 3x)
- DPB1*0101
- DRB1*1501: Sarcoidosis in whites
- DRB1*0401: Eye involvement in blacks and whites
- DRB3: Bone marrow in blacks
- DPB1*0101: Hypercalcemia in whites
Macrophagic myofasciitis
- HLA-DRB1*01

Inflammatory myopathies: Association with neoplasms¹⁵

Frequency may depend on ethnic background
Risk of malignant disease
- Highest: Near (3 years) time of myositis diagnosis
- Lower but possibly still present: > 3 years after diagnosis
- Mainly in adults
  - Higher with increasing age but risk also increased < 45 years
  - Male = Female
- Stronger association with dermatomyositis than polymyositis
Screening: Especially appropriate for specific associated cancers at time of diagnosis and at follow up
Dermatomyositis (White, Northern Europeans or Australians)⁵⁰
- Risk
  - Overall 32% (3x to 6x increased)
  - 58% of neoplasms developed after DM diagnosis
- Specific associations
  - Neoplasm types: Ovarian (10.5x) > Lung (5.9x) > Pancreatic (3.8x) >
    Non Hodgkin lymphoma (3.6x) > Stomach (3.5x) > Colorectal (2.5x)
  - Cell types: Squamous (Especially males); Adeno; Hematological
  - Myositis-specific/associated antibodies: Higher risk for neoplasm when absent
  - p155/140 antibody
    - Associated with dermatomyositis (29%)
    - Higher risk for neoplasm when present
    - Frequency in neoplasm-associated dermatomyositis: 50%
    - Frequency of neoplasm-associated dermatomyositis when present: 44%
  - Mortality: Increased; Due to neoplasm
Dermatomyositis (Asian; Tunisia)
- Neoplasm type: Nasopharyngeal
Polymyositis (White, Northern Europeans)
- Risk
  - Overall 15% (1.4x to 2x increased)
  - 69% of neoplasms developed after DM diagnosis
- Specific associations
  - Organ: Non Hodgkin lymphoma (3.7x) > Lung (2.8x) > Bladder (2.4x)
  - Cell type: Hematological
Other malignancy associated myopathies
- Necrotic myopathy
- Dermatomyositis with cancer
- Other
- ? Inclusion body myositis

Serum Antibodies

Electrodiagnostic changes

Short duration polyphasic motor unit potentials
Spontaneous activity: Fibrillations; Positive sharp waves
Frequency of typical findings
- Most: Dermatomyositis & Polymyositis
- Exception: Long-standing, slowly progressive syndromes
  - May have long duration potentials, or lack spontaneous activity

MRI³³

Technical: Signal sequence used is fat suppressed T2 weighted
Results
- Patchy involvement of muscle ("edema")
- Most commonly positive in weak muscles
- PM vs. DM: Similar changes in muscle; DM may also have "edema" in soft tissues

Pathology

Pathological classification of
immune & inflammatory myopathies

Microvasculopathies
Dermatomyositis, childhood type
SRP myopathy
Myopathies with microvasculopathy
Myopathy with pipestem capillaries
Perimysial pathology
Myopathies + Jo-1 or t-RNA synthetase Ab
Myopathies + Interstitial lung disease
Dermatomyositis-like syndromes, adult
Fasciitis
Perimyositis
Focal mononuclear inflammation
Aggregates, Inclusions or Mitochondrial Δ
Polymyositis with mitochondrial disorder
Inclusion body myositis
B-cell inflammation
Brachio-Cervical inflammatory myopathy
Dermatomyositis, childhood type
Necrotic
Malignancy-associated

Inflammation
Muscle fiber pathology
Capillaries
Mitochondrial
Connective tissue
Matrix metalloproteinase
MHC-I

Foci of mononuclear cell inflammation
- Prominent
  - Brachiocervical inflammatory myopathy: Perivascular, Perimysial & Endomysial
  - Polymyositis with mitochondrial disorder
  - Inclusion body myositis
  - Dermatomyositis, childhood: Some patients; Perivascular
- B-cells (CD20 positive):
  - Most commonly occur in
    - Dermatomyositis
    - Brachio-Cervical Inflammatory Myopathy
  - Rare or Absent in
    - Inclusion body myositis
- Selective or prominent localization in endomysium
  - Polymyositis with mitochondrial disorder
  - Inclusion body myositis
- Associated adhesion molecules on inflammatory cells³¹
  - Early inflammation: SLe^x/E-selectin
  - Intermediate inflammation: LFA-1/ICAM-1; Low in polymyositis
  - Late inflammation: VLA-4/VCAM-1; Common in "polymyositis"
- Minor or None
  - Acute polymyositis: Inflammation mainly associated with necrotic muscle fibers
  - Some childhood dermatomyositis
  - Paraneoplastic necrotic myopathy
  - Anti-Decorin (BJ) myopathy
  - Paraneoplastic
  - SRP syndrome
Muscle fiber pathology
- Necrosis: Abundant
  - Paraneoplastic: Regional necrosis
  - Jo-1 associated myositis: Scattered necrotic fibers
  - SRP syndrome: Scattered necrotic fibers
  - Pipestem capillaries
- Focal invasion by CD8 cells & macrophages
- Size
  - Varied: Usually atrophic & normal
  - Hypertrophy: Rare, except in IBM
- Regenerating & Immature fibers: Common in most subtypes of immune myopathies
- Perifascicular muscle fiber pathology: Morphologic patterns
  - Atrophy: Dermatomyositis; Focal myositis
  - Myopathic changes (degeneration & regeneration): Jo-1 associated myositis
  - Little myopathic change: Fasciitis; Perimyositis
- Mitochondrial pathology
  - Scattered COX- & SDH + fibers: Inclusion body myositis; Polymyositis with COX- muscle fibers
  - Perifascicular muscle fibers with reduced COX staining: Dermatomyositis, childhood type
Capillary pathology
- Dermatomyositis, childhood type: Reduced in number in perifascicular regions; Enlarged; C_5b-9 deposition
- SRP myopathy syndrome: Enlarged; C_5b-9 deposition
- Pipestem capillaries: Enlarged; Thickened walls
Connective tissue
- Endomysium
  - Usual: Mild, patchy increase in endomysial connective tissue
  - Markedly & rapidly increased: SRP myopathy
- Perimysium
  - Patterns of pathology
    - Fragmentation
    - Widening
  - Prominently abnormal in
Matrix metalloproteinase up regulation¹⁶
- MMP-1 (Interstitial collagenase)
  - Location: Around muscle fiber sarcolemma; Fibroblasts
  - Disorders: Espcially DM & PM
- MMP-2 (Gelatinase A)
  - Myositis: Non-necrotic & MHC class-I-expressing muscle fibers; Inclusions in IBM
  - Myositis & other disorders: Endomysial vessels; Regenerating muscle fibers
- MMP-9 (Gelatinase B)
  - T-lymphocytes (Cytotoxic)
  - Myositis & other disorders: Endomysial vessels; Regenerating muscle fibers
Major histocompatibility complex class I (MHC-I)⁴⁵
- Normal muscle
  - Endothelial capillaries: Strongly expressed
  - Muscle fibers: Absent
- Regenerating muscle fibers: MHC-I commonly expressed
- Immune myopathies
  - Muscle fibers
    - Expressed on surface & variably in sarcoplasm
    - Commonly present on muscle fibers with normal morphology
    - May occur in absence of inflammation
    - Subcellular: May accumulate in endoplasmic reticulum
      - Aberrantly folded proteins extracted from ER into cytosol: Derlin-1 plays role
      - Leads to degradation by 26S proteasomes (ERAD) in cytosol
    - Dermatomyositis: May be prominent selectively on perifascicular muscle fibers
    - Inclusion body myositis: Common in regions of focal invasion of muscle fibers
  - Inflammatory cells: Strongly expressed
- MHC class I protein composition: Trimolecular complex
  - Transmembrane heavy-chain glycoprotein (H)
  - β2-microglobulin: Non-covalently associated soluble protein
  - Short peptide: 8–10 AA derived from endogenous proteins
- MHC class I protein superfamily
  - Classic: Present intracellular antigens to cytotoxic CD8⁺ T-lymphocytes
    - Human: HLA-A, HLA-B & HLA-C
    - Mouse: H-2K, H-2D & H-2L
  - Nonclassic: Functions distinct from antigen presentation
    - Human: HLA-E, HLA-F & HLA-G
    - Mouse Qa1, TL
    - MHC class I related chain

Treatment

Corticosteroids
- Dosage regimens
  - Prednisone: Oral; Daily or qod; Initial dose 60 to 100 mg per day
  - Solumedrol: IV; Initial dose for adults 1 gm qd x 5 days; Follow up 1 gm q week
- Features predicting Steroid response of immune myopathy
- Features predicting Steroid resistance of immune myopathy
  - Clinical
    - Pattern of weakness
      - Focal
      - Asymmetric
    - Time course: Very chronic or acute
    - Family history
  - Laboratory
    - Serum CK: Normal or Low
      - Exceptions: Dermatomyositis; BCIM
    - Antibodies: Signal recognition particle (Chronic, Untreated)
  - Pathology
    - Focal invasion of muscle fibers by inflammatory cells
    - Mononuclear inflammation mainly in endomysoum
    - Vacuoles or aggregates in muscle fibers
    - No alkaline phosphatase reactivity in vessels or perimysium
    - Mitochondrial changes in muscle fibers
Human immune globulin (IVIg): Most useful for
- Childhood dermatomyositis
- Esophageal dysfunction
Azathioprine
Methotrexate
Cyclophosphamide
Rituximab: For microvasculopathies

IMMUNE MYOPATHIES ("Polymyositis" + Other syndromes)

Subtypes
Clinical features
Laboratory
Treatment

IMMUNE MYOPATHIES: Clinical features

Muscle weakness
- Proximal > Distal
- Symmetric
- Selective regions of weakness: Dysphagia; Posterior neck; Quadriceps
Onset age: Usually > 20 years
Progression: Months
Pain
- 30%; Especially with associated connective tissue disease
- Rule out: Polymyalgia; Arthritis; Fasciitis; Rhabdomyolysis
Associated disorders
- Cardiac: Arhythmias; Inflammatory cardiomyopathy
- Pulmonary: Respiratory muscle weakess; Interstitial lung disease
- Esophageal paresis
  - Upper 1/3 with muscle weakness
  - Lower 2/3 with scleroderma
- Malignancy: Mild increased risk
- Autoimmune
  - Lupus
  - Sjögren's
  - Anti-phospholipid antibodies & syndrome⁹: 5% to 8%
- Thyrotoxicosis
  - Rare
  - High CK: CK in hyperthyroid is usually low
  - May resolve with anti-thyroid medication alone

IMMUNE MYOPATHIES (Polymyositis): Laboratory features

Serum CK: Normal or High (Up to to 100 times normal)
EMG: Irritative myopathy
- Small amplitude, brief, polyphasic motor units
- Fibrillations; Positive sharp waves
Antibodies
- Disease specific
- Disease associated

IMMUNE MYOPATHIES (Polymyositis): Muscle Pathology

IMMUNE MYOPATHIES (Polymyositis): Syndromes

Syndrome	Distinctive features
Idiopathic	Proximal weakness; High CK; Inflammatory myopathy
Collagen vascular disease	Myalgias; Younger onset Scleroderma & Mixed connective tissue disease
Anti-t-rna synthetase antibodies Jo-1 antibodies	Interstitial pneumonitis; Raynauds; Arthritis Perimysial pathology
Signal recognition particle antibody	Acute onset; Severe weakness Capillary pathology; Fibrosis
MAS antibody	Acute onset; Rhabdomyolysis
Brachio-Cervical	Brachiocervical weakness; B-cell inflammation
Drug-induced	D-penicillamine
Familial	Homozygosity at HLA-DQA1 locus
Graft-vs-host disease	7 to 24 months post BMT
Granulomatous	Sarcoid; Immune; Infections
Sarcoidosis	Myopathy; Neuropathy; Lung disease
Malignancy (Necrotic)	Rapid onset; Older patients; Necrotic myopathy
Mitochondrial (P-COX)	Quadriceps weakness; Older onset age; Steroid resistant
Other systemic disorders	HIV; Fasciitis

Idiopathic immune myopathy (Polymyositis)
- Weakness: Proximal > Distal; ± Face (Mild); Symmetric
- Myalgia: Only 20%
- Serum CK: High
- EMG: Myopathy; Irritative with fibrillations & + sharp waves
- Muscle biopsy: Myopathy; Inflammation
Myositis + Collagen vascular diseases

Charcot
- General
  - Younger: Average age = 35 years
  - Female:Male = 9:1
  - Muscle pain & arthralgia more common
  - Myositis-overlap antibodies
  - More likely response to lower doses of corticosteroids
- Scleroderma
  - Onset: Adult or childhood
  - Muscle disease
    - Frequency: 14% to 17%
    - Weakness
      - Proximal: Often mild
      - Onset: Mean = 6 years after SSc onset
      - Course: Often non-progressive
    - Associations
      - Age: Lower than average; 44 vs 51 years
      - Male:Female ratio: Higher than average
      - Diffuse cutaneous SSc > Limited cutaneous SSc
      - Higher prevalence of
        
        Cardiac involvement
        
        Pulmonary fibrosis
        
        Skin: Pigmentation; Mechanic's hands reported
        
        Finger contractures
      - Antibodies
        
        vs PM-Scl-75
        
        No anticentromere
  - Clinical: Other
    - Dysphagia due to lower esophageal dysfunction
    - Raynaud's phenomenon
    - Skin changes: Scleroderma-like; On hands & face
    - Cardiomyopathy, dilated: Mild to severe; Myocardial perfusion defects; Children
    - Pulmonary disease: Restrictive
  - Laboratory
    - PM-Scl antibody
    - ANA: Homogeneous nucleolar pattern
    - EMG: Myopathic
    - Serum CK: May be high
    - Muscle pathology: Not well defined
  - Treatment: Corticosteroids; Cyclosporine; Methotrexate
- Mixed connective tissue disease
  - SLE; systemic sclerosis; inflammatory mypopathy
  - Muscle disease often mild & non-progressive
  - U1-RNP antibody
- Also see: Brachio-Cervical Inflammatory Myopathy
Myositis + Mitochondrial abnormalities in muscle ⁴²
- Onset age: Mean 61 years; Range 43 to 71 years
- Weakness
  - Quadriceps early & most severe (90%)
  - Proximal
  - Distal (30%)
  - Face (50%)
  - Symmetric (80%)
  - Progression: Slow
    - Overall: 4% per year
    - Knee extension: 8% per year
- Laboratory
  - Serum CK: Normal or mildly elevated; Range 54 to 1200
  - Muscle pathology
    - Cytochrome oxidase negative & SDH positive muscle fibers: 4% to 27% of all fibers
    - Endomysial inflammation
    - Focal invasion of muscle fibers by inflammatory cells
    - mtDNA deletions (90%): Multiple
- Treatment
  - Methotrexate: 10 mg/week; More effective in patients with < 10% of fibers COX-
  - Patients unresponsive to treatment may have IBM on repeat muscle biopsy
  - Corticosteroid therapy: NO response

Anti-Jo-1 antibody syndrome

Mid-Thoracic

Lower-Thoracic

Interstitial pneumonitis: Jo-1 myositis

Linear pattern predominating at bases
Progression from fine to coarse
Honeycombing
Small lungs
Hilar adenopathy is present in this patient

General
- Disease classification: Immune myopathy with perimysial pathology (IMPP)
- Other similar IMPP syndromes may occur without anti-Jo-1 antibodies
- Characteristic IMPP features
  - Mypopathy with myalgias or cramps and weakness
  - Systemic disorders: Skin; Joints; Lungs
  - Muscle: Perimysial pathology
    - Fragmentation
    - Acid phosphatase positive cellularity
    - Necrosis & Regeneration of neighboring muscle fibers
Clinical
- Epidemiology
  - Onset: Often in Spring
  - Female > Male
  - Ethnic occurrence
    - Relatively common in Caucasians (20% to 30%)
    - Uncommon in Mestizo (5%)
- Onset: May be weakness or systemic feature
- Weakness
  - Distribution: Proximal; Symmetric
  - Degree: Mild to severe
  - Prevalence: Occurs in many but not all anti-Jo-1 patients
- Myalgias
- Skin
  - Raynaud's: 60%
  - Mechanic's hands (Hyperkeratotic rash at edge of fingers): 20% to 70%
  - Leukocytoclastic vasculitis: Iowa external link
- Interstitial lung disease
  - Dyspnea; Cough
  - Pathology
    - Types
      - Nonspecific interstitial pneumonia (NSIP)
      - UIP
      - Bronchiolitis obliterans organizing pneumonia (BOOP)
    - Inflammation
    - No granulomas
  - Course
    - Responsive to steroids in some
    - Progressive in others (30%)
  - External link: Upstate
- Arthritis
  - Non-erosive
  - Seronegative
  - Hands
  - Hand X-rays: External links A & B
    - Swelling: IP joints & near ulnar styloid process
    - Periarticular osteopenia
    - Small, symmetrical erosions at joint edges: PIP & IP of thumbs
- Systemic: Fever
Laboratory
- Anti-Jo-1 antibodies
  - Target antigen: Histidyl t-RNA synthetase
  - Serum IgG1
  - HEp-2 immunofluorescence pattern: Speckled cytoplasmic
  - Specificity > 95%
  - Other associated antibody: Anti-Ro52
  - Titers of anti-Jo-1 antibodies may be associated with disease activity
  - Histidyl t-RNA synthetase effects²⁹
    - Induces leukocyte migration
      - Interacts with CC chemokine receptor-5
      - Similar to other antigenic tRNA synthetases (serine; asparagine)
    - Non-antigenic tRNA synthetases: No effect
  - Clinical specificity: Myositis or Systemic features of syndrome
- Serum CK: Mildly to Very high (300 to 30,000)
- HLA associations
  - HLA-DRw52; DR3 (90%); DQ2 (80%)
  - Anti-synthetase, general: DRB1*0301; DQA1*0501
- Sedimentation rate: High in 60%
- ANA: High (> 1:160) in 10%
- Anemia (30%)
- EMG: Irritable myopathy
- Calcinosis (24%)
- Chest X-ray or CT
  - Interstitial fibrosis in peripheral & basilar distribution
  - External link: Upstate
Muscle pathology
- Perimysial connective tissue
  - Fragmentation
  - Inflammation: Macrophage predominant
- Myopathy
  - Perifascicular atrophy, degeneration & regeneration
  - More common in regions near the connective tissue pathology
  - Most prominent in patients with more severe weakness
  - Inflammation in endomysial and perivascular regions less common than other types of PM
- Capillary density: Normal
Prognosis: High mortality 2° to systemic (lung) involvement
Treatment: Corticosteroids
Jo-1 antigen: Histidyl t-RNA synthetase
- Protein locations: High expression in heart, kidney & skeletal muscle
- Function: Accessory role in regulation of protein synthesis
- Family
  - Aminoacyl-transfer RNA synthetase
  - External link: Expasy
  - Also see
    - Myositis-specific antibodies vs other tRNA synthetases
    - Genetic disorders of glycyl tRNA synthetase: Distal SMA, type V; CMT 2D

Signal recognition particle (SRP) antibody syndrome
- Epidemiology
  - Female > Male
  - Onset
    - Age of onset: 4th & 5th decade
    - Acute: Weeks to months
    - Fall season: July to January
- Clinical
  - Weakness
    - Severe: 0/5 in some proximal muscules
    - Proximal > Distal (40%)
    - Symmetric
    - Arms & Legs
  - Myalgias
  - Systemic
    - Cardiac: Palpitations; Dyspnea on exertion
    - Raynaud phenomenon (30%)
    - No skin changes
  - Course
    - Severe or fulminant
    - Recurrences frequent
    - Mortality: High
- Laboratory
  - Serum CK: High to Very high
  - HLA
    - DRw52; DR5 (57%)
    - Increased vs controls: DRB1*02-DQA1*01-DQB1*06 & DRB1*11-DQA1*05-DQB1*03
    - Increased risk: HLA-B*5001; DQA1*0104
  - Antibody target: Anti-signal recognition particle, 54 kD & 72kD subunits
- Muscle pathology
  - Myopathy: Degeneration; Regeneration; Varied fiber size (Bimodal)
  - Endomysial connective tissue: Increased early in disease course
  - Endomysial capillaries: Reduced number; Enlarged; C_5b-9 deposition
  - Inflammation: Little or none
- Treatment: Corticosteroids
  - More effective: Early in course; With mild weakness
Anti-MAS antibody syndrome
- Age of onset: Average ~36 years
- Disease duration: Short (Acute onset)
- Clinical
  - Rhabdomyolysis: Alcoholic
  - Myalgias (50%)
  - Cardiac: Palpitations
- Laboratory
  - Anti-Mas Antibody target
    - tRNA^Ser binding protein
    - Plays role in seleno-cysteine incorporation
  - Serum CK: High
  - HLA associations: DRw53; DR4
- Treatment: Steroid responsive
Myositis with antibodies to U1-small nuclear ribonucleoprotein (U1-snRNP)²⁸
- Epidemiology: Predominantly Females
- Onset
  - Age: Mean 36 to 48 years
  - Signs: Swollen hands; Raynaud's phenomenon; Weakness
- Clinical
  - Muscle
    - Weakness: Proximal; Mild to severe
    - Dysphagia
    - Discomfort: Myalgias; Cramps
  - Other organ systems
    - Lung: Interstitial pneumonitis; Vital capacity reduced due to 1° lung disease
    - Arthritis: Symmetrical; Non-destructive; Distal joints
    - Raynaud's: Some patients
    - Sicca: Some patients
    - Lymphadenopathy (20%)
    - Neurologic: Lymphocytic meningitis (20%)
    - Systemic: Fever; Weight loss
- Laboratory
  - Serum antibody binding to snRNP
  - ANA: 1 to 1,600
  - Serum CK: 560 to 14,000
  - Inflammation markers: High sedimentation rate & C-reactive protein; Hyperfibrinaemia; Polyclonal hypergammaglobulinaemia
  - Rheumatoid factor
  - EMG: Irritative myopathy
  - Muscle biopsy: Active myopathy; Lymphocytic & macrophage inflammation
- U1-snRNP antibodies
  - General category: Myositis-overlap antibodies
  - Types
    - Nuclear U1-snRNP antibodies
      - Bind only to U1-snRNP
      - Targets: Proteins in U1-snRNP particle; U1-70k, U1A, U1C (Occasional)
      - Disease association: Mixed connective tissue disorder; May be related to disease activity
    - Sm antibodies
      - Bind to Sm proteins
      - Also precipitate U1, U2, U4/U6 proteins
      - Disease association: Systemic lupus erythematosis
- Treatment: Rapid improvement with corticosteroids (Weeks)
- U1-snRNP protein: Function
  - Pre-mRNA splicing
  - See Spliceosomes
Myositis with OJ antibodies⁴⁹
- OJ antibody = Anti-isoleucyl-tRNA synthetase
- Clinical syndrome
  - Age: 25 to 75 years
  - Interstitial lung disease (100%)
  - Myopathy: Weakness (57% to 89%)
  - Polyarthritis (57%)
  - Skin rash: None
- Laboratory
  - EMG: Irritative myopathy
  - Serum CK: Normal to 3300; High with weakness
  - Muscle biopsy: Myositis
- Treatment: Corticosteroids
Myositis with other myositis-specific antibodies
- Clinical syndrome
  - Similar to Jo-1
  - More frequent skin involvement: Especially with anti-EJ
  - Systemic features with less frequent myositis: anti-PL-12; anti-OJ
  - anti-PL-12: Common in Southwest US
- Target antigen: Often t-RNA synthetase
- HLA: DR2 (45%); DR8 (27%); DQ1 (70%)
Malignancy-associated necrotic myopathy
- Older patients
  - Most > 40 years
  - More likely with increasing age
- Weakness: Proximal; Symmetric
- Course
  - Rapid; Disabling severe weakness in < 2-3 months
  - Survival: Related to ability to treat neoplasm
- Neoplasms
  - Lung
  - GI: Stomach & Colon (Adenocarcinoma)
  - Prostate
  - Gynecological (Breast)
- Work-up
  - Physical exam: + Gynecological & Rectal
  - Chest & abdominal CT
  - Stool guaiac
- Serum CK: Increased 8x to 100x normal
- Muscle Histology
  - Muscle fiber necrosis: Small & large foci
  - Macrophages: Phagocytosis & in endomysium
  - Few focal T-cell infiltrates
  - Connective tissue: Alkaline phosphatase positive
  - C5b-9 complement deposition in muscle fibers
- Treatment: Corticosteroids; Improves myopathy when neoplasm controlled
Brachio-Cervical Inflammatory Myopathy⁴⁷
- Clinical
  - Onset
    - Age: 24 to 82 years, Mean 55 years
    - Weakness: Proximal arms
  - Weakness
    - Arms > Legs
    - Proximal > Distal
    - Posterior neck (60%)
    - Asymmetry: Some patients
    - Dysphagia (30%)
    - Respiratory (30%)
    - Maximal weakness: 0% to 53% of normal
    - Progression to maximal weakness: Months
    - Ocular: Ptosis or ophthalmoplegia in 30%
  - Myalgias (20%)
  - Other
    - Skin: Rash (10%)
    - Prominent weight loss (30%)
    - Rheumatoid arthritis (20%)
- Laboratory
  - ANA +: 100%; Titers 1:80 to 1:5120
  - Serum CK: Normal to 10x elevated
  - EMG: Myopathic; Spontaneous activity
  - Repetitive nerve stimulation decrement: 40%
  - Anti-AChR antibody: 30%
- Muscle pathology
  - Muscle fiber necrosis & regeneration
  - Focal invasion of muscle fibers: 60%
  - C5b-9 (MAC) deposition: Diffusely in endomysium
  - Mononuclear focal infiltrates: 90%
    - Composition: B-cells present in most patients; Some foci without B-cells
    - Location: Perivascular & Perimysial
  - MHC-I expression in muscle fibers: 90%
  - MxA capillary staining: 90%
Myositis + Myasthenia gravis⁴³
- Also see: Brachiocervical inflammatory myopathies
- Clinical
  - Patients described with polymyositis or dermatomyositis
  - Weakness
    - Respiratory
    - Bulbar
    - General: Proximal > Distal; May be Arms > Legs
    - Ophthalmoplegia
- Clinical associations
  - Thymoma: Common
  - Cardiomyopathy
- Laboratory
  - Serum CK: Mildly high
  - Anti-AChR antibodies: Positive
  - Ryanodyne receptor antibodies: Present
Myositis + Sarcoid
- Granuloma in muscle
- Myopathy
- More likely response to immunotherapy than granulomatous myopathy without sarcoid
Drug induced myositis
- D-penicillamine
  - D-penicillamine
  - Epidemiology
    - Dose: No clear relation
    - Frequency: ~ 1%
    - Disease treated: Rheumatoid arthritis
  - Onset
    - Any time during treatment
    - Weaks to years after onset of drug treatment
  - Clinical
    - Muscle
      - Weakness: Proximal
      - Dysphagia (40%)
      - Myalgias
    - Skin: Rash in some patients
    - Cardiac
      - Myocarditis
      - Conduction block
    - Treatment
      - Drug withdrawal
      - ± Corticosteroid treatment
      - Recovery common
  - Laboratory
    - Serum CK: High (75%) or Normal
    - EMG: Irritative myopathy
    - Jo-1 antibody: One patient reported
    - AChR antibodies: Some patients (25%)
    - ANA positive: 80%
    - Associations
      - Complement factor C2 deficiency
      - HLA type DR4
  - D-penicillamine may also induce
    - Myasthenia gravis
    - Neuromyotonia
    - Pemphigus
- Lupus ± myositis: Procainamide; Hydralazine
- Interferon-α
- Phenytoin: Inflammatory myopathy with fever, rash, lymphadenopathy & eosinophilia
- Toxic oil: Vasculitis in muscle
- Drugs with possible relationship with myositis
  - Penicillin; Ipecac; Sulfonamide; Levodopa; Cimetidine;
    Leuprolide; Propylthiouracil; Carbimazole
Graft-versus-host disease (GVHD)²
- Definition & Features
  - Cell mediated immune reaction
  - Mediated by: Donor cytotoxic T-cells (CD8+) & Lymphokine secreting helper T-cells
  - Produce delayed-type hypersensitivity reaction vs. recipient cells
  - T-cell activation & GVHD most severe
    - Donor-recipient HLA major histocompatibility complex disparity
    - Incomplete matching in HLA-A,B,C,Dr loci
    - Minor histocompatibility antigens may also play a role
    - May also occur with genotypically identical HLA-matched siblings
  - Clinical heterogeneity
    - Temporal
      - Some with sequential additive end organ involvement
      - Some resolve in one organ then flare in another
    - Different end organ involvement
  - Phases
    - Acute
      - < 100 days after bone marrow transplant
      - 1° involvement
        
        Skin: Maculopapular exanthem; Epidermal necrolysis
        Liver: Similar to 1° biliary cirrhosis
        Bowel; Microangiopathy
    - Chronic
      - > 80 days after bone marrow transplant
      - Varied clinical involvement
        
        Skin: Lichen planus-like; Scleroderma-like; Vitiligo
        Lichenoid lesions: Oral & Esophageal
        Keratoconjunctivitis sicca
        Bronchiolitis ® Obstructive pulmonary failure
        Myositis
        Myasthenia gravis
        Chronic immune demyelinating polyneuropathy (CIDP)
        ? Guillain-Barré
        Fasciitis
        CNS (Rare): Myelitis; Optic neuritis
      - Antibodies vs: Nuclei; dsDNA; Smooth muscle
  - Risk factors
    - Age > 20
    - Chronic GVHD: Prior Acute GVHD
  - Treatment
    - Cyclosporine
    - Prednisone & Azathioprine: Associated with infectious complications
- Graft vs Host Disease (GVHD) + Myositis³⁰
  - Relation to transplant (bone marrow or stem cell)
    - Onset: 7 to 55 months post transplant
    - Associations
      - Always with chronic GVHD
      - Prior acute GVHD in ~ 35%
      - Female donors
      - Never with autologous transplants
    - Frequency: 0.6%; 49 per 100,000 person-years
    - Mechanism: ? Allo-autoimmune responses
  - General
    - Age: 4 to 46 years; Similar to general transplantation population
    - Male = Female
  - Muscle: Clinical
    - Weakness
      - Proximal
      - Legs > Arms
      - Symmetric
      - Severity: Mild to Moderate
      - Onset: Acute or Subacute
    - Myalgias: 60%
  - Other organ involvement
    - Frequency: 80%
    - Mouth & Mucous membranes
    - Liver
    - Eyes
    - GI: Esophagus
    - Lung: Restrictive > Obstructive
    - Arthritis
    - Skin: Lichen planus-like; Scleroderma-like; Vitiligo; No dermatomyositis-like rash
  - Differential diagnosis
    - Autoimmune hypothyroidism
    - Myosin-loss myopathy
    - Myasthenia gravis
  - Laboratory
    - Serum CK: High in 70%; Range 49 to 8,400 U/L
    - Aldolase: High in 66%; Range 5 to 88
    - Liver enzymes: High in 90%; Mildly elevated
    - Antibodies: ANA 33%; Smooth muscle 33%; No myositis-specific Ab
    - HLA: No association with B8/DR3
    - EMG: Irritable myopathy
  - Muscle pathology
    - Inflammation
      - Perimysium: Macrophages or Dendritic cells (Acid phosphatase +)
      - Endomysium: Occasional; Cytotoxic T-cells (CD8 +)
    - Muscle fiber necrosis & regeneration: Especially perifascicular
    - ? Hemosiderin & Lipofuscin in muscle fibers
  - Treatment
    - Prednisone ± Cyclosporine, Azathioprine or Tacrolimus
    - In absence of chronic GVHD treatment may be stopped after 1 to 2 years
    - Chronic GVHD signs may develop while myositis is in remission
    - Response
      - Time: 2 to 7 months
      - Degree of response not related to changes in GVHD
  - Animal model
    - Stimulus: Transfer of parental splenocytes into some strains of mice
    - Disease syndrome: Systemic lupus erythematosus-like
      - Myositis
      - Glomerulonephritis
    - Laboratory
      - Antibodies: ANA; Amino acid tRNA synthetase; Transfer RNP
      - EMG: Irritable myopathy
- GVHD + Neuropathies
  - Sensory motor polyneuropathy
    - Onset: With GVHD or 6 to 8 months later
    - Signs: Symmetric; Distal; Sensory loss
  - Vasculitic neuropathy ⁷: 1 case with chronic GVHD
  - ? CIDP
Myositis + other systemic disorders
- Acquired immune deficiency syndrome
- Lymphoproliferative disease & Monoclonal gammopathy
- Fasciitis
- Hypereosinophilic syndrome
- Myasthenia gravis: Often associated with thymoma & Ryanodyne receptor antibodies
Familial idiopathic inflammatory myopathy
- Clinical: Similar to sporadic PM
- Reduced frequency of myositis-specific autoantibodies
- Genetic risk factor: Homozygosity at HLA-DQA1 locus
- Probably related to multigenic factors
- Also see: Hereditary inflammatory myopathies
Multinodular Polymyositis¹⁷
- Epidemiology: Case & Pathology reports
- Onset
  - Age: 40 to 76 years
  - Progression over months
- Clinical
  - Weakness
    - Proximal
    - Symmetric
    - Dysphagia (80%)
  - Nodules: Masses
    - Multiple
    - Locations
      - Muscles in limbs & trunk
      - May vary over time
    - Mildly tender
  - Associated disorders
    - HIV infection
    - Hepatitis C infection
  - Course
    - Improvement with immunosuppressive treatment reported
    - Spontaneous improvement may occur
  - Rule out
    - Focal myositis
    - Myositis ossificans
    - Granulomatous myositis
- Laboratory
  - Serum CK: Normal to Very high (15x)
  - CD4 count: 390
  - ANA: Often positive
  - EMG: Irritable myopathy
  - MRI: Increased T2 signal in enlargements; Gadolinium enhancement
  - Muscle biopsy
    - Inflammation
      - Plasma cells
      - Lymphocytes: B-cells > T-cells
      - Some regions may appear granulomatous
    - Muscle fibers: Necrosis; Replacement by cells
    - Perimysium: Widening; Cellularity
- Treatment
  - Corticosteroids
  - Anti-retroviral therapy

Polymyositis: Treatment options

Solumedrol (i.v.): Fewer side effects than oral prednisone
Prednisone
- Oral 100 mg q.d.; then taper
- Latency before benefit: 1 to 6 months
Azathioprine
- 2.5 - 3mg/kg/day
- Used to reduce Prednisone dose
- Latency before benefit: 6 to 12 months
Methotrexate
- 7.5 to 22.5 mg/week
- Given as 1 or 2 doses on weekends
- Latency before benefit: 3 to 6 months
Cyclosporine
- Starting dose: 2.5 mg/kg b.i.d
- Latency before benefit: 2 to 6 months

DERMATOMYOSITIS

MYOSITIS + SKIN CHANGES

Dermatomyositis
Clinical features
Laboratory
Pathology
Description
Histology
Treatment

Classification
Dermatomyositis
Childhood
Adult
Amyopathic
Mi-2 antibody negative
Malignancy-associated
Jo-1 antibody positive
EJ antibody positive
PM-Scl
Childhood & Adult
Mi-2 antibody positive

Tim Miller

Dermatomyositis: Clinical features, general

Epidemiology: Higher frequency in Mesoamerica; Lower in Northern cities
Clinical features: Common
- Frequency: > 90% of inflammatory myopathies in children
- Skin
  - Erythematous rash: Heliotrope
    - Face & Eyelids
    - Sun-exposed areas
    - Extensor joint surfaces
  - Periorbital edema
- Muscle weakness: Proximal; Dysphagia
- Joint contractures
- Other occasional systemic features
  - Ocular: Retinopathy; Conjunctivitis; Iritis; Uveitis
  - Cardiac
    - Small vessel disease
    - Abnormal vasoconstriction
      - Prinzmetal's angina: ? associated with Raynaud's
Dermatomyositis syndromes: Specific features
- Childhood (Juvenile) Dermatomyositis⁵³
  - Epidemiology & Associations²³
    - Incidence
      - May vary with geography & genetic background
      - 0.14 to 0.5 per 100,000
    - Female > Male: 1.7x to 5x
    - Prodrome: ? Upper respiratory infection
    - Other possible associated factors
      - Hepatitis B vaccine
      - Growth hormone replacement
      - Sun exposure: Excessive
      - Drugs: Carticaine; Penecillamine
      - Viral prodrome: Coxsackie B; Parvovirus; Echovirus with X-linked hypogammaglobulinemia
      - Microchimerism
        
        Maternal: Persistence of maternal blood cells transferred by the placenta during development
        
        In muscle & peripheral blood
        
        In inflammatory lesions in DM skin & muscle
        Associated with DQA1*0501 allele in mother
      - Seasonal birth patterns⁵²
        
        Hispanic patients: Birth more in September to November; Mean birth date October 16
        
        HLA DRB1*0301: Birth more in July to January
        p155 antibody
        
        Positive: Birth more in December to April
        
        Negative: Birth more in May to August
      - Tumor necrosis factor-α gene polymorphisms
        
        G-to-A substitution at NCOI restriction site
        High-production of TNF
        Clinical relations
        
        Longer-lasting disease: > 3 years
        
        Calcifications
        
        TNF-α-308A allele: Increased vascular occlusion in JDM
      - HLA
        
        Class II: DQα1*0501 antigen (88%)
        DM: DMA*0103 & DMB*0102
        HLA-A*68; DQA1*01
  - Clinical features
    - Onset age: 2/3 between 4 and 12 years
    - Weakness
      - Generalized: Proximal > Distal
      - Symmetric
      - Bulbar: 20%
    - Muscle discomfort
      - Pain
      - Tenderness
      - Swelling
    - Skin
      - Rash
        
        Distribution: Extensor surfaces of joints (Most common); Periorbital; Anterior neck & Chest
        
        Heliotrope
        
        Associated with edema & telangectasia
        
        Exacerbated by light
        Generalized rash & Ulceration: May have worse prognosis
      - Gottron’s papules
        
        Nosology: Collodion patches
        
        Features: Flat-topped, Violaceous or Red, Scaly (Some patients)
        
        Similar nonpalpable (macular) rash: Gottron’s sign
        
        Location: Skin over extensor joints
        Course: May develop atrophic white center with telangiectasia
      - Nailfold capillary & cuticular changes
        
        Capillary loss
        
        Correlations: Disease activity; Length of untreated disease
        
        Cuticular hypertrophy
      - Pruritis
      - Scalp: Atrophic, erythematous, scaly plaques
    - Joints
      - Arthritis & Arthralgis
        
        Early in disease course: First 6 months
        
        Location: Knees, Wrists, Elbows & fingers
        
        Pauciarticular (67%) or Polyarticular (33%)
        
        Good response to JIIM therapy
        
        Severe: Overlap syndrome more common
      - Contractures: Ankles, Flexors & other joints
    - Vasculitis
      - Visceral infarction
      - GI bleeding
      - Associated with poor prognosis
    - Calcinosis
      - Frequency: 30% to 70%
      - Subcutaneous
      - Under discolored areas of skin
      - Onset: Later in disease course
      - Locations
        
        Most common: Elbows, Knees, Other acral regions
        
        Trauma sites
        Deep or Superficial
        May be anywhere
      - Risk factors
        
        Disease severity
        
        Delayed treatment: Reduced frequency with early corticosteroid treatment
      - Related to hydroxyapatite accumulation
    - Lipodystrophy
      - Onset: Later in disease course
      - Frequency: 14% to 25%
      - Progressive, slow, symmetrical loss of subcutaneous fatty tissue
      - Mainly involves the upper body
      - ? Female preponderance
    - Gastrointestinal
      - Esophageal dysmotility
      - Malabsorption
      - Infarction
    - Other
      - Pulmonary: Uncommon
      - CNS: Rare
      - Cardiac: Rare
    - Prognosis
      - Mortality: 7%
      - Incomplete recovery: Common
      - Long term remission: 37%
    - Variant: Amyopathic JDM
      - Normal strength & muscle enzymes for 2 years
      - Calcinosis: Low frequency
  - Laboratory
    - B-lymphocytes: Increased percentage of circulating lymphocytes
    - Serum CK
      - May be normal at presentation
      - High in some patients
    - Immunoglobulin γ-chain allotypes
      - Mestizo children: Gm 1,3,17 5,13,21
    - Antibody: p155 (29%)
  - Treatments
    - Corticosteroids: IV or Oral
    - Intravenous immunoglobulin
    - Methotrexate
    - Rituximab
    - Cyclophosphamide: Refractory cases
- Adult Dermatomyositis: Mi-2 antibody negative
  - Effusions
  - Arhythmias
  - Interstitial lung disease
  - Increased risk of malignancy
  - Hands: Raynaud's; Mechanic's; Edema
  - Other connective tissue disorders
    - Rheumatoid arthritis; Scleroderma; CREST
  - Autoantibodies
    - Jo-1 (with arthritis); PM-Scl; ANA
- Dermatomyositis: Mi-2 antibody positive
  - Epidemiology
    - More common in Mestizo (Mexico & Guatamala)
    - Frequency related to: Surface ultraviolet radiation intensity³⁸
  - Onset age: Childhood > 3 years; Adult
  - Clinical
    - Onset: Acute
    - Similar to Mi-2 negative syndrome
    - Skin: Rash - V-sign, Shawl sign
    - Nailfold involvement: Common; Cuticular overgrowth
    - Associated clinical connective tissue disorders: Rare
    - Course
      - Better prognosis
      - Less interstitial lung disease
  - Laboratory
    - ANA + (100%)
    - HLA type: Associations vary with ethnicity²⁷
      - DR7 (75%), Tryptophan at position 9 of DRβ chain; DRB1*0701
      - Caucasian (Mi-2): DRB1*07; DQA1*0201
      - Mestizo adults (Mi-2): DRB1*04; DQA1*03
    - Immunoglobulin γ-chain allotypes
      - Mestizo adults: Gm 1, 17, 21; Km 3; Also Gm 2, 3, 23, 5, 13
- Dermatomyositis: Malignancy associated
  - Females > Males
  - ? Age related: Mean 50 years
  - Skin disorder: Cutaneous vasculitis
  - Neoplasms³⁶
    - Ovarian advanced stage & uniform epithelial +...
    - Nasopharyngeal (China; Tunisia)
    - Breast
  - Survival: 5 year 38%; Mean 3 to 4 years; Death mostly related to cancer
  - Antibody: p155 (TIF-1γ)
- Amyopathic Dermatomyositis²⁴
  - Epidemiology
    - Frequency: 8% to 20 % of DM
    - Onset age: Usually middle aged adults; Occasional juvenile or 9th decade
    - Sex: Female > Male, except in China
  - Clinical features
    - Skin lesions
      - Heliotrope erythema (69%)
      - Gottron's nodules (54%)
      - Periungual lesions
      - Pruritis: Occasional patients
      - Erythematous violaceous macules & papules: Malinancy associated in Chinese
    - Other clinical features
      - Raynauds
      - Arthralgias
      - Interstitial lung disease
    - Strength: Normal
  - Laboratory
    - Serum CK: Normal
    - Antibodies
      - CADM-140
      - Antinuclear antibodies: 50% to 90%; Speckled pattern
      - No Jo-1; Mi-2; PM-Scl
    - Muscle: Some patients with minimal myopathic or inflammatory changes
  - Treatment
    - Often conservative without immunosuppression
    - Corticosteroids: Systemic or Topical
    - Hydroxychloroquine
- EJ antibody positive
- PM-Scl antibody positive
- Drug induced: D-penicillamine

Dermatomyositis: Laboratory features

Serum CK: Normal or High (up to 30 times normal)
Antibodies
- Uncommon in North American patients
- Atypical DM: Mi-2; Jo-1
Myoglobinuria (sustained): May be presenting feature
HLA types (Juvenile DM)
- Increased frequency: B8, DR3 & A1 + B8 + DR3
Tumor necrosis factor-α (TNF-α): Associations with 308A allele
- Increased frequency in DM
- Long disease course
- Calcifications
- Increased production of TNF-α
EMG: Irritative myopathy
- Motor units: Small amplitude; Brief; Polyphasic
- Spontaneous activity: Fibrillations; Positive sharp waves
DM: Pathology
- Muscle fibers:
  - Distribution: Perifascicular regions
  - Myopathic changes
    - Muscle fiber atrophy
    - Some patients: Necrosis + phagocytosis; Regeneration
  - Cyotochrome oxidase activity: Reduced in perifascicular regions
  - CD59 : Reduced on muscle fibers & capillaries
- Vessels
  - Microvascular deposits or upregulation
    - IgM
    - Complement components (C_5b-9)
    - TNF-α
    - ICAM-1: Increased in capillaries & perimysial vessels;
    - 75-kd TNF receptor
    - Cytokines: CXCL12 ; CCL2 (MCP-1)
      - Expressed diffusely on arterioles (perimysial & perifascicular) & capillaries²⁶
  - Endothelium
    - Swelling
    - Microvacuoles
    - Inclusions
  - Endomysial capillaries
    - Reduced Number: Especially in regions of perifascicular atrophy
    - Enlarged
- Inflammation (50%)
  - Usually perivascular
  - May contain B-cell foci

Dermatomyositis: Immunosuppressive treatment

Solumedrol (i.v.)
- Dose: 30 mg/kg (Children) up to 1 gm per day
- Fewer side effects than oral prednisone when given intermittently
Oral Prednisone: Typical chronic Rx
- Initial Rx: 1 to 2 mg/kg/q.d. (up to 100mg) p.o.
- Follow-up
  - Change to every other day Rx at same total dose
  - Taper slowly 10 mg/month to 60mg; then 5 mg/month
  - Children can frequently be tapered off entirely
  - Adults often need long term immunosuppression
Azathioprine
Methotrexate
Human immune globulin (IVIg)
Severe or refractory weakness: Treatments before chronic Rx
- Intravenous methylprednisolone: 1 gram/day for 3 to 5 days
- Human immune globulin: 1 gram/kg/day for 2 days

INCLUSION BODY MYOSITIS ²²

Epidemiology
- Male preponderance: 60% to 75%
- Sporadic
Onset
- Age: > 50 years in 80%
- Weakness
  - Legs: 70%; Difficulty with chairs or stairs
  - Arms, Distal: 15%
  - Swallowing difficulty: 10%
Clinical features
- Weakness
  - Proximal & Distal: Distal predominant in 20%
  - Upper & Lower extremities
  - Asymmetric
  - Focal regions with more severe weakness
    - Arms: Wrist & finger flexors;
    - Legs: Quadriceps; Foot dorsiflexors
  - Muscles commonly spared
    - Deltoid
    - Pectoralis
    - Interossei (Hands)
    - Face
  - Progression
    - Slow over 5 to 20 years
    - ? More rapid progression to disability with onset after 60 years
- Muscle atrophy: Proportionate to weakness
- Tendon reflexes: Diminished with disease progression, especially knee
- Dysphagia (30%): Upper 1/3 of esophagus; Especially females
- Polyneuropathy¹⁴
  - Usually subclinical
  - Sensory > Motor
  - Loss of myelinated axons in sural nerve
- Systemic involvement
  - Rare
  - No strong systemic disease associations
  - Reports of associated: Immune disorders, Polyneuropathy
  - No association with malignancy
Laboratory
- Serum CK: Mildly elevated 2 to 5 fold; May be normal
- EMG: Irritable myopathy; Long duration potentials may occur
- Muscle Pathology
  - Inflammation: Mononuclear cells
    - Locations
      - Endomysium: Most common
      - Also in some patients: Perimysium & Perivascular
    - Focal invasion of muscle fibers
      - Common feature of muscle fiber damage
      - CD8 cells & Macrophages
  - Myopathic changes
    - Varied muscle fiber size
    - Regenerating muscle fibers
    - Groups of small fibers
    - Endomysial connective tissue: Variably increased or normal
  - Rimmed vacuoles with granular material & filaments
    - Histochemistry: Best visualized with Congo Red stain
    - Contain
      - Filaments: 15 to 18 nm
      - Several proteins β-Amyloid, Desmin; Ubiquitin; Transglutaminases 1 & 2
  - Aggregates
    - Stain with SMI-31 antibody (? contain phosphorylated tau)
    - Often not related to vacuoles
    - May also stain for β-amyloid, VCP, ubiquitin, αB-crystallin
  - Mitochondrial disorders
    - COX- muscle fibers
    - SDH+ muscle fibers
    - Multiple mDNA deletions in 50% of IBM
  - Muscle fiber hypertrophy: More common than in polymyositis
  - MHC-I
    - Expression on surface of most fibers
    - Occurs on morphologically normal muscle fibers
Barium swallow: Cricopharyngeus dysfunction
Nerve conduction studies: Absent sural potentials in some patients > 60 years
Muscle MRI: Fatty infiltration of medial head of gastrocnemius
Other
- M-protein (20%): Most IgG; λ > κ
- HLA types: DRβ1*0301, DRβ3*0101 (or DRβ3*0202) & DQβ1*0201
- e4 allele of apolipoprotein E: ? Excess frequency in males with IBM
- Transglutaminase activity: 20x elevated level inf muscle
- HIV & HTLV viral infection: ? Increased frequency of sIBM

Treatment: None; Few reports of response to IV Ig or immunoabsorption

Variant: Autosomal dominant inheritance

Similar clinical features to sporadic IBM
No HLA type association

INFLAMMATORY MYOPATHIES: Other variants

Absent chondroitin sulfate C
Experimental autoimmune myositis
Fasciitis
Focal myositis
Granulomatous
Hemophagocytic lymphohistiocytosis
Hereditary
Infection
Necrotizing with pipestem capillaries
Orbital
Perimyositis

Granulomatous myopathies

Clinical features
- Weakness: Proximal; Dysphagia
- Muscle hypertrophy: Occasional
- Progression: Slow; Occasionally acute with pain
- Post-menopausal females
- Some patients with progressive flexion contractures of arms
Laboratory
- Serum CK: Normal or High
- Aldolase: ? More often elevated than CK
Pathology
- Granulomas
  - Non-caseating
  - Location in muscle
    - Endomysial or Perimysial: May occur selectively in either
  - May occur systemically: Even in absence of other common features of sarcoid
  - Differential diagnosis: Wide
- Myopathic changes
  - Variation in muscle fiber size
  - Location: Both near & distant from granulomas
Treatment
- Corticosteroids: Benefit in 40% to 80%
Differential diagnosis
- Sarcoidosis
- Immune disorders
  - Connective tissue: Rheumatoid arthritis; Mixed CTD; Wegener's
  - Myasthenia gravis (rare): Associated with¹⁸
    - Myocarditis
    - Thymoma ¹⁹
    - Antibodies to Ryanodine receptors
  - Crohn's
- Infections

Necrotizing myopathy with pipestem capillaries¹

Myopathy: Clinical
- Onset
  - Age: 5th to 7th decade
  - Subacute or Episodic weakness after exercise
- Myalgias: Exercise-induced; Onset after 12 to 48 hours
- Weakness
  - Proximal
  - May be severe
  - Episodic weakness after exercise: Occasional patient
- ± Dermatomyositis-like rash
Associated disorders (In some patients)
- CNS: Multiple cerebral infarctions (Vasculitis)
- Neoplasm: Bladder transitional cell (1 patient)
- Systemic: Myocarditis; Connective tissue disease (Undifferentiated)
Laboratory
- CK: High; 15 to 50 times normal
- Muscle pathology
  - Muscle fibers
    - Necrosis: Scattered muscle fibers
    - Regeneration
  - Capillaries: Pipestem
    - Enlarged
    - Thickened "pipestem" walls: Deposits of amorphous PAS + material
    - Deposits of complement membrane attack complex
    - Number: Overall normal; Focal reductions
  - Inflammation: Minimal
Treatment: Corticosteroids

Myopathy with deficient chondroitin sulfate C in skeletal muscle connective tissue³

Epidemiology: 2 patients
Clinical
- Onset: Adult, 42 & 70 years
- Weakness
  - Diffuse
  - Symmetric
  - Proximal > Distal
  - Respiratory failure
  - Course: Becomes severe over months
- Cranial nerves
  - Dysphagia
  - Ophthalmoplegia in 1 patient
Laboratory
- Serum CK & aldolase: Normal
- ANA: Positive in 1 patient
- EMG: Myopathic; Occasional fibrillations & positive sharp waves
- NCV: Normal
Muscle pathology
- Type 2 muscle fiber atrophy
- No or few active myopathic changes
- Inflammation: Mild perimysial and perivascular
- Chondroitin sulfate staining: Absent in endomysium
Treatment: Corticosteroids produce improvement over months

Benign acute childhood myositis⁸

Epidemiology
- Male (84%) > Female
- Onset
  - Age: Mean 8 years; Range 3 to 13 years
  - Timing: 1 to 4 days after resolution of prodrome
- Associated with influenza
- Occurs in temporal clusters: Seasonal, Winter (68%), Summer (2%)
- Occasional occurrence in siblings
Prodrome: Fever (80%); Cough (59%); Headache (37%)
Clinical features
- Pain & Tenderness (75%)
  - Most severe & common: Calf
  - Generalized: Occasional patient
- Strength
  - Weakness: Usually ≥ 3/5
  - Normal: Majority of patients
- Difficulty walking: Toe walking (32%); Stiff-legged (17%); Other unusual (32%)
- Tendon reflexes: Normal
- Systemic: Fever >38°C (25%)
- Course
  - Recovery within 1 week in most
  - Recurrence in 8%
Laboratory features
- Serum CK:
  - Acute phase: High (100%); 250 to 14,000
  - After recovery (1 month): Normal
- Viral titers + (42%): Influenza B in 21%
Muscle pathology
- Necrotic muscle fibers: Scattered
- Some inflammation

Idiopathic orbital myositis

Definition: One or more extraocular muscles is infiltrated by an idiopathic inflammatory process
Epidemiology
- Male:Female = 1:2
- Onset: Average = 30 to 40; Range = 3 to 84
Course: Acute, Relapsing or Chronic
General findings
- Vision: Diplopia; Normal acuity
- Proptosis; Edema (Periorbital & eyelid)
- Conjunctival injection & chemosis
- Pain
Ptosis
Eye movements
- Acute: Paretic
- Chronic: Restrictive
- Usually > 1 muscle & often bilateral
- Muscles commonly involved: Medial rectus (43%); Superior rectus (19%); Lateral rectus (17%)
- Muscles involved 5% to 10%: Obliques; Inferior rectus
Differential diagnosis
- Thyroid: Chronic; No pain; Inferior rectus paresis common; Lid retraction
- Orbital infections: Fever & malaise; Reduced visual acuity
- Orbital neoplasms: No sharp, acute pain or chemosis
- Carotid-cavernous fistula & AVM: Bruits; No severe pain
- Cavernous sinus thrombosis: Fever; N&V; Altered consciousness
Imaging (A-scan echography): Enlarged muscles; Thickened tendons; Low internal reflectivity
Pathology: Edematous muscle; Inflammation (Eosinophils in some); Fibrosis (Late)
Treatment
- Corticosteroids > Other immunosuppressants
- Chronic: Diplopia management with surgery or botulinum injections

Masticator Myopathy³⁷

Epidemiology
- Rare in humans
- Common in dogs: Alsatian & Large breeds; Young & Middle aged
Course
- Progression: Over days
- Spontaneous remission: Weeks
- Relapses may occur: Especially in dogs
- Chronic form recognized in dogs
Clinical
- Muscles
  - Painful
  - Swollen
  - Location: Masseter; Temporal; Pterygoid
- Restricted jaw mobility
Laboratory
- MRI: High T2 signal intensity
- Peripheral blood: Eosinophilia
- Serum CK: Normal or High
- Serum IgG: Reduced by 20%
- Antibodies vs type 2M muscle fibers (Dogs): External link
Muscle pathology
- Inflammation: Eosinophils; Lymphocytes (TCRγδ+ cells); Macrophages
- Hemorrhage & Edema
- Perimysium: Widened
Treatment: May improve with corticosteroids

Hemophagocytic lymphohistiocytosis⁴¹

Hemophagocytosis: General
- Definition: Activated macrophages, engulf erythrocytes, leukocytes, platelets & precursor cells
- Clinical
  - Fever, persistent: 60% to 100%
  - Pancytopenia
  - Organomegaly
    - Splenomegaly: 35% to 100%
    - Hepatomegaly: 39% to 97%
    - Lymphadenopathy: 17% to 52%
  - CNS: 7% to 47%
    - Seizures
    - Cerebral edema
    - Delayed development
  - Rash: 3% to 65%
  - Myalgias
  - Hemophagocytosis: Bone marrow, liver, lymph nodes, brain
- Laboratory
  - Liver function tests: Abnormal; Especially LDH (90%)
  - Serum ferritin (macrophage activation marker): High (90%); Reflects disease activity
  - Coagulopathy
  - Pancytopenia
  - Hypertriglyceridemia (50%)
  - Bone marrow: Hemophagocytosis
  - CSF
    - WBCs: Commonly 20 to 60
    - Protein: Normal to 300
    - Neopterin (CNS disease marker): High
  - NK cell activity
    - Familial disease: Persistently low or absent
    - Secondary HLH: Normalizes with remission of illness
- Treatment
  - Familial types: Etoposide + Prednisone ± Cyclosporine
  - Sporadic: May respond to prednisone alone
Genetic types: Several
- Type 1 : Lethal in early childhood
  l Chromosome 9q21.3-q22; Recessive
- Type 2
  l Perforin-1 ; Chromosome 10q22; Recessive
- Other
  - Chediak-Higashi
  - Griscelli syndrome
  - X-linked lymphoproliferative syndrome
Sporadic forms: Similar to macrophage activation syndromes
- Later onset: Children & Adolescents
- Associations
  - Infection: Viruses (EBV), Bacteria, Fungi, Rickettsia, Protozoae
  - Lymphoid neoplasms: Histiocytosis X ; Acute lymphoblastic leukemia; Germ cell tumors; Non-Hodgkin’s lymphoma
  - Immune disorders
    - Allograft recipients
    - Leukemia
    - Collagen vascular disease
      - Types
        
        Juvenile rheumatoid arthritis
        
        Also: SLE, Juvenile dermatomyositis, Kawasaki disease
      - Severe
      - With high-dose corticosteroids
- Course
  - Often monophasic
  - Relapses: 16%
Myopathy in occasional child or teen: ? Sporadic disease
- Weakness: Proximal ± Distal; Symmetric
- Myalgias
- Serum CK: High
- Muscle
  - Focal invasion of muscle fibers by multinucleated phagocytic cells (Myophagocytosis)
  - Muscle fiber necrosis: Associated with phagocytic cells
Neuropathy
- 1 patient with AIDP & acquired HLH after Epstein-Barr virus (EBV) infection
External link: CDC

Hereditary inflammatory myopathies

FSH dystrophy
Limb-Girdle dystrophy
- 2B
- ? 2A
Inclusion Body Myositis: Familial
Familial idiopathic inflammatory myopathy
Schmidt syndrome (Diabetes mellitus, Addison disease, Myxedema)
TRAPS

Myositis: Infectious agents

Viral
- Benign acute myositis
- Acute: Influenza A & B; Parainfluenza; Adenovirus;
  Coxsackie B (Bornholm disease; Epidemic pleurodynia)
- Retrovirus: HIV; HTLV-1
Bacterial
- Legionnaires'
- Leptospirosis
- Lyme
- Pyomyositis
- Clostridia perfringens
- Tuberculosis
Parasitic
- Protozoa: Toxoplasmosis; Trypanosomiasis; Microsporidosis; Malaria
- Cestode: Cysticercosis; Echinococcosis;
- Nematode: Trichinosis; Larva Migrans
Other: Candida; Cryptococcus; Cumminghamella