Inflammatory Myopathy

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Inflammatory and Immune Myopathies: Acquired

GENERAL FEATURES

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

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

Animal Models
Experimental autoimmune myositis
MHC class I upregulation

SPECIFIC IMMUNE OR INFLAMMATORY MYOPATHIES
Immune myopathies (Polymyositis +...) General aspects Clinical Laboratory Subtypes & Comparative features Brachio-Cervical Inflammatory (BCIM) Collagen vascular disease Complement: C2 deficiency Drug-induced Graft-vs-host disease HMGCR (200/100) antibody Idiopathic Malignancy-associated MAS antibody Perimysial pathology (IMPP) Jo-1 OJ t-RNA synthetase antibodies PM + Mitochondrial (PM/COX-) Sarcoidosis Signal recognition particle antibody Systemic disorders & Myositis U1-snRNP antibodies Dermatomyositis Childhood (Juvenile) Adult: Mi-2 antibody Adult: Malignancy-associated Adult: EJ antibody + Adult: PM-Scl antibody + Adult: Amyopathic Mi-2 antibody + Adult: Drug-induced IMPP IM-VAMP Inclusion body myositis (IBM) IM-Mito (PM/COX-)		Other "Myopathies" Benign acute childhood myositis Celiac disease Chondroitin sulfate C deficient Decorin antibody (BJ) myopathy Eosinophilia myalgia syndrome Fasciitis Focal myositis Quadriceps; Other TRAPS Granulomatous Hemophagocytic lymphohistiocytosis Hereditary IM + abundant Macrophages Infection Influenza Lyme myositis Macrophagic myofasciitis Masticator myopathy Multinodular polymyositis Myasthenia gravis Brachio-Cervial Inflammatory (BCIM) Myositis Lymphorrhages Necrotizing with Encephalopathy Paraneoplastic with Pipestem capillaries SRP antibodies Neonatal perifascicular myopathy Orbital Perimyositis Polymyalgia Rheumatica Pyomyositis Sarcocystis Sarcoidosis Trichinosis

PATHOLOGIC CLASSIFICATION ⁶⁸

Perimysial pathology (IMPP)
Feature: Connective tissue pathology
Aldolase high
Dermatomyositis with IMPP
Amyopathic (CADM-140)
Fasciitis
Focal myositis
Graft-vs-host disease
t-RNA synthetase antibodies: Jo-1

Myovasculopathies
Feature: Damage to large or small vessels
Dermatomyositis with Vascular Pathology
(DM-VP; Childhood Dermatomyositis)

Immune Polymyopathies
Features: Little inflammation; Necrosis
HMGCR (200/100) antibody
Paraneoplastic
Pipestem capillaries
Signal recognition particle antibody

IM + Endomysial Pathology (IM-EP)
Features: C_5b9 deposits; Glycoprotein Δ
Brachio-Cervical Inflammatory (BCIM)
Chondroitin sulfate C deficient
Decorin antibody (BJ) myopathy

Histiocytic Myopathies
Feature: Foci of histiocytic cells
Granulomatous
Hemophagocytic lymphohistiocytosis
IM + Abundant Macrophages (IMAM)
Macrophagic myofasciitis

IM-VAMP syndromes
Features: Foci of T-cells but not B-cells
Vacuoles, Aggregates or Mito Path
No response to immunomodulation
Inclusion body myositis
IM + Mitochondrial Pathology

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
External links
- Classification of skin lesions
- Images

Weakness

Proximal: Most Dermatomyositis & Polymyositis
Distal: Inclusion body myositis (Finger flexion; Ankle dorsiflexion; Quadriceps)
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
Neoplasm
Lung
- Ventilatory failure: Due to muscle weakness
- Interstitial lung disease³²
  - Frequency in PM/DM: 19% to 23%
  - Timing: Relation to myositis
    - Before myopathy: 13% to 20%
    - With myopathy: 41% to 47%
    - After myopathy: 39% to 40%
  - Clinical features
    - Dyspnea
    - Cough
    - Fever
    - Course: Acute or Slowly progressive
    - Lung disease type
      - Non-specific interstitial pneumonia (56%)
      - Acute interstitial pneumonia (23%)
      - Idiopathic pulmonary fibrosis (13%)
      - Cryptogenic organizing pneumonia (7%)
    - May be asymptomatic
  - Clinical associations
    - Anti-synthetase syndrome
    - Onset age: Older
    - Neoplasm: Unusual
    - Treatment response: More often refractory to corticosteroids
    - Muscle pathology: IMPP
    - Poor prognosis: High morbidity & mortality (14% to 50%) associations
      - Hamman-Rich�like pattern: Acute lung disease
      - Initial diffusing capacity of CO less than 45%
      - Neutrophil alveolitis
      - Interstitial pneumonia, acute
      - Male gender
  - Antibodies
    - Myositis-associated
      - Anti-Jo-1
      - Anti-tRNA-synthetase antibody syndromes: 31%
      - Lower frequency: Associated skin changes without myositis
    - Also occurs without myositis-associated antibodies
  - Other laboratory: Higher values of
    - Erythrocyte sedimentation rate
    - C-reactive protein
    - Aldolase: Relative to CK
  - 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
Vascular ⁶²
- Inflammatory myopathies may be associated with increased frequency of
  - Myocardial infarction
  - Stroke
- Risk increased with: Associated hypertension or lipid disorders
- Risk reduced with: Non-steroidal immunosuppressive treatment
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) & Aldolase

Very high
Normal or mildly elevated CK
- Inclusion body myositis; Polymyositis with cytochrome oxidase negative muscle fibers
- Dermatomyositis
  - Adults with selective fascia pathology
  - Some childhood DM
Elevated aldolase with normal CK
- Immune myopathies with perimysial pathology ⁵⁹

Immune myopathies: HLA & genetic 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
Polymyositis & Dermatomyositis
- Protein tyrosine phosphatase N22 gene (PTPN22) : R620W variant (Also associated with diabetes )

Inflammatory myopathies: Association with neoplasms¹⁵

Frequency may depend on ethnic background
Risk of malignant disease
- Temporal
  - Highest: Near time of myositis diagnosis (1 to 3 years)
  - Lower but possibly still present: > 3 years after diagnosis
- Age: Mainly in adults
  - Dermatomyositis
    - Higher risk at all adult ages, especially > 45 years
  - Polymyositis
    - May be higher risk at younger adult ages
    - Lower risk than dermatomyositis
  - 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
  - Clinical: Cutaneous necrosis⁵⁶
  - Neoplasm types
    - General: Breast; Ovarian (8x to 32x; Less in Asians) > Lung (5.9x) > Pancreatic (3.8x) >
      Non Hodgkin lymphoma (3.6x) > Stomach (3.5x) > Colorectal (2.5x); Melanoma
    - Asian (Southeastern) & Tunisia: Nasopharyngeal
      - Related to chronic active infection by Epstein-Barr virus (EBV)
  - Neoplasm cell types: Squamous (Especially males); Adeno; Hematological
  - Laboratory
    - Higher CK, > 1000
    - 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
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
- Asian
  - Highest risk in 3rd decade
  - Bone & Joint, Brain, Nasopharyngeal, Melanoma
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

Classification

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

Foci of mononuclear cell inflammation
- Prominent
  - Brachio-Cervical inflammatory myopathy: Perivascular, Perimysial & Endomysial
  - Polymyositis with mitochondrial disorder
  - IIM + VAMP: Inclusion body myositis
  - Dermatomyositis, childhood (DM-VP): Some patients; Perivascular
- B-cell (CD20 positive) foci:
  - 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 pathology
  - 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 (Immune polymyopathies)
  - Paraneoplastic necrotic myopathy
  - SRP antibody syndrome
  - HMGCR (200/100) antibody
  - Chondroitin sulfate C deficient: Reduced Chondroitin sulfate C
  - Anti-Decorin (BJ) myopathy
  - Childhood dermatomyositis: Occasional
  - Acute polymyositis: Inflammation mainly associated with necrotic muscle fibers
Muscle fiber pathology
- Necrosis: Abundant early in disease course
  - Paraneoplastic: Regional necrosis
  - HMGCR (200/100) antibody
  - IM + Encephalopathy
  - SRP antibody syndrome: Scattered necrotic fibers
  - Pipestem capillaries
  - Jo-1 associated myositis: Scattered necrotic fibers, especially perifascicular
- Focal invasion by CD8 cells & macrophages
- Size
  - Varied: Usually atrophic & normal
  - Hypertrophy: Rare, except in IBM
  - Atrophy: Dermatomyositis with vascular pathology (DM-VP); Focal myositis
- Regenerating & Immature fibers: Common in most subtypes of immune myopathies
- Perifascicular muscle fiber pathology: Morphologic patterns
  - Atrophy: Dermatomyositis; Focal myositis
  - Internal architecture abnormal: Dermatomyositis with vascular pathology (DM-VP) (Childhood)
  - Myopathic changes (Necrosis & Regeneration): Jo-1 antibody myopathy
  - Perimysial pathology with little myopathy: Fasciitis; Perimyositis
- Mitochondrial pathology
  - Scattered COX- & SDH+ fibers: IIM + VAMP syndromes
    - Inclusion body myositis
    - Polymyositis with COX- muscle fibers
  - Regionally reduced COX staining in perifascicular muscle fibers: Dermatomyositis with vascular pathology (DM-VP) (Childhood)
Capillary pathology
- Dermatomyositis with vascular pathology (DM-VP) (Childhood)
  - Small & Endothelial pathology: Perifascicular regions with muscle fiber atrophy; C_5b-9 deposition
  - Enlarged: Regions neighboring perifascicular atrophy
- 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
  - Other Features: C_5b9 deposits; Glycoprotein pathology
  - Disorders
    - Brachio-Cervical Inflammatory (BCIM): C_5b9 deposits
    - Chondroitin sulfate C deficient: Reduced Chondroitin sulfate C
    - Decorin antibody (BJ) myopathy: Serum IgM binding to endomysium
- 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 pattern
  - 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 most prominent on perifascicular muscle fibers
    - IM-VAMP (Inclusion body myositis)
      - Commonly diffuse: Present on most or all fibers
      - Associated with 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 (Polymyositis): 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
    - HLA class II: HLADRB1*03-DQA1*05-DQB1*02
  - tRNA-synthetase antibodies
  - Perimysial connective tissue pathology (IMPP)
- Esophageal paresis
  - Upper 1/3 with muscle weakness
  - Lower 2/3 with scleroderma
- Malignancy: Mild increased risk
- Autoimmune: Associated syndromes
  - 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 & INFLAMMATORY MYOPATHIES: Clinical Syndromes

Syndrome	Distinctive features
Perimysial pathology (IMPP)	Interstitial pneumonitis; Raynauds; Arthritis Graft-vs-host disease Aldolase selectively high Antibodies: Jo-1; t-RNA synthetase
Signal recognition particle antibody HMGCR antibody Immune polymyopathy	Acute onset; Severe weakness Serum CK: Very high Necrosis, Fibrosis ± Capillary pathology
Brachio-Cervical	Brachiocervical weakness B-cell inflammation
Histiocytic myopathy	Sarcoid; Immune; Infections Myopathy; Neuropathy; Lung disease Granulomas
Malignancy (Necrotic)	Rapid onset; Older patients Necrotic muscle fibers: Many
IIM + VAMP (Vacuoles, Aggregates or Mito Path) Inclusion body myositis (IBM) Mitochondrial (P-COX; PM-Mito)	Quadriceps & Finger flexor weakness; Older onset age; Steroid resistant Endomysial inflammation; COX- muscle fibers Inclusions; Aggregates; Vacuoles
Dermatomyositis	Weakness; Skin rash Perifascicular pathology Muscle fiber atrophy; COX reduced; Capillary pathology
Drug-induced	D-penicillamine
Other systemic disorders	HIV; Fasciitis
Idiopathic	Proximal weakness; High CK; Inflammatory myopathy
Collagen vascular disease	Myalgias; Younger onset Scleroderma & Mixed connective tissue disease
MAS antibody	Acute onset; Rhabdomyolysis
Familial	Homozygosity at HLA-DQA1 locus

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
        
        PM-Scl-75
        
        U3-RNP
        Ku
        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
    - Pulmonary arterial hypertension
    - Neuropathy
  - Laboratory
    - Antibodies
      - PM-Scl
      - U3-RNP: Association with myopathy & pulmonary arterial hypertension
    - 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 myopathy
  - Muscle disease often mild & non-progressive
  - U1-RNP antibody
- Also see: Brachio-Cervical Inflammatory Myopathy

Anti-Jo-1 antibody syndrome

From: Dr M Harms

Mechanic's Hands

General
- Disease classification: Immune myopathy with perimysial pathology (IMPP)
- Other similar IMPP syndromes may occur without anti-Jo-1 antibodies
- Characteristic IMPP features
  - Myopathy 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

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

Anti-Jo-1 antibodies
- Target antigen: Histidyl t-RNA synthetase
- Serum IgG1
- HEp-2 immunofluorescence pattern: Speckled cytoplasmic
- Specificity > 95%
- Associated antibody: Anti-Ro52 (40% to 72%) ⁶⁹
  - Myositis: More progressive
  - Joint involvement
    - More common
    - Hydroxyapatite calcifications
    - Erosions of metacarpophalangeal and interphalangeal joints & wrists
  - Interstitial lung disease: More symptomatic; Dyspnea; Cough
  - Skin: Mechanic's hands more common
  - Neoplasm: 19%; Usually > 50 years of age; Colon, Ovarian & Breast
  - Survival rate: Reduced
- 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

Myopathy with Signal Recognition Particle (SRP) antibodies
- Epidemiology
  - Female > Male
  - African-Americans: Increased frequency
  - Onset
    - Age of onset
      - Usual: 4th & 5th decade; Range 36 to 51 years
      - Occasional: Childhood; 5 to 16 years ⁶⁶
    - 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
  - Muscle fibers: Myopathy
    - Active: Necrosis & Regeneration; Early in course
    - Fiber size: Varied (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
Myopathy with HMGCR (200/100) antibodies⁶⁴
- Epidemiology
  - 16 patients described
  - Females 63%
  - Associated with statin use: 63%
    - Higher frequency than other immune myopathies: 15%
    - Not higher than IBM: 36%
- HMG CoA Reductase (HMGCR) protein
  - Catalyzes a rate-limiting step in cholesterol biosynthesis
  - Inhibited by statins
- Clinical
  - Onset age: 22 to 74 years; Mean 58 years
  - Weakness
    - Proximal
    - Variable: Severe to Mild
    - Wheelchair use 25%
  - Myalgias 75%
  - Systemic features
    - Dysphagia 63%
    - Arthralgias 50%
    - Malignancy 13%
    - Raynaud's phenomenon 13%
    - Rash 44%
    - Interstitial lung disease 0%
  - Treatment
    - Prednisone
      - Often incomplete response
      - ? Required in maintenance
    - Rituximab
    - IVIg
    - Strength may become normal with CK still somewhat high
- Laboratory
  - HMGCR (200/100) antibody
    - Recognizes 200 kD & 100 kD antigens
      - 100 kD antigen: 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase (HMGCR)
      - 200 kD antigen: ? HMGCR dimer or co-precipitant
    - Associations
      - Antigenic target: C-terminal fragment of HMGCR
        
        HMGCR protein location: Endoplasmic reticulum
        
        HMGCR activity: Inhibited by statins
      - Prior statin use: 67%; 92% over 50 years of age
      - Muscle biopsy: Active myopathy
      - Not present with SRP myopathy
    - HMGCR protein: Upregulated in regenerating muscle fibers
  - Serum CK: Very high; 3000 to 24,000
  - ANA > 1:160: 6%
  - ESR high: 38%
  - EMG: Irritable myopathy (88%)
  - MRI: Muscle "edema" & atrophy
  - Muscle pathology
    - Necrosis & Regeneration: Common
    - Inflammation: 33%
    - Capillaries: Walls thickened; Normal number
    - MHC Class I: Normal or mildly increased
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 Myopathy ⁴⁷
- 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 strength
    - Ocular: Ptosis or ophthalmoplegia in 30%
    - Course: Progression to maximal weakness over months
  - Myalgias (20%)
  - Associated systemic features
    - Skin: Rash (10%)
    - Weight loss: Prominent (30%)
  - Other associated disease syndromes: Most patients
    - Myasthenia gravis (30%)
    - Rheumatoid arthritis (20%)
    - Mixed connective tissue disease
    - Sjögren
    - Scleroderma
- Laboratory
  - ANA +: 95%; Titers 1:80 to 1:5120; Mean 1:640
  - Serum CK: Normal to 15x elevated
  - Electrodiagnostic
    - EMG: Myopathic; Spontaneous activity
    - Repetitive nerve stimulation decrement: 40%
  - Anti-AChR antibody: 30%
- Muscle pathology
  - Muscle fiber pathology
    - Necrosis & regeneration
    - Focal invasion of muscle fibers: 60%
  - C_5b-9 complement (MAC) deposition: Diffusely in endomysium
  - Mononuclear focal infiltrates: 90%
    - Composition
      - B-cells present in some foci most patients
      - Some foci without B-cells
    - Location: Perivascular & Perimysial
    - Associated vessels: Intermediated-sized; Rarely have elastin fibrils
  - MHC-I expression in muscle fibers: 90%
  - MxA capillary staining: 90%
Myositis + Myasthenia gravis⁴³
- Also see: Brachiocervical inflammatory myopathy
- 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
      - Associated with HLA-DR1
      - Clinical: Similar to other autimmune MG
      - Remits on withdrawal of drug
    - Neuromyotonia
    - Pemphigus
- Lupus ± myositis: Procainamide; Hydralazine
- Minocycline
  - Immune myopathy with perimysial pathology (IMPP)⁶³
    - 1 case report
    - Clinical
      - Progression: 2 months
      - Weakness: Proximal
      - Myalgias: Exacerbated by exercise
      - Fatigue
      - Arthralgias: Hands; Feet
      - Skin: Painful erythematous plaques over legs; Edema
    - Laboratory
      - CK: 2100
      - EMG: Irritative myopathy
      - Muscle: Perimysial cellularity
  - Also may produce: Rhabdomylysis syndrome
- 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
  - Genetic susceptibility
    - Interleukin-10 promoter variation
  - 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: IMPP
    - 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 with Vasular Pathology
Childhood
Adult
Childhood & Adult
Mi-2 antibody positive
Dermatomyositis: Other Adult
Amyopathic
Drug-related
Mi-2 antibody negative
Malignancy-associated
Jo-1 antibody positive
EJ antibody positive
PM-Scl

Tim Miller

Dermatomyositis: Clinical features, general

Epidemiology
- Higher frequency: Mesoamerica
- Lower frequency: Northern cities
- Frequency in children: > 90% of immune myopathies
Clinical features: Common ⁶⁵
- 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
  - Hemophagocytic syndrome ⁵⁵
Differential diagnosis: Immune myopathy with perimysial pathology (IMPP)
- Dermatomyositis vs IMPP

Dermatomyositis syndromes: Specific features

Childhood (Juvenile) Dermatomyositis (Dermatomyositis with Vascular Pathology; DM-VP) ⁵³

Clinical
Epidemiology
Laboratory
Treatment
- Variant: Dermatomyositis with Mi-2 antibodies
- Epidemiology & Associations²³
  - Incidence
    - General: May vary with geography & genetic background
    - Range in children: 0.14 to 0.5 per 100,000 per year; US = 0.32
  - Female > Male: Range = 1.7x to 5x; US = 2.3 to 1; UK 5 to 1
  - Race (US & Canada): White (non-Hispanic) 65% to 83%; Hispanic 0% to 14%; African-American 5% to 11%; Asian 0% to 6%
  - Prodrome
    - ? Upper respiratory or GI infection: Common in 3 months before onset
    - No clear association with with specific tested pathogens
  - Other possible associated factors
    - Hepatitis B vaccine
    - Growth hormone replacement
    - Sun exposure: Excessive
    - Drugs: Carticaine; Penicillamine
    - 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 in JDM
        
        Increased vascular occlusion
        
        Longer course
    - Interleukin-1 receptor antagonist gene (IL-1RN) : A1 allele
      - Associated with increased proinflammatory activity
      - Risk factor for Caucasians with JDM
    - Type-1 interferons: Serum IFN-α activity associated with
      - Higher serum levels of muscle enzymes
      - Shorter duration of untreated disease
    - HLA
      - Class II: DQα1*0501 antigen (88%)
      - DM: DRB1*0301; DQA1*0301; DQA1*0501; DMA*0103; DMB*0102
      - HLA-A*68; DQA1*01
    - Protein tyrosine phosphatase gene N22
    - Allotypes: Gm; KM
- Clinical features
  - Onset
    - Age
      - Mean: 7 years
      - Range: 2/3 between 4 and 12 years
      - Famales: 2 peaks at 6 & 11 years
      - Males: Most < 10 years
    - Rash: 50%
    - Weakness: 25%
  - Weakness
    - Generalized: Proximal > Distal
    - Symmetric
    - Bulbar (Dysphonia or Dysphagia): 20%
  - Muscle discomfort
    - Pain (25% to 50%)
    - Tenderness
    - Swelling
  - Muscle atrophy: 45%
  - 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
      - Photosensitivity: 50%
    - 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
      - Macular lesions = Gottron's sign
    - Nailfold capillary & cuticular changes (80% to 90%)
      - Capillary loss
      - Correlations: Disease activity; Length of untreated disease
      - Cuticular hypertrophy
    - Pruritis
    - Cutaneous ulcerations
      - Related to complement deposition with occlusive endarteropathy of dermal vessels
      - Frequency: 10%
      - May predict
        
        Severe course of illness
        
        Persistent weakness,
        
        Widespread calcinosis
        
        Poor response to therapy
    - Scalp: Atrophic, erythematous, scaly plaques
  - Edema
    - Face: 34%
    - Body: 15%
  - Joints
    - Arthritis & Arthralgis
      - Frequency: 6% to 58%
      - 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
      - Locations: Ankles, Flexors & other joints
      - Frequency: 25% to 30%
  - Vasculitis
    - Visceral infarction
    - GI bleeding
    - Associated with poor prognosis
  - Calcinosis: Images
    - Frequency: 24% 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
      - Tumor necrosis factor alpha (TNF-α) 308 allele
      - Increased production of TNF-α
    - Related to hydroxyapatite accumulation
    - Increased local production of TNFα
  - Lipodystrophy⁵⁷
    - Pathology: Loss of mature, functional adipocytes
    - Onset: Later in disease course; Mean 4 to 5 years after diagnosis
    - Frequency: 8% to 40%
    - May occur in otherwise well treated dermatomyositis
    - Distribution
      - May be generalized, partial or focal
      - May be defined by MRI
    - Generalized LD
      - Subcutaneous fatty tissue loss
        
        Distribution
        
        Face; Trunk; Extremities
        Relative sparing of medial thighs
        
        Symmetrical
        
        Fat gain: Intra-abdominal
        Course: Progressive, slow
      - Associated with: Anti-p155 autoantibody
    - Partial LD
      - Associated with: Panniculitis
      - Distribution
        
        Mainly involves upper body
        
        Relative sparing of medial thighs
    - Focal lipoatrophy
      - Distribution
        
        Extremity or Buttock
        
        At site of calcinosis
      - Associated features
        
        Joint contractures
        
        Calcinosis
        
        Chronic disease course
        
        Facial erythema
        
        Panniculitis
        
        Dysphonia
    - Associated features
      - Acanthosis nigricans
      - Hirsutism
      - Fat redistribution
      - Steatosis/nonalcoholic steatohepatitis
      - Insulin resistance
      - Lipids: Hypertriglyceridemia; HDL low
    - Associated DM features
      - Calcinosis
      - Muscle atrophy
      - Joint contractures
      - Facial rash
      - Chronic course
    - ? Female preponderance
  - Gastrointestinal
    - Esophageal dysmotility
    - Malabsorption
    - Infarction: Abdominal pain
    - Dysphagia: 25%
    - Dysphonia
  - Constitutional features
    - Fever: 16�65%
    - Adenopathy: 20%
    - Lethargy: 10%
  - Other
    - Pulmonary: Uncommon (7% to 43%)
      - Dyspnea
      - Interstitial lung disease: Rare
    - CNS: Rare
    - Cardiac
      - Clinically significant: Unusual
      - EKG: Right bundle branch block; ST-T wave abnormalities
  - Prognosis
    - Mortality: 2% to 7%
    - Incomplete recovery: Common
    - Relapses (polycyclic): Common
    - Chronic course requiring medication > 3 years: 30% to 60%
    - Long term remission (Monophasic)
      - Frequency: 37%
      - Mean time to remission off medications: 4 to 5 years
    - Worse with
      - Inadequate treatment
      - Gottron's papules & nailfold pathology persisting after initial treatment
  - Variant: Amyopathic JDM
    - Normal strength & muscle enzymes for 2 years
    - Calcinosis: Low frequency
    - SAE antibody
  - Variant: Overlap JDM
    - Frequency: 3% to 10% of juvenile immune myopathies
    - Myositis: May be milder
    - Most common association: Features of scleroderma
    - Other associated immune disorders
      - Systemic lupus erythematosus
      - Juvenile idiopathic arthritis
      - Inflammatory bowel disease
      - Diabetes mellitus, type 1
      - Coeliac disease
- Laboratory
  - B-lymphocytes
    - Increased percentage of circulating lymphocytes
    - B-cell foci may occur in muscle
  - Serum CK
    - May be normal at presentation
    - High in some patients: 50% to 67%
  - Serum aldolase: 84% high; May be high with normal CK
  - Immunoglobulin γ-chain allotypes
    - Mestizo children: Gm 1,3,17 5,13,21
  - Antibodies ⁷¹
    - p155 (29%): Neoplasm-associated
    - MJ (p140): Juvenile Dermatomyositis with Calcinosis
    - SAE & IFIH1: Amyopathic dermatomyositis
    - Mi-2: Dermatomyositis without other connective tissue disorders; 3% to 10%
    - ANA: 40% to 59%
    - Cardiolipin: IgM 41%; IgG 12%
    - Organ specific: 27%
      - Thyroid (Thyroglobulin; Thyroid peroxidase (TPO); TSH): 15%
      - Type I diabetes (Insulin; GAD; Tyrosine phosphatase (IA2)): 15%
      - May not be associated with clinical disease
    - Rare (< 3%): Anti-synthetase antibodies; dsDNA; Ro; Scl70
  - MRI of muscle
    - Features: Bright areas on short-tau inversion recovery-weighted images
    - Frequency: 76% abnormal
  - Nailfold capillaroscopy
    - May also be abnormal in scleroderma, overlap myositis, or mixed connective-tissue disease
    - Useful to distinguish DM from hereditary myopathies
  - Muscle biopsy
- Treatments
  - Corticosteroids: IV or Oral
  - Intravenous immunoglobulin
  - Methotrexate: 15 mg/m² per week; Oral or Subcutaneous
  - Rituximab
  - Cyclophosphamide: Refractory cases
  - Photoprotection
Adult Dermatomyositis: Mi-2 antibody negative
- Clinical
  - 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
- Pathology
  - IMPP
  - Also see: DM adult variant
Dermatomyositis: Mi-2 antibody positive
- Epidemiology
  - More common in Mestizo (Mexico & Guatamala)
  - Higher UV index in US⁶¹
    - Women: Increased frequency of DM & Mi-2 antibodies
    - Men: No association
    - No association with: Synthetase or SRP antibodies
  - 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 ⁶⁷
- Females > Males
- Risk factors
  - Age related
    - Mean 50 to 60 years
    - Especially > 52
    - May occur in adults of any age
  - Dysphagia
  - Rapid onset
  - Skin: Necrosis; Periungual edema
  - No interstitial lung disease or ? Jo-1 antibody
  - Complement factor C4: Low
- Protective: Low lymphocyte count
- Skin disorder: Cutaneous vasculitis
- Neoplasms³⁶: Especially adenocarcinoma
  - Ovarian: Advanced stage & uniform epithelial +...
  - Nasopharyngeal (China; Korea; Tunisia)
  - Breast
  - Lung
  - Hematologic: Lymphoma/Leukemia
- 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
  - Also see: Hydroxyurea
- 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
      - Antigen: MDA5 (IFIH1)
      - Interstitial lung disease: Rapidly progreesive; Asians
    - Antinuclear antibodies: 50% to 90%; Speckled pattern
    - Other: 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
Drug induced Dermatomyositis⁵⁴
- General
  - Male = Female
  - Mean age: 57 years
  - Common involvement: Skin
  - Myopathy: 39%
  - Pulmonary: 11%
- D-penicillamine
- Hydroxyurea
  - Epidemiology
    - Associated malignancy: Chronic myelogenous leukemia (CML)
    - Onset age: Mean 61 years
    - Time from drug onset: 60 months
  - Clinical
    - Skin: Typical rash & other features
    - Myositis & Weakness: Not present
    - Time to resolution: Mean = 2 months
  - Laboratory
    - ANA: Infrequent; 16%
- Other possible drugs
  - Atorvastatin
  - Carticaine
  - Niflumic acid
Other antibody related
- EJ antibody positive
- PM-Scl antibody positive

Dermatomyositis: Laboratory features

Serum CK: Normal or High (up to 30 times normal)
Antibodies
- p155/140
- CADM-140
- MJ (p140)
- SAE
- Mi-2
- Atypical DM (IMPP syndromes): 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: Muscle Pathology
- Muscle fibers
  - Myopathic changes
    - Distribution: Perifascicular regions
    - Type
      - Muscle fiber atrophy
      - Abnormal internal architecture
      - Occasional patients: Necrosis + phagocytosis; Regeneration
      - Vacuolation
  - Cyotochrome oxidase staining
    - Reduced: Mainly in regions in or near perifascicular atrophy
    - SDH staining in same muscle fibers is normal
  - Caveolin-3 aggregates: In muscle fibers in & near regions of perifascicular atrophy
  - MHC Class I expression on muscle fibers ⁶⁰
    - Frequency: 95%
    - May be selective or more prominent on perifascicular muscle fibers
    - Normal muscle: None; Present only on vessels
  - MHC Class II expression on muscle fibers
    - Present in minority of biopsies
    - Associated with: Prominent inflammation; Increased connective tissue
  - CD59 : Reduced on muscle fibers & capillaries
  - Proteins in perifascicular atrophic muscle fibers
    - ISG15 protein & conjugation pathway
      - Upregulation
      - ISG15 protein
        
        Ubiquitin-like
        
        Conjugated to many cellular proteins upon activation by interferons: α (IFNA ) & β (IFNB )
    - Titin: Reduced to 3% of controls
    - Nebulin; TNNC2: Moderately reduced
- 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) & capillaries ²⁶
  - Endothelium
    - Swelling
    - Microvacuoles
    - Inclusions
  - Endomysial capillaries
    - Reduced Number: Especially in regions of perifascicular atrophy
    - Enlarged
  - Arteries & Intermediate-sized vessels
    - Regions most often associated with mononuclear cell inflammation
    - May be occluded or damaged
    - May have deposits of complement & immune components
      - Types or depositis: C3d; C4d; C5; Fibrinogen
      - Clinical associations: Gastrointestinal involvement; Chronic disease
- Inflammation (50%)
  - Usually perivascular
  - T-cells: Common
  - May contain B-cell foci
  - Few macrophages
Skin pathology: May include
- Vacuolar interface change
- Dyskeratotic keratinocytes
- Dermal mucin: Increased
- Papillary dermal blood vessels: Dilated
- Perivascular infiltrate: Superficial; In absence of epidermal spongiosis

Dermatomyositis treatment: Immunosuppressive & Other

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: 15 mg/m² per week; Oral or Subcutaneous
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
Skin lesions
- Hydroxychloroquine: 200 mg bid; Not effective for myopathy

Inflammatory Myopathies with Vacuoles, Aggregates & Mitochondrial Pathology (IM-VAMP)

Subtypes
Inclusion body myositis (IBM)
Muscle Pathology
Inflammatory myopathy with mitochondrial pathology (IM-Mito)
Muscle pathology

Inclusion Body Myositis (IBM) ²²

Epidemiology
- Male preponderance: 57% to 75%
- Sporadic
Onset
- Age
  - > 50 years in 80%
  - > 60: More common in males
- 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
    - Loss of strength
      - Rate: 4% to 5% per year
      - Slower in Inflammatory myopathy with Mitochondrial pathology
      - Fastest in lower legs
      - Mean time to wheelchair: 14 years
      - More rapid
        
        In lower legs
        
        Symptoms begin after age 60
        
        Males
        ? in patients treated with immunosuppressants
    - Causes of death
      - Respiratory
      - GI: Aspiration; Dysphagia; Cachexia
    - Life expectancy: Near normal
- 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
  - General
    - Inflammatory myopathy with Vacuoles, Aggregates & Mitochondrial Pathology (IM-VAMP)
  - 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
    - Cell types in foci
      - CD4: Most common
      - CD8: Present in some CD4 foci
      - Not CD20
  - 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
      - LC-3
    - 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
    - No specific association with inflammatory cells or foci
- 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
- Antibody, Serum: 43-kDa muscle antigen (52%) ⁷⁰
Treatment
- None definite
- Few reports of response to IV Ig or immunoabsorption
- Methotrexate: Some variants may have some improvement in strength
Variant syndromes
- Polymyositis with mitochondrial pathology
  - Slower progression of weakness
  - No vacuoles in muscle biopsy
- Autosomal dominant inheritance
  - Similar clinical features to sporadic IBM
  - Less or no: Inflammation: MHC-I upregulation by muscle fibers
  - No HLA type association