Inflammatory & Immune Myopathies

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Inflammatory & Immune Myopathies (IIM): Acquired

IIM: General Features

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

Pathology
Differential disagnosis
Pathology

Animal Models
Experimental autoimmune myositis
MHC class I upregulation

History
Dermatomyopathies
IIM: Possible 1st case, Hepp 1887
Berliner Klinische Wochenschrift

Immune or Inflammatory Myopathies (IIM): Syndromes
Immune myopathies General aspects Clinical Laboratory Subtypes & Comparative features Brachio-Cervical Inflammatory (BCIM) Checkpoint Inhibitor Collagen vascular disease Complement: C2 deficiency Drug-induced Graft-vs-host disease HMGCR (200/100) antibody Idiopathic IMPP MAS antibody Megaconial Nup antibody Perimysial pathology (IMPP) Jo-1 OJ t-RNA synthetase antibodies PM + Mitochondrial (PM/COX-) Regional ischemic (RIIM) Sarcoidosis Signal recognition particle Ab (SRP) Systemic disorders & Myositis U1-snRNP antibodies Dermatomyopathies Childhood (Juvenile) Adult Drug-induced Malignancy-associated NXP-2 antibody p155 (TIF-γ) Ab Regional ischemic (RIIM) MDA-5 antibody PM-Scl antibody + Amyopathic Mi-2 antibody + Perimysial pathology (IMPP) EJ antibody Jo-1 antibody Histiocytic Giant Cell Granulomatous Mitochondrial antibody Sarcoidosis IMPP IM + Abundant Macrophages LHIM Macrophagic myofasciitis		IM-VAMP Inclusion body myositis (IBM) IM-Mito (PM/COX-) Other "Immune Myopathies" Benign acute childhood myositis Celiac disease Chondroitin sulfate C deficient Decorin antibody (BJ) myopathy Eosinophilia myalgia syndrome Fasciitis Focal myositis Orbital Quadriceps; Other TRAPS Hemophagocytic lymphohistiocytosis Hereditary Infections Influenza Lyme myositis Pyomyositis Sarcocystis Toxoplasmosis Trichinellosis (Trichinosis) LHIM Lupus Masticator myopathy Multinodular polymyositis Myasthenia gravis Brachio-Cervical Inflammatory (BCIM) Myositis Lymphorrhages Necrosis, Abundant Encephalopathy HMGCR antibody Jo-1 antibody LHIM Pipestem capillaries Regional Ischemic Immune (RIIM) SRP antibodies Necrosis syndromes Neonatal perifascicular myopathy NMO + AQP4 Ab Perimyositis Polymyalgia Rheumatica Systemic Sclerosis (Scleroderma)

IIM: Pathologic Characterization ⁶⁸

Myofasciopathy
Tissue Δ: Connective tissue + Muscle fibers
Perimysial Pathology(IMPP)
Features
Perimysial damage & Histiocytes
Aldolase high
Dermatomyopathy with IMPP
Amyopathic (MDA5 Ab)
Fasciitis
t-RNA synthetase antibodies: Jo-1
IMPP + Necrosis
HMGCR (200/100) antibody
Endomysial Pathology
Features: C_5b-9 deposits; Glycoprotein Δ
Brachio-Cervical Inflammatory (BCIM)
Graft-vs-host disease
Chondroitin sulfate C deficient
Decorin antibody (BJ) myopathy
Endomysial + Perimysial Pathology
Feature: Connective tissue proliferation
SRP antibody
Focal myositis

Myovasculopathy
Tissue Δ: Vessels + Muscle fibers
Dermatomyositis with Vascular Pathology
(DM-VP; Childhood Dermatomyositis)
Regional Ischemic (RIIM; Paraneoplastic)
DM + NXP-2 antibodies
DM + TIF1γ antibodies
Pipestem capillaries
Systemic Sclerosis

Histiocytic Myopathy
Tissue Δ: Muscle; Histiocyte Inflammation
Granulomatous
Mitochondrial antibody
Sarcoid
Hemophagocytic lymphohistiocytosis
IM + Abundant Macrophages (IMAM)
IRIS
LHIM
Macrophagic myofasciitis

Primary Myopathy
Tissue Δ: Muscle fibers
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
LHIM
Also see: Muscle fiber necrosis

Multiple Tissue Pathology
Focal myositis
Graft-vs-host disease

Immune or Inflammatory Myopathies

General Features ³⁴

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

Skin
Involvement ⁷⁴

From: M Al-Lozi
DM-VP: Rash

Rash: Erythema
From: Chinju, South Korea

Gottron's papules

Nailfold lesions

Immune (Dermato)Myopathy syndromes: Differential Diagnosis
- Dermatomyositis, Childhood (Vascular) type
- Malignancy-associated
- Graft-versus-Host disorders
- Regional Ischemic Immune Myopathies (RIIM)
- Immune Myopathies with Perimysial Pathology (IMPP)
- Antibody-related
  - Jo-1 & t-RNA synthetase
  - Mi-2
  - MDA5
  - PM-Scl
  - NXP-2
  - Tif1-γ
Heliotrope rash
- Red-purple edematous ± erythema
- Distribution
  - Face & Upper eyelids
  - Exensor surfaces of joints
  - Symmetric
  - Sun exposed regions
- External links
  - Facial rash
  - Face & Upper eyelids
Gottron papules
- Color: Red-purple (erythematous to violaceous)
- Papules or macules
- Other descriptions: Keratotic or Atrophic
- Distribution
  - Extensor surfaces of joints: Especially MCP, PIP & Distal IP
  - Linear extension: Skin between MCP & IP joints
  - Some patients: Elbows & Knees
  - Often symmetric
- Disease association: Dermatomyositis
Erythema
- Red-purple
- Slightly raised
- Distribution: Extensor surfaces of hands, elbows or knees; Face
Heliotrope eruption
- Color: Erythematous to Violaceous
- Distribution: Periorbital skin; Upper > lower eyelid
- Association: Edema
Poikiloderma
- Photodistributed
- Color: Hyperpigmentation & Hypopigmentation
- Telangiectasias
- Epidermal atrophy
- Regions
  - Upper back (Shawl sign)
  - V of neck & upper chest (V-sign)
- Pruritic: Differs from nonpruritic rash in SLE
- More prominent later in disease course
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, Periungual
- Capillaries: Dilation & Dropout
- Cuticular hypertrophy
- 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
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 disease ³²
  - Usual interstitial pneumonia (UIP): Features on lung imaging
    - Honeycombing
    - Teticulations
    - Basilar predominance
  - Epidemiology: Frequency in PM/DM = 19% to 23%
  - Clinical features
    - Timing (Onset): Relation to myositis
      - Before myopathy: 13% to 20%
      - With myopathy: 41% to 47%
      - After myopathy: 39% to 40%
    - 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
    - IMPP & Anti-synthetase syndromes
    - Onset age: Adults
    - Neoplasm: Unusual
    - Treatment response: More often refractory to corticosteroids
    - Prognosis
      - Poor: 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
      - Survival: Myositis-associated Interstitial Pneumonia ¹⁰¹
        
        Better than: Idiopathic pulmonary fibrosis (IPF)
        Mean: 16 years vs 5 years for IPF
        Common causes of death: Respiratory failure (Pulmonary fibrosis) > Infection
    - Antibodies
      - Myositis-specific
        
        Chronic & recurrent ILD
        
        Anti-tRNA-synthetase antibody syndromes: 31%
        
        Anti-Jo-1: Myositis + ILD
        OJ, PL-12 & KS: ILD > Myositis
        PL-7: PM-Scleroderma + ILD
        
        Lower frequency: Associated skin changes without myositis
        
        Acute progressive ILD
        
        CADM-140 (MDA5/IFIH1): Especially amyopathic DM
        
        Lung pathology: Diffuse alveolar damage (DAD)
      - ILD also occurs without myositis-associated antibodies
        
        Systemic Sclerosis
        
        Topoisomerase I (Scl70)
        
        Th/To
        
        U11/U12 ribonucleoprotein
        
        U1RNP
        Eukaryotic initiation factor 2B (eIF2B)
        
        Overlap syndromes
        
        PM/Scl
        
        Ku
        
        Other
        
        Neutrophil cytoplasmic antibody
        
        Sjögren
        
        Mixed connective tissue disease
    - Muscle pathology: IMPP
    - Other laboratory
      - Higher values of
        
        Erythrocyte sedimentation rate
        
        C-reactive protein
        
        Aldolase: Relative to CK
      - Disease activity markers: Serum
        
        KL-6 (Krebs von den Lungen-6)
        
        SP-D (Surfactant protein-D)
        
        Ferritin
    - 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 ¹¹⁸
  - General: Involvement
    - Often asymptomatic
    - Clinical: 9%
    - May be more common with immune checkpoint inhibitor IIM
  - Types of involvement
    - Myocarditis (PM)
      - Prevalence: 3%
      - EKG changes (100%)
        
        Arhythmias
        
        Conduction block
      - Antimitochondrial antibody M2
      - Late gadolinium enhancement
    - Small vessel disease (DM)
    - Abnormal vasoconstriction (DM)
      - Prinzmetal's angina: ? Associated with Raynaud's
    - Heart failure
    - Conduction defects
  - Laboratory
    - Cardiac troponin T (cTnI)
      - More specific for cardiac involvement than cardiac troponin T (cTnT)
      - May be useful to screen for asymptomatic cardiac disease
    - cTnT
      - More common
      - Correlates with muscle disease activity
    - EKG
      - Non-specific
      - ST-T wave changes
      - LVH: Worse prognosis
    - Transthoracic echocardiography: Most common features
      - Ejection fraction: Abnormal
      - Diastolic dysfunction: Subclinical; ? Associated with disease duration
      - Systolic function: Often normal
    - Cardiac MRI
      - Late gadolinium enhancement in non-ischemic distribution
      - Asymptomatic involvement common
- 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
  - Ulcerative colitis: Dermatomyositis syndromes (China; OR 6.19) ⁹³
- 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
  - NXP-2 antibody
  - External links
    - Dermis, images
    - Pediatric Rheumatology, Review

IIM: Prognosis

Worse
- Onset: Acute; Older age
- Cardiac involvenment
- Fever
- Arthritis
- Hypergammaglobulinemia
- Lung fibrosis: Interstitial lung disease; TLCO reduced
- Malignancy
- Antibodies: Synthetase; SRP
- Systemic Sclerosis/Polymyositis Overlap Syndromes worse than SSc only (Antitopoisomerase I +) ⁹⁷
Causes of death ⁹⁶
- Lung involvement: Interstitial disease
- Infections: Pneumonia
- Malignancy: Different organs
- Cardiac: Myocardial infarction
- Mortality rate, General: 18% at 10 years; 34% at 20 years

Immune Myopathies: Serum Creatine Kinase (CK) & Aldolase

Very high
- SRP myopathy
- RIIM (Paraneoplastic)
- Jo-1 myositis
- Myopathy with HMGCR (200/100) antibody
- Large Histiocyte Immune Myopathy (LHIM)
Normal or Mildly elevated CK
- Inclusion body myositis; Polymyositis with cytochrome oxidase negative muscle fibers
- Dermatomyositis
  - Adults with selective fascia pathology
  - Childhood DM: Some patients
Elevated aldolase with normal CK
- Immune myopathies with perimysial pathology (IMPP) ⁵⁹
- Dermatomyositis, childhood type

Immune myopathies: HLA & Genetic associations ⁴⁶

Immune myopathies in Caucasians
- Most risk: Major Histocompatibility Complex (MHC) region
- Intronic variant of HLA-DQA1 (rs9272729-A)
- Human leukocyte antigen (HLA) 8.1 ancestral haplotype (AH8.1; HLA A1-B8-DR3-DQ2)
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 & DQA1*05
Interstitial lung disease
- Increased HLA-DRB1*03-DQA1*05-DQB1*02 haplotype
Jo-1 & Anti-Synthetase antibodies
- HLA-DRw52; DR3 (90%); DQ2 (80%)
- Anti-synthetase & Anti-PM-Scl
  - General: DRB1*0301; DQA1*0501; & DQB1*02
- AGER & PSMB8 in MHC locus
Anti-SRP antibodies
- 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 ethnicity ²⁷
- 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
- Susceptibility region: 172 kb encompassing HLA-DRB3, HLA-DRA & BTNL2
- HLA types: DRβ1*0301, DRβ3*0101 (or DRβ3*0202) & DQβ1*0201
Sarcoidosis: Class II HLA allelic variation ³⁹
- 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 & IBM ¹⁰²
- Protein tyrosine phosphatase N22 gene (PTPN22) : R620W variant (C1858T polymorphism)
  - Also associated with diabetes , rheumatoid arthritis & myasthenia gravis
ADA2 deficiency

Immune & Inflammatory Myopathies: Neoplasm Associations ¹⁵

General
Antibodies
Dermatomyositis
Syndromes
Neoplasms
Pathology
Muscle
Skin
Polymyositis
Risk
Screening

Immune & Inflammatory Myopathies Risk Stratification for Neoplasm Screening
	High	Intermediate	Low
IIM Subtype	DM-VP, Adult RIIM	BCIM DM, Amyopathic	DM-VP, Child IMPP IIM + Connective tissue disease IBM
Clinical Feature	Onset age > 40 yrs Dysphagia Cutaneous necrosis Treatment resistant	Males	Raynaud Arthropathy ILD
Serum Antibody	Tif1-γ NXP2	SAE1 HMGCR Mi2 MDA5 Jo-1 + Ro52	Jo-1 Other Synthetase SRP54 PM/Scl
High Risk Patient: ≥ 2 High risk features

General
- Risk stratification
- Neoplasm frequency may depend on ethnic background
Risk of malignant disease ¹³⁰
- Temporal
  - Highest: Near time of myositis diagnosis (1 to 3 years)
  - Lower but possibly still present: > 3 years after diagnosis
- Age: Mainly in adults
  - General: Increased with older ages
  - 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
- Dermatomyositis > Polymyositis > IM-VAMP (IBM)
- Other clinical: Higher association with
  - Cutaneous ulceration
  - Dysphagia
  - Severe/Refractory disease
- Reduced neoplasm association
  - Childhood
  - Interstitial lung disease
  - Raynaud phenomenon
  - Arthritis
- Antibodies
  - Increased neoplasm risk: NXP-2; Tif1-γ
  - Reduced neoplasm risk: Synthetase; SRP
  - No association: HMGCR; MDA5
  - ANA: Increased risk with Nucleolar pattern
Screening
- Especially appropriate
  - Specific associated cancers at time of diagnosis & at follow up
- Timing: Patients within 3 years of onset
- Risk levels
- Basic
  - Comprehensive History & Physical examination
  - Blood
    - CBC
    - Liver function
    - ESR and/or Plasma viscosity
    - C-reactive protein
    - Protein electrophoresis & Free light chains
  - Urinalysis
  - Plain chest X-ray radiograph
- Enhanced risk
  - CT (Neck/Chest/Abdomen/Pelvis)
  - Females: Cervical & Mammography screening
  - Males: PSA
  - Tumor markers: CA125
  - Ultrasound: Testicular or Gynecological
  - GI: Endoscopy; Occult blood
  - PET: Especially Tif1-γ antibodies
  - Timing: Annually x 4 years
Dermatomyositis: Malignancy associated, General ^50,⁶⁷
- Risk
  - Overall 32% (2.2x to 7.7x increased)
  - Females > Males
  - 58% of neoplasms developed after DM diagnosis
  - Age related: Increased
    - Mean 50 to 60 years
    - Especially > 52
    - May occur in adults of any age
  - Rapid onset
  - Complement factor C4: Low
  - Protective: Low lymphocyte count
- Clinical features
  - Age: Increased; Adult (> 50 years)
  - Disease progression: More rapid
  - Timing: 1 year before to > 3 years after Dx
  - Dysphagia: More
  - Skin disorders
    - Cutaneous vasculitis
    - Necrosis
    - Periungual edema
  - Neoplasm association: Less
    - Arthritis
    - Interstitial lung disease (ILD)
    - Connective tissue diseases (CTD)
    - Jo-1 antibody
  - Survival
    - Mortality: Increased; Due to neoplasm
    - 5 year 38%; Mean 3 to 4 years
- Laboratory features
  - Erythrocyte sedimentation rate (ESR): Higher
  - Hemoglobin levels: Lower
  - Higher CK, > 1000
  - Serum albumen: Low (< 35 g/L)
  - Antibodies
    - Reduced risk of neoplasm
      - Myositis-specific/associated antibodies: tRNA-synthetase
      - Anti-Nuclear Antibodies (ANA) ¹⁰⁹
    - Increased risk of neoplasm: Antibodies
      - TIF1-γ
      - NXP-2
  - Muscle Pathology Syndromes
    - DM-VP, Adult
    - RIIM
  - Skin pathology ¹²⁹
    - Subepidermal melanophages
    - CD123+ plasmacytoid dendritic cells: Superficial distribution
    - Basement membrane thickening
- Neoplasms ³⁶: Especially adenocarcinoma
  - 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
  - Cell types: Squamous (Especially males); Adeno; Hematologic
  - Sex
    - Males: Lung
    - Females: Breast; Thyroid; Cervical
    - Ovarian: Advanced stage & uniform epithelial +...
  - Geography
    - Scandinavia: Ovary, Lung, Pancreas, GI, non�Hodgkin lymphoma
    - Scotland: Cervical, Ovary, Lung
    - Asia: Nasopharyngeal (North China), Lung, Breast, GI, Ovary, Liver
    - Nasopharyngeal: Asian
      - Southeastern (China; Korea; Tunisia)
      - Related to chronic active infection by Epstein-Barr virus (EBV)
  - Other types
    - Breast
    - Lung
    - Lymphoma
      - B-cell type: 63%
      - IM before or during lymphoma: 68%
      - Age: Older than average IM
      - Less common: Joint involvement; Jo-1 antibody
- Specific Dermatomyopathy paraneoplastic syndromes
  - Regional Ischemic Immune Myopathy (RIIM)
  - DM + TIF1γ antibodies
    - TIF1γ antibody
    - vs other Cancer-associated myositis
      - Younger
      - Lower mortality rate
    - Frequency in neoplasm-associated dermatomyositis: 50%
    - Frequency of neoplasm-associated dermatomyositis when present: 44% to 75%
  - Cutaneous necrosis ⁵⁶
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
- Regional ischemic immune (RIIM)
- Dermatomyositis with cancer (p155 (TIF-1γ) antibody)
- Other
- ? Inclusion body myositis: M-proteins; Large cell lymphoma

Serum Antibodies

IIM: 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

IIM: MRI ³³

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

IIM Pathology: Differential Diagnosis

Classification

Inflammation
Muscle fibers
Necrosis
Capillaries
Mitochondrial
Connective tissue
Matrix metalloproteinase
MHC-I

Endomysial inflammation

Oppenheim 1894

Foci of mononuclear cell inflammation
- Prominent
  - Brachio-Cervical inflammatory myopathy: Perivascular, Perimysial & Endomysial
  - IM-VAMP: Endomysial; CD4 & CD8 cells
    - Polymyositis with Mitochondrial Pathology
    - IIM + VAMP: Inclusion Body Myositis
  - DM-VP: Perivascular (Perimysial)
- B-cell (CD20+) foci
  - Common
  - Rare or Absent in
    - Inclusion body myositis
- Histiocytes
  - Scattered
    - IMPP
    - Fasciitis
    - IRIS
    - LHIM (Myophagy)
  - Foci
    - Granulomas: Sarcoid
    - IMAM
    - MMF
    - ICI
    - Cryptococcus
    - Giant Cell
- Selective or prominent localization in
  - Endomysium: IM-VAMP syndromes
    - Polymyositis with mitochondrial pathology
    - Inclusion body myositis
  - Perimysium
    - IMPP
    - Fasciitis
- Associated adhesion molecules on inflammatory cells ³¹
  - 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
  - Large Histiocyte Immune Myopathy (LHIM)
  - Acute polymyositis: Inflammation mainly associated with necrotic muscle fibers
Muscle fiber pathology
- Necrosis: Abundant early in disease course
  - Regional Ischemic Immune Myopathy (RIIM; Paraneoplastic): Regional (clustered) necrosis
  - HMGCR (200/100) antibody
  - SRP antibody syndrome: Scattered necrotic fibers
  - Large Histiocyte Immune Myopathy (LHIM)
  - Jo-1 associated myositis: Necrotic fibers, Perifascicular predominant
  - IM + Encephalopathy
  - Pipestem capillaries
- Focal invasion of muscle fibers: By CD8 lymphocytes & Macrophages
- Size
  - Varied: Usually Atrophic & Normal
  - Hypertrophy: Unusual
    - Common in IBM (IM-VAMP)
  - Atrophy with no necrosis
- 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; MDA5 antibody (Pauci-myopathic Dermatomyopathy)
- 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)
Capillary pathology
- Dermatomyositis with vascular pathology (DM-VP)
  - Small & Endothelial pathology
    - Perifascicular regions with muscle fiber atrophy
    - C_5b-9 deposition
  - Enlarged: Regions neighboring perifascicular atrophy
- Chronic Graft vs Host Disease (cGvHD)
- SRP myopathy syndrome: Enlarged; C_5b-9 deposition
- Pipestem capillaries: Enlarged; Thickened walls
- Systemic Sclerosis (Scleroderma)
- Microvasculopathy
- Gastrocnemius muscle
Connective tissue
- Endomysium
  - Usual: Mild, patchy increase in endomysial connective tissue
  - Increased, Markedly & Rapidly
    - SRP myopathy
    - Focal Myositis
  - Glycoprotein pathology
    - Chronic Graft vs Host Disease (cGvHD)
    - Chondroitin sulfate C deficient: Reduced Chondroitin sulfate C
    - Decorin antibody (BJ) myopathy: Serum IgM binding to endomysium
  - C_5b9 deposits
    - Brachio-Cervical Inflammatory (BCIM): C_5b9 deposits
- Perimysium
  - Patterns of pathology
  - Prominently abnormal in
Matrix metalloproteinase up regulation ¹⁶
- 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 & SRP myopathy

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 & syndrome ⁹: 5% to 8%
  - Myasthenia gravis
  - Cardiomyopathy
  - ICI
- 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; PL-7, PL-12, 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 myopathies	Sarcoid; Immune; Infections Myopathy; Neuropathy; Lung disease Granulomas
Regional Ischemic	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 ICI
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 inflammatory myopathy (IIM; ? Polymyositis)

Weakness: Proximal > Distal; ± Face (Mild); Symmetric
Myalgia: Only 20%
Serum CK: High
EMG: Myopathy; Irritative with fibrillations & + sharp waves
Muscle biopsy
- Myopathy: Varied fiber size; No hypertrophy
- Inflammation: Mononuclear cell
Differential diagnosis
- Brachio-Cervical Inflammatory Myopathy (BCIM)
- Rule out: IM-VAMP

Myositis + Collagen vascular diseases

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 + Myopathy
Mixed connective tissue disease
- SLE; Systemic sclerosis; Inflammatory myopathy
- Muscle disease often mild & non-progressive
- U1-RNP antibody
Also see: Brachio-Cervical Inflammatory Myopathy

Charcot

Anti-Jo-1 antibody syndrome

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
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 tRNA synthetases
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
  - Calcinosis (8%)
- 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
  - Esophageal disorders
- Prognosis
  - High mortality 2° to systemic (lung) involvement
  - Residual disability: Common
- Treatments
  - Corticosteroids
  - 2nd medications with similar efficacy: Azathioprine; Methotrexate ¹¹⁴
  - ?? IvIg ¹¹⁵
Laboratory
- Anti-Jo-1 antibodies ⁸⁷
  - Target antigen: Histidyl t-RNA synthetase
  - Serum IgG1
  - HEp-2 immunofluorescence pattern: Speckled cytoplasmic
  - Specificity > 95%
  - Jo-1 antibody titers: May be associated with disease activity
  - Histidyl t-RNA synthetase effects ²⁹
    - Induces leukocyte migration
      - Interacts with CC chemokine receptor-5
      - Similar to other antigenic tRNA synthetases
        
        Serine; Asparagine
    - Non-antigenic tRNA synthetases: No effect
  - Associated antibody: Anti-Ro52 (40% to 72%) ⁶⁹
    - Myositis: More progressive
    - Joint involvement
      - More common
      - Hydroxyapatite calcifications
      - Erosions: Metacarpophalangeal & Interphalangeal; Wrists
    - Interstitial lung disease: More symptomatic; Dyspnea; Cough
    - Skin: Mechanic's hands more common
    - Neoplasm
      - Frequency: 19%
      - Age: Usually > 50 years
      - Types: Colon, Ovarian, Breast
    - Survival rate: Reduced
  - 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%
- CRP: Often high
- 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
- Chemokine associations (Serum)
  - IFN-γ-inducible, CXCR3-binding
    - CXCL9 (MIG)
    - CXCL10
  - BAFF (B cell activating factor; TNFSF13B )
Muscle pathology
- Perimysial connective tissue
  - Fragmentation
  - Inflammation: Macrophage predominant
- Myopathy
  - Perifascicular: Necrosis & Regeneration
  - More common in regions near perimysial connective tissue pathology
  - Most prominent: Patients with more severe weakness
  - Inflammation in endomysial & perivascular regions: Less than other IIM
  - Myonuclei: Actin aggregates ⁸⁴
- Capillary density: Normal

IMPP: Skin Rash

Mechanic's Hands

From: Dr M Harms

Feet

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

Immune myopathy with OJ antibodies ⁴⁹
- OJ antigens: Macromolecular complex with several ribonucleoprotein subunits ¹³⁴
  - Isoleucyl-tRNA synthetase (IARS)
  - Lysyl-tRNA Synthetase 1 (KARS)
- Clinical syndrome
  - Age: 25 to 75 years
  - Interstitial lung disease (100%)
  - Myopathy: Weakness (57% to 89%)
  - Polyarthritis (57%)
  - Skin rash: None
  - Treatment: Corticosteroids
- Laboratory
  - EMG: Irritative myopathy
  - Serum CK: Normal to 3300; High with weakness
  - Muscle pathology: IMPP
  - OJ serum IIF Hep2 cell staining pattern: Cytoplasmic in 50%
Immune myopathy with Zo antibodies ¹¹³
- Zo antigen: Phenylalanyl-tRNA synthetase
- Clinical
  - Onset age: 35 to 79 years
  - Weakness: Proximal (50%)
  - Myalgia (30%)
  - Lung disease, interstitial (80%)
  - Raynauds (90%)
  - Arthralgia (70%)
  - Skin: Mechanic's hands (45%)
  - Malignancy: Unusual
- Laboratory
  - Associated antibody: Ro52
  - Serum CK: 255 to 9,000
  - Muscle biopsy: Varied
  - ANA: Negative
  - Hep2 cells: Cytoplasmic speckle
  - HLA-DRB1*03: 01
Immune myopathy with Ha antibodies ¹⁴³
- Ha antigen: Tyrosyl-tRNA synthetase
- Clinical
  - Onset age: 4 to 75 years; Median 33 years
  - Female 67%
  - Weakness: Proximal; Symmetric
  - Myalgia (50%)
  - Lung disease, interstitial (20%)
  - Arthralgia (70%)
  - Skin (75%)
  - Raynauds (33%)
  - Malignancy: Rare
- Laboratory
  - Associated antibody: Ro52 in 25%
  - Serum CK: 38 to 2701
  - Muscle biopsy
    - Muscle fibers: Necrotic, scattered (58%); MHC-1 upregulated 100%); MxA (25%; Perifascicular)
    - Lymphocyte inflammation: Endomysial, Perimysial or Perivascular
    - Capillaries: C_5b-9 in 25%
Immune myopathy with other myositis-specific t-RNA synthetase antibodies
- Clinical syndrome
  - Similar features to: Jo-1 immune myopathy
  - More frequent skin involvement: Especially with anti-EJ
  - Systemic features with less frequent myositis: anti-PL-7; anti-PL-12; anti-OJ
- HLA: DR2 (45%); DR8 (27%); DQ1 (70%)
Myopathy with Signal Recognition Particle (SRP) antibodies ⁸⁵
- Epidemiology
  - Female (60%) > Male
  - African-Americans: Increased frequency
  - Little overlap with other connective tissue diseases
- Clinical
  - Onset
    - Age of onset
      - Usual: 4th & 5th decade; Range 4 to 82 years
      - Occasional: Childhood 5 to 16 years; Older adult to 82 years ⁶⁶
    - Acute: Weeks to months
    - Fall season: July to January
  - Weakness
    - Severe: 0/5 in some proximal muscules
    - Proximal > Distal (60%)
    - Symmetric (85%)
    - Legs > Arms: Hip flexors most severe
    - Dysphagia (15% to 40%)
    - Neck (70%)
    - Respiratory (15%)
    - Face (10%)
  - Myalgias (34% to 50%)
  - Muscle atrophy (66%)
  - Systemic: Some patients
    - Cardiac: Palpitations; Dyspnea on exertion
    - Raynaud phenomenon (30%)
    - Skin changes (3%): Normal or Raynauds
    - Lung disease, interstitial (13% to 22%)
    - Neoplasm (3% to 5%)
  - Course ⁹¹
    - Severe weakness: Common
    - Progression: Rapid over months
    - Recurrences: Frequent
    - Response to treatment: Often incomplete
    - Worse prognosis
      - Onset age: Younger; Especially < 15 years
      - More severe muscle weakness or atrophy
    - Mortality: High
    - Treatments
      - Corticosteroids
        
        More effective: Early in course or with Mild weakness
        
        Other drugs required: 80%
      - Rituximab
        
        Most likely long-term effective treatment (75%)
        
        Dose: 375 mg/M² q 10 to 12 weeks
        Relapse after short term treatment: Common in 6 to 9 months
        More prolonged benefit after 2 year course (q 10 to 12 weeks)
      - Other: IVIg; Methotrexate; Cyclophosphamide
- Laboratory
  - Serum CK: High to Very high
    - Mean: 3,300 to 6,000
    - Range: 1,000 to 9,000
    - Higher in black patients
    - Often remains high after treatment
  - EMG: Myopathic
  - 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
  - Signal recognition particle (SRP) antibody
    - SRP complex
      - In signal recognition particle with 6 SRP proteins and 7SL-RNA
        
        SRP9
        SRP14
        SRP19
        SRP54
        SRP68
        SRP72
      - Function: Transfers secretory proteins from ribosome to TRAM (translocating chain-associating membrane protein)
      - Interacts with: RNPS1
    - Antibody targets
      - 54 kD subunit
        
        Frequency: 82%
        
        Higher titers: Immune myopathy
        
        Mutations: Neutropenia with Shwachman-Diamond-like features, Dominant (SCN8)
      - 72 kD subunit
      - 7S RNA (100%)
    - Antibody type: IgG
    - Antibody location: Serum
    - Epidemiology
      - Prevalence in connective tissue disorders: 0.5%
      - Specificity for immune myopathies: 66%
      - Other associated disorders: RA-like erosive arthritis
      - HLA association: DRw52
      - Myositis specificity
  - Muscle MRI ⁸¹
    - Fatty infiltration (T1): Adductor magnus; Hamstrings
    - Edema (Short tau inversion recovery): Vastus lateralis; Rectus femoris; Gluteus maximus
- 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
  - MHC Class I: Often normal on muscle fibers
Myopathies with HMG CoA Reductase (HMGCR) antibodies ⁶⁴
- Nosology: 200/100 antibodies
- Epidemiology
  - General incidence/year: 0.9 to 2.4/1,000,000
  - Populations
    - Females 66%
    - American Indians: 100x increased frequency ¹²⁵
    - Polynesians: 5x increased frequency vs Europeans ¹⁴¹
    - Other associations: Diabetes mellitus; Hyperlipidemia; Statin exposure
  - Association with statin use
    - General: 15% to 94% in different adult series
    - Patients > 50 years: 40% to 80% frequency
    - Asian populations: Lower association; India 0%
    - Juvenile onset HMGCR myopathies: 0%
    - Other immune myopathies: 15%
    - IBM controls: 36%
    - Most common reported statin: Atorvastatin
  - HLA associations
    - Risk factors
      - General: DRB1*11:01
      - Juvenile myopathy: HLA-DRB1*07:01
    - Protective: DQA1; DQB6
- HMG CoA Reductase (HMGCR) protein
  - Catalyzes rate-limiting step in cholesterol biosynthesis
  - Inhibited by: Statins
  - Mutations: Limb-Girdle Myopathy syndrome
- Clinical
  - Onset
    - Age: 1 to 83 years; Mean 50 to 58 years
    - Course: Subacute to Chronic
  - Weakness (84%)
    - Proximal > Distal
    - Pattern: Often more severe in posterior thigh
    - Variable: Severe to None
    - Respiratory: Mild
    - Wheelchair use 25%
    - Dysphagia: 20% to 63%
  - Myalgias 75%
  - Systemic features
    - Arthralgias 50%
    - Malignancy
      - Frequency: 11% to 13% (2.6x control)
      - No predictable type
    - Raynaud's phenomenon 13%
    - Rash: 25% to 44%; May be more in children & statin-naïve adults
    - Interstitial lung disease 20%
    - Cardiac: Clinical 12% (Normal); EKG Δ up to 60%
  - Course
    - Initial onset: Months
    - May stabilize or have slow progression over years
  - Distinguishing featuress from LGMD
    - Onset: Sub-chronic
    - Weakness: Posterior thigh prominent
    - EMG: Irritative myopathy
    - Muscle biopsy: Alkaline phosphatase staining of perimysium
    - Serum: HMGCR antiboldies
  - Treatment
    - Prednisone
      - Often incomplete response
      - ? Required in maintenance
    - Rituximab
    - IVIg: May produce benefit in otherwise-treatment-refractory patients
    - Course
      - Strength may become normal with CK still somewhat high
      - Patients with history of statin use: May be more responsive
      - Less response to treatment: Younger onset age; Lower CK
      - Often require continued treatment to maintain improvement
  - Pediatric patients ⁹⁵
    - Clinical
      - Onset age: 10 months to 13 years
      - Statin history: Usually none
      - Weakness (90%)
        
        Proximal;
        
        Progression: Subacute or Chronic
      - Myalgia (25%)
      - Skin rash (25%)
      - Treatment: Variable improvement with corticosteroids or IVIg
    - Laboratory
      - Serum CK: 900 to 11,000
      - Muscle biopsy
        
        Muscle fibers: Necrosis & Regeneration
        
        Endomysial connective tissue: Increased
        
        Inflammation (45%): Perivascular
      - Muscle MRI: Edema
    - Differential diagnosis: Muscular dystrophy (Hereditary myopathy)
- 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
        
        Frequencies: 67%; 92% over 50 years of age
        
        Less in African-Americans
        More response to treatment
      - Clinical: Higher titers correlate with increased disease activity
        
        Strength: Less
        
        CK levels: Higher
        
        Lower titers: With improvement after treatment
        Not present: SRP myopathy
    - Course: Usually persist, even with successful treatment
    - HMGCR protein: Upregulated in regenerating muscle fibers
  - Serum CK: High 83%; 26 to 27,000
  - ANA > 1:160: 6%
  - ESR high: 38%
  - EMG: Myopathic (75%); Irritable
  - MRI
    - Muscle "Edema" & Atrophy
    - More involvement: Hamstrings; Thigh Adductors
  - Muscle pathology
    - General
      - HMGCR antibodies: Pathology patterns
        
        Varied
        
        Correlations ¹³⁶
        
        Presence of muscle fiber necrosis
        Not individual pathology syndromes
      - Muscle Fiber Necrosis: Common
      - IMPP pattern: Common
    - Necrosis & Regeneration
      - Common
      - Variable in different regions
      - More near damaged perimysium
    - Myonuclei: Often enlarged or aggregated
    - Inflammation: 33%; Occasionally around perimysial vessel
    - Capillaries: Normal number
    - MHC Class I
      - Increased in regions with active muscle fiber pathology
      - Normal, or Mildly increased: In other areas or Early in disease course
    - Perimysium
      - Cells (70%): Histiocytic; Acid phosphatase+
      - Connective tissue: Alkaline phosphatase stain (50%)
    - Gene expression: APOA4 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; U1-RNP; SNRNP70) ²⁸
- Epidemiology
  - Predominantly: Females
  - More commonly: Black
- Clinical
  - Onset
    - Age: Mean 36 to 48 years
    - Signs: Swollen hands; Raynaud's phenomenon; Weakness
  - Muscle
    - Weakness: Proximal; Mild to Severe
    - Dysphagia
    - Spared: Neck Flexors & Extensors
    - Discomfort: Myalgias; Cramps
  - Other organ systems
    - Lung: Interstitial pneumonitis; Vital capacity reduced due to 1° lung disease
    - Arthritis: Symmetric; Non-destructive; Distal joints
    - Skin: Dermatitis; Sclerodactyly; Mechanic's hands (50%)
    - Raynaud's (80%)
    - Sicca: Some patients
    - Lymphadenopathy (20%)
    - Glomerulitis (25%): Associated with Ro52 antibodies
    - Pericarditis (40%): Associated with Ro52 & dsDNA antibodies
    - GI: GE reflux; Dysphagia
    - Neurologic: Lymphocytic meningitis (20%)
    - Systemic: Fever; Weight loss
    - Neoplasm: Rare
  - Treatment: Rapid improvement with corticosteroids (Weeks)
- 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
  - Ro52 antibodies (75%)
  - EMG: Irritative myopathy
  - Muscle biopsy
    - Active myopathy: Muscle fiber necrosis in 57%
    - Inflammation: Lymphocyte & Macrophage
    - Capillary pathology: Large size; Numbers reduced; C_5b-9 deposition
- U1-snRNP antibodies
  - General category: Myositis-overlap antibodies
  - U1-snRNP protein: Function
    - Pre-mRNA splicing
    - See Spliceosomes
  - Antibody Types
    - Nuclear U1-snRNP : 70 kDa polypeptide
      - Bind only to U1-snRNP
      - Targets: Proteins in U1-snRNP particle; U1-70k, U1A, U1C (Occasional)
      - ANA: Coarse speckled nuclear pattern
      - Disease associations
        
        Mixed connective tissue disease (MCTD): 95% to 100%
        
        Swollen hands & fingers
        Synovitis
        Muscle: Myositis or Myalgia
        Systemic immune disorders
        
        Systemic Sclerosis
        
        SLE
        
        Raynaud's
        ± Acrosclerosis
        May be related to disease activity
        
        Other disorders: Antibody is not specific
        
        SLE: 30%
        
        Lupus-overlap syndrome
        
        Scleroderma (Systemic Sclerosis): 15%
        
        Rheumatoid arthritis
        
        Clinical association: Raynaud�s phenomenon
    - Sm antibodies
      - ANA: Coarse speckled nuclear pattern
      - Targets
        
        Sm Proteins: Sm-B/B'; D
        
        Core proteins of U-snRNPs
      - Cross reactions: Some antibodies
        
        May cross-react with U-nRNPs
        
        Also precipitate U1, U2, U4/U6 proteins
      - Disease association: Systemic lupus erythematosis
        
        Prevalence: 15% to 30%
        
        Specificity: 99%
        
        More often in SLE in patients without dsDNA antibodies
        Correlation with
        
        Disease activity: Less association than dsDNA
        CNS involvement

Regional Ischemic Immune Myopathy (RIIM) ⁸²

Epidemiology: Female > Male
Clinical: Dermatomyopathy, Often paraneoplastic
- Onset
  - Age
    - Most > 40 years
    - More likely with increasing age
    - Range: 12 to 92 years
  - Weakness
    - Subacute
    - Before or after neoplasm diagnosis
- Weakness
  - Proximal > Distal
  - Symmetric
  - Dysphagia (80%)
  - Maximal severity: 1 to 6 weeks
- Myalgias (100%)
- Skin
  - Rash (75%)
  - Subcutaneous edema
- Course
  - Rapid onset: Disabling severe weakness in < 2-3 months
  - Survival
    - Related to presence of, & ability to treat, neoplasm
    - With neoplasm: Often < 1 year
- Associations
  - Malignancy: Older patients; Neoplasms varied
    - Lung
    - GI: Stomach & Colon (Adenocarcinoma)
    - Prostate
    - Gynecological (Breast)
    - Endometrial
    - Renal
  - Immune Checkpoint Inhibitors (ICI)
- Evaluation
  - Physical exam: + Gynecological & Rectal
  - Chest, pelvis & abdominal CT
  - Stool guaiac
  - ? PET
- Treatment
  - Corticosteroids: Often improves myopathy when neoplasm controlled
  - Monitor for neoplasm
Laboratory
- Serum CK: Increased 8x to 100x normal; Range 145 to 210,000
- ANA (60%): ≤ 1:1280
- EMG: Irritative myopathy
- Serum autoantibodies
  - NXP2
  - Tif1-γ
- Muscle Histology
  - Muscle fiber necrosis & regeneration: Small & large foci
    - C_5b-9 complement deposition in necrotic muscle fibers
  - Vessels: Veins with damaged walls
  - Lymphocytic inflammation: Rare


RIIM: Skin rash	From: R Bucelli

Brachio-Cervical Inflammatory Myopathy (BCIM) ⁴⁷
- Nosology
  - B-Cell Inflammatory Myopathy (BCIM; BIM)
  - May be same syndrome as: Multinodular Polymyositis
- 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
  - PM/Scl-100 antibodies: 65%
  - PM/Scl-75 antibodies: 35%
  - Serum CK: Normal to 15x elevated
  - Electrodiagnostic
    - EMG: Myopathic; Spontaneous activity
    - Repetitive nerve stimulation decrement: 40%
  - Anti-AChR antibody: 30%
  - Muscle MRI
- Muscle pathology
  - Muscle fiber pathology
    - Necrosis & regeneration
    - Focal invasion of muscle fibers: 60%
  - C_5b-9 complement (MAC) deposition: Diffuse in endomysium
  - Mononuclear focal infiltrates (90%): Ectopic lymphoid structures
    - Composition
      - B-cells present in some foci most patients
      - T-cells & Scattered Histiocytes also present type="circle"
      - Some foci without B-cells
    - Locations
      - Perivascular
      - Perimysium: May extend into Endomysium
    - Associated vessels (In, or near, cell foci)
      - Intermediated-sized
      - Rarely have elastin fibrils
      - Endothelial cells: Esterase+; VCAM-1; ICAM-1
  - MHC-I expression diffusely by muscle fibers: 90%
  - MxA capillary staining: 90%
Myositis + Myasthenia gravis ⁴³
- Also see
  - Brachiocervical inflammatory myopathy
  - Check point inhibitors: Side-effects
  - Lymphorrhages
- Clinical
  - General syndromes: Polymyositis, BCIM, Dermatomyositis
  - Onset age: 36 to 70 years
  - Weakness
    - Respiratory
    - Bulbar
    - Limbs
      - Proximal > Distal
      - May be Arms > Legs
    - Ophthalmoplegia
  - Systemic associations
    - Thymoma: Up to 70%
    - Cardiomyopathy
  - Treatment: Corticosteroids often effective
- Laboratory
  - Serum CK: Often high; 250 to 10,000
  - Antibodies
    - Anti-AChR antibodies: 80%
    - Ryanodine receptor or Titin antibodies: 75%
    - Myositis- associated: Uncommon
  - Repetitive nerve stimulation: Decrement
  - EMG: Irritable myopathy; Spontaneous activity
  - Muscle pathology
    - Inflammtory Cells
      - Location: Endomysium; Perimysium
      - CD8+, CD45RA- T-lymphocytes (9/9)
      - Endomysial programmed cell death 1 (PD-1)+ cells (9/9)
    - Muscle fibers
      - Necrosis & Regeneration
      - MHC1 upregulation
Multinodular Polymyositis ¹⁷
- Epidemiology
  - Case & Pathology reports
  - See: B-cell Inflammatory Myopathy
- Clinical
  - Onset
    - Age: 40 to 76 years
    - Progression over months
  - 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
- 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: Foci of lymphocytes
      - Plasma cells
      - Lymphocyte types: B-cells > T-cells
      - Scattered histiocytes
      - Associated vessels
        
        Endothelium stains for: Esterase; VCAM-1; ICAM-1
    - Muscle fibers: Necrosis; Replacement by cells
    - Perimysium: Widening; Cellularity
- Treatment
  - Corticosteroids
  - Anti-retroviral therapy
Myositis + Sarcoid
- Granuloma: Muscle
- Myopathy
Drug induced Immune & Inflammatory myopsthies

Aromatase inhibitors
cGvHD
Checkpoint inhibitor
D-penicillamine
Hydralazine
Interferon-α
Ipecac
Minocycline
Osimertinib
Other
Phenytoin
Procainamide
TNF-α
Toxic oil
Also see: Toxic
- D-penicillamine
  - D-penicillamine
  - Epidemiology
    - Dose: No clear relation
    - Frequency: ~ 1%
    - Disease treated: Rheumatoid arthritis
  - Clinical
    - Onset
      - Any time during treatment
      - Weeks to years after onset of drug treatment
    - 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
    - Copper deficiency
- 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
- Tumor necrosis-α inhibitors (Anti-TNF-α)
  - Drugs: Adalimumab (Humera); Etanercept (Enbrel); Infliximab
  - Epidemiology: 11 patients described
  - Clinical
    - Onset: 6 weeks to 9 months after treatment begun
    - Myalgias
    - Weakness
      - Proximal > Distal
      - Arms & Legs
      - Symmetric
    - Skin changes: Some patients
    - Course: Improves with
      - Drug cessation
      - Corticosteroid treatment
    - Anti-TNF-α treatments may also exacerbate ongoing immune myopathies
  - Laboratory
    - Serum CK: Usually High; Normal to 12,000
    - Serum aldolase: High
    - Muscle pathology: IMPP + Lymphocyte inflammation
    - Jo-1 antibody: May be present before Anti-TNF-α treatment
- Interferon-α
- Phenytoin: Inflammatory myopathy with fever, rash, lymphadenopathy & eosinophilia
- Checkpoint inhibitors
- Aromatase inhibitors ¹²⁰
  - Uses: Hormone receptor positive breast cancer in post-menopausal women
  - Clinical associations
    - Bone loss: Osteoporosis
    - Joints
      - Arthralgia (50%)
      - Spondyloarthropaty
    - Immune disorders
      - Rheumatoid arthritis: Most common
      - Sjögren syndrome
      - Systemic erythematosus lupus
      - Systemic sclerosis
      - Immune Myopathy
        
        Few reports
        
        Types: Anti-synthetase Ab; Dermatomyopathy; Fasciitis
      - Antiphospholipid syndromes
- Osimertinib myopathy ¹¹⁶
  - Mechanism: Irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI)
  - Clinical: Muscle weakness; Fatigue; Cramps
  - Laboratory: Serum CK High
- 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

General
Myopathy
Neuropathy
Pathology

GVH: 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
    - Pathogenic Phases
      - I
        
        Damage- & Pathogen-Associated molecules (DAMP & PAMP) released
        
        Activation of antigen producing cells
        
        Interleukin 1β release
        
        Endothelial injury
        
        Microvessels: Reduced density
      - II
        
        Expansion of alloreactive B- & T-cells
        
        Thymic injury
        
        Lack of: Regulatory T-, B- & NK-cells
        
        Loss of peripheral tolerance
      - III
        
        Histiocyte & Fibroblast activation
        
        Interleukin-17
        
        Extracellular matrix: Damage, Deposition & Sclerosis
        
        BAFF → Immunoglobulin deposition → Organ damage & fibrosis
    - Onset & Evolution
      - Time: 60 days to 6 years after bone marrow transplant
      - Course: Slowly progressive
    - Varied clinical involvement
      - Skin: Lichen planus-like; Scleroderma-like; Vitiligo
      - Lichenoid lesions: Oral & Esophageal
      - Keratoconjunctivitis sicca
      - Bronchiolitis → Obstructive pulmonary failure
      - Neuromuscular disorders: Frequency 8% ⁷⁷
        
        Myasthenia gravis
        
        Frequency: Rare
        
        Timing
        
        Often late after transplant
        
        With immunosuppressant tapering
        
        AChR Antibody +
        
        Immune myopathy: IMPP
        Fasciitis
        Polyneuropathy: Sensory & Motor
        Possible associations
        
        ? Chronic immune demyelinating polyneuropathy (CIDP)
        ? Guillain-Barré
      - CNS (Rare): Myelitis; Optic neuritis
    - Laboratory
      - Antibodies vs: Nuclei; dsDNA; Smooth muscle; ANA
      - T-cells: CD4 reduced (85%), CD8 increased (60%)
      - Pathology
        
        Fibrosis
        
        Cells
        
        Anti-inflammatory Th2
        
        Pathogenic B
        
        Histiocytes
        
        Allo- & Autoantibodies
- Risk factors
  - Age > 20
  - Chronic GVHD: Prior Acute GVHD
- Treatment
  - Cyclosporine
  - Prednisone & Azathioprine: Associated with infectious complications
Graft vs Host Disease (GvHD) + Immune myopathy ³⁰
- 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
- Clinical
  - General
    - Onset Age: 4 to 46 years; Similar to general transplantation population
    - Male = Female
  - Muscle
    - Onset: With tapering of immunosuppression
    - 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
  - Course
    - Progressive
    - 2 year survival: 38%
  - 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
- Laboratory
  - Serum CK: High in 20% to 70%; Range 49 to 8,400 U/L
  - Aldolase: High in 65% to 80%; Range 5 to 88
  - Liver enzymes: High in 90%; Mildly elevated
  - Antibodies
    - ANA 33% to 60%
    - Smooth muscle 33%
    - Myositis-specific Ab: Infrequent
    - Ro-52 20%
    - NT5C1a 30%
  - HLA: No association with B8/DR3
  - EMG: Irritable myopathy
- Muscle pathology
  - General: Often damage to several tissues, including
    - Connective tissue
    - Capillaries
    - Muscle fibers
  - Perimysial connective tissue Δ (IMPP)
    - Inflammation: Histiocyte predominant
      - Perimysium: Macrophages or Dendritic cells (Acid phosphatase +)
      - Endomysium: Occasional; Cytotoxic T-cells (CD8 +)
    - Structure: Fragmentation
  - Muscle fibers
    - Surface carbohydrate moieties reduced: α-Dystroglycan; Decorin
    - Necrosis & Regeneration (Few patients): Especially in perifascicular areas
  - Capillary damage (Endomysial)
    - Reduced numbers
    - Endothelial cell loss
    - Distribution: Scattered; Not perifascicular
  - Occasional
    - Perivascular: Lymphocytes
    - Hemosiderin deposits
    - Lipofuscin increased in muscle fibers
- Differential diagnosis
  - Autoimmune hypothyroidism
  - Myosin-loss myopathy
  - Myasthenia gravis
- Animal model
  - Stimulus: Transfer of parental splenocytes into some strains of mice
  - Disease syndrome: Systemic lupus erythematosus-like
    - Myositis
    - Glomerulonephritis
  - Laboratory
    - Antibodies: Amino acid tRNA synthetase; Transfer RNP
    - EMG: Irritable myopathy
GVHD + Neuropathies
- Sensory-Motor polyneuropathy
  - Frequency: 6% to 90%; Higher with electrodiagnostic ascertainment
  - Clinical: Sensory > Motor
    - Onset time: With GVHD or Up to year later; Median 6 to 9 months
    - Cramps (33% to 50%): Varied muscles
    - Paresthesias (26%)
    - Sensory loss
      - Panmodal
      - Distal
      - Symmetric
    - Weakness: Few patients
  - Electrodiagnostic: Axon loss
  - Nerve pathology
- Other neuropathies with GVHD
  - Vasculitic neuropathy ⁷: 1 case with chronic GVHD
  - Entrapment neuropathies: With dermal sclerosis; Median, Ulnar, Fibular
  - Thalidomide
  - Immune, other: CIDP; AIDP

Immune-Mediated Megaconial Myopathy ¹⁴²

Epidemiology: 5 patients
Clinical
- Onset age: 19 to 45 years
- Weakness
  - Proximal
  - Legs & Arms
  - Course: Subacute
- Myalgias
- Systemic
  - Pancreatic disease
    - Insufficiency (Cystic fibrosis)
    - Cancer
    - Inflammation
  - Possible treatments
    - IVIg
    - Corticosteroids
    - Mycophenolate
Laboratory
- Serum CK: 1200 to 5900
- Myositis-related antibodies: None
- EMG: Myopathic; Spontaneous activity
- Selenium: Normal or Mildly low
- Muscle pathology
  - Muscle fiber necrosis
  - Sarcolemma
    - MHC1 upregulation
    - C_5b-9 deposition
  - Mitochondria: Large; Peripheral or Diffuse
  - Inflammation: None or Perimysial
  - Capillary loss: Multifocal

From: O Ni

Immune myopathy + Other systemic disorders
- Acquired immune deficiency syndrome
- Lymphoproliferative disease & Monoclonal gammopathy
- Fasciitis
- Hypereosinophilic syndrome
- Myasthenia gravis: Often associated with thymoma & Ryanodyne receptor antibodies
- Neuromyelitis Optica + Aquaporin-4 (AQP4) 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
Myopathy with Neuromyelitis Optica + Aquaporin-4 (AQP4) antibodies ¹¹²
- Epidemiology: 12 adult patients
- AQP-4 protein
  - Tetramer
  - Membrane spanning
  - Muscle: More on type 2 fibers
- Clinical
  - Onset ages: 7 to 72 years
  - CNS: NMO relapsing
  - Muscle
    - Myalgia
    - Weakness
  - Course
    - Relapsing
    - Myopathic features may correspond to NMO sx
- Laboratory
  - Serum CK: Normal or High; Up to 63,000; May normalize with treatment
  - EMG: Irritative Myopathy
  - Muscle
    - Fiber sizes: Varied
    - Perimysial pathology
    - C_5b-9 on muscle fiber surface
    - AQP4: Reduced on muscle fiber surface

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

DERMATOMYOPATHIES, IMMUNE

MYOPATHIES + SKIN DISORDERS, IMMUNE

Dermatomyositis
Clinical features
Comparative features
Laboratory
Pathology
DM-VP: Description
IMPP
RIIM
Treatment

History: Firsts
? 1st Case: 1863 Wagner
Archiv der Heilkunde
Unverricht: Use of term
Batten: Pathology

Dermatomyopathy Types
Dermatomyopathy with Vascular Pathology
Childhood
Adult
Childhood & Adult
Mi-2 antibody positive
NXP2
RIIM
TIF1γ (p155) antibody
IMPP
Jo-1 antibody positive
EJ antibody positive
Enterovirus
PM-Scl
cGvHD
Scleroderma (SSc)
Dermatomyopathy: Other Adult
Amyopathic
Drug-related
HSF1 antibody
MDA5 antibody
Mi-2 antibody negative
Malignancy-associated
Scleromyxedema

Tim Miller

Dermatomyopathies & Dermatomyositis: Clinical features, general

Types: Comparative features
Epidemiology
- Higher frequency: Mesoamerica
- Lower frequency: Northern cities
- Frequency in children: > 90% of immune myopathies
Clinical features: Common ⁶⁵
- Skin
  - DM-VP
    - Erythematous rash
      - Heliotrope
      - Face & Eyelids
      - Sun-exposed areas
      - Extensor joint surfaces
    - Periorbital edema
    - Gottron's papules
    - Calcinosis
  - IMPP
    - Mechanic's hands
- 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

Dermatomyositis syndromes: Specific features

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

Clinical
Epidemiology
Laboratory
Pathology
Treatment
- Epidemiology & Associations ²³
  - 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 patterns ⁵²
      - Hispanic patients: Birth more in September to November; Mean birth date October 16
      - HLA DRB1*0301: Birth more in July to January
      - TIF1γ (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 loops: 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
    - Calcinosis cutis
      - Involves extremities
      - Causes discomfort & morbidity
    - 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%
  - Gastrointestinal: Vascular
    - Bleeding
    - Pain
    - Perforation
    - Pathology: Arterial narrowing or occlusion
  - Vasculitis
    - Visceral infarction
    - GI bleeding
    - Associated with poor prognosis
  - Calcinosis
  - Lipodystrophy ⁵⁷
    - 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-TIF1γ (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 ⁸⁰
      - Clinically significant: Unusual
      - EKG: Right bundle branch block; ST-T wave abnormalities
      - More cardiac dysfunction in active JDM with high
        
        Eotaxin (CCL11)
        
        MCP-1 (CCL2)
        
        IP-10
        Cholesterol (Upper range of normal)
  - 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
  - Interferon-β, serum
    - High in 64%
    - Reduced with treatment
  - Antibodies ⁷¹
    - TIF1γ (p155/p140; TRIM33)
      - Common MSA in JDM: 29% to 32%
      - Neoplasm-association: Adults not children
      - Disease course: Chronic
      - CK levels: Lowest
      - Muscle pathology patterns
    - NXP2 (p140; MJ): Juvenile Dermatomyositis with Vascular pathology & Calcinosis
      - Frequency in JDM: 20%
      - Clinical: Cramps, Dysphonia, Calcinosis; More severe weakness
      - Disease course: Monophasic; More disease activity after 2 years
      - CK levels: Intermediate
      - Muscle pathology patterns
    - Mi-2
      - Dermatomyositis without other connective tissue disorders
      - Frequency: 3% to 10%: Higher in Hispanics
      - CK levels: High
      - Mortality: Low
    - SAE & IFIH1: Amyopathic dermatomyositis
    - No MSA detected
      - Linear extensor erythema
      - Arthralgia
      - Disease course: Monophasic
    - 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
    - Oral: 1 to 2 mg/kg/day up to 60 mg
  - Intravenous immunoglobulin
  - Methotrexate: 15 mg/m² (maximum 40 mg) per week; Subcutaneous > Oral
  - Hydroxychloroquine
    - Dose: 5mg/kg/day, maximum 400 mg
    - Especially for: Skin predominant syndromes
  - Rituximab
  - Cyclophosphamide: Refractory cases
  - Photoprotection
- Variant: Dermatomyositis with Mi-2 antibodies
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 US ⁶¹
    - Women: Increased frequency of DM & Mi-2 antibodies
    - Men: No association
    - No association with: Synthetase or SRP antibodies
  - Frequency related to: Surface ultraviolet radiation intensity ³⁸
- Clinical
  - Onset
    - Age: Childhood > 3 years; Adult
    - Timing: Acute
  - Skin: Rash - V-sign, Shawl sign; Calcinosis uncommon
  - Nailfold involvement: Common; Cuticular overgrowth
  - Associated clinical
    - Dysphagia (50%)
    - Connective tissue disorders: Unusual
    - Neoplasms: No increased frequency
  - Course
    - Better prognosis
    - Less interstitial lung disease
- Laboratory
  - ANA + (100%)
  - HLA type: Associations vary with ethnicity ²⁷
    - 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
  - Muscle pathology
    - Muscle Fiber Necrosis: Common
    - Inflammation: Unusual
Amyopathic Dermatomyositis ^24, ⁵³
- Epidemiology
  - Frequency: 8% to 20 % of DM
  - Onset age
    - General, Adults: Younger than full dermatomyositis syndromes
    - Usual: Middle aged adults
    - Occasional: Juvenile or 9th decade
  - Sex: Female > Male, except in China
  - Also see: Hydroxyurea
- Clinical features: Heterogeneous
  - Skin lesions
    - Heliotrope erythema (69%)
    - Gottron's nodules (54%)
    - Palmar ulcers: MDA5 antibodies
    - Periungual lesions
    - Pruritis: Some patients
    - Erythematous violaceous macules & papules: Malignancy associated in Chinese
  - Clinical features, Other
    - Raynauds
    - Joints: Arthralgias & Arthritis
    - Pulmonary: Interstitial lung disease
  - Strength: Normal
- Laboratory
  - Serum CK: Normal or Mildly high
  - Antibodies
    - CADM-140
      - Antigen: MDA5 (IFIH1)
      - Interstitial lung disease: Rapidly progreesive; Asians
    - Tif1-γ ⁵³
    - SAE: Dermatitis with less Muscle involvement ¹³⁸
    - Antinuclear antibodies: 50% to 90%; Speckled pattern
    - Other: No Jo-1; Mi-2; PM-Scl
  - Muscle
    - Myopathic or Inflammatory changes: Minimal
    - MHC-I upregulated by muscle fibers: Some patients
- Treatment
  - Corticosteroids: Systemic or Topical
  - Hydroxychloroquine
  - Other immunomodulating agents
  - Muscle: Often conservative without immunosuppression
Drug induced Dermatomyositis ⁵⁴
- 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
Immune Dermatomyopathies: Muscle Pathology (3 different patterns)
- Dermatomyositis with Vascular pathology (DM-VP): Common in childhood
- Immune myopathies with Perimysial pathology (IMPP): 50% of adult Dermatomyositis
- Regional Ischemic Immune Myopathy (RIIM): Common association with neoplasms
DM-VP (Vascular or Juvenile type): Muscle Pathology
- Muscle fibers
  - Myopathic changes
    - Distribution: Perifascicular (Vessel Border-zone distribution) 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
  - 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
    - Caveolin-3 aggregates
    - LC3 aggregates
- 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
    - Small perifascicular capillaries: Endothelium lost or absent
    - Enlarged capillaries: Swelling; Microvacuoles; Inclusions
    - Tubuloreticular inclusions
  - Endomysial capillaries
    - Reduced Number: Especially in regions of perifascicular atrophy
    - Enlarged
  - Arteries & Intermediate-sized vessels
    - Regions most often associated with mononuclear cell inflammation
    - Structure: May be
      - Occluded
      - Damaged: Perimysial vascular remnants
      - Abnormal vessel wall: Reduced filaments in arteries & veins
    - May have deposits of complement & immune components
      - Types or depositis: C3d; C4d; C5; Fibrinogen
      - Clinical associations: Gastrointestinal involvement; Chronic disease
- Inflammation (50%): Ectopic lymphoid structures
  - 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

First use of term "Dermatomyositis"

Full article 1891
Unverricht's first description of a case of Dermatomyositis: Polymyositis acuta progressive. Z Klin Med 1887;12:553

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

Subtypes
Inclusion body myositis (IBM)
Antibodies
Clinical
Epidemiology
Laboratory
Muscle Pathology
Inflammatory myopathy + Mitochondrial pathology (IM-Mito)
Muscle pathology

Inclusion Body Myositis (IBM) ²²

Nosology: Pathology groups
- Inflammatory Myopathy with Vacuoles, Aggregates & Mitochondrial Pathology (IM-VAMP)
- Inflammatory myopathy + Mitochondrial pathology
Epidemiology ⁹⁴
- Sporadic: No family history
- Males
  - Preponderance: 57% to 75%
  - Later onset
- Frequency (Prevalence)
  - General populations: 1 to 10/10⁶
  - > 50 years of age: 139/10⁶
  - Norway: 33/10⁶
  - Turkey: 1/10⁶
- HIV ¹⁰³
  - IM-VAMP is most common associated inflammatory myopathy
  - May present with
    - Onset age: 10 years younger than other IBM
    - Proximal weakness
    - Serum CK high
  - NT5C1A antibodies (64%)
- HTLV
- Sarcoid & Granulomatous myopathies
  - May have association with IBM clinical syndromes
- Genetics
  - HLA & Other associations
  - Increased frequency of FYCO1 missense variants (11% vs 2.6% in controls) ¹⁰⁰
  - Klinefelter syndrome (47XXY; 47XXX) ³³: 4% of IBM
- Other possible disease associations

Clinical features

Onset

Age
- > 50 years in 80%
- > 60: More common in males
- Younger in some patients with HIV or HTLV infections
Weakness
- Legs: 70%; Difficulty with chairs or stairs
- Arms, Distal: 15%
- Swallowing difficulty: 10%

Weakness

General
- Proximal & Distal: Distal predominant in 20%
- Upper & Lower extremities
  - Early disease: May selectively involve arms or legs
Asymmetric
- ? More severe on non-dominant side
Focal regions with more severe involvement
- Arms
  - Weakness
    - Wrist & Finger flexors: Especially males
  - Ultrasound ⁷⁶
    - Flexor digitorum profundus >
      Flexor carpi ulnaris
    - Homogeneous involvement of muscle
      - Other IIM: Heterogeneous pattern
- Legs
  - Weakness
    - Quadriceps
    - Foot dorsiflexors
  - Atrophy: Affected muscles
- Dysphagia (30% to 70%) ¹²⁷
  - Epidemiology & Frequency
    - General: 65%
    - Females: Up to 90%
    - More with: Increased age
    - Less limb mucle involvement
  - Location of dysfunction
    - Upper 1/3 of esophagus
    - Cricopharyngeal
  - Course: May be related to increased mortality
  - Effects
    - Achalasia, functional
    - Upper esophageal sphincter: Impaired relaxation
    - Risk: Aspiration pneumonia
  - Muscle pathology: Fibrosis
  - Videofluoroscopy; Cricopharyngeal bar (33%)
  - Possible treatments
    - Botulinum toxin
    - Myotomy
    - Balloon dilation
- Face: 30%; Mild
- Trunk
  - Neck muscles
  - Scapular winging ¹³⁹

From: Chris Weihl

IBM: Cricopharyngeal bar
(Videofluoroscopy)

Muscles commonly spared
- Deltoid
- Pectoralis
- Interossei (Hands)
- Flexor digitorum superficialis
- 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
    - Inflammatory myopathy with Mitochondrial pathology (PM-Mito)
  - More rapid
    - Lower legs
    - Symptoms begin after age 60
    - Males
    - ? After treatment with immunosuppressants
    - Vacuoles present in muscle biopsy
  - Mean time to wheelchair: 14 years
- Causes of death
  - Respiratory
  - GI: Aspiration (20%); Dysphagia; Cachexia
- Life expectancy: Near normal or Reduced (1.7x)
  - 39% 10 year IBM survival vs 59% of control population ¹¹⁹
Muscle atrophy: Proportionate to weakness
Tendon reflexes: Diminished with disease progression, especially knee
Polyneuropathy ¹⁴
- Usually subclinical
- Sensory > Motor
- Loss of myelinated axons in sural nerve
- MRI: Enlargement of sciatic & tibial nerves ¹³¹
Systemic involvement
- Immune disorders: Sjögren syndrome (6% to 10%)
- Malignancy
  - M-protein
  - T-cell large granular lymphocytic leukemia
- Other co-morbidities ¹⁰⁸
  - Hypertension (66% vs 22%)
  - Hyperlipidemia (47% vs 18%)
  - Myocardial infarction (13% vs 2%)
Treatment
- None definite
- Few reports of response to IV Ig or immunoabsorption
- Methotrexate: Some variants may have some improvement in strength

Laboratory
- Serum CK: Mean 600; Range - Normal to 15x high
- Electrodiagnostic
  - EMG: Irritable myopathy; Long duration potentials may occur
  - Nerve conduction studies: Absent sural potentials in some patients > 60 years
- Muscle Pathology
  - Inflammatory Myopathy with Vacuoles, Aggregates & Mitochondrial Pathology (IM-VAMP)
  - Variant syndrome: PM-Mito
- Barium swallow: Cricopharyngeus dysfunction
- Muscle MRI
  - Abnormalities: Fatty infiltration; "Edema"; Atrophy
  - Anatomy
    - Flexor digitorum profundus (Arm): Commonly involved
    - Upper leg: Anterior muscles; Rectus femoris relatively spared
    - Lower leg: All muscles; Medial head of gastrocnemius more involved
- Antibodies, Serum (IM-VAMP (IBM-like disorders))
  - M-protein (20%): Most IgG; λ > κ
  - Cytosolic 5'-nucleotidase IA (NT5C1A; cN-IA; cN1A; cN-1A; Mup44 antigen) ⁷⁰
    - NT5C1A protein: 44-kDa muscle antigen
    - Frequency of NT5C1A antibodies
      - IM-VAMP syndromes
        
        NT5C1A antibody titers: High in sIBM syndromes
        
        IM-VAMP
        
        sIBM
        
        IM-Mito
        
        Western blot methods
        
        sIBM: 51% to 75% sensitivity
        
        IBM-like syndromes with no vacuoles in muscle (IM-VAMP): 64%
        Higher specificity: False positives 10%
        
        ELISA & Cell-based methods
        
        Sensitivity: Lower; 33% to 55% ¹⁰⁴
        
        False positive results: More (Up to 30%)
      - Other immune myopathies
        
        DM & PM: 4% to 20%
      - Systemic immune disorders: Increased frequency
        
        Sjögren syndrome: 20% to 37%
        
        Systemic lupus erythematosus: 14% to 20%
      - Other controls: Few
      - Normals: Rare
      - HLA association: HLA-DRB1*03:01 & position 74 arginine
    - NT5C1A antibodies: Associations in IBM (IM-VAMP) ⁸⁶
      - Females 2.3x > Males
      - Weakness
        
        Respiratory: Vital capacity reduced
        Bulbar: Dysphagia
        Face: Weakness more frequent
        Proximal arms at onset: Less
        Finger flexion
        Severity: More disabling
      - Mortality risk: Higher (1.89x); Respiratory deaths
      - Laboratory: Lower frequency of hepatitis C virus antibodies
      - Muscle pathology
        
        COX- muscle fibers: More frequent
        
        Type 2 muscle fibers: Smaller
    - NT5C1A antibodies: Associations in other immune & inflammatory myopathies
      - Juvenile: More severe disease; More ¹⁰⁶
        
        Pulmonary symptoms
        
        Frequent hospitalisations
        
        Medications
      - Adult dermatomyositis: More severe disease phenotype
    - NT5C1A antibodies: Experimental effects ¹⁰⁴
      - p62/SQSTM1-positive sarcoplasmic aggregates in myofibers
      - Endomysial macrophages: Increased
      - No effect on function
  - Non-organ specific autoantibodies: Increased frequency ⁷³
    - ANA: 30% to 40%
    - Ro52 (SSA): More in females (Up to 39%)
    - Ro60
    - La
    - RNP
- Other IBM associations
  - Rheumatologic disease, coexisting (25%)
    - Most common: Sjögren syndrome
  - Genetic
    - HLA
      - Types: DRβ1*0301, DRβ3*0101 (or DRβ3*0202) & DQβ1*0201
      - Extended 8.1 ancestral haplotype (AH)
    - Apolipoprotein E ⁸³
      - APOE genotype e3/e3: Later sIBM onset
      - e4 allele: ?? Excess frequency in males with sIBM
    - TOMM40
      - ≥ 1 VL polyT repeat allele: 4 years later sIBM onset, especially with APOE genotype e3/e3
    - VCP mutations
      - Observed in some patients with vacuolar myopathies misdiagnosed with sIBM
    - p62: Rare gene variants observed in sIBM patients
  - Transglutaminase activity: 20x elevated level in muscle
  - Infections
    - HIV & HTLV viral infection: ? Increased frequency of sIBM
    - HIV: Younger onset of sIBM, Mean age 55, Youngest 38 years ⁸⁹
    - Hepatitis C virus (HCV) antibodies: 28% ⁸⁸
      - No clinical differences between HCV antibody + & - patients
  - Immune sensescence
- Neoplasms & IBM ¹²⁸
  - Chronic lymphocytic leukemia: ? Association with sIBM ⁷⁸
  - T cell large granular lymphocytic leukemia (T-LGL) ⁹⁰
    - Large granular lymphocytes (LGLs; CD8+, CD57+; CD28-; Kv1.3+): in blood
    - CD4/CD8 ratios: Lower
Variant syndromes
- Inflammatory myopathy 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

Inflammatory Myopathy + Mitochondrial Pathology in muscle (IM-Mito), subtype of IM-VAMP ⁴²

Clinical
- Onset age: Mean 61 years; Range 43 to 71 years
- Weakness
  - Quadriceps: Early & most severe (90%)
  - Proximal
  - Distal (40%): Wrist & finger flexion
  - Face (50%)
  - Symmetric (70%)
  - Progression: Slow
    - Overall: 1% to 4% per year
    - Knee extension: 3% to 8% per year
    - Slower than IBM
- Treatment
  - Long term: No clear benefit
  - Methotrexate
    - Dose: 10 to 20 mg/week
    - More effective: Patients with < 10% of fibers COX-
  - Patients unresponsive to treatment may have IBM on repeat muscle biopsy
  - Corticosteroid therapy: NO response
Laboratory
- Serum CK: Normal or mildly elevated; Range 54 to 1200
- Muscle pathology
Variant syndromes
- Inclusion body myositis
- IM-VAMP

INFLAMMATORY MYOPATHIES: Other variants

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

Granulomatous Myopathies ¹³²

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
- Treatment
  - Corticosteroids: Benefit
    - General: 40% to 80%
    - More likely: Associated systemic sarcoidosis
    - Less likely: Isolated granulomatous myopathy; IBM-like clinical syndrome
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 or granulomatous disease
  - Differential diagnosis: Wide
  - IBM: Possibly increased association
- Myopathic changes
  - Variation in muscle fiber size
  - Location: Both near & distant from granulomas
Differential diagnosis
- General
- Myopathy
  - Sarcoidosis
  - Mitochondrial antibodies
- Immune disorders
  - Connective tissue: Rheumatoid arthritis; Mixed CTD; Wegener's
  - Myasthenia gravis (rare): Associated with ¹⁸
    - Myocarditis
    - Thymoma ¹⁹
    - Antibodies to Ryanodine receptors
  - Crohn's
- Infections

Granulomatous & Inflammatory Myopathies with Anti-mitochondrial antibodies ⁷²

Epidemiology
- Geography
  - Tokyo: 11% of inflammatory myopathies
  - France: 8% of IIM
- Female:Male = 15:9
Clinical
- Onset age: 33 to 72 years; Mean 49 years
- Systemic
  - Primary biliary cirrhosis: 30%; Often asymptomatic
  - Cardiac: 33% to 71%
    - Arrhythmias: Atrial tachycardia
    - Cardiomyopathy: Reduced ejection fraction
    - Myocarditis 20%
    - Associated with Biliary cirrhosis
- Muscle
  - Weakness
    - Proximal > Distal
    - Arms & Legs
    - Moderate degree: 3/5 to 4/5
    - Scapular winging
    - Paraspinal (11%)
  - Atrophy: 55%
  - Respiratory: Reduced vital capacity 33%
  - Course: Chronic 55%
- Skin rash: Uncommon
- Associated disorders
  - Malignancy: 13%; Colon
  - Other immune: 43%
  - Uncommon: Interstitial lung disease; Skin disorders
- Treatment: Variable & Mild improvement with corticosteroids
Laboratory
- Antibodies
  - Mitochondrial antibodies (AMA-M2)
    - Targets
      - Major autoantigen: E2-subunit of pyruvate dehydrogenase complex (PDC-E2; DLAT)
        
        Mutated in infantile encephalopathy
      - 2-oxoacid dehydrogenase: On inner mitochondrial membrane
      - Other occasional autoantigens: OGDC-E2; BCOADC-E2
    - Clinical associations
      - Systemic disorders
        
        Liver: Primary biliary cirrhosis
        
        Cardiac: Myocarditis; Dilated cardiomyopathy
      - Immune & Inflammatory Myopathies (IIM) ¹¹⁰
        
        1st reports: Granulomatous myopathies
        
        May occur with many IIM types
        Possible association with treatable or refractory IIM
        
        Clinical associations ¹¹⁷
        
        Weakness: Persistent; Paravertebral
        Raynaud�s phenomenon
        
        Dysphagia
        
        Cardiomyopathy
        
        Disease severity
        
        Respiratory failure
        Weight loss
        Malignancy: 35%; Breast
        May occur with asymptomatic high CK
        
        Laboratory
        
        Muscle pathology
        
        Muscle fibers: Necrosis (70%)
        Inflammation: Granulomas in > 50%
        
        Serum CK: Moderately high
  - Other myositis-specific or associated
    - Frequency: Rare (Japan) to Common (Europe)
    - Ro-52: 35%
    - Synthetase: 18%
  - ANA or dsDNA: 50%
- Serum CK: High; 220 to 4,400
- Alkaline phosphatase: Commonly high
- EMG: Irritable myopathy
- Muscle MRI: "Edema"
- Muscle
  - Chronic myopathy: Endomysial fibrosis
  - Necrosis & Regeneration
  - Focal invasion: Rare
  - Muscle fiber size: Varied
  - Inflammation: Common
  - Granulomas
    - Frequency: 0% (Europe) to 45% (Japan)
    - Location: Endomysium & Perimysium
    - Cell types: Histiocytes; CD4+ cells
  - MHC1: Commonly diffusely increased on muscle fiber surfaces

Myopathy with Muscle fiber necrosis & Pipestem capillaries ¹

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 Chondroitin sulfate C loss in skeletal muscle endomysium ³

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
- Treatment: Corticosteroids produce improvement over months
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
Also see: Myopathy with serum IgM binding to Decorin

Benign Acute Childhood Myositis (BACM) ⁸

Nosology: Myalgia Cruris Epidemica
Epidemiology
- Male (66% to 84%) > Female
- Associated with: Influenza, B > A
- Seasonal: Winter (68%) >> Summer (2%; More in India)
- Occurs in temporal clusters
- Occasional occurrence in siblings
Clinical features
- Prodrome
  - Fever (80%)
  - Upper airway: Cough, Rhinorrhea or Respiratory (59%)
  - Headache (37%)
- Onset
  - Age: Mean 5 to 14 years; Median 6.5 years; Range 3 to 54 years
  - Timing: 1 to 4 days after prodrome
- Pain & Tenderness (75%)
  - Most severe & common: Calf
  - Generalized: Some patients (5% to 10%)
  - Refusal to walk
- Strength
  - Weakness (50%): Usually ≥ 3/5
  - Normal: Majority of patients
- Difficulty walking: Toe walking (32%); Stiff-legged (17%); Claudication; Other unusual (32%)
- Tendon reflexes: Normal or Reduced
- Systemic: Fever >38°C (25%)
- Treatment: Anagesia; Rest; Hydration
- Course
  - Monophasic
  - Hospitalize for: Myoglobinuria
  - Recovery: Within 1 week in most; 4 to 10 days
  - Recurrence
    - Frequency: 8% to 10%
    - More common with higher CK
Laboratory features
- Serum CK
  - Acute phase: High (100%); 250 to 36,000
  - Rhabdomyolysis: More common in females
  - After recovery (1 month): Normal
- Platelets: May be low
- Leukopenia (70%)
- Viral titers + (42% to 65%): Influenza B in 21%
- EMG: Myopathic (50%) or Normal
- NCV: Normal
- Muscle pathology
  - Necrotic muscle fibers: Regional > Scattered
  - Perimysial connective tissue: Fragmentation; Edema; Some inflammation
  - Endomysial capillaries: C_5b-9 deposition

Influenza-Associated Myositis

Epidemiology
- Male > Female; 2:1
- Onset age: Mean = 8.5 years; range 2 to 14 years
Virus
- Influenza B: 76%
- Influenza A: 24%
Clinical
- Time after influenza onset: Mean 3 days; Range 0 to 18 days
- Localization
  - Calf muscles only (69%)
  - Other additional muscles (31%)
  - Arms (20%)
- Muscle
  - Pain: Myalgias; Muscle tenderness
  - Swelling
  - ? Weakness
  - Rhabdomyolysis (3% to 20%): More often females & influenza A
- Gait disorder
- Course: 1 to 2 weeks; Spontaneous improvement
Laboratory
- Serum CK: High; Range 200 to 100,000
- Muscle biopsy: Necrosis & Regeneration; Inflammation (18%)
Also see: BACM

Orbital (Ocular) Myositis, Idiopathic ⁹⁸

Nosology
- Ocular myositis
- Orbital pseudotumor
- Idiopathic orbital inflammatory syndrome
Definition
- Extraocular muscle disorder
  - Inflammatory process, Idiopathic
  - Involvement of one or more muscles
Epidemiology
- Male:Female = 1:2
Clinical
- Onset age: Average = 30 to 40; Range = 3 to 84
- Eyes
  - Vision
    - Diplopia
    - Normal acuity
  - Proptosis: Usually mild
  - Edema (Periorbital & Eyelid)
  - Conjunctiva
    - Injection & Chemosis: Near muscle insertions
  - Pain
    - Mild or Severe
    - Worse with eye movement
- Eye movements
  - Limitation
    - In direction & Opposite direction of muscle action
    - Acute: Paretic
    - Chronic: Restrictive
  - Muscles commonly involved
    - Medial rectus (43%)
    - Superior rectus (19%): Upgaze impairment
      - More on adduction than abduction
    - Lateral rectus (17%)
    - Other: 5% to 10%; Obliques; Inferior rectus
    - Ptosis
    - Usually > 1 muscle
    - Bilateral: 20% to 40%; More in children
- Course
  - Onset: Acute, or Chronic
  - Relapse: 50%; May be associated with treatment taper
- Pediatric disorders
  - Bilateral: More common
  - Associated disorders: More common than adults
    - Uveitis
    - Disc edema
    - Eosinophilia
- Associated disorders
  - Eye
    - Uveitis
    - Periocular inflammation
    - Disc edema
  - Infectious
  - Systemic
    - Sarcoid
    - Psoriasis
    - Rheumatoid arthritis
    - Systemic lupus erythematosus
    - Crohn�s disease
    - Eosinophilia
  - Muscle & Heart
    - Giant Cell Myositis
  - Drugs
    - Checkpoint inhibitors
- Treatment
  - Corticosteroids > Other immunosuppressants
  - Chronic: Diplopia management
    - Surgery
    - Botulinum injections
  - Radiotherapy
Laboratory
- Imaging
  - Methods
    - A-scan echography
    - MRI of orbits
      - Contrast-enhanced, T1-weighted,
        Fat suppressed, Coronal
  - Pathology
    - Enlarged muscles
    - Thickened tendons
    - Low internal reflectivity
- Muscle Pathology
  - Inflammatory foci: Ectopic lymphoid structures
    - Lymphocytes: B-cells & T-cells
    - Eosinophils: In some
    - Plasma cells: Scattered
    - Venules
  - Fibrosis: Late
  - Edema
- Thyroid autoantibodies: Negative
Differential diagnosis
- Thyroid ophthalmopathy
  - Course: Chronic
  - Inferior rectus paresis: Common
  - Lid retraction
  - No pain
  - Poor response to corticosteroid treatment
- IgG4 disease
- 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

Orbital Myositis: Medial Rectus enlargement, Asymmetric

Masticator Myopathy ³⁷

Epidemiology
- Rare in humans
- Common in dogs: Alsatian & Large breeds; Young & Middle aged
Clinical
- Muscles
  - Painful
  - Swollen
  - Location: Masseter; Temporal; Pterygoid
- Restricted jaw mobility
- Course
  - Progression: Over days
  - Spontaneous remission: Weeks
  - Relapses may occur: Especially in dogs
  - Chronic form recognized in dogs
- Treatment: May improve with corticosteroids
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

Large Histiocyte Immune Myopathy (LHIM) ¹¹¹

Epidemiology: 4 patients described
Clinical
- Onset
  - Ages: 18 to 52 years
  - Progression: 1 to 6 weeks
- Prodrome: Myalgias; Weight loss (50%)
- Weakness
  - Proximal > Distal
  - Arms & Legs
  - Moderate degree
  - Symmetric
- Systemic
  - Anemia (100%)
  - Other (1 patient each): EBV; HLH; Liver disease; Raynaud's; Sguamous Cell Cancer; Cardiomyopathy
  - Skin: Normal
- Outcome
  - Improved in 3 patients (75%)
  - Death in 1 patient due to associated neoplasm
Laboratory
- Serum CK: 10,000 to 102,000
- EMG: Myopathy ± Fibrillations, or Normal
- Muscle biopsy
  - Muscle fiber necrosis: Histiocyte-associated
- Serum Ferritin: High in 50%

Giant Cell Myositis

Epidemiology: Female > Male
Clinical
- Onset: 6th & 7th decades; Range 16 to 82 years
- Weakness
  - Proximal ≥ Distal
  - Respiratory
  - Dysphagia
  - Symmetric
- Associations
  - Myasthenia gravis
  - Thymoma
  - Cardiomyopathy: Myocarditis
  - Orbital myositis
- Prognosis: Death in 35%
Laboratory
- Antibodies
  - Striational: Titin
  - AChR binding
- Hypercalcemia
- Serum CK: Normal or High
- Muscle pathology
  - Myopathy
  - Giant cells: Multinucleated
  - No granulomas
- EMG: Myopathic

Hemophagocytic Lymphohistiocytosis ⁴¹

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
Hemophagocytosis Genetic types
- Type 1 (FHL1) : Lethal in early childhood
  ● Chromosome 9q21.3-q22; Recessive
- Type 2 (FHL2)
  ● Perforin-1 ; Chromosome 10q22; Recessive
- Type 3 (FHL3)
  ● UNC13D ; Chromosome 17q25.1; Recessive
- Type 4 (FHL4)
  ● STX11 Chromosome 6q24.2; Recessive
- Other
  - Chediak-Higashi
  - Griscelli syndrome
  - X-linked lymphoproliferative syndrome
  - GATA2
Hemophagocytosis: Sporadic forms
- Similar to: Macrophage activation syndromes
- Epidemiology: ? More common in Summer
- Clinical
  - Onset age
    - Later than hereditary forms
    - Children, Adolescents & Adults
  - Fever
  - Organomegaly: Liver, Spleen, Lymph nodes
  - Skin
    - Rash: Maculopapular or Nodular
    - Face edema
  - CNS
    - Seizures
    - Encephalopathy
    - Meningismus
  - Myopathy
    - See: Large Histiocyte Immune Myopathy
    - Epidemiology
      - Child, Teen or Adult
      - Sporadic disease
    - Clinical
      - Weakness
        
        Proximal ± Distal
        
        Symmetric
      - Myalgias
      - May occur with few or many systemic signs
    - Laboratory
      - Serum CK: High
      - Muscle
        
        Myophagocytosis: Progressive phagocytosis of muscle fibers by histiocytic cells
        Muscle fibers: Become necrotic at early stages of association with myophagocytes
  - Neuropathy
    - 1 patient with AIDP & acquired HLH after Epstein-Barr virus (EBV) infection
  - Course
    - Often monophasic
    - Relapses: 16%
  - Treatment
    - Corticosteroids: Pulse, high dose
    - IVIg
    - Etoposide-based chemotherapy
    - Anti-interleukin
- 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, Dermatomyositis, Kawasaki disease
      - Severe
      - With high-dose corticosteroids
  - Drug induced
    - Lamotrigine: Improvement after drug withdrawal
- Laboratory
  - LDH & Liver enzymes: High
  - High
    - Ferritin
    - Triglycerides
    - C-reactive protein
    - Soluble CD25 (IL-2 receptor)
    - Cytokines: IL-2, INF-α, IL-6, IFN-γ
    - Bilirubin
    - Lactate dehydrogenase
  - Hypofibrinogenemia
  - Disseminated intravascular coagulation
  - Hemophagocytosis: Bone marrow, Spleen, Lymph nodes, CNS
  - Blood cells
    - Anemia
    - Thrombocytopenia
    - Nitro-blue tetrazolium reduction by monocytes

Hereditary Inflammatory Myopathies

FSH dystrophy
Limb-Girdle dystrophy
- 2B
- ? 2A
Inclusion Body Myositis: Familial
Familial Idiopathic Inflammatory Myopathy
Immune system disorders ¹⁴⁰
- IPEX: FOXP3
- TRAPS: TNFRSF1A
- FMF : MEFV
- Cryopyrin-Associated Periodic Syndrome (NLRP3-AID) : NLRP3
- NLRP12-AID : NLRP12
- HIDS, Hyperimmunoglobulinemia D & Periodic fever syndrome : MVK
- Yao: NOD2, IVS8+158
- Blau (Granulomatous) : NOD2, Exon 4
- Schmidt syndrome (Diabetes mellitus, Addison disease, Myxedema)
HLA associations

Myositis: Infectious agents

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

Inflammatory myopathy: Other

Focal myositis: Quadriceps & other muscles

Fasciitis

Syndromes
- Autoimmune
- Eosinophilia-Myalgia: Inflammation in perimysium ± myositis
- Spanish toxic oil
- Eosinophilic fasciitis
- Macrophagic myofasciitis
- Graft vs host disease
- Perimyositis
General Pathology

INFLAMMATORY MYOPATHIES: Animal Models

MHC class I: Conditional up-regulation in muscle fibers ¹¹
- Animal: Mouse
- Clinical features: Weakness; Reduced growth
- Muscle fibers: Necrosis; Macrophage infiltration
- Antibodies: vs Histidyl-tRNA synthetase (Jo-1) in 30%
- Differences from human disease
  - Polymyositis: No clear lymphocytic infiltration
  - Jo-1 myositis: No perimysial inflammation
Absent SOCS-1 gene & Heterozygous for IFN-γ gene ¹²
- Animal: Mouse
- Myositis
- Myocarditis
- Pathology: Inflammation in many tissues
Experimental autoimmune polymyositis ⁶
- Animal: Rat
- Target antigen (Immunization with)
  - Myosin: Mild inflammation
  - C-protein: Severe inflammation
CBA/J mice infected with T. cruzi ³⁵
- Chronic focal inflammation in muscle: Endomysial; T-cells; Focal invasion

Sarcoidosis

General features
Clinical
NM syndromes
Myopathy
Acute
Chronic
Nodular
Neuropathy
Sensory
Mononeuropathies
VII
Multiple Mononeuropathy
Vasculitis
Myelopathy
Laboratory
Pathology
Histopathology
Treatment

General features
- Prevalence
  - General: 1 to 60 cases per 100,000 persons
  - Geography
    - Lowest: Far East
    - Highest (20-180/100,000)
      - Sweden
      - US: African-American
      - British: West Indian
  - Race
    - U.S.: Black 10x > White; ZNF592
    - Europe: White
  - Exposures
    - Nonsmokers > Smokers
    - Central air conditioning
    - Occupations
      - Agriculture
      - Insecticide & Bioaerosol exposure
  - Females: More neurological & eye manifestations
- Genetic associations ⁵¹
  - Familial risk
    - Siblings: 5-fold
    - White siblings: 18-fold
    - Lower in African-Americans
  - ABCC7 (CFTR) mutations ¹³
    - 35% of patients with sarcoid heterozygous for mutations: ? Especially R75Q
    - Sarcoid patients with mutations: More disease progression; ? More extra-pulmonary disease
    - ABCC7 (CFTR)
      - Receptor for Pseudomonas aeruginosa & Salmonella typhi
      - Homozygous gene mutations cause cystic fibrosis
  - Class II HLA: Allelic variation ³⁹ (SS1 )
    - DPB1*0101
    - DPB1*0101: Hypercalcemia in whites
    - DQB1*0201: Decreased risk & Lack of disease progression
    - DRB1*1101: Associated with sarcoid in blacks & whites (2x to 3x)
    - DRB1*1501: Sarcoidosis in whites
    - DRB1*0401: Eye involvement in blacks and whites
    - DRB3: Bone marrow in blacks
    - DRB1*0301/DQB1*0201: Good prognosis in Löfgren�s syndrome
    - DRB3*1501 Loöfgren�s syndrome
    - DRB1*04: Protection
  - BTNL2
    - B7 family costimulatory molecule
    - Associated with sarcoidosis (SS2 )
  - ANXA11 (SS3 ): Between exons 5 & 14
  - Familial granulomatous diseases
    - Blau : NOD2/CARD15 gene
    - Crohn : NOD2/CARD15 gene

Clinical Sarcoidosis: General

Onset age
- Usual: 20 to 40 years
- Occasional: Children & Older patients
Systemic syndromes
- Skin: Erythema nodosum; Papules
  - External image: Papules
- Ocular
- Interstitial lung disease
- Arthritis
- Thoracic lymphadenopathy: External image
- Endocrine
  - Hypercalcemia
  - Lacrimal gland enlargement: External image
Course
- Chronic
- Episodic: Some patients

Hilar adenopathy

Clinical sarcoidosis: Neuromuscular features

Myopathies ¹²¹
- Symptomatic Myopathy: 5% of Sarcoidosis
- Chronic sarcoid myopathy
  - Epidemiology: Middle-aged females
  - Clinical
    - Features similar to granulomatous myopathy
    - Weakness
      - Symmetric; Proximal ± Distal
      - Selective respiratory failure may occur
    - Occasional: Pain or Cramps
    - Often other systemic signs of sarcoidosis
  - Laboratory
    - Serum CK: Moderately high
    - Muscle MRI: Few changes
  - Muscle pathology
    - Myopathy
    - Granulomas with Giant cells: Non-caseating
- Acute sarcoid myositis ¹⁰
  - Clinical
    - Onset
      - Symptoms
        
        Tenderness & Myalgias
        
        Proximal weakness
      - Age: Often < 50 years; Range 15 to 75 years
      - Females: 60%
      - May occur in patients with
        
        Chronic myopathy
        
        No previous weakness
    - Myalgias
    - Weakness
      - Symmetric
      - Proximal > Distal
      - Occasional: Respiratory
    - Systemic
      - Fever
      - Polyarthritis
      - Erythema nodosum
    - Progression: Days to Months
    - Treatment
      - Often responsive
      - Corticosteroids (Prednisone 60 mg/day)
      - Methotrexate
  - Laboratory
    - Serum CK: High; Range 90 to 12,000
    - Serum aldolase: High
  - Muscle Pathology
    - Muscle fibers: Necrosis & Regeneration
    - Granulomas with Giant cells: Non-caseating
    - T-cell inflammation
- Nodular myopathy: Nodules in muscles
  - Age: Mean 4th decade
  - Nodules
    - Small & Soft
    - Progression: Grow in size & Become painful over time
  - Differential diagnosis: Nodular myositis with rheumatoid arthritis
  - Muscle MRI lesions
    - Star-shaped
    - Hypointense
    - Surrounded by increased signal
  - Pathology: Fibrosis surrounded by granulomatous inflammation
- Overlap Myopathy syndromes
  - Inclusion body myositis-like ¹²³
  - Anti-synthetase ¹²²
  - Orbital myopathy ¹²⁴
- Asymptomatic Sarcoid in muscles
  - Granulomas in muscle in 50% to 80% of sarcoid
  - Serum CK: Usually normal
Neuropathy: Sensory predominant ¹⁰⁵
- Epidemiology
  - Female > Male
  - Caucasian > Black or Other
  - Frequency: 10% to 14% of neurosarcoid
- Clinical
  - General: Small fiber sensory ± Autonomic syndromes common
  - Onset age: Mean 46 to 50 years
  - Sensory
    - Paresthesias
    - Loss
      - Non-length dependent: May involve face, trunk & limbs
      - Small fiber > Pan-Modal
    - Discomfort (80%)
      - Pain
      - Burning (33%): Most severe symptom
      - Numbness
      - Migratory
      - Intermittent
  - Weakness
    - Few patients
    - Distribution: Distal; Legs > Arms
  - Tendon reflexes: Reduced at ankles
  - Autonomic features (50%)
    - Cardiac: Orthostasis, Palpitations
    - Gastrointestinal
    - Sweating dysfunction
  - Cranial nerves & CNS: Involvement uncommon
  - Progression: Slow; Over months to years; May remain subclinical
  - Treatment: IVIg or Anti-TNF drugs
- Laboratory
  - Electrodiagnostic: Axon loss or Normal
  - QSART: Abnormal in some
  - CSF: Abnormal
- Nerve pathology
  - Granulomas: May be present in nerve or other tissues
  - Axon loss: May be normal; Large > Small in few patients
  - Skin biopsy: Axon loss (Small fiber), Often non-length dependent
Mononeuropathies
- Onset: Often acute
- Cranial neuropathies: II; VII; VIII; IX & X
  - VII ¹²⁶
    - Original description: 1909 Uveopareotid fever by Christian Heerfordt
    - Most common cranial nerve involved with sarcoid
    - Neurosarcoid relations
      - 10% to 16% of patients with neurosarcoid
      - Often initial presentation of neurosarcoid (74%)
      - May preceed multiple frequent attacks of neurosarcoid (65%)
    - Syndromes
      - Onset: Acute (70%)
      - Upper + Lower face (100%)
      - Unilateral or Bilateral (13%)
      - Dysgeusia or Hyperacusis: 25%
      - May occur alone
      - Association with other cranial neuropathies (43%): V, II, VIII
    - Treatment
      - Corticosteroids+
      - Recovery: Often (60% to 80%) good: Similar to idiopathic VII palsy
    - Laboratory
      - CSF: Pleocytosis & High protein common
      - MRI: Leptomeningitis; Cranial nerve enhancement
  - II: Visual loss; Papilledema
- Major nerves: Phrenic; Ulnar; Median; Radial; Truncal; Peroneal
- Radiculopathies & Plexopathies
Associated Guillain-Barré-like syndrome
- Young average age
- May be due to acute sarcoid vasculitis & neuropathy
Multiple Mononeuropathy ¹³⁵
- Clinical
  - Onset
    - Age: 6th to 9th decade
    - Numbness
    - Initial feature may be neuropathy (50%)
  - Weakness (70%)
  - Sensory loss
  - Pain: Uncommon
  - Course: Progression over 1 to 13 months
- Laboratory
  - CSF: Cells < 15; Protein < 70
  - Eletrodiagnostic
    - CMAP & SNAP amplitudes: Reduced
    - NCV: Mean 39 to 51 M/s
  - Nerve pathology
    - Granulomas
      - Location: Epineurium, Perineurium, Endoneurium
      - May be perivascular
      - Non-caseating
    - Axon loss
    - Larger axons without myelin: Near granuloma
    - Vasculitis: 10%

Sarcoid & Vasculitis ⁴⁸

Clinical
- Onset
  - May be presenting sign of sarcoidosis
  - Age: 23 to 83 years
- Weakness
  - Frequency: 60%
  - Distribution
    - Multifocal 55%
    - Distal symmetric 36%
    - Diffuse with respiratory failure 9%
    - Face 9%
- Sensory loss
  - Distal
  - Mild
  - Symmetric or Asymmetric
  - Frequency: Most patients
- Course
  - Subacute
  - Progressive
  - Improvement with steroid treatment
- Associated involvement of other organs
  - Common
  - Especially lymph nodes, muscle & lung
Laboratory
- Serum ACE: Normal in 82%
- Serum Ca⁺⁺: Normal
- CSF: Unremarkable
- NCV: Multifocal axon loss
- Nerve pathology
  - Inflammation: Invasion of endoneurium;
  - Granulomas: Epineurial & Endoneurial; Giant cells
  - Perineuritis
  - Vessels: Necrotizing vasculitis 64%
  - Axon loss: Differential fascicular involvement
- Muscle pathology: Denervation; Granulomas

Polyradiculopathy/Myelopathy ⁹⁹

Epidemiology
- Frequency: < 1% of sarcoidosis patients
- Patient origin: Caucasian; Sub-Saharan Africa
- Male > Female
- Onset age: Commonly < 40 years
Clinical
- Onset
  - Age 17 to 48 years
  - Weakness: Lower extremities
  - May be presenting feature of sarcoid
- Weakness: Proximal & Distal; Symmetric
- Sphincter dysfunction: 35% to 45%
- Sensory: Loss (65%); May be normal
- Tendon reflexes: Reduced in Legs
- Pain: Back & Leg; Dull ache
- Course
  - Progressive over months
  - Subacute or Acute onset: Few patients
  - Prognosis: Related to severity at initial presentation
- Systemic
  - Mediastinal lymphadenopathy: 85%
  - Peripherla lymph nodes: 35%
  - Posterior uveitis: 10%
  - Liver: 20%
  - Joints: 15%
- Treatment
  - Corticosteroids: Often high dose methylprednisolone
  - anti-TNF-α antibodies (Infliximab or Adalimumab)
    - Infliximab: 3 to 7 mg/kg q 4 weeks
  - Methotrexate
MRI & Imaging: Variable
- Spinal cord
  - Patterns
    - Intramedullary lesions
      - May be diffuse
      - Spinal cord edema (35%)
      - Heterogeneous & Patchy
      - Longitudinal involvement
        
        Often > 3 spinal segments
    - Subpial & Leptomeningeal enhancement (40%)
  - Levels: All; Cervical & Thoracic most common
- Nerves: Nodular lesions on roots or nerves
- PET scan: Lesions may be positive
Laboratory
- Electrodiagnostic
  - EMG: Denervation
  - SSEP: Reduced potential amplitude
- CSF
  - Protein: High
  - Glucose: May be low; Rule out lymphoma
  - WBC: 6 to 45 lymphs
- Muscle biopsy: Granulomas

CNS: Mass lesions; Chronic meningitis

T1 contrast Multiple lesions in cord & roots	T2 Cord edema
MRI: CNS Sarcoid; Myelopathy & Radiculopathy

Laboratory
- Serum CK: High with myopathy
- CSF (with CNS involvement)
  - Color: Mildly xanthochromic
  - Glucose: Reduced
  - Protein: Increased: Mean 300; Range 50 to 1145 mg/dL
  - Pleocytosis: Mean 150 cells/mm³
- Myelogram: Nerve root & intramedullary pathology
- Chest CT (90% abnormal): Hilar adenopathy; Nodular interstitial fibrosis
- Muscle biopsy (Blind): Often with granulomas
- Angiotensin converting enzyme (ACE): High in 66%; False positive 5%
- Imaging for systemic disease
  - Body CT
  - MRI
  - PET
  - Gallium scan
- Chitotriosidase: Increased activity in bronchioalveolar lavage
Pathology
- Granulomas
  - Non-caseating
  - 50% may have asymptomatic granulomas in muscle
  - Some may be nodular & palpable or visible on imaging studies
- Inflammatory cell types: TH1 type response
  - Mononuclear T-helper lymphocytes
    - CD4+
    - Oligoclonal T cell receptors: Consistent with response to an environmental antigen
  - Phagocytes
- Increased levels of IL-2 and INFγ
Treatment
- Corticosteroids: Response in 50% to 70%
- Surgical for mass lesions
- Immunosuppression: Methotrexate; Cyclophosphamide; Cyclosporine
- Anti-TNF-α (Infliximab) ²¹

Trichinellosis (Trichinosis) ⁷⁵

History
- Discovered by James Paget & Richard Owen in 1835
Infectious agents ¹³³
- Trichinella spiralis: Most common in humans
  - Helminth type roundworms (Nematode)
  - Animal host
    - Domestic pig
    - Highest frequencies in pigs
      - Countries with low Human Development Index
      - Tropical wet climates
      - Non-intensive (Open housing) pig farming systems
- Other Trichinella species may infect humans
  - Trichinella murrelli: Wildlife
  - T. nativa: Arctic bears; More resistant to freezing
  - T. nelsoni: African predators & scavengers
  - T. britovi
    - Carnivores
    - Europe, North Africa, Middle East & Western Asia
  - Non-encapsulated types
    - T. pseudospiralis
      - Hosts: Mammals & Birds
      - Worldwide
      - Smaller size than other Trichinella
    - T. papuae
      - Pigs (Boar): Wild & Domestic pigs
      - Papua New Guinea & Thailand
      - Infections: Often subclinical; Male > Female
    - Trichinella zimbabwensis
      - Parasitize mammals & reptiles: Crocodiles in Africa
      - No known associations with human disease
Epidemiology
- General
  - Cases worldwide
  - 10,000 cases per year
  - Mortality rate: 0.2%
- Sources
  - Inadequately cooked meat
  - More common in areas also with infected rodents (rats)
- United States
  - Most US cases: Trichinella spiralis or murrelli
  - United States cases
    - Current (2010 to 2020): 20 to 50 per year
    - More common in patients of Asian descent
    - 1940's: 400 per year
  - Most common region: Pacific
  - Age range: 81% between 20 & 69 years
- France & Italy: Raw horse meat; Pigs
- Southeast Asia, Iran & Slovakia: Wild boar
- China & Korea: Dog
- Japan: Bear
- Arctic
  - Marine mammals (Walrus; kopalkhen)
  - Trichinella nativa; Seroprevalence 24%
- Earliest case: Egyptian mummy in 1300 BCE
Pathogenesis: Life cycle
- Source: Undercooked meats containing the Nurse cell-larva complex
- Larvae from ingested infected meat
  - Released from Cysts → Gut by gastric acid & pepsin
- Liberated larvae
  - Develop into adult males & females: In duodenum & jejunum
  - Mate & Bear offspring
  - Larvae into gut wall: Intestinal motility increased; Diarrhea
- Larvae migration (Parenteral stage)
  - Migrate: Via lymphatics into blood stream
  - Embolize: To skeletal muscle vessels
- Invasion & Inflammation in muscle
  - Associated with: Pain & Weakness
- Course in organs
  - Larvae in muscle: Stages
    - Early
      - Stages: Larvae
        
        Invade muscle fibers
        Mature
        Escape from damaged muscle fibers
        Free in muscle: No cyst
        
        Induce immune, histiocytic reaction
      - Macrophage migration inhibitory factor (MIF)
        
        May be virulence factor expressed by worm
    - Intermediate: Encystation (Encapsulation)
      - Encysted along with Nurse cells
      - Nurse cells
        
        May be derived from myocytes
        
        Transformed due to "parakine" molecules
      - Property of some Trichinella species, but not others
      - Capsule forming clades: Infect only mammals
    - Late
      - Larvae in cysts die
      - Calcification
  - Adult larvae in GI tract: Expelled in stools
- Other aspects of T. spiralis life cycle
  - Endemicity: Full life cycle maintained in carnivorous rodents & rats
  - Food animals: Ingest infected meat or animals
Clinical: Phasic course
- Incubation period: 1 to 38 days
- Prodrome: Enteral
  - Diarrhea 1 to 7 days after ingestions (Especially in severe cases)
  - Abdominal pain
  - Early symptoms: May be due to enteral or parenteral infection
  - Larvae: Released into intestinal mucosa
  - Disease severity: Related to number of larvae ingested
    - Asymptomatic: < 70
    - Gastroenteritis & Diarrhea: ≥ 70
- Systemic (Parenteral)
  - General: Fever (75%); Headache
  - Edema: Periorbital or Facial
  - Skin (75%): Maculopapular, pruritic rash; Splinter hemorrhages
  - GI: Abdominal pain; Vomiting; Diarrhea
  - Respiratory: Cough; Dyspnea
  - Cardiac: Myocarditis or Pericarditis → Congestive failure; Arrhythmias
  - Encephalitis: Normal spinal fluid
  - Eosinophilia
  - Death: Related to myocarditis, meningoencephalitis, or pneumonitis
- Myopathy
  - Onset: 1 to 6 weeks after cyst-containing meat
  - Pain: Myalgia, Swelling & Weakness; Very common
  - Weakness
  - Fatigue
  - Disease may be self limitied
- Disease course
  - Disease may be self limited: Full recovery after 2 to 6 months
  - Poor prognosis: Myositis, Cardiopathy or Encephalitis
- Treatment
  - Effects
    - Eliminates adult worms from intestine
    - Prevents production of new larvae
    - Eliminates larvae in lymphatic system & blood vessels
  - Albendazole: Enteral phase
    - 400 mg tid (or 500 bid) x 2 weeks
    - Not in children or pregnant women
  - Mebendazole
    - 200 to 400 mg three times a day by mouth for 3 days
    - Then 400 to 500 mg three times a day by mouth for 10 days
  - Corticosteroids: Severe cases; 30 to 60 mg/day for 10 to 14 days
  - Timing
    - Start soon after ingestion of infected meat, if possible
    - May still be useful 4 to 6 weeks after infection
    - Later treatment may require longer course
    - Pregnancy: Treatment may be safe after 1st trimester
  - Analgesics
  - Prophylactic: Mebendazole within 6 days after exposure
  - Prevention: Meat heated to ≥ 77°C
Laboratory
- Eosinophilia
  - Frequency: 5% to 90%
  - Early in disease course
  - Higher levels may correlate with
    - Disease severity
    - Cardiac & CNS involvement
- Leukocytosis
- Serum Creatine Kinase: High in 80%
- EMG: Myopathic; Irritable
- X-rays: Muscle calcifications later in course
- Muscle biopsy: Obtain large sample
  - Diagnostic test: Higher sensitivity ≥ 4 weeks after infection
  - Allows molecular identification of Trichinella species or genotype
  - Acute
    - Cysts with larva
    - Histiocytic inflammation
    - Active myopathic changes
  - Chronic
    - Cysts (Often empty or with calcification)
    - No inflammation or active myopathic changes
- Antibody testing
  - Method: ELISA IgG vs Trichinella antigens
  - Positive after 12 to 14 days
  - Draw samples several weeks apart: Look for rising titer
Other
- ? Cause of death of Mozart ²⁰
- eMedicine
- Image
- Trichinella site
- CDC hotline: parasites@cdc.gov

	CDC
From CDC Trichinella larva in pressed bear meat From CDC Trichinella larva in Cyst

Sarcocystis (Sarcosporidiosis) ^⁴⁴

From USDA

Sarcocystis in muscle

From: CDC

Epidemiology
- Organisms: Sarcocystis
  - Heteroxenous parasite
  - Beef ingestion: Sarcocystis hominis
  - Pork ingestion: Sarcocystis suihominis
- Geography: Infections common in Malaysia
  - 20% of Autopsies
  - 20% with serologic evidence of infection
  - Most cases asymptomatic
  - Definitive hosts
    - Malaysia: Python which preys on various monkey species
    - Other regions: Wild fowl, Cats, Dogs, Cattle
  - Animal disease: Macaca monkeys
  - Other countries with symptomatic cases: Thailand; Egypt
  - North American hosts: Paddle ducks & Grackles
- Symptomatic cases: < 100 reported
  - Most have skeletal muscle involvement
  - Some have cardiomyopathy
- Transmission: Predator-prey lifecycle
  - Foodbourne zoonosis
  - Definitive host: ? Python in Malaysia
  - Humans are often accidental intermediate hosts
    - Intestinal disease: Ingestion of raw meat; Diarrhea
    - Muscle disease: Ingestion of sporocysts
  - Organism forms
    - Metrocytes: Characteristic of acute infections
    - Bradyzoite: Differentiated forms
Clinical
- Systemic
  - Fever
  - Weight loss
  - Pulmonary
    - Bronchospasm
    - Cough
  - Skin
    - Nodules: Subcutaneous
    - Rash: Transient, Pruritic
  - Lymphadenopathy
  - Cardiomyopathy
  - Enteritis: Segmental
- Muscle
  - Pain: Myalgias; Tenderness
  - Wasting
- Course: Monophasic or Recurrent Symptoms over years
Laboratory
- Eosinophilia
- Sed rate: High
- Serum CK: 300 to 2200
- Muscle biopsy
  - Sarcocysts within muscle
- Diagnosis: Serology; Biopsy
Treatment
- Albendazole (400 mg bid): May ameliorate symptoms

Toxoplasmosis

H&E stain: From CDC

Toxoplasma gondii cyst
Contains bradyzoites

Epidemiology
- Organism: Toxoplasma gondii
- Animal hosts: Cats (43%); Goats; Hogs; Dogs; Cattle; Sheep
- Geographic: Ubiquitous
  - France: Common ingestion of undercooked meats
  - Central America: Frequent stray cats
- Transmission to humans
  - Ingestion of cysts
  - Sources: Partly cooked meat; Cat feces
  - GI tract: Bradyzoites released from cysts
  - Multiplication: Tachyzoites damage cells & disseminate
  - Cysts (Bradyzoites): May persist in tissues for long periods
- Increased risk: Immunodeficiency
  - Muscle involvement in 4% of AIDS
  - May be due to reactivation of latent infection
Clinical
- Infection is most often asymptomatic
- Systemic features
  - Lymphadenopathy
  - Hepatosplenomegaly
  - Pericarditis
  - Eye: Chorioretinitis; Uveitis
  - Meningoencephalitis
  - General: Fever; Cachexia
- Myopathy
  - Discomfort: Myalgia & Muscle tenderness
  - Weakness: Proximal; Arms & Legs
  - Associated with systemic features
- Treatment
  - Pyrimethamine + Sulfadiazine or Trisulfapyrimidines
  - Less effective vs encysted organisms
  - Spiramycin
  - External link: CDC
Laboratory
- Serum CK: High, 5x to 60x
- ANA: Often positive
- EMG: Irritable myopathy
- Muscle pathology
  - Cysts: Contain bradyzoites; PAS+; No septae; Remote from inflammation
  - Tachyzoites: Groups in intracellular vacuoles; Stained by Wright or Giemsa
  - Inflammation: Histiocytes (May contain bradyzoites); Lymphocytes (CD4 & CD8); Giant cells
  - Muscle fibers
    - Necrosis & Regeneration
    - Varied size
    - MHC Class I expression
    - Vacuoles: Often contain Toxoplasma or eosinophilic structures
    - External link: Bradyzoite cluster in a muscle fiber
- Diagnostic
  - Antigen specific PCR
  - Tissue identification
  - Sabin-Feldman dye test
  - Recent infection: ELISA identification of IgM, IgE or IgA antibodies
  - Chronic: IgG antibodies
  - Skin test
  - External link: CDC
External link: CDC

Eosinophilic Fasciitis ¹³⁷

Nosology: Shulman syndrome
Epidemiology
- Age: 30 to 60 years
- Male > Female; 2 to 1
- Triggers
  - Muscle trauma
  - Drugs: Statins: Phenytoin; Ramipril; Heparin (SubQ); Trichoroethylene
  - Infections: Borrelia burgdorferi & B. afzelii; Mycoplasma arginini
  - Hematologic disorders
  - Neoplasms
  - Autoimmune
  - Physical: Burns; Radiotherapy
Clinical features
- Prodrome: Fever; Myalgia & Arthralgia; Fatigue
- Onset: Acute
- General
  - Weight loss
  - Fatigue
- Skin & Subcutaneous tissue
  - Thickened; "Peau d'orange"
  - Subcutaneous hardening: Limbs & Trunk
  - Groove sign
    - Linear depressions in skin parallel to course of superficial veins
  - Peau d'orange
  - Distribution
    - Symmetric, Often
    - May be unilateral
    - Limbs > Trunk
  - No Raynaud's or Digit involvement
- Edema
- Joints: Contractures
  - Limitation of movement
  - Progressive
  - Distal > Proximal
- Pain
  - Location: Muscle & Joint
  - Character: Constant; Diffuse
Associated disorders
- Carpal tunnel syndrome
- Bone marrow & lymphoproliferative
  - Aplastic anemia; Lymphoma; Leukemia
- Course: Progression or Spontaneous remission
- Treatment: Corticosteroids
- Differential diagnosis
  - Systemic sclerosis
  - Morphea
  - Epidemic fasciitis (Toxic): Myalgia-eosinophilia; Toxic oil
  - Peripheral T cell lymphomas
  - Eosinophilia-Myalgia
Laboratory
- Serum CK: Normal or Mildly increased
- Aldolase: Normal or High
- Hypergammaglobulinemia (74%): Polyclonal IgG
- Eosinophilia (> 1000/mm³): > 6%, especially with repeated exams
- Erythrocyte sedimentation rate: High
- CRP: High
- Hypergammaglobulinemia (74%)
- Immune complexes: Circulating
- MRI T2: Fascia Hyperintense
- EMG: Myopathy; Carpal tunnel syndrome
Pathology
- Fascia: Thickened in subcutaneous regions ± perimysium
- Inflammation
  - Macrophages ± Eosinophils; Lymphocytes & Plasma cells
  - Occasional granulomas
- Muscle
  - Affected in areas close to damaged fascia
  - Perimysial inflammation: Macrophages ± Eosinophils
  - Perifascicular atrophy
Eosinophils ⁵
- Properties & Staining
  - Size: 12 to 17 μ
  - Nucleus: Segmented
  - Express cytoplasmic granules
    - Contain: Basic proteins
    - Bind acidic dyes: Eosin; Romanowsky
- Development
  - Location: Bone marrow
  - Progenitor cell stimulated by: Interleukin-5
- Mature eosinophils in circulation: Adhere to endothelial receptors via
  - Selectins
  - Integrins
    - CD18 (β₂ integrins): Bind to ICAM-1; All leukocytes
    - Very late antigen (VLA) 4 (β₁ integrins)
      - Bind to VCAM-1
      - Eosinophils & mononuclear cells
    - Resting eosinophis express β₁ & β₂ integrins
  - Circulating
    - Half-life: 4.5 to 8 hours
    - < 5% of circulating leukocytes
    - Eosinophilia: Circulating eosinophils > 500/mm³
  - Tissue survival: 8 to 12 days
- Activation factors in marrow & tissues
  - From T-cells & macrophages
  - Prolong eosinophil survival
  - Factors
    - IL-3
    - IL-5
      - Major cytokine responsible for eosinophil production & activation
      - Parasitic infections: Produced by Th-2 lymphocytes
      - Serum levels high: EGPA without MPA-ANCA
    - GM-CSF
- Chemokines
  - Non-selective
    - Leukotriene β₄
    - Platelet activating factor
    - Interleukins: 10, 14, 16
  - Selective
    - Eotaxin-1
    - Eotaxin-2
- Eosinophil toxic proteins
  - Eosinophil cationic protein (ECP)
    - Causes voltage-insensitive ion-nonselective toxic pores
  - Major basic protein 1 (MBP1)
    - Increases smooth muscle reactivity
      - Via vagal muscarinic M2 receptors
    - Degranulation of mast cells & basophils
  - Eosinophil-derived neurotoxin (EDN): Ribonuclease
  - Eosinophil peroxidase (EOP): Generates H₂O₂ & Halide acids
  - Chemoattractant: RANTES
- Disorders
- Pathology images
  - Vasculitis
    - Eosinophilic
  - Muscle fiber necrosis

Eosinophilic Fasciitis
Chronic skin lesions

H&E stain

Eosinophils
Amid histiocytes replacing necrotic muscle fiber

Perimyositis ²⁵

Clinical
- Myalgias: Increased by activity or passive motion
- Course: Chronic
Laboratory
- Serum CK: Normal
- Eosinophilia: Common
- EMG & NCV: Normal
Muscle pathology
- Inflammation
  - Location: Perimysium & Epimysium
  - Cell types: Macrophages, Lymphocytes, Eosinophils
- Muscle fibers: Normal
Also see

Macrophagic Myofasciitis ⁴

Epidemiology
- Most reported cases French
- Male = Female
- Onset age: 3rd to 5th Decade
- Disease duration: 3 to 48 months
- Associated with: Injections of aluminum-containing vaccines
  - Timing: 3 months to 8 years before onset of symptoms
  - Immunization type: Hepatitis B (86%); Tetanus (58%); Hepatitis A (19%)
Pathogenesis
- Persistence of vaccine-derived aluminum hydroxide at site of IM injection
- MMF patients may be of HLA-DRB1*01 group
- ? Protracted low level immune stimulation due to persistence of adjuvant in antigen presenting cells
Clinical
- Pain & Discomfort
  - Myalgias (80%): Proximal > Distal
  - Arthralgias (60%): Especially large joints
- Weakness (43%): Mild; Proximal
- CNS (9% symptomatic)
  - Pyramidal signs (7%)
  - Hemisensory or sensory-motor symptoms (5%)
  - Cerebellar (5%)
  - Visual loss (3%)
  - Other: Cognitive or Bladder dysfunction
- Systemic
  - General (43%): Fatigue; Asthenia; Fever
  - Pulmonary: Dyspnea; Cough
  - Skin: Normal
  - Concurrent autoimmune disorder (34%)
Lab
- Serum CK: Normal 60%, 3x to 5x Increased 35%, Very high 5%
- Hematologic
  - Sedimentation rate: Normal (55%) to 115
  - C-reactive protein: 40% Increased
  - Anemia (25%)
- EMG: Normal (55%); Myopathic (30%); Neuropathic (15%)
- CNS testing
  - MRI: Multifocal or single regions of CNS demyelination (12%)
  - Sensory evoked potentials: Often abnormal
  - CSF: High protein; Oligoclonal bands; Cells (5-29/mm³)
Associations
- Chloroquine or hydroxychloroquine (36%)
- Systemic immune disorder (20%)
Muscle pathology
- Infiltration with macrophages
  - Collections in regions but not nodular
  - Location: Epimysium & Perimysium > Endomysium (Peripheral regions)
  - Non-epithelioid; CD68 +
  - Inclusions
    - PAS +
    - Osmophilic
    - Intracytoplasmic
    - Aluminum hydroxide crystals (Morin stain)
  - No giant cells
  - Distribution: Regions near vaccination site; Especially deltoid muscle
  - Rule out: Multicentric reticulohistiocytosis; Whipple's
- Muscle fibers
  - No necrosis
  - Mild variation in size in infiltrated regions
- Connective tissue: No necrosis
Treatment: Symptoms may be reduced with prednisone & antibiotics

Inflammatory Myopathy with Abundant Macrophages (IMAM) ⁴⁰

Clinical
- Onset
  - Ages: Childhood to 78 years
  - Progression: Days to Weeks
- Children
  - Most commonly asymptomatic
- Skin
  - Rash: May be similar to dermatomyositis
  - Edema
- Muscle
  - Weakness: Proximal; Mild to Marked
  - Myalgias
- Systemic features (25%)
  - Arthralgias
  - Raynaud's
  - Lung infiltrate
- Treatment
  - Corticosteroids
  - Other immunomodulation
- Course
  - Remission in some: After immunomodulating treatment
  - Death: Occasional; Multiple organ failure may occur
Laboratory
- Serum CK: Normal or Mildly high
- Aldolase: May be high with normal CK
- Serum autoantibodies: No consistent pattern
Muscle pathology
- Histiocyte (Macrophage) inflammation
  - Predominant cell type
  - Histiocyte (Macrophage) cytoplasm: Abundant; Mildly PAS positive
  - Mostly scattered in perimysial connective tissue
  - Express MRP-14 (S100-A9) , an early inflammation marker
- Hemophagocytosis: More severe cases
- Distribution of lesions: Diffuse
- Muscle fiber damage
  - Necrosis: Some patients
  - Not always near macrophage inflammation
- Inclusions: Endothelial cells
  - Type: Tubulo-reticular
  - No crystalline inclusions
Rule out
- Immune Myopathies with Perimysial Pathology
  - Jo-1 myositis
- Cytophagic histiocytic panniculitis
- Hemophagocytic syndrome
- Macrophagic myofasciitis
- LHIM
- Fasciitis