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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)
  Collagen vascular disease
  Complement: C2 deficiency
  Drug-induced
  Graft-vs-host disease
  HMGCR (200/100) antibody
  Idiopathic
  IMPP
  MAS antibody
  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
      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 (200/100) 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: C5b-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
Weakness Pain Other systemic features
IIM: Prognosis
Immune Myopathies: Serum Creatine Kinase (CK) & Aldolase
Immune myopathies: HLA & Genetic associations 46
Inflammatory myopathies: Neoplasm Associations 15

Serum Antibodies


Electrodiagnostic changes
MRI 33
IIM Pathology: Differential Diagnosis

Classification

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

Oppenheim 1894

Treatment

IMMUNE MYOPATHIES ("Polymyositis" + Other syndromes)

Subtypes
Clinical features
Laboratory
Treatment


IMMUNE MYOPATHIES (Polymyositis): Clinical features IMMUNE MYOPATHIES (Polymyositis): Laboratory features IMMUNE MYOPATHIES (Polymyositis): Muscle Pathology IMMUNE & INFLAMMATORY MYOPATHIES: Clinical Syndromes
Polymyositis: Treatment options

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 Dermatomyositis syndromes: Specific features Dermatomyositis: Laboratory features Dermatomyositis treatment: Immunosuppressive & Other

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


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



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


Granulomatous & Inflammatory Myopathies with Anti-mitochondrial antibodies 72


Myopathy with Muscle fiber necrosis & Pipestem capillaries 1


Myopathy with Chondroitin sulfate C loss in skeletal muscle endomysium 3


Benign Acute Childhood Myositis (BACM) 8


Influenza-Associated Myositis


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
    • 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


Large Histiocyte Immune Myopathy (LHIM) 111


Giant Cell Myositis


Hemophagocytic Lymphohistiocytosis 41


Hereditary inflammatory myopathies


Myositis: Infectious agents


Inflammatory myopathy: Other


INFLAMMATORY MYOPATHIES: Animal Models


Sarcoidosis

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

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
        • Animals: Pork, Boar, Bear, Walrus, Horse & Crocodile
        • Predilection muscles in bears: Tongue, Masseter, Diaphragm
      • 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


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

Toxoplasmosis


H&E stain: From CDC
Toxoplasma gondii cyst
Contains bradyzoites

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
    • Development
      • Location: Bone marrow
      • Progenitor cell stimulated by: Interleukin-5
    • Mature eosinophils in circulation: Adhere to endothelial receptors via
      • Selectins
      • Integrins
        • CD182 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

Eosinophilic Fasciitis
Chronic skin lesions

































H&E stain
Eosinophils
Amid histiocytes replacing necrotic muscle fiber

Perimyositis 25


Macrophagic Myofasciitis 4


Inflammatory Myopathy with Abundant Macrophages (IMAM) 40


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