Neuromuscular

Immune Myopathies with Perimysial Pathology (IMPP) 1

Clinical syndromes
  Dermatomyositis: Adult > Child onset
  Graft-vs-Host
  Myopathies with
    Anti-Jo-1 Antibodies
    Other tRNA synthetase antibodies
    High Aldolase & Normal CK
    Scleroderma
    Enterovirus
  Drug-related
    Minocycline
    Anti-TNF-α
Dermatomyositis vs IMPP
IMPP muscle pathology
  Adult-onset IMPP
  HMGCR antibody
  Jo-1 antibody + pathology
  PL-12 antibody + pathology
  Enterovirus (EVIM)


IMPP: General

Clinical Features
  • Immune myopathies: Similar to Jo-1 & tRNA synthetase antibody related immune myupathies
  • Increased frequency of associated
  • Neoplasms: Less than in other IIM
  • Risk: Increased in smokers
Pathology

Immune Dermatomyopathies: Comparative Features

Features

Immune Dermatomyopathy Syndromes

IM + Perimysial
Pathology (IMPP)
Dermatomyositis +
Vascular pathology
Regional Ischemic
  Immune Myopathy
DM: Pauci-
Myopathic
cGvHD Dermatomyopathy
+ Mi-2 antibody

Clinical

Age at Onset Adult > Child Child or Adult Older Adult Adult Adult Child or Adult
Weakness Proximal > Distal Proximal > Distal Proximal > Distal Uncommon Proximal
  ± Distal (50%)
Proximal (98%)
Myalgias Common Common Common None or Mild Some  
Skin pathology 2 Raynaud's
Rash
  Mechanic's hands
  Psoriasiform
  Eczematous
  Dyskeratotic cells
Rash: Heliotrope Rash (70%) Palmar: Papules
  & Ulcers
MxA+ Epidermal
  keratinocytes
Type I IFN
Alopecia
Sclerosis
Dyskeratosis
Rash
Raynaud
Interstitial lung disease Common Uncommon No Common Common Rare
Neoplasm association * No Adults Common; 72%
  Esp > 60 yrs
No Prior,
  hematologic
No
Systemic, Other Joints Calcification; GI     GI; Mucous
  membranes
Joints; GI

Serum

Myositis-associated
 antibody
Jo-1
tRNA synthetase
TIF1γ NXP-2 MDA5
  (CADM140)
Varied Mi-2
CK > 1,000 Some Few Most No No Most

Muscle
  Pathology

Inflammation
  Focal
  Location
  Type

Some
Perimysium
Histiocyte

Yes (80%)
Perivascular,
Lymphocyte, CD20
No No Uncommon
Yes (50%)
Perivascular
Perimysium pathology
  Fragmentation
  Immune Cells
    Location
  Without myopathy
  Alkaline phophatase +

Common
Histiocyte
    Scattered
Some
Some

Occasional
Lymphocyte (B-cell)
    Perivascular
No
Uncommon

Necrotic regions
Histiocytic
    Necrotic regions
No
Yes

Some
Histiocytes
    Scattered
Often

Common
Histiocytes

Often
Some

 
Histiocyte

Uncommon
Common
Muscle fiber pathology
  General
  Perifascicular
    COX staining reduced
    Necrosis & Regeneration
    Internal architecture
    LC-3 aggregates
    Atrophy
  Necrosis
  Myonuclei


Often
Never
Common
Coarse
Rare
Uncommon
Perifascicular
Actin aggregates


Yes
Most patients
Unusual
Vacuoles & Aggregates
Common
Common
No
 


No





Regional
 

Mild or No; NOS2
No





No

Glycosylation ↓
No





No


Yes




Common (60%)
Perifascicular
 
Capillaries
 Near myofiber pathology

  Ulex staining
  C5b-9 deposition
  Alkaline phophatase stain
 Amid myofiber pathology
  Ulex staining
  C5b-9 deposition
  Alkaline phophatase +
Normal #

Normal
Absent 
Absent

Normal
Absent 
Absent
Reduced #

Large
Few 
Common

Absent
Common 
Absent


Large
Common
Common

Absent
Absent
Absent
Normal # Reduced # Normal #
Large Vessel Pathology No Artery + Vein Vein No No No

* Dermatomyopathies, General: Neoplasm associations 3

IMPP Muscle Pathology (Jo-1 antibody positive)

Perimysial Pathology
  Cellularity
    Endomysial
    Perimysial
  Structure: Damage
  Alkaline phosphatase staining
Muscle fiber pathology

Jo-1 myopathy: Perimysial Pathology
Perimysial Fragmentation

H&E stain
Perimysial Damage
  Loculation: Small & Large holes (Above)
  Pallor (Below)
Muscle Fibers
  Small or immature in regions neighboring \perimysial pathology


H&E stain
Perimysium with:
  Damaged structure (Irregular, Pale regions)
  Cellularity: Large cells with cytoplasm & large nuclei
Neighboring myopathology:
  Muscle fibers: Necrotic & Regenerating (Small, Basophilic)

Gomori trichrome stain

VvG stain


Gomori trichrome stain
Fragmented Perimysium

Gomori trichrome stain

Jo-1 myopathy: C5b-9 deposited on permysium
  C5b-9 may also be deposited on neighboring endomysial connective tissue

C5b-9 stain

Perimysium: Inflammation, Usually histiocytic


H&E stain
Cells in Perimysium
  Size: Large
  Nuclei: Large
  Cytoplasm: Visible around nucleus
  Distribution: Scattered in regions of perimysium

H&E stain

H&E stain

Cells in perimysium: Histiocytic
  Stain for Acid phosphatase, Esterase & CD68

H&E stain

Esterase
Esterase positive macrophages

CD68 stain
CD-68 positive cells in perimysium
  and endomysium


Esterase
Perimysium: Esterase positive macrophages


Acid phosphatase

Acid phosphatase
Acid phosphatase positive cells: Predominantly in Perimysium; Scattered in endomysium

Acid phosphatase


CD4 stain
Jo-1 myopathy: CD4 cells in permysium

CD4 stain


Acid phosphatase stain
Endomysial histiocytes
  Scattered in endomysium
  Often with neighboring: Capillary (Arrow) or Small endomysial vessel
  Pattern is common to many active myopathies: Not specific for Jo-1

Acid phosphatase stain


Alkaline phosphatase stain
Alkaline phosphatase staining
  Perimysium
  Extends into endomysium
  Muscle fiber cytoplasm (Smaller, immature fibers)

Alkaline phosphatase stain

Jo-1 myopathy: Muscle fiber pathology
Type: Necrosis & Regeneration
Distribution: Perifascicular; Near damaged perimysium (Arrows)

H&E stain
Jo-1 Muscle Fiber Pathology
  Myopathic
    Necrotic & Immature Muscle Fibers
    Predominantly at edge of fascicles, near damaged perimysium (Arrows)

H&E stain


H&E stain
Perifascicular myopathy
  Regeneration & Necrosis of perifascicular
    muscle fibers

NCAM stain
N-CAM positive atrophic muscle fibers
 

H&E stain


NADH stain
Perifascicular atrophy: Small Muscle fibers are more frequent at the edge of fascicles

NADH stain

Perifascicular Myopathy
  Immature (Smaller, Intermediate-stained) muscle fibers: More common at edge of fascicles

ATPase pH 4.3 stain


MHC-I stain

MHC Class 1 staining
Positive muscle fibers are
  Perifascicular (Above), or
  Diffuse (Right)
  Have Similar patterns in
    DM + Vascular Pathology
Perimysial cells also stain (Below)

MHC-I stain

MHC-I stain

Jo-1 Immune Myopathy: Muscle Fiber Necrosis & Regeneration

H&E stain
General Pattern
  Muscle fiber pathology: More prominent near edges of fascicles
Necrotic Muscle Fibers (Dark arrow)
  Pale cytoplasm
  Invaded by histiocytic cells
Regenerating Muscle Fiber (White arrow)
  Nuclei: Large
  Cytoplasm: Basophilic

H&E stain

C5b-9 stain
Jo-1 myopathy: C5b-9 complement deposition
  Necrotic muscle fibers with cytoplasm staining for C5b-9
    More common in near edge of fascicles
    Scattered in these areas
  C5b-9 is also present on the surface of muscle fibers

C5b-9 stain


LC3 stain
Jo-1 myopathy: Abnormal muscle fibers
  Scattered, small LC3 aggregates in muscle fiber cytoplasm (Above)
  Abnormal vacuoles in muscle fiber cytoplasm (Below)

MHC-1 stain

Return to Inflammatory myopathies
Return to Jo-1 myositis

References
1. Curr Opin Rheumatol 2011;23:595-604, Neurol Neuroimmunol Neuroinflamm 2018;5:e434
2. JAMA Dermatol 2019 Jul 10
3. Medicine (Baltimore) 2020;99:e21733

8/28/2020