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
  Sarcoidosis
  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
Laboratory
  • Serum CK: High or Normal
  • Serum Aldolase: May be high with normal CK
  • EMG: Irritable myopathy
  • Muscle MRI: Fascial & Sub-Fascial pathology
Pathology
  • Perimysial connective tissue damage: Defining feature
    • Cells: Histiocytes
    • Structure: Fragmented or Rarified
  • Muscle fibers
    • Necrosis & Regeneration: More prominent near perimysium
  • Gene expression
    • Increased CAMK1G , EGR4 , CXCL8 (Interleukin 8)

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		 Systemic
Sclerosis

Clinical

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

Serum

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

Muscle
  Pathology

 Inflammation
  Focal
  Location
  Type
Some
Perimysium
Histiocyte
Yes (80%)
Perivascular,
Lymphocyte, CD20		 No No Uncommon
Yes (50%)
Perivascular
 No
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		 No
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
 		 MHC1 upregulated
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 # Thick walls
Large Vessel Pathology No Artery + Vein Vein No 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

H&E stain
Perimysial Pathology

VvG stain

H&E stain
Perimysial Connective Tissue: Damage
  Loculation: Small & Large holes (Above)
  Pallor (Below)
  Cells: Many scattered histiocytes (Cells with large nuclei)
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

C5b-9 stain
Jo-1 myopathy: Dark C5b-9 staining of damaged permysium
  C5b-9 may also stain
    Neighboring endomysial connective tissue around muscle fibers
    Surface of muscle fibers
    Cytoplasm of nearby necrotic muscle fibers

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

Myopathy with Jo-1 antibodies

MHC-I stain
  Diffusely on muscle fiber surface membranes
  Cytoplasm of perifascicular muscle fibers
  Perimysium: Damaged connective tissue & Scattered cells

MHC-I 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, Best Pract Res Clin Rheumatol 2022 Aug 12

4/8/2024