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)
H&E stain

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
Muscle Pathology
  • Perimysial connective tissue damage: Defining feature
    • Cells: Histiocytes
    • Structure: Fragmented or Rarified
  • Muscle fibers: Pathology more prominent near perimysium
    • Necrosis & Regeneration
    • MHC1 & MHC2 expression
  • Gene expression
    • Increased CAMK1G , EGR4 , CXCL8 (Interleukin 8)

Immune Dermatomyopathies: Comparative Features

Immune Dermatomyopathy Syndromes

Features/Pathology
 IM + Perimysial
Pathology (IMPP)		 Dermatomyositis +
Vascular pathology		 DM-VP +
Inflammation		 Regional Ischemic
  Immune Myopathy		 DM: Pauci-
Myopathic		 cGvHD Systemic
Sclerosis

Clinical

 Age at Onset Adult > Child Child or Adult Child or Adult Older Adult Adult Adult Adult
Weakness Proximal > Distal Tif1γ: Proximal > Distal
NXP2: Proximal +
    Finger extensor
    Dysphagia
 Proximal (98%) Proximal > Distal Uncommon Proximal ±
  Distal (50%)		 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
Tif1γ: Photosensitive
    Palm hyperkeratosis
NXP2: Edema		 Rash
Raynaud		 Rash (70%) Palmar: Papules
  & Ulcers
MxA+ Epidermal
  keratinocytes
Type I IFN
Alopecia		 Sclerosis
Dyskeratosis		 Scleroderma
Raynaud
Capillary Δ
  Telangectasia
Interstitial lung disease Common Uncommon Rare No Common Common Some
Neoplasm association No Adults No Common; 72%
  Esp > 60 yrs		 No Prior,
  hematologic		 No
Systemic, Other Joints NXP2: Calcinosis
GI		 Joints; GI     GI; Mucous
  membranes		 GI: Esophagus
  Small bowel
Calcinosis

Serum

 Antibody Jo-1
tRNA synthetase		 TIF1γ
NXP-2		 Mi-2 TIF1γ
NXP-2		 MDA5
  (CADM140)		 Varied PMScl-75
Ku; U3-RNP
CK > 1,000 Some Few Most Most No No Some

Muscle
  Pathology

 Inflammation
  Focal
  Location


  Cell Type
Some
Perimysium


Histiocyte
Mild (80%)
Perivascular


Lymphocyte, CD20		 Yes
Yes
Perivascular
Perimysial &
    Endomysial
Lymphocyte		 No No Uncommon No
Perimysium pathology
  Fragmentation
  Immune Cells
    Location
  Without myopathy
  Alkaline phophatase +
Common
Histiocyte
    Scattered
Some
Some
 
Histiocyte

Uncommon
Common
Occasional
Lymphocyte (B-cell)
    Perivascular
No
Uncommon
Necrotic regions
Histiocytic
    Necrotic regions
No
Yes
Some
Histiocytes
    Scattered
Often
Common
Histiocytes

Often
Some		 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
 

Yes




Common (60%)
Perifascicular
SCRT1 ↑

No





Regional
 
Mild or No; NOS2
No





No
Glycosylation ↓
No





No		  
MHC1 ↑
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

Large
Common
Common

Absent
Absent
Absent		 Normal # Reduced # Thick walls
Large Vessel Pathology No Artery + Vein Yes Vein No No No
Dermatomyopathies, General/Other

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

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

Endomysial Histiocytes: Activated

  Stain: Acid phosphatase
  Location: Often near endomysial capillaries
  Commonly occur with: MHC-I upregulation by neighboring muscle fibers

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

3/23/2026