IMPP & Jo-1 Myositis

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
- Interstitial lung disease
- Raynauds's
- Skin rash
- Joint disorders
- Antibodies: Anti-synthetase
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
Features		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)
Serum	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 C_5b-9 deposition Alkaline phophatase stain Amid myofiber pathology Ulex staining C_5b-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

Clinical
- Onset age: Adult (> 50 years)
- Timing: 1 year before to > 3 years after Dx
- Interstitial Lung disease: Uncommon
Laboratory
- Serum albumen: Low (< 35 g/L)
- Antibodies: NXP2; Tif1γ
Muscle Pathology Syndromes
- DM-VP
- RIIM
Neoplasm types
- General: Squamous cell; Adenocarcinoma
- Males: Lung
- Females: Breast; Thyroid; Cervical
- Geography
  - Scandinavia: Ovary, Lung, Pancreas, GI, non–Hodgkin lymphoma
  - Scotland: Cervical, Ovary, Lung
  - Asia: Nasopharyngeal (North China), Lung, Breast, GI, Ovary, Liver

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

The perimysium is loculated with many focal clear and darker areas
Cells in the perimysium are most frequently macrophages. Features include
- Large nuclei
- Prominent cytoplasm
- Staining for Acid Phosphatase, Esterase and CD-68
Adjacent muscle fibers may show
- Perifascicular myopathy: Regeneration & Necrosis
- Small size

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: C_5b-9 deposited on permysium
C_5b-9 may also be deposited on neighboring endomysial connective tissue

C_5b-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

C_5b-9 stain

Jo-1 myopathy: C_5b-9 complement deposition
Necrotic muscle fibers with cytoplasm staining for C_5b-9
More common in near edge of fascicles
Scattered in these areas
C_5b-9 is also present on the surface of muscle fibers

C_5b-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

8/17/2022

Immune Myopathies with Perimysial Pathology (IMPP) 1

IMPP: General

Immune Dermatomyopathies: Comparative Features

Features

Immune Dermatomyopathy Syndromes

Clinical

Serum

Muscle Pathology

IMPP Muscle Pathology (Jo-1 antibody positive)

Perimysium: Inflammation, Usually histiocytic

Immune Myopathies with Perimysial Pathology (IMPP) ^¹

Muscle
Pathology