Dermatomyositis (DM)
A classication of DM cannot be made in the
absence of DM rash (Gottron’s sign, Gottron’s
papules, heliotrope rash).
In the presence of DM-like rash, DM can be
diagnosed if a DM-specic autoantibody is
present, or if denitive DM muscle biopsy
features are present and are combined with
clinical signs of proximal muscle weakness or
elevated muscle enzymes.
- Denitive DM muscle biopsy ndings: perifas-
cicular atrophy and/or perifascicular MxA
overexpression (Fig. 1) with rare or absent peri-
fascicular necrosis.
- Suggestive DM muscle biopsy ndings:
lymphocytic inltrates (often perivascular), evi-
dence of perifascicular disease (perifascicular
predominant bers that are pale on COX
staining and/or positive on NCAM staining).
- DM specic autoantibodies: Mi2, NXP2,
, MDA5, SAE. Patients are subclassied
according to that autoantibody (e.g., anti-
DM, anti-NXP2 DM). Patients who
have DM without a DM-specic autoantibody
are subclassied as having “autoantibody
negative DM.”
Antisynthetase syndrome (ASyS)
Issue 21 || December 2022
Chunyu Cai
Department of Pathology, University of Texas
Southwestern Medical Center, Dallas, TX, USA
Corresponding Author: Chunyu Cai, MD, PhD
Department of Pathology, University of Texas
Southwestern Medical Center, Dallas, Texas, USA
E-mail: Chunyu.Cai@utsouthwestern.edu
Chunyu Cai
This compilation of new changes in the diagnosis
and treatment of muscle and nerve disease is
extracted from the latest publications from the
European Neuromuscular Centre International
workshops, FDA.gov and clinicaltrials.gov.
Classification of idiopathic
inflammatory myopathies (IIM)
European Neuromuscular Centre (ENMC)
clinico-sero-pathological classication divides
IIM into 4 subclasses, which are associated with
myositis specic antibodies (MSAs), as outlined
in Table 1.
MSA testing is preferentially performed prior
to immune suppression treatment but should
also be performed in patients with suspected
IIM or interstitial lung disease of unknown
etiology without prior MSA testing.
Polymyositis no longer exists as an IIM
Dened by the presence of an antibody to
aminoacyl tRNA synthetase (ARS), together
with a single or combination of the following
clinical manifestations:
- Myositis
- Polyarthritis
- Interstitial lung disease
- Mechanic hands
- Raynaud phenomenon
ASyS patients with a DM-like rash are not
classied as DM, but as “ASyS with a DM-like
Pathology is characterized by:
- Perifascicular pathology with necrotic myo-
bers and nonnecrotic bers with sarcolemmal
C5b-9 (MAC) expression
- Perimysial connective tissue with substantial
edema, fragmentation, and mixed mononucle-
ar inammation
- MHC1 sarcoplasmic expression and nuclear
actin inclusions in myobers
Immune mediated necrotizing
myopathies (IMNM)
Anti-HMGCR and anti-SRP autoantibodies
are considered specic for IMNM.
Patients with anti-HMGCR antibody and a
DM-like rash will be classied as having
“anti-HMGCR myopathy with a DM-like
rash,” while patients with anti-SRP antibody
and a DM-like rash will be classied as having
“anti-SRP myopathy with a DM-like rash.”
Pathology requires diffusely scattered necrotic
bers at different stages of resolution and
macrophage dominant, pauci-lymphocytic
Sporadic inclusion body myositis
The pathologic criteria for sIBM include:
- Endomysial T cell inammation with invasion
of non-necrotic bers
- Rimmed vacuoles
Sponsored by an unrestricted grant from Roche
Fig. 1. Sarcoplasmic MxA expression is considered a
sensitive and specific marker for dermatomyositis.
Table 1. IIM subtypes and their associated autoantibodies
Dermatomyositis (DM) Mi2, NXP2, TIF1
Inclusion body myositis (IBM) cN1A*
Immune mediated necrotizing myopathy (IMNM) SRP, HMGCR
Anti-synthetase syndrome (ASys) Jo-1, PL7, PL12, EJ, OJ, KS, Zo, Ha
*MSAs are usually mutually exclusive and specific for IIM subclasses, with the exception of cN1A
Histologically characterized by sarcoplasmic
pleomorphic amorphous, granular or hyaline
protein aggregates on Gomori trichrome
(Fig. 2), and positive for desmin immunostain.
Most contain mutations in Z disk associated
protein coding genes: DES, CRYAB, MYOT,
Patients with mutations in FHL1, DNAJB6,
have also been associated with MFM pheno-
Myotonic dystrophy (DM1/DM2)
Autosomal dominant multi-system diseases
with the common features of myotonia and
progressive muscle weakness. There are two
main forms: DM1 and DM2.
DM1 is caused by CTG trinucleotide repeats in
the 3’ untranslated region of DMPK. DM1
shows striking anticipation, with age at onset
decreasing by 20-30 years per generation.
DM1 muscle pathology is characterized by
markedly increased internalized nuclei, often in
chains and ring bers, in a background of
chronic myopathy.
DM2 is caused by CCTG repeat expansion in
intron 1 of CNBP (ZNF9). Additionally,
CLCN1 and SCN4A are disease modifying
genes whose mutations may exaggerate DM2
phenotype; they therefore should be included
Fig. 2. Myofibrillar myopathy on Gomori trichrome
- P62 or TDP-43 positive protein aggregates or
15-18 nm laments (tubulolamentous
inclusions) on electron microscopy
Anti-cN1A autoantibody is present in 30%–
70% of sIBM patients but has also been found
in DM and other systemic autoimmune diseases
such as Sjögren’s and lupus.
Clinically, elderly patients with asymmetric
muscle weakness and atrophy of proximal and
distal muscle groups, with predilection for
wrist and nger exors and knee extensors.
Usually refractory to immunosuppressive
Limb girdle muscular dystrophies
The denition and nomenclature of LGMD
have been re-dened in the 2017 ENMC
international workshop as a genetically inher-
ited condition that primarily affects skeletal
muscle leading to progressive, predominantly
proximal muscle weakness at presentation
caused by a loss of muscle bers.
All LGMD subclasses must fulll all of the
- Described in at least two unrelated families
- Patients have achieved independent walking (to
differentiate from congenital muscular
- Elevated serum creatine kinase
- Degenerative changes on muscle imaging over
the course of disease
- Dystrophic changes on muscle histology,
ultimately leading to end-stage pathology
New nomenclature: change from the alphanu-
meric system to include the name of the
affected protein and mode of inheritance (D for
dominant, R for recessive, X for X-linked);
examples listed in Table 2.
Some previous LGMD subclasses no longer
fulll the new LGMD denition (Table 3).
Myofibrillar myopathies (MFM)
MFM is a group of disorders associated with
myobrillar degradation that begins in the Z
Dr. Chunyu Cai has been part of the
PathologyOutlines.com editorial board and
the Deputy Editor in Chief for Neuropathology
since 2020. He is a pathologist and an
Associate Professor at University of Texas
Southwestern Medical Center. His research
focuses on neuromuscular diseases and brain
Meet the Author
in DM2 genetic screening.
DM2 muscle pathology is characterized by type
2 atrophy and frequent internalized nuclei
predominantly in type 2 bers.
Gene replacement therapies for
hereditary neuromuscular diseases
Adeno-associated virus (AAV) based gene deliv-
ery vectors can produce replacement proteins in
patients with loss of function mutations, such
as spinal muscular atrophy (SMA) or Duch-
enne’s muscular dystrophy. The vector does not
integrate into the patient’s genome and has a
low immunogenicity.
CRISPR-Cas9-mediated gene editing does
incorporate into the patient’s genome and can
permanently replace a deleterious mutation in
patient with conditions such as hereditary
transthyretin-mediated (hATTR) amyloidosis.
Both methods entail only a single intravenous
injection and thus have a clear advantage over
siRNA based and antisense oligonucleotide
(ASO) based therapies, which require serial
FDA approved gene therapy for
neuromuscular diseases
Zolgensma (Novartis) is the rst ever FDA
approved (2019), intravenously delivered,
AAV9 vector mediated SMN gene therapy for
spinal muscular atrophy.
New gene therapies currently in clinical
NTLA-2001 is a CRISPR-Cas9-mediated gene
editing construct that targets hATTR amyloi-
dosis in a phase II-III trial for adults with
polyneuropathy or cardiomyopathy
SRP-9001 (Sarepta), SGT-001 (Solid Biosci-
ences) and PF-06939926 (Pzer) are AAV
based micro-dystrophin constructs in phase III
trials for DMD (NCT03375164,
NCT03769116, NCT04281485).
SPK-3006 (Spark Therapeutics) is an AAV
based human GAA gene construct in a phase I/
II trial for adult onset Pompe disease
Table 2. Old vs new LGMD nomenclature
Previous name Gene New name
LGMD 1I CAPN LGMD D4 Calpain3-related
LGMD 2A CAPN LGMD R1 Calpain3-related
LGMD 2B DYSF LGMD R2 Dysferlin-related
Table 3. Previous LGMD subtypes that are no longer considered LGMD
Previous name Gene New name
LGMD 1A MYOT Myofibrillar myopathy
LGMD 1B LMNA Emery–Dreifuss muscular dystrophy
LGMD 1C CAV3 Rippling muscle disease
LGMD 1E and 2R DES Myofibrillar myopathy
LGMD 1H unknown n/a
LGMD 2V GAA Pompe disease/acid maltase deficiency
n/a, not available