1. Acquired Myopathies January 30, 2017 Christina M. Ulane, MD, PhD
Neuromuscular Medicine
EMG Laboratory

2. Acquired Myopathies Inflammatory/Immune Toxic/Drug-induced Infectious
Dermatomyositis
Polymyositis
Inclusion body myositis
Necrotizing
Toxic/Drug-induced
Infectious

3. Dermatomyositis (DM)-clinical
Rash
Purplish discoloration of cheeks, eyelids: blanches (heliotrope)
Periorbital edema
Gottron’s papules (mimics psoriasis)
V- sign/shawl sign
Weakness
Symmetric weakness, proximal >distal
Often relapse-remit
Pain not prominent

4. Dermatomyositis (DM)-clinical
Associated cancer (10-15%)
Breast, lung, ovarian, gastric, lymphoma
Other vascular manifestations
Raynaud’s
Cardiac
Interstitial lung disease
Smooth muscle involvement (GI)
Juvenile form
Clinically amyopathic dermatomyositis

5. Bohan and Peter Criteria for Myositis
Definite PM: 4 criteria
Definite DM: 3 or 4 criteria plus rash
Possible PM: 2 criteria
Possible DM: 1 criterion plus rash
PM=Polymyositis, DM=Dermatomyositis
Criterion
Description
Symmetric proximal weakness (over weeks to months)
Neck flexors, limb-girdle musculature
Consistent muscle biopsy findings
Necrosis, regeneration, phagocytosis, atrophy, mononuclear cell infiltrates
Elevated muscle enzymes
Creatine kinase, aldolase, transaminases, lactate dehydrogenase
Electromyographic evidence for myopathy
Muscle fiber irritability (positive sharp waves, fibrillations), short duration, small amplitude, polyphasic motor unit potentials, with spontaneous bizarre high-frequency discharges
Characteristic skin rash
Gottron’s sign, Gottron’s papules, heliotrope

6. DM-rash

7. Myositis specific antibodies
Antibody
Clinical features
Antisynthetase antibodies
Anti Jo-1
Anti PL-7
Anti PL-12
Anti EJ
Anti OJ
Anti KS
Anti Zo
Anti Ha
Seen in Polymyositis, Dermatomyositis and Interstitial Lung Disease
Dermatomyositis specific antibodies
Anti Mi-2
Treatment responsive
Anti MDA5 (CADM-140)
Minimal myopathy; ILD
Anti 155/140
Cancer associated
Anti 140
Juvenile dermatomyositis, calcinosis
Anti SAE
Amyopathic DM
Antibodies in immune mediated necrotizing myopathy
Anti SRP
Severe, acute presentation, resistant to treatment
Anti HMGCR
Related to statin use
Adapted from: Albayda, J and Mammen, AL. Is statin-induced myositis part of the polymyositis disease spectrum? Curr Rheumatol Rep 2014;16:433.

8. DM-Pathology EMG: spontaneous activity, myopathic motor units
Laboratory
CK normal or mildly elevated (aldolase)
Antibodies
tRNA synthetases (Jo-1 assoc w/ interstitial lung dsease)
Anti- Mi-2 (20%)
Other myositis specific antibodies
May have ANA, RF positive if part of overlap syndrome
EMG: spontaneous activity, myopathic motor units

9. DM-Pathology Vasculitis Perivascular and perimysial inflammation
Capillaries and small blood vessels
Perivascular and perimysial inflammation
No inflammatory cell invasion of non-necrotic fibers
Increased expression of IFN1- inducible proteins
Humoral response
CD4+ cells and B-cells
Complement and immunoglobulin deposition on capillaries

10. DM-perimysial inflammation
(a–f) Immune myopathy with perimysial pathology (IMPP): (a) Perimysial pathology includes fragmented connective tissue with rounded clear
regions (blue arrow) and abnormal cells with large nuclei and abundant cytoplasm (black arrows) (H&E stain). (b) Many of the cells in the perimysium
stain red with acid phosphatase. (c) Perimysial cells often appear elongated with extended processes (Esterase stain). (d) Small muscle fibers at the
edge of fascicles may be necrotic or regenerating [large nuclei with basophilic cytoplasm (arrows)] (H&E stain). (e) Perimysial connective tissue
between fascicles stains darkly (alkaline phosphatase stain). (f) Muscle fibers, often histologically normal, at the edge of fascicles have abnormal
expression ofMHCclass I around their rimand in cytoplasm. (

11. DM-perivascular inflammation

12. Polymyositis 1863-Wagner 1950s-1970s: Rowland, Eaton, Bohan and Peter
Clinical:
Proximal > distal weakness
May have systemic symptoms at onset
CPK always elevated

13. PM-endomysial inflammation
(g–i) Immune polymyopathy: (g) scatteredmuscle fibers, early in the disease course, are
necrotic (large blue arrow) or regenerating (small black arrow) (H&E stain); (h) necrotic muscle fibers contain cells that stain red (acid phosphatase
stain); (i) rapid accumulation of endomysial connective tissue (within 7 months of onset of weakness) (H&E stain). (j, k) Immune myopathy with
endomysial pathology: (j) endomysial deposition of C5b-9 complement (brown) around muscle fibers; (k) control muscle with no deposition of C5b-9
complement.

14. MRI in myositis

15. DM and PM Treatment Glucocorticoids Immunosuppressive/steroid-sparing
High dose for at least 4-6wks, taper over 1yr
80mg or 1mg/kg
No RCTs, NIH series with 39% normalized CPK, 25% regained full strength
Immunosuppressive/steroid-sparing
Azathioprine
Randomized trial vs prednisone alone, better functional outcome at 3yrs
Methotrexate (pulmonary fibrosis)
Can be started simultaneously
Hydroxychloroquine (skin disease but not muscle)

16. Treatment resistant Consider alternative diagnosis (IBM) Rituximab
IVIG
Other: CSA, tacrolimus, MMF

17. Features differentiating dermatomyositis from polymyositis
Typical dermatologic manifestations
May be associated with malignancy
Not generally associated with systemic rheumatologic disease, except sometimes scleroderma
Childhood form exists
Muscle biopsy findings (perimysial and perivascular inflammation)
Polymyositis
No rash unless lupus associated
Not typically associated with malignancy
Often associated with a systemic rheumatologic disease, including lupus, systemic sclerosis, vasculitis
Adult disease
Muscle biopsy findings (endomysial inflammation)

18. Differential Diagnosis of Polymyositis
Mimic
Differentiating characteristics
Dermatomyositis
Associated rash, specific pathological findings on muscle biopsy, Myositis specific antibodies
Necrotizing myopathy
Specific pathological findings on muscle biopsy, drug/statin exposure, more resistant to immunosuppressant therapy
Inclusion body myositis
Slower progression, older age of onset, distribution of muscle weakness, specific pathological findings on muscle biopsy, lack of response to immunosuppressants
Overlap syndrome
Associated rheumatologic diagnosis (e.g. lupus, rheumatoid arthritis)
Muscular dystrophy
Age of onset, slower progression, family history, specific pathological findings on muscle biopsy, genetic testing, lack of response to immunosuppressants
Metabolic myopathy
Age of onset, slower progression, family history, pathology, genetic testing, lack of response to immunosuppressants
Fibromyalgia
Prominent pain, no weakness, normal muscle biopsy
Polymyalgia rheumatica
High ESR/CRP, normal CK, normal EMG

19. Inclusion body myositis
Most common myopathy >50yrs
Men>women
Clinical:
Distal predominence
FF, WF, quads, anterior tibial
atrophy
Asymmetrical
1/3 with dysphagia, facial weakness

20. Differential diagnosis for Inclusion Body Myositis (IBM)
Dermatomyositis
Associated skin findings
Muscle pathology
Polymyositis
Assosciated autoantibodies
Hereditary distal myopathies
Family history
Early age of onset
Genetic testing
Drug induced (toxic) myopathies
History of toxic or medication exposure
Motor neuron disease
Upper motor neuron findings
Electrodiagnostic testing
Muscle biopsy – neurogenic changes
Myasthenia gravis
Ocular and prominent bulbar symptoms
Acetylcholine receptor or muscle specific kinase (Musk) antibodies
Abnormal repetitive stimulation
Response to immunotherapy

21. Diagnostic criteria for IBM from the European Neuromuscular Center (ENMC) Workshop, 2011
Adapted from Barohn et al 2014/Machado P, Brady S, Hanna MG. Update in inclusion body myositis. Curr Opin Rheumatol 2013;25(6):763–71;
Classification
Clinical Features
Pathologic Features
Clinicopathologically defined IBM
Duration over 12 months
Age at onset over 45 years
Quadricep weakness greater than hip flexor weakness and/or finger flexor weakness greater than shoulder abductor weakness
Serum CK not greater than 15x the upper limited of normal
Endomysial inflammation
and Rimmed vacuoles
and Protein accumulation (amyloid or other proteins) Or
Filaments 15–18 nm
Clinically defined IBM
One or more of the following:
or Increased MHC-1 staining
or Rimmed vacuoles
or Protein accumulation (amyloid or other proteins)
or Filaments 15–18 nm
Probable IBM
Endomysial exudate
or increased MHC-1 staining

22. IBM

23. IBM-pathology CPK may be normal or mildly elevated
EMG: myopathic, spontaneous activity, may have small and large polyphasic MUPs
Muscle biopsy
Similar to PM
Rimmed vacuoles (with amyloid deposits)
EM: tubuloreticular aggregates
Plasma cells, MHCI, CD8+
Nondx bx in 20-30%

24. IBM-endomysial inflammation

25. IBM-inclusions

26. IBM treatment Relatively resistant
Prednisone, methotrexate, azathioprine
IVIG

27. Other Immune Myopathies
Necrotizing
Often with anti-SRP antibodies
HMGCR antibodies
U1-snRNP
Anti-MAS
Sarcoid
GVHD
Brachio-cervical inflammatory myopathy

28. Key Features of Inflammatory and Necrotizing Autoimmune Myopathies
Dermatomyositis
Polymyositis
Inclusion body myositis
Necrotizing autoimmune myopathy
Autoantibodies
Antisynthetase antibodies (anti-Jo-1 and others)
Dermatomyositis specific antibodies (anti-Mi-2 and others)
Antibodies of systemic rheumatologic disease
Possibly anti-cytosolic 5’-nucleotidase 1A (cN1A)
Anti-SRP
Anti-HMGCR
Muscle enzymes
Up to 50x ULN
Up to 15x ULN
Often >10x ULN
Associated disorders
Interstitial lung disease (antisynthetase)
Malignancy (ovarian, lung, others)
Systemic rheumatologic disorders
None
HMGCR – statin use
Treatment
Prednisone 
Azathioprine
Methotrexate
Rituximab
IVIG
Others
Prednisone

29. Toxic Myopathies Necrotizing: Amphiphilic drug myopathy:
Cholesterol lowering agents
Cyclosporine, tacrolimus
Amphiphilic drug myopathy:
Chloroquine
Amiodarone
Antimicrotubular myopathy:
colchicine
Non-specific:
Steroids (type 2 atrophy)
Drug-induced mitochondrial myopathy:
Zidovudine (RRF)

30. SUSPECTED STATIN RELATED NEUROTOXICITY
Statins:
Highest risk: cerivastatin (withdrawn from market) and atorvastatin
Intermediate risk: simvastatin, lovastatin, pravastatin, red yeast rice (similar to lovastatin)
Lowest risk: fluvastatin
Additional history:
Is the patient taking a CYP3A4 inhibitor? (most common: clarithromycin, verapamil, diltiazem, cyclosporine A)
Is the patient taking a fibrate?
Could the patient be an asymptomatic carrier for a metabolic myopathy or mitochondrial disorder?
Is the patient taking a proton pump inhibitor? (increased risk for polymyositis and dermatomyositis)
CLINICAL SYNDROMES :
Myalgias
Cramps
Asymptomatic hyperCKemia
Rare: necrotizing myopathy, acute rhabdomyolysis/myoglobinuria/acute renal failure

31. TREATMENT OF STATIN-INDUCED MYOPATHY:
Asymptomatic or mild hyperCKemia
Can continue statin, monitor closely
Drug cessation: most will resolve in 2-3 months
Switch to a lower-risk statin
If the symptoms persist or progressmuscle biopsy to look for underlying neuromuscular disorder or myositis
Retrial with lower dose or less potent statin after period of recovery
Acute rhabdomyolysis/myoglobinuria/renal failure: hospital admission, IV hydration, supportive measures, hemodialysis if needed
Other:
Risk/benefit analysis regarding need for statin
Potential role for vitamin D, Coenzyme Q10

32. Critical Illness Myopathy
First described 1980s
Affects 1/3 to ½ of all critically ill
Profound residual weakness (months to years)
Often with CIP
Criteria:
Critically ill
Limb weakness
Difficulty weaning from vent
Cardiac/pulm causes excluded
CMAP amp <80% LLN without CB
Normal SNAPs
Myopathic EMG +/- fibs, PSWs
No decrement on RNS
Biopsy: myosin loss or necrosis
CMAP duration prolonged

33. CIM-risk factors Sepsis SIRS MOF ARDS >1 wk ICU stay
Prolonged mechanical ventilation
Other: duration of vasopressor support, hyperglycemia, female sex, renal failure/ replacement therapy, TPN, low albumin

34. Copyright © 2014 American Medical Association. All rights reserved.
From: Acute Skeletal Muscle Wasting in Critical Illness
JAMA. 2013;310(15): doi: /jama
Figure Legend:
outline) for green, and 4',6-diamidion-2-pheylidole (a nuclear marker) for blue.
Date of download: 3/11/2014
Copyright © 2014 American Medical Association. All rights reserved.

35. Infectious Myopathies
Bacterial
Viral
Mild, myalgias
Severe with rhabdo: influenza, cocksackievirus, EBV, HSV, HIV, measles, dengue
Chronic: echovirus w/ hypogammaglobulinemia, HIV
Pathophysiology: direct muscle invasion vs cytokine response
Parasitic