Recognition, Investigation
and Treatment of
Myopathies
Hanni Bouma
August 14, 2013
Overview
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Statin-induced myopathy
Idiopathic inflammatory myopathies
– Dermatomyositis
– Polymyositis
– Inclusion body myositis
Etiological Classification
of Myopathies
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Hereditary
Muscular Dystrophies
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– Duchenne’s
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Myotonias
Channelopathies
Congenital Myopathies
Metabolic Myopathies
– PM, DM, IBM
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Mitochondrial
myopathies
Endocrine
– thyroid
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– Pompe’s disease
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Acquired
Inflammatory
myopathies
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Associated with other
systemic illness
Drug-induced and toxic
myopathies
– EtOH, steroids, statins
Statin-induced Myopathy
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1.5-3% of statin users in RCTs and 10-13%
of participants enrolled in prospective
clinical studies develop myalgias; rates of
myositis lower (~0.1-0.5%) & dosedependent
Mean duration of statin therapy before
onset of Sx.: 6 months
Mean duration of myalgias after stopping
statin therapy: 2 months
Questions
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What if a patient develops a myopathy
after several years of taking a statin?
Are some statins more likely to cause
muscle damage? Which ones?
Management
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Significant muscle Sx.: discontinue statin
Asymptomatic but with CK>10x ULN:
discontinue statin
Rhabdo: no statins at any time due to risk
of recurrence
If requires a statin but muscle toxicity other
than rhabdo: discontinue statin
– Once Sx. have resolved and the CK has returned
to baseline, can try pravastatin or fluvastatin
with careful monitoring
Questions

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When are EMG or muscle biopsy
necessary in suspected statin
myopathy?
Is Coenzyme Q10 helpful?
Statin-associated
necrotizing myopathy
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Myopathy which persists or progresses
after stopping statin
Linked to autoantibodies against HMGCoA reductase
Distinct muscle biopsy findings:
– macrophagocytic infiltrate engulfing
necrotic muscle fibers
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Responds to immune therapy
Statin-associated
necrotizing myopathy
Onto the inflammatory
myopathies…
DM: Clinical
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Slow, progressive, symmetric limb-girdle
weakness
Activity-induced muscle pain
Rash usually accompanies or precedes
weakness (but not always)
Associated features:
– Adults: Myocarditis, ILD, vasculitis, other
CTDs (RA, Scl, CREST)
– Children: Contractures, subQ calcinosis,
intestinal ulceration
Malignancy: adenocarcinomas, ovarian,
DM: Investigations
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CK normal (20-30%) or increased up to 50x
ANA+ (24-60%)
Myositis specific antibodies:
– Mi-2 (15%)
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acute onset, nailfold ulcers & good response to therapy
– Anti-Jo-1 (~20%)
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ILD, mechanic’s hands, arthritis, Raynaud’s
EMG
Muscle biopsy
MRI
Other Investigations: DM
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Increased risk of Ca. within first 2-3 yrs of
diagnosis
– Treatment of malignancy sometimes
improves muscle strength
– Malignancy workup in all patients:
 CT CAP
 Mammogram
 Breast & pelvic exams
 Colonoscopy
 And/OR PET scan
CXR, High res CT chest (ILD)
Polymyositis
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“Diagnosis of exclusion”
– Often mistaken diagnosis of PM in cases
of DM w/o rash (yet) or IBM w/o
inclusions on biopsy
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Adults with prox symmetric weakness:
limb girdle distribution + neck flexors
Also ass’d with other autoimmune
disorders
Myocarditis, arthritis, Raynaud’s, ILD
IBM
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Most common myopathy
> 50 yo
Insidious onset; Dx.
usually several yrs after
onset
Early dysphagia
Different pattern of
weakness:
– Distal UE, Prox LE
– Early atrophy &
weakness of WF, FF &
quads
– Hip girdle, TA muscles
EMG findings (all IM)
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Fibs, PSWs, CRDs
at rest
Increased
insertional
activity
Why fibs?
1) Distal, healthy portion of muscle fibre gets separated from the part attached
to the endplate
2) Infarction of small intramuscular nerve twigs by surrounding interstitial
inflammation
EMG findings
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Polyphasic, low
amplitude, short
duration MUPs with
voluntary activation
Rapid recruitment
of MUPs w/ full
interference pattern
of low amplitude on
weak effort
Muscle biopsy findings…
Diagnosis?
PM
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Mediated by CD8+ T-cells which attack
muscle fibres
Endomysial mononuclear inflammatory cell infiltrate
invading and surrounding non-necrotic muscle fibres
DM
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Humorally-mediated microangiopathy
1) Perifascicular necrosis/atrophy
2) Perivascular & perimysial inflammation:
macrophages, B cells, CD4+ cells
IBM
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Similar to PM: CD8+ T cells & macrophages
Modified Gomori trichrome stain
Same features as PM + rimmed vacuoles + amyloid deposits
Question

Is it possible to have IBM without
inclusions on biopsy?
MRI
•DM: inflammation mainly in anterior muscle compartments
w/ preserved muscle mass
•PM/IBM: fatty infiltration/muscle atrophy in all muscle groups
Treatment of DM & PM
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Overall lack of “EBM” to guide
treatment; we don’t know:
– Which second line therapies are most
beneficial
– The doses required to see an effect
– The best time to initiate 2nd or 3rd line
agents
– If some agents are more effective in
certain types of myositis
Treatment: Step 1
Initiate corticosteroids
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Treatment of choice in DM & PM:
– Majority of patients will improve with
pred, but response may be incomplete
Start prednisone at ~1 mg/kg/day up to 100
mg qd
In severe weakness, treatment often
initiated w/ short course of IV Solumedrol 1
g x 3 days prior to pred
Treatment: Step 1
Post-initiation of steroids
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Close clinical F/U q2-4 weeks initially
Maintain dose until muscle strength
normalizes, improvement plateaus, or
CK normalizes (at least 4-6 wks at
high dose)
Then slow taper: by 5 mg q2-3
weeks, below 20 mg by 2.5 q2wks
Treatment: Step 1
Side effect considerations for steroids
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Monitor fasting glucose, K+ levels
Septra for PCP prophylaxis
– If concurrent ILD or pred + other immunosuppressant
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Bone density scan at baseline & qyearly
Calcium 1 g/day + Vit D 1000 IU/day
Bisphosphonate used if postmenopausal
Record BP at each visit (accelerated HTN & renal
failure is a risk)
– Coexistence of scleroderma & other MCTDs
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Periodic eye exams for glaucoma & cataracts
Question

What should I do if there is no
response after an adequate trial of
high dose prednisone?
Question
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How can I tell if the patient is weaker
because of refractory disease or
because of chronic steroid use?
Treatment: Step 2
Add immunosuppressant
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Indications:
– Moderate or severe weakness
– Other organ system inv’t (ILD, myocarditis)
– Increased risk of steroid complications (diabetic,
OP, postmenopausal women)
– Failure to significantly improve after 2-4 months
of steroids
– Any pt expected to need steroids for 10-12 mos
or more
Treatment: Step 2
Immunosuppression
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Options:
–
–
–
–
–
Azathioprine
Methotrexate
IVIG
Cellcept
Cyclophosphamide
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Generally used as
3rd line, if refractory
to other Rx.:
–
–
–
–
Rituximab
PLEX
Ciclosporine
Tacrolimus
Azathioprine
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Effective in DM/PM (retrospective
studies), but takes 6-18 mos to work
Prior to starting, can screen for TPMT
deficiency (BM toxicity in
homozygotes) or just monitor CBC
Begin at 50 mg/d, increase by 50 mg
q2wks up to 2-3 mg/kg/d
Azathioprine
Monitoring & SEs
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Major SEs: 12% develop systemic rxn
(fever, abdo pain, N/V) within first few
wks requiring discontinuation of drug;
BM & liver toxicity, pancreatitis,
teratogenicity, oncogenicity, infection
Leukopenia
Monitor CBC, LFTs closely
Methotrexate
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Most DM & PM respond to MTX
(retrospective studies only)
Begin at 7.5 mg/wk po, increase
gradually by 2.5 mg each week up to
25 mg/wk
If no improvement after 1 month on
25 mg, switch to weekly subQ &
increase dose by 5 mg qwk up to 60
mg/wk
Methotrexate
Monitoring & SEs
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Major SEs: alopecia, stomatitis,
pulmonary fibrosis, teratogenicity,
oncogenicity, infection; renal, liver &
BM toxicity
Avoid MTX in pts with ILD or anti-Jo1+
Avoid MTX in heavy drinkers
Treat all pts with folate 5 mg qwk
IVIG
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One prospective, double-blind,
placebo-controlled study in 15 pts w/
DM showed significant improvement
Little RCT evidence of benefit as
monotherapy but plenty of anecdotal
evidence that IVIG is effective, even
alone
Cyclophosphamide
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Used often if ILD
SEs: infections, secondary
malignancies, hemorrhagic cystitis,
sterilization, BM toxicity, GI upset,
alopecia
– Usually given pulsed; higher risk of
cystitis po
Treatment: Step 3
If refractory to other modalities…
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Rituximab -> monoclonal Ab against
CD20, depletes B cells
– Warnings re: PML risk…
SI
Side
Effects & Monitoring
Non-medical therapies
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PT & OT
Dietician consult if on steroids
Aerobic exercise programs
– Prevents contractures
– May help w/ steroid SEs (weight gain, OP,
type 2 fibre atrophy)
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Speech therapy
– Esp if concomitant dysphagia
Question

What is the value of monitoring serum
CK levels in the treatment of DM &
PM?
Question

How does the treatment of IBM differ
from that of PM & DM?
IBM
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Glucocorticoids have limited role
– In largest published series, muscle
strength continued to deteriorate in all of
25 pred-treated patients followed for at
least 2 yrs
– CK levels often normalize, but this doesn’t
correlate with clinical benefit
IBM: suggested approach
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If ++inflammation seen on Bx.,
consider trial of steroids +/- Imuran (3
mos) early in disease
Discontinue all therapy if continued
decline in strength
For most patients, no treatment
Overview of the IM
References
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Dr. Erin O’Ferrall
Amato & Barohn. Evaluation and treatment of
inflammatory myopathies. Journal of Neurology,
Neurosurgery & Psychiatry 2009; 80: 1060-1068.
Sathasivam & Lecky. Statin induced myopathy. BMJ
2008; 337: a2286.
Preston & Shapiro. Electromyography and
neuromuscular disorders: Clinical-electrophysiologic
correlates. 2nd ed. 2005.
Up to Date: Statin myopathy &