Transcript Treatment of Myopathies

Treatment of Myopathies
Hanni Bouma
Overview
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Inflammatory myopathies
– Dermatomyositis
– Polymyositis
– Inclusion body myositis
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Clinical features
Investigations
Treatment approach
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
Overview of the IM
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
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Cancers: adenocarcinomas, ovarian, breast, lung,
lymphoma/leukemia
DM: Investigations
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CK normal (20-30%) or increased up to 50x
– Does not correlate with severity of weakness
– Aldolase may be elevated while CK still normal
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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
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:
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CT CAP
Mammogram
Breast & pelvic exams
Colonoscopy
CXR, High res CT chest (ILD)
EKG (myocardial inv’t) or Echo if CHF
Swallowing assessment if dysphagia
Polymyositis
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“Diagnosis of exclusion”
– Often mistaken diagnosis of PM in cases
of DM w/o rash (yet), IBM w/o inclusions
on biopsy
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Prox symmetric weakness
Associated with other autoimmune
disorders
Myocarditis, arthritis, Raynaud’s, ILD
IBM
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Most common myopathy
over 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, ant. tibial
muscles
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 (late finding)
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
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Is it possible to have IBM without
inclusions on biopsy?
Treatment
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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)
Then slow taper: by 5 mg q2-3 weeks,
below 20 mg by 2.5 q2wks
*Most will need to stay on a small dose of
pred (10 mg qd) or need a 2nd line agent to
stay in remission
Step 1: Steroids
Side effect considerations
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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
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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
* Must weigh risks of immunosuppression vs.
possible benefits (faster improvement, steroidsparing)
Treatment: Step 2
Immunosuppression
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Options:
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Azathioprine
Methotrexate
IVIG
Cellcept
Cyclophosphamide
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Generally used as
3rd line, if refractory
to other Rx.:
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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) w/i first few wks requiring
discontinuation of drug; BM & liver toxicity (avoid
allopurinol), pancreatitis, teratogenicity,
oncogenicity, infection
Monitor CBC, LFTs closely; D/C if LFTs double (esp.
GGT)
Leukopenia: can develop at 1 wk to as late as 2 yrs
post-initiation; decrease dose if WBCs fall to <4,
D/C altogether if <2.5 or ANC <1; usually reverses
w/i 1 mo., can then rechallenge
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-Jo-1+
Avoid MTX in heavy drinkers
Treat all pts with folate 5 mg qwk
Monitor LFTs, CBC q2wks until on stable dose,
then q1-3 mos
Check GGT because AST/ALT can be elevated
from muscle inv’t; consider liver Bx. if
cumulative dose exceeds 2 g
Monitor PFTs periodically
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
IVIG
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2 g/kg over 2-5 days, repeated at
monthly intervals for at least 3 mos
Then decrease or spread out dose (40
g q2wks)
SEs:
– Renal failure (esp. diabetics), flu-like Sx.,
rash, aseptic meningitis, MI, stroke, CHF
Cyclophosphamide
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Used often if ILD
SEs: infections, secondary
malignancies, hemorrhagic cystitis,
sterilization, BM toxicity, GI upset,
alopecia
– Usually given pulsed (0.5-1 g/ IV/m2/mo.
for 6-12 mos), higher risk of cystitis po
Mycophenolate mofetil
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Blocks purine synthesis in lymphs
Actual benefit unknown
Main advantage: lack of renal or liver
toxicity
Starting dose 1.0 g bid, increased to 1.5 bid
if needed
Limit 1 g/d if renal insufficiency
Side effects: N/V, diarrhea, fever,
leukopenia, severe infections possible
Treatment: Step 3
If refractory to other modalities…
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Rituximab -> monoclonal Ab against
CD20, depletes B cells
– Dose 750 mg/m2 (up to 1 g) x 1, repeat
in 2 wks & then q6-9mos
– Warnings re: PML risk…
Treatment: Step 3
If refractory to other modalities…
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Ciclosporine & tacrolimus -> renal
toxicity, HTN, electrolyte imbalance, GI
upset, hypertrichosis, gingival
hyperplasia, cancers, tremor, infection
PLEX -> few small open label series
suggested benefit in DM, PM & IBM
– Controlled trial of 36 pts w/ DM & PM
comparing PLEX, leukopheresis & sham
apheresis showed no improvement
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
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What is the value of monitoring serum
CK levels in the treatment of DM &
PM?
Question
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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
– Exception: Cases of IBM ass’d w/ other CTDs
(Sjogren’s, SLE, cutaneous DM) may have
clinically important benefit from steroids
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MTX, Imuran: minor benefit at best
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
Cricopharyngeal myotomy may be
helpful if severe dysphagia
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.
UptoDate
Lambert-Eaton
Myasthenic Syndrome
Hanni Bouma
Symptoms
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Slowly progressive proximal muscle weakness
(legs>>arms)
Muscle fatigability or cramping after exercise
Autonomic dysfunction:
– Dry mouth**
– ED
– Blurred vision, constipation
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CN dysfunction (less prominent than in MG & rarely
the presenting symptom)
– Ptosis most common
– Diplopia, dysarthria, dysphagia, difficulty chewing
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Respiratory failure late in course
Signs
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Proximal muscle weakness without
atrophy
– Functional difficulties often worse than
exam findings
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Depressed or absent reflexes
– Isometric contraction of relevant muscle can
temporarily bring out reflexes or improve
muscle weakness (postactivation facilitation)
– More sustained physical exercise  muscle
fatigability
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Paradoxical eyelid elevation with
sustained upgaze
Symmetric, sluggish pupillary responses
Reduced salivation
Pathophysiology
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VGCC
antibodies:
interfere with
normal
calcium influx
required for
Ach release 
reduced Ach
release from
presynaptic
nerve
terminals
Epidemiology
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Annual incidence & prevalence 0.48 & 2.32
per million
½ of cases associated w/ malignancy
– Usually starts after age 50
– SCLC most commonly (84%), Hodgkin’s
lymphoma
– Presence of LEMS implies better prognosis in
SCLC pts
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In non-paraneoplastic forms, younger age
of onset
Treatment
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1) Treatment of underlying malignancy
– causes remission of LEMS in many but not all
paraneoplastic forms; may be only intervention
necessary
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2) Symptomatic therapies
– increase amt. of Ach available at postsynaptic
membrane
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3) Immunologic therapies
– reduce aberrant immune response causing
formation of VGCC antibodies
– Regimens similar to those used in MG
Aminopyridines
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MoA: significant prolongation of nerve
terminal membrane depolarization 
calcium channels kept open longer, which
improves release of Ach
3,4-Diaminopyridine: limited CNS
penetration, few SEs (perioral & extremity
paresthesias, seizures at higher doses)
Guanidine
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MoA: inhibits VGKC & enhances release of
Ach
First beneficial agent for symptomatic
treatment of LEMS
Significant bone marrow, liver & renal
toxicity at higher doses
Max dose 1000 mg/d.
AChEI
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MoA: reduce metabolism of Ach,
thereby increasing amt. available for
AchR binding
Pyridostigmine: best-tolerated
Only marginally effective used in
isolation
Immunologic therapies
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Indications:
– Significant weakness
– Limited response to symptomatic Rx.
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Options: the usual suspects…
– IVIG
– Steroids
– Azathioprine, myocophenolate, cyclophos
– PLEX, Rituximab
Treatment Approach
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If mild persistent weakness, with or
without malignancy
– Trial of pyridostigmine 30-120 mg q3-6hrs
– If response inadequate, 3,4-DAP can be
added (10-25 mg tid to qid)
– OR add low-dose guanidine (5-10
mg/kg/d given in 3-4 divided doses)
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Not used much anymore
Approach
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If significant weakness refractory to
symptomatic therapies, with treated
malignancy or without malignancy
Two options:
1) Course of IVIG (2 g/kg over 2-5 days)
– Temporary improvement (4-8 weeks)
– Requires maintenance w/ repeat infusions at 412 week intervals
– used if good response to initial IVIG course
Approach
2) Prednisone (1 mg/kg/day) and
azathioprine (starting at 50 mg bid,
increasing by 50 mg qweek up to 2-3
mg/kg/d)
– May take several months for clinically
significant improvement (remission)
– Then attempt to taper or discontinue
prednisone
Approach
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PLEX not as effective for LEMS as MG
Slower response, short-term benefit
Can be used if IVIG intolerance or
refractory disease with severe clinical
course