Recognition, Recognition, Investigation and Investigation and Treatment of Treatment of MyopathiesMyopathies
Hanni BoumaHanni Bouma
August 14, 2013August 14, 2013
OverviewOverview
Statin-induced myopathyStatin-induced myopathy Idiopathic inflammatory Idiopathic inflammatory
myopathiesmyopathies– DermatomyositisDermatomyositis– PolymyositisPolymyositis– Inclusion body myositisInclusion body myositis
Etiological Etiological Classification of Classification of MyopathiesMyopathies HereditaryHereditary Muscular DystrophiesMuscular Dystrophies
– Duchenne’s Duchenne’s MyotoniasMyotonias ChannelopathiesChannelopathies Congenital Congenital
MyopathiesMyopathies Metabolic MyopathiesMetabolic Myopathies
– Pompe’s diseasePompe’s disease Mitochondrial Mitochondrial
myopathiesmyopathies
AcquiredAcquired Inflammatory Inflammatory
myopathiesmyopathies– PM, DM, IBMPM, DM, IBM
EndocrineEndocrine– thyroidthyroid
Associated with Associated with other systemic other systemic illnessillness
Drug-induced and Drug-induced and toxic myopathiestoxic myopathies– EtOH, steroids, EtOH, steroids, statinsstatins
Statin-induced Statin-induced MyopathyMyopathy 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%) & dose-dependent
Mean duration of statin therapy before Mean duration of statin therapy before onset of Sx.: onset of Sx.: 6 months6 months
Mean duration of myalgias after Mean duration of myalgias after stopping statin therapy: stopping statin therapy: 2 months2 months
QuestionsQuestions
What if a patient develops a What if a patient develops a myopathy after several years of myopathy after several years of taking a statin?taking a statin?
Are some statins more likely to Are some statins more likely to cause muscle damage? Which cause muscle damage? Which ones?ones?
ManagementManagement Significant muscle Sx.: discontinue Significant muscle Sx.: discontinue
statinstatin Asymptomatic but with CK>10x ULN: Asymptomatic but with CK>10x ULN:
discontinue statindiscontinue statin Rhabdo: no statins at any time due to Rhabdo: no statins at any time due to
risk of recurrence risk of recurrence If requires a statin but muscle toxicity If requires a statin but muscle toxicity
other than rhabdo: discontinue statinother than rhabdo: discontinue statin– Once Sx. have resolved and the CK has Once Sx. have resolved and the CK has
returned to baseline, can try returned to baseline, can try pravastatinpravastatin or or fluvastatinfluvastatin with careful monitoring with careful monitoring
QuestionsQuestions
When are EMG or muscle biopsy When are EMG or muscle biopsy necessary in suspected statin necessary in suspected statin myopathy?myopathy?
Is Coenzyme Q10 helpful?Is Coenzyme Q10 helpful?
Statin-associated Statin-associated necrotizing myopathynecrotizing myopathy
Myopathy which persists or Myopathy which persists or progresses after stopping statinprogresses after stopping statin
Linked to autoantibodies against Linked to autoantibodies against HMG-CoA reductaseHMG-CoA reductase
Distinct muscle biopsy findings:Distinct muscle biopsy findings:– macrophagocytic infiltrate engulfing macrophagocytic infiltrate engulfing
necrotic muscle fibers necrotic muscle fibers Responds to immune therapyResponds to immune therapy
Statin-associated Statin-associated necrotizing myopathynecrotizing myopathy
Onto the inflammatory Onto the inflammatory myopathies…myopathies…
DM: ClinicalDM: Clinical
Slow, progressive, symmetric limb-girdle Slow, progressive, symmetric limb-girdle weaknessweakness
Activity-induced muscle painActivity-induced muscle pain Rash usually accompanies or precedes Rash usually accompanies or precedes
weakness (but not always)weakness (but not always) Associated features:Associated features:
– Adults: Myocarditis, ILD, vasculitis, other Adults: Myocarditis, ILD, vasculitis, other CTDs (RA, Scl, CREST)CTDs (RA, Scl, CREST)
– Children: Contractures, subQ calcinosis, Children: Contractures, subQ calcinosis, intestinal ulceration intestinal ulceration
MalignancyMalignancy: : adenocarcinomas, ovarian, adenocarcinomas, ovarian, breast, lung, lymphoma/leukemia breast, lung, lymphoma/leukemia
DM: InvestigationsDM: Investigations
CK normal (20-30%) or increased up to CK normal (20-30%) or increased up to 50x 50x
ANA+ (24-60%) ANA+ (24-60%) Myositis specific antibodies: Myositis specific antibodies:
– Mi-2Mi-2 (15%) (15%) acute onset, nailfold ulcers & good response to acute onset, nailfold ulcers & good response to
therapytherapy– Anti-Jo-1Anti-Jo-1 (~20%) (~20%)
ILD, mechanic’s hands, arthritis, Raynaud’sILD, mechanic’s hands, arthritis, Raynaud’s EMGEMG Muscle biopsyMuscle biopsy MRIMRI
Other Investigations: DMOther Investigations: DM Increased risk of Ca. within first 2-3 yrs of diagnosisIncreased risk of Ca. within first 2-3 yrs of diagnosis
– Treatment of malignancy sometimes improves muscle Treatment of malignancy sometimes improves muscle strengthstrength
– Malignancy workup in all patients: Malignancy workup in all patients: CT CAPCT CAP MammogramMammogram Breast & pelvic examsBreast & pelvic exams ColonoscopyColonoscopy And/OR PET scanAnd/OR PET scan
CXR, High res CT chest (ILD)CXR, High res CT chest (ILD) EKG (myocardial inv’t) or Echo if CHFEKG (myocardial inv’t) or Echo if CHF Swallowing assessment if dysphagiaSwallowing assessment if dysphagia
PolymyositisPolymyositis
““Diagnosis of exclusion” Diagnosis of exclusion” – Often mistaken diagnosis of PM in cases of Often mistaken diagnosis of PM in cases of
DM w/o rash (yet) or IBM w/o inclusions on DM w/o rash (yet) or IBM w/o inclusions on biopsybiopsy
AdultsAdults with prox symmetric weakness: with prox symmetric weakness: limb girdle distribution + neck flexorslimb girdle distribution + neck flexors
Also ass’d with other autoimmune Also ass’d with other autoimmune disordersdisorders
Myocarditis, arthritis, Raynaud’s, ILDMyocarditis, arthritis, Raynaud’s, ILD
IBMIBM Most common myopathy Most common myopathy
> 50 yo> 50 yo Insidious onset; Dx. Insidious onset; Dx.
usually several yrs after usually several yrs after onsetonset
Early dysphagiaEarly dysphagia Different pattern of Different pattern of
weakness: weakness: – Distal UE, Prox LEDistal UE, Prox LE– Early atrophy & Early atrophy &
weakness of WF, FF & weakness of WF, FF & quadsquads
– Hip girdle, TA musclesHip girdle, TA muscles
EMG findingsEMG findings (all IM)(all IM)
Fibs, PSWs, Fibs, PSWs, CRDs at restCRDs at rest
Increased Increased insertional insertional activityactivity
Why fibs?Why fibs?
1) Distal, healthy portion of muscle fibre gets separated from the part attached to the endplate2) Infarction of small intramuscular nerve twigs by surrounding interstitialinflammation
Polyphasic, low Polyphasic, low amplitude, short amplitude, short duration MUPs with duration MUPs with voluntary activationvoluntary activation
Rapid recruitment Rapid recruitment of MUPs w/ full of MUPs w/ full interference interference pattern of low pattern of low amplitude on weak amplitude on weak effort effort
EMG findings
Muscle biopsy Muscle biopsy findings…findings…
Diagnosis?Diagnosis?
PMPM
Endomysial mononuclear inflammatory cell infiltrate invading and surrounding non-necrotic muscle fibres
Mediated by CD8+ T-cells which attack Mediated by CD8+ T-cells which attack muscle fibresmuscle fibres
DMDM Humorally-mediated Humorally-mediated
microangiopathymicroangiopathy
1) Perifascicular necrosis/atrophy 2) Perivascular & perimysial inflammation: macrophages, B cells, CD4+ cells
IBMIBM
Similar to PM: CD8+ T cells & macrophagesSimilar to PM: CD8+ T cells & macrophages
Same features as PM + rimmed vacuoles + amyloid depositsModified Gomori trichrome stain
Is it possible to have IBM without Is it possible to have IBM without inclusions on biopsy?inclusions on biopsy?
QuestionQuestion
MRIMRI
•DM: inflammation mainly in anterior muscle compartments w/ preserved muscle mass•PM/IBM: fatty infiltration/muscle atrophy in all muscle groups
Treatment of DM & PMTreatment of DM & PM Overall lack of “EBM” to guide Overall lack of “EBM” to guide
treatment; we don’t know:treatment; we don’t know:– Which second lineWhich second line therapies are most therapies are most
beneficialbeneficial– The doses required to see an effectThe doses required to see an effect– The best time to initiate 2The best time to initiate 2ndnd or 3 or 3rdrd line line
agentsagents– If some agents are more effective in If some agents are more effective in
certain types of myositiscertain types of myositis
Treatment: Step 1Treatment: Step 1Initiate corticosteroidsInitiate corticosteroids
Treatment of choice in DM & PM:Treatment of choice in DM & PM:– Majority of patients will improve with Majority of patients will improve with
pred, but response may be pred, but response may be incompleteincomplete
Start prednisone at ~1 mg/kg/day up Start prednisone at ~1 mg/kg/day up to 100 mg qd to 100 mg qd
In severe weakness, treatment often In severe weakness, treatment often initiated w/ short course of IV initiated w/ short course of IV Solumedrol 1 g x 3 days prior to predSolumedrol 1 g x 3 days prior to pred
Treatment: Step 1Treatment: Step 1Post-initiation of steroidsPost-initiation of steroids
Close clinical F/U q2-4 weeks initiallyClose clinical F/U q2-4 weeks initially Maintain dose until muscle strength Maintain dose until muscle strength
normalizes, improvement plateaus, normalizes, improvement plateaus, or CK normalizes (at least 4-6 wks at or CK normalizes (at least 4-6 wks at high dose)high dose)
Then Then slowslow taper: by taper: by 5 mg q2-3 5 mg q2-3 weeksweeks, below 20 mg by 2.5 q2wks, below 20 mg by 2.5 q2wks
Treatment: Step 1Treatment: Step 1Side effect considerations for steroidsSide effect considerations for steroids
Monitor fasting glucose, K+ levelsMonitor fasting glucose, K+ levels Septra for PCP prophylaxisSeptra for PCP prophylaxis
– If concurrent ILD or pred + other If concurrent ILD or pred + other immunosuppressantimmunosuppressant
Bone density scan at baseline & qyearlyBone density scan at baseline & qyearly Calcium 1 g/day + Vit D 1000 IU/dayCalcium 1 g/day + Vit D 1000 IU/day Bisphosphonate used if postmenopausalBisphosphonate used if postmenopausal Record BP at each visit (accelerated HTN & Record BP at each visit (accelerated HTN &
renal failure is a risk) renal failure is a risk) – Coexistence of scleroderma & other MCTDsCoexistence of scleroderma & other MCTDs
Periodic eye exams for glaucoma & cataractsPeriodic eye exams for glaucoma & cataracts
QuestionQuestion
What should I do if there is no What should I do if there is no response after an adequate trial response after an adequate trial of high dose prednisone?of high dose prednisone?
QuestionQuestion
How can I tell if the patient is How can I tell if the patient is weaker because of refractory weaker because of refractory disease or because of chronic disease or because of chronic steroid use?steroid use?
Treatment: Step 2Treatment: Step 2Add immunosuppressantAdd immunosuppressant
Indications:Indications:– Moderate or severe weaknessModerate or severe weakness– Other organ system inv’t (ILD, Other organ system inv’t (ILD,
myocarditis)myocarditis)– Increased risk of steroid complications Increased risk of steroid complications
(diabetic, OP, postmenopausal women)(diabetic, OP, postmenopausal women)– Failure to significantly improve after 2-4 Failure to significantly improve after 2-4
months of steroidsmonths of steroids– Any pt expected to need steroids for 10-12 Any pt expected to need steroids for 10-12
mos or moremos or more
Treatment: Step 2Treatment: Step 2ImmunosuppressionImmunosuppression
Options:Options:– AzathioprineAzathioprine – MethotrexateMethotrexate– IVIG IVIG – CellceptCellcept– CyclophosphamidCyclophosphamid
ee
Generally used Generally used as 3as 3rdrd line, if line, if refractory to refractory to other Rx.:other Rx.:– Rituximab Rituximab – PLEX PLEX – CiclosporineCiclosporine– TacrolimusTacrolimus
AzathioprineAzathioprine
Effective in DM/PM (retrospective Effective in DM/PM (retrospective studies), but takes 6-18 mos to studies), but takes 6-18 mos to workwork
Prior to starting, can screen for Prior to starting, can screen for TPMT deficiency (BM toxicity in TPMT deficiency (BM toxicity in homozygotes) or just monitor CBChomozygotes) or just monitor CBC
Begin at 50 mg/d, increase by 50 Begin at 50 mg/d, increase by 50 mg q2wks up to 2-3 mg/kg/dmg q2wks up to 2-3 mg/kg/d
AzathioprineAzathioprineMonitoring & SEsMonitoring & SEs
Major SEs:Major SEs: 12% develop systemic 12% develop systemic rxn (fever, abdo pain, N/V) within rxn (fever, abdo pain, N/V) within first few wks requiring first few wks requiring discontinuation of drug; BM & liver discontinuation of drug; BM & liver toxicity, pancreatitis, teratogenicity, toxicity, pancreatitis, teratogenicity, oncogenicity, infectiononcogenicity, infection
LeukopeniaLeukopenia Monitor CBC, LFTs closelyMonitor CBC, LFTs closely
MethotrexateMethotrexate
Most DM & PM respond to MTX Most DM & PM respond to MTX (retrospective studies only)(retrospective studies only)
Begin at 7.5 mg/wk po, increase Begin at 7.5 mg/wk po, increase gradually by 2.5 mg each week gradually by 2.5 mg each week up to 25 mg/wkup to 25 mg/wk
If no improvement after 1 month If no improvement after 1 month on 25 mg, switch to weekly subQ on 25 mg, switch to weekly subQ & increase dose by 5 mg qwk up & increase dose by 5 mg qwk up to 60 mg/wkto 60 mg/wk
MethotrexateMethotrexateMonitoring & SEsMonitoring & SEs
Major SEs:Major SEs: alopecia, stomatitis, alopecia, stomatitis, pulmonary fibrosis, pulmonary fibrosis, teratogenicity, teratogenicity, oncogenicity, infection; renal, liver oncogenicity, infection; renal, liver & BM toxicity& BM toxicity
Avoid MTX in pts with ILD or anti-Avoid MTX in pts with ILD or anti-Jo-1+Jo-1+
Avoid MTX in heavy drinkersAvoid MTX in heavy drinkers Treat all pts with folate 5 mg qwkTreat all pts with folate 5 mg qwk
IVIGIVIG
One prospective, double-blind, One prospective, double-blind, placebo-controlled study in 15 pts placebo-controlled study in 15 pts w/ DM showed significant w/ DM showed significant improvementimprovement
Little RCTLittle RCT evidence of benefit as evidence of benefit as monotherapy but plenty of monotherapy but plenty of anecdotal evidence that IVIG is anecdotal evidence that IVIG is effective, even aloneeffective, even alone
CyclophosphamideCyclophosphamide
Used often if ILDUsed often if ILD SEs: infections, secondary SEs: infections, secondary
malignancies, hemorrhagic malignancies, hemorrhagic cystitis, sterilization, BM toxicity, cystitis, sterilization, BM toxicity, GI upset, alopeciaGI upset, alopecia– Usually given pulsed; higher risk of Usually given pulsed; higher risk of
cystitis pocystitis po
Treatment: Step 3Treatment: Step 3If refractory to other modalities…If refractory to other modalities…
RituximabRituximab -> monoclonal Ab -> monoclonal Ab against CD20, depletes B cellsagainst CD20, depletes B cells– Warnings re: PML risk…Warnings re: PML risk…
SISide Effects & Side Effects & MonitoringMonitoring
Non-medical therapiesNon-medical therapies
PT & OTPT & OT Dietician consult if on steroidsDietician consult if on steroids Aerobic exercise programsAerobic exercise programs
– Prevents contracturesPrevents contractures– May help w/ steroid SEs (weight May help w/ steroid SEs (weight
gain, OP, type 2 fibre atrophy)gain, OP, type 2 fibre atrophy) Speech therapySpeech therapy
– Esp if concomitant dysphagiaEsp if concomitant dysphagia
QuestionQuestion
What is the value of monitoring What is the value of monitoring serum CK levels in the treatment serum CK levels in the treatment of DM & PM?of DM & PM?
QuestionQuestion
How does the treatment of IBM How does the treatment of IBM differ from that of PM & DM?differ from that of PM & DM?
IBMIBM
Glucocorticoids have limited roleGlucocorticoids have limited role– In largest published series, muscle In largest published series, muscle
strength continued to deteriorate in strength continued to deteriorate in all of 25 pred-treated patients all of 25 pred-treated patients followed for at least 2 yrsfollowed for at least 2 yrs
– CK levels often normalize, but this CK levels often normalize, but this doesn’t correlate with clinical benefitdoesn’t correlate with clinical benefit
IBM: suggested IBM: suggested approachapproach If ++inflammation seen on Bx., If ++inflammation seen on Bx.,
consider trial of steroids +/- consider trial of steroids +/- Imuran (3 mos) early in diseaseImuran (3 mos) early in disease
Discontinue all therapy if Discontinue all therapy if continued decline in strengthcontinued decline in strength
For most patients, For most patients, no treatmentno treatment
Overview of the IMOverview of the IM
ReferencesReferences
Dr. Erin O’FerrallDr. Erin O’Ferrall Amato & Barohn. Evaluation and treatment Amato & Barohn. Evaluation and treatment
of inflammatory myopathies. of inflammatory myopathies. Journal of Journal of Neurology, Neurosurgery & Psychiatry Neurology, Neurosurgery & Psychiatry 2009; 2009; 80: 1060-1068.80: 1060-1068.
Sathasivam & Lecky. Statin induced Sathasivam & Lecky. Statin induced myopathy. myopathy. BMJ BMJ 2008; 337: a2286.
Preston & Shapiro. Electromyography and neuromuscular disorders: Clinical-electrophysiologic correlates. 2nd ed. 2005.
Up to Date: Statin myopathy & Up to Date: Statin myopathy &