The Treatment of MG: The Treatment of MG: State of the ArtState of the Art

May 2010May 2010

Gil I. Wolfe, M.D.Gil I. Wolfe, M.D.Univ. of Texas Southwestern Univ. of Texas Southwestern

Medical CenterMedical Center

Dallas, TXDallas, TX

Therapy goals in MGTherapy goals in MG

Return patients to normal functionReturn patients to normal function Achieve remissionAchieve remission Minimize side effectsMinimize side effects

Individualize therapyIndividualize therapy Disease severity and distributionDisease severity and distribution Rate of progressionRate of progression Lifestyle and career choicesLifestyle and career choices Coexisting diseaseCoexisting disease Patient age and sexPatient age and sex Cost considerationsCost considerations

Symptomatic Rx: Anticholinesterase Symptomatic Rx: Anticholinesterase agentsagents

PyridostigminePyridostigmine Initiate at 30-60 mg 3-4 Initiate at 30-60 mg 3-4

times a day initiallytimes a day initially Clinical response in 15-30 Clinical response in 15-30

min lasting 3-4 hrsmin lasting 3-4 hrs tt1/2 1/2 200 min (60 mg)200 min (60 mg) Peak plasma levels in 1-2 Peak plasma levels in 1-2

hrshrs Monitoring levels not usefulMonitoring levels not useful

Individualize dosingIndividualize dosing Dosing >120 mg every 3 hrs Dosing >120 mg every 3 hrs

unlikely to be helpfulunlikely to be helpful

Anticholinesterase agentsAnticholinesterase agents

Countering muscarinic side effectsCountering muscarinic side effects Glycopyrrolate 1 mgGlycopyrrolate 1 mg Hyoscyamine sulfate 0.125 mgHyoscyamine sulfate 0.125 mg Atropine 0.4 mgAtropine 0.4 mg Loperamide 2-4 mg (OTC)Loperamide 2-4 mg (OTC)

Can be given prn or on fixed schedule in Can be given prn or on fixed schedule in concert with pyridostigmine dosesconcert with pyridostigmine doses

ACE in MuSK Ab+ MGACE in MuSK Ab+ MG

Anticholinesterase Anticholinesterase responsesresponses

Non-responsivenessNon-responsiveness Hypersensitivity-sx Hypersensitivity-sx

worsenworsen Intolerance-severe Intolerance-severe

cholinergic AEscholinergic AEs No improvementNo improvement

MuSKMuSK

Ab +Ab +

SeronegSeroneg AchRAchR

Ab +Ab +

ACE non-ACE non-responseresponse

10/1410/14

71%71%

4/224/22

18%18%

13/7313/73

18%18%

ACEACE

hypersenshypersens3/143/14 1/221/22 0/730/73

ACE ACE intoleranceintolerance

4/144/14 2/222/22 13/7313/73

No improve-No improve-

mentment4/144/14 1/221/22 0/730/73

Tensilon Tensilon test +test +

5/105/10 16/1916/19 32/3332/33

PyridostigPyridostig

responseresponse3/143/14 21/2221/22 71/7371/73

Hatanaka et al. Neurology2005;65:1508

CorticosteroidsCorticosteroids

Ocular MGOcular MG

n=147, retrospectiven=147, retrospective Prednisone titrated to 50-60 Prednisone titrated to 50-60

mg/d, tapered to 2.5-10 mg mg/d, tapered to 2.5-10 mg qd or qodqd or qod

Generalization at 2 yr f/uGeneralization at 2 yr f/u (n=94) (n=94)

4/58 on prednisone (7%)4/58 on prednisone (7%) 13/36 untreated (36%)13/36 untreated (36%)pp=.001=.001

Kupersmith et al. Kupersmith et al. Arch NeurolArch Neurol 2003;60:243 2003;60:243

Immunosuppressive agentsImmunosuppressive agents

MedicationMedication Controlled studiesControlled studies

AzathioprineAzathioprine ++

CyclosporineCyclosporine ++

MycophenolateMycophenolate ++

CyclophosphamideCyclophosphamide ++

TacrolimusTacrolimus ++

IVIGIVIG ++

AzathioprineAzathioprine Randomized, double-blind trial (n=34)Randomized, double-blind trial (n=34)

Palace et al. Palace et al. NeurologyNeurology 1998;50:1778 1998;50:1778

Azathioprine 2.5 mg/kg qd vs. placeboAzathioprine 2.5 mg/kg qd vs. placebo All patients received prednisoloneAll patients received prednisolone

1.5 mg/kg qod with 100 mg qod ceiling1.5 mg/kg qod with 100 mg qod ceiling At 2 & 3 yrs, prednisolone dose reduced in At 2 & 3 yrs, prednisolone dose reduced in

AZA group (AZA group (pp=0.02)=0.02) >80% reduction at 2 yrs>80% reduction at 2 yrs

Disease relapse rate lower in AZA group Disease relapse rate lower in AZA group ((pp=0.024)=0.024)

Side effects lower in AZA groupSide effects lower in AZA group

AzathioprineAzathioprinePalace et al.Palace et al.

placebo

AZA

p =0.02 at 24 mo

placebo

AZA

AzathioprineAzathioprine

Steroid-sparing effects Steroid-sparing effects (Palace et al.)(Palace et al.)

Lower median weight gain at 2,3 yrsLower median weight gain at 2,3 yrs Less dyspepsia, back pain at 1,2,3 yrsLess dyspepsia, back pain at 1,2,3 yrs 30% reduction in steroid dose by 15 mos30% reduction in steroid dose by 15 mos Temporal arteritis studies show 30% Temporal arteritis studies show 30%

reduction substantially reduces adverse reduction substantially reduces adverse eventsevents

Nesher et al. Nesher et al. Clin Exp RheumatolClin Exp Rheumatol 1997;15:303 1997;15:303 Rubinow et al. Rubinow et al. Ann OphthalmolAnn Ophthalmol 1984;16:258 1984;16:258

Mycophenolate mofetilMycophenolate mofetil

Blocks IMP dehydrogenase/purine synthesisBlocks IMP dehydrogenase/purine synthesis Selective inhibition of B & T lymphocytesSelective inhibition of B & T lymphocytes

Widely used in transplant medicineWidely used in transplant medicine Utility in MGUtility in MG

First-line agentFirst-line agent Steroid-sparing agentSteroid-sparing agent

Dosing Dosing 500 mg bid initially, increasing to 1000-1500 mg 500 mg bid initially, increasing to 1000-1500 mg

bid by 500-1000 mg increments every 2-4 wksbid by 500-1000 mg increments every 2-4 wks Can use tid regimen if diarrhea occursCan use tid regimen if diarrhea occurs

Mycophenolate mofetilMycophenolate mofetil Adverse eventsAdverse events

No major organ toxicityNo major organ toxicity Diarrhea, nausea, abdominal painDiarrhea, nausea, abdominal pain Infections Infections (PML)(PML) Peripheral edemaPeripheral edema Drug-induced feverDrug-induced fever Leukopenia Leukopenia

CBC q wk x 4, q2 wks x 4, then monthlyCBC q wk x 4, q2 wks x 4, then monthly Neoplasia (lymphoma)Neoplasia (lymphoma)

Primary CNS lymphoma after 3 yrs of treatmentPrimary CNS lymphoma after 3 yrs of treatmentVernino et al. Vernino et al. NeurologyNeurology 2005;65:639 2005;65:639

Lymphocytopenia (260/Lymphocytopenia (260/µL); CD4 158µL); CD4 158 Near complete resolution with d/c of MM, steroids, Near complete resolution with d/c of MM, steroids,

rituximabrituximab

Mycophenolate mofetilMycophenolate mofetil

Retrospective analysis of 85 MG ptsRetrospective analysis of 85 MG pts 14 pts considered “refractory”14 pts considered “refractory”

Meriggioli et al. Meriggioli et al. Neurology Neurology 2003;61:14382003;61:1438

OutcomesOutcomes 73% remission/minimal manifestation/improved73% remission/minimal manifestation/improved MMT/QMG scores improved significantlyMMT/QMG scores improved significantly 5/13 Class IV pts (38%) did not improve5/13 Class IV pts (38%) did not improve

Steroid doseSteroid dose Reduced by Reduced by >> 50% in 23 pts 50% in 23 pts Reduced by < 50% in 13 ptsReduced by < 50% in 13 pts Unchanged in 14 ptsUnchanged in 14 pts Increased in 1 ptIncreased in 1 pt

Mycophenolate mofetilMycophenolate mofetil

Retrospective analysis of 85 MG ptsRetrospective analysis of 85 MG pts Onset of action relatively rapidOnset of action relatively rapid

Improvement observed at 9-11 wksImprovement observed at 9-11 wks May take up to 40 wksMay take up to 40 wks

Maximal improvement at mean of 27 wksMaximal improvement at mean of 27 wks TolerabilityTolerability

5/85 pts discontinued5/85 pts discontinued GI intolerance (diarrhea)GI intolerance (diarrhea) No significant leukopeniaNo significant leukopenia

Meriggioli et al. Meriggioli et al. Neurology Neurology 2003;61:14382003;61:1438

Mycophenolate mofetilMycophenolate mofetilRandomized, double-blinded, controlled Randomized, double-blinded, controlled

studies in generalized AChRAb+ MGstudies in generalized AChRAb+ MG

MSG-RocheMSG-Roche AsprevaAspreva

Patients (n)Patients (n) 8080 136136

DurationDuration 3 mo/6 mo open 3 mo/6 mo open labellabel

9 mo9 mo

MM doseMM dose 1250 mg bid vs. 1250 mg bid vs. placeboplacebo

1000 mg bid vs. 1000 mg bid vs. placeboplacebo

Prednisone at entryPrednisone at entry NoneNone ≥ ≥ 20 mg qd or qod 20 mg qd or qod equivalentequivalent

Prednisone during studyPrednisone during study 20 mg qd20 mg qd Tapered to 7.5 mg qd Tapered to 7.5 mg qd or 15 mg qodor 15 mg qod

Primary outcomePrimary outcome ΔΔ QMG score QMG score Reaching MMS or PR Reaching MMS or PR from wks 32-36 from wks 32-36

Mycophenolate mofetilMycophenolate mofetil MSG-Roche studyMSG-Roche study

n=39 on pred/placebo; 41 on pred/MMn=39 on pred/placebo; 41 on pred/MM No significant difference in No significant difference in ΔΔQMG at 3 moQMG at 3 mo

-4.4 on MM vs. -3.6 on placebo (p=0.71)-4.4 on MM vs. -3.6 on placebo (p=0.71) No significant difference in 2° outcomesNo significant difference in 2° outcomes

MG-ADL, MMT, SF-36, AChRAb levelsMG-ADL, MMT, SF-36, AChRAb levels MM was well toleratedMM was well tolerated

Diarrhea in 16%, infection in 13% in blinded phase on Diarrhea in 16%, infection in 13% in blinded phase on MMMM

Muscle Study Group. Muscle Study Group. NeurologyNeurology 2008;71:394 2008;71:394

Mycophenolate mofetilMycophenolate mofetil Aspreva studyAspreva study

n=88 on pred/placebo; 88 on pred/MMn=88 on pred/placebo; 88 on pred/MM n=144 completed studyn=144 completed study

No significant different in reaching treatment response of No significant different in reaching treatment response of MMS/PRMMS/PR 44.3% on MM vs. 38.6% on placebo (p=0.541)44.3% on MM vs. 38.6% on placebo (p=0.541)

No significant difference in 2° outcomesNo significant difference in 2° outcomes QMG, MG-ADL, SF-36, global assessmentsQMG, MG-ADL, SF-36, global assessments Trend for greater prednisone dose reduction, decline in AChRAb, Trend for greater prednisone dose reduction, decline in AChRAb,

hospitalizations if on MM, but not significanthospitalizations if on MM, but not significant MM overall well toleratedMM overall well tolerated

Headache (12%), nausea (9%) most common side effectsHeadache (12%), nausea (9%) most common side effects One death related to study drug (pneumonia in MM group)One death related to study drug (pneumonia in MM group)

Sanders et al. Sanders et al. NeurologyNeurology 2008;71:400 2008;71:400

What did we learn about MMF What did we learn about MMF from these two studies?from these two studies?

MM is not better than prednisone alone as initial MM is not better than prednisone alone as initial treatment in mild-moderate MG, and has no treatment in mild-moderate MG, and has no steroid-sparing effect within the timeframe of steroid-sparing effect within the timeframe of these studies (up to 36 wks)these studies (up to 36 wks)

It may take longer than predicted to show benefit It may take longer than predicted to show benefit from MMfrom MM

Prednisone is more effective than predicted, and Prednisone is more effective than predicted, and at a lower dose than expectedat a lower dose than expected

Exacerbations after prednisone may also occur Exacerbations after prednisone may also occur at lower doses than expectedat lower doses than expected

Tacrolimus (FK506)Tacrolimus (FK506)

Same pharmacologic class as cyclosporineSame pharmacologic class as cyclosporine Less nephrotoxicLess nephrotoxic Utility in MGUtility in MG

Monotherapy (not “first-line”)Monotherapy (not “first-line”) Steroid-sparing agentSteroid-sparing agent

Effects seen after 1-2 monthsEffects seen after 1-2 months DosingDosing

3-5 mg/d3-5 mg/d

TacrolimusTacrolimus

16 wk open trial in 16 wk open trial in thymectomized generalized thymectomized generalized MG (n=19)MG (n=19)

Konishi et al. Konishi et al. Muscle Muscle NerveNerve 2003;28:570 2003;28:570

QMG improved in 13/19QMG improved in 13/19 Fell at least 3 pts in 7/19 Fell at least 3 pts in 7/19

(used 27 pt version)(used 27 pt version) Therapy continued for 2 Therapy continued for 2

yrs in 12/19yrs in 12/19 Efficacy maintainedEfficacy maintained

Adverse eventsAdverse events No change in serum CrNo change in serum Cr Increased HbA1c in one ptIncreased HbA1c in one pt

TacrolimusTacrolimus n=212 in open studyn=212 in open study

Ponseti et al. Ponseti et al. Ann NY Acad SciAnn NY Acad Sci 2008;1132:254 2008;1132:254

Dose: 0.1 mg/kg/d adjusted to 7-8 ng/mlDose: 0.1 mg/kg/d adjusted to 7-8 ng/ml Assessments x4 in first month, then at Assessments x4 in first month, then at

least every 3 monthsleast every 3 months Mean f/u 49.3 moMean f/u 49.3 mo OutcomesOutcomes

Muscle strengthMuscle strength QMGQMG MGFA post-intervention statusMGFA post-intervention status

TacrolimusTacrolimus

MGFA PISMGFA PIS 13.7% complete stable 13.7% complete stable

remissionremission 73.8% pharmacologic 73.8% pharmacologic

remissionremission 5.4% minimal manifestation 5.4% minimal manifestation

statusstatus Prednisone withdrawn in Prednisone withdrawn in

95%95% Favorable response Favorable response

irrespective of irrespective of thymectomy or thymomathymectomy or thymoma

Discontinuation from AEs Discontinuation from AEs in 4.9%in 4.9%

QMG scores over timep<0.05

Ponseti et al. 2008

Tacrolimus/CSATacrolimus/CSAPredictors of responsePredictors of response

n=62 (56 generalized)n=62 (56 generalized) Retrospective analysis of 6 mo exposureRetrospective analysis of 6 mo exposure Response measuresResponse measures

>> 3 pt QMG drop: 53% 3 pt QMG drop: 53% >> 25% reduction in prednisolone: 49% 25% reduction in prednisolone: 49%

Predictors of responsePredictors of response Shorter disease duration (4.6 vs. 11.2 yrs)Shorter disease duration (4.6 vs. 11.2 yrs) Thymoma (30% vs. 9%)Thymoma (30% vs. 9%)

Nagane et al. Nagane et al. Muscle Nerve Muscle Nerve 2010;41:2122010;41:212

TacrolimusTacrolimus Adverse eventsAdverse events

HyperglycemiaHyperglycemia HypertensionHypertension HeadacheHeadache HyperkalemiaHyperkalemia NephrotoxicityNephrotoxicity Nausea/vomiting/diarrheaNausea/vomiting/diarrhea InfectionInfection LymphomaLymphoma

Drug interactions similar to CSADrug interactions similar to CSA MonitoringMonitoring

BUN/Cr, glu, KBUN/Cr, glu, K++, trough drug levels (<10 ng/ml) , trough drug levels (<10 ng/ml) Every 2-4 weeks initially, then less frequentlyEvery 2-4 weeks initially, then less frequently

AChRAb+, Class II-IVNo thymoma, 18-65 yo

XTS + ISXTS + ISprednisone prednisone

1.5 mg/kg AD1.5 mg/kg AD

IS aloneIS aloneprednisone prednisone

1.5 mg/kg AD1.5 mg/kg AD

MMS: prednisone taperMMS: prednisone taper MMS: prednisone taperMMS: prednisone taper

1° Composite AUQTC, AUDTC,1° Composite AUQTC, AUDTC, AEs at 3 yrsAEs at 3 yrs2° prednisone AUDTC at 1,2 yrs2° prednisone AUDTC at 1,2 yrs time to MMStime to MMS ∆ ∆QMG, MG-ADL at 1,2,3 yrsQMG, MG-ADL at 1,2,3 yrs ∆ ∆SF-36 at 1,2,3 yrsSF-36 at 1,2,3 yrs hospital days at 2 yrshospital days at 2 yrs

1° Composite AUQTC, AUDTC1° Composite AUQTC, AUDTC AEs at 3 yrsAEs at 3 yrs2° prednisone AUDTC at 1,2 yrs2° prednisone AUDTC at 1,2 yrs time to MMStime to MMS ∆ ∆QMG, MG-ADL at 1,2,3 yrsQMG, MG-ADL at 1,2,3 yrs ∆ ∆SF-36 at 1,2,3 yrsSF-36 at 1,2,3 yrs hospital days at 2 yrshospital days at 2 yrs

randomizerandomize

outcomeoutcomemeasuresmeasures

Thymectomy TrialThymectomy Trial79 centers in N. America, Europe, S. America, S. Africa, 79 centers in N. America, Europe, S. America, S. Africa, Asia, Australia (n=200)Asia, Australia (n=200)

New/future approachesNew/future approaches RituximabRituximab TerbutalineTerbutaline Monarsen/EN101Monarsen/EN101 Etanercept Etanercept Rowin et al. Rowin et al. NeurologyNeurology 2004;63:2390 2004;63:2390

TNFTNFαα receptor blocker receptor blocker 6/11 patients improved in pilot study (8 completed 6-6/11 patients improved in pilot study (8 completed 6-

month trial)month trial) 2/11 worsened, one requiring urgent PE2/11 worsened, one requiring urgent PE

Upregulation of TNFUpregulation of TNFαα levels levels Eculizimab Eculizimab

Monoclonal Ab, blocks C5 activationMonoclonal Ab, blocks C5 activation Phase II randomized DBPC crossover trialPhase II randomized DBPC crossover trial

MethotrexateMethotrexate Phase II DBPC trial Phase II DBPC trial

RituximabRituximab Monoclonal Ab to CD20Monoclonal Ab to CD20 Improvement within several weeks in case Improvement within several weeks in case

reportsreports Zaja et al. 2000; Wylam et al. 2003; Gajra et al. 2004Zaja et al. 2000; Wylam et al. 2003; Gajra et al. 2004

Benefit in ongoing studies/pilot trials in Benefit in ongoing studies/pilot trials in AChR/MuSK+ MGAChR/MuSK+ MG n=19 totaln=19 total Initial dosing 375 mg/mInitial dosing 375 mg/m2 2 q1-2 wks for 4 wks q1-2 wks for 4 wks Maintenance: none or 375 mg/mMaintenance: none or 375 mg/m2 2 q4-10 wksq4-10 wks Onset in 4-12 wksOnset in 4-12 wks

Rojas-Garcia et al., Tandan et al., Gardner et al., Rojas-Garcia et al., Tandan et al., Gardner et al., Frenay et al. (2008 AAN abstracts)Frenay et al. (2008 AAN abstracts)

RituximabRituximab Refractory MG Refractory MG (n=6 females, AChR or MuSK-Ab)(n=6 females, AChR or MuSK-Ab)

Unable to lower immunosuppressionUnable to lower immunosuppression Uncontrolled on immunosuppressionUncontrolled on immunosuppression Intolerable side effectsIntolerable side effects

1-4 cycles (q1-4 cycles (q 4-12 mos)4-12 mos) 375 mg/m375 mg/m2 2 weekly infusionsweekly infusions

ResultsResults 4/6 pts asymptomatic4/6 pts asymptomatic 1 pt with diplopia1 pt with diplopia 1 pt with dysarthria1 pt with dysarthria No significant side effectsNo significant side effects

Zebardast et al. Zebardast et al. Muscle Nerve Muscle Nerve 2010;41:3752010;41:375

RituximabRituximab AEsAEs

Skin: pruritis to pemphigus/Stevens-JohnsonSkin: pruritis to pemphigus/Stevens-Johnson Nausea, vomitingNausea, vomiting HeadacheHeadache Anemia, leukopenia, thromocytopeniaAnemia, leukopenia, thromocytopenia Chest painChest pain >25 PML cases in SLE/hematological >25 PML cases in SLE/hematological

malignancy patientsmalignancy patients Premedicate with acetaminophen, Premedicate with acetaminophen,

diphenhydraminediphenhydramine

Monarsen/EN101Monarsen/EN101

Antisense oligonucleotide to AchE Antisense oligonucleotide to AchE mRNAmRNA

Oral agentOral agent Prevents translationPrevents translation

mRNA susceptible to degradationmRNA susceptible to degradation Clinical effectiveness up to 72 hoursClinical effectiveness up to 72 hours

Sussman. Sussman. Drug Disc TodayDrug Disc Today 2003;8:516 2003;8:516

MonarsenMonarsenArgov et al. Argov et al. NeurologyNeurology 2007;69:699 2007;69:699

Open-label study Open-label study (n=16, 1 protocol violation)(n=16, 1 protocol violation) 500 500 µµg/kg/d x 3dg/kg/d x 3d AEs monitored for 1 monthAEs monitored for 1 month

ResultsResults 13/15 with improved QMG on day 413/15 with improved QMG on day 4 Mean Mean ΔΔQMG -6.13 pts (baseline 14.9)QMG -6.13 pts (baseline 14.9) Effects last 24-48 hrs after doseEffects last 24-48 hrs after dose 4 pts on Monarsen for 4 weeks maintained improvement 4 pts on Monarsen for 4 weeks maintained improvement

2 resumed pyridostigmine2 resumed pyridostigmine

AEsAEs 56% with transient dry mouth/eyes56% with transient dry mouth/eyes

Treatment of MGTreatment of MGSpecial scenariosSpecial scenarios

MG crisisMG crisis Hold anticholinesterases Hold anticholinesterases Plasma exchange (50cc/kg x 4-Plasma exchange (50cc/kg x 4-

6 exchanges)6 exchanges) IVIGIVIG

PregnancyPregnancy Pyridostigmine, steroids, PE, Pyridostigmine, steroids, PE,

IVIGIVIG

Ocular MGOcular MG Ptosis: crutches, tape, Ptosis: crutches, tape,

blepharoplastyblepharoplasty Diplopia: alternate patching, Diplopia: alternate patching,

prisms, surgeryprisms, surgery

Treatment of ocular symptomsTreatment of ocular symptomsRetrospective analysisRetrospective analysis

Corticosteroids vs. AChE inhibitorsCorticosteroids vs. AChE inhibitors n=35n=35 Rx: 14 epochs with AChE inhibitors, 27 epochs with Rx: 14 epochs with AChE inhibitors, 27 epochs with

corticosteroids (median prednisone dose 20 mg qd)corticosteroids (median prednisone dose 20 mg qd) Outcome: ocular items from QMGOutcome: ocular items from QMG ResultsResults

Ocular QMG improvement favored corticosteroids (3.6 Ocular QMG improvement favored corticosteroids (3.6 vs. 1.1 pt change; vs. 1.1 pt change; pp=0.0021)=0.0021)

Symptom resolution in 70% of steroid epochs vs. 29% Symptom resolution in 70% of steroid epochs vs. 29% AChE inhibitors epochsAChE inhibitors epochs

AEsAEs IGT in 67%IGT in 67% Reduced bone density in 20%Reduced bone density in 20%

Bhanushali, Wuu & Benatar. Bhanushali, Wuu & Benatar. NeurologyNeurology 2008;71:1335 2008;71:1335

MuSK Ab+ MG Treatment ResponseMuSK Ab+ MG Treatment Response Pasnoor et al. Pasnoor et al. Muscle & Nerve Muscle & Nerve 2010;41:3702010;41:370

52/53 pts required 52/53 pts required ≥2 ≥2 forms of therapyforms of therapy

5 Rx categories5 Rx categories PyridostigminePyridostigmine PrednisonePrednisone IS agentsIS agents PEPE IVIGIVIG

ImprovementImprovement MGFA Class 0MGFA Class 0 CSR/PR/MMSCSR/PR/MMS MGFA classification: ≥2 MGFA classification: ≥2

class improvementclass improvement

Rx Rx categoriescategories

% of pts% of pts

(n=53)(n=53)

55 3636

44 2323

33 2121

22 1919

MuSK Ab+ MG Treatment ResponseMuSK Ab+ MG Treatment Response Pasnoor et al. Pasnoor et al. Muscle & NerveMuscle & Nerve 2010;41:370 2010;41:370

AgentAgent PatientsPatients ImprovedImproved

%%

Improved as Improved as monotherapy (%)monotherapy (%)

ACEACE 8/518/51 1616 00

CorticosteroidsCorticosteroids 27/5127/51 5353 9/14 (64)9/14 (64)

Immunosuppressive Immunosuppressive agentsagents

16/3916/39AZA 7/17 AZA 7/17

MMF 8/17MMF 8/17

MTX 0/2MTX 0/2

CTX 1/3CTX 1/3

4141AZA 41AZA 41

MMF 47MMF 47

MTX 0MTX 0

CTX 33CTX 33

3/3 (100)3/3 (100)

IVIG IVIG 5/255/25 2020 00

Plasma exchangePlasma exchange 17/3317/33 5151 00

Treatment and outcomesTreatment and outcomesKawaguchi et al. Kawaguchi et al. J Neurol SciJ Neurol Sci 2004;224:43 2004;224:43

0

10

20

30

40

50

60

70

80

90n=470, 19 tertiary centers

thymectomy steroids other IS anti-AchE

Outcomes (mean f/u 8 yrs, minimum 1 yr)Remission 30%Ocular 35%Generalized 35% (only 4% with moderate to severe disability)MGFA 0-II increased from 78.7% to 96.7% (p<0.01)

perc

ent

MG vignetteMG vignette 69 yo former rodeo professional from Brooklyn, 69 yo former rodeo professional from Brooklyn,

NY with MGNY with MG Refractory bulbar symptomsRefractory bulbar symptoms

DysarthriaDysarthria DysphagiaDysphagia

Prior treatmentsPrior treatments Mestinon 60 mg tid to qidMestinon 60 mg tid to qid Prednisone diabetes, weight gainPrednisone diabetes, weight gain

Unable to taper below 40 mg qodUnable to taper below 40 mg qod Transsternal thymectomy (no thymoma)Transsternal thymectomy (no thymoma) Failed IVIGFailed IVIG No response to azathioprine ( LFTs), mycophenolateNo response to azathioprine ( LFTs), mycophenolate Requiring plasma exchange q 1-2 wks for disease controlRequiring plasma exchange q 1-2 wks for disease control

Lives on ranch 100 miles from UT SouthwesternLives on ranch 100 miles from UT Southwestern

Initiate and adjust pyridostigminefor maximal control

Options include:-Initiate pred alone or with steroid-sparing agent-Initiate MM or AZA as monotherapy, keeping in mind AZA's slow onset -Consider thymectomy

Continue pyridostigmine;Consider thymectomy

In remission

Not improved

-Initiate slow pred AD taper with objective of smallest dose that maintains improved status-Steroid-sparing agents can be tapered slowly over time as tolerated

Options include:-Initiate cyclosporine-Initiate IVIG or PE-Plan on thymectomy when stable

-Stop taper, initiate incremental increases in agent that has been lowered-High-dose steroids may need to be reinitiated

In case of relapse Improved

Not improved

Improved/ in remission

Not improved

Options include:-Long-term PE or IVIG-Cyclophosphamide-Tacrolimus-Rituximab

Treatment algorithm in generalized MGTreatment algorithm in generalized MG

Not in remission

Improved/ in remission

Lifetime Course of MGLifetime Course of MGGrob et al. Grob et al. Muscle NerveMuscle Nerve 2008;37:141 2008;37:141

David Grob, MD, 1919-2008David Grob, MD, 1919-2008

Transternal thymectomy Transternal thymectomy effect on remissioneffect on remission 1940-571940-57

Significant effect (20% Significant effect (20% vs. 10%)vs. 10%)

1958-19651958-1965 Similar remission and Similar remission and

improvement rates improvement rates 1966-20001966-2000

Slightly higher mortality Slightly higher mortality and lower remission and lower remission rates in thymectomy rates in thymectomy groupgroup

P values vs. 1940-57