Transcript state of the art treatment - Myasthenia Gravis Foundation of

The Treatment of MG:
State of the Art
May 2010
Gil I. Wolfe, M.D.
Univ. of Texas Southwestern
Medical Center
Dallas, TX
Therapy goals in MG

Return patients to normal function
Achieve remission
 Minimize side effects


Individualize therapy
Disease severity and distribution
 Rate of progression
 Lifestyle and career choices
 Coexisting disease
 Patient age and sex
 Cost considerations

Symptomatic Rx: Anticholinesterase
agents

Pyridostigmine
Initiate at 30-60 mg 3-4
times a day initially
 Clinical response in 15-30
min lasting 3-4 hrs
 t1/2 200 min (60 mg)
 Peak plasma levels in 1-2
hrs



Monitoring levels not useful
Individualize dosing

Dosing >120 mg every 3 hrs
unlikely to be helpful
Anticholinesterase agents

Countering muscarinic side effects
Glycopyrrolate 1 mg
 Hyoscyamine sulfate 0.125 mg
 Atropine 0.4 mg
 Loperamide 2-4 mg (OTC)

Can be given prn or on fixed schedule in
concert with pyridostigmine doses
ACE in MuSK Ab+ MG
MuSK
Ab +
Seroneg
AchR
Ab +
ACE nonresponse
10/14
71%
4/22
18%
13/73
18%
ACE
hypersens
3/14
1/22
0/73
Hypersensitivity-sx
worsen
Intolerance-severe
cholinergic AEs
No improvement
ACE
intolerance
4/14
2/22
13/73
No improve- 4/14
ment
1/22
0/73
Tensilon
test +
5/10
16/19
32/33
Hatanaka et al. Neurology
2005;65:1508
Pyridostig
response
3/14
21/22
71/73
Anticholinesterase
responses
Non-responsiveness



Corticosteroids
Ocular MG


n=147, retrospective
Prednisone titrated to 50-60
mg/d, tapered to 2.5-10 mg
qd or qod
Generalization at 2 yr f/u (n=94)
4/58 on prednisone (7%)
 13/36 untreated (36%)
p=.001

Kupersmith et al. Arch Neurol 2003;60:243
Immunosuppressive agents
Medication
Controlled studies
Azathioprine
+
Cyclosporine
+
Mycophenolate
+
Cyclophosphamide
+
Tacrolimus
+
IVIG
+
Azathioprine

Randomized, double-blind trial (n=34)

Palace et al. Neurology 1998;50:1778
Azathioprine 2.5 mg/kg qd vs. placebo
 All patients received prednisolone



1.5 mg/kg qod with 100 mg qod ceiling
At 2 & 3 yrs, prednisolone dose reduced in
AZA group (p=0.02)

>80% reduction at 2 yrs
Disease relapse rate lower in AZA group
(p=0.024)
 Side effects lower in AZA group

Azathioprine
Palace et al.
AZA
placebo
AZA
p =0.02 at 24 mo
placebo
Azathioprine

Steroid-sparing effects (Palace et al.)
Lower median weight gain at 2,3 yrs
 Less dyspepsia, back pain at 1,2,3 yrs
 30% reduction in steroid dose by 15 mos
 Temporal arteritis studies show 30%
reduction substantially reduces adverse
events



Nesher et al. Clin Exp Rheumatol 1997;15:303
Rubinow et al. Ann Ophthalmol 1984;16:258
Mycophenolate mofetil

Blocks IMP dehydrogenase/purine synthesis



Selective inhibition of B & T lymphocytes
Widely used in transplant medicine
Utility in MG
First-line agent
 Steroid-sparing agent


Dosing

500 mg bid initially, increasing to 1000-1500 mg
bid by 500-1000 mg increments every 2-4 wks
 Can
use tid regimen if diarrhea occurs
Mycophenolate mofetil

Adverse events
No major organ toxicity
 Diarrhea, nausea, abdominal pain
 Infections (PML)
 Peripheral edema
 Drug-induced fever
 Leukopenia



CBC q wk x 4, q2 wks x 4, then monthly
Neoplasia (lymphoma)

Primary CNS lymphoma after 3 yrs of treatment
Vernino et al. Neurology 2005;65:639


Lymphocytopenia (260/µL); CD4 158
Near complete resolution with d/c of MM, steroids,
rituximab
Mycophenolate mofetil

Retrospective analysis of 85 MG pts

14 pts considered “refractory”


Meriggioli et al. Neurology 2003;61:1438
Outcomes
73% remission/minimal manifestation/improved
 MMT/QMG scores improved significantly
 5/13 Class IV pts (38%) did not improve


Steroid dose
Reduced by > 50% in 23 pts
 Reduced by < 50% in 13 pts
 Unchanged in 14 pts
 Increased in 1 pt

Mycophenolate mofetil

Retrospective analysis of 85 MG pts

Onset of action relatively rapid

Improvement observed at 9-11 wks



May take up to 40 wks
Maximal improvement at mean of 27 wks
Tolerability
5/85 pts discontinued
 GI intolerance (diarrhea)
 No significant leukopenia


Meriggioli et al. Neurology 2003;61:1438
Mycophenolate mofetil
Randomized, double-blinded, controlled
studies in generalized AChRAb+ MG
MSG-Roche
Aspreva
Patients (n)
80
136
Duration
3 mo/6 mo open
label
9 mo
MM dose
1250 mg bid vs.
placebo
1000 mg bid vs.
placebo
Prednisone at entry
None
≥ 20 mg qd or qod
equivalent
Prednisone during study 20 mg qd
Primary outcome
Δ QMG score
Tapered to 7.5 mg qd
or 15 mg qod
Reaching MMS or PR
from wks 32-36
Mycophenolate mofetil

MSG-Roche study


No significant difference in ΔQMG at 3 mo


-4.4 on MM vs. -3.6 on placebo (p=0.71)
No significant difference in 2° outcomes


n=39 on pred/placebo; 41 on pred/MM
MG-ADL, MMT, SF-36, AChRAb levels
MM was well tolerated

Diarrhea in 16%, infection in 13% in blinded phase on
MM

Muscle Study Group. Neurology 2008;71:394
Mycophenolate mofetil

Aspreva study



No significant different in reaching treatment response of
MMS/PR


44.3% on MM vs. 38.6% on placebo (p=0.541)
No significant difference in 2° outcomes



n=88 on pred/placebo; 88 on pred/MM
n=144 completed study
QMG, MG-ADL, SF-36, global assessments
Trend for greater prednisone dose reduction, decline in AChRAb,
hospitalizations if on MM, but not significant
MM overall well tolerated


Headache (12%), nausea (9%) most common side effects
One death related to study drug (pneumonia in MM group)

Sanders et al. Neurology 2008;71:400
What did we learn about MMF
from these two studies?




MM is not better than prednisone alone as initial
treatment in mild-moderate MG, and has no
steroid-sparing effect within the timeframe of
these studies (up to 36 wks)
It may take longer than predicted to show benefit
from MM
Prednisone is more effective than predicted, and
at a lower dose than expected
Exacerbations after prednisone may also occur
at lower doses than expected
Tacrolimus (FK506)



Same pharmacologic class as cyclosporine
Less nephrotoxic
Utility in MG




Monotherapy (not “first-line”)
Steroid-sparing agent
Effects seen after 1-2 months
Dosing
 3-5 mg/d
Tacrolimus

16 wk open trial in
thymectomized generalized
MG (n=19)


QMG improved in 13/19


Fell at least 3 pts in 7/19
(used 27 pt version)
Therapy continued for 2
yrs in 12/19


Konishi et al. Muscle
Nerve 2003;28:570
Efficacy maintained
Adverse events


No change in serum Cr
Increased HbA1c in one pt
Tacrolimus

n=212 in open study





Ponseti et al. Ann NY Acad Sci 2008;1132:254
Dose: 0.1 mg/kg/d adjusted to 7-8 ng/ml
Assessments x4 in first month, then at
least every 3 months
Mean f/u 49.3 mo
Outcomes
Muscle strength
 QMG
 MGFA post-intervention status

Tacrolimus

MGFA PIS





QMG scores over time
p<0.05

13.7% complete stable
remission
73.8% pharmacologic
remission
5.4% minimal manifestation
status
Prednisone withdrawn in
95%
Favorable response
irrespective of
thymectomy or thymoma
Discontinuation from AEs
in 4.9%
Ponseti et al. 2008
Tacrolimus/CSA
Predictors of response



n=62 (56 generalized)
Retrospective analysis of 6 mo exposure
Response measures
> 3 pt QMG drop: 53%
 > 25% reduction in prednisolone: 49%


Predictors of response
Shorter disease duration (4.6 vs. 11.2 yrs)
 Thymoma (30% vs. 9%)


Nagane et al. Muscle Nerve 2010;41:212
Tacrolimus

Adverse events










Hyperglycemia
Hypertension
Headache
Hyperkalemia
Nephrotoxicity
Nausea/vomiting/diarrhea
Infection
Lymphoma
Drug interactions similar to CSA
Monitoring

BUN/Cr, glu, K+, trough drug levels (<10 ng/ml)

Every 2-4 weeks initially, then less frequently
Thymectomy Trial
79 centers in N. America, Europe, S. America, S. Africa,
Asia, Australia (n=200)
AChRAb+, Class II-IV
No thymoma, 18-65 yo
XTS + IS
prednisone
1.5 mg/kg AD
IS alone
prednisone
1.5 mg/kg AD
randomize
MMS: prednisone taper
1° Composite AUQTC, AUDTC,
AEs at 3 yrs
2° prednisone AUDTC at 1,2 yrs
time to MMS
∆QMG, MG-ADL at 1,2,3 yrs
∆SF-36 at 1,2,3 yrs
hospital days at 2 yrs
MMS: prednisone taper
outcome
measures
1° Composite AUQTC, AUDTC
AEs at 3 yrs
2° prednisone AUDTC at 1,2 yrs
time to MMS
∆QMG, MG-ADL at 1,2,3 yrs
∆SF-36 at 1,2,3 yrs
hospital days at 2 yrs
New/future approaches




Rituximab
Terbutaline
Monarsen/EN101
Etanercept Rowin et al. Neurology 2004;63:2390



TNFα receptor blocker
6/11 patients improved in pilot study (8 completed 6month trial)
2/11 worsened, one requiring urgent PE



Upregulation of TNFα levels
Eculizimab
 Monoclonal Ab, blocks C5 activation
 Phase II randomized DBPC crossover trial
Methotrexate
 Phase II DBPC trial
Rituximab


Monoclonal Ab to CD20
Improvement within several weeks in case
reports


Zaja et al. 2000; Wylam et al. 2003; Gajra et al. 2004
Benefit in ongoing studies/pilot trials in
AChR/MuSK+ MG




n=19 total
Initial dosing 375 mg/m2 q1-2 wks for 4 wks
Maintenance: none or 375 mg/m2 q4-10 wks
Onset in 4-12 wks

Rojas-Garcia et al., Tandan et al., Gardner et al.,
Frenay et al. (2008 AAN abstracts)
Rituximab

Refractory MG (n=6 females, AChR or MuSK-Ab)




1-4 cycles (q 4-12 mos)


Unable to lower immunosuppression
Uncontrolled on immunosuppression
Intolerable side effects
375 mg/m2 weekly infusions
Results




4/6 pts asymptomatic
1 pt with diplopia
1 pt with dysarthria
No significant side effects

Zebardast et al. Muscle Nerve 2010;41:375
Rituximab

AEs
Skin: pruritis to pemphigus/Stevens-Johnson
 Nausea, vomiting
 Headache
 Anemia, leukopenia, thromocytopenia
 Chest pain
 >25 PML cases in SLE/hematological
malignancy patients


Premedicate with acetaminophen,
diphenhydramine
Monarsen/EN101
 Antisense
oligonucleotide to AchE
mRNA
 Oral agent
 Prevents translation
 mRNA susceptible to degradation
 Clinical effectiveness up to 72 hours

Sussman. Drug Disc Today 2003;8:516
Monarsen
Argov et al. Neurology 2007;69:699

Open-label study (n=16, 1 protocol violation)



500 µg/kg/d x 3d
AEs monitored for 1 month
Results




13/15 with improved QMG on day 4
Mean ΔQMG -6.13 pts (baseline 14.9)
Effects last 24-48 hrs after dose
4 pts on Monarsen for 4 weeks maintained improvement


2 resumed pyridostigmine
AEs

56% with transient dry mouth/eyes
Treatment of MG
Special scenarios

MG crisis




Pregnancy


Hold anticholinesterases
Plasma exchange (50cc/kg x 46 exchanges)
IVIG
Pyridostigmine, steroids, PE,
IVIG
Ocular MG


Ptosis: crutches, tape,
blepharoplasty
Diplopia: alternate patching,
prisms, surgery
Treatment of ocular symptoms
Retrospective analysis





Corticosteroids vs. AChE inhibitors
n=35
Rx: 14 epochs with AChE inhibitors, 27 epochs with
corticosteroids (median prednisone dose 20 mg qd)
Outcome: ocular items from QMG
Results



Ocular QMG improvement favored corticosteroids (3.6
vs. 1.1 pt change; p=0.0021)
Symptom resolution in 70% of steroid epochs vs. 29%
AChE inhibitors epochs
AEs


IGT in 67%
Reduced bone density in 20%

Bhanushali, Wuu & Benatar. Neurology 2008;71:1335
MuSK Ab+ MG Treatment Response
Pasnoor et al. Muscle & Nerve 2010;41:370


52/53 pts required ≥2
forms of therapy
5 Rx categories






Pyridostigmine
Prednisone
IS agents
PE
IVIG
Improvement



MGFA Class 0
CSR/PR/MMS
MGFA classification: ≥2
class improvement
Rx
categories
5
% of pts
(n=53)
36
4
23
3
21
2
19
MuSK Ab+ MG Treatment Response
Pasnoor et al. Muscle & Nerve 2010;41:370
Agent
Patients
Improved as
monotherapy (%)
8/51
Improved
%
16
ACE
Corticosteroids
27/51
53
9/14 (64)
Immunosuppressive
agents
16/39
41
3/3 (100)
AZA 7/17
MMF 8/17
MTX 0/2
CTX 1/3
AZA 41
MMF 47
MTX 0
CTX 33
IVIG
5/25
20
0
Plasma exchange
17/33
51
0
0
Treatment and outcomes
Kawaguchi et al. J Neurol Sci 2004;224:43
90
n=470, 19 tertiary centers
80
percent
70
60
50
40
30
20
10
0
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)
MG vignette
69 yo former rodeo professional from Brooklyn,
NY with MG

Refractory bulbar symptoms



Dysarthria
Dysphagia
Prior treatments


Mestinon 60 mg tid to qid
Prednisone
diabetes, weight gain





Unable to taper below 40 mg qod
Transsternal thymectomy (no thymoma)
Failed IVIG
No response to azathioprine ( LFTs), mycophenolate
Requiring plasma exchange q 1-2 wks for disease control

Lives on ranch 100 miles from UT Southwestern
Treatment algorithm in generalized MG
Initiate and adjust pyridostigmine
for maximal control
Not in remission
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
Improved/
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
In case of relapse
Continue pyridostigmine;
Consider thymectomy
Options include:
-Initiate cyclosporine
-Initiate IVIG or PE
Improved/
in remission -Plan on thymectomy when stable
Improved
-Stop taper, initiate incremental increases
in agent that has been lowered
-High-dose steroids may need to be
reinitiated
Not improved
Not
improved
Options include:
-Long-term PE or IVIG
-Cyclophosphamide
-Tacrolimus
-Rituximab
Lifetime Course of MG
Grob et al. Muscle Nerve 2008;37:141
David Grob, MD, 1919-2008
Transternal thymectomy
effect on remission

1940-57


1958-1965


Similar remission and
improvement rates
1966-2000

P values
vs. 1940-57
Significant effect (20%
vs. 10%)
Slightly higher mortality
and lower remission
rates in thymectomy
group