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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