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The Treatment of MG: State of the Art May 2010

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

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The Treatment of MG: State of the Art May 2010

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  1. The Treatment of MG: State of the ArtMay 2010 Gil I. Wolfe, M.D. Univ. of Texas Southwestern Medical Center Dallas, TX

  2. 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

  3. 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

  4. 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

  5. ACE in MuSK Ab+ MG Anticholinesterase responses Non-responsiveness • Hypersensitivity-sx worsen • Intolerance-severe cholinergic AEs • No improvement Hatanaka et al. Neurology 2005;65:1508

  6. 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

  7. Immunosuppressive agents

  8. 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

  9. AzathioprinePalace et al. AZA placebo placebo AZA p =0.02 at 24 mo

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. Mycophenolate mofetilRandomized, double-blinded, controlled studies in generalized AChRAb+ MG

  16. Mycophenolate mofetil • MSG-Roche study • n=39 on pred/placebo; 41 on pred/MM • 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 • 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

  17. Mycophenolate mofetil • Aspreva study • n=88 on pred/placebo; 88 on pred/MM • n=144 completed 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 • 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

  18. 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

  19. 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

  20. Tacrolimus • 16 wk open trial in thymectomized generalized MG (n=19) • Konishi et al. Muscle Nerve 2003;28:570 • 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 • Efficacy maintained • Adverse events • No change in serum Cr • Increased HbA1c in one pt

  21. 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

  22. Tacrolimus • MGFA PIS • 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% QMG scores over time p<0.05 Ponseti et al. 2008

  23. Tacrolimus/CSAPredictors 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

  24. 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

  25. Thymectomy Trial 79 centers in N. America, Europe, S. America, S. Africa, Asia, Australia (n=200) AChRAb+, Class II-IVNo thymoma, 18-65 yo XTS + ISprednisone 1.5 mg/kg AD randomize IS aloneprednisone 1.5 mg/kg AD MMS: prednisone taper 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 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 outcome measures

  26. New/future approaches • Rituximab • Terbutaline • Monarsen/EN101 • EtanerceptRowin et al. Neurology 2004;63:2390 • TNFα receptor blocker • 6/11 patients improved in pilot study (8 completed 6-month 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

  27. 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)

  28. Rituximab • Refractory MG (n=6 females, AChR or MuSK-Ab) • Unable to lower immunosuppression • Uncontrolled on immunosuppression • Intolerable side effects • 1-4 cycles (q 4-12 mos) • 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

  29. 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

  30. 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

  31. MonarsenArgov 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

  32. Treatment of MGSpecial scenarios • MG crisis • Hold anticholinesterases • Plasma exchange (50cc/kg x 4-6 exchanges) • IVIG • Pregnancy • Pyridostigmine, steroids, PE, IVIG • Ocular MG • Ptosis: crutches, tape, blepharoplasty • Diplopia: alternate patching, prisms, surgery

  33. Treatment of ocular symptomsRetrospective 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

  34. MuSK Ab+ MG Treatment ResponsePasnoor 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

  35. MuSK Ab+ MG Treatment ResponsePasnoor et al. Muscle & Nerve 2010;41:370

  36. Treatment and outcomesKawaguchi et al. J Neurol Sci 2004;224:43 n=470, 19 tertiary centers percent 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)

  37. 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

  38. Treatment algorithm in generalized MG Initiate and adjust pyridostigmine for maximal control Not in remission 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 Continue pyridostigmine; 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 Options include: -Initiate cyclosporine -Initiate IVIG or PE -Plan on thymectomy when stable Improved/ in remission In case of relapse Improved Not improved Options include: -Long-term PE or IVIG -Cyclophosphamide -Tacrolimus -Rituximab -Stop taper, initiate incremental increases in agent that has been lowered -High-dose steroids may need to be reinitiated Not improved

  39. Lifetime Course of MGGrob et al. Muscle Nerve 2008;37:141David Grob, MD, 1919-2008 Transternal thymectomy effect on remission • 1940-57 • Significant effect (20% vs. 10%) • 1958-1965 • Similar remission and improvement rates • 1966-2000 • Slightly higher mortality and lower remission rates in thymectomy group P values vs. 1940-57

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