pearls and pitfalls: using immunosuppressive medications
TRANSCRIPT
2021
Pearls and Pitfalls: Using Immunosuppressive
Medications in Myasthenia Gravis
Christyn Edmundson, MD
2021
Financial Disclosure• Dr. Edmundson has received consulting fees from Alexion, Argenx and Morgan Stanley
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Objectives• Review the use of corticosteroids and steroid-sparing immunosuppressives in
myasthenia gravis. • Review guidelines for use, dose initiation, adverse reactions and monitoring parameters. • Touch on the implications of immunosuppression in today‘s world (COVID19
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Outline• MG Intro• Corticosteroids• Oral IS• Rapid acting therapies• Emerging and targeted therapies
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Case 1• 28yo woman presents for a second opinion for management of myasthenia gravis. • 2 years prior she developed ptosis, diplopia and fatigable arm and leg weakness.• She was seen by an ophthalmologist who sent acetylcholine receptor (AChR) antibodies,
which were positive. • CT Chest showed no thymoma.
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Myasthenia Gravis• Disorder of the post-synaptic
neuromuscular junction
• Caused by antibody mediated attack on membrane proteins
• Characterized by fluctuating weakness in ocular, limb and respiratory muscles.
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Myasthenia GravisDistinguish:
• Thymomatous v. non-thymomatous
• Ocular v. Generalized
• Serostatus (AChR, MuSK, LRP4, seronegative)
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Case 1• 28yo woman presents for a second opinion for management of myasthenia gravis.
• 6 months prior she developed ptosis, diplopia and fatigable arm and leg weakness.Generalized
• She was seen by an ophthalmologist who sent acetylcholine receptor (AChR) antibodies, which were positive.
Seropositive• CT Chest showed no thymoma.
Nonthymomatous
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MG Treatment GoalsAchieve:
• Remission or minimal manifestations
• With minimal side effects from medications
Narayanaswami et al. Neurology. 2021 Jan 19; 96(3): 114–122. Sanders et al. Neurology. 2016 Jul 26;87(4):419-25.
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Note on Myasthenic CrisisManifest Crisis: Worsening of myasthenic weakness requiring intubation or noninvasive ventilation to avoid intubation.
Impending Crisis: Rapid clinical working of MG that could lead to crisis in days to weeks.
• Treatment: Hospitalization, treatment with rapid-acting therapy (PLEX/IVIG), supportive care (NG tube, intubation, etc)
• Remainder of this talk addresses chronic management, not management of MG crisis
Sanders et al. Neurology. 2016 Jul 26;87(4):419-25.
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Pyridostigmine (Mestinon)• Acetylcholinesterase inhibitor: prevents breakdown of ACh in the synaptic cleft• Short-acting: typically dosed 30-120mg q4h or ER at bedtime• NOT disease modifying: Used to treat ocular MG, mild generalized MG, or in concert
with immunotherapy in more severe disease• Common side effects: diarrhea, nausea, muscle twitching, secretions. Rarely cholinergic
crisis
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Case 1Our Patient: 28yo F with ~2 years of generalized, seropositive (AChR Abs), non-thymomatous, myasthenia gravis
• On diagnosis, pyridostigmine started -> partial improvement in arm/leg weakness • Corticosteroids or IS therapy should be used in all patients with MG who have not met
treatment goals after an adequate trial of pyridostigmine
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Case 1Our Patient: 28yo F with ~2 years of generalized, seropositive (AChR Abs), non-thymomatous, myasthenia gravis
• On diagnosis, pyridostigmine started -> partial improvement in arm/leg weakness • Decision made to start prednisone
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Corticosteroids/glucocorticoids• Reduce inflammation by promoting synthesis of anti-inflammatory proteins, and
inhibiting transcription of inflammatory genes
• Rapid-intermediate onset effect in MG (2-3 weeks)
• High doses cause transient worsening in ~50% of MG patientso Start low, go slow (start prednisone 20mg daily and increase daily dose by 5mg per week until reaching ~1mg/kg dailyo If started immediately after PLEX/IVIG, can initiate at high dose (50-80mg daily)
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Corticosteroids/glucocorticoids• Side Effects: Many, particularly at high doses.
• Monitoring:o HbA1c every few monthso Blood pressureo Bone density monitoring (vitamin D ppx)o Eye exams for glaucoma/cataracts
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Case 1Our Patient: 28yo F with ~2 years of generalized, seropositive (AChR Abs), non-thymomatous, myasthenia gravis • On diagnosis, pyridostigmine started -> partial improvement in arm/leg weakness• Started prednisone 20mg daily, gradually uptitrated to 50mg daily -> improvement in
generalized weakness and ocular symptoms but ongoing fluctuating weakness. • Referred for thymectomy ~6 months after diagnosis.
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Thymectomy in MG• Thymomatous MG: Thymectomy indicated
• Non-thymomatous, generalized AChR Ab positive MG:o Single-blind RCT showed thymectomy improves clinical outcome (better clinical scores, lower prednisone dose).o Consider thymectomy in such patients 18–50 years, early in disease. o Strongly consider thymectomy in such patients who fail to respond initial immunotherapy or have intolerable side effects.o Thymectomy is elective and should be performed when the patient is overall stable.
• Seronegative: May consider thymectomy if refractory
• Ocular: May consider thymectomy if refractory and AChR Abs +
• MuSK or LRP4 Abs +: No clear benefit
Wolfe. N Engl J Med 2016;375(6):511–522.Narayanaswami et al. Neurology. 2021 Jan 19; 96(3): 114–122.
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Case 1Our Patient: 28yo F with ~2 years of generalized, seropositive (AChR Abs), non-thymomatous, myasthenia gravis • On diagnosis, pyridostigmine started -> partial improvement in arm/leg weakness• Started prednisone -> partial improvement• Post-thymectomy, mild fatigable arm and leg weakness, intermittent diplopia and ptosis. • Experiencing weight gain, easy bruising, cushingoid appearance. • Attempts to wean prednisone result in symptom exacerbation.
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Case 1Our Patient: 28yo F with ~2 years of generalized, seropositive (AChR Abs), non-thymomatous, myasthenia gravis
• Nonsteroidal IS agent should be used INITIALLY with corticosteroids when the risk of side effects is high.
• Nonsteroidal IS agent should be ADDED when: o Steroid response is inadequateo Steroid dose can’t be reduce o Significant steroid side effects develop
• In rare cases Nonsteroidal IS may be started alone
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Most Common Oral IS• Mycophenolate Mofetil• Azathioprine
• Methotrexate – data lacking but may be considered
• Cyclosporine/tacrolimus – data also limited, rarely use
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Mycophenolate Mofetil• Mechanism: Suppresses cell-mediated immune response and Ab formation.
• Time to therapeutic effect: 2-3 months at the earliest, usually closer to 6 months.
• Drug initiation: o Start 500mg BIDo Increase to 1000mg BID after ~2 weeks, may increase as high as 1500mg BID
• Side effects: diarrhea, vomiting, leukopenia.o Contraindicated in pregnancy
• Monitoring:o CBC weekly for 1 month, monthly for 1 year, then q3 months or so.
Sanders et al. Neurology. 2016 Jul 26;87(4):419-25.
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Azathioprine • Mechanism: Blocks nucleotide synthesis and T-lymphocyte proliferation.
• Time to therapeutic effect: 6-10 months for initial effect, up to 2 years for maximal benefit.
• Drug initiation:o Check TPMT enzyme activity if possible o Start 50mg dailyo Increase by 50mg every 1-2 weeks to target dose of 2.5-3mg/kg/day
• Side effects: idiosyncratic flu-like reaction (up to 10%), non-melanomatous skin cancers, leukopenia, hepatotoxicity, pancreatitiso Considered acceptable in pregnancy by most experts.
• Monitoring:o CBC and LFTs weekly for 1 month, then every 1-3 months.
Sanders et al. Neurology. 2016 Inman et al. Nature Communications. 2018.
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Infections and prophylaxis• Potpential screening prior to immunosuppression (I check all of these before any IS):
o Hep B – especially rituximabo Hep Co HIVo TB
• PCP: Prophylaxis if on nonsteroidal IS PLUS prednisone 20mg dailyo Bactrim, atovaquone, dapsone
• COVID: MG patients still need to be treatedo Counsel regarding risks of immunosuppression and COVID exposureo Try to vaccinate fully prior to initiating immunosuppressiono Booster dose for Pfizer and Moderna
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Case 1Our Patient: 28yo F with ~2 years of generalized, seropositive (AChR Abs), non-thymomatous, myasthenia gravis • On diagnosis, pyridostigmine started -> partial improvement in arm/leg weakness• Started prednisone -> partial improvement• s/p thymectomy.• Ongoing symptoms, inability to wean prednisone, steroid SE. • Tried azathioprine, developed flu-like reaction. • Started mycophenolate mofetil 500mg BID, increased to 1000mg BID.
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Case 1Our Patient: 28yo F with ~2 years of generalized, seropositive (AChR Abs), non-thymomatous, myasthenia gravis • On diagnosis, pyridostigmine started -> partial improvement in arm/leg weakness• Started prednisone -> partial improvement. S/p thymectomy.• Ongoing symptoms, inability to wean prednisone, steroid SE. • Did not tolerate azathioprine. • Started mycophenolate mofetil 500mg BID, increased to 1000mg BID -> after 6
months symptoms improved further, but she continued to have symptom exacerbation with attempted steroid wean.
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Refractory Myasthenia Gravis• Persistent symptoms after:
o Corticosteroids AND
o Trial of at least 2 other steroid sparing agents• used in adequate doses for an adequate duration or• with side effects that limit functioning
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Case 1Our Patient: 28yo F with ~2 years of generalized, seropositive (AChR Abs), non-thymomatous, myasthenia gravis • On diagnosis, pyridostigmine started -> partial improvement in arm/leg weakness• Started prednisone -> partial improvement. S/p thymectomy.• Ongoing symptoms, inability to wean prednisone, steroid SE. • Did not tolerate azathioprine. • Started mycophenolate mofetil 500mg BID, increased to 1000mg BID -> persistent
symptoms and steroid dependence. • At this point, presents to my clinic for consideration of complement inhibition.
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Complement Inhibition• C5a – recruits pro-inflammatory cytokines• C5b – facilitates formation of membrane attack complex
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Eculizumab• Mechanism: Monoclonal antibody which inhibits enzymatic cleavage of C5. Approved for generalized,
AChR Ab+ MG.
• Time to therapeutic effect: Rapid acting, within weeks in many patients
• Drug initiation:o Requires vaccination for N. meningidities A and B
• Wait 2 weeks after 1st dost, or abx prophylaxis until 2 weeks after 1st dose• Must give boosters for duration of therapy
o Start 900mg IV weekly x4 weekso Then 1200mg IV on week 5 and q2 weeks thereafter
• Side effects: meningococcal infection, other infections (particularly encapsulated bacteria), infusion reaction, headache, diarrhea, nausea.
• Monitoring: No routine monitoring. Often on other agents requiring lab check.
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Eculizumab• Benefits:
o Rapid actingo Clinical response in >75% of refractory MG patientso MMS or Remission in ~50% of refractory MG patients
• Downsides:o Infecious SEo Cost ~700k per year ($60,000 per month) in the United Stateso Limited data on monotherapy, discontinuation (rebound?), duration of therapy needed, etco Frequent dosing. Note: multiple other complement inhibitors in the pipeline.
• Ravulizumab, q2 month maintenance dosing• Zilucoplan, daily SQ dosing
• Current role in treatment: o Should be considered in the treatment of severe, refractory, AChR-Ab+ generalized MG. o In clinical practice is sometimes used earlier (though difficult to get covered by insurance)
Howard et al. Lancet Neurology. 2017 Narayanaswami et al. Neurology. 2021 Jan 19; 96(3): 114–122.
2021
Case 1Our Patient: 28yo F with ~2 years of generalized, seropositive (AChR Abs), non-thymomatous, myasthenia gravis • On diagnosis, pyridostigmine started -> partial improvement in arm/leg weakness• Started prednisone -> partial improvement. S/p thymectomy.• Ongoing symptoms, inability to wean prednisone, steroid SE. • Did not tolerate azathioprine. • Started mycophenolate mofetil 500mg BID, increased to 1000mg BID -> persistent symptoms
and steroid dependence. • Started on eculizumab (after Men A+B vaccination) -> Rapid improvement in symptoms. • At 2 months after initiation achieved MMS, prednisone was weaned to <10mg/day, azathioprine
wean started.
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Weaning IS TherapyCorticosteroids:• Gradually taper once patients achieve treatment goals.• Low dose long-term can help to maintain the treatment goal.
Nonsteroidal IS:• Once treatment goals have been achieved and maintained for 6 months to 2 years, the
IS dose should be tapered slowly to the minimal effective amount. • Dosage adjustments every 3–6 months at the fastest.
If MG flares, many patients can get back to pharmacologic remission or MMS, but not all.• As with medication initiation, weaning must be tailored to individual patient
Sanders et al. Neurology. 2016 Jul 26;87(4):419-25.
2021
Case 2• 36yo woman with several months of fluctuating diplopia, ptosis, proximal arm/leg
weakness and occasional dysphagia. • NCS with rep stim showed decrement c/w an NMJ disorder. • AChR antibodies were negative. MuSK antibodies were positive.
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MuSK+ Myasthenia Gravis• Often more severe and difficult to treat.
• Many patients respond poorly to pyridostigmine.
• Patients respond well to PLEX, while IVIg seems to be less effective.
• Patients tend to remain dependent on prednisone despite concomitant treatment with steroid sparing agents.
• Often responds well to Rituximab, which should be considered as an early therapeutic option.
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Case 2• 36yo woman with several months of fluctuating diplopia, ptosis, proximal arm/leg
weakness and occasional dysphagia. Found to have MUSK+ MG.• Pyridostigmine started with minimal effect. Simultaneously prednisone started 20mg
daily, gradually increased to 60mg daily.• On follow up 2 months later she is visibly dyspneic and reports that she has been unable
to take POs the past several days due to dysphagia. • Reported that she was recently diagnosed with a UTI and started on ciprofloxacin.• Admitted directly from clinic for impending myasthenic crisis.
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PLEX and IVIg for MG CrisisPlasma Exchange (PLEX):• Mxn: Direct removal of antibodies
• Treatment regimen: 5-6 exchanges on QOD
• Time to effect: 2-3 exchanges
• Side effects: complication of catheters, fluid shifts. Contraindicated in sepsis and hypotension.
IV Immunoglobulin (IVIg):• Mxn: Multiple proposed mechanisms
• Treatment regimen: 1-2gm/kg over 2-5 days
• Time to effect: 1-2 weeks
• Side effects: idiosyncratic reactions, aseptic meningitis, thrombosis, fluid overload.
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PLEX versus IVIg• Clinical trials suggest they are equally effective for myasthenic crisis
• Expert consensus suggests that PLEX is more effective and works more quickly.
• The choice between PLEX and IVIg depends on individual patient factors and availability/institutional factors.
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IVIg and PLEX Maintenance• IVIg:
o Considered for patients with refractory MG, or when IS are contraindicated.o Maintenance dose: 0.4-1gm/kg q4 weeks. Dose and frequency can be adjusted depending on response. o Monitoring: BUN/Creat monthly initially, then q3-6 months. t/c checking IgA level
• PLEXo Uncommonly used for maintenance. t/c PORT or peripheral PLEX to avoid complication of catheters.o Maintenance dose: tailored to patiento Monitoring: catheter for infection
• Not immunosuppressive• Issues with insurance coverage• Requires specialized nursing care
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Case 2• 36yo woman with several months of fluctuating diplopia, ptosis, proximal arm/leg
weakness and occasional dysphagia. Found to have MUSK+ MG.• Pyridostigmine and prednisone started -> UTI + impending crisis leading to
hospitalization.• Required intubation in the ER, admitted to the NICU.• Treated with 5 sessions of PLEX over 10 days. • Extubated. Generalized and ocular symptoms improved with PLEX but remained on
high dose prednisone and significantly symptomatic on discharge.
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Rituximab• Mechanism: Anti-CD20 monoclonal antibody
• Time to therapeutic effect: ~3-6 months
• Drug initiation: o Traditionally 1000mg IV x2 divided by 2 weeks. Some emerging data that lower doses may be
equally effective.o Repeat q6-12 months.
• Side effects: Infusion reaction, infection
• Monitoring:o Hep B prior to initiation, ongoing monitoring/prophylaxis depending on serostatuso CBC at baseline and every 2-4 monthso Some clinicians monitor CD20 levels and quantitative immunoglobulins
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Rituximab• Little prospective data.
• International consensus guidelines:o Consider early in MuSK+ MGo May be considered in refractory AChR+ MG
• May be more effective early in disease course.
Hehir et al. Neurology. 2017;89:1069–1077. Narayanaswami et al. Neurology. 2021 Jan 19; 96(3): 114–122.
Brauner et al. JAMA Neurology. 2020;77(8)
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Case 2• 36yo woman with several months of fluctuating diplopia, ptosis, proximal arm/leg
weakness and occasional dysphagia. Found to have MUSK+ MG.• Pyridostigmine and prednisone started -> UTI + impending crisis leading to
hospitalization.• Required intubation. PLEX with improvement. Remained symptomatic on high-dose
prednisone.• After checking Hep B serostatus, she was treated with Rituximab 1000mg IV x2 over 2
weeks. • Infusion tolerated well. Over the following 4-6 months, symptoms improved markedly
and prednisone was weaned to <20mg daily.
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Infections and prophylaxis• Potpential screening prior to immunosuppression (I check all of these before any IS):
o Hep B – especially rituximabo Hep Co HIVo TB
• PCP: Prophylaxis if on nonsteroidal IS PLUS prednisone 20mg dailyo Bactrim, atovaquone, dapsone
• COVID: MG patients still need to be treatedo Counsel regarding risks of immunosuppression and COVID exposureo Try to vaccinate fully prior to initiating immunosuppressiono Booster dose for Pfizer and Moderna
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Case 2• 36yo woman with several months of fluctuating diplopia, ptosis, proximal arm/leg
weakness and occasional dysphagia. Found to have MUSK+ MG.• Pyridostigmine and prednisone started -> UTI + impending crisis leading to
hospitalization.• Required intubation. PLEX with improvement. Remained symptomatic on high-dose
prednisone.• Treated with Rituximab 1000mg IV x2 over 2 weeks -> symptomatic improvement
allowing prednisone wean. • Patient initially declined COVID19 vaccine once it first became available. • Unfortunately contracted and died of COVID in May of this year.
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Experimental Therapies• FcRn Inhibitors
• New data for efficacy of efgartigimod in MG
Howard et al.Lancet Neurology. 2021;20(7):527-536
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Future Immunotherapies in MG• CV-MG01 – vaccine that induces anti-AChR Ab. • CFZ533 – anti-CD40 Ab that blocks B cell activity.• Belimumab – inhibits B-cell activating factor.• And more….
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Cost ComparisonDrug Administration CostPrednisone Daily PO ~$15/monthAzathioprine Daily or BID PO ~$200/monthMycophenolate Mofetil
BID PO ~$350/month
IVIG Q2-4 weeks IV $20-35,000/course (2gm/kg)PLEX Q1-4 weeks $20-35,000/course (5 exchanges)Rituximab Q6-12 months IV $20-40,000 annually
+infusion costsEculizumab IV weekly x4 weeks,
then every 2 weeks~$60,000/month+infusion costs
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References• Ciafaloni, E. Myasthenia Gravis and Congenital Myasthenic
Syndromes. Continuum 2019 Dec; 25(6):1767-1784.
• Brauner, et al. Comparison Between Rituximab Treatment for New-Onset Generalized Myasthenia Gravis and Refractory Generalized Myasthenia Gravis. JAMA Neurology 2020;77(8):974-981
• Hehir MK, Burns TM, Alpers J, et al. Mycophenolate mofetil in AChR-antibody-positive myasthenia gravis: outcomes in 102 patients. Muscle Nerve. 2010;41(5):593.
• Hehir MK, Hobson-Webb LD, Benatar M, et al. Rituximab as treatment for anti-MuSK myasthenia gravis: multicenter blinded prospective review. Neurology 2017;89:1069–1077.
• Howard JF, Bril V, Vu T, et al. Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): a multicentre, randomised, placebo-controlled, phase 3 trial. Lancet Neurology. 2021;20(7):527-536
• Howard JF, Utsugisawa K, Benatar M et al. Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study. Lancet Neurol. 2017; 16: 976-986
• Inman GJ, Wang J, Nagano A, et al. The genomic landscape of cutaneous SCC reveals drivers and a novel azathioprine associated mutational signature. Nature Communications. 2018.
• Narayanaswami P, Sanders DB, Wolfe G, et al. International Consensus Guidance for Management of Myasthenia Gravis: 2020 Update. Neurology 2021 Jan 19;96(3):114-122.
• Sanders DB, Wolfe GI, Benatar M, et al. International consensus guidance for management of myasthenia gravis: executive summary. Neurology 2016;87:419–425
• Wolfe GI, Kaminski HJ, Aban IB, et al. Randomized trial of thymectomy in myasthenia gravis. N Engl J Med 2016;375:511–522
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