Myasthenia Gravis
Weekly Recap 19
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Chapter 440: Myasthenia Gravis and other Disease of the Neuromuscular Junction
Myasthenia Gravis
Is defined as:
A neuromuscular junction (NMJ) disorder characterized by weakness and fatigability of skeletal muscles
The underlying defect is the:
Decrease in the number of available acetylcholine receptors (AchRs) at NMJs due to an antibody- mediated autoimmune attack
Core defects in MG:
Decrease in the number of available AchRs at the postsynaptic muscle membrane
Flattening or “simplified” postsynaptic folds
Core defects in MG would lead to:
Decreased efficiency of neuromuscular transmission thus leading to weakness in muscle contraction
Edrophonium Test
Is the most commonly used drug for diagnostic testing of MG
Initial dose: 2 mg IV
Improvement of muscle strength: is a (+) result for MG
Test should be discontinued
Additional 8 mg IV
Should be given if there is no change seen after the initial dose is given
Endpoint to evaluate the effect of edrophonium:
Weakness of extraocular muscles
Impairment of speech
Length of time that the patient can maintain the arms forward
Onset: 30 sec
Duration of effect: 5 minutes
Side effects of edrophonium:
Nausea
Diarrhea
Salivation
Fasciculations
Syncope
Bradycardia
Underlying Defects:
Myasthenia Gravis:
Decreasing numbers of acetylcholine receptors at neuromuscular junction due to an antibody mediated attack.
Parkinson’s Disease:
Degeneration of dopaminergic neurons in the substansia nigra.
Multiple Sclerosis
Demyelination
Myasthenic Crisis
Is the exacerbation of weakness sufficient to endanger life including:
Ventilatory failure due to diaphragmatic and intercostal muscle weakness
Possible cause:
Excessive anticholinesterase medication or “cholinergic crisis”
Intercurrent infection: most common cause of crisis
Management of myasthenic crisis:
Plasmapheresis
IVIg
Now Let’s Dive into: ADAPT Trial
Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis: a multicentre, randomised, placebo-controlled, phase 3 trial.
(Reference: Howard, J. F., Bril, V., Vu, T., Karam, C., Peric, S., Margania, T., Murai, H., Bilinska, M., Shakarishvili, R., Smilowski, M., Guglietta, A., Ulrichts, P., Vangeneugden, T., Utsugisawa, K., Verschuuren, J., Mantegazza, R., de Bleecker, J. L., de Koning, K., de Mey, K., . . . Frishberg, B. (2021). Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): a multicentre, randomised, placebo-controlled, phase 3 trial. The Lancet Neurology, 20(7), 526–536. https://doi.org/10.1016/s1474-4422(21)00159-9)
Published: July, 2021
Population:
Patients at least 18 years with generalised myasthenia gravis, regardless of anti-acetylcholine receptor antibody status including:
A Myasthenia Gravis Activities of Daily Living (MG-ADL) score of at least 5 (>50% non-ocular).
On a stable dose of at least one treatment for generalised myasthenia gravis.
Intervention:
Efgartigimod (10 mg/kg) given as four infusions per cycle with one infusion per week. This may be repeated as needed depending on clinical response no earlier than 8 weeks after the start of the previous cycle.
Control:
Placebo given as four infusions per cycle with one infusion per week. This may be repeated as needed depending on clinical response no earlier than 8 weeks after the start of the previous cycle.
Primary Outcome:
The proportion of acetylcholine receptor antibody-positive patients who were MG-ADL responder in the first treatment cycle.
MG-ADL responders are defined as:
≥2-point MG-ADL improvement that is sustained for ≥4 weeks.
Method:
A Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase 3 Clinical Trial.
Results:
Study population: Out of a total of 167 patients:
84 people were randomly assigned in the efgartigimod group
83 people were randomly assigned in the placebo group
Primary outcome results: 129 people or 77% of the population were acetylcholine receptor antibody-positive.
Of these patients:
The efgartigimod group were MG-ADL responders in cycle 1 compared to the placebo group
65 of the 84 patients in the efgartigimod group and 70 of 83 in the placebo group had treatment-emergent adverse events including:
Headache: most frequent being headache
Nasopharyngitis
Conclusion:
Efgartigimod is a well tolerated and efficacious drug that can be used in patients with generalised myasthenia gravis.
One highlight in the ADAPT trial was the individualised dosing based on clinical response.
Stay Tuned For Next Week’s Topic
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