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A Randomized, Double-Blind, Placebo-Controlled Trial of the Corticosteroid-Sparing Effects of Immunoglobulin in Myasthenia Gravis
Bril V, Szczudlik A, Vaitkus A, Rozsa C, Kostera-Pruszczyk A, Hon P, Bednarik J, Tyblova M, Köhler W, Toomsoo T, et al
Neurology. 2022
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Editor's Choice
Abstract
BACKGROUND AND OBJECTIVES Myasthenia gravis (MG) is an autoimmune disease characterized by dysfunction at the neuromuscular junction. Treatment frequently includes corticosteroids (CS) and intravenous immunoglobulin (IVIG). This study was conducted to determine if immune globulin (human), 10% caprylate/chromatography purified (IGIV-C) could facilitate CS dose reduction in CS-dependent MG patients. METHODS In this randomized, double-blind, placebo-controlled trial, CS-dependent MG patients (MGFA class II-Iva; AChR+) received a loading dose of 2 g/kg IGIV-C over 2 days (maximum 80 g/day) or placebo at week 0 (baseline). Maintenance doses (1 g/kg IGIV-C or placebo) were administered every three weeks through week 36. Tapering of CS was initiated at week 9 and continued through week 36 unless the patient worsened (QMG score ≥ 4 points from baseline). CS doses were increased (based on current CS dose) in patients who worsened. Patients were withdrawn if worsening failed to improve within 6 weeks or if a second CS increase was required. The primary efficacy endpoint (at week 39) was a ≥ 50% reduction in CS dose. Secondary and safety endpoints were assessed throughout the study and follow-up (weeks 42 and 45). The study results and full protocol are available at: ://clinicaltrials.gov/ct2/show/NCT02473965. RESULTS The primary endpoint (≥ 50% reduction in CS dose) showed no significant difference between the IGIV-C treatment (60.0% of patients) and placebo (63.3%). There were no significant differences for secondary endpoints. Safety data indicated that IGIV-C was well-tolerated. DISCUSSION In this study, IGIV-C was not more effective than placebo in reducing daily CS dose. These results suggest that effects of IGIV-C and CS are not synergistic and may be mechanistically different. TRIAL REGISTRATION INFORMATION The trial was registered on clinicaltrialsregister.eu (EudraCT #: 2013-005099-17) and clinicaltrials.gov (identifier NCT02473965). CLASSIFICATION OF EVIDENCE This study provides Class II evidence that IVIG infusions in adult patients with MG do not increase the percentage of patients achieving a ≥ 50% reduction in corticosteroid dose compared to placebo.
PICO Summary
Population
Corticosteroids-dependent myasthenia gravis patients (n= 60).
Intervention
Immune globulin injection, 10% caprylate/chromatography purified IGIV-C (n= 30).
Comparison
Placebo (n= 30).
Outcome
The primary endpoint (≥ 50% reduction in corticosteroids dose) showed no significant difference between the IGIV-C treatment (60.0% of patients) and placebo (63.3%). There were no significant differences for secondary endpoints. Safety data indicated that IGIV-C was well-tolerated.
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Safety of plasma exchange therapy in patients with myasthenia gravis
Ebadi H, Barth D, Bril V
Muscle & Nerve. 2013;47((4):):510-4.
Abstract
INTRODUCTION Plasma exchange (PLEX) is effective in myasthenia gravis (MG), but there are concerns about its safety. METHODS We collected data prospectively from 42 patients randomized to PLEX treatment in a comparison study with intravenous immunoglobulin (IVIg). Detailed information on the PLEX treatment methodology and adverse events are reported. RESULTS Forty of 42 patients completed PLEX. Ninety percent were treated in an outpatient setting. Fifty-five percent had no complications, and 45% had mild-moderate reactions that did not require stopping treatment; the majority were citrate reactions and peripheral vascular issues that were easily treated. Fifty-seven percent of patients responded to treatment, and 83% completed PLEX via peripheral venous access. Two patients had severe adverse events: 1 related and 1 unrelated to PLEX. Comorbid disease and age did not predict reactions. CONCLUSION PLEX is safe, effective, and well tolerated in patients with MG. Our results do not raise concerns about the safety of PLEX in patients with moderate-severe MG. Copyright 2012 Wiley Periodicals, Inc.
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Changes in quality of life scores with intravenous immunoglobulin or plasmapheresis in patients with myasthenia gravis
Barnett C, Wilson G, Barth D, Katzberg HD, Bril V
Journal of Neurology, Neurosurgery & Psychiatry. 2013;84((1):):94-7.
Abstract
BACKGROUND Intravenous immunoglobulin (IVIG) and plasmapheresis (plasma exchange (PLEX)) have comparable efficacy in reducing the Quantitative Myasthenia Gravis Score for disease severity (QMGS) in patients with moderate to severe myasthenia gravis (MG). OBJECTIVE To determine if the improvement in the quality of life (QOL) after immunomodulation is comparable with either IVIG or PLEX. METHODS 62 patients participated in the MG-QOL-60 study, completing the questionnaire at baseline and at day 14 after treatment. The MG-QOL-15 scores were computed from the MG-QOL-60 questionnaire responses. We analysed the change in the QOL scores from baseline to day 14 in both treatment groups. RESULTS The scores in both QOL scales decreased at day 14 in the IVIG and PLEX groups, without significant difference between groups (QOL-15: IVIG -5.7 +/- 8.5, PLEX -7.0 +/- 7.6, p=0.52; QOL-60: IVIG -13.3 +/- 16.9, PLEX -18.5 +/- 22.0, p = 0.41). The improvement in QOL showed a good correlation with the decrease in QMGS. There was an excellent correlation between the MG-QOL-15 and MG-QOL-60 scores at baseline and at day 14. CONCLUSIONS This study of MG-QOL changes supports recent findings that IVIG and PLEX are comparable in the treatment of patients with moderate to severe MG and worsening symptoms. Furthermore, our study supports the use of the MG-QOL-15 as a secondary outcome measure in future clinical trials in MG.
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IVIG and PLEX in the treatment of myasthenia gravis
Bril V, Barnett-Tapia C, Barth D, Katzberg HD
Annals of the New York Academy of Sciences. 2012;1275((1):):1-6.
Abstract
Intravenous immunoglobulin (IVIG) and plasma exchange (PLEX) are used to treat myasthenia gravis (MG) but with little trial evidence. While a class I study provided evidence for the efficacy of IVIG treatment, the empirical support for PLEX has been less convincing until recently. In a randomized controlled single-masked study of 84 MG patients with moderate to severe disease, IVIG and PLEX had comparable efficacy as demonstrated by reduction in the Quantitative Myasthenia Gravis Score (QMGS) for disease severity, percentage of responders, persistence of treatment effect, and tolerability, which were similar in both treatment arms. The change in QMGS was accompanied by improved disease-specific quality of life. The only factor predicting response to treatment was baseline severity. FcR polymorphisms did not predict response to IVIG therapy, but an inhibitory polymorphism was associated with baseline disease severity. These studies support the choice of either IVIG or PLEX as comparable treatments in adult patients with moderate to severe MG. 2012 New York Academy of Sciences.
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Comparison of IVIg and PLEX in patients with myasthenia gravis
Barth D, Nabavi Nouri M, Ng E, Nwe P, Bril V
Neurology. 2011;76((23):):2017-23.
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Abstract
OBJECTIVE Both IV immunoglobulin (IVIg) and plasma exchange (PLEX) are immunomodulatory treatments used to treat patients with myasthenia gravis (MG), but the choice of which treatment to administer to patients is limited due to lack of evidence from adequately powered, masked, randomized, standardized trials. METHODS We randomized 84 patients with moderate to severe MG defined as a Quantitative Myasthenia Gravis Score for disease severity (QMGS) of >10.5 and worsening weakness to IVIg (Gamunex®, Talecris Biotherapeutics) 1 g/kg/day for 2 consecutive days or PLEX (Caridian Spectra) 1.0 plasma volume exchanges for 5 exchanges. The patients were evaluated at day 14 after treatment for the primary efficacy parameter of change in QMGS and secondary clinical and electrophysiologic parameters and were followed for a total of 60 days. RESULTS Both IVIg and PLEX reduced the QMGS, and IVIg was comparable to PLEX in efficacy. The dropout rate was the same for both treatment arms and both treatments were well-tolerated. The presence of acetylcholine receptor antibodies and greater baseline disease severity predicted a better response to therapy. The postintervention status revealed that the same proportion of patients improved with treatment: 69% on IVIg and 65% on PLEX. The duration of improvement was similar with both treatments. CONCLUSIONS IVIg has comparable efficacy to PLEX in the treatment of patients with moderate to severe MG. Both treatments are well-tolerated, and the duration of effect is comparable. Either treatment may be offered to patients depending on availability of resources. Classification of evidence: This study provides Class I evidence that IVIg and PLEX have comparable efficacy and are equally tolerated in adult patients with moderate to severe MG within 2 weeks of treatment.
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Surrogate therapeutic outcome measures in patients with myasthenia gravis
Zinman L, Baryshnik D, Bril V
Muscle & Nerve. 2008;37((2):):172-6.
Abstract
Treatment of acquired myasthenia gravis (MG) with immunotherapies successfully relieves symptoms and improves strength as documented by the Quantitative Myasthenia Gravis Score for disease severity (QMGS). Neuromuscular function, as demonstrated by the surrogate measures of repetitive nerve stimulation (RNS) and single-fiber electromyography (SFEMG), is sensitive for diagnosis and staging disease severity. This study of 51 patients treated with immunomodulation confirmed that RNS and SFEMG are useful to stage disease severity, but found that clinical measures such as the QMGS are more sensitive to change than electrophysiological parameters. The presence of blocking on SFEMG did predict responsiveness to intravenous immunoglobulin (IVIG) treatment, providing clinicians with an objective, reliable, quantitative measure to help determine which patients will benefit from this costly treatment.
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IV immunoglobulin in patients with myasthenia gravis: a randomized controlled trial
Zinman L, Ng E, Bril V
Neurology. 2007;68((11):):837-41.
Abstract
OBJECTIVE We aimed to determine the effectiveness of IV immunoglobulin (IVIG) in the treatment of patients with myasthenia gravis (MG) and worsening weakness in a randomized, placebo-controlled, masked study. METHODS Fifty-one patients with worsening weakness due to MG were randomized to infusion with 2 g/kg of IVIG or an equivalent volume of IV dextrose 5% in water. The Quantitative Myasthenia Gravis (QMG) Score for Disease Severity, a validated clinical composite scale, was calculated by a masked observer at baseline and days 14 and 28. RESULTS In IVIG-treated patients, a clinically meaningful improvement in QMG Score for Disease Severity was observed at day 14 and persisted at day 28. The greatest improvement occurred in patients with more severe disease as defined by a QMG Score for Disease Severity greater than 10. 5. CONCLUSION This study provides level 1 evidence for the effectiveness of IV immunoglobulin in patients with worsening weakness due to myasthenia gravis.