Wolfe GI, Kaminski HJ, Aban IB, Minisman G, Kuo HC, Marx A, Ströbel P, Mazia C, Oger J, Cea JG, Heckmann JM, Evoli A, Nix W, Ciafaloni E, Antonini G, Witoonpanich R, King JO, Beydoun SR, Chalk CH, Barboi AC, Amato AA, Shaibani AI, Katirji B, Lecky BR, Buckley C, Vincent A, Dias-Tosta E, Yoshikawa H, Waddington-Cruz M, Pulley MT, Rivner MH, Kostera-Pruszczyk A, Pascuzzi RM, Jackson CE, Garcia Ramos GS, Verschuuren JJ, Massey JM, Kissel JT, Werneck LC, Benatar M, Barohn RJ, Tandan R, Mozaffar T, Conwit R, Odenkirchen J, Sonett JR, Jaretzki A 3rd, Newsom-Davis J, Cutter GR; MGTX Study Group.
Randomized Trial of Thymectomy in Myasthenia Gravis.
N Engl J Med. 2016 Aug 11;375(6):511-22. doi: 10.1056/NEJMoa1602489.
Abstract/Text
BACKGROUND: Thymectomy has been a mainstay in the treatment of myasthenia gravis, but there is no conclusive evidence of its benefit. We conducted a multicenter, randomized trial comparing thymectomy plus prednisone with prednisone alone.
METHODS: We compared extended transsternal thymectomy plus alternate-day prednisone with alternate-day prednisone alone. Patients 18 to 65 years of age who had generalized nonthymomatous myasthenia gravis with a disease duration of less than 5 years were included if they had Myasthenia Gravis Foundation of America clinical class II to IV disease (on a scale from I to V, with higher classes indicating more severe disease) and elevated circulating concentrations of acetylcholine-receptor antibody. The primary outcomes were the time-weighted average Quantitative Myasthenia Gravis score (on a scale from 0 to 39, with higher scores indicating more severe disease) over a 3-year period, as assessed by means of blinded rating, and the time-weighted average required dose of prednisone over a 3-year period.
RESULTS: A total of 126 patients underwent randomization between 2006 and 2012 at 36 sites. Patients who underwent thymectomy had a lower time-weighted average Quantitative Myasthenia Gravis score over a 3-year period than those who received prednisone alone (6.15 vs. 8.99, P<0.001); patients in the thymectomy group also had a lower average requirement for alternate-day prednisone (44 mg vs. 60 mg, P<0.001). Fewer patients in the thymectomy group than in the prednisone-only group required immunosuppression with azathioprine (17% vs. 48%, P<0.001) or were hospitalized for exacerbations (9% vs. 37%, P<0.001). The number of patients with treatment-associated complications did not differ significantly between groups (P=0.73), but patients in the thymectomy group had fewer treatment-associated symptoms related to immunosuppressive medications (P<0.001) and lower distress levels related to symptoms (P=0.003).
CONCLUSIONS: Thymectomy improved clinical outcomes over a 3-year period in patients with nonthymomatous myasthenia gravis. (Funded by the National Institute of Neurological Disorders and Stroke and others; MGTX ClinicalTrials.gov number, NCT00294658.).
Pascuzzi RM, Coslett HB, Johns TR.
Long-term corticosteroid treatment of myasthenia gravis: report of 116 patients.
Ann Neurol. 1984 Mar;15(3):291-8. doi: 10.1002/ana.410150316.
Abstract/Text
One hundred sixteen patients, aged 8 to 82 years, with myasthenia gravis were treated with prednisone, 60 to 80 mg daily, until the onset of improvement, followed by lower-dose alternate-day therapy of several years' duration. Of all patients, 80.2% achieved either remission (27.6%) or marked improvement (52.6%). Moderate improvement occurred in 14.7%, and 5.2% showed no improvement. Increasing age correlated with a favorable outcome, but sex, duration of illness prior to treatment, severity and distribution of weakness at the time of onset of treatment, and presence of thymoma were not factors in the response to therapy.
Arsura E, Brunner NG, Namba T, Grob D.
High-dose intravenous methylprednisolone in myasthenia gravis.
Arch Neurol. 1985 Dec;42(12):1149-53. doi: 10.1001/archneur.1985.04060110031011.
Abstract/Text
Corticosteroids have been useful in the management of myasthenia gravis (MG), but their efficacy has been limited by the slow onset of improvement, initial worsening of MG, refractoriness of some patients, and side effects of large daily doses. High-dose intravenous methylprednisolone pulses have been reported to produce rapid improvement in several immunologic disorders. In this study we administered 2 g of methylprednisolone intravenously every five days to 15 consecutive patients who had exacerbation of generalized MG. Satisfactory improvement occurred in ten of 15 patients after two courses and in two of five patients after a third course. Onset of improvement began a mean (+/- SD) of 3 +/- 1.1 days after the first infusion, 2.1 +/- 1 days after the second, and 2.4 +/- 1 days after the third, and reached its maximum level 8.9 +/- 6.1 days after the last infusion. A decrease in strength occurred in three patients 1.43 +/- 1.30 days after each infusion, was not marked, and lasted three days, following which improvement generally occurred. Side effects were minimal. After improvement, a daily dose of prednisone (30 mg) was used to maintain improvement. Use of pulse therapy at five-day intervals for the management of severe MG seems to have an advantage in that it produces less initial worsening and more rapid improvement in MG, enabling smaller daily maintenance doses to be employed, with fewer side effects.
Utsugisawa K, Nagane Y, Suzuki S, Suzuki N.
Monitoring treatment with cyclosporine microemulsion in myasthenia gravis.
Eur J Neurol. 2008 Jun;15(6):598-604. doi: 10.1111/j.1468-1331.2008.02130.x. Epub 2008 Apr 9.
Abstract/Text
PURPOSE: To examine whether the monitoring of cyclosporine (CsA) blood concentrations is of benefit in CsA microemulsion pre-concentrate (MEPC) therapy for myasthenia gravis (MG).
METHODS: We measured CsA blood concentrations both 2 h after administration (C2) and immediately before administration (C0) and examined associations with changes to clinical parameters in 20 MG patients treated with CsA MEPC in an unblinded, 6-month prospective open trial.
RESULTS: Initial dose of CsA MEPC (4.7 +/- 0.5 mg/kg/day) provided both high C2 levels and safe C0 levels. Disease severity, daily dose of prednisolone, acetylcholine receptor-antibody titre levels and levels of interleukin-2 production by peripheral blood mononuclear cells were significantly reduced following treatment with CsA MEPC. A significant correlation existed between C2 levels following the initial dose and clinical improvement in responder MG patients. C0 levels were significantly higher in patients who exhibited increased serum creatinine or hypertension compared with patients free from side effects. Body mass index of individual patients was significantly correlated with C0 level, and may thus offer a useful marker to predict C0 levels.
DISCUSSION: CsA MEPC was effective at suppressing symptoms and T-cell-dependent pathogenesis of MG, and monitoring of C2 and C0 levels can be useful to estimate efficacy and safety of the drug.
Yoshikawa H, Kiuchi T, Saida T, Takamori M.
Randomised, double-blind, placebo-controlled study of tacrolimus in myasthenia gravis.
J Neurol Neurosurg Psychiatry. 2011 Sep;82(9):970-7. doi: 10.1136/jnnp-2011-300148. Epub 2011 Jul 22.
Abstract/Text
OBJECTIVES: To evaluate the ability of tacrolimus to reduce the corticosteroid dose in patients with myasthenia gravis (MG) and the drug's safety in a double-blind, placebo-controlled, parallel group study.
METHODS: Patients being treated with oral prednisolone at doses equivalent to 10-20 mg/day, and with stable symptoms, were randomised to tacrolimus or placebo in a 28-week double-blind study. The dose of corticosteroid was tapered with the procedures specified in the protocol. The primary efficacy endpoint was the mean daily prednisolone dose given in the last 12 weeks of the study.
RESULTS: Eighty patients received the study drug (40 patients in each group) and were included in the full analysis set. In the full analysis set, there was no significant difference in the primary efficacy endpoint between the two groups (p = 0.078). However, some secondary analyses suggested the steroid-sparing effect of tacrolimus. Tacrolimus was well tolerated, and no safety concerns were noted.
CONCLUSIONS: This study suggests that tacrolimus has a potential advantage as a steroid-sparing agent in the treatment of MG patients.
CLINICAL TRIAL REGISTRATION NUMBER: NCT00309088. Name of the trial registry: FK506 Phase 3 STUDY: A STUDY for Steroid Non-Resistant MG Patients.
Grob D, Simpson D, Mitsumoto H, Hoch B, Mokhtarian F, Bender A, Greenberg M, Koo A, Nakayama S.
Treatment of myasthenia gravis by immunoadsorption of plasma.
Neurology. 1995 Feb;45(2):338-44. doi: 10.1212/wnl.45.2.338.
Abstract/Text
We treated 16 patients with moderately severe to severe generalized myasthenia gravis (MG) by immunoadsorption (perfusion through a resin that adsorbs proteins) of 2,500 ml plasma on each of four alternate days. Fourteen patients who completed treatment all had significant improvement in strength (6 excellent, 6 good, and 2 fair), which began a mean of 42 hours after the first immunoadsorption, reached a maximum 4 days after the fourth immunoadsorption (mean, 250% of baseline strength), and returned to baseline over a mean of 2 months. Thirty-seven grams of plasma proteins were removed during each immunoadsorption, which required no replacement, compared with 175 grams during plasma exchange, which requires replacement with albumin. Serum or plasma concentration of all proteins fell, more so for most of the larger proteins than for the smaller ones: acetylcholine receptor antibody (AChR Ab) fell to a mean of 23% of original level, fibrinogen to 26%, C4 to 29%, IgM to 33%, IgG to 35%, CH50 to 41%, C3 to 42%, IgA to 54%, and albumin to 76%. All proteins, including AChR Ab, returned to their original levels within 1 to 3 weeks after the last immunoadsorption, while improvement in strength lasted a mean of 6 weeks longer. One seronegative patient had excellent improvement lasting more than a month. Activated complement C5a and white blood cell count rose during each immunoadsorption, while activated complement C3a fell, and each returned to its original level within hours. Eight patients had transient symptomatic hypotension attributable to withdrawal of blood more rapidly than it was returned; this hypotension was prevented or ameliorated by intravenous saline.(ABSTRACT TRUNCATED AT 250 WORDS)
Gajdos P, Chevret S, Clair B, Tranchant C, Chastang C.
Clinical trial of plasma exchange and high-dose intravenous immunoglobulin in myasthenia gravis. Myasthenia Gravis Clinical Study Group.
Ann Neurol. 1997 Jun;41(6):789-96. doi: 10.1002/ana.410410615.
Abstract/Text
We have conducted a trial to randomly assess the efficacy and tolerance of intravenous immunoglobulin (i.v.Ig) or plasma exchange (PE) in myasthenia gravis (MG) exacerbation and to compare two doses of i.v.Ig. Eighty-seven patients with MG exacerbation were randomized to receive either three PE (n = 41), or i.v.Ig (n = 46) 0.4 gm/kg daily further allocated to 3 (n = 23) or 5 days (n = 23). The main end point was the variation of a myasthenic muscular score (MSS) between randomization and day 15. The MSS variation was similar in both groups (median value, +18 in the PE group and +15.5 in the i.v.Ig group, p = 0.65). Similar efficacy, although slightly reduced in the 5-day group was observed with both i.v.Ig schedules. The tolerance of i.v.Ig was better than that of PE with a total of 14 side effects observed in 9 patients, 8 in the PE group and 1 in the i.v.Ig group (p = 0.01). Although our trial failed to show a pronounced difference in the efficacy of both treatments, it exhibited a very limited risk for i.v.Ig. i.v.Ig is an alternative for the treatment of myasthenic crisis. The small sample sizes in our trial, however, could explain why a difference in efficacy was not observed. Further studies are needed to compare PE with i.v.Ig and to determine the optimal dosage of i.v.Ig.
Qureshi AI, Choudhry MA, Akbar MS, Mohammad Y, Chua HC, Yahia AM, Ulatowski JA, Krendel DA, Leshner RT.
Plasma exchange versus intravenous immunoglobulin treatment in myasthenic crisis.
Neurology. 1999 Feb;52(3):629-32. doi: 10.1212/wnl.52.3.629.
Abstract/Text
We performed a retrospective multicenter chart review to compare the efficacy and tolerance of plasma exchange (PE) and intravenous immunoglobulin (i.v.Ig) in treatment of 54 episodes of myasthenic crisis. After adjustment for other variables, PE (compared with i.v.Ig) was associated with a superior ventilatory status at 2 weeks (partial F = 6.2, p = 0.02) and 1 month functional outcome (partial F = 4.5, p = 0.04). However, the complication rate was higher with PE compared with i.v.Ig (13 versus 5 episodes, p = 0.07).
Stricker RB, Kwiatkowska BJ, Habis JA, Kiprov DD.
Myasthenic crisis. Response to plasmapheresis following failure of intravenous gamma-globulin.
Arch Neurol. 1993 Aug;50(8):837-40. doi: 10.1001/archneur.1993.00540080046012.
Abstract/Text
Myasthenic crisis is a potentially life-threatening complication of myasthenia gravis that requires aggressive therapy. We describe four patients in whom myasthenic crisis developed and who failed to respond to initial treatment with intravenous gamma-globulin. All four patients subsequently responded to intensive plasma exchange. Based on our experience, plasmapheresis appears to be superior to intravenous gamma-globulin for the treatment of myasthenic crisis in certain patients. Prognostic factors that determine the effectiveness of intravenous gamma-globulin vs plasmapheresis in these patients merit further investigation.
Oyama M, Okada K, Masuda M, Shimizu Y, Yokoyama K, Uzawa A, Kawaguchi N, Ikeguchi R, Hoshino Y, Hatano T, Ozawa Y, Nakahara J, Aizawa H, Kitagawa K, Hattori N, Kuwabara S, Murai H, Suzuki S.
Suitable indications of eculizumab for patients with refractory generalized myasthenia gravis.
Ther Adv Neurol Disord. 2020;13:1756286420904207. doi: 10.1177/1756286420904207. Epub 2020 Mar 18.
Abstract/Text
BACKGROUND: Eculizumab is a humanized monoclonal antibody that targets complement protein C5 and inhibits terminal complement-mediated damage at the neuromuscular junction. Recently, the REGAIN study showed that eculizumab was effective and well tolerated in patients with anti-acetylcholine receptor antibody-positive refractory generalized myasthenia gravis (gMG). However, there is no consensus regarding which kind of patients with gMG are selected to preferentially receive eculizumab.
METHODS: Between January and December 2018, we followed 1388 patients with MG at seven hospitals located in Tokyo and Chiba. We evaluated the clinical features of MG and the patients' quality of life. Clinical status and severity were determined by the recommendations of the Myasthenia Gravis Foundation of America.
RESULTS: Of 1388 patients with MG, 12 (0.9%) patients received eculizumab. A total of 11 patients who were anti-acetylcholine receptor antibody-positive with refractory gMG (M:F = 3:8) completed the 26-week treatment with eculizumab. The disease subtypes represented included five cases of early onset MG, one of late-onset MG, and five of thymoma-associated MG. Overall, seven patients had experienced myasthenic crisis. The mean quantitative MG score ranged from 18.6 at baseline to 9.1 at week 26 (p = 0.008). Similarly, the mean MG activities of daily living score ranged from 10.8 at baseline to 4.2 at week 26 (p = 0.002). There were marked improvements in all patients' quality of life status. Overall, seven patients were able to reduce the dose of prednisolone at week 26. All but one patient did not require additional rescue treatment. Overall, one patient with early onset MG could not continue the eculizumab treatment due to nausea and vertigo.
CONCLUSION: We demonstrate that eculizumab provided remarkable benefits for refractory gMG in practical real-world experience as well as in the REGAIN study. Patients with refractory gMG with myasthenia crisis and thymoma-associated MG are suitable for eculizumab administration.
© The Author(s), 2020.
Tokuyasu D, Suzuki S, Uzawa A, Nagane Y, Masuda M, Konno S, Kubota T, Samukawa M, Sugimoto T, Ishizuchi K, Oyama M, Yasuda M, Akamine H, Onishi Y, Suzuki Y, Kawaguchi N, Minami N, Kimura T, Takahashi MP, Murai H, Utsugisawa K.
Real-world experience with eculizumab and switching to ravulizumab for generalized myasthenia gravis.
Ann Clin Transl Neurol. 2024 May;11(5):1338-1346. doi: 10.1002/acn3.52051. Epub 2024 Apr 4.
Abstract/Text
OBJECTIVE: Eculizumab and ravulizumab are complement protein C5 inhibitors, showing efficacy and tolerability for patients with anti-acetylcholine receptor-positive (AChR+) generalized myasthenia gravis (gMG) in phase 3 clinical trials and subsequent analyses. The purpose of the present study was to evaluate the clinical significance of eculizumab and switching to ravulizumab for refractory AChR+ gMG patients in the real-world experience.
METHODS: Among the database of Japan MG registry survey 2021, we studied AChR+ gMG patients who received eculizumab. We also evaluated these patients who switched from eculizumab to ravulizumab. Responder was defined as an improvement of at least 3 points in MG-ADL. We performed a questionnaire of preference between eculizumab and ravulizumab.
RESULTS: Among 1,106 patients with AChR+ gMG, 36 patients (3%) received eculizumab (female 78%, mean age 56.0 years). Eculizumab was preferentially used in severe and refractory MG patients. The duration of eculizumab treatment was 35 months on average. MG-ADL improved from 9.4 ± 4.9 to 5.9 ± 5.1, and 25 (70%) of the 36 gMG patients were responders. Postintervention status was markedly improved after the eculizumab treatment. Of 13 patients who did not continue eculizumab, 6 showed insufficiencies. Early onset MG was most effective. However, 15 patients switching from eculizumab to ravulizumab kept favorable response and tolerability. Questionnaire surveys showed preference for ravulizumab over eculizumab.
INTERPRETATION: Eculizumab and switching to ravulizumab showed to be effective for refractory AChR+ gMG patients in clinical settings.
© 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
Suzuki S, Uzawa A, Nagane Y, Masuda M, Konno S, Kubota T, Samukawa M, Ishizuchi K, Tokuyasu D, Handa H, Yasuda M, Kawaguchi N, Kimura T, Suzuki Y, Sugimoto T, Minami N, Takahashi MP, Murai H, Utsugisawa K.
Therapeutic Responses to Efgartigimod for Generalized Myasthenia Gravis in Japan.
Neurol Clin Pract. 2024 Jun;14(3):e200276. doi: 10.1212/CPJ.0000000000200276. Epub 2024 Mar 25.
Abstract/Text
BACKGROUND AND OBJECTIVES: Efgartigimod, which has been well tolerated and efficacious in individuals with generalized myasthenia gravis (MG), is available in Japan not only for the treatment of anti-acetylcholine receptor-positive (AChR+) but also anti-muscle-specific receptor tyrosine kinase (MuSK+) and seronegative generalized MG. We report details of the use of efgartigimod for generalized MG in clinical practice in Japan.
METHODS: We included patients with generalized MG in the 2021 survey of Japan Myasthenia Gravis Registry (JAMG-R) study group who received an initial cycle of efgartigimod between May and September 2022. We defined "responders" as patients who achieved a score ≥2 points for MG activities of daily living (MG-ADL) in the first treatment cycle. The MG composite and the Revised scale of the 15-item Myasthenia Gravis-Quality of Life scale (MG-QOL15-r) were also evaluated.
RESULTS: Of 1,343 JAMG-R patients, 36 (2.7%) started efgartigimod (female 68%, age 53 years). Their serologic profiles were as follows: AChR+, n = 19 (53%); MuSK+, n = 6 (17%); and seronegative, n = 11 (31%). Twenty-six patients (72%) had refractory MG. There were 81 cycles of efgartigimod during the 26-week observation in 34 patients (average, 2.4 cycles). The mean interval between cycles was 5.9 weeks. A continuous 4-weekly infusion of efgartigimod was performed in 65 (80%) of 81 cycles. In the first cycle, the MG-ADL score of the 34 patients decreased significantly from 10.5 ± 4.3 to 6.9 ± 5.1 (p = 0.003). Similarly, the mean MG composite and MG-QOL15-r decreased from 18.4 ± 13.6 to 11.8 ± 9.6 (p = 0.004) and from 19.2 ± 6.3 to 14.2 ± 8.3 (p = 0.007), respectively. Twenty-one (62%) patients were responders. Therapeutic responses were observed in the subsequent cycles. The duration of effectiveness of efgartigimod was varied among the responders; 4 responders had only a single effective cycle. Significant improvement was observed in the MuSK+ patients. Prednisolone dose of 7 patients was reduced. Our examination of the patients' postintervention status revealed that 6 patients achieved minimal manifestations. COVID-19 occurred in 5 patients. We failed to detect clinical or laboratory findings associated with responders.
DISCUSSION: Efgartigimod can be considered for the treatment of patients with generalized MG who do not achieve minimal manifestations, with a broad flexibility of patient selection and treatment schedules.
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
