乌鸦传媒

In patients with myasthenia gravis who are being initiated on eculizumab therapy because their disease is to standard treatments, the safety of an abbreviated washout period in transitioning from intravenous immunoglobulin (IVIG) to eculizumab has not been determined.

Clinicians reported a series of 13 patients (seven male) with treatment-refractory generalized myasthenia gravis who presented to their hospital from October 2017 to May 2018.

All had persistent symptoms and a Myasthenia Gravis Composite Score (MGCS) >11. They had significant persistent symptoms despite ongoing maintenance IVIG therapy along with immunosuppressant .

Treatment before transition to eculizumab in most patients:

• ≥3 immunosuppressants + IVIG (n=8)
• ≥3 immunosuppressants + IVIG + plasmapheresis (n=5)

At the time of the transition, all 13 patients were receiving at least one immunosuppressant, i.e.:

• Mycophenolate mofetil (n=13)
• Prednisone (n=8)
• Methotrexate (n=8)

Patients ranged in age from 30 to 78 years, with a median age of 71. Eleven of the 13 were older than age 60, and the two remaining (females) were age 30 and 34.

Eight of the patients had been diagnosed with myasthenia gravis from 2-7 years previously, and the remaining 5 had been diagnosed from 9-17 years previously. Median time since diagnosis was 6 years.

Clinicians used a standardized transition from IVIG to eculizumab, with a 10-14 day washout period between the last IVIG infusion and initiation of eculizumab.

As per the product monograph for eculizumab, all patients were acetylcholine receptor (AChR) antibody-positive and had received meningococcal vaccines at least 2 weeks before beginning treatment, in accordance with the product monograph [15].

Treatment and outcome

Each patient continued with their existing immunosuppressant treatments during the transition and the 6-week evaluation period.

Eculizumab dosing protocol was:

• Weeks 0-4: 900 mg/week
• Week 5: 1,200 mg/week
• Week 6+: 1,200 mg/2 weeks

Clinicians' assessment of each patient's clinical status before initiation of eculizumab identified a median MGCS score of 21 (range 11–29). Repeat assessment after eculizumab treatment showed that all patients had a significant improvement, as demonstrated by a ≥ 3 point decrease in the 6 weeks after starting treatment with eculizumab. (Figure)

Six weeks after the transition median MGCS score was 12 (range 6-18); the median change was 8 (range 4-17).

Two patients experienced mild myalgia after beginning eculizumab treatment, but they did not require changes to the eculizumab dose. No other adverse events were reported.

Discussion

Authors reporting this ¹ of patients with generalized myasthenia gravis refractory to conventional treatment noted that this is the first description of a standardized protocol used to transition patients from IVIG to eculizumab.

Eculizumab, a terminal complement inhibitor, is indicated for the treatment of adult patients with generalized myasthenia gravis who are anti-AChR antibody-positive,² based on randomized, double-blind, placebo-controlled studies^3,4 showing its effectiveness in patients who are refractory to immunosuppressant and/or IVIG therapies.

Clinical trials of eculizumab have required a minimum 4-week interval between the last IVIG infusion and initiation of eculizumab, presumably to ensure that there was no crossover effect of IVIG, authors wrote.

Case authors noted that in patients deriving some benefit from IVIG treatment, a washout period of 4 weeks represents a treatment interruption that could result in further clinical deterioration. Thus, their study protocol incorporates a shorter 10-14 day washout period to transition patients from IVIG to the terminal complement inhibitor eculizumab.

Their aim was to determine whether eculizumab could be safely initiated before complete IVIG washout, in order to prevent transient worsening during the period of onset of eculizumab's effects.

The background on myasthenia gravis

Myasthenia gravis is an autoimmune condition mediated by autoantibodies to components of the postsynaptic muscle endplate; the antibodies target the acetylcholine receptor (AChR) in approximately 85% of cases.⁵ Due to the high specificity of AChR antibodies for myasthenia gravis, their presence confirms the diagnosis in patients with muscle weakness.⁶

Treatment with acetylcholinesterase inhibitors in combination with immunosuppressants is effective in all but about 10%-15% patients with myasthenia gravis.⁷

Management of treatment-refractory myasthenia gravis

Therapeutic options for patients with treatment-refractory myasthenia gravis include corticosteroids, methotrexate, mycophenolate mofetil, azathioprine, and intravenous immunoglobulin (IVIG).^8-10

Operational criteria for "refractory" generalized myasthenia gravis include the failure of multiple therapies, the need for regular use of IVIG or plasma exchange to manage disease symptoms, or the presence of severe adverse reactions to conventional treatments.¹¹

IVIG has been used for many years in the treatment of myasthenia gravis, with good evidence to support its short-term use, authors noted, although its considerable cost (US$150 000–$200 000/year) may be a concern for patients.^12-13

Long-term IVIG maintenance therapy has only been studied retrospectively. Adverse effects such as fever, nausea, and headache are of moderate severity and self-limiting. However, rare but potentially serious adverse effects of IVIG such as thrombotic events, renal dysfunction, and hemolytic anemia have been reported.¹⁴

Research suggests that the complement system plays an important role in the pathogenesis of myasthenia gravis,¹⁵ but none of the conventional treatments target complement directly.

Transitioning from IVIG to eculizumab

Eculizumab is a humanized murine monoclonal antibody that blocks formation of the terminal complement complex by binding to C5 and preventing its enzymatic cleavage to C5a and C5b,^16-17 authors explain.

Significant effects of eculizumab (versus placebo) in myasthenia gravis patients have been observed as early as Week 1 and continued to accrue until approximately Week 12 in a Phase III eculizumab trial.

Use of IVIG in myasthenia gravis has shown a beneficial effect beginning at Day 14 and persisting through Day 28,¹⁸ according to results of a randomized, placebo-controlled trial.

Concerns regarding concurrent treatment with eculizumab and IVIG noted in the product monograph include that it may decrease serum eculizumab concentrations, and that the additional protein may increase the risk of thrombosis and renal dysfunction in patients receiving IVIG.

In this series using a 10-14 day interval between treatments, there were no clinically evident efficacy or safety issues associated with the overlap in the pharmacodynamic effects of the two treatments. Two patients reported adverse effects of mild myalgia, consistent with the known safety profile of eculizumab.

As well, they note, the shorter interval was associated with clinically significant improvements (decrease in MGCS ≥3) in all patients after 6 weeks. In fact, 12 of the 13 patients had a decrease of ≥6 in the MGCS, a validated clinical measure of myasthenia gravis.¹⁹

Authors acknowledge limitations of their evaluation include the retrospective case-series design, and the small number of patients included, which restricts generalizability of the results. As well, given that there is no accepted definition of "refractory" disease, clinicians identified patients to receive eculizumab based on their medical history, the presence of significant symptoms, and their MGCS.

Nevertheless, they noted that these patients' characteristics and treatment history reflect those of the wider treatment-refractory myasthenia gravis population, and patients likely to be treated with eculizumab in clinical practice.

The lack of a control group limits conclusions about the efficacy of eculizumab, they wrote; however, the aim of this case series was not to examine its efficacy per se, but to determine the suitability of this transition protocol, in particular, the safety and tolerability of the abbreviated washout period.

Case authors concluded by acknowledging that the transition protocol assessed in their series is not necessarily the only protocol that could be used in these patients. However, the results indicate these patients can be transitioned to eculizumab 10-14 days after their last IVIG infusion without significant safety concerns and with clinically significant improvements in outcomes.

References

1. Levine TD: Safety of an abbreviated transition period when switching from intravenous immunoglobulin to eculizumab in patients with treatment-refractory myasthenia gravis: A case series Am J Case Rep, 2019; 20: 965-970

2. Alexion Pharmaceuticals, Inc. Soliris (eculizumab) injection; Prescribing information

3. Howard JF Jr., et al: MG Study Group: A randomized, double-blind, placebo-controlled phase II study of eculizumab in patients with refractory generalized myasthenia gravis. Muscle Nerve, 2013; 48: 76–84

4. Howard JF Jr., et al: REGAIN Study Group: 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(12): 976-986

5. Silvestri NJ, Wolfe GI: Treatment-refractory myasthenia gravis. J Clin Neuromuscul Dis, 2014; 15: 167–78

6. Gilhus NE, Verschuuren JJ: Myasthenia gravis: Subgroup classification and therapeutic strategies. Lancet Neurol, 2015; 14: 1023–36

7. Suh J, et al: Clinical characteristics of refractory myasthenia gravis patients. Yale J Biol Med, 2013; 86: 255–60

8. Alabdali M, et al: Intravenous immunoglobulin as treatment for myasthenia gravis: Current evidence and outcomes. Expert Rev Clin Immunol, 2014; 10: 1659–65

9. Gajdos P, et al: Intravenous immunoglobulin for myasthenia gravis. Cochrane Database Syst Rev, 2012; 12: CD002277

10. Hellmann MA, et al: Maintenance IVIG therapy in myasthenia gravis does not affect disease activity. J Neurol Sci, 2014;338: 39–42

11. Mantegazza R, Antozzi C: When myasthenia gravis is deemed refractory: Clinical signposts and treatment strategies. Ther Adv Neurol Disord, 2018;11: 1756285617749134

12. Guptill JT, et al: Cost analysis of myasthenia gravis from a large U.S. insurance database. Muscle Nerve, 2011; 44: 907–11

13. Heatwole C, et al: Plasma exchange versus intravenous immunoglobulin for myasthenia gravis crisis: An acute hospital cost comparison study. J Clin Neuromuscul Dis, 2011; 13: 85–94

14. Guo Y, et al: Adverse effects of immunoglobulin therapy. Front Immunol, 2018; 9: 1299

15. Howard JFJ: Myasthenia gravis: The role of complement at the neuromuscular junction. Ann NY Acad Sci, 2018; 1412: 113–28

16. Davis J: Eculizumab. Am J Health Syst Pharm, 2008; 65: 1609–15

17. Rother RP, et al: Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Nat Biotechnol, 2007; 25: 1256–64

18. Zinman L, et al: IV immunoglobulin in patients with myasthenia gravis: A randomized controlled trial. Neurology, 2007; 68: 837–41

19. Burns TM, et al: The MG Composite: A valid and reliable outcome measure for myasthenia gravis. Neurology, 2010; 74: 1434–40

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