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Clinical and Experimental Immunology

I N T E R L A K E N L E A D E R S H I P AWA R D S

doi:10.1111/cei.12542

Intravenous immunoglobulin for preparing myasthenia gravis patients for thymectomy and other surgical procedures preventing myasthenic crisis

J. Gamez Myasthenia Gravis Unit, Neuromuscular Disorders Clinic, Neurology Department, Hospital Universitari Vall d’Hebron, VHIR, Autonomous University of Barcelona, Barcelona, Spain Correspondence: J. Gamez. E-mail: [email protected]

Myasthenia gravis (MG) is a chronic autoimmune disease caused by a failure of neuromuscular transmission [1]. This failure results from the binding of autoantibodies to signalling proteins, in particular the nicotinic acetylcholine receptor (AChR), at the neuromuscular junction. At least three mechanisms have been proposed to explain how anti-AChR antibodies compromise neuromuscular transmission: (i) complement binding and activation at the neuromuscular junction; (ii) accelerated degradation of AChR molecules (antigenic modulation); and (iii) functional block of AChRbinding sites [1]. MG is characterized by painless muscle weakness that is exacerbated by repetitive use of the affected muscle. Its prevalence is estimated to be 14·2 per 100 000 and women are more often affected than men, with a female to male ratio of 3:2. However, the incidence is greater in elderly men than women. Current treatment options are considered effective, albeit that there are only limited data from controlled clinical trials to underpin this [2]. Acetylcholinesterase inhibitors improve neuromuscular transmission and should be considered as first-line therapy for the management of MG. Conversely, oral steroids are recommended as a first-line drug in patients who require immunosuppression [3]. Both plasma exchange (PE) and intravenous immunoglobulins (IVIg) provide short-term modulation of the autoimmune response and are used to induce a rapid improvement in patients with an exacerbation of the disease [3]. However, their beneficial effect is only temporary, lasting 4–5 weeks [2]. Thymectomy is mandatory in patients with thymoma, which is a benign epithelial tumour found in approximately 10–20% of patients [2]. Thymectomy is also recommended as an option for patients with non-thymomatous MG to increase the probability of remission or improvement [3]. The life-time prevalence of acute episodes of respiratory muscle weakness in MG patients that are severe enough to require intubation and mechanical ventilation (myasthenic crisis) is approximately 20–30% [4]. A significant number 134

of these myasthenic crises occur in the context of surgical procedures, particularly thymectomies, and often lead to prolonged post-operative intubation and extended hospital stays. Risk factors include: chronic myasthenia (≥ 6 years); pre-existing respiratory illness; large doses of the acetylcholinesterase inhibitor pyridostigmine; marginal preoperative vital capacity; and severe bulbar weakness. The first-line therapies for the treatment of myasthenic crises are IVIg and PE [5]. Although there is some evidence to suggest PE may be more effective than IVIg in the treatment of myasthenic crisis [6], other studies have found these treatments to be equally effective [7,8]. In addition, PE has been used to prepare patients for thymectomy and has been shown to improve post-operative outcomes [9]. There are isolated reports that have described cases of IVIg also being able to prevent myasthenic crisis [10,11]. However, no double-blind trials have been carried out. Therefore, we are currently conducting a study to investigate if preoperatively administered IVIg is an effective preparatory measure for reducing the incidence of myasthenic crises, and if it should be included in the pre-operative protocol for MG patients. This study is a prospective, randomized, double-blind clinical trial comparing IVIg treatment versus placebo in MG patients undergoing surgery with general anaesthesia. Inclusion criteria include patients aged > 18 years with a diagnosis of MG and the need for surgical procedures requiring general anaesthesia, including thymectomy. Candidate patients for recruitment belong to the cohort of MG patients (n = 269) monitored by our MG unit and new cases in which thymectomy is indicated. The treatment group will receive IVIg (0·4 mg/kg/day) for 5 consecutive days before surgery and the placebo group will receive saline solution for the same time-period and under the same conditions. Our pharmacy department will use photoprotective bags and opaque tubes to mask the vials of immunoglobulin and the placebo so that the patient, the treating investigator,

© 2014 British Society for Immunology, Clinical and Experimental Immunology, 178: 134–135

IVIg therapy in myasthenia gravis

evaluating investigator and nurses will be blinded to treatment. The two groups are age-matched, with similar functional status, and classified according to the recommendations for clinical research standards of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America (MGFA). The primary end-point is the incidence of myasthenic crises, which will be evaluated after surgery and every day thereafter while the patient remains in hospital. The secondary end-points are evaluation time to extubation, length of stay in the post-operative recovery room and functional status as measured by the MGFA. The time-frame for the project is 3 years. The first year of the project was spent seeking authorization for the clinical trial from the Spanish Ministry of Health and the Spanish Agency of Medicines and Medical Devices, and obtaining EudraCT registration (no. 2012-001544-21) [12]. A total of 15 patients were recruited to the trial between 31 January 2013 and 31 December 2013. The trial is aiming to recruit 84 patients and results are expected in December 2016.

Acknowledgements The study presented by J. G. was supported by the ILA program. J. G. is the recipient of a grant from the Spanish Fondo de Investigaciones Sanitarias (PI13-01272). J. G. is indebted to the patients and their relatives for their cooperation, and would like to thank Meridian HealthComms Ltd for providing medical writing services.

Disclosure J. G. has no conflicts of interest to disclose.

References 1 Conti-Fine BM, Milani M, Kaminski HJ. Myasthenia gravis: past, present, and future. J Clin Invest 2006; 116:2843–54. 2 Mantegazza R, Bonanno S, Camera G, Antozzi C. Current and emerging therapies for the treatment of myasthenia gravis. Neuropsychiatry Dis Treat 2011; 7:151–60. 3 Skeie GO, Apostolski S, Evoli A et al. Guidelines for the treatment of autoimmune neuromuscular transmission disorders. Eur J Neurol 2006; 13:691–9. 4 Chaudhuri A, Behan PO. Myasthenic crisis. QJM 2009; 102:97– 107. 5 Wendell LC, Levine JM. Myasthenic crisis. Neurohospitalist 2011; 1:16–22. 6 Qureshi AI, Choudhry MA, Akbar MS et al. Plasma exchange versus intravenous immunoglobulin treatment in myasthenic crisis. Neurology 1999; 52:629–32. 7 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; 41:789–96. 8 Murthy JM, Meena AK, Chowdary GV, Naryanan JT. Myasthenic crisis: clinical features, complications and mortality. Neurol India 2005; 53:37–40; discussion. 9 Sarkar BK, Sengupta P, Sarkar UN. Surgical outcome in thymic tumors with myasthenia gravis after plasmapheresis – a comparative study. Interact Cardiovasc Thorac Surg 2008; 7:1007–10. 10 Huang CS, Hsu HS, Kao KP, Huang MH, Huang BS. Intravenous immunoglobulin in the preparation of thymectomy for myasthenia gravis. Acta Neurol Scand 2003; 108:136–8. 11 Jensen P, Bril V. A comparison of the effectiveness of intravenous immunoglobulin and plasma exchange as preoperative therapy of myasthenia gravis. J Clin Neuromuscul Dis 2008; 9:352–5. 12 European Union Clinical Trials Register. Available at: https://www .clinicaltrialsregister.eu/ctr-search/trial/2012-001544-21/ES#A (accessed 4 July 2014).

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Intravenous immunoglobulin for preparing myasthenia gravis patients for thymectomy and other surgical procedures preventing myasthenic crisis.

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