Title: Ravulizumab for treating generalised myasthenia gravis [ID4019]
Funder: Department of Health and Social Care

Abstract: Myasthenia gravis is a long-term condition which causes certain muscles to become weak and tire easily. It is caused by a problem with the immune system, which mistakenly produces antibodies against the nicotinic acetylcholine receptor (AChR) “or muscle-specific tyrosine kinase (MuSK). The antibodies block the chemical signals between nerves and muscles, meaning that muscles are unable to tighten (contract). The thymus gland is the main source of the abnormal antibodies. The muscles around the eyes are commonly affected first, which causes drooping of the eyelid and double vision (ocular myasthenia gravis). Muscles controlling facial expression, chewing, swallowing, speaking and, less commonly, breathing and neck and limb movements can also be affected. When muscle groups other than the eye muscles are affected, the condition is known as generalised myasthenia gravis. In very severe cases, muscle weakness causes life-threatening difficulties with breathing and swallowing. This is known as myasthenic crisis. _x000D_ _x000D_ Myasthenia gravis affects about 15 in every 100,000 people in the UK. [1] It can develop at any age, but most commonly affects women under 40 years of age and men over 60 years of age. [2],[3] Around 80% of people with ocular myasthenia gravis will progress to generalised myasthenia gravis within 2 years.[2] About 80% to 90% of people with myasthenia gravis have detectable antibodies against AChR, while 3% to 7% have antibodies against MuSK.[4-6] In around 10% of people antibodies are not detected.[7] It is difficult to estimate the number of people with myasthenia gravis whose disease does not respond to currently available treatments; estimates range from about 10% to 20%. [8],[9] _x000D_ _x000D_ Mild myasthenia gravis and some cases of moderate disease are usually treated with cholinesterase inhibitors such as pyridostigmine which delay the breakdown of acetylcholine, the chemical which stimulates muscle contraction.[10] If treatment with cholinesterase inhibitors is not effective, or they are not suitable for long term use, then corticosteroid tablets such as prednisolone are used. Immunosuppressive therapies such as azathioprine are offered in addition to steroids, with the aim of reducing the steroid dose over time. If the disease does not respond to the first immunosuppressive treatment, alternative immunosuppressants may be offered (including mycophenolate mofetil, methotrexate, ciclosporin and rituximab). Surgery to remove the thymus gland (thymectomy) is an option for people with mild disease and antibodies against AChR, and people with moderate disease. Myasthenic crisis is treated in hospital with mechanical ventilation, intravenous injections of antibodies (immunoglobulins) from healthy donor blood, or by removing plasma from the blood to reduce the number of abnormal antibodies (known as plasmapheresis or plasma exchange) and supportive care. [10]_x000D_ _x000D_ References_x000D_ 1 Spillane J, Higham E, Kullmann DM (2012) Myasthenia gravis. BMJ; 345:e8497._x000D_ 2 Patient (2017) Myasthenia Gravis. Accessed May 2022._x000D_ 3 Meriggioli MN and Sanders DB (2009) Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity. Lancet Neurology; 8(5):475-90._x000D_ 4 Guptill JT and Sanders DB (2010) Update on muscle-specific tyrosine kinase antibody positive myasthenia gravis. Current Opinion Neurology; 23(5):530-5._x000D_ 5 Ruff RL and Lisak RP (2018) Nature and action of antibodies in myasthenia gravis. Neurologic Clinics; 36(2):275-91._x000D_ 6 Maddison P, Ambrose PA, Sadalage G et al. (2019) A Prospective Study of the Incidence of Myasthenia Gravis in the East Midlands of England. Neuroepidemiology; 53(1-2):93-99._x000D_ 7 Leite M, Jacob S, Viegas S et al. (2008) IgG1 antibodies to acetylcholine receptors in 'seronegative' myasthenia gravis. Brain 131:1940-52_x000D_ 8 Mantegazza R and Antozzi C (2018) When myasthenia gravis is deemed refractory: clinical signposts and treatment strategies. Therapeutic Advances in Neurological Disorders; 11:1756285617749134._x000D_ 9 Schneider-Gold C, Hagenacker T, Melzer N et al. (2019) Understanding the burden of refractory myasthenia gravis. Therapeutic Advances in Neurological Disorders; 12:1756286419832242._x000D_ 10 BMJ Best Practice (2021) Myasthenia gravis. Accessed May 2022.

Lay abstract: To appraise the clinical and cost effectiveness of ravulizumab within its marketing authorisation for treating generalised myasthenia gravis.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;MUSCULOSKELETAL