Neuromuscular Disease

The Role of Rituximab in the Treatment of Myasthenia Gravis Olivier Benveniste1

and David Hilton-Jones2

1. Professor of Internal Medicine, Institute of Myology, Pitié-Salpêtrière Hospital, Pierre and Marie Curie University; 2. Clinical Director, Myasthenia Centre and Muscle and Nerve Centre, Department of Neurology, John Radcliffe Hospital, University of Oxford

Abstract

Rituximab, a chimaeric monoclonal antibody against CD20, depletes B cells. It was initially approved for the treatment of B-cell lymphomas, but more recently has been approved for use in rheumatoid arthritis. It has been used extensively ‘off-label’ for the treatment of other autoimmune diseases with some evidence of efficacy, but there remain some as yet unanswered concerns about safety. Myasthenia gravis is the paradigm of an antibody-mediated disorder, and B cells are believed to play a crucial role. This article reviews experience of the efficacy and safety of rituximab in myasthenia gravis and considers predictive factors for the success and failure of rituximab in this disease.

Keywords

Rituximab, myasthenia gravis, antiacetylcholine receptor (anti-AChR), antimuscle-specific tyrosine kinase (anti-MuSK), predictive factors, clinical response

Disclosure: The authors have no conflicts of interest to declare. Received: 20 September 2010 Accepted: 8 November 2010 Citation: European Neurological Review, 2010;5(2):95–100 Correspondence: Olivier Benveniste, Service de Médecine Interne 1, Groupe Hospitalier Pitié-Salpêtrière, 47-83, boulevard de l’Hôpital, 75651 Paris Cedex 13, France. E: olivier.benveniste@psl.aphp.fr

Myasthenia gravis (MG) is an autoimmune disease associated with circulating antibodies, either against the nicotinic acetylcholine receptor (anti-AChR; ~80% of patients with generalised MG) or muscle-specific tyrosine kinase (anti-MuSK, 10% of patients),1

that

induce a dysfunction of neuromuscular transmission owing to loss of functional receptors. Less commonly, MG remains confined to the ocular muscles. Only about 50% of such patients have antibodies detectable by standard assay (almost invariably anti-AChR) and most respond well to moderate doses of steroids without the need for more aggressive immunosuppression. In addition to anticholinesterase drugs, most patients with generalised MG require long-term treatment with steroids and immunosuppressive drugs, of which the most commonly used include azathioprine, mycophenolate mofetil and ciclosporin.2–5

such treatment.2,6 considered, including cyclophosphamide,7 tacrolimus8

Between 5 and 10% of patients remain refractory to Other immunosuppressive drugs may then be and etanercept,9

whose efficiency has not been assessed on the basis of double-blind clinical trials. Intravenous immunoglobulins (IVIg)10 exchange11

and plasma

are used for acute exacerbations while waiting for other treatments to become effective, but have no sustained beneficial effect. Newer effective molecules with a good safety profile are undoubtedly needed.

Rituximab (RTX), a chimaeric monoclonal antibody specific for human CD20 that targets B lymphocytes, was first developed (and licensed) for the treatment of B-cell lymphoma12,13

and is used at a dose of

375mg/m2/body surface area once weekly for four weeks. It was noted that in patients with lymphoma treated with RTX and concomitantly suffering from autoimmune diseases (rheumatoid

© TOUCH BRIEFINGS 2010

arthritis [RA]14

or MG15

) the autoimmune diseases were ameliorated.

Subsequent to these early reports, RTX has been used in many autoimmune diseases where B cells seem to play a role, not only in RA. These pivotal studies16,17

led to the molecule being licensed in

cases of RA resistant to antitumour necrosis factor (anti-TNF) first-line therapy (RTX 1g on days one and 15), and also being used (off-label) in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis,18,19 multiple sclerosis,20,21

thrombocytopenic purpura (ITP)23

systemic lupus erythematosus (SLE),22 and pemphigus.24

immune

To date, the experience of the use of RTX in MG has been mainly in the form of single case reports,15,25–37

short series of patients38–44 and a report

of all 10 MG patients in the UK who were identified through personal contact as having received RTX,45

representing overall to date 53 RTX-

treated MG patients (see Table 1). Among them, 47 were reported as being improved after a follow-up of six to 48 months (see Table 1), with some in complete stable remission. Of the other six patients, three were unchanged, two worsened and one died after RTX treatment (see Table 1). It is highly probable that there is reporting bias and that failures of RTX in MG are not published (either not submitted by authors or rejected by journals), a notable exception being the compilation of all UK-treated patients;45

were described in this study.45

reporting bias and to better evaluate the efficacy and safety of RTX in refractory MG, we are currently conducting a prospective phase II open trial (identifier: NCT00774462). Given that RTX is clearly not 100% effective, it is appropriate to ask whether there are predictive factors for response and, more generally, where if at all RTX should stand in the order of treatment options.

95

it is noteworthy that four of the six failures recorded to date To circumvent this likely positive