Rituximab is an effective treatment for refractory myasthenia gravis, especially for patients who are antibody positive. It works by depleting B cells and plasma cells to reduce autoantibody production. Rituximab administration typically involves 4 weekly infusions followed by 2 monthly infusions and may produce persistent symptom improvement for many patients lasting months or years with only 1-2 treatment cycles. Potential infusion-related side effects include hypotension, fever, and chills but are usually mild and self-limiting.

1. RITUXIMAB IN TREATMENT-REFRACTORY MYASTHENIA
GRAVIS
ADE WIJAYA, MD
FEBRUARY 2018

2. INTRODUCTION
 Myasthenia gravis (MG) is a rare disorder of the neuromuscular junction, caused by antibodies (Ab)
against postsynaptic membrane proteins
 AChR-Ab can be detected in up to 85–90 % of MG patients
 40 % of patients with AChR-negative MG have serum Ab to the muscle-specific tyrosine-kinase (MuSK).
Meriggioli MN, Sanders DB (2012) Muscle antibodies in myasthenia gravis: beyond diagnosis? Expert Rev Clin Immunol 8:427–438
Verschuuren JJ, Huijbers MG, Plomp JJ et al (2013) Pathophysiologyof myasthenia gravis with antibodies to the acetylcholine receptor, muscle-specific kinase and low-density lipoprotein receptor-related protein 4.
Autoimmun Rev 12:918–923

3. Murai, H. (2014). Myasthenia gravis: past, present and future.Rinsho shinkeigaku= Clinical
neurology, 54(12), 947-949.
Mori, S., Kubo, S., Akiyoshi, T., Yamada, S., Miyazaki, T., Hotta, H., ... & Miyazawa, A. (2012). Antibodies
against muscle-specific kinase impair both presynaptic and postsynaptic functions in a murine model of
myasthenia gravis. The American journal of pathology, 180(2), 798-810.

4. INTRODUCTION
 Rituximab (RTX), is a mouse/human chimeric IgG1 monoclonal antibody that binds to CD20 B
lymphocytes surface antigen, which is involved in B-cell activation, differentiation and growth
 Initially developed for B-cell lymphoma and the rheumatoid arthritis
 Recent studies have suggested that administration of RTX can relieve symptoms in several other
autoimmune diseases and it has been recently employed for the treatment of patients with refractory or
severe MG
Reff ME, Carner K, Chambers KS et al (1994) Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 83:435–445
Gu¨rcan HM, Keskin DB, Stern JN, Nitzberg MA, Shekhani H, Ahmed AR (2009) A review of the current use of rituximab in autoimmune diseases. Int Immunopharmacol 9:10–25
Iorio R, Pittock SJ (2014) Neuromyelitis optica and the evolving spectrum of autoimmune aquaporin-4 channelopathies. Clin Exp Neuroimmunol 5:175–187
Iorio R, Assenza G, Tombini M, Colicchio G, Della Marca G, Benvenga A, Damato V, Rossini PM, Vollono C, Plantone D, Marti A, Batocchi AP, Evoli A (2014) The detection of neural autoantibodies in patients with
antiepileptic-drug-resistant epilepsy predicts response to immunotherapy. Eur J Neurol

5. MECHANISM OF ACTION
 RTX primarily acts by depleting the precursors of plasma cells
 RTX may influence the T-cell response, which has an important role in MG providing the ‘‘help’’ to B cells
for autoantibody production
 First, RTX can increase the percentage of T regulatory cells
 Second, RTX may abrogate the antigen-presenting function of B cells, redirecting it to other cells, such
as dendritic cells and/or macrophages, which would then be able to stimulate different T-cell subsets
 Depleting T-cell subset producing pro-inflammatory cytokines
Iorio, R., Damato, V., Alboini, P. E., & Evoli, A. (2015). Efficacy and safety of rituximab for myasthenia gravis: a systematic review and meta-analysis. Journal of neurology, 262(5), 1115-1119.

7. DOSING & ADMINISTRATION
 375-mg/m2 rituximab infusions weekly for 4 consecutive weeks then monthly for 2 months or with a
repeat course in 6 months
 Premedication with diphenhydramine and acetaminophen may attenuate infusion-related events
 Because transient hypotension may occur during infusion, consider withholding antihypertensive
medications 12 hr prior to infusion
 Administer by slow IV infusion only
 First IV infusion rate: Start 50 mg/hr; increase by 50 mg/hr q30min, not to exceed 400 mg/hr
 Subsequent IV infusion rate: Standard IV infusions: Start 100 mg/hr, increase by 100 mg/hr q30min, not
to exceed 400 mg/hr;
 Drug is associated with hypersensitivity reactions which may respond to adjustments in infusion rate
Tandan, R., Hehir, M. K., Waheed, W., & Howard, D. B. (2017). Rituximab treatment of myasthenia gravis: A systematic review.Muscle & nerve, 56(2), 185-196.
reference.medscape.com

8. INFUSION-RELATED ADVERSE EFFECTS
 Hypotension, bronchospasm, angioedema, fever, and chills have occurred as part of an infusion-related
symptom complex
 Interrupt infusion for severe reactions and resume at a 50% reduction in rate (eg, from 100 to 50 mg/hr)
when symptoms have completely resolved
 Treatment of these symptoms with diphenhydramine and acetaminophen is recommended
 Additional treatment with bronchodilators or IV saline may be indicated
 Discontinue infusions if serious or life-threatening cardiac arrhythmias
reference.medscape.com
Silvestri, N. J., & Wolfe, G. I. (2017). Rituximab in treatment-refractory myasthenia gravis. JAMA neurology, 74(1), 21-23.

9. SUMMARY
 Rituximab is an effective treatment for AChR- and MuSK-antibody positive MG patients, typically in most
with moderate to severe refractory disease already being treated with several immune-based therapies
 More effective in MUSK-antibody positive MG
 Post-treatment antibody titers decreased in both responders and non-responders to rituximab.
 Half of the patients with AChR antibody–positive MG only needing 2 cycles.
 Other options in refractory MGsuch as maintenance IVIg or PE provide benefits that last only a few
weeks per cycle and mandate repeated administration that can stretch for years, 1 or 2 cycles of
rituximab appear to produce persistent improvement lasting months or years.
 Rare longterm adverse effect reported  PML
Iorio, R., Damato, V., Alboini, P. E., & Evoli, A. (2015). Efficacy and safety of rituximab for myasthenia gravis: a systematic review and meta-analysis. Journal of neurology, 262(5), 1115-1119.
Silvestri, N. J., & Wolfe, G. I. (2017). Rituximab in treatment-refractory myasthenia gravis. JAMA neurology, 74(1), 21-23.
Tandan, R., Hehir, M. K., Waheed, W., & Howard, D. B. (2017). Rituximab treatment of myasthenia gravis: A systematic review.Muscle & nerve, 56(2), 185-196.