Rituxan and Multiple Sclerosis

Question from an MS Patient: 
Is Rituxan an effective treatment for SPMS? What are the benefits or disadvantages? i.e. pros & cons etc. Are there any life-threatening side effects? Would you consider this is a good drug to treat SPMS long term? Do you feel the drug can cause complications-manifest other diseases or illnesses? Are there any results from clinical trials conducted using Rituxan published?

Rituxan (Rituximab) is a chimeric monoclonal antibody that is currently approved for the treatment of two forms of cancer (CD20 positive Non Hodgkin’s Lymphoma (NHL) and chronic lymphocytic leukemia (CLL)) and two immune medicated disorders (moderate to severe rheumatoid arthritis and Wegener’s granulomatosis). It was first approved in 1997 and has been widely used off label to treat a number of rare immune medicated conditions, including neuromyelitis optics (NMO), often with dramatic success. In fact is it currently considered the first line treatment for NMO in many centers around the world. It binds to a protein expressed on the surface of B Cells called CD20 and causes complement mediated lysis of these cells lasting for variable periods of time depending on the dose administered. The mechanism of action in MS is unclear; B cells clearly play a role in the inflammatory response in MS and their elimination seems to benefit many patients. What is unknown is the exact role played by the B cell; for instance some believe the B cell only becomes a problem in MS when co-infected with Epstein Barr Virus.  

Studies of Rituximab in the treatment of relapsing or progressive forms of MS have been few, yet it remains a key treatment option by many MS specialists for certain situations; namely, as an induction therapy for patients with an aggressive onset to their condition, as ongoing treatment in relapsing patients not responsive to other therapies including tysabri or in patients rapidly transitioning to secondary progressive MS despite other available treatment options.  

Why would a drug not even approved by the FDA be considered such an important treatment option by MS specialists? First, those studies that have been done in relapsing forms of MS demonstrate rather dramatic benefits that persist for 6 to 12 months after treatment. MS specialists using the drug in practice report similar benefits in their patients. Studies in progressive forms of MS have reported mixed results which can be expected given the challenges of treating MS at this stage of the disease.  The large phase III study by Genentech in primary progressive MS was a negative study when the entire study population was considered in the analysis. When considering only those patients under the age of 51, those patients with gadolinium enhancing lesions at the beginning of the study or patients with both features, rituximab given every 6 months for 4 courses of treatment significant reduced the rate of sustained disability progression.  A small retrospective analysis of 25 secondary progressive MS patients treated with rituximab every 6 months at the University of Massachusetts in Worcester reported that 84% of patients stabilized or improved while on treatment.

Rituximab is generally safe in most MS patients. The most common side effects are caused by infusion reactions which decrease over time and can be further decreased by administering corticosteroids prior to the infusion. There is also a slight increase in serious infections, though these are treatable. Progressive Multifocal Leukoencephalopathy (PML) has been reported but does not appear as frequently as in Tysabri treated patients. What is unknown are the long term consequences of treatment with Rituximab and the most appropriate dose and dosing interval. Most current dosing regimens are based on the very high doses used to treat cancers, yet we were able to achieve a very good response in relapsing patients given 1/20th of this dose (100 mg) every 6 months for over 3 years of continuous treatment.

Further studies of rituximab are not likely to occur since there is no further patent protection. There are several other monoclonal antibodies in MS clinical trials that target CD20 and delete B cells including ocrelizumab and ofatumumab. Whether these newer treatments offer improvements in safety or efficacy in comparison to rituximab is unclear at this time.

--Dr. Kinkel

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