B cell depletion in progressive MS appears to be marginal

Castillo-Trivino T, Braithwaite D, Bacchetti P, Waubant E. Rituximab in relapsing and progressive forms of multiple sclerosis: a systematic review. PLoS One. 2013 ;8(7):e66308

BACKGROUND:Rituximab is an anti-CD20 monoclonal antibody approved for non Hodgkin lymphoma and rheumatoid arthritis. It is being considered for the treatment of MS.
OBJECTIVES:To evaluate the efficacy and safety of rituximab for MS treatment.
DATA COLLECTION:Studies were selected if they were clinical trials, irrespective of the dosage or combination therapies.
MAIN RESULTS: Four studies with a total of 599 patients were included. One assessed the efficacy of rituximab for primary progressive (PP) MSwhile the other three focused on relapsing-remitting (RR) MS. In the PPMS study, rituximab delayed time to confirmed disease progression (CDP) in pre-planned sub-group analyses. The increase in T2 lesion volume was lower in the rituximab group at week 96 compared with placebo. For the RRMS studies, an open-label phase I study found that rituximab reduced the annualized relapse rate to 0.25 from pre-therapy baseline to week 24, while in the randomized placebo-controlled phase II trial, annualized relapse rates were 0.37 in the rituximab group and 0.84 in the placebo group (p = 0.04) at week 24. Rituximab dramatically reduced the number of gadolinium-enhancing lesions on brain MRI scans for both RRMS studies. Off-labelrituximab as an add-on therapy in patients with breakthrough disease on first-line agents was associated with an 88% reduction when comparing the mean number of gadolinium-enhancing lesions prior to and after the treatment. Although frequent adverse events classified as mild or moderate occurred in up to 77% of the patients, there were no grade 4 infusion-related adverse events. A

UTHOR’S CONCLUSION: Despite the frequent mild/moderate adverse events related to the drug, rituximab appears overall safe for up to 2 years of therapy and has a substantial impact on the inflammatory disease activity (clinical and/or radiological) of RRMS. The effect of rituximab on disease progression in PPMS appears to be marginal.

I am really happy that the blog is empowering you guys. 

However, with all this knowledge you  can ask some tough questions that we can't answer, because we don't know the answer. (Does this make us look stupid..or just human)  or we can't answer because the blog is not the correct forum for us to answer. 

However the musing of scientists can obviously get you guys thinking and you can put "2 and 2 together".

Whilst ProfG has built up the idea that MS DMT may be killing a causative infection that prevent relapsing MS, some other scientists have come up with the idea of B cells in the brain causing progressive MS, because they find progressive MSers having B cell clusters in their brains. 

Therefore pwMS may think about giving up their T cell therapies in favour of anti-B cell treatment is the way because of we have present the argument that way, but there are always differences in opinion.

However it has to be said that some pathologists think this is just the product of the BBB, not the blood brain barrier but the British Beer-drinking Body (pathologists & nothing to do with me:) seeing things that others can't see. 

This has given people the thought that depleting B cells is going to be good for PPMS. However the data at present does not support this idea.  It is clear that RRS responds to CD20-B cell depletion and whilst some PPMSers respond to anti-CD20 depletion, to date it is only relapsing PPMSers or PPMSers with gadolium-enhancing lesions who show clear benefit.

Some people think that this is because immunosuppression of the white cells in the blood can inhibit relapses but the drugs can't reach the immune response within the brain, because of the BBB (blood brain barrier) and so don't work. Therefore some people think if they inject anti-B cell therapy into the brain it will work.

Cyclophosphamide is an anti-B cell drug and is one of the few MS drugs that can get into the brain in high concentrations to have an effect.  This is used at very high concentrations in HSCT to kill immune cells and get the stemcellsto come into the blood.This ose is effective at inhibiting relapsing EAE. This is the exclusively-immunology world-view held by many senior people. I no longer buy into this idea and think that the immune response preconditions a neurodegenerative effect that no longer responds to immunotherapy that blocks relapses ( I could be wrong). So you need to think outside the immunological box if you want to really get to grips with progressive MS. 

This concept is supported by the HSCT as it appears that progressive MS responds poorly. Likewise so does progressive MS respond poorly to B cell depletion as shown in this analysis.

In reality I believe that the immune response is part of the problem and solution of PPMS/SPMS and optimal therapy will require combinations of treatment to protect and repair and stop immunity in the CNS