Jonathan_Edwards replied to jvandermeer on 28 Oct 2011 at 17:10 GMT:
The criticism made here contains several errors. There is nothing peculiar about the late response.
It is to be expected.
I was responsible for both the phase I and the proof of concept phase II (NEJM 2004) studies in rheumatoid disease, which formally established the validity of B cell depletion in autoimmune disorders. From the very outset in 2000 we reported that responses could take many months to develop, in line with autoantibody decline. An partial early response element was usually seen as well but was consistent with adjuvant use of corticosteroid or other agents.
I am not aware of any hard evidence for rituximab working in autoimmune disorders not mediated by autoantibodies.
Where there have been proper trials, as for psoriatic arthropathy, the results have been clearly negative as far as I am aware.
The suggestion that rituximab works through an action on antigen presentation is pure speculation for which I cannot think of any positive supportive evidence and there is much unsupportive evidence, including the very common very slow response kinetics that follow antibody decline. This is an idea popularised before we actually had any data and still often repeated in reviews despite the wealth of evidence against.
It is hard to see how killing B cells at day one would affect antigen presentation by B cells six months later, putatively responsible for further decline in inflammation to nine months.
The trial's authors give the account that is by far the most consistent with the data - that benefit occurs as short lived plasma cells die off and autoantibodies decline but that benefit is often incomplete as expected from the existence of long lived plasma cells and continued lower levels of antibody.
The absence of a clearly defined autoantibody population in this particular group is not in any way surprising. It is likely to be immunopathologically heterogeneous and new autoantibodies are being found all the time.
Jonathan Edwards Professor Emeritus, UCL
No competing interests declared.
(Jonathan Edwards, Professor Emeritus, Department of Medicine, University College London)
1 comment:
Psoriatic arthropathy - these patients did not respond positively in the norwegian test either. But as you might be aware of - 67 % did in this double blinded test ;)
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