Update on B Lymphocyte Depletion Therapy
(13.06.2005)
B cell depletion therapy is now in trials for a number of autoimmune conditions. In many of these conditions
major improvement has been seen in a good proportion of cases in pilot studies, particularly
in rheumatoid arthritis, lupus, dermatomyositis,
autoimmune neuropathies, immune thrombocytopenic purpura and haemolytic anaemia.
In rheumatoid arthritis benefit has now been confirmed by results
from a formal randomised controlled trial, and further trials are expected to report very soon.
The first major trial suggests that about 80% of patients can benefit and that
about 45% of patients gain major benefit. This level of improvement is similar to that seen with
drugs like etanercept (Enbrel) or infliximab (Remicade) although it is difficult to make direct
comparisons. The advantage of B cell depletion is that a short course of treatment lasts many months
and in open trials up to almost four years in some cases.
So far the evidence from treatment of a few patients is that B cell depletion has no effect
on psoriasis. It had no effect in the first few cases of arthritis not associated with autoantibodies
("seronegative arthritis")
but further trials may show that some seronegative cases can benefit. The absence of response in psoriasis
is not unexpected. In one case
of Crohn's disease B cell depletion was actually followed in the short term by a worsening of the
condition. Again, this is not so surprising. Crohn's disease is commonly associated with autoantibodies
but not in all cases and their involvement in the disease is less clear than in arthritis.
Trials are now in progress in multiple sclerosis and hopefully some indication of results may be
available in 2005.
The treatment generally appears to be safe but more information is needed to confirm this.
There is a possible suggestion from the treatment of rheumatoid arthritis that
there may be an increase in risk of chest infections. If susceptibility to infection is a real
problem it seems unlikely that it will be greater than with some other treatments used for
rheumatoid arthritis that suppress other parts of the immune system. However, it is something
that will need careful further observation.
So far it has proved possible to repeat the
treatment whenever needed with good results. However, what we do not know is whether or not repeated
treatments may weaken the immune system over a longer period of time. Again, further careful
studies are needed.
The main drug used for B cell depletion is rituximab, which belongs to a family of genetically
engineered drugs known as monoclonal antibodies.
Many of the studies in autoimmune disease show that rituximab works well on its own. The recommended
dosage for rituximab in other conditions is an intravenous infusion of 375mg per metre squared of
body surface area,
once a week for four weeks. In recent studies in rheumatoid arthritis and lupus the drug has been
given as two
double doses instead of four single doses, each double dose being rounded up to 1 gram (2 grams total,
not dependent on body surface area).
A number of studies have added steroid drugs to the rituximab, just for the short period of the
infusions. These may add to the B cell depletion effect and also prevent allergic reactions to
rituximab. However, it seems likely that the addition of steroids is not essential.
The first major trial in rheumatoid arthritis indicates that rituximab works very well if given
with steroid cover. Treatment with rituximab alone, under steroid cover, produced a 50% or greater
improvement (ACR50 grade) in 43% of patients, which is probably as good as any other available
therapy. The patients studied were also taking methotrexate throughout the study,
but there is no reason to think
that this contributed to the improvement following rituximab. (Other information suggests that
methotrexate is unlikely to be needed for the rituximab to work, that is, it is unlikely to be
synergistic.) Patients who had their methotrexate
stopped at the same time as being given rituximab did slightly less well. This
means that the effects of rituximab and methotrexate can probably be additive.
The trial also indicated that results are likely to be better if rituximab is combined with another drug
which is traditionally used for B cell depletion, cyclophosphamide (cytoxan). Cyclophosphamide can
make people feel sick and has other potential problems with side effects, so it is not as attractive
as a treatment as methotrexate, even though cyclophosphamide acts on B cells together with rituximab
whereas methotrexate probably does not.
The companies involved in the production of rituximab have indicated that they hope to obtain
a license for use in rheumatoid arthritis for patients unable to benefit from other licensed therapies,
such as anti_TNF agents, by early 2006. In lupus further trials will be needed but several centres
are using rituximab quite frequently for severe forms of lupus unresponsive to standard therpies.
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