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Rheumatoid Arthritis
Targeting B Cells – Perspectives in Rheumatic Arthritis
a report by
Shouvik Dass and Paul Emery
Academic Unit of Musculoskeletal Disease, University of Leeds
B cells and the therapies that target them have recently become the focus would appear to include potentially increased risks of malignancy,
of intense interest in the treatment of rheumatoid arthritis (RA). Scientific especially lymphoma, and of certain types of infections. Other concerns
insights into the roles of B cells as key players in the pathogenesis of RA
1
in clinical practice have been the development of lupus-like illnesses and
have been followed this year by the publication of multicentre, neurological disorders following anti-TNF therapy.
randomised clinical trials demonstrating the safety and efficacy of the
selective B-cell-depleting agent rituximab in RA.
2,3
On the basis of these B-cell-directed therapies have emerged in the frontline of the search for
trials, rituximab has been licensed by the US Food and Drug new treatment, although other cells, cytokines, and mechanisms are also
Administration (FDA) and the European Agency for the Evaluation of targets of novel therapies. Scientific interest in the role of B cells has
Medicinal Products (EMEA) for use in RA patients who have had an recently increased after many years in which T cells were regarded as the
inadequate response to anti-tumour necrosis factor (TNF) therapy. The key factor in RA pathogenesis. The most obvious role for B cells to play
specific license points to another reason for interest in B cell therapies, revolves around the production of auto-antibodies and it may be that in RA
namely the recognition that significant numbers of RA patients have there is a vicious cycle of auto-antibody production and loss of immune
clinical needs that are not fully met by currently available therapies. tolerance. However, not all cases of autoimmune disease, and indeed RA,
are characterised by auto-antibody production and B cells also have roles in
The advent of anti-TNF therapies in RA has led to considerable advances antigen presentation and T-cell activation and in the production of
in the treatment of RA patients, both in terms of clinical outcomes and inflammatory cytokines. Furthermore, it is known that the synovium in RA
underlying structural disease, and has hugely altered the aims and can carry B-cells and produce growth factors to enhance B cell survival.
5
expectations of patients and healthcare professionals when dealing with
RA. However, it has become increasingly clear that there is still a burden These scientific understandings underpinned efforts to use B-cell-depletion
of disease activity that is not addressed by anti-TNF therapy. Some therapy in RA. The chimaeric monoclonal antibody rituximab, licensed for
patients may either not respond to therapy from the outset, or lose an the treatment of non-Hodgkin’s lymphoma in 1997, seemed to have
initial response.
4
The quality and depth of response is also variable, with potential as an ideal agent. Rituximab targets the CD20 antigen expressed
moderate disease activity still detectable in significant numbers of on the surface of certain B-cells; it is not expressed on either stem cells or
patients who have nevertheless demonstrated some improvement from pre-B cells, nor is it expressed on plasma cells, which are the major
the severe levels before receiving biologic therapy. In addition to issues of antibody-producing cells. CD20 is also a useful target because it is not
efficacy, the ‘real life’ use of anti-TNF therapy after licensing and the internalised or shed on binding the anti-CD20 antibody.
subsequent collection of data in patient registries has increased our
awareness of the potential side effects and risks of such therapies. These Rituximab was originally used in a few individual cases, before a clinical
trial program was established. Results have now been published from a
Phase IIa study, the Phase III DANCER study (Dose-Ranging Assessment
Shouvik Dass is currently Specialist Registrar and Research
International Clinical Evaluation of Rituximab in RA) and the pivotal
Fellow in Rheumatology based at the Academic Unit of
Musculoskeletal Disease at the University of Leeds and the
Phase IIb REFLEX study (Randomised Evaluation oF Long-term Efficacy of
Leeds Teaching Hospitals Trust, UK. He attended medical Rituximab in RA). The last of these demonstrated the benefit of two
school at Cambridge University. His major research work is in
infusions of 1,000mg of rituximab, given two weeks apart, with
B cell depletion therapy allied with clinical interests in both
resistant rheumatoid arthritis and connective
continuing background methotrexate over methotrexate alone at six
tissue disease.
months after therapy in patients who had had an inadequate response
to anti-TNF agents. This benefit was apparent in measures such as
Paul Emery is Arthritis Research Campaign Professor of
response by the American College of Rheumatology (ACR) criteria, as
Rheumatology and Head of the Academic Unit of
Musculoskeletal Medicine at the University of Leeds. He is
well as disease activity responses based on the European League Against
Clinical Director of Rheumatology at the Leeds Teaching
Rheumatism (EULAR) criteria. Improvements were seen across the
Hospitals Trust in the UK. Professor Emery’s research
individual components of such criteria, including patient and physician
interests centre around the immunopathogenesis and
immunotherapy of rheumatoid arthritis and connective tissue responses, swollen and tender joint counts and reduction in
diseases. He has a special interest in the factors leading to
inflammatory markers. This study formed the basis for the regulatory
persistent inflammation and is a founder member of Early
Rheumatoid Arthritis Study, Leeds Early Arthritis Project,
approvals granted in 2006.
Yorkshire Early Arthritis Register and the Leeds
Musculoskeletal Imaging Group.
However, the studies provoked further questions, as well as offering
answers regarding the safety and efficacy of rituximab therapy in RA.
14 © TOUCH BRIEFINGS 2007
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