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Targeting B Cells – Perspectives in Rheumatic Arthritis
First, the effect of rituximab in patients who did not have detectable patient outcomes. It will also be important to study the other side of the
auto-antibodies is not entirely clear, a situation complicated by high coin to depletion, namely what occurs when B-cells return, which occurs
placebo responses. Second, there remains debate over the optimum dose in most patients several months after therapy. The nature of the
of rituximab. The DANCER study indicated that a difference in clinical reconstitution of B cells may be crucial in determining whether patients
outcomes was seen when two infusions of 1,000mg each were used experience relapse on return of B cells or not. Initial studies have indicated
instead of two infusions of 500mg each, but that this difference was some patterns in the return of B-cells, but correlation with clinical
evident only when the most stringent clinical outcomes were considered outcomes is not yet clear.
8,9
and the two doses seemed equivalent in allowing patients to reach
moderate clinical improvements. The study did confirm that intravenous B-cell depletion, even when repeated, appears to be safe. Following the
methylprednisolone prior to each infusion reduced the incidence of first cycle of rituximab, there appears to be only a marginally increased
infusion reactions (many of which are thought to be due to B cell lysis and incidence of serious infections (mainly respiratory) and this does not
hence much more common after the first infusion), but that oral steroids appear to change with further infusions. Importantly, this is also the case
between the two infusions were unnecessary for either safety or efficacy. in those patients whose immunoglobulin (Ig) levels fall below the lower
limit of normal, as happens to IgM in approximately 25% of those
The next major issue to consider arises as a result of the different regimen patients receiving a third cycle of rituximab.
of therapy that rituximab employs. Unlike other agents, it is not
continuously administered but rather a response is expected after a short The full safety profile of rituximab will become more apparent as its use
course of two infusions. Eventually, in most patients, these responses increases following licence approval. Concern over B-cell depletion has
diminish and patients can then be re-treated. Data from extension studies been one of the reasons behind the development of agents that
of the studies indicate that in patients who are inadequate responders to modulate or partially deplete B cells. A number of these agents are
anti-TNF, the median time to repeat treatment is 30 weeks. Repeat currently in clinical development.
treatment appears to be as effective as the initial course, and in fact may
be more effective, possibly due to the fact that patients are receiving Belimumab, a fully humanised monoclonal antibody against
further therapy without deteriorating to the disease activity levels prior to B-lymphocyte stimulator (BlyS), has been well tolerated and has shown
receiving the initial course of rituximab. Furthermore, the efficacy of some clinical response in phase II studies.
10
However, further research is
rituximab appears to persist into the third and fourth cycle of repeat required to demonstrate a wider range of responses, and particularly to
therapy, although the numbers of patients from which this data is derived demonstrate any dose effect. TACI-Fc Ig binds to B-cell activating factor
is relatively small.
6
(BAFF), thereby preventing its binding to receptor, and has shown
selective binding and a suitable safety profile in murine and monkey
Rituximab therefore offers a novel approach to therapy in that it is aimed studies;
11
further trials in humans are now under way. Finally, humanised
at a new target in RA and offers a different treatment regimen. versions of anti-CD20 agents are becoming available, including
However, this latter brings a new challenge in that clinicians and ocrelizumab, a fully humanised version of rituximab, and HuMax-CD20,
patients need to be aware of disease relapse, since the current treatment which targets a novel epitope of CD20.
strategy delivers responses but these will not be sustained in most cases.
Ideally, we would have a treatment strategy that would either deliver The strategy of targeting B cells in RA has therefore moved rapidly from
consistent control of disease activity from the outset or could anticipate being rediscovered as a scientific interest to being available in the clinical
and treat before impending relapse. Much current research is directed at arena. Rituximab has attracted most attention as the first agent in the
why different patients display differing patterns of response and field and its initial efficacy and safety profile appear encouraging; more
whether it is possible to predict outcomes. It was initially thought that study will reveal its long-term safety profile, as well as ways to optimise
rituximab therapy produces uniform B-cell depletion in all patients, but therapeutic regimens. Furthermore, the advent of newer agents targeting
more sensitive analysis of peripheral blood has identified differences in B cells may allow us to manipulate the body’s immunological repertoire
the depth of depletion and potential correlation of this with depth and with more sophistication. Undoubtedly, many RA patients are
duration of response.
7
inadequately served by current therapies and B-cell targeting is a valuable
addition to the clinical armamentarium, as well as advancing our
This suggests that the depth of B-cell depletion is important in influencing understanding of the disease itself. ■
1. Edwards JC, Cambridge G, Abrahams VM, et al., Do self- 5. Panayi GS, B cells: a fundamental role in the pathogenesis of antibodies in rheumatoid arthritis, Arthritis Rheum, 2006;54(8):
perpetuating B lymphocytes drive human autoimmune disease?, rheumatoid arthritis, Rheumatology, 2005;44 Suppl 2:ii3–ii7. 2377–2286.
Immunology, 1999;97:188–196. 6. Keystone E, Fleischmann R, Emery P, et al., Long-term efficacy 10. McKay J, Chwalinska-Sadowska H, Boling E, et al., Belimumab
2. Emery P, Fleischmann RM, Filipowicz-Sosnowska A, et al., The and safety of a repeat treatment course of rituximab in (BmAb), a Fully Human Monoclonal Antibody to B-Lymphocyte
efficacy and safety of Rituximab in Patients with Active rheumatoid arthritis patients with an inadequate response to Stimulator (BLyS), Combined with Standard of Care Therapy
Rheumatoid Arthritis Despite Methotrexate Treatment: Results one or more TNF inhibitors, Ann Rheum Dis, 2006;54(suppl II): Reduces the Signs and Symptoms of Rheumatoid Arthritis in a
of a Phase IIb Double-Blind, Placebo-controlleds, Dose-ranging 323. Heterogenous Subject Population, Arthritis Rheum, 2005;
Trial (DANCER), Arthritis Rheum, 2006;54:2793–806. 7. Dass S, Rawstron AC, Vital E, et al., Specific peripheral blood B- 52(9, suppl):S710.
3. Cohen SB, Emery P, Greenwald M, et al., Rituximab for lineage cells predict response to rituximab therapy in RA: a 11. Peano S, Ponce R, Bertolino M, et al., Nonclinical Safety,
Rheumatoid Arthritis Refractory to Anti-Tumor Necrosis Factor study with high sensitivity flow-cytometry, Ann Rheum Dis, Pharmacokinetics, and Pharmacodynamics of TACI-Ig, a Soluble
Therapy, Arthritis Rheum, 2006;54:2793–806. 2006;65(suppl II):185. Receptor Fusion Protein Antagonist of BLyS (B Lymphocyte
4. Buch MH, Seto Y, Bingham SJ, et al., C-reactive protein as a 8. Leandro MJ, et al., Reconstitution of peripheral blood B cells Stimulator) and APRIL (A Proliferation-Inducing Ligand),
predictor of infliximab treatment outcome in patients with after depletion with rituximab in patients with rheumatoid Arthritis Rheum, 2005;52(9, suppl):S285.
rheumatoid arthritis: defining subtypes of nonresponse and arthritis, Arthritis Rheum, 2006;54(2):613–20.
subsequent response to etanercept, Arthritis Rheum, 2005);52: 9. Roll P, Palanichamy A, Kneitz C, et al., Regeneration of B cell
42–8. subsets after transient B cell depletion using anti-CD20
EUROPEAN MUSCULOSKELETAL REVIEW 2007 15
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