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Gregg J. Silverman, MD
Professor of Medicine
Director, Rheumatic Diseases Core Center
University of California, San Diego
La Jolla, California

New Biologic Therapies for RA

What makes you so excited about the new biologic therapies for rheumatoid arthritis? Why has there been so much recent interest in
B cells?

With the FDA release of rituximab to market for rheumatoid arthritis (RA) in early 2006, I feel that we have entered an exciting era in the development of new therapeutics for the rheumatic diseases. Over the past two decades, our insights into autoimmune pathogenesis, and how cells interact to drive inflammation, have rapidly progressed. These efforts are coming to fruition, with new biologic agents being developed and now becoming available in the rheumatology clinic. Many of the earlier development programs for biologic agents for RA focused primarily on interrupting central cytokine networks, specifically tumor necrosis factor (TNF) and interleukin 1 (IL-1), which are prime end-effector factors in pathologic chronic inflammatory diseases like RA. These biologic agents changed the face of disease-modifying therapy in RA, and our patients have benefited from dramatic improvements in prognosis and quality of life. As a direct consequence, the benchmark for clinical efficacy by which we judge new therapies has been substantially raised. At the same time, postmarketing surveys have shown that anti-TNF agents carry a greatly increased risk for malignancies and serious infections—including sepsis, tuberculosis, and atypical mycobacterial and other opportunistic infections—that appears inherently linked to this potent mechanism of action.¹ There also appears to be an increased risk for congestive heart failure, demyelinating diseases, and systemic lupus erythematosus.²

While therapeutic B-cell targeting is a new idea for most rheumatologists, for hematologist-oncologists it is well accepted. In 1997, rituximab became the first antibody to be released to market for the treatment of cancer (ie, non-Hodgkin's lymphoma [NHL]). Based on its attractive safety and efficacy profile, rituximab has rapidly become part of the standard of care for NHL, and it has been shown to also have efficacy in clinical trials in other forms of B-cell malignancy. While NHL represents a clonal outgrowth of malignant B cells, the pathogenesis of RA is quite different, with many types of leukocytes involved in the synovial sites of inflammation. Moreover, despite experimental evidence of central regulatory roles of T lymphocytes, earlier controlled trials of T-cell–targeted suppression/depletion in RA demonstrated only limited clinical benefits. For many rheumatologists, it was therefore somewhat unexpected that targeted B-cell depletion has proven to be a highly effective therapeutic approach to RA treatment, with clinical responses comparable to those attainable with currently approved TNF-blocking agents. The challenge for rheumatologists/B-cell researchers like myself is to educate our peers regarding the special therapeutic opportunities and mechanisms of action of this new class of biologic therapy. While it has been shown that both seronegative and seropositive RA patients respond to rituximab, we also need to learn when such new agents can provide the greatest benefits during the course of clinical disease progression. I also believe that in the future we may be able to use agents like rituximab in new, more efficacious and potentially more cost-effective dosing and cotreatment regimens. With the expansion of treatment choices and better efficacy, we may see expanding use of biologic therapies in RA in general, and B-cell–depleting agents will likely become accepted approaches for other autoimmune diseases as well.

While rituximab is the first B-cell–depleting agent to be approved for the treatment of a rheumatic disease, others are also in different stages of clinical development. At present, there are a number of additional antibody-based agents in development that also target CD20 or that are directed at other B-cell–specific markers. For example, CD19 and CD22 are also expressed only on B-lineage cells, but because they are expressed at different levels on the cell membrane or are expressed at different stages of lymphocyte differentiation, treatment with antibodies to these targets may have different immunobiologic implications that could convey advantages for inducing B-cell depletion in RA or other immunologic diseases. There are also alternative B-cell–targeted approaches that do not use antibodies but instead use recombinant versions of naturally occurring receptors that can soak up or block essential B-cell survival factors, to indirecly cause the death of B cells. Decoy receptors, like TACI-Ig and BR3-Ig, bind B-cell survival factors like BAFF (B-cell activating factor, also called B-lymphocyte stimulator [BLyS]) as well as the closely related protein factor APRIL (a proliferation-inducing ligand), which are now either at advanced stages of preclinical development or already in clinical trials. There is great hope that these B-cell agents will provide us with new therapeutic opportunities, but much needs to be learned regarding the relative biologic activity, clinical efficacy and safety, and best dosing regimens for these very new types of agents. If one or more succeed in later clinical trials, the lessons learned may help us better identify which other autoimmune conditions may also be responsive. We will also need to consider which types of B-cell–directed therapeutic agents or combination regimens are for the initial induction phase versus which are for use during the maintenance phase of the disease treatment.