In West Yorkshire, UK, one scientist has new hope for patients with autoimmunity. Paul Emery, Arthritis Research Campaign Professor of Rheumatology at the University of Leeds and at Chapel Allerton Hospital sees patients such as those with RA who've gone through all the traditional treatments but with no relief. Emery treats patients with innovative biologic compounds such as MabThera (rituximab), a chimeric mouse-human monoclonal antibody that was originally developed to treat non-Hodgkin's lymphoma. In 2006, the US Food and Drug Administration (FDA) and the European Commission approved this drug as an RA treatment. The most exciting feature of the new MabThera/Rituxan therapy, says Emery, is the positive results: "We were able to take the worst patients - who were nonresponsive to other therapy - and they got better."

RA is among the most common autoimmune diseases, with a prevalence of one percent. Traditional treatment with corticosteroids and disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, treat pain and inflammation, but these compounds have serious side effects, including toxicity and immunosuppression. For many years, research on RA focused on T cells, particularly on inhibition of the tumor-necrosis-factor (TNF) cascade to prevent inflammation. However, approximately 40% of all patients with RA are refractive to treatment with DMARDs and TNF inhibitors.

In the late 1990s, there was growing recognition that B cells, which produce both normal antibodies and autoantibodies (antibodies to self), could play a broader role in the pathology of autoimmune diseases. Jonathan Edwards, professor in connective tissue medicine at University College London, proposed that self-perpetuating B lymphocytes may lie at the heart of autoimmune diseases. He speculated that autoimmune disorders could potentially be treated by eliminating B cells from the body, thus breaking the cycle of autoantibody production, and possibly inducing long-term remission. ¹

Edwards and his colleagues began to explore the use of B-cell depletion therapy. "Our basic research on cellular interaction in RA indicated that it ought to work, so we tried it," says Edwards. His group used rituximab. The antibody binds to the CD20 receptor, which is expressed on the surface of B cells throughout most stages of B-cell maturation. The drug most likely causes destruction of the B cells by a combination of antibody-dependent cell-mediated cytotoxicity, complement-mediated lysis, and induction of apoptosis. In 2002, at the American College of Rheumatology (ACR) annual meeting, Edwards presented promising preliminary results that generated a furor of excitement in the scientific and patient communities.

The groundbreaking results were published in 2004. ² The randomized, double-blind, controlled study examined 161 patients with active RA despite ongoing treatment with methotrexate. The clinical outcome was evaluated using the standard ACR criteria: ACR20, ACR50, and ACR70, which indicate improvements of 20%, 50%, and 70%, respectively, as measured by physician assessment, pain assessment, and levels of acute-phase indicators. After 24 weeks: 73% of patents treated with intravenous rituximab and methotrexate showed an ACR20 versus 38% of the control with methotrexate alone; 43% achieved ACR50 versus 13% in control; and 23% achieved ACR70 versus 5% in control. Patients were also assessed at 48 weeks with slightly lower but similar distributions. There were several adverse effects, but the majority of them were mild. These results indicated an overall positive effect of rituximab treatment.

In a Phase III study, completed in 2006, Emery and his colleagues evaluated the effects of B-cell depletion on 520 patients who were refractive to therapy with both DMARDs and anti-TNF drugs. ³ Patients treated with rituximab demonstrated "huge improvements," describes Emery. "To be honest, our results were better than we had expected." At 24 weeks, in patients treated with rituximab and methotrexate versus methotrexate alone, the ACR20 was 51% versus 18%, the ACR50 was 27% versus 5%, and the ACR70 was 12% versus 1%. The patients treated with rituximab exhibited less fatigue, higher health-related quality of life, and a trend of slower progression of joint structural damage as measured by radiographic progression. What makes these results so significant, says Emery, is that "this is the first therapy that can be effective when patients fail anti-TNF therapy." Emery continues, "The more data we have, the more favorable it looks, especially from a safety standpoint."

Nonetheless, significant challenges and questions remain. Treatment with rituximab does not permanently deplete B cells. The drug seems to clear out the B cells for a few months without changing how the cells function when they return, says Jeffrey Browning, senior director of immunobiology at Biogen Idec in Cambridge, Mass., but other approaches could moderate B-cell response, perhaps permanently. "We need to find out why B-cell depletion does not last longer for all patients," says Edwards. "In some cases it lasts for four to five years, but in most for a shorter period. In theory, it is reasonable to hope that if B-cell depletion is engineered correctly, long-term benefit could be achieved in many cases."

As Emery points out, "rheumatoid arthritis is a lifelong disease." To improve B cell-depletion therapy, he believes that patients need to be medicated with rituximab earlier in the treatment cycle and possibly continue treatment throughout the duration of the disease. According to Emery, his group has conducted as many as six retreatments with positive effects, in some cases over a period of five and a half years. Assessment of the safety and efficacy of sequential, repetitive dosing with rituximab is essential. He cautions that "there may be issues about keeping patients B-cell depleted."

Potential Roles of B Cells in the Immunopathogenesis of RA

B cells participate in a series of pathways in rheumatoid arthritis. These culminate in the production of a range of cytokines, which lead to joint damage.

Source: Randall Stevens of Roche presentation in a 6 November 2006 teleconference.

B cell-depletion therapy also holds great promise for systemic lupus erythematosus (SLE). On Jan. 13, 2007, Heather Won Tesoriero wrote in the The Wall Street Journal : "The last time a new drug was approved to treat lupus, a serious autoimmune disorder that afflicts an estimated 1.5 million Americans, Dwight D. Eisenhower was president." Jennifer H. Anolik, assistant professor of medicine, R. John Looney Jr., professor of medicine, and their colleagues at the University of Rochester aim to change that statistic.

They conducted the first prospective open-label Phase I/II trial to determine the safety and efficacy of rituximab in patients with active SLE. ⁴ Patients were treated with three escalating doses of rituximab, and B-cell depletion was achieved in 11 out of 17 patients. At two and three months, as assessed by the Systemic Lupus Activity Measure score, the 11 patients with B-cell depletion exhibited reduced disease activity, in some cases persisting for 12 months. "The most exciting and perhaps also surprising result is the possibility of inducing remission of disease with such a targeted therapy," observes Anolik.

Several studies indicate that patients with SLE who attain B-cell depletion with rituximab also show significant improvement. Moreover, some patients achieved complete and long-term remission after rituximab treatment, but Anolik cautions, "This probably occurs in only a small fraction of patients. Additionally, although the majority of SLE patients seem to have at least some response, this has only been reported so far in open-label studies, which need to be interpreted with caution."

Other reagents that bind to surface proteins on B cells and could trigger B-cell depletion are also being studied. In particular, epratuzumab, a humanized anti-CD22 monoclonal antibody, from Morris Plains, NJ-based Immunomedics has demonstrated some effectiveness in inducing B-cell depletion in patients with SLE during early clinical trials.

Alternative therapies seek to manipulate B cells by disrupting pathways involved with B-cell survival and proliferation. One likely therapeutic target is a cytokine called B cell-activating factor of the TNF family, also known as BAFF or Blys. An essential signal for B-cell maturation and survival, BAFF acts by binding to three different receptors on B cells: TACI, BCMA, and BAFF-R. Transgenic mice that overexpress BAFF exhibit symptoms similar to SLE. In addition, BAFF appears to be linked to other autoimmune diseases, because patients with SLE, RA, and Sjögren's Syndrome have elevated amounts of BAFF in serum samples. Excess levels of BAFF might prevent the normal apoptosis of B cells.

Belimumab, marketed as LymphoStat-B by Human Genome Sciences, is a human monoclonal antibody to BAFF. The antibody blocks binding of BAFF to its receptors. Several early-phase clinical trials showed that belimumab reduced peripheral B cells and disease activity in patients with SLE.

"The BAFF antagonism approach, in general, shows great promise in terms of what we know about the role of BAFF in SLE disease pathogenesis," says Anolik. "It is also exciting because of the number of different molecular approaches to antagonizing this complex pathway." Additional biological drugs that act as BAFF antagonists include AMG-623 (from Amgen), which is in Phase I trials for SLE, and BR3-Fc (from Genentech), which is in Phase I trials for RA.

Interleukin-6 (IL-6), another cytokine, also plays a role in inflammation and immune-system regulation. IL-6 stimulates B-cell proliferation and activates the transformation of B cells into plasma cells by binding to a membrane-bound and a soluble receptor. Excess production of IL-6 is observed in patients with RA, SLE, juvenile idiopathic arthritis (JIA), and Crohn disease, and IL-6 has been isolated from sites of inflammation. The humanized monoclonal antibody tocilizumab (known also as Actemra), being codeveloped by Chugai and Hoffmann-La Roche, binds to both IL-6 receptors and blocks the ability of IL-6 to stimulate transmembrane signaling. In early clinical studies, the antibody has been effective in treating RA, JIA, and Crohn disease.

Large-scale Phase II studies in Europe and Japan demonstrated significant improvements for patients with RA who were treated with tocilizumab. The European trials analyzed 359 patients who were nonresponsive to methotrexate therapy. ⁵ After 16 weeks, patients treated with tocilizumab plus methotrexate at the highest dose achieved an ACR20 of 74% versus 41% with methotrexate alone; ACR50 was 53% versus 29%, and ACR70 was 37% versus 16%. For monotherapy at the same dose, the ACR20 response was 63% versus 41% for controls. Some side effects were seen, but the compound was mostly tolerated.

Biologic therapies that target B cells are extremely effective and safe, and further studies should hone the clinical use of these compounds. "A dozen potentially very useful drugs are now available, and I think progress rests largely on the opportunity to study different combinations in the context of detailed pharmacodynamic analysis," Edwards speculates. "If we really understood the pathogenesis, it should be possible to induce permanent remission in a good proportion of cases."

According to Anolik, "One of the most exciting aspects about the new biologic therapies is the mechanistic studies that are being done in conjunction with the clinical trials in an effort to better understand the disease pathogenesis. For example, from the use of B-cell depletion in SLE, we have learned that B cells are required for ongoing disease, and their roles are complex - going beyond simply autoantibody production." As scientists learn more about the role of B cells in autoimmunity, even more therapies might be developed. In addition, a better understanding of the mechanism of action behind various autoimmune diseases and potential therapies could lead to dividing the patients into treatment groups that, says Anolik, "may respond to different therapies, and predict response to treatment."