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ACR Special Report: Philadelphia, PA, October 18-21, 2009

From the Lab to the Clinic: Lessons Learned About Lupus

In a major session related to progress in lupus research, three researchers focused on recent findings from the laboratory and how they can move the entire field of lupus research and treatment forward.

Thomas Tedder, PhD, of Duke University Medical Center in Durham, NC, discussed recent work that identified a rare IL-10-competent B-cell subset in humans similar to those discovered earlier in animals. “Harnessing the capacity of these cells to regulate inflammation will be important for the future,” he said. The other important message of his talk: B cells differ based on their point of differentiation, something that needs to be taken into account in drug development and clinical trials, as well as in the timing of treatment.

Meanwhile, Anne Davidson, MB, of the Feinstein Institute for Medical Research in Manhasset, NY, an ALR grantee, discussed her work in lupus nephritis. She noted that disease stage is very important in treatment and that the disease has a great deal of heterogeneity. Sometimes, she said, the body’s natural tendency towards balance, or homeostasis, “counteracts what we’re trying to do.”

“Lupus nephritis is a challenge,” she admitted. “The disease course is unpredictable and response to therapy is unpredictable.” Given the failure of several biologic agents in the disease, “we need something different.” Her team, she said, “is interested in an integrative approach that will be multidisciplinary and multi-institutional to get a better sense of the disease process in the individual patient and target therapy to the mechanism that is actually destroying the kidney in that patient rather than guessing.”

To that end, her work focuses on identifying the genetic “switch” that triggers lupus nephritis. When genes identified in animal studies are overlaid with those from lupus nephritis patients, she said, “We see quite a lot of similarities.”

Finally, Bevra H. Hahn, MD, of the University of California-Los Angeles School of Medicine, another ALR grantee and Scientific Advisory Board member, discussed the challenges of clinical trials in lupus, suggesting that a focus on highly targeted therapies may not be the most appropriate approach “unless we want short-term results. We probably have to do something not only about the B and T cells but about the ‘cross talk’ with innate immunity and the effectors of damage and inflammation on the activation of complement.”

Clinical trials for lupus drugs are difficult because there are so many different immune system pathways involved in the disease. That’s why therapies with multiple targets like glucocorticoids are effective: “They hit the innate immune system and the effects of damage,” Dr. Hahn said.

She focused on the results of two major clinical trials: the ALMS (Aspreva Lupus Management Study) study, which compared induction therapy with mycophenolate mofetil to cyclophosphamide; and the BLISS studies for belimumab.

Although some considered the ALMS trial a failure because it didn’t demonstrate superiority of mycophenolate over cyclosporine, the fact that both were equally effective and neither was more toxic than the other “were very important findings.”

In addition, the trial showed that African Americans and Hispanics had a higher response rate to mycophenolate than IV cyclosporine. “This is a very valuable lesson for this trial,” she said, given “signals” prior to the study that African Americans were not as responsive as whites to IV cyclosporine. Also important was that the study involved patients early in the diagnosis, when “we all think we’re most likely to get our best responses.”

The Phase III trials for belimumab were not only successful, she said, but “clinically important.” The primary outcome was novel compared to primary outcomes in other lupus clinical trials, like those in rituximab and abatacept, which, despite expectations, were not successful. It is also important that all patients were seropositive for autoantibodies at the start of the trial. “The other thing I like is that the efficacy of the drug could be detected on a background of steroids and either mycophenolate, methotrexate, or azathioprine. That’s a very high bar to ask something to look better than this background therapy,” she said.

The conclusion, Dr. Hahn said, is that multiple targets will need to be targeted in lupus while, the lack of homogeneity in patients means that studies should be powered to observe response in subsets of patients. Overall, she said, despite some setbacks “we have certainly made progress in clinical trials in lupus in the past couple of years.”


More information about lupus and treatment advances can be found by visiting www.lupusresearch.org.

The 2010 American College of Rheumatology Meeting Special Report was made possible in part by generous support from Biogen Idec, Genentech and Johnson & Johnson.

©2010 Alliance for Lupus Research. All Rights Reserved.

Contents herein may not be reproduced, republished or distributed without the prior written permission of the Alliance for Lupus Research. To request permission to reproduce, republish or distribute any part of this report, contact us at 212-218-2840 or email info@lupusresearch.org.


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