Jonathan Kay, MD; Allan Gibofsky, MD

Disclosures

August 21, 2012

Editor's Note:
After the 2012 European League Against Rheumatism (EULAR) annual congress, held in Berlin, Germany, June 6-9, Jonathan Kay, MD, Professor of Medicine at the University of Massachusetts Medical School in Worcester, Massachusetts, spoke with Allan Gibofsky, MD, Professor of Medicine and Public Health at Weill Medical College of Cornell University in New York, New York, about important new data in lupus therapeutics.

The Latest in Lupus: Introduction

Dr. Kay: Allan, at the recent EULAR meeting in Berlin, what new information about systemic lupus erythematosus did you find to be interesting and important?

Dr. Gibofsky: Jon, several items come to mind. First, as you know, Rich Furie reported negative results for abatacept in lupus nephritis.[1] I found it interesting that David Wofsy went back and analyzed the data using criteria from another study and showed that if different primary outcomes are chosen, different results can be achieved.[2] David did not mean to imply that Furie's study was positive, but rather that it heightened the difficulties of choosing appropriate primary outcomes in studies of systemic lupus erythematosus (SLE).

Dr. Kay: Why did David Wofsy choose to apply criteria from a negative study of rituximab in lupus nephritis to reanalyze the negative study of abatacept in that same disease? What were the conclusions of this reanalysis?

Dr. Gibofsky: Beats me, Jon. Ask him. I think David wanted to show the difficulties in doing SLE clinical trials -- in particular, selecting clinically relevant and meaningful endpoints. Unlike in rheumatoid arthritis, where there are fairly standard and agreed-upon endpoints (eg, the DAS28 [Disease Activity Score] or ACR20 [American College of Rheumatology criteria]), that is not the case in SLE; there is no uniform agreement on an outcome measure, because it depends on the clinical manifestations of the disease. For example, a skin score or a joint count would be irrelevant if the major manifestation of SLE in a patient was nephritis; conversely, serum creatinine would be irrelevant as an outcome measure if the major manifestation of SLE in a patient was arthralgia. In the absence of a uniform and agreed-upon outcome measure, what may happen is that a trial will be negative, but if a different endpoint was predefined, it might be positive.

Another interesting presentation was one suggesting that protease inhibition may be an effective mechanism of action for SLE.[3]

Dr. Kay: Protease inhibition is an interesting novel mechanism of action to treat an autoimmune disease. What protease is being targeted? Why is it believed that this would be an effective treatment for lupus? What did the data show?

Dr. Gibofsky: Bortezomib is a protease inhibitor that kills long-lived plasma cells and is used to treat multiple myeloma. It was shown to ameliorate lupus nephritis in a lupus mouse model. This was the rationale for its use in a human pilot trial.

In this study of only 13 patients,[3] the Systemic Lupus Erythematosus Activity Index (SLEDAI) decreased from 15 to 5, and nephritis, anti-double-stranded DNA antibody, extractable nuclear antigens, and C3/C4 values all improved. At the same time, adverse events were not major: reversible polyneuropathies (3 patients), decreased hepatitis B and tetanus toxoid titers, a mild decrease in IgG, and no infections. Thus, further studies in larger populations are planned.

Apropos a drug that was recently approved for lupus, 2 poster presentations suggested that belimumab seemed to have the greatest efficacy in patients with the most severe cases of SLE who were receiving concomitant mycophenolate mofetil (MMF).[4,5]

Dr. Kay: Allan, was belimumab synergistic with MMF in patients with severe lupus, or was MMF therapy a marker for a population of patients with more active disease who were more likely to respond to B-cell-directed therapy?

Dr. Gibofsky: Although MMF is an effective agent, belimumab seemed to be synergistic and worked better as an "add-on" to MMF. It did not seem to be the case that MMF is a clinical marker for a specific population of patients, although clearly MMF is given to sicker patients. Furthermore, this was a post hoc analysis rather than a predefined outcome. A prospective study would be required to adequately address this question.

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