Although the challenges in systemic lupus erythematosus (SLE) research are many, the use of biomarkers and surrogate markers may further current understanding of the pathogenesis of SLE and also promote the development of effective SLE therapies, according to the authors of a conference summary published in the August issue of Arthritis and Rheumatism.

The conference, held March 31 to April 1, 2003, in Bethesda, Maryland, included industry representatives as well as participants from the National Institutes of Health (NIH) and the Food and Drug Administration (FDA).

Noting that "only 3 drugs have been approved for…the treatment of SLE" and that "in the last 3 decades, no new drugs have been approved" to treat the disease, the authors pointed out the need for new approaches in SLE research.

The attendees proposed that SLE biomarkers could have several functions in trials, including improvement of several features of the efficiency and design of trials, facilitating the understanding of a drug's effects and its potential uses, assessment of the drug's efficacy in a new setting, support for the trial results, and furthering the understanding of the pathogenesis of SLE.

"Although at this time it is difficult to recommend specific markers to include in all clinical trials, the development of surrogate markers and biomarkers is an important goal, especially in the development of new therapies for a disorder as diverse and complex and challenging as SLE," lead author Joel Schiffenbauer, MD, told CiaoMed. Dr. Schiffenbauer is the medical officer of the Division of Anti-Inflammatory, Analgesic, and Ophthalmic Drug Products within the FDA's Center for Drug Evaluation and Research.

In particular, the participants were interested in the role of B-lymphocyte stimulator (BLyS) and its receptors in SLE, as well as cytokines. Other biomarkers of interest were anti-dsDNA, anti-Sm, antiphospholipid antibodies, interferon-alpha, tumor necrosis factor-alpha, transforming growth factor-beta, and interleukins 6 and 10.

Among surrogate markers, those for end-stage renal failure, such as serum creatinine, proteinuria, and hematuria, were considered useful; however, the authors reported that conference participants had concerns regarding the ethics of repeat biopsies on patients with clinical remission.

Dr. Schiffenbauer expressed hope that "investigators studying [SLE] will develop and utilize markers that will lead to improved efficiency of the drug development process" and advocated that investigators include biomarkers appropriate for the endpoints studied in all future clinical trials…to allow for validation of these markers as predictors of clinical outcomes."

B-Cell Depletion: New Approach to SLE Therapy

In new research published in the same issue of Arthritis and Rheumatism, investigators reported that B-cell depletion with rituximab (RemicadeR) may be a safe and effective way to treat SLE.

"The data indicate that rituximab is well tolerated in this disease and that B-cell depletion appears to be effective in reducing overall disease activity," the authors wrote. Noting that the findings raise questions about the role of B cells and plasma cells in SLE, they added that the study "highlights the opportunities afforded by clinical trials of biologic agents to study the pathogenesis of human autoimmunity," and support, in particular, controlled trials of such agents for SLE.

In a phase I/II dose-escalation trial of rituximab as adjuvant therapy for SLE, the investigators recruited 18 subjects who had had moderately active SLE for an average of 11 years. The patients were an average of 37 years old.

Among the 17 evaluable patients, 11 had effective B-cell depletions, which the study defined as a peripheral CD19+ B-lymphocyte count of <5 cells/µL. Among the 6 patients who received low doses of rituximab (one infusion of 100 mg/m²), B-cell depletion was present in 4. B cell depletion was also documented in 4 of the 7 patients in the intermediate-dose group, who received a single dose of 375 mg/m², and 3 of the 4 patients in the high-dose group, who received four infusions, one each week, at a dose of 375 mg/m².

References

Schiffenbauer J, et al. Biomarkers, surrogate markers, and design of clinical trials of new therapies for systemic lupus erythematosus. Arthritis Rheum. 2004;50(8):2415-2422.

Looney RJ, et al. B-cell depletion as a novel treatment for systemic lupus erythematosus: a phase I/II dose-escalation trial of rituximab. Arthritis Rheum. 2004;50(8):2580-2589.