Mar. 22, 2012

Lupus Biomarker Changes Key to Benlysta Therapy

Belimumab reduces autoantibodies, normalizes low complement, and reduces select B-cell populations in patients with systemic lupus erythematosus
Stohl W, Hiepe F, Latinis KM, Thomas M, Scheinberg MA, Clarke A, Aranow C, Wellborne FR, Abud-Mendoza C, Hough DR, Pineda L, Migone TS, Zhong ZJ, Freimuth WW, and Chatham WW; on Behalf of the Bliss-52 and -76 Study Groups.  Arthritis & Rheumatism. 2012 Jan 24. doi: 10.1002/art.34400. [Epub ahead of print]

What is the topic?

In 2011, the U.S. Food and Drug Administration recommended belimumab (Benlysta™) for approval as a treatment for lupus and the drug is now currently available for treatment of this disease. Researchers continue to work to further understand the biological mechanisms by which belimumab is useful for the treatment of lupus.

Many people with lupus show increased levels of autoantibodies circulating in the blood. In addition, lupus disease activity is directly related to circulating levels of B-lymphocyte stimulator (BLyS), a protein whose abnormal function significantly contributes to the autoimmune mechanisms typical of lupus. Belimumab works by neutralizing (and therefore reducing the actions of) BLyS proteins circulating in the blood. A further understanding of the effects of belimumab on immune functions will facilitate greater understanding of its mechanisms and perhaps conditions for its optimal use.

What did the researchers hope to learn?

The researchers hoped to learn about the effects of belimumab treatment on lupus biomarkers, such as levels of autoantibodies (antibodies directed against a person’s own proteins) and complement proteins (markers of active lupus) in the blood.

Who was studied?

The study included patients from the 52-week (n=865) and 76-week (n=819) randomized, double-blind, placebo-controlled clinical trials comparing belimumab (1 or 10 mg/kg) with placebo (all plus lupus standard of care medications).

How was the study conducted?

Patients were randomly assigned to receive either belimumab at one of two doses (either 1 or 10 milligrams per kilogram of body weight) plus “standard of care” (medications the patients were already taking upon entry to the study) or standard of care alone (hereafter referred to as “placebo”). Standard of care included treatment with steroids, immune-suppressing drugs, and/or anti-malarial drugs. All patients stayed on the treatments they were getting upon entry to the study and were allowed to have the dose increased during the study, if needed. The effects of belimumab plus standard of care were compared to those of standard of care alone.

The main outcome measure was the percentage of patients showing significant improvement at 52 and 76 weeks. Improvement was measured by the SLE Responder Index (SRI), which combines a measurement of improvement in overall disease activity with evidence that there is no worsening in any given part of the body.

For purposes of analysis of changes in lupus biomarkers (markers of active lupus), results from the 52-week and 76-week studies were pooled into a single data set. These biomarkers included autoantibodies (anti-double-stranded DNA, anti-nuclear antibodies, anti-Smith antibodies, as well as anti-cardiolipin, and anti-ribosomal P antibodies), complement proteins (C3 and C4), and immunoglobulins (IgG, IgM, and IgA), all of which were measured at multiple times throughout the study.

What did the researchers find?

After eight weeks of treatment with belimumab (both 1 mg/kg and 10 mg/kg), levels of IgG (a type of antibodies, some of which may be autoantibodies) and anti-ds-DNA antibodies were significantly reduced in lupus patients when compared to those treated with placebo, and this pattern continued for the remainder of the 52-week study. In addition, for both doses, belimumab treatment resulted in a significantly greater number of patients converting from being positive to negative status for anti-ds-DNA and anti-cardiolipin antibodies, as compared to those taking placebo, by week 52. This pattern was also observed for other autoantibodies, such as anti-Smith and anti-ribosomal P antibodies, in those taking 1 mg/kg of belimumab, as compared to those taking placebo.

Among patients with low levels of complement proteins C3 and C4 upon study entry, belimumab treatment significantly increased levels of both C3 and C4, as compared to those taking placebo, as early as week 4 and this trend was maintained through week 52. In addition, normalization of levels of C3, C4, and IgG (in those with high levels upon study entry) occurred in significantly more patients taking either 1 mg/kg or 10 mg/kg belimumab than in those taking placebo.

SRI rates (indicative of improvement in lupus) at week 52 were significantly higher in patients treated with either dose of belimumab as compared to those taking placebo. The risk of severe lupus flare was significantly reduced in patients taking either dose of belimumab as compared to those taking placebo.

Regardless of the treatment being received, patients with specific kinds of changes in lupus biomarkers were significantly more likely to have a significantly increased SRI at some point in the study (time indicated in parentheses), including those with normalized levels of C4 (weeks 4, 28, and thereafter) and those with normalized levels of IgG (weeks 24, 40, and 52). In addition, regardless of the treatment being received, the risk of severe lupus flare was significantly decreased in patients with early normalization of C3 (at week 4 or 8) or with decreases in anti-ds-DNA antibodies (at week 8).

What were the limitations of the study?

Some biomarkers were measured in the 52-week study and others in the 76-week study. Also, little is known about changes in lupus biomarkers induced by belimumab treatment that may occur differentially according to ethnicity.

What do the results mean for you?

Taken together, the results indicate that belimumab treatment significantly reduces autoantibody levels and increases levels of complement proteins C3 and C4. Overall, the results suggest that belimumab is most effective in lupus patients having high disease activity and, specifically, those with abnormal levels of lupus biomarkers in the blood. However, it should be noted that the effects of belimumab in very severe cases of systemic lupus remain unclear.


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