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Full peer-reviewed results from the closely watched have now been published, confirming that systemic lupus erythematosus (SLE) patients can benefit from a one-two biologic punch.

SLE patients receiving belimumab (Benlysta) following a course of rituximab had rates of severe SLE flares that were nearly three-quarters lower (HR 0.27, 95% CI 0.07-0.98) than patients getting placebo after rituximab in the randomized, double-blind study, according to Michael Ehrenstein, MBBS, PhD, of University College London, and colleagues.

As well, levels of anti-double stranded DNA (anti-dsDNA) antibodies at treatment completion were halved in the belimumab group relative to placebo, indicating a substantial disease-modifying effect.

No increase in serious adverse events was seen with belimumab, including infections, the researchers reported in . The publication follows at a meeting earlier this year.

Although belimumab carries a specific indication for SLE and rituximab does not, the former has faced difficulty in becoming the universal first-line biologic therapy. As Ehrenstein and colleagues explained, belimumab's cost-effectiveness is seen as less than optimal, especially in Britain, where rituximab remains the treatment of choice for most patients who don't respond or can't tolerate conventional therapy with corticosteroids and/or immunosuppressive agents such as azathioprine.

But, the researchers noted, two large phase III studies failed to confirm a clear benefit with rituximab, because too many participants did no better with it than placebo. It's also the case in clinical practice that many patients continue to suffer SLE flares after rituximab, even with multiple courses. Ehrenstein and colleagues pointed to a potential reason: increases in B-cell activating factor (BAFF) levels following the course of rituximab, which may remain elevated even after B cells grow back.

Since BAFF is belimumab's target, the group hypothesized that the drug, started after the rituximab course was finished, would forestall that effect and reduce flare rates.

BEAT-LUPUS enrolled 52 adult patients in Great Britain for whom rituximab had been recommended. Patients who had received two rituximab infusions were then randomized to follow-up therapy with belimumab or placebo. Infusions of the latter were given three times during the first 4 weeks, then every 4 weeks for the rest of the study's 1-year duration. Participants could also receive certain conventional SLE drugs including prednisolone, azathioprine, mycophenolate mofetil, and methotrexate, although site investigators were "encouraged" to reduce the steroid doses by half over the first 6 months.

Anti-dsDNA levels were set as the trial's primary outcome; at week 52, geometric means were 47 IU/mL with belimumab versus 103 IU/mL in the placebo group (P<0.001). Additionally, in 25 participants with data on B-cell restoration at week 52, those treated with belimumab showed mean levels one-third that seen with placebo (12 vs 37 × 10⁶ cells/L).

On the clinical side, 10 participants assigned to placebo experienced severe flares, compared with three in the belimumab group.

Six patients in each group experienced a total of 21 adverse events rated as serious. Seven of these were infections: four in the placebo group and the other three in the belimumab group. Other serious events spanned a wide range of types and most were likely related to SLE. Milder events, including infections, occurred about equally in the two groups.

"These findings support further exploration of belimumab after rituximab as the first combination biologic therapy for patients with SLE," Ehrenstein and colleagues concluded, "at least in those whose disease is refractory to conventional therapy and/or requires high corticosteroid dosages."

In an accompanying editorial, Medha Barbhaiya, MD, MPH, of the Hospital for Special Surgery in New York City, and Katherine P. Liao, MD, MPH, of Brigham and Women's Hospital in Boston, agreed but also noted that the study came with a host of limitations, not only the small number of patients.

The pair weren't happy that a biomarker was the primary endpoint rather than clinical outcomes, particularly since anti-dsDNA antibodies couldn't be detected in some participants at baseline. "[U]se of a primary clinical composite endpoint may provide better clinical interpretability and improve the ability to compare results with other SLE trials," the editorialists suggested.

Finally, that the study was conducted in Britain limits the generalizability, since protocols for rituximab in SLE are different in the U.S., the pair noted.

With those caveats in mind, however, the one-two biologic approach deserves further study, Barbhaiya and Liao concluded.

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