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Adding a cycle of rituximab (Rituxan) to weekly treatment with belimumab (Benlysta) didn't improve most outcomes for people with systemic lupus erythematosus (SLE) in a randomized trial, researchers found.

With 263 patients and major endpoints mainly focused on clinical responses, the phase III trial failed to show statistically significant benefits for these outcomes, although weak trends favored the combination therapy, according to Cynthia Aranow, MD, of Northwell Health in Manhasset, New York, and colleagues.

But biomarkers did show significant improvement with the addition of rituximab, the group . This finding suggests that the specific treatment protocol examined in the study may not have been optimal and that clear clinical benefits could yet be achievable with a rituximab-belimumab combination, Aranow and colleagues concluded.

Misbehaving B cells are believed to be at the root of SLE, and the best hopes for achieving lasting remission have centered on reining in this rogue B-cell activity. Belimumab is one such approach -- it targets an activating factor known as B-lymphocyte stimulator or BLyS -- yet in clinical trials, after 1 year. Most patients who don't respond that well must then stay on long-term corticosteroids, which comes with a host of adverse effects.

One idea has been to double down on suppressing B-cell activity. The most obvious way to do so is with the B-cell depleting agent rituximab. As Aranow and colleagues noted, several phase II studies found that a belimumab-rituximab combination improved both clinical and laboratory measures of lupus activity.

The new trial, , enrolled patients with active SLE who were candidates for standard subcutaneous belimumab therapy at 200 mg/week. Half the sample were assigned to receive add-on rituximab (BEL/RTX), at 1,000 mg given at weeks 4 and 6, and with conventional immunosuppressants withdrawn over a 4-week tapering period, and steroid doses were reduced to a maximum of 5 mg/day in prednisone equivalents by week 26.

The other half were divided into two control groups: one treated similarly except with placebo infusions in place of rituximab (BEL/PBO), while the other received no concomitant infusions and remained on standard conventional therapy in addition to belimumab (BEL/ST). Belimumab treatment was halted at week 52 in the BEL/RTX and BEL/PBO groups; it continued through week 104 for those in BEL/ST.

Major outcome measures were based on the . The primary endpoint was the proportion of patients achieving disease control, defined as a reduction of at least 2 points in SLEDAI-2K scores without conventional immunosuppressants and steroid doses of no more than 5 mg/day in prednisone equivalents, at 52 weeks.

Two major secondary endpoints were tracked as well: disease control at 104 weeks, and clinical remission (SLEDAI-2K score of zero without steroids or immunosuppressants) at 64 weeks.

Rates for the primary endpoint in the three arms were as follows:

• BEL/RTX: 19.4%

• BEL/PBO: 16.7%

• BEL/ST: 25.5%

A similar pattern was seen for the two major secondary outcomes. The BEL/RTX group's remission rate was 6.3% -- slightly higher than in the BEL/PBO arm but less than the 10.6% rate seen with BEL/ST. Likewise, disease control at 104 weeks was achieved by 11.1% in BEL/RTX, 6.9% in BEL/PBO, and 21.3% in BEL/ST. None of the differences between BEL/RTX and BEL/PBO came close to statistical significance.

One clinical finding, duration of disease control through week 52 among patients achieving it at some point, did favor BEL/RTX. In those patients, the average was 105 days, versus 60 days for those in BEL/PBO (P=0.019). BEL/ST patients with disease control were able to keep it for a mean of 87 days (P not calculated).

Aranow and colleagues hypothesized that perhaps the 4-week tapering of standard immunosuppressants was too aggressive. "The patients in this study had a median disease duration of 7 years and a baseline mean daily corticosteroid dose of 10 mg/day," the team wrote, "perhaps making them better suited to a less stringent tapering regimen, further supporting one of the important learnings of this informative study design."

Meanwhile, the researchers were encouraged by the biomarker results. As long as patients remained on belimumab, anti-double stranded DNA (anti-dsDNA) antibody titers declined, and significantly more rapidly with the addition of rituximab. Among patients in the BEL/RTX group who had such antibodies at baseline, 24.3% tested negative for them at week 52; the corresponding figure for the BEL/PBO group was 5.7% (P=0.019).

B cell counts also declined more with add-on rituximab. Once belimumab was withdrawn at week 52, however, anti-dsDNA titers and other biomarkers gradually worsened, although some (such as CD20+/CD27+ memory B cells) remained below baseline levels.

Safety findings were as expected, with similar numbers and types irrespective of whether rituximab was taken.

Chief among the study's limitations was that the treatment protocols were not designed to reflect standard practice (in which belimumab is an add-on to conventional immunosuppressants) but rather to see whether treatment-free remission was possible. As well, the endpoints based on responder rates did not capture improvements in symptoms that fell short of disease control or remission as defined.

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