Background/Purpose:

Systemic lupus erythematosus (SLE) is a disease characterized by production and deposition of anti-dsDNA antibody. In recent years, treatment methods targeting antibody-producing B cell line have been reported as new approaches to SLE treatment. Bortezomib is a proteasome inhibitor targeting plasma cells, and is widely used in the treatment of plasma cell tumors. Here, we evaluated the efficacy and safety of bortezomib versus placebo for the treatment of SLE cases in which disease activity could not be controlled by conventional combined use of immunosuppresssants and steroids.

Methods:

Fourteen patients in whom the dose of predonine could not be reduced to ≤10 mg/day despite the concomitant immunosuppressive therapy and moderate disease activity persisted (SLEDAI, ≥6 points; positive for anti-dsDNA antibody) were randomized by using the anti-dsDNA antibody as a randomization factor. Bortezomib, 1.3 mg/m², or placebo was administered twice weekly, 8 times in total to patients. Endpoints were changes in anti-dsDNA antibody titer at Week 24 and SLE responder index (SRI).

Results:

Among the 14 patients, 8 and 6 patients were assigned to the bortezomib group and the placebo group, respectively; however, 4 of the 8 patients in the bortezomib group and 2 of the 6 patients in the placebo group discontinued the trial. The reason for discontinuation was inability to continue the trial due to adverse reactions in all of the 4 patients in the bortezomib group, and insufficient effects in both of the 2 patients in the placebo group. In the bortezomib group, only one patient could complete the treatment as planned, while 7 others failed to complete the minimum protocol treatment because of adverse reactions. Four patients each in the bortezomib and placebo groups, who could complete the trial, were included in the following analysis.

The percent change of the anti-dsDNA antibody titer at treatment 24, which was defined as the primary endpoint, was 4.24% in the bortezomib group and -1.96% in the placebo group, which did not support the efficacy of bortezomib. However, when LOCF analysis was used by including the patients who discontinued the treatment, -11.34% and 23.88% were obtained as reference values in the bortezomib and placebo groups, respectively, suggesting that the patients who needed to discontinue the trial because of adverse reactions might have responded well to bortezomib. On the other hand, the SRI at Week 12 was 75% in the bortezomib group and 40% in the placebo group. Although the difference did not reach statistical significance, these results appear to be promising in terms of the efficacy of bortezomib.

Conclusion:

Since bortezomib therapy for SLE is associated with many adverse reactions, it is necessary to select indications carefully and to establish the protocol aiming at the prevention of adverse reactions. On the other hand, we observed improvement of clinical findings such as skin symptoms, regardless of the anti-dsDNA antibody titer, in a patient in the bortezomib group. In fact, SRI tended to be high in the bortezomib group. These findings suggest that bortezomib may be effective in treating various symptoms of SLE though the mechanism other than inhibition of anti-dsDNA antibody production.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-first-randomized-control-trial-to-evaluate-the-effectiveness-of-bortezomib-for-refractory-systemic-lupus-erythematosus/