Background/Purpose: Two randomized, controlled trials of rituximab in patients with lupus and lupus nephritis (LN) did not meet their primary endpoints. A potential explanation is the observation that after treatment with rituximab, serum BAFF levels are elevated and may lead to disease flare by facilitating expansion of and re-population with autoreactive B cells. The CALIBRATE study (NCT 02260934) was designed to test this hypothesis, to determine whether addition of anti-BAFF (belimumab) could enhance the clinical effects of anti-CD20 (rituximab), and assess safety of the combination.

Methods: 43 subjects with active, proliferative LN despite conventional therapy were enrolled in a prospective, randomized, open-label trial that compared two therapeutic regimens. All subjects received iv rituximab (1000mg), cyclophosphamide (750mg), and methylprednisolone (100mg) at wks 0 and 2, and an initial prednisone dose of 40mg/d with taper to 10mg/d by wk 12. At wk 4, subjects were randomized to belimumab (10mg/kg iv at wks 4, 6, 8, and every 4 wks) plus prednisone (RCB group, n=21) versus prednisone alone (RC group, n=22). Complete response (CR) was defined as: (i) urine protein:creatinine ratio (UPCR) <0.5; (ii) eGFR ≥120 or, if <120, eGFR >80% of screening; and (iii) prednisone dose of 10 mg/d. Partial response (PR) differed only in the UPCR criterion (>50% reduction).

Results: The rate of renal response at wk 48 was similar between the two groups (Table I). CR rate was 32% in the RC group and 38% in the RCB group. B cell depletion occurred in both groups by wk 12, but repopulation occurred at different rates (Table II). Median IgG levels remained well within the normal range in both groups (Table II). 5 subjects in the RC group and 2 in the RCB group experienced grade 3 or higher infectious adverse events, and all resolved.

Conclusion: There was no difference in the rate of renal response at wk 48 in subjects who received anti-CD20 therapy followed by anti-BAFF therapy compared with anti-CD20 therapy alone. Anti-BAFF resulted in delayed peripheral B cell repopulation, but was not associated with hypogammaglobulinemia or an increase in serious infectious adverse events. Further analyses at wk 96 will provide information on the effects of anti-BAFF on B cell repertoire and longer term clinical outcomes.

Table I

Table II

*Includes subjects who failed at any point due to lack of renal response, inability to taper steroids, renal flare, or non-renal flare.

**Includes subjects withdrawn for reasons unrelated to lupus.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/phase-2-trial-of-induction-therapy-with-anti-cd20-rituximab-followed-by-maintenance-therapy-with-anti-baff-belimumab-in-patients-with-active-lupus-nephritis/