Background/Purpose: Belimumab treatment in autoantibody-positive systemic lupus erythematosus (SLE) patients for up to 76 weeks results in sustained reduction in several circulating B cell subsets, including naïve and activated B cells, as well as in serum immunoglobulin (Ig) levels. The purpose of the present analysis was to examine long-term changes in B cell subsets and IgG beyond 76 weeks through 172 weeks of continued belimumab treatment.

Methods: B cell, B cell subset and IgG data were collected in the Phase 3 Study BLISS-76 (NCT00410384; N=819) and in its US extension study (NCT00724867; N=268). All B cell subsets were measured at baseline, Weeks 8, 24, 52, 76, 100, 124, 148 and 172. Subjects randomized to 1 mg/kg or 10 mg/kg cohorts in BLISS-76 received bi-weekly doses of belimumab for the first month followed by dosing every 4 weeks thereafter. Placebo subjects, who chose to enter the extension study, received 10 mg/kg belimumab every 4 weeks starting at Week 76.  Subjects in all cohorts received standard of care SLE agents (eg. corticosteroids, immunosuppressants, and/or antimalarials).

Results:

Most B cell subsets in peripheral blood showed a rapid initial decline over the first 24 weeks followed by a comparatively slower decline or sustained suppression. Memory B cells were an exception and roughly doubled by Week 8, followed by a slow and sustained decline through Week 172.  Beyond 76 weeks of treatment, B cell reductions either stabilized (naïve and plasma B cells), or continued to gradually decrease (CD19+ /CD20+ B cells, memory cells, plasmacytoid B cells) leading to net reductions of about 80–90% for naïve, activated, and plasmacytoid B cells, 70–75% for CD19+/CD20+ B cells and 50–60% for plasma cells after 172 weeks of continued belimumab dosing.  Over 172 weeks, a 20–30% reduction in IgG levels was observed. Only 1 completer (10 mg/kg) experienced a shift from no to Grade 3 hypogammaglobulinemia (HGG; <400 mg/dL). Of all belimumab treated subjects, 3 subjects (0.5%) experienced a Grade 3/4 HGG shift. Development of Grade 3/4 HGG was not associated with severe infections.

Results for 1 and 10 mg/kg groups in the timing and magnitude of the response were similar for most measures.  Results for placebo patients, who received 10 mg/kg at Week 76, confirmed the response patterns observed for patients who received belimumab at Week 0.

Response in Week 172 completers:

Response parameter	Median % change from baseline (N)
	Placebo → 10 mg/kg	1 mg/kg	10 mg/kg
CD20+ B cells	-69.3 (57)	-74.3 (63)	-72.2 (46)
CD19+ B cells	-69.2 (65)	-70.6 (68)	-72.2 (51)
CD20+/CD27+ memory B cells	-16.7 (57)	-35.6 (63)	-37.7 (46)
CD20+/CD27– naïve B Cells	-79.4 (57)	-79.7 (63)	-81.6 (46)
CD20+/CD69+ activated B cells	-90.8 (68)	-89.9 (80)	-85.5 (54)
CD20+/CD138+ plasmacytoid B cells	-88.6 (61)	-89.8 (70)	-87.9 (50)
CD20–/CD138+ plasma B cells	-64.1 (61)	-47.2 (70)	-57.9 (51)
IgG	-19.6 (65)	-23.4 (69)	-26.2 (53)

Conclusion:

Treatment of SLE patients with belimumab for 172 weeks results in substantial, but subtotal, declines in circulating B cell subsets. These declines are associated with a modest decline in IgG levels and do not appear to be associated with development of severe infections.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/sustained-reductions-in-circulating-b-cell-populations-and-immunoglobulin-g-levels-with-long-term-belimumab-treatment-in-patients-with-systemic-lupus-erythematosus/