Background/Purpose: Primary Sjögren’s syndrome (pSS) is characterized by B-cell hyperactivity and elevated serum and saliva B-lymphocyte stimulator (BLyS) levels.¹ Sequential administration of belimumab (BEL; anti-BLyS) and rituximab (RTX; anti-CD20) is a promising strategy to target B cells through distinct but complementary mechanisms.² This analysis assesses the changes in minor salivary gland (MSG) and peripheral blood B cells following sequential administration of subcutaneous (SC) BEL and intravenous (IV) RTX (BEL/RTX) in patients with pSS.

Methods: This Phase 2, double-blind study (GSK Study 201842; NCT02631538) randomized 86 adults with active pSS to placebo (PBO; N=13), BEL/RTX (N=24; BEL 200 mg SC weekly to Week [Wk] 24 followed by PBO SC weekly to Wk 52 plus RTX 1000 mg IV, Wk 8 + 10), BEL monotherapy (N=24; BEL 200 mg SC weekly to Wk 52), or RTX monotherapy (N=25; RTX 1000 mg IV, Wk 8 + 10). Primary and secondary endpoints were safety and efficacy.³ Reported here are the exploratory biomarker endpoints, performed on the completer population (N=60; patients who completed the treatment phase and follow-up). The analyses include CD20+ B-cell, plasma cell and memory B-cell quantification within MSG biopsies (baseline + Wk 24), and changes in peripheral blood B-cell numbers over time to Wk 68.

Results: MSG histology demonstrated that the numbers of infiltrating CD20+ B cells at Wk 24 were lowest in the BEL/RTX arm, with incomplete depletion observed in the monotherapy and PBO arms (Table). Although the levels of MSG memory B cells (CD20+, CD27+) were also lowest in the BEL/RTX and RTX arms, plasma cell numbers were maintained irrespective of treatment. Total peripheral blood CD19+ B cells in circulation were almost completely depleted in the BEL/RTX and RTX arms (Table). In the BEL/RTX arm, after BEL discontinuation at Wk 24, a trend of delayed repopulation of total B cells in circulation was evident relative to RTX. In the BEL/RTX and BEL arms, circulating memory B cells increased initially (baseline [BL]/Wk 1 median [interquartile range, IQR] number of cells/mm³: BEL/RTX: 28.0 [13.0, 36.0]/47.0 [30.0, 72.5], BEL: 18.0 [14.0, 30.0]/45.0 [19.0, 63.0]), and then returned toward baseline levels over time. However, in the BEL/RTX arm, following the BEL-induced increase, circulating memory B cells reached near complete depletion (Wk 24 median [IQR]: BEL/RTX: 0.2 [0.1, 0.4] cells/mm³) and remained supressed until Wk 68 (median [IQR]: 3.5 [1.5, 5.0] cells/mm³).

Conclusion: Relative to BEL or RTX monotherapy, BEL/RTX showed trends for near complete depletion of B cells in MSG, greater depletion of circulating memory B cells, and a longer period of sustained B-cell depletion. Overall, these data support the hypothesis that combined anti-BLyS and anti-CD20 act in a mechanistically complementary manner in pSS. This sequential therapy represents a novel treatment option for patients with pSS with moderate-to-severe disease activity.

Funding: GSK

References:
¹Lavie F, et al. Scand J Immunol 2008;67:185–92
²Teng YKO, et al. BMJ Open 2019;9:e025687
³Mariette X, et al. Ann Rheum Dis 2021;80(Suppl 1):78­–9

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/sequential-administration-of-belimumab-and-rituximab-in-primary-sjogrens-syndrome-reduces-minor-salivary-gland-resident-b-cells-and-delays-b-cell-repopulation-in-circulation/