Long-term effects of combined B-cell immunomodulation with rituximab and belimumab in severe, refractory systemic lupus erythematosus: 2-year results

Abstract

Background: Anti-CD20 B-cell depletion has not shown superior efficacy to standard immunosuppression in patients with systemic lupus erythematosus (SLE). Besides trial design, potential explanations are incomplete B-cell depletion in relation to substantial surges in B-cell-activating factor (BAFF). To improve B-cell targeting strategies, we conducted the first study in SLE patients aimed at investigating immunological effects and feasibility of combining rituximab (RTX; anti-CD20) and belimumab (BLM; anti-BAFF).

Methods: Reported is the long-term follow-up of a Phase 2 proof-of-concept study in 15 patients with SLE including 12 (80%) with lupus nephritis (LN).

Results: In 10/15 (67%) patients, a clinical response was observed by achievement of lupus low disease activity state, of which 8 (53%) continued treatment (BLM + ≤7.5 mg prednisolone) for the complete 2 years of follow-up. Five patients (33%) were referred to as 'non-responders' due to persistent LN, major flare or repetitive minor flares. Out of 12 LN patients, 9 (75%) showed a renal response including 8 (67%) complete renal responders. All anti-dsDNA+ patients converted to negative, and both anti-C1q and extractable nuclear antigen autoantibodies showed significant reductions. CD19+ B cells showed a median decrease from baseline of 97% at 24 weeks, with a persistent reduction of 84% up to 104 weeks. When comparing responders with non-responders, CD20+ B cells were depleted significantly less in non-responders and double-negative (DN) B cells repopulated significantly earlier.

Conclusions: Combined B-cell targeted therapy with RTX and BLM prevented full B-cell repopulation including DN B cells, with concomitant specific reduction of SLE-relevant autoantibodies. The observed immunological and clinical benefits in a therapy-refractory SLE population prompt further studies on RTX + BLM.

Keywords: autoantibodies; autoimmune glomerulonephritis; immune complex-mediated membranoproliferative; lupus nephritis; rituximab/belimumab; systemic lupus erythematosus.

FIGURE 1

Flow diagram of patients.

FIGURE 2

Overview of the clinical responses, renal responses and concomitant immunosuppression upon RTX + BLM treatment. (A) Achievement of LLDAS over time. (B) Achievement of a renal response in patients included with active LN (n = 12). CRR was achieved when proteinuria ≤0.7 g/day, normal serum albumin, stable kidney function and normal urinary sediment; partial response: >0.7–2.9g/24 h with a decrease in proteinuria of ≥50% from baseline, serum albumin >30 g/L and stable kidney function. When patients did not meet any of these criteria, they were considered to have persistent active LN. (C) Overview of concomitant treatment with BLM, MMF and prednisolone throughout the study’s follow-up. Patient numbers mentioned on the y-axis correspond between the three figures. SACQ, serologically active (positive antibody and or low complement) clinically quiescent.

FIGURE 3

Longitudinal kinetics of circulating immune cells >2 years of follow-up after RTX + BLM treatment (n = 8 responders). (A and B) RTX + BLM prevents the complete repopulation of circulating B cells. Depicted are individual values of all responders with the median in bold representing change of CD19⁺ B cells in (A) absolute numbers and (B) the percentage of change from baseline. (C and D) Repopulation of B-cell subsets upon RTX + BLM. Depicted are the median change from baseline in (C) absolute numbers and (D) the percentage of change of the following B-cell subsets: plasmablasts (CD3⁻CD38^brightCD27^brightCD19⁺), non-switched memory B cells (CD3⁻CD19⁺CD27⁺IgD⁺), switched memory B cells (CD3⁻CD19⁺CD27⁺IgD⁻), naïve B cells (CD3⁻CD19⁺CD27⁻IgD⁺), DN B cells (CD3⁻CD19⁺CD27⁻IgD⁻) and transitional B cells (CD3⁻CD19⁺ CD38^brightCD24^bright). (E) Significant reconstitution of circulating CD4⁺ T cells (CD3⁺CD4⁺), CD8⁺ T cells (CD3⁺CD8⁺) and NK cells (CD16⁺CD56⁺). Depicted are the median changes from baseline in absolute numbers.

FIGURE 4

RTX + BLM resulted in prolonged, specific reduction of autoantibody levels >2 years follow-up (n = 8 responders). (A–D) Percentage change of physiological antibody levels are depicted, i.e. total IgG, anti-tetanus toxoid (TT), anti-rubella and anti-VZV antibodies. (E–G) Percentage change of SLE-relevant autoantibodies are depicted, i.e. anti-dsDNA (n = 8), anti-U1RNP (n = 4), anti-RNP70 (n = 3), anti-Sm antibodies (n = 3) and anti-C1q antibodies (n = 7). (J) To illustrate specific reductions in physiological antibody (anti-TT, anti-rubella and anti-VZV) and autoantibody levels (anti-dsDNA, anti-RNP70, anti-U1RNP, anti-Sm and anti-C1q), normalized ratio over total IgG was calculated and compared with baseline.