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.

Sustained low‐dose interleukin‐2 therapy alleviates pathogenic humoral immunity via elevating the Tfr/Tfh ratio in lupus

“…For example, autoantigen–autoantibody complexes and complement components (particularly C3) deposit at the glomerular basement membrane of kidneys, which attract robust immune cell infiltration and exacerbate local inflammation and tissue damage 11,12 . Belimumab (anti‐BAFF) alone or in combination with rituximab (anti‐CD20) sequentially depleting or reducing circulating B cells shows objective efficacies in treating patients with active refractory lupus and reduces cumulative dose of corticosteroids, stressing the significance of pathogenic B cells in SLE 13–16 …”

Modifications of the BAFF/BAFF-Receptor Axis in Patients With Pemphigus Treated With Rituximab Versus Standard Corticosteroid Regimen

“…Another strategy to prevent these short-term relapses might be to combine RTX maintenance infusion and anti-BAFF therapy, or to use anti-BAFF therapy alone as maintenance therapy. A phase-3 study is currently conducted to evaluate and compare the efficacy and tolerance of subcutaneous injections of belimumab in association to 2 cycles of RTX or a placebo in patients with SLE, after promising results in refractory SLE (19,20).…”

Next stop in the treatment of refractory systemic lupus erythematosus: B-cell targeted combined therapy

“…This is indirect evidence that a maintenance regimen may be important following a single course of rituximab and cyclophosphamide therapy in patients with recurrent or refractory lupus nephritis. The Synbiose study 22 has recently been published showing that combined therapy (with weekly subcutaneous injection of belimumab prior to two infusions of rituximab with continuation of the belimumab as maintenance therapy), despite a small number of patients, is a promising long-term strategy in severe refractory SLE, without major safety concerns. Finally, the BLISS-BELIEVE study, a phase 3 randomized controlled study is comparing the efficacy, safety and tolerability of subcutaneous belimumab for 52 weeks plus rituximab 1,000 mg at weeks 4 and 6, with that of belimumab alone, and belimumab plus standard of care.…”