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 (anti-CD20) and belimumab(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 (LLDAS) of which 8(53%) continued treatment (belimumab+≤7,5 mg prednisolone) during the complete 2 years of follow-up. Five patients (33%) were referred to as ‘non-responders’ due to persistent LN, major flare or repeated minor flare. 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 (ENAs) 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 to non-responders, CD20+B-cells were depleted significantly less in non-responders and double negative (DN) B-cells repopulated significantly earlier.
Conclusion Combined B-cell targeted therapy with rituximab (RTX) and belimumab (BLM) prevented full B-cell repopulation including DN B-cells, with concomitant specific reduction of SLE-relevant autoantibodies. The observed clinical and immunological benefits in a therapy-refractory SLE population prompt further studies on RTX+BLM.
Acknowledgements This work is funded by the Dutch Kidney Foundation (KJPB12.028), Clinical Fellowship from the Netherlands Organization for Scientific Research (90713460) and GlaxoSmithKline (GSK) provided belimumab and an unrestricted grant for the clinical study.
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