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.