OP0042 LONG-TERM EFFECTS OF SYNERGETIC B CELL IMMUNOMODULATION WITH RITUXIMAB AND BELIMUMAB COMBINATION TREATMENT IN SEVERE, REFRACTORY SLE: TWO YEAR RESULTS
Authors: Tineke Kraaij, E.J. Arends, Laura van Dam, Sylvia Kamerling, Paul L.A. van Daele, Obbo Winne Bredewold, Argho Ray, Jaap Bakker, Ingeborg Bajema, Hans Ulrich Scherer, Thomas Huizinga, Ton Rabelink, Cees van Kooten, Y.K. Onno Teng
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> We conducted a phase 2, proof-of-concept study (SynBioSe study) in which we combined rituximab and belimumab (RTX+BLM) for treatment of SLE patients with severe, refractory disease. We have previously reported that RTX+BLM effectively reduced relevant anti-nuclear autoantibodies (ANAs) and showed a clinical response at 24 weeks<sup>1</sup>. <h3>Objectives</h3> The aim of the present study is to investigate the long-term immunological and clinical effects of RTX+BLM in severe, refractory SLE patients. <h3>Methods</h3> Fifteen severe, refractory SLE patients were included and followed for 2 years. Patients received RTX at week 0 and 2 and BLM at week 4, 6, 8 and then 4-weekly until week 104. Clinical response was assessed by achievement of low level of disease activity (LLDAS). By using specific antibody assays and high sensitivity flowcytometry (HS-FACS), we longitudinally followed, respectively, levels of SLE-specific ANAs and B-cell subsets. <h3>Results</h3> Ten patients (67%) showed a good clinical response after 24 weeks, referred to as 'responders'. Two of these patients (13%) switched treatment after 24 weeks due to a pregnancy wish and 8 patients (53%) continued study treatment throughout the complete 2 years of follow-up. Five patients (33%) discontinued treatment due to persistent LN (n=2), major flare (n=2) or relapsing minor flare (n=1), together referred to as 'non-responders'. Responders achieved LLDAS at a median of 24 weeks [range 12-36] and remained in LLDAS for 76 weeks [56-92] out of 104 weeks of follow-up. In 7 patients with active LN, 6 attained a complete renal response. In responders, ANAs showed significant and specific reduction throughout 2 years with achievement of seronegative anti-dsDNA immunofluorescence in 6 out of 6 anti-dsDNA positive patients at baseline while total IgG, anti-tetanus and anti-rubella antibodies remained stable. By using HS-FACS, a median decrease of 97% [-99;+35] CD19+ B-cell depletion was achieved at 24 weeks. Long-term follow-up showed that B-cell repopulation was inhibited throughout 2 years with a persistent median decrease of 84% [-92;+22] compared to baseline. Further analysis of B-cell subsets revealed that in the responders, double negative (DN) B cells (CD27-IgD-) reached maximum depletion at 4 weeks (median 1.09*10<sup>6</sup> cells/liter [range 0.23*10<sup>6</sup>-4.31*10<sup>6</sup>]), which lasted up to week 72 with a median of 1.26*10<sup>6</sup> cells/liter [0.79*10<sup>6</sup>-4.11*10<sup>6</sup>] at week 72, similar to values at nadir. This was in contrast to non-responders, where maximum depletion of DN B-cells was reached at 12 weeks (0.48*10<sup>6</sup> [0.17*10<sup>6</sup>-5.86*10<sup>6</sup>], after which these cells increased to 2.29*10<sup>6</sup> [0.49*10<sup>6</sup>-4.39*10<sup>6</sup>] at 24 weeks. <h3>Conclusion</h3> Over 2 years follow-up, RTX+BLM for severe, refractory SLE patients prevented complete B-cell repopulation with persistent and specific reduction of ANAs. Clinical response was observed in 67% of patients and treatment discontinuation due to high disease activity was associated with early repopulation of DN B-cells. These data warrant further studies on clinical and immunological benefits of combination treatment RTX+BLM. <h3>Reference</h3> [1] Kraaij T, Kamerling SWA, de Rooij ENM, et al. The NET-effect of combining rituximab with belimumab in severe systemic lupus erythematosus. J Autoimmun2018;91:45-54.doi: 10.1016/j.jaut.2018.03.003. Trial registration: ClinicalTrials.gov NCT02284984 <h3>Disclosure of Interests</h3> Tineke Kraaij: None declared, E.J. Arends: None declared, Laura van Dam: None declared, Sylvia Kamerling: None declared, Paul LA van Daele: None declared, Obbo Winne Bredewold: None declared, Argho Ray: None declared, Jaap Bakker: None declared, Ingeborg Bajema Consultant for: GSK, Hans Ulrich Scherer Grant/research support from: Sanofi, BMS, Thomas Huizinga Consultant for: Merck, UCB, Bristol Myers Squibb, Biotest AG, Pfizer, GSK, Novartis, Roche, Sanofi-Aventis, Abbott, Crescendo Bioscience Inc., Nycomed, Boeringher, Takeda, Zydus, Epirus, Eli Lilly, Ton Rabelink: None declared, Cees van Kooten: None declared, Y.K. Onno Teng Grant/research support from: Received lecture fees/consultancy fees from GSK and from Aurinia Pharmaceuticals.