Long-term safety and efficacy of the combination of belimumab and rituximab in the treatment of severe and refractory SLE: a preliminary report

Abstract

Objective: Combination therapy with rituximab and belimumab is a novel treatment strategy for severe SLE and lupus nephritis. Phase II studies have shown promising results, although long-term data are currently lacking. To address this, we analysed outcomes of patients with severe treatment-refractory SLE who previously participated in the phase II Synbiose Study, with a particular focus on immunological parameters.

Methods: Eight patients continued belimumab treatment beyond the 2-year duration of the original trial. We conducted a descriptive study to evaluate the course of treatment and immunological parameters over an extended follow-up. Our analyses include blood cell counts, immunoglobulins, autoantibodies, complement markers and clinical disease activity parameters. Additionally, we examined long-term effects on the B cell compartment employing high-sensitivity flow cytometry.

Results: Over a median follow-up period of 6.8 years, six out of eight previously treatment-refractory patients maintained long-term clinical remission, while two experienced a major flare. Among those in remission, two patients achieved immunosuppression-free remission, and four continued belimumab. Long-term effects on humoral (auto-)immunity were a persistent decrease in IgM levels, while IgG normalised. Most patients maintained low autoantibody titres, and complement markers remained normal. On the cellular level, belimumab treatment after rituximab prevented B cell repopulation. Notably, patients exhibited a stable reduction of double-negative (DN) B cells, irrespective of continuing or stopping belimumab.

Conclusions: Long-lasting remission was observed in patients with SLE following combination treatment with rituximab and belimumab. We observed no significant hypogammaglobulinaemia and, notably, persistent reduction of DN B cells.

Keywords: Autoimmunity; B-Lymphocytes; Biological Products; Lupus Erythematosus, Systemic; Lupus Nephritis.

Figure 1. Treatment timelines and clinical parameters. (A) Illustration of the treatment course of all eight patients in clinical remission on maintenance belimumab at the end of the Synbiose Trial (EoS). Two patients achieved immunosuppression-free remission. Four patients remained in remission on long-term belimumab, two with concomitant low-dose prednisolone. Two patients had major disease flares. Patient 7 had a flare on belimumab/prednisolone and achieved remission with the sole reinstatement of rituximab, then switching to tacrolimus because of a pregnancy wish. Patient 8 had two major flares, the first after switching to tacrolimus and azathioprine because of a pregnancy wish, and the second after a period of treatment non-adherence. Both were successfully treated with obinutuzumab and belimumab. All but patient 7 had lupus nephritis at BL. (B) Renal outcomes and prednisone use of patients 1–6, in long-term remission. Boxes represent median and IQR, whiskers represent range. *, switch from intravenous to subcutaneous belimumab. +1, median of all values from the first half of the extended follow-up period; +2, median of all values in the second half of the extended follow-up period; 24, week 24; 48, week 48; BEL, belimumab; BL, baseline; EFU, extended follow-up. EoS, end of study; GC, glucocorticoids; MMF, mycophenolate mofetil; OBI, obinutuzumab; RTX, rituximab.

Figure 2. Immunological outcomes of patients in long-term remission. Haemoglobin (A), blood cells (B–F), immunoglobulins (G–I), ESR (J), anti-dsDNA (K) and complement markers (L–O) of all six patients in long-term remission. Boxes represent median and IQR, whiskers represent range. +1, median of all values from the first half of the extended follow-up period; +2, median of all values in the second half of the extended follow-up period; 24, week 24; 48, week 48; AP; alternative pathway; BL, baseline; CP, classical pathway; dsDNA double stranded DNA; EFU, extended follow-up; EoS, end of study; ESR, erythrocyte sedimentation rate; Hb, haemoglobin.

Figure 3. Long-term course of B cell subsets. Total peripheral B cells (A) and B cell subsets (B–F) in six patients with complete (brown) and with incomplete (blue) B cell repopulation. NB: one patient had no available subset BL data. +1, median of all values from the first half of the extended follow-up period; +2, median of all values in the second half of the extended follow-up period; 24, week 24; 48, week 48; BL, baseline; EFU, extended follow-up. EoS, end of study.