Disparity in peripheral and renal B-cell depletion with rituximab in systemic lupus erythematosus: an opportunity for obinutuzumab?

Abstract

Objectives To investigate key factors that may contribute to the variability of rituximab-mediated peripheral and renal B cell depletion (BCD) in Systemic Lupus Erythematosus (SLE). Methods We analysed: 1) CD19+ B cell counts in patients with SLE before and one, two, three and six months after treatment with rituximab, comparing them with Rheumatoid Arthritis (RA) patients; 2) the presence of B cells in renal biopsies after rituximab therapy; 3) whether the duration of BCD correlated with patient demographics and B cell expression of CD20 and FcγRIIb; and 4) the effect of BAFF on the efficiency of rituximab and obinutuzumab at inducing BCD in whole blood assays, in vitro. Results In SLE (n = 71), the duration of BCD was shorter compared with RA (n = 27). B cells were detectable in renal biopsy samples (n = 6) after treatment with rituximab in all patients with poor response whilst peripheral blood B cells remained low or undetectable in the same patients. There were no significant relationships between peripheral BCD and patient age, disease duration, serum C3 levels or the level of expression of B cell surface proteins CD20 and FcγRIIb. Obinutuzumab was more efficient than rituximab at inducing BCD in whole blood assays, regardless of excess BAFF. Conclusions BCD in SLE is less efficient than in RA. Renal B cell presence following rituximab treatment was associated with poor outcomes. No significant relationships between any measured B cell related, clinical or laboratory parameters and the efficiency of BCD by rituximab was found. Obinutuzumab was superior to rituximab at inducing BCD.

Duration biased distribution of clinical and immunological phenotypes in active SLE

“…This duration-associated dampened humoral immune response may further lead to a discrepant response to B-cell-targeted therapies. Recently, a small study found that SLE patients with longer durations had difficulties achieving complete depletion of peripheral B cells ( 18 ), and a small observation shows that a shorter duration of LN responds better to rituximab ( 19 ). Our findings merits more detailed profiling of B cell in duration courses, especially the balance of physiological/pathological B cells, which may give a better interpretation of this phenomenon.…”

B cells and antibodies in refractory immune thrombocytopenia

“…Similarly, 1 month after the first infusion of rituximab (1 g administered on day 1 and 15), the inguinal lymph nodes of rheumatoid arthritis patients show the persistence of several B‐cell follicular structures and the persistence of memory B cells 56 . Residual B cells have also been described in the synovium from patients with rheumatoid arthritis, 57–59 salivary glands of patients with Sjögren syndrome 60 and renal biopsy samples of SLE patients with lupus nephritis 61 …”

“…56 Residual B cells have also been described in the synovium from patients with rheumatoid arthritis, [57][58][59] salivary glands of patients with Sjögren syndrome 60 and renal biopsy samples of SLE patients with lupus nephritis. 61 Strikingly, none of the residual B cells have detectable surface expression of CD20. The absence of CD20 expression is in part due to epitope masking, but is also contributed to by antigen modulation through CD20 internalization [62][63][64] or trogocytosis [65][66][67][68] (Figure 1).…”

Progress and prospects of biologics and small molecules for the treatment of patients with systemic lupus erythematosus

“…Obinutuzumab is more effective at evoking Fcγ receptor-mediated effector mechanisms as compared with rituximab. It was superior to rituximab at inducing B-cell depletion [26]. More clinical trials are needed to confirm its availability in clinical application in the future.…”