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Objectives To investigate key factors that may contribute to the variability of rituximab-mediated peripheral and renal B cell depletion (BCD) in SLE. Methods We analysed: (i) CD19+ B cell counts in patients with SLE before and 1, 2, 3 and 6 months after treatment with rituximab, comparing them with RA patients; (ii) the presence of B cells in renal biopsies after rituximab therapy; (iii) whether the duration of BCD correlated with patient demographics and B cell expression of CD20 and FcγRIIb; and (iv) the effect of B cell activation factor (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 while 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.

Objectives To compare membranous lupus nephritis (MLN) and proliferative lupus nephritis (PLN) with respect to survival, demographic, clinical and laboratory characteristics; and to investigate predictors of renal and patient survival. Methods Single-centre retrospective observational study. Patients with biopsy-proven PLN, MLN and mixed lupus nephritis were included. Groups were compared using appropriate statistical tests and survival was analysed through the Kaplan-Meier method. Cox regression analysis was performed to investigate predictors of renal and patient survival. Results A total of 187 patients with biopsy-proven lupus nephritis (135 with PLN, 38 with MLN and 14 with mixed LN) were followed for up to 42 years (median 12 years). There was a higher proportion of MLN amongst Afro-Caribbeans than amongst Caucasians (31% vs 15%, P = 0.010). Patients with MLN had significantly lower anti-dsDNA antibodies (P = 0.001) and higher C3 levels (P = 0.018) at diagnosis. Cumulative renal survival rates at 5, 10, 15 and 20 years were 91, 81, 75 and 66% for PLN and 100, 97, 92 and 84% for MLN, respectively (P = 0.028). Cumulative patient survival at 5, 10, 15 and 20 years was 94, 86, 80 and 76%, with no difference between PLN and MLN. Urinary protein-creatinine ratio above 42 mg/mmol and eGFR below 76 ml/min/1.73 m2, one year after the diagnosis of LN, were the strongest predictors of progression to end-stage renal disease. eGFR below 77 ml/min/1.73 m2, at one year, development of end-stage renal disease and Afro-Caribbean ethnicity were associated with higher mortality. Conclusion Patients with MLN and PLN differ significantly regarding serological profiles and renal survival, suggesting different pathogenesis. Renal function at year one predicts renal and patient survival.

Background Despite the improvement in survival of patients with lupus nephritis (LN) over the last decades, LN is associated with progression to end-stage renal disease (ESRD) in a significant proportion of patients. We aimed to investigate the factors influencing renal survival in patients with LN. Methods Single-centre retrospective observational study. Patients with biopsy-proven proliferative, membranous or mixed LN were included. Individual clinical files were reviewed to obtain demographic, clinical, laboratory and pathological data. Cox regression analysis was performed to investigate predictors of progression to ESRD and Kaplan-Meier curves were obtained. Results We studied 187 LN patients (135 proliferative, 38 membranous and 14 mixed LN), followed for up to 42 years (mean 13±9 years). Cumulative renal survival rates at 5, 10, 15 and 20 years were 93%, 85%, 78% and 70%, respectively. In univariable analysis, urinary protein/creatinine ratio (uPCR) above 42 mg/mmol or estimated glomerular filtration rate (eGFR) below 76 mL/min/1.73m2, one year after the diagnosis of LN, were the strongest predictors of progression to ESRD, with hazard ratios (HR) of 8.081 [95%CI:1.856-35.179] and 4.985 [95%CI:1.964-12.651], respectively. HR for uPCR and eGFR at the time of diagnosis were considerably smaller (2.508 [95%CI:1.062-5.922] and 2.833 [95%CI:1.156-6.945] respectively). Other factors associated with increased risk of ESRD were Afro-Caribbean ethnicity (HR = 3.861 [95%CI:1.817-8.206]), proliferative LN (HR = 3.423 [95%CI:1.049-11.173]), not having taken antimalarials (HR = 2.180 [95%CI:1.089-4.363]) and poorly controlled diastolic blood pressure (HR = 1.016 [95%CI:1.001-1.030]). The effect of uPCR and eGFR at one year remained significant after adjusting for ethnicity, histological class, uPCR and eGFR at the time of diagnosis, use of antimalarials and diastolic blood pressure (Table 1). Conclusion uPCR above 42 mg/mmol and eGFR below 76 mL/min/1.73m2, one year after the diagnosis of LN, were the strongest predictors of progression to ESRD. Disclosures F. Farinha None. R.J. Pepper None. D.G. Oliveira None. T. McDonnell None. D.A. Isenberg None. A. Rahman None.

OBJECTIVES: Glucocorticoids (GCs) are a mainstay of treatment for patients with ANCA-associated vasculitis (AAV) but are associated with significant adverse effects. Effective remission induction in severe AAV using extremely limited GC exposure has not been attempted. We tested an early rapid GC withdrawal induction regimen for patients with severe AAV. METHODS: Patients with active MPO- or PR3-ANCA vasculitis or ANCA-negative pauci-immune glomerulonephritis were included. Induction treatment consisted of two doses of rituximab, 3 months of low-dose CYC and a short course of oral GC (for between 1 and 2 weeks). Clinical, biochemical and immunological outcomes as well as adverse events were recorded. RESULTS: A total of 49 patients were included, with at least 12 months of follow-up in 46. All patients achieved remission, with decreases observed in creatinine, proteinuria, CRP, ANCA level and BVAS. Three patients requiring dialysis at presentation became dialysis independent. Two patients required the introduction of maintenance GC for treatment of vasculitis. Overall outcomes were comparable to those of two matched cohorts (n = 172) from previous European Vasculitis Society (EUVAS) trials, but with lower total exposure to CYC and GCs (P < 0.001) and reduced rates of severe infections (P = 0.02) compared with the RITUXVAS (rituximab versus cyclophosphamide in AAV) trial. We found no new cases of diabetes in the first year compared with historic rates of 8.2% from the EUVAS trials (P = 0.04). CONCLUSION: Early GC withdrawal in severe AAV is as effective for remission induction as the standard of care and is associated with reduced GC-related adverse events.

Objectives: B cells are central to the pathology of ANCA-associated vasculitis (AAV), a disease characterized by autoantibodies and effectively treated by rituximab. In addition to promoting inflammation, a subset of B cells act to suppress harmful autoimmune responses (Breg). The balance of effector and regulatory B cell subsets in AAV is not known. This study was conducted to assess the relative frequency of these subsets during different states of disease activity. / Methods: B memory (Bmem), naive (Bnaive) and regulatory (Breg) subsets were defined by their relative expression of CD24 and CD38. Function was assessed by cytokine production and suppressive action on CD4(+) Th1 activation evaluated in a co-culture system. / Results: Compared with healthy controls, the frequency of Breg (CD24(hi)CD38(hi)) was significantly reduced during disease remission in both proteinase 3 (PR3)- and MPO-ANCA patients and during acute disease in PR3-ANCA patients, while the frequency of memory cells (CD24(hi)CD38(lo)) was reduced during active disease and restored during remission. Breg cell frequency showed a positive correlation, while Bmem had an inverse correlation with IL-10 production in vitro. B and T cell co-cultures revealed that memory and naive B cell subsets augmented Th1 activation in vitro, which was prevented by Breg, and this pattern did not differ between remission AAV patients and controls. / Conclusion: In remission there is a numerical, but not functional, deficiency in Breg and preservation of Bmem associated with reduced IL-10 production and increased Th1 activation in vitro. This imbalance may contribute to the high rate of relapse observed in AAV, especially in PR3-ANCA patients.

OBJECTIVES Rituximab is effective in inducing remission in ANCA-associated vasculitis (AAV), with randomized evidence to support its use as four infusions of 375 mg/m(2) (the conventional lymphoma dosing schedule). As B cell depletion (BCD) appears to occur very rapidly after the first dose, we questioned the need for repeat dosing and adopted a standard single-dose protocol of 375 mg/m(2) to treat active AAV. METHODS All consecutive cases with newly diagnosed or relapsing AAV for whom conventional immunosuppression was contraindicated or ineffective were enrolled. All were rituximab naive. Circulating CD19(+) B cells and clinical and serological markers of disease activity were recorded at regular intervals. Complete remission (CR) was defined as the absence of clinical features of AAV with a prednisolone dose 500 μM). Eight (42%) were on additional immunosuppression at the time of rituximab treatment. Satisfactory BCD (