Management of severe renal disease in anti-neutrophil-cytoplasmic-antibody-associated vasculitis: the place of rituximab and plasma exchange?

OBJECTIVE: The optimal induction therapy for severe glomerulonephritis of ANCA-associated vasculitis (AAV) is debated. We compared the efficacy of glucocorticoid and rituximab (RTX) or CYC induction therapy for severe AAV-related glomerulonephritis and evaluated the potential benefit of plasma exchange (PE) as adjunct therapy to CYC. METHODS: This retrospective, multicentre study included AAV patients with severe renal active disease (serum creatinine level ≥350 µmol/l and/or estimated glomerular filtration ratio ≤15 ml/min/1.73 m2). Propensity-score analysis was used to adjust for potential confounders. RESULTS: Between 2005 and 2017, 153 patients with AAV-related glomerulonephritis were studied (96 [60%] men; mean [s.d.] age 63 [13.1] years): 19 (12%) were treated with RTX and 134 (88%) with CYC. Remission rates did not differ between RTX- and CYC-treated groups. Although more patients with RTX than CYC were dialysis-free at month (M) 12 (79% vs 68%), the difference was not significant after adjustment. Among 134 patients with CYC-treated glomerulonephritis, 76 (57%) also had PE. M3 and M6 remission rates were comparable for weighted CYC groups with or without PE. For weighted groups, the dialysis-free survival rate with CYC was higher with than without PE at M6 (72% vs 64%; odds ratio 2.58) and M12 (74% vs 60%; odds ratio 2.78) reaching statistical significance at M12. CONCLUSION: We could not find any difference between RTX and CYC as induction therapy for patients with severe AAV-related glomerulonephritis. In patients receiving CYC induction regimen, the addition of PE conferred short-term benefits with higher dialysis-free rate at M12.

Pneumococcal infection in patients with systemic lupus erythematosus.

OBJECTIVE: Our study aimed to analyze the risk factors associated with the occurrence and severity of pneumococcal infection (PI) in systemic lupus erythematosus (SLE) patients. METHODS: Medical records of all SLE patients admitted in our department from January 2005 to December 2014 were retrospectively reviewed. SLE patients were separated in 2 groups according to whether they had PI or not. Medical records of all consecutive patients (with and without SLE) admitted in our department for PI over the same period of time were also reviewed. Clinical characteristics associated with PI occurrence and severity were analyzed in SLE patients. RESULTS: One hundred and ninety SLE patients (42.2+14.9 years; 87.4% females) were hospitalized over a 10-year period. PI was the reason for admission in 6 (3.2%) patients, including 5 cases of invasive infection. With a follow-up of 2112.8 patient-years for the total cohort, incidence of invasive PI in SLE was of 236/100,000 patient-years. PI occurred at a younger age (43.5+14.9 versus 65.3+18.7 years, P<0.01) and were more severe, with a higher frequency of invasive infection (P<0.001) and higher need for ICU admission (P<0.05) in SLE as compared to non SLE patients. Risk factors associated with PI in SLE patients were a serum gammaglobulin level<5g/L (P<0.01) and a past history of lupus nephritis (P<0.05), only. Steroids (P<0.001) and immunosuppressive drugs (P<0.05) were associated with infection severity. CONCLUSION: SLE is a disease of high susceptibility for invasive pneumococcal infections. Our study points to the need for vaccination against Streptococcus pneumoniae in SLE.

Regulatory T Cell Responses to High-Dose Methylprednisolone in Active Systemic Lupus Erythematosus.

BACKGROUND/PURPOSE: A slight increase in the proportion of circulating regulatory T (Treg) cells has been reported in systemic lupus erythematosus (SLE) patients taking oral prednisone. The effects of intravenous (IV) high dose methylprednisolone (MP) on Tregs have not yet been described, especially in active SLE. METHODS: We prospectively analyzed the proportion of circulating CD4+ Treg cell subsets defined as follows: (1) naïve Treg (nTreg) FoxP3lowCD45RA+ cells; (2) effector Treg (eTreg) FoxP3highCD45RA- cells; and (3) non-suppressive FoxP3lowCD45RA- cells (non-regulatory Foxp3low T cells). Peripheral blood mononuclear cells of patients with active SLE were analyzed before the first infusion of IV high dose MP (day 0) and the following days (day 1, day 2, ±day 3 and ±day 8). The activity of SLE was assessed by the SLEDAI score. RESULTS: Seventeen patients were included. Following MP infusions, the median (range) percentage of eTregs significantly increased from 1.62% (0.53-8.43) at day 0 to 2.80% (0.83-14.60) at day 1 (p = 0.003 versus day 0), 4.64% (0.50-12.40) at day 2 (p = 0.06 versus day 1) and 7.50% (1.02-20.70) at day 3 (p = 0.008 versus day 2), and declined to baseline values at day 8. Expanding eTreg cells were actively proliferating, as they expressed Ki-67. The frequency of non-regulatory FoxP3low T cells decreased from 6.39% (3.20-17.70) at day 0 to 4.74% (1.03-9.72) at day 2 (p = 0.005); nTreg frequency did not change. All patients clinically improved immediately after MP pulses. The absence of flare after one year of follow up was associated with a higher frequency of eTregs at day 2. CONCLUSION: IV high dose MP induces a rapid, dramatic and transient increase in circulating regulatory T cells. This increase may participate in the preventive effect of MP on subsequent flares in SLE.

Safety and efficacy of rituximab in systemic lupus erythematosus: results from 136 patients from the French AutoImmunity and Rituximab registry.

OBJECTIVE: A number of open-label studies have suggested the potential benefit of rituximab (RTX) in systemic lupus erythematosus (SLE). However, in 2 recent randomized controlled trials (RCTs) of RTX, the primary end points were not met. We undertook this study to evaluate the safety and efficacy of RTX in off-trial patients with SLE seen in regular clinical practice. METHODS: We analyzed prospective data from the French AutoImmunity and Rituximab (AIR) registry, which includes data on patients with autoimmune disorders treated with RTX. RESULTS: One hundred thirty-six patients received treatment for SLE. The mean +/- SD score on the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the SLE Disease Activity Index (SLEDAI) was 11.3 +/- 8.9 at baseline. Severe infections were noted in 12 patients (9%), corresponding to a rate of 6.6/100 patient-years. Most severe infections occurred within the first 3 months after the last RTX infusion. Five patients died, due to severe infection (n = 3) or refractory autoimmune disease (n = 2). Overall response was observed in 80 of 113 patients (71%) by the SELENA-SLEDAI assessment. Efficacy did not differ significantly between patients receiving RTX monotherapy and those receiving concomitant immunosuppressive agents (who had higher baseline disease activity). Articular, cutaneous, renal, and hematologic improvements were noted in 72%, 70%, 74%, and 88% of patients, respectively. Among responders, 41% experienced a relapse of disease, with a response in 91% after retreatment with RTX. CONCLUSION: Data from the AIR registry show a satisfactory tolerance profile and clinical efficacy of RTX in patients with SLE. The contrasting results with those from recent RCTs leave open the question of the therapeutic use of RTX in SLE. Additional controlled studies with new designs are needed to define the place of RTX in the therapeutic arsenal for SLE.