Dataset Information

Long-term follow-up of a combined rituximab and cyclophosphamide regimen in renal anti-neutrophil cytoplasm antibody-associated vasculitis.

ABSTRACT:

Background

Current guidelines advise that rituximab or cyclophosphamide should be used for the treatment of organ-threatening disease in anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV), although few studies have examined the efficacy and safety of these agents in combination.

Methods

We conducted a single-centre cohort study of 66 patients treated with a combination of oral corticosteroids, rituximab and low-dose pulsed intravenous cyclophosphamide followed by a maintenance regimen of azathioprine and tapered steroid for the treatment of biopsy-proven renal involvement in AAV. Patients were followed for a median of 56 months. Case-control analysis with 198 propensity-matched cases from European Vasculitis Study Group (EUVAS) trials compared long-term differences in relapse-free, renal and patient survival.

Results

At entry, the median Birmingham Vasculitis Activity Score (BVAS) was 19 and estimated glomerular filtration rate was 25 mL/min. Cumulative doses of rituximab, cyclophosphamide and corticosteroids were 2, 3 and 4.2 g, respectively, at 6 months. A total of 94% of patients achieved disease remission by 6 months (BVAS < 0) and patient and renal survival were 84 and 95%, respectively, at 5 years. A total of 84% achieved ANCA-negative status and 57% remained B cell deplete at 2 years, which was associated with low rates of major relapse (15% at 5 years). The serious infection rate during long-term follow-up was 1.24 per 10 patient-years. Treatment with this regimen was associated with a reduced risk of death {hazard ratio [HR] 0.29 [95% confidence interval (CI) 0.125-0.675], P = 0.004}, progression to end-stage renal disease (ESRD) [HR 0.20 (95% CI 0.06-0.65), P = 0.007] and relapse [HR 0.49 (95% CI 0.25-0.97), P = 0.04] compared with propensity-matched patients enrolled in EUVAS trials.

Conclusions

This regimen is potentially superior to current standards of care, and controlled studies are warranted to establish the utility of combination drug approaches in the treatment of AAV.

SUBMITTER: McAdoo SP

PROVIDER: S-EPMC6322443 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Publications

Long-term follow-up of a combined rituximab and cyclophosphamide regimen in renal anti-neutrophil cytoplasm antibody-associated vasculitis.

McAdoo Stephen P SP Medjeral-Thomas Nicholas N Gopaluni Seerapani S Tanna Anisha A Mansfield Nicholas N Galliford Jack J Griffith Megan M Levy Jeremy J Cairns Thomas D TD Jayne David D Salama Alan D AD Pusey Charles D CD

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 20190101 1

<h4>Background</h4>Current guidelines advise that rituximab or cyclophosphamide should be used for the treatment of organ-threatening disease in anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV), although few studies have examined the efficacy and safety of these agents in combination.<h4>Methods</h4>We conducted a single-centre cohort study of 66 patients treated with a combination of oral corticosteroids, rituximab and low-dose pulsed intravenous cyclophosphamide followed b ...[more]

PMID: 29462348

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Project description:BackgroundCyclophosphamide and glucocorticoids have been the cornerstone of remission-induction therapy for severe antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis for 40 years. Uncontrolled studies suggest that rituximab is effective and may be safer than a cyclophosphamide-based regimen.MethodsWe conducted a multicenter, randomized, double-blind, double-dummy, noninferiority trial of rituximab (375 mg per square meter of body-surface area per week for 4 weeks) as compared with cyclophosphamide (2 mg per kilogram of body weight per day) for remission induction. Glucocorticoids were tapered off; the primary end point was remission of disease without the use of prednisone at 6 months.ResultsNine centers enrolled 197 ANCA-positive patients with either Wegener's granulomatosis or microscopic polyangiitis. Baseline disease activity, organ involvement, and the proportion of patients with relapsing disease were similar in the two treatment groups. Sixty-three patients in the rituximab group (64%) reached the primary end point, as compared with 52 patients in the control group (53%), a result that met the criterion for noninferiority (P<0.001). The rituximab-based regimen was more efficacious than the cyclophosphamide-based regimen for inducing remission of relapsing disease; 34 of 51 patients in the rituximab group (67%) as compared with 21 of 50 patients in the control group (42%) reached the primary end point (P=0.01). Rituximab was also as effective as cyclophosphamide in the treatment of patients with major renal disease or alveolar hemorrhage. There were no significant differences between the treatment groups with respect to rates of adverse events.ConclusionsRituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease. (Funded by the National Institutes of Allergy and Infectious Diseases, Genentech, and Biogen; ClinicalTrials.gov number, NCT00104299.)

Project description:ObjectiveThe objective of this study was to compare the efficacy and safety of two rituximab (RTX) regimens for the induction of remission in severe antineutrophil cytoplasm antibody-associated vasculitis (AAV): the four-dose (375 mg/m2 intravenously weekly) versus the two-dose (1000 mg intravenously biweekly) regimen.MethodsA systematic review was performed to identify studies using the four- and/or two-dose RTX regimens for induction of remission in severe AAV. Disease status 6 months after RTX infusion was required for inclusion. Patients were excluded if they received concomitant cyclophosphamide or plasma exchange. The primary end point was the proportion of patients in complete remission at 6 months. The pooled estimate was obtained by using meta-analysis methods for proportions with random effects. Secondary end points included antineutrophil cytoplasm antibody status, number of patients with B-cell depletion, mean prednisone dose, infections, and death.ResultsA total of 27 studies and 506 patients were included for analysis: 361 patients received the four-dose regimen, and 145 patients received the two-dose regimen. Most patients had relapsing disease at inclusion (83% and 92% of patients, respectively). There was no significant difference between the four- and two-dose regimens, with a complete remission achieved in 85% (95% confidence interval [CI]: 70-96) and 91% (95% CI: 79-99) of patients, respectively. At 6 months, both regimens were associated with a similar mean daily prednisone dose (8.1 mg), infections (12% in both), and death (1% vs. 0%, respectively).ConclusionNo difference was found in terms of efficacy or safety between the four- and two-dose RTX regimens for induction of remission in severe AAV. https://onlinelibrary.wiley.com/doi/10.1002/acr2.11274 Bénard V, Farhat C, Zarandi-Nowroozi M, Durand M, Charles P, Puéchal X, et al. Comparison of two rituximab induction regimens for antineutrophil cytoplasm antibody-associated vasculitis: systematic review and meta-analysis. ACR Open Rheumatol 2021;3:484-94.

Project description:BackgroundAnti-neutrophil cytoplasmic antibodies associated vasculitides (AAV) are characterized by autoimmune small vessel inflammation. Eosinophils are multifunctional cells with both pro-inflammatory and immunoregulatory properties. Tissue activated eosinophils secrete cyto- and chemokines and form extracellular traps (EETs), they release free granules and produce reactive oxygen species. The role of eosinophils is well established in eosinophilic granulomatosis with polyangiitis (EGPA) but very little is known about their role in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).MethodsThe expression of surface markers CD11c, CD11b, CD16, CD35, CD62L, CD64, CD88, Siglec-8 and CD193 and reactive oxygen species production by peripheral blood eosinophils were studied using flow cytometry. Fluorescence microscopy was used to visualize the release of eosinophil extracellular DNA traps (EETs). 98 GPA and MPA patients and 121 healthy controls were included in the study.ResultsBoth GPA and MPA patients had decreased frequency of eosinophils in peripheral blood compared with healthy controls (p < 0.0001), which could not solely be explained by corticosteroid treatment. The patient's eosinophils showed increased surface expression of the Fc receptors CD16 (p < 0.0001) and CD64 (p = 0.0035) as well as CCR3 (CD193) (p = 0.0022). Decreased expression was found of the complement receptors CD35 (p = 0.0022), CD88 (p < 0,0001) as well as CD11c (p < 0,0001), CD11b (p = 0.0061) and Siglec-8 (p = 0,0015). Moreover, GPA and MPA eosinophils, showed decreased capacity to produce ROS (p < 0.0001). ANCA stimulation of eosinophils from GPA and MPA patients after C5a priming enhanced EETosis (p = 0,0088).ConclusionsThe percentage of eosinophils were decreased in peripheral blood in GPA and MPA patients and showed altered surface marker expression and function. The enhanced EETosis after ANCA stimulation, suggests that eosinophil can contribute to the autoantibody driven inflammatory process.

Dataset Information

Long-term follow-up of a combined rituximab and cyclophosphamide regimen in renal anti-neutrophil cytoplasm antibody-associated vasculitis.

Background

Methods

Results

Conclusions

Publications

Long-term follow-up of a combined rituximab and cyclophosphamide regimen in renal anti-neutrophil cytoplasm antibody-associated vasculitis.

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