Project description:Remission in the majority of ANCA vasculitis patients is not sustained after a single course of rituximab, and risk of relapse warrants development of a successful strategy to ensure durable remission.A retrospective analysis of ANCA vasculitis patients who underwent maintenance therapy using rituximab-induced continuous B-cell depletion for up to 7 years was performed. Maintenance therapy with rituximab was initiated after achieving remission or converting from other prior maintenance therapy. Continuous B-cell depletion was achieved in all patients by scheduled rituximab administration every 4 months. Disease activity, serologic parameters, adverse events, and survival were examined.In the study, 172 patients (mean age=60 years, 55% women, 57% myeloperoxidase-ANCA) treated from April of 2006 to March of 2013 underwent continuous B-cell depletion with rituximab. Median remission maintenance follow-up time was 2.1 years. Complete remission (Birmingham Vasculitis Activity Score [BVAS] = 0) was achieved in all patients. Major relapse (BVAS ? 3) occurred in 5% of patients and was associated with weaning of other immunosuppression drugs. Remission was reinduced in all patients. Survival mirrored survival of a general age-, sex-, and ethnicity-matched United States population.This analysis provides evidence for long-term disease control using continuous B-cell depletion. This treatment strategy in ANCA vasculitis patients also seems to result in survival rates comparable with rates in a matched reference population. These findings suggest that prospective remission maintenance treatment trials using continuous B-cell depletion are warranted.
Project description:ObjectivesFollowing a maintenance course of rituximab (RTX) for ANCA-associated vasculitis (AAV), relapses occur on cessation of therapy, and further dosing is considered. This study aimed to develop relapse and infection risk prediction models to help guide decision making regarding extended RTX maintenance therapy.MethodsPatients with a diagnosis of AAV who received 4-8 grams of RTX as maintenance treatment between 2002 and 2018 were included. Both induction and maintenance doses were included; most patients received standard departmental protocol consisting of 2× 1000 mg 2 weeks apart, followed by 1000 mg every 6 months for 2 years. Patients who continued on repeat RTX dosing long-term were excluded. Separate risk prediction models were derived for the outcomes of relapse and infection.ResultsA total of 147 patients were included in this study with a median follow-up of 63 months [interquartile range (IQR): 34-93]. Relapse: At time of last RTX, the model comprised seven predictors, with a corresponding C-index of 0.54. Discrimination between individuals using this model was not possible; however, discrimination could be achieved by grouping patients into low- and high-risk groups. When the model was applied 12 months post last RTX, the ability to discriminate relapse risk between individuals improved (C-index 0.65), and once again, clear discrimination was observed between patients from low- and high-risk groups. Infection: At time of last RTX, five predictors were retained in the model. The C-index was 0.64 allowing discrimination between low and high risk of infection groups. At 12 months post RTX, the C-index for the model was 0.63. Again, clear separation of patients from two risk groups was observed.ConclusionWhile our models had insufficient power to discriminate risk between individual patients they were able to assign patients into risk groups for both relapse and infection. The ability to identify risk groups may help in decisions regarding the potential benefit of ongoing RTX treatment. However, we caution the use of these prediction models until prospective multi-centre validation studies have been performed.
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:IntroductionRemission induction in antineutrophil cytoplasmic autoantibody (ANCA) vasculitis may be complicated by slow response to treatment and toxicity from glucocorticoids. We describe outcomes with a novel remission induction regimen combining rituximab with a short course of low-dose, oral cyclophosphamide and an accelerated prednisone taper.MethodsPatients were included in this retrospective study if they had newly diagnosed or relapsing ANCA vasculitis with a Birmingham Vasculitis Activity Score for Wegener Granulomatosis (BVAS-WG) ≥3 and received a standardized remission induction regimen. The primary outcome was complete remission, defined as a BVAS-WG of 0 and a prednisone dose of ≤7.5 mg/d.ResultsWe identified 129 patients who met the inclusion criteria, 31% of whom also received plasma exchange (PLEX) for rapidly progressive glomerulonephritis (RPGN) or diffuse alveolar hemorrhage. Seventy percent of patients had myeloperoxidase (MPO)-ANCA and 9% had relapsing disease. Median time to complete remission was 4 months (interquartile range [IQR] 3.9-4.4), and by 5 months 84% of patients were in complete remission. Prednisone was tapered to discontinuation as tolerated, such that the median prednisone dose at 8 months was 0 mg/d (IQR 0-2.5). In patients with RPGN, proteinase 3-ANCA was associated with a greater increase in eGFR at 6 months compared with MPO-ANCA (16 vs. 5.6 ml/min per 1.73m2; P = 0.028). During the year following remission, 1 major relapse occurred over 122 patient-years. Serious infections occurred more frequently in patients receiving PLEX and were associated with increasing age and diffuse alveolar hemorrhage. Four deaths occurred, 3 of which were associated with serious infections.ConclusionCombination therapy was efficacious, allowed for rapid tapering of high-dose glucocorticoids and was well tolerated.
Project description:IntroductionThe value of antineutrophil cytoplasmic antibody (ANCA) measurements among patients with an established diagnosis of ANCA-associated vasculitis (AAV) to assess disease activity or predict relapse remains controversial, but recent evidence suggests a possible role for rituximab-treated patients.Patients and methodsAll patients with active vasculitis and positive proteinase 3 (PR3)-ANCA who were starting a 2-year treatment course of rituximab for induction of remission at Addenbrooke's Hospital between January 2011 and January 2016 were included in this study. Common department practice consists of 6 g of rituximab given over 2 years, concomitant corticosteroids (0.5-1.0 mg/kg) with rapid taper over 3 months, and cessation of oral maintenance immunosuppressive agents at time of first rituximab dose. Clinical and laboratory data were collected retrospectively using electronic patient records.ResultsFifty-seven patients with current PR3-ANCA positivity were included in the analysis. Median follow-up was 59 months. PR3-ANCA negativity was achieved in 25 patients (44%) with a median time of 14 months. Clinical remission was achieved in 53 patients (93%) with a median time of 3 months. Among the 53 patients who achieved remission during follow-up, 24 (45%) relapsed with a median time to relapse of 36 months from remission. Both PR3-ANCA-negative status and 50% reduction in PR3-ANCA from baseline (as time-varying covariates) were significantly associated with a longer time to relapse (PR3-ANCA-negative status: hazards ratio, 0.08 [95% confidence interval, 0.01-0.63, p = 0.016]; 50% reduction in PR3-ANCA: hazards ratio, 0.25 [95% confidence interval, 0.18-0.99, p = 0.046]).ConclusionsAchieving and maintaining PR3-ANCA negativity after rituximab was associated with longer-lasting remission.
Project description:Rituximab (RTX) is non-inferior to cyclophosphamide (CYC) followed by azathioprine (AZA) for remission-induction in severe ANCA-associated vasculitis (AAV), but renal outcomes are unknown. This is a post hoc analysis of patients enrolled in the Rituximab for ANCA-Associated Vasculitis (RAVE) Trial who had renal involvement (biopsy proven pauci-immune GN, red blood cell casts in the urine, and/or a rise in serum creatinine concentration attributed to vasculitis). Remission-induction regimens were RTX at 375 mg/m(2) × 4 or CYC at 2 mg/kg/d. CYC was replaced by AZA (2 mg/kg/d) after 3-6 months. Both groups received glucocorticoids. Complete remission (CR) was defined as Birmingham Vasculitis Activity Score/Wegener's Granulomatosis (BVAS/WG)=0 off prednisone. Fifty-two percent (102 of 197) of the patients had renal involvement at entry. Of these patients, 51 were randomized to RTX, and 51 to CYC/AZA. Mean eGFR was lower in the RTX group (41 versus 50 ml/min per 1.73 m(2); P=0.05); 61% and 75% of patients treated with RTX and 63% and 76% of patients treated with CYC/AZA achieved CR by 6 and 18 months, respectively. No differences in remission rates or increases in eGFR at 18 months were evident when analysis was stratified by ANCA type, AAV diagnosis (granulomatosis with polyangiitis versus microscopic polyangiitis), or new diagnosis (versus relapsing disease) at entry. There were no differences between treatment groups in relapses at 6, 12, or 18 months. No differences in adverse events were observed. In conclusion, patients with AAV and renal involvement respond similarly to remission induction with RTX plus glucocorticoids or CYC plus glucocorticoids.
Project description:To study the impact of glucocorticoid maintenance dose and treatment duration on outcomes in patients with AAV (ANCA-associated vasculitis) with emphasis on infectious complications. A total of 130 AAV patients from two German vasculitis centers diagnosed between August 2004 and January 2019 treated with cyclophosphamide and glucocorticoids for induction therapy and glucocorticoids for maintenance therapy were retrospectively enrolled. We investigated the influence of glucocorticoid maintenance therapy on patient survival, time to relapse, kidney function, infectious complications and irreversible physical damage. The patients were divided into the following groups: patients treated according to the predefined reduction scheme (< 7.5 mg) or patients treated with glucocorticoids ≥ 7.5 mg after 6 months. Compared to patients receiving < 7.5 mg glucocorticoids after 6 months, patients receiving [Formula: see text] 7.5 mg had an increased rate of infectious episodes per patient (1.7 vs. 0.6; p < 0.001), including urinary tract infection (p = 0.007), pneumonia (p = 0.003), opportunistic pneumonia (p = 0.022) and sepsis (p = 0.008). Especially pneumonia during the first 24 months after disease onset [hazard ratio, 3.0 (95% CI 1.5 - 6.1)] led to more deaths from infection (p = 0.034). Glucocorticoid maintenance therapy after 6 months had no impact on relapse rate or patient survival and decline in kidney function was comparable. Glucocorticoid maintenance therapy with [Formula: see text] 7.5 mg after 6 months is associated with more severe infectious complications leading to an increased frequency of deaths from infection. Glucocorticoid maintenance therapy has no effect on time to relapse or patient survival and should therefore be critically revised throughout the aftercare of AAV patients.
Project description:BackgroundThe primary challenge of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) patient care is the early detection of relapses to prevent organ damage and increase survival. Potential biomarkers for relapses are ANCA and B cells, but their predictive value is a matter of debate. Therefore this study investigated how ANCA and B-cell status related to relapses in AAV patients treated with rituximab (RTX) as remission induction (RI).MethodsThis single-centre cohort study identified 110 ANCA-positive AAV patients treated with RTX between 2006 and 2018. Serial ANCA, CD19+ B-cell status and relapses were assessed >2 years.ResultsPatients (31/110) relapsed within 2 years after RTX RI treatment. Patients who achieved and maintained PR3-ANCA negativity (n = 29) had few relapses (3%), while persistent proteinase 3 (PR3)-ANCA positivity (n = 49) and reappearance of PR3-ANCAs (n = 10) associated significantly with more relapses (37%, P = 0.002 and 50%, P = 0.002). Patients with incomplete B-cell depletion (n = 11) had significantly more relapses (54%) as compared with patients with B-cell depletion [n = 76 (26%), P = 0.02]. Also, patients with repopulation of B cells (n = 58) had significantly more relapses (41%) as compared with patients without B-cell repopulation [n = 27 (15%), P = 0.03]. Overall, the absence of PR3- or myeloperoxidase (MPO)-ANCA positivity was highly predictive for remaining relapse-free. In PR3-ANCA-positive patients, 96% of the relapses occurred with persistent or reappearance of PR3-ANCAs and 81% with B-cell repopulation. In MPO-ANCA-positive patients, all relapses were restricted to patients with persistent MPO-ANCAs and B-cell repopulation.ConclusionsUpon RI treatment with RTX in AAV patients, ANCA and B-cell status were predictive of the majority of relapses and specifically their absence strongly predicted a relapse-free status. Therefore the implementation of ANCA and B-cell monitoring could guide therapeutic decision-making to prevent relapses in AAV patients treated with RTX.
Project description:ANCA associated vasculitides (AAV) often present with a chronic relapsing course. Relapse leads to increased immunosuppressive exposure and consequent toxicity. While two randomized controlled trials have shown rituximab (RTX) to be the most effective induction treatment in patients with relapsing disease, the optimal treatment duration and RTX dose remain debated. Whether to administer a maintenance dose to every patient, at a fixed time interval or on the basis of B cell count and ANCA titre or only when disease manifestations do occur is still debated as well.11 patients (5 with granulomatosis with polyangiitis, 4 with microscopic polyangiitis-MPA-, and 2 with eosinophilic granulomatosis with polyangiitis -EGPA-) intolerant or refractory to conventional therapies including cyclophosphamide were enrolled. All patients received the so called "improved 4+2" RTX scheme as a rescue therapy. Following RTX administration, immunosuppressive drugs were rapidly tapered and no immunosuppressive maintenance therapy had been given.After a mean follow-up of 85 months since the "4+2" RTX protocol: four out of 11 patients (37%, 1 EGPA and 3 MPA, all MPO-positive) remained in remission after one cycle of "4+2" RTX infusion protocol with no relapse for a median 66 months [60-108]). Seven relapsing patients were re-treated once with RTX (again as monotherapy with the same protocol) after a median of 54 months (24-96). Following re-treatment, they again showed complete remission over a median of 32 months (12-96) of observation.In one of the longest-term observation (85 months) studies, sustained clinical remission without immunosuppressive maintenance therapy (and a negligible dose of prednisone since the 5thmonth) was obtained by the "4 + 2" RTX infusion protocol in patients with ANCA-associated vasculitis intolerant or refractory to conventional therapy.
Project description:Background and objectivesB cell significance in ANCA disease pathogenesis is underscored by the finding that ANCA alone can cause disease in mouse models and by the effectiveness of rituximab as therapy in ANCA-small vessel vasculitis (ANCA-SVV). To avoid infections and adverse events from therapy, clinicians require improved markers of disease activity and impending relapse to guide immunosuppression strategies after rituximab treatment.Design, setting, participants, & measurementsThe B cell phenotype was investigated in patients with active ANCA-SVV and in remission. From 2003 to 2009, 54 patients were followed longitudinally for 4-99 months and compared with 68 healthy controls. In a subset of 19 patients, the B cell immunophenotype was examined in samples after rituximab therapy.ResultsPatients with active ANCA-SVV had lower %CD5(+) B cells, whereas %CD5(+) B cells from patients in remission were indistinguishable from healthy controls. After rituximab, median time to relapse was 31 months in patients maintaining normalized %CD5(+) B cells, with or without maintenance immunosuppression. Among patients whose B cells repopulated with low %CD5(+) B cells or had a sharply declining %CD5(+) B cells, those who were on low or no maintenance immunosuppression relapsed sooner (median 17 months) than patients who were maintained on high levels of oral maintenance immunosuppression (29 months; P=0.002).ConclusionsThe %CD5(+) B cells, as a component of the human B regulatory cell phenotype, is a useful indicator of disease activity, remission, and future relapse, and thus may guide remission maintenance therapy after rituximab treatment.