Dataset Information

Evaluation of PR3-ANCA Status After Rituximab for ANCA-Associated Vasculitis.

ABSTRACT:

Introduction

The 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 methods

All 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.

Results

Fifty-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]).

Conclusions

Achieving and maintaining PR3-ANCA negativity after rituximab was associated with longer-lasting remission.

SUBMITTER: McClure ME

PROVIDER: S-EPMC7612177 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Publications

Evaluation of PR3-ANCA Status After Rituximab for ANCA-Associated Vasculitis.

McClure Mark E ME Wason James J Gopaluni Seerapani S Tieu Joanna J Smith Rona M RM Jayne David R DR Jones Rachel B RB

Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases 20190801 5

<h4>Introduction</h4>The 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.<h4>Patients and methods</h4>All patients with active vasculitis and positive proteinase 3 (PR3)-ANCA who were starting a 2-year treatment course of rituximab for induction of remissio ...[more]

PMID: 30896460

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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:BackgroundThe ANCA autoantigens proteinase 3 (PR3) and myeloperoxidase (MPO) are exclusively expressed by neutrophils and monocytes. ANCA-mediated activation of these cells is the key driver of the vascular injury process in ANCA-associated vasculitis (AAV), and neutrophil serine proteases (NSPs) are disease mediators. Cathepsin C (CatC) from zymogens activates the proteolytic function of NSPs, including PR3. Lack of NSP zymogen activation results in neutrophils with strongly reduced NSP proteins.MethodsTo explore AAV-relevant consequences of blocking NSP zymogen activation by CatC, we used myeloid cells from patients with Papillon-Lefèvre syndrome, a genetic deficiency of CatC, to assess NSPs and NSP-mediated endothelial cell injury. We also examined pharmacologic CatC inhibition in neutrophil-differentiated human hematopoietic stem cells, primary human umbilical vein cells, and primary glomerular microvascular endothelial cells.ResultsPatients with Papillon-Lefèvre syndrome showed strongly reduced NSPs in neutrophils and monocytes. Neutrophils from these patients produced a negative PR3-ANCA test, presented less PR3 on the surface of viable and apoptotic cells, and caused significantly less damage in human umbilical vein cells. These findings were recapitulated in human stem cells, in which a highly specific CatC inhibitor, but not prednisolone, reduced NSPs without affecting neutrophil differentiation, reduced membrane PR3, and diminished neutrophil activation upon PR3-ANCA but not MPO-ANCA stimulation. Compared with healthy controls, neutrophils from patients with Papillon-Lefèvre syndrome transferred less proteolytically active NSPs to glomerular microvascular endothelial cells, the cell type targeted in ANCA-induced necrotizing crescentic glomerulonephritis. Finally, both genetic CatC deficiency and pharmacologic inhibition, but not prednisolone, reduced neutrophil-induced glomerular microvascular endothelial cell damage.ConclusionsThese findings may offer encouragement for clinical studies of adjunctive CatC inhibitor in patients with PR3-AAV.

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:BackgroundSequential B cell-targeted immunotherapy with BAFF antagonism (belimumab) and B cell depletion (rituximab) may enhance B cell targeting in ANCA-associated vasculitis (AAV) through several mechanisms.MethodsStudy design: COMBIVAS is a randomised, double-blind, placebo-controlled trial designed to assess the mechanistic effects of sequential therapy of belimumab and rituximab in patients with active PR3 AAV. The recruitment target is 30 patients who meet the criteria for inclusion in the per-protocol analysis. Thirty-six participants have been randomised to one of the two treatment groups in a 1:1 ratio: either rituximab plus belimumab or rituximab plus placebo (both groups with the same tapering corticosteroid regimen), and recruitment is now closed (final patient enrolled April 2021). For each patient, the trial will last for 2 years comprising a 12-month treatment period followed by a 12-month follow-up period.ParticipantsParticipants have been recruited from five of seven UK trial sites. Eligibility criteria were age ≥ 18 years and a diagnosis of AAV with active disease (newly diagnosed or relapsing disease), along with a concurrent positive test for PR3 ANCA by ELISA.InterventionsRituximab 1000 mg was administered by intravenous infusions on day 8 and day 22. Weekly subcutaneous injections of 200 mg belimumab or placebo were initiated a week before rituximab on day 1 and then weekly through to week 51. All participants received a relatively low prednisolone (20 mg/day) starting dose from day 1 followed by a protocol-specified corticosteroid taper aiming for complete cessation by 3 months.OutcomesThe primary endpoint of this study is time to PR3 ANCA negativity. Key secondary outcomes include change from baseline in naïve, transitional, memory, plasmablast B cell subsets (by flow cytometry) in the blood at months 3, 12, 18 and 24; time to clinical remission; time to relapse; and incidence of serious adverse events. Exploratory biomarker assessments include assessment of B cell receptor clonality, B cell and T cell functional assays, whole blood transcriptomic analysis and urinary lymphocyte and proteomic analysis. Inguinal lymph node and nasal mucosal biopsies have been performed on a subgroup of patients at baseline and month 3.DiscussionThis experimental medicine study provides a unique opportunity to gain detailed insights into the immunological mechanisms of belimumab-rituximab sequential therapy across multiple body compartments in the setting of AAV.Trial registrationClinicalTrials.gov NCT03967925. Registered on May 30, 2019.

Dataset Information

Evaluation of PR3-ANCA Status After Rituximab for ANCA-Associated Vasculitis.

Introduction

Patients and methods

Results

Conclusions

Publications

Evaluation of PR3-ANCA Status After Rituximab for ANCA-Associated Vasculitis.

Similar Datasets

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