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BACKGROUND: Sequential 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. METHODS: Study 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. PARTICIPANTS: Participants 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. INTERVENTIONS: Rituximab 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. OUTCOMES: The 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. DISCUSSION: This 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 REGISTRATION: ClinicalTrials.gov NCT03967925. Registered on May 30, 2019.

Funder: Vifor Pharma; Id: http://dx.doi.org/10.13039/501100006484, Objective: COVID‐19 is a novel infectious disease with a broad spectrum of clinical severity. Patients with systemic vasculitis have an increased risk of serious infections and may be at risk of severe outcomes following COVID‐19. We undertook this study to establish the risk factors for severe COVID‐19 outcomes in these patients, including the impact of immunosuppressive therapies. Methods: A multicenter cohort was developed through the participation of centers affiliated with national UK and Ireland vasculitis registries. Clinical characteristics and outcomes are described. Logistic regression was used to evaluate associations between potential risk factors and a severe COVID‐19 outcome, defined as a requirement for advanced oxygen therapy, a requirement for invasive ventilation, or death. Results: The cohort included 65 patients with systemic vasculitis who developed COVID‐19 (median age 70 years, 49% women), of whom 25 patients (38%) experienced a severe outcome. Most patients (55 of 65 [85%]) had antineutrophil cytoplasmic antibody–associated vasculitis (AAV). Almost all patients required hospitalization (59 of 65 [91%]), 7 patients (11%) were admitted to intensive care, and 18 patients (28%) died. Background glucocorticoid therapy was associated with severe outcomes (adjusted odds ratio [OR] 3.7 [95% confidence interval 1.1–14.9]; P = 0.047), as was comorbid respiratory disease (adjusted OR 7.5 [95% confidence interval 1.9–38.2]; P = 0.006). Vasculitis disease activity and nonglucocorticoid immunosuppressive therapy were not associated with severe outcomes. Conclusion: In patients with systemic vasculitis, glucocorticoid use at presentation and comorbid respiratory disease were associated with severe outcomes in COVID‐19. These data can inform clinical decision‐making relating to the risk of severe COVID‐19 in this vulnerable patient group.

Additional file 1: Supplementary Figure. Consort diagram illustrating patient disposition throughout the trial.

Objective:\ud COVID‐19 is a novel infectious disease with a broad spectrum of clinical severity. Patients with systemic vasculitis have an increased risk of serious infections and so may be at risk of severe outcomes following COVID‐19. It is important to establish the risk factors for severe COVID‐19 outcomes in these patients, including the impact of immunosuppressive therapies.\ud \ud Methods:\ud A multi‐centre cohort was developed through the participation of centres affiliated with national UK and Ireland vasculitis registries. Clinical characteristics and outcomes were described. Logistic regression was used to evaluate associations between potential risk factors and severe COVID‐19 outcome, defined as a requirement for advanced oxygen therapy, invasive ventilation, or death.\ud \ud Results:\ud Sixty‐five cases of patients with systemic vasculitis who developed COVID‐19 were reported (median age 70 years, 49% female) of whom 25 (38%) experienced a severe outcome. Most cases (55/65, 85%) had ANCA‐associated vasculitis (AAV). Almost all patients required hospitalization (59/65, 91%), 7 patients (11%) were admitted to intensive care and 18 patients (28%) died. Background glucocorticoid therapy was associated with severe outcome (adjusted odds ratio [aOR] 3.7 (1.1‐14.9, p=0.047)) as was comorbid respiratory disease (aOR 7.5 (1.9‐38.2, p=0.006)). Vasculitis disease activity and non‐glucocorticoid immunosuppression were not associated with severe outcome.\ud \ud Conclusion:\ud In patients with systemic vasculitis, glucocorticoid use at presentation and comorbid respiratory disease were associated with severe outcomes in COVID‐19. These data can inform clinical decision making relating to risk of severe COVID‐19 in this vulnerable patient group.

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.

Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) is an autoimmune disease characterised by inflammation of small blood vessels that leads to organ dysfunction. Auto-reactive B cells produce pathogenic antibodies against the neutrophil enzymes, myeloperoxidase (MPO) and proteinase 3 (PR3). Genome-wide association studies that identified the relationship between MHC class II genes and ANCA specificity strongly support the role of CD4 T helper cells in the pathogenesis of AAV. Recently a new subset of T cells called peripheral T helper (PTH) cells, characterised by the PD1+CXCR5- phenotype, was described in the context of auto-immune diseases, driving organ inflammation. These pathogenic cells were shown to infiltrate sites of inflammation and have the necessary machinery to provide B cell help in the peripheral tissues. This thesis is aimed at establishing the role of these cells in systemic AAV and their potential role in disease pathogenesis. PTH cells have been studied by flow cytometry, transcriptomic and functional assays across multiple compartments of lymph node, peripheral blood, kidney tissue and urine of AAV patients. A newer angle is the use of single cell transcriptomic technology to understand the clonal and transcriptomic relationship of these cells to the traditional T follicular helper (TFH) cells. This thesis established that PTH cells were expanded within the circulatory compartment of AAV patients irrespective of their disease status and were seen in the urine and kidney tissue of AAV patients with nephritis. Transcriptomic analysis revealed them to express cytotoxic and chemokine receptor signatures that could aid their migration to sites of inflammation. T cell receptor analysis identified the clonal relationship between different subsets, giving newer insight into the development of these cells. Furthermore, possible targets for therapeutic intervention were identified., Experimental Medicine Initiative (EMI) - a GSK/University of Cambridge collaboration

OBJECTIVE: The treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) aims to suppress disease activity and prevent subsequent disease flare. This study sought to explore the association of early disease control with long-term outcomes to validate early disease control as an end point for future clinical trials in AAV. METHODS: Data from 4 European Vasculitis Society inception clinical trials in AAV (1995-2002) and subsequent data on long-term outcomes from the trial data registry were studied. Clinical parameters in patients with AAV at baseline and at 3 and 6 months after diagnosis were assessed to study the long-term risk of death and end-stage renal failure (ESRF). At 6 months, outcomes were defined based on a disease status of either sustained remission (remission by 3 months, sustained to 6 months), late remission (remission after 3 months and by 6 months), relapsing disease (remission by 3 months but relapse by 6 months), or refractory disease (no remission by 6 months). RESULTS: Of the 354 patients with AAV who were followed up for a median of 5.7 years, 46 (13%) developed ESRF, 66 (18.6%) died, and 89 (25.1%) had either died or developed ESRF. At 6 months, predictors of the composite end point of death or ESRF were as follows: age (hazard ratio [HR] 1.02, 95% confidence interval [95% CI] 1-1.05; P = 0.012), estimated glomerular filtration rate (HR 0.94, 95% CI 0.92-0.95; P < 0.001), and disease status at 6 months (late remission, HR 2.94, 95% CI 1.1-7.85 [P = 0.031]; relapsing disease, HR 8.21, 95% CI 2.73-24.65 [P < 0.001]; refractory disease, HR 4.89, 95% CI 1.96-12.18 [P = 0.001]). Similar results were observed when these analyses were performed separately for death and for ESRF. CONCLUSION: The results of this study suggest that disease status at 3 and 6 months following the diagnosis of AAV may be predictive of the long-term risk of mortality and ESRF, and therefore these may be valid end points for induction trials in AAV. The current findings need to be validated in a larger data set.

BACKGROUND: Rituximab is effective as therapy for induction of remission in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). However, the effect of rituximab is not sustained, and subsequent relapse rates are high, especially in patients with a history of relapse. There is a need to identify whether maintenance therapy with rituximab is superior to the current standard of azathioprine or methotrexate for prevention of relapse following induction with rituximab. METHODS/DESIGN: RITAZAREM is an international, multicenter, open-label, randomized controlled trial designed to demonstrate the superiority of repeated doses of intravenous rituximab compared to daily orally administered azathioprine as a relapse prevention strategy in patients with AAV with relapsing disease who undergo induction of remission with rituximab. Patients with AAV will be recruited at the time of relapse and will receive rituximab and glucocorticoid induction therapy. If the disease is controlled by 4 months, patients will be randomized in a 1:1 ratio to receive rituximab (1000 mg every 4 months for five doses) or azathioprine (2 mg/kg/day) as maintenance therapy. Patients will be followed for a minimum of 36 months. The primary outcome is the time to disease relapse. It is estimated that 190 patients will need to be recruited to ensure that at least 160 are randomized. DISCUSSION: The RITAZAREM trial will provide the largest trial dataset for the use of rituximab as remission-induction therapy for patients with AAV comparing two remission-maintenance strategies following induction with rituximab, and explore whether prolonged B-cell depletion leads to sustained treatment-free remissions after discontinuation of immunosuppressive therapy. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01697267 . Registered on 31 August 2012.

Background: Ear, nose and throat involvement in granulomatosis with polyangiitis (GPA) is frequently the initial disease manifestation. Previous investigations have observed a higher prevalence of Staphylococcus aureus in patients with GPA, and chronic nasal carriage has been linked with an increased risk of disease relapse. In this cross-sectional study, we investigated changes in the nasal microbiota including a detailed analysis of Staphylococcus spp. by shotgun metagenomics in patients with active and inactive granulomatosis with polyangiitis (GPA). Shotgun metagenomic sequence data were also used to identify protein-encoding genes within the SEED database, and the abundance of proteins then correlated with the presence of bacterial species on an annotated heatmap. Results: The presence of S. aureus in the nose as assessed by culture was more frequently detected in patients with active GPA (66.7%) compared with inactive GPA (34.1%). Beta diversity analysis of nasal microbiota by bacterial 16S rRNA profiling revealed a different composition between GPA patients and healthy controls (P = 0.039). Beta diversity analysis of shotgun metagenomic sequence data for Staphylococcus spp. revealed a different composition between active GPA patients and healthy controls and disease controls (P = 0.0007 and P = 0.0023, respectively), and between healthy controls and inactive GPA patients and household controls (P = 0.0168 and P = 0.0168, respectively). Patients with active GPA had a higher abundance of S. aureus, mirroring the culture data, while healthy controls had a higher abundance of S. epidermidis. Staphylococcus pseudintermedius, generally assumed to be a pathogen of cats and dogs, showed an abundance of 13% among the Staphylococcus spp. in our cohort. During long-term follow-up of patients with inactive GPA at baseline, a higher S. aureus abundance was not associated with an increased relapse risk. Functional analyses identified ten SEED protein subsystems that differed between the groups. Most significant associations were related to chorismate synthesis and involved in the vitamin B12 pathway. Conclusion: Our data revealed a distinct dysbiosis of the nasal microbiota in GPA patients compared with disease and healthy controls. Metagenomic sequencing demonstrated that this dysbiosis in active GPA patients is manifested by increased abundance of S. aureus and a depletion of S. epidermidis, further demonstrating the antagonist relationships between these species. SEED functional protein subsystem analysis identified an association between the unique bacterial nasal microbiota clusters seen mainly in GPA patients and an elevated abundance of genes associated with chorismate synthesis and vitamin B12 pathways. Further studies are required to further elucidate the relationship between the biosynthesis genes and the associated bacterial species.

BACKGROUND: Ear, nose and throat involvement in granulomatosis with polyangiitis (GPA) is frequently the initial disease manifestation. Previous investigations have observed a higher prevalence of Staphylococcus aureus in patients with GPA, and chronic nasal carriage has been linked with an increased risk of disease relapse. In this cross-sectional study, we investigated changes in the nasal microbiota including a detailed analysis of Staphylococcus spp. by shotgun metagenomics in patients with active and inactive granulomatosis with polyangiitis (GPA). Shotgun metagenomic sequence data were also used to identify protein-encoding genes within the SEED database, and the abundance of proteins then correlated with the presence of bacterial species on an annotated heatmap. RESULTS: The presence of S. aureus in the nose as assessed by culture was more frequently detected in patients with active GPA (66.7%) compared with inactive GPA (34.1%). Beta diversity analysis of nasal microbiota by bacterial 16S rRNA profiling revealed a different composition between GPA patients and healthy controls (P = 0.039). Beta diversity analysis of shotgun metagenomic sequence data for Staphylococcus spp. revealed a different composition between active GPA patients and healthy controls and disease controls (P = 0.0007 and P = 0.0023, respectively), and between healthy controls and inactive GPA patients and household controls (P = 0.0168 and P = 0.0168, respectively). Patients with active GPA had a higher abundance of S. aureus, mirroring the culture data, while healthy controls had a higher abundance of S. epidermidis. Staphylococcus pseudintermedius, generally assumed to be a pathogen of cats and dogs, showed an abundance of 13% among the Staphylococcus spp. in our cohort. During long-term follow-up of patients with inactive GPA at baseline, a higher S. aureus abundance was not associated with an increased relapse risk. Functional analyses identified ten SEED protein subsystems that differed between the groups. Most significant associations were related to chorismate synthesis and involved in the vitamin B12 pathway. CONCLUSION: Our data revealed a distinct dysbiosis of the nasal microbiota in GPA patients compared with disease and healthy controls. Metagenomic sequencing demonstrated that this dysbiosis in active GPA patients is manifested by increased abundance of S. aureus and a depletion of S. epidermidis, further demonstrating the antagonist relationships between these species. SEED functional protein subsystem analysis identified an association between the unique bacterial nasal microbiota clusters seen mainly in GPA patients and an elevated abundance of genes associated with chorismate synthesis and vitamin B12 pathways. Further studies are required to further elucidate the relationship between the biosynthesis genes and the associated bacterial species.