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Background. Sequential B cell targeted immunotherapy with BAFF antagonism (belimumab) and B cell depletion (rituximab) and may enhance B cell targeting in ANCA-associated vasculitis (AAV) through several mechanisms. 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 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 March 2021). For each patient, the trial will last for two 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 ³18 years, 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 1000mg was administered by intravenous infusions on Day 8 and Day 22. Weekly subcutaneous injections of 200mg 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 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 status. The final patient was recruited in March 2021. Last subject last visit will be March 2023. ClinicalTrials.gov Identifier: NCT03967925, May 30, 2019.

ObjectiveFollowing induction of remission with rituximab in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) relapse rates are high, especially in patients with history of relapse. Relapses are associated with increased exposure to immunosuppressive medications, the accrual of damage and increased morbidity and mortality. The RITAZAREM trial compared the efficacy of repeat-dose rituximab to daily oral azathioprine for prevention of relapse in patients with relapsing AAV in whom remission was reinduced with rituximab.MethodsRITAZAREM was an international randomised controlled, open-label, superiority trial that recruited 188 patients at the time of an AAV relapse from 29 centres in seven countries between April 2013 and November 2016. All patients received rituximab and glucocorticoids to reinduce remission. Patients achieving remission by 4 months were randomised to receive rituximab intravenously (1000 mg every 4 months, through month 20) (85 patients) or azathioprine (2 mg/kg/day, tapered after month 24) (85 patients) and followed for a minimum of 36 months. The primary outcome was time to disease relapse (either major or minor relapse).ResultsRituximab was superior to azathioprine in preventing relapse: HR 0.41; 95% CI 0.27 to 0.61, pConclusionsFollowing induction of remission with rituximab, fixed-interval, repeat-dose rituximab was superior to azathioprine for preventing disease relapse in patients with AAV with a prior history of relapse.Trial registration numberNCT01697267; ClinicalTrials.gov identifier

To recommend an international multidisciplinary medical and surgical algorithm of treatment in nasal vasculitis, which will create a more streamlined approach.A two-centre, international retrospective analysis of granulomatosis with polyangiitis (GPA) and levamisole-associated vasculitis (LAV) cases presenting between 2005 and 2019 was carried out. Demographic data, and surgical and medical treatment were recorded. Patients' signs and symptoms were analysed, and recommended treatment strategies outlined with key surgical procedures described.Forty-one GPA patients and 11 LAV patients were included in the study with a mean age of 38.6 and 38.8 years, respectively. A stepwise surgical management approach with reconstructive options is described and includes: (1) examination under general anaesthesia, biopsy, and insertion of silastic nasal splints; (2) septal perforation repair (with caution); (3) mild-to-moderate saddle nose reconstruction with costal cartilage; (4) severe saddle nose reconstruction with osseocartilaginous rib grafts; (5) soft-tissue reconstruction techniques.The management of nasal vasculitis is a particular challenge in facial plastic surgery. It requires a close collaborative approach with a physician skilled in the medical management of vasculitis. Surgery must be planned judiciously, with realistic patient expectations and only after a sustained period of remission. For more severe saddle deformities, the modified osseocartilaginous Andrews technique gives excellent long-term results.

We explored the potential impact of staff opinions and service provision upon patient's willingness to recruit to a clinical trial studying the effects of extended treatment time (TT) on haemodialysis (HD), six hours versus four hours for a period of twenty-four weeks.We conducted a local survey of dialysis nurses and a national survey of multidisciplinary HD staff opinions to extended TT including clinical benefits, tolerance to, prescription and ability to accommodate extended TT on in-centre HD programmes.The survey was completed by 56/134 (42%) local nurses and the national survey by 15/72 (21%) of dialysis providers across the UK (35% nurses and 75% other healthcare professionals). The majority of respondents felt extended TT was clinically beneficial but only 42% of nurses would recommend extended TT compared to 95% of non-nursing healthcare professionals (p0.0001). Although 45% of nurses felt that it was well tolerated, non-nursing healthcare professionals suggested this was significantly higher at 75% (p0.05). The negative impact on service provision was agreed by 83% of nurses with the need to facilitate shifts within a finite time period and pressure to find session spaces being cited.There is conflict between the understanding that extended TT is clinically beneficial and its prescriptiondelivery to patients. Enrolment to studies examining HD delivery strategies may be influenced by service provision and staff attitudes. In centre HD has been designed to maximise patient throughput and we may need to consider more flexible settings in which to deliver longer treatment time: Home HD maybe a solution.

Follow-up data from the RAVE trial have shown that rituximab is as effective as immunosuppression with cyclophosphamide followed by azathioprine in antineutrophil cytoplasmic antibody (ANCA) associated vasculitis. Rituximab is likely to become the standard of care for many patients with ANCA disease. However, an individualized approach is needed to identify those who require more-intense or prolonged therapy.

Antiglomerular basement membrane disease (anti-GBM disease, also known as Goodpasture’s disease) is a rare autoimmune disease caused by pathogenic autoantibodies directed against the noncollagenous, C-terminal domain of the α‎-3 chain of type IV collagen (α‎3(IV)NC1). Immunohistology is characteristic, with linear deposition of IgG (sometimes with IgA or IgM) and complement C3 along the GBMs....

Background/Aims: There is now considerable evidence implicating T cells and macrophages in glomerular injury in crescentic glomerulonephritis. Recently, it has been shown that interleukin-11 (IL-11) has an immune modulatory function through its effect on both macrophages and T cells. We, therefore, examined the therapeutic effect of IL-11 in a murine model of experimental glomerulonephritis. Method: Accelerated nephrotoxic nephritis was induced in C57BL/6 mice. IL-11 at a dose of 0.5 mg/kg/day (n = 10) in vehicle was given daily subcutaneously from the day of sensitization until day 14 after initiation of glomerulonephritis. Control mice (n = 10) received injection of vehicle alone with the same schedule. Results: IL-11 treatment markedly decreased albuminuria (6.2 ± 1.9 vs. 18.2 ± 4.5 mg/day, p < 0.05), the number of glomerular macrophages (1.1 ± 0.2 vs. 1.7 ± 0.3 cells/glomerular cross-section, p < 0.05) and glomerular fibrin deposition (fibrin score 0.9 ± 0.3 vs. 2 ± 0.3, p < 0.05). There was no difference in the glomerular T cell numbers between the IL-11-treated and the vehicle group. Glomerular NF-ĸB activity was markedly suppressed by 75% in the treated group (p = 0.0015). Conclusion: In this study, we provide the first in vivo evidence that IL-11 treatment decreases glomerular NF-ĸB activity and reduces renal injury in experimental glomerulonephritis.