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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.

Interleukin-4 ameliorates experimental glomerulonephritis and up-regulates glomerular gene expression of IL-1 decoy receptor. Monocytes/ macrophages and pro-inflammatory cytokines such as interleukin (IL)-1 are important in the pathogenesis of acute glomerulonephritis. The aim of this study was to examine whether IL-4, a cytokine with anti-inflammatory activity, could modulate glomerular inflammation and reduce injury in vivo . Treatment with recombinant rat IL-4 in a model of anti-glomerular basement membrane (GBM) antibody mediated glomerulonephritis in rats reduced glomerular injury. Albuminuria was less (73% less at day 4) and a lower proportion of glomeruli had capillary thrombi (79% less at day 4). In IL-4 treated rats, there was a moderate reduction in the number of macrophages in the glomeruli and also suppression of pro-inflammatory activities of the macrophages. Northern blot analysis of glomerular RNA showed that treatment with IL-4 up-regulated mRNA levels of type II IL-1 receptor (IL-1RTII). IL-1RTII, also known as IL-1 decoy receptor, may act as a decoy molecule to inhibit the effect of IL-1β. To our knowledge, this is the first demonstration of (i) recombinant IL-4 reducing glomerular inflammation in vivo and (ii) a treatment that increases IL-1RTII expression in association with reduction of tissue injury in vivo .

Abrogation of glomerular injury in nephrotoxic nephritis by continuous infusion of interleukin-6. Interleukin-6 (IL-6) has been reported to have pro- and anti-inflammatory effects. It has also been shown to cause mesangial cell proliferation in vitro and has been suggested as a mediator of injury in proliferative nephritis. We have assessed the effects of continuous infusion of human recombinant (hr) IL-6, by osmotic minipump, on the degree of glomerular injury, and on glomerular and interstitial cell proliferation, in the accelerated autologous phase of nephrotoxic nephritis. Two groups of rats were pre-immunized with 1mg of normal rabbit IgG in Freund's complete adjuvant. One week later, nephritis was induced by an intravenous injection of 1ml of rabbit nephrotoxic serum. One day before the induction of nephritis, group 1 (N = 9) was subcutaneously implanted with osmotic minipumps filled with 50 µg (200 µl) of IL-6 (equivalent to a dose of 6 µg/day), while in group 2 (N = 11) the minipumps were filled with 200 µl of normal saline. In group 3 (N = 6) normal rats were infused with 50 µg of IL-6 alone. The rats were killed seven days after implantation of minipumps. The administered hrIL-6 was detectable in the circulation within the pathophysiological range, and induced a hepatic acute phase response, as assessed by α2-macroglobulin levels. Continuous treatment with IL-6 resulted in a significant reduction in albuminuria (from 195 ± 37mg/20hr to 60 ± 15mg/20hr on day 1, and from 494 ± 52mg/20hr to 238 ± 30mg/20hr on day 7, P < 0.002) and in the prevalence of glomerular capillary thrombosis (from 19 ± 3% to 5 ± 1%, P < 0.002). There was also a reduction in macrophage infiltration (ED1+ve cells from 524 ± 34 to 466 ± 14 per 50 glomeruli, P < 0.02) and activation (ED3+ve cells from 106 ± 13 to 42 ± 5 per 50 glomeruli, P < 0.002). Immunohistology showed fewer interstitial Ia+ve cells (OX3 and OX4) in the IL-6 treated group. Similar results were obtained in a second set of experiments in which the IL-6 treatment was extended until day 14. Kidney sections taken from nephritic rats infused with IL-6 showed no increase in glomerular or interstitial cell proliferation when stained with antibodies to proliferating cell nuclear antigen. There was no difference in the deposition of rabbit IgG or rat IgG along the glomerular basement membrane (GBM), and the titer of rat anti-rabbit IgG was similar in the IL-6 and control treated rats. Infusion of IL-6 alone in normal rats had no functional or pathological effects. In conclusion, these results show that IL-6 has powerful anti-inflammatory effects in a rat model of anti-GBM nephritis, and does not induce mesangial cell proliferation in vivo.