A randomised study of rituximab and belimumab sequential therapy in PR3 ANCA-associated vasculitis (COMBIVAS): design of the study protocol

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

Rituximab versus azathioprine as therapy for maintenance of remission for anti-neutrophil cytoplasm antibody-associated vasculitis (RITAZAREM): study protocol for a randomized controlled trial.

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

Bullying Victimisation, Internalising Symptoms, and Conduct Problems in South African Children and Adolescents: A Longitudinal Investigation

Bullying victimisation has been prospectively linked with mental health problems among children and adolescents in longitudinal studies in the developed world. However, research from the developing world, where adolescents face multiple risks to social and emotional development, has been limited by cross-sectional designs. This is the first longitudinal study of the psychological impacts of bullying victimisation in South Africa. The primary aim was to examine prospective relationships between bullying victimisation and internalising and externalising symptoms in South African youth. Secondary aims were to examine gender and age-related differences in experiences of bullying victimisation. Children and adolescents (10–17 years, 57 % female, n = 3,515) from high HIV-prevalent (>30 %) communities in South Africa were interviewed and followed-up 1 year later (97 % retention). Census enumeration areas were randomly selected from urban and rural sites in two provinces and door-to-door sampling included all households with a resident child/adolescent. Exposure to multiple experiences of bullying victimisation at baseline predicted internalising symptoms and conduct problems 1 year later. Additionally, baseline mental health scores predicted later bullying victimisation, demonstrating bi-directionality of relationships between bullying victimisation and mental health outcomes in this sample. Expected gender differences in physical, verbal, and relational bullying victimisation were evident and predicted declines in bullying victimisation over time were observed. In the developed world, school-based anti-bullying programmes have been shown to be effective in reducing bullying and victimisation. Anti-bullying programmes should be implemented and rigorously evaluated in South Africa, as this may promote improved mental health among South African children and adolescents

Integrated Heart - Coupling multiscale and multiphysics models for the simulation of the cardiac function

Mathematical modelling of the human heart and its function can expand our understanding of various cardiac diseases, which remain the most common cause of death in the developed world. Like other physiological systems, the heart can be understood as a complex multiscale system involving interacting phenomena at the molecular, cellular, tissue, and organ levels. This article addresses the numerical modelling of many aspects of heart function, including the interaction of the cardiac electrophysiology system with contractile muscle tissue, the sub-cellular activation-contraction mechanisms, as well as the hemodynamics inside the heart chambers. Resolution of each of these sub-systems requires separate mathematical analysis and specially developed numerical algorithms, which we review in detail. By using specific sub-systems as examples, we also look at systemic stability, and explain for example how physiological concepts such as microscopic force generation in cardiac muscle cells, translate to coupled systems of differential equations, and how their stability properties influence the choice of numerical coupling algorithms. Several numerical examples illustrate three fundamental challenges of developing multiphysics and multiscale numerical models for simulating heart function, namely: (i) the correct upscaling from single-cell models to the entire cardiac muscle, (ii) the proper coupling of electrophysiology and tissue mechanics to simulate electromechanical feedback, and (iii) the stable simulation of ventricular hemodynamics during rapid valve opening and closure

Are Adolescents Engaged in the Problematic Use of Social Networking Sites More Involved in Peer Aggression and Victimization?

The problematic use of social networking sites is becoming a major public health concern. Previous research has found that adolescents who engage in a problematic use of social networking sites are likely to show maladjustment problems. However, little is known about its links with peer aggression and victimization. The main goal of this study was to analyze the relationship between problematic use of online social networking sites, peer aggression ¿overt vs. relational and reactive vs. instrumental¿, and peer victimization ¿overt physical and verbal, and relational¿, taking into account gender and age (in early and mid-adolescence). Participants were selected using randomized cluster sampling considering school and class as clusters. A battery of instruments was applied to 1,952 adolescents¿ secondary students from Spain (Andalusia) (50.4% boys), aged 11 to 16 (M = 14.07, SD = 1.39). Results showed that girls and 14¿16 adolescents were more involved in a problematic use of online social networking sites. Furthermore, adolescents with high problematic use of online social networking sites were more involved in overt¿reactive and instrumental¿and relational¿reactive and instrumental¿aggressive behaviors, and self-reported higher levels of overt¿physical and verbal¿and relational victimization. Even though boys indicated higher levels of all types of victimization, girls with high problematic use of online social networking sites scored the highest on relational victimization. Relating to age, early adolescents (aged 11¿14) with higher problematic use of online social networking sites reported the highest levels of overt verbal and relational victimization. Overall, results suggested the co-occurrence of problematic use of online social networking sites, peer aggression and victimization. In addition, results showed the influence that gender and age had on peer victimization. This study highlights the continuity between offline and online domains with regard to maladjustment problems in adolescence.Departamento de Educación y Psicología SocialVersión del edito

Rituximab as therapy to induce remission after relapse in ANCA-associated vasculitis

Funder: Research Committee on Intractable Vasculitides; The Ministry of Health, Labour and Welfare of Japan.Objectives: Evaluation of rituximab and glucocorticoids as therapy to induce remission after relapse in ANCA-associated vasculitis (AAV) in a prospective observational cohort of patients enrolled into the induction phase of the RITAZAREM trial. Methods: Patients relapsing with granulomatosis with polyangiitis or microscopic polyangiitis were prospectively enrolled and received remission-induction therapy with rituximab (4×375 mg/m2) and a higher or lower dose glucocorticoid regimen, depending on physician choice: reducing from either 1 mg/kg/day or 0.5 mg/kg/day to 10 mg/day by 4 months. Patients in this cohort achieving remission were subsequently randomised to receive one of two regimens to prevent relapse. Results: 188 patients were studied: 95/188 (51%) men, median age 59 years (range 19–89), prior disease duration 5.0 years (range 0.4–34.5). 149/188 (79%) had previously received cyclophosphamide and 67/188 (36%) rituximab. 119/188 (63%) of relapses had at least one major disease activity item, and 54/188 (29%) received the higher dose glucocorticoid regimen. 171/188 (90%) patients achieved remission by 4 months. Only six patients (3.2% of the study population) did not achieve disease control at month 4. Four patients died in the induction phase due to pneumonia (2), cerebrovascular accident (1), and active vasculitis (1). 41 severe adverse events occurred in 27 patients, including 13 severe infections. Conclusions: This large prospective cohort of patients with relapsing AAV treated with rituximab in conjunction with glucocorticoids demonstrated a high level of efficacy for the reinduction of remission in patients with AAV who have relapsed, with a similar safety profile to previous studies

Rituximab as therapy to induce remission after relapse in ANCA-associated vasculitis

Funder: Research Committee on Intractable Vasculitides; The Ministry of Health, Labour and Welfare of Japan.Objectives: Evaluation of rituximab and glucocorticoids as therapy to induce remission after relapse in ANCA-associated vasculitis (AAV) in a prospective observational cohort of patients enrolled into the induction phase of the RITAZAREM trial. Methods: Patients relapsing with granulomatosis with polyangiitis or microscopic polyangiitis were prospectively enrolled and received remission-induction therapy with rituximab (4×375 mg/m2) and a higher or lower dose glucocorticoid regimen, depending on physician choice: reducing from either 1 mg/kg/day or 0.5 mg/kg/day to 10 mg/day by 4 months. Patients in this cohort achieving remission were subsequently randomised to receive one of two regimens to prevent relapse. Results: 188 patients were studied: 95/188 (51%) men, median age 59 years (range 19–89), prior disease duration 5.0 years (range 0.4–34.5). 149/188 (79%) had previously received cyclophosphamide and 67/188 (36%) rituximab. 119/188 (63%) of relapses had at least one major disease activity item, and 54/188 (29%) received the higher dose glucocorticoid regimen. 171/188 (90%) patients achieved remission by 4 months. Only six patients (3.2% of the study population) did not achieve disease control at month 4. Four patients died in the induction phase due to pneumonia (2), cerebrovascular accident (1), and active vasculitis (1). 41 severe adverse events occurred in 27 patients, including 13 severe infections. Conclusions: This large prospective cohort of patients with relapsing AAV treated with rituximab in conjunction with glucocorticoids demonstrated a high level of efficacy for the reinduction of remission in patients with AAV who have relapsed, with a similar safety profile to previous studies

Involvement in bullying and suicide-related behavior at 11 years : a prospective birth cohort study

Objective To study the prospective link between involvement in bullying (bully, victim, bully/victim), and subsequent suicide ideation and suicidal/self-injurious behavior, in preadolescent children in the United Kingdom. Method A total of 6,043 children in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort were assessed to ascertain involvement in bullying between 4 and 10 years and suicide related behavior at 11.7 years. Results Peer victimization (victim, bully/victim) was significantly associated with suicide ideation and suicidal/self-injurious behavior after adjusting for confounders. Bully/victims were at heightened risk for suicide ideation (odds ratio [OR]; 95% confidence interval [CI]): child report at 8 years (OR = 2.84; CI = 1.81–4.45); child report at 10 years (OR = 3.20; CI = 2.07–4.95); mother report (OR = 2.71; CI = 1.81–4.05); teacher report (OR = 2.79; CI = 1.62–4.81), as were chronic victims: child report (OR = 3.26; CI = 2.24–4.75); mother report (OR = 2.49; CI = 1.64–3.79); teacher report (OR = 5.99; CI = 2.79–12.88). Similarly, bully/victims were at heightened risk for suicidal/self-injurious behavior: child report at 8 years (OR = 2.67; CI = 1.66–4.29); child report at 10 years (OR = 3.34; CI = 2.17–5.15); mother report (OR = 2.09; CI = CI = 1.36–3.20); teacher report (OR = 2.44, CI = 1.39–4.30); as were chronic victims: child report (OR = 4.10; CI = 2.76–6.08); mother report (OR = 1.91; 1.22–2.99); teacher report (OR = 3.26; CI = 1.38–7.68). Pure bullies had increased risk of suicide ideation according to child report at age 8 years (OR = 3.60; CI = 1.46–8.84), suicidal/self-injurious behavior according to child report at age 8 years (OR = 3.02; CI = 1.14–8.02), and teacher report (OR = 1.84; CI = 1.09–3.10). Conclusions Children involved in bullying, in any role, and especially bully/victims and chronic victims, are at increased risk for suicide ideation and suicidal/self-injurious behavior in preadolescence