Rituximab In Children Research Articles

Recovery from rituximab-associated persistent hypogammaglobulinaemia in children with nephrotic syndrome.

There are limited data on the long-term outcomes and risk factors for non-recovery after development of rituximab (RTX)-associated persistent hypogammaglobulinaemia among children with idiopathic nephrotic syndrome (NS). A nationwide Japanese survey was conducted to determine the prognosis of patients with childhood-onset idiopathic NS who developed persistent hypogammaglobulinaemia after RTX administration. Specifically, predictors of IgG level recovery and risk factors for serious infection were examined. The cohort comprised 118 patients (66.1% boys; median age at initial RTX administration, 7.5 years). Among the 121 patients diagnosed with persistent hypogammaglobulinaemia, only 31 (26.3%) recovered within a median observation period of 2.8 years; approximately 70% of patients continued to exhibit persistent hypogammaglobulinaemia. Among the patients who recovered from hypogammaglobulinaemia, the median time to recovery was 14.1 months. Patients with a history of steroid-resistant NS were less likely to recover from persistent hypogammaglobulinaemia (hazard ratio, 0.28; 95% CI, 0.09-0.87). In addition, of the 118 eligible patients, 18 (15.3%) developed serious infections requiring hospitalization, and the main risk factor for infection during hypogammaglobulinaemia was agranulocytosis (a well-known adverse effect of RTX in children). A significant portion of patients with RTX-associated persistent hypogammaglobulinaemia did not exhibit recovery even after 1 year. Moreover, the data indicate that patients with a history of steroid-resistant NS have a significantly lower probability of recovering from this condition. Agranulocytosis under hypogammaglobulinaemia was significantly associated with an elevated risk of serious infections.

The experience of anti-b-cell therapy with rituximab in children with chronic inflammatory demyelinating polyradiculoneuropathy with a description of the clinical case

The experience of anti-b-cell therapy with rituximab in children with chronic inflammatory demyelinating polyradiculoneuropathy with a description of the clinical case

Безопасность долгосрочного применения ритуксимаба у пациентов с ювенильным идиопатическим артритом: результаты когортного ретроспективного исследования

Juvenile idiopathic arthritis (JIA) is the most frequent rheumatic disease of childhood. The goal of juvenile arthritis therapy is to achieve durable clinical and laboratory remission and a good quality of life. Various groups of drugs are used in the treatment of JIA, one of which is the anti-CD20 drug rituximab. Rituximab causes B-cell depletion, which may lead to decreased immunoglobulin levels, decreased antigen-presenting function of B-lymphocytes and impaired T-cell response. The main side effects of rituximab administration are infusion reactions, hypogammaglobulinaemia, neutropenia and infectious complications. Safety studies of rituximab use have been conducted mainly in adult patients with rheumatoid arthritis, in paediatric patients with oncological diseases and diffuse connective tissue diseases. There have been no long-term safety studies of rituximab in children with JIA. Objective. To evaluate the safety of long-term use of rituximab in patients with juvenile idiopathic arthritis. Patients and methods. A cohort retrospective study of patients with JIA aged from 2 to 17 years with evaluation of adverse events on the background of rituximab therapy was carried out; the maximum duration of follow-up was 165 months. Rituximab was administered by intravenous drip at a dose of 375 mg/m2 body surface area by 4 weekly injections (61% of all courses given) or 2 injections of 1000 mg 2 weeks apart (29%). 4% had 1 administration per course; 6% had 3 consecutive weekly administrations. The indication for repeat rituximab administration and the number of administrations were determined on an individual basis. Safety was assessed by registration of adverse events (AEs) according to medical records; AEs registered during the patient's hospitalisation and anamnestic data on AEs during the interhospital period were taken into account; infectious, infusion and other AEs were considered separately. Results. Rituximab demonstrated a sufficiently high safety profile: 88/102 (86%) patients did not report any serious AEs (grade ≥3); life-threatening AEs (grade 4-5) were reported in 7/102 (7%) patients, included 4 episodes of severe pneumonia, 3 episodes of sepsis; their incidence was 2.5 cases per 100 PY. The incidence of infectious AEs was 57.4/100 patient-years; 85% of them corresponded to mild severity; most often infectious AEs were registered in the first year of rituximab therapy; pneumonia (16/100 PY) and ENT infections (11.3/100 PY) prevailed in the structure. Infusion reactions developed with an incidence of 34.8/100 PY, most frequently registered at the first rituximab administration and manifested as influenza-like syndrome (18.4/100 PY) and rash (10.3/100 PY). The incidence of neutropenia was 17/100 PY, erythropenia 0.7/100 patient-years; decreased blood immunoglobulin levels (IgA – 5.3 episodes, IgM – 6.7, IgG – 3.4/100 patient-years), increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity – 3.9/100 PY, 1 episode of increased serum urea levels. Conclusion. The use of rituximab in patients with JIA may be accompanied by the development of AEs, which include infusion reactions, infectious complications, cytopenias, decreased level of immunoglobulins in blood, increased activity of ALT and AST. Implementation of the algorithm for the management of patients with JIA under rituximab treatment into clinical practice will allow to ensure monitoring of AEs, their detection at early stages, timely initiation of adequate therapy to prevent the development of severe complications. Key words: juvenile idiopathic arthritis, safety of therapy, rituximab, adverse events, infusion reactions, infectious complications

Severe Reaction to Rituximab in Children

Background: Rituximab is a chimeric monoclonal antibody used in various pathologies involving CD20-positive cells. While it is usually well tolerated, infusion-related reactions are frequent but usually mild. Severe reactions such as anaphylaxis and serum sickness nevertheless can occur. Rituximab-induced serum sickness (RISS) is a rare delayed hypersensitivity reaction that may be unrecognized, as it can be confused with severe infection or in some circumstances with primary disease flare-up. We aim to extend our knowledge about severe infusion related reactions to rituximab in children, focusing on RISS and anaphylaxis. Objectives: Our study objective was to study severe reactions to rituximab by evaluating all children and adolescents who received rituximab in our center. Methods: Children and adolescents who received rituximab between 2014 and 2021 at CHU Sainte-Justine, a tertiary and leading pediatric center in Quebec, Canada, were included in the study. Data was collected retrospectively from our electronic medical records in CHU Ste-Justine. The diagnostic criteria proposed by the World Allergy Organization in 2020 were used to classify patients in the anaphylaxis subgroup. Patients with RISS were included if they developed fever and at least rash and/or arthralgia, starting 1 to 30 days following rituximab infusion, and if no other confirmed diagnosis explained symptoms. The study was approved by local Institutional Review Board. Results and discussion: 1534 rituximab infusions in 391 patients were analyzed. A severe infusion reaction to rituximab occurred in 14 patients (3.6%); none resulted in death. Rituximab was prescribed for an auto-immune disease in 61% of cases. Seven patients presented with RISS (1.8%); all were treated for an auto-immune disease including 4 for immune thrombocytopenia (ITP). Mean time from rituximab to RISS was 9 days (ranging from 6 to 12 days). All RISS patients but one presented with the classical triad of fever, rash and arthralgia. Increased C-reactive protein or sedimentation rate was documented in all patients, and decreased complement in 83%. Three patients required admission to intensive care unit due to hemodynamic instability. Patients received corticosteroids and/or intravenous immunoglobulins; mean duration of RISS was 4 days (ranging from 3 to 6 days). Rituximab was reinfused after RISS in one patient; she presented an immediate anaphylactoid reaction after which rituximab was permanently discontinued. Patients who received lower doses of rituximab were less likely to present RISS compared to patients who received higher doses (risk ratio 0.14, CI 0.03-0.74, p=0.016). Although few ITP patients developed RISS, RISS was associated with a greater chance of achieving partial or complete ITP remission (risk ratio 3, CI 1.47-6.14, p=0.033). Such possible association was not observed in other diseases. Seven patients developed severe anaphylaxis (1.8%), 3 of them reacted after the first dose (42.8%). Five of them were able to receive further rituximab infusion, using desensitization protocols. Conclusion: RISS is a rare hypersensitivity reaction in children. To this day, our study is the first to report more than 3 patients in a pediatric setting. RISS in children seems to be more frequent when rituximab is administered for an autoimmune condition, especially ITP. Although the classic triad of fever, rash and arthralgia appears more frequent in children than in adults, RISS should be considered in the differential diagnosis of any suggestive symptom developing within 30 days of infusion. Presence of biological inflammation and/or low serum complement can further support the diagnosis. In all patients, evolution was favorable within a few days with steroids. However, in contrast with anaphylaxis, RISS should be considered as a contraindication for further rituximab therapy.

Population Pharmacodynamic Modelling of the CD19+ Suppression Effects of Rituximab in Paediatric Patients with Neurological and Autoimmune Diseases.

Limited pharmacotherapy and the failure of conventional treatments in complex pathologies in children lead to increased off-label use of rituximab. We aimed to characterize the time course of CD19+ B lymphocytes (CD19+) under treatment with intravenous rituximab in children with neurologic and autoimmune diseases and to evaluate the impact of covariates (i.e., demographics, diagnosis and substitution between innovator and biosimilar product) on rituximab pharmacodynamics and disease activity. Pre- and post-drug infusion CD19+ in peripheral blood were prospectively registered. A population pharmacodynamic model describing the time course of CD19+ was developed with NONMEM v7.4. Simulations of three different rituximab regimens were performed to assess the impact on CD19+. Logistic regression analysis was performed to identify predictors of clinical response recorded through disease activity scores. 281 measurements of CD19+ lymphocyte counts obtained from 63 children with neurologic (n = 36) and autoimmune (n = 27) diseases were available. The time course of CD19+ was described with a turn-over model in which the balance between synthesis and degradation rates is disrupted by rituximab, increasing the latter process. The model predicts half-lives (percent coefficient of variation, CV(%)) of rituximab and CD19+ of 11.6 days (17%) and 173.3 days (22%), respectively. No statistically significant effect was found between any of the studied covariates and model parameters (p > 0.05). Simulations of different regimens showed no clinically significant differences in terms of CD19+ repopulation times. A trend towards a lack of clinical response was observed in patients with lower CD19+ repopulation times and higher areas under the CD19+ versus time curve. Rituximab pharmacodynamics was described in a real-world setting in children suffering from autoimmune and neurologic diseases. Diagnosis, substitution between innovator rituximab and its biosimilars or type of regimen did not affect rituximab-induced depletion of CD19+ nor the clinical response in this cohort of patients. According to this study, rituximab frequency and dosage may be chosen based on clinical convenience or safety reasons without affecting CD19+ repopulation times. Further studies in larger populations are required to confirm these results.

Clinical improvement in early onset interstitial lung disease using rituximab in children with anti-MDA5 positive juvenile dermatomyositis.

Children with juvenile dermatomyositis (JDM) and antibodies to melanoma differentiation associated gene 5 (anti-MDA5) are at increased risk of severe disease complications, including interstitial lung disease (ILD). Data regarding treatment of disease complications in this patient population is limited. In this study, we examined the disease course of children with JDM and anti-MDA5 antibodies before and after treatment with rituximab (RTX). Patients (age 2-21 years) seen at the Children's Hospital at Montefiore between July 2012 and August 2021, with a diagnosis of JDM, positive anti-MDA5 positive antibodies, evidence of ILD, and who were treated with rituximab were eligible for inclusion. Retrospective clinical and laboratory data were reviewed. Five out of 8 patients with positive anti-MDA5 antibodies had evidence of ILD (62.5%). Four patients had data available for review. All patients received at least 5 courses of RTX infusions, with discontinuation of steroids by an average of 12 months after starting RTX and a decrease to fewer than two concurrent medications by fifth course of RTX. Indicators of ILD on high-resolution computed tomography (HRCT) and pulmonary function tests (PFTs) either improved or fully resolved over the course of RTX treatment for all patients. Patients also demonstrated resolution of active cutaneous manifestations and musculoskeletal disease activity. This is the first study to examine the use of RTX in children with JDM and anti-MDA5 antibodies, with notable improvements ILD, cutaneous and musculoskeletal manifestations. Further studies are needed to better understand the efficacy of RTX on JDM disease related complications.

A Systematic Review and Meta-analysis of Rituximab-Associated Infections Among Children and Adolescents With Glomerular Disease: Focus on the Risk of Infections.

This systematic review and meta-analysis aimed to explore rituximab (RTX) associated infectious complications in children with glomerular disease. We performed an electronic search of PubMed, International Scientific Information (ISI), Scopus, and EMBASE between January 2010 and July 2021. Infection rates and total drug-related adverse events were the outcomes. Statistical heterogeneity was evaluated by using the I2 statistic. When there was statistical evidence of heterogeneity (I2 > 50%, p > 0.1), a random-effect model was adopted. Data analysis was performed with Stata17.0 software. A total of 7 studies with 668 patients (136 with lupus nephritis [LN] and 532 with nephrotic syndrome were included in the meta-analysis. The pooled risk ratio showed that the administration of RTX was significantly associated with lower risk of infectious complications in patients with LN and nephrotic syndrome (0.72 [95% CI 0.58, 0.85]) when compared with population data of patients without glomerular disease (p = 0.2). There was no significant difference between the LN and nephrotic syndrome groups in terms of total serious adverse events or the occurrence of infections. There was significant heterogeneity among the reported studies (Q = 42.39, p < 0.001, I2 = 81%). Administration of RTX in children with glomerular disease is associated with a lower rate of infections when compared with population data of patients without LN or nephrotic syndrome. Additional high-quality randomized controlled trials with long-term follow-up are needed to identify the long-term potential complications. Trial registration PROPERO ID: CRD42021274869 (https://www.crd.york.ac/prospero/display_record.php?).

Cost-effectiveness analysis alongside the inter-B-NHL ritux 2010 trial: rituximab in children and adolescents with B cell non-Hodgkin’s lymphoma

ObjectivesThe randomized controlled trial Inter-B-NHL ritux 2010 showed overall survival (OS) benefit and event-free survival (EFS) benefit with the addition of rituximab to standard Lymphomes Malins B (LMB) chemotherapy in children and adolescents with high-risk, mature B cell non-Hodgkin’s lymphoma. Our aim was to assess the cost-effectiveness of rituximab-chemotherapy versus chemotherapy alone in the French setting.MethodsWe used a decision-analytic semi-Markov model with four health states and 1-month cycles. Resource use was prospectively collected in the Inter-B-NHL ritux 2010 trial (NCT01516580). Transition probabilities were assessed from patient-level data from the trial (n = 328). In the base case analysis, direct medical costs from the French National Insurance Scheme and life-years (LYs) were computed in both arms over a 3-year time horizon. Incremental net monetary benefit and cost-effectiveness acceptability curve were computed through a probabilistic sensitivity analysis. Deterministic sensitivity analysis and several sensitivity analyses on key assumptions were also conducted, including one exploratory analysis with quality-adjusted life years as the health outcome.ResultsOS and EFS benefits shown in the Inter-B-NHL ritux 2010 trial translated into the model by rituximab-chemotherapy being the most effective and also the least expensive strategy over the chemotherapy strategy. The mean difference in LYs between arms was 0.13 [95% CI 0.02; 0.25], and the mean cost difference € − 3 710 [95% CI € − 17,877; € 10,525] in favor of rituximab-chemotherapy group. For a € 50,000 per LY willingness-to-pay threshold, the probability of the rituximab-chemotherapy strategy being cost-effective was 91.1%. All sensitivity analyses confirmed these findings.ConclusionAdding rituximab to LMB chemotherapy in children and adolescents with high-risk mature B-cell non-Hodgkin's lymphoma is highly cost-effective in France.Trial registrationClinicalTrials.gov identifier: NCT01516580.

The Efficacy and Safety of Rituximab in Children with Steroid-Dependent or Frequently Relapsing Nephrotic Syndrome: A Meta-Analysis of Randomized Controlled Trials

IntroductionTo explore the efficacy and safety of Rituximab (RTX) in children with steroid-dependent nephrotic syndrome (SDNS) or frequently relapsing nephrotic syndrome (FRNS) through meta-analysis.Material and methodsMeta-analysis searches were performed before November 30th, 2021, using the PubMed, Embase, Web of Science, and Cochrane Library databases to collect randomised controlled trials (RCTs). FRNS or SDNS children younger than 18 years of age were included. The RTX group was treated with RTX combined with conventional therapy, whereas the control group was given conventional therapy. Review Manager 5.3 and STATA 15.0 were used to perform the statistical analyses.ResultsOf 1450 screened articles, a total of eight studies eligible for inclusion involving 476 patients were included. As compared to the control group, the RTX group had a significantly higher rate of long-term complete remission [RR (95% CI), 1.91 (1.16, 3.14), p&lt;0.05]. RTX did not show significant improvement in the short term [RR (95% CI), 2.48 (0.85, 7.25), p=0.10]. However, the RTX group achieved a higher short-term complete remission rate when two studies with heterogeneity were excluded [RR (95% CI), 2.17 (1.65, 2.84), p&lt;0.001]. Proteinuria levels were reduced more effectively in the RTX group [MD (95% CI), −1.84 (−2.42, −1.26), p &lt;0.001)]. The RTX group and the control group had no significant differences in adverse events.ConclusionsRTX can be considered as an effective and safe treatment option for children with SDNS or FRNS. However, it is necessary to conduct further studies via RCTs to evaluate the persistent long-term effects.

Efficacy and safety of rituximab in children and adolescents with mature B-cell non-Hodgkin's lymphoma: a Meta analysis

To study the efficacy and safety of rituximab combined with chemotherapy in the treatment of children and adolescents with mature B-cell non-Hodgkin's lymphoma (B-NHL) through a Meta analysis. The databases including PubMed, Embase, the Cochrane Library, ClinicalTrials.gov, Web of Science, China National Knowledge Infrastructure, Wanfang Data, and Weipu were searched to obtain 10 articles on rituximab in the treatment of mature B-NHL in children and adolescents published up to June 2022, with 886 children in total. With 3-year event-free survival (EFS) rate, 3-year overall survival (OS) rate, complete remission rate, mortality rate, and incidence rate of adverse reactions as outcome measures, RevMan 5.4 software was used for Meta analysis, subgroup analysis, sensitivity analysis, and publication bias analysis. The rituximab+chemotherapy group showed significant increases in the 3-year EFS rate (HR=0.38, 95%CI: 0.25-0.59, P<0.001), 3-year OS rate (HR=0.29, 95%CI: 0.14-0.61, P=0.001), and complete remission rate (OR=3.72, 95%CI: 1.89-7.33, P<0.001) as well as a significant reduction in the mortality rate (OR=0.31, 95%CI: 0.17-0.57, P<0.001), as compared with the chemotherapy group without rituximab. There was no significant difference in the incidence rate of adverse reactions between the two groups (OR=1.28, 95%CI: 0.85-1.92, P=0.24). The addition of rituximab to the treatment regimen for children and adolescents with mature B-cell non-Hodgkin's lymphoma can bring significant survival benefits without increasing the incidence of adverse reactions.

Randomized controlled trial to compare safety and efficacy of mycophenolate vs. cyclosporine after rituximab in children with steroid-resistant nephrotic syndrome.

The comparative safety and efficacy of maintenance mycophenolate mofetil (MMF) and cyclosporine (CYC) following rituximab (RTX) in children with steroid-resistance nephrotic syndrome are uncertain. Multicenter randomized controlled trial. Sixty-six children between 2 and 6 years of age with SRNS. Patients were randomized to receive either MMF 1000 mg/m2 /day (n=32) or CYC 5mg/kg/day (n=34) for 12months following RTX induction therapy (375 mg/m2 ) given as needed for B-cell count. Complete remission and adverse events (AEs). Complete remission was observed in 26 patients (83.1%) in the MMF group compared with 21 patients (61.7%) in the CYC group (p=0.02). The median time to remission was shorter in the MMF group than in the CYC group (2.64 vs. 3.4 months; hazard ratio [HR], 0.61; 95% CI, 0.74-0.90, p=0.03). The median time to first relapse was longer in the MMF group compared with the CYC group (10.8 vs. 8.0 months; HR, 1.12; 95% CI, 1.31-1.54, p=0.01), and this was significantly correlated with the median time to B-cell recovery in the two groups (8.6 vs. 5.2 months in MMF and CYC, respectively, p=0.02). The overall incidence of adverse drug events was lower in the MMF group compared with the CYC group (59.3% vs. 76.4%, p=0.03). MMF-RTX is superior to CYC-RTX in maintaining remission with fewer AEs in children with initial SRNS. Additional high-quality randomized control trials with long-term follow-up are needed to identify the long-term potential complications.

Rituximab use in the treatment of children with nephrotic syndrome

Background. High recurrence rates of nephrotic syndrome in children and consequences in the form of steroid dependence and a high risk of side effects from corticosteroids as a result involve immunosuppressive steroid-preserving agents that would increase long-term remission. Rituximab, a chimeric anti-CD20 monoclonal antibody that inhibits CD20-mediated B-cell proliferation and differentiation, has been identified as a possible alternative treatment. The purpose of the study — to estimate the efficacy and safety of treatment recurrence of nephrotic syndrome in children using rituximab like we did it on three clinical cases. Materials and methods. The experience of rituximab in children was analyzed according to the databases of Scopus, Web of Science, MedLine, The Cochrane Library, EMBASE, Global Health and our own study of the treatment of three children with steroid-sensitive nephrotic syndrome was presented. Results. Treatment of nephrotic syndrome in three children who are 5 to 7 years with rituximab was conducted. One child had a second recurrence, two children had a first recurrence. The previous episode of nephrotic syndrome in all children was treated according to the recommendations of KDIGO 2021. All patients received rituximab (two intravenous injections two weeks apart) at a dose of 15 mg/kg for 5–6 hours with prior administration of methylprednisolone at a dose of 7–10 mg/kg. One child had side effects to the first administration of rituximab in the form of hypotension 70/40 and tachycardia 116–118. Reducing the speed of administration helped to eliminate side effects. The next injection in two weeks the child endured well. The other two children had no side effects to both rituximab injections. Moreover after 1 month of rituximab administration was without side effects or hematological changes. The next administration of rituximab is scheduled in 6 months after the last administration with prior control of CD20 level. Conclusions. In general a review of studies of rituximab confirms the high efficacy of the medication in nephrotic syndrome in children and the requirement for long-term evaluation. Rituximab can be considered as a first-line treatment for recurrence of nephrotic syndrome, including in resource-limited settings. Our own experience with rituximab in recurrent nephrotic syndrome has revealed slight short-term side effects.

FC066: Circulating Anti-Rituximab Antibodies Do Not Affect Response to Rituximab in Steroid-Dependent Nephrotic Syndrome

Abstract BACKGROUND AND AIMS Previous studies reported that the chimeric anti-CD20 monoclonal rituximab may lead to the production of anti-rituximab antibodies (Anti-RTX-Abs), due to the chimeric nature, impairing the efficacy of further infusions. In the context of glomerulonephritis, recent findings have described that the incidence of anti-RTX-Abs development may affect the efficacy of rituximab in paediatric steroid dependent nephrotic syndrome (SDNS) [Fujinaga et al. Pediatr Nephrol. 2020 Oct; 35(10): 2003–2008] and in membranous nephropathy [Boyer-Suavet et al. Front Immunol. 2020 Jan 13; 10: 3069]. The improved patient outcomes and cost-effectiveness have led to the development of a new generation of fully human anti-B cell agents in haematological and autoimmune diseases [Klomjit et al. Am J Kidney Dis. 2020 Dec; 76(6): 883–888]. Therefore, elucidating the role of Anti-RTX-Abs with the aim to develop personalized therapies is mandatory. In a randomized clinical trial, we compared the efficacy of fully humanized anti-CD20 antibody ofatumumab versus rituximab in children and young adults with SDNS [Ravani et al. JASN Oct 2021, 32 (10) 2652–2663]. METHOD We randomized 140 subjects to single infusion of rituximab or ofatumumab. Follow-up was of 24 months. We measured anti-rituximab IgG antibodies (LISA- TRACKER, Theradiag© Croissy Beaubourg, France) at the enrollment in 64/140 (46%) patients who previously received rituximab, regardless of the randomization arm, and at 6 months in 54/70 of the patients in the rituximab arm. (Fig. 1) Median time of last rituximab treatment was 36 months (13–54) before enrollment. RESULTS Anti-RTX-Abs were detected in none of the patients receiving more than or equal to one rituximab infusion before enrollment. At 6 months, Anti-RTX-Abs are detected in 14/54 patients (26%) who received rituximab (Fig. 2A). Patients developing anti-RTX-Abs or not had similar characteristics at enrollment. At T6, anti-RTX-Abs was not statistically different comparing who received rituximab before enrollment and who did not (Fig. 2B). Of the 54 patients treated with rituximab, 35 (65%) relapsed in 12 months of follow-up. Incidence of patients with anti-RTX-Abs at T6 was not statistically different comparing who experienced relapse with who did not (Fig. 2C). Time to relapse is reported in Fig. 2D. According to the protocol study, the 35 relapsing received a further infusion of rituximab. In this subgroup, incidence of patients with anti-RTX-Abs at T6 was not statistically different comparing who experienced further relapses with who did not (Fig. 2E). Both patients with and without anti-RTX-Abs had similar levels of total B-cell counts before rituximab therapy and at month 6 and 12 thereafter, showing similar B-cell reconstitution (Fig. 2F). We found similar percentages for memory B-cells comparing patients with and without Anti-RTX-Abs at enrollment, at month 6 and at month 12 of follow-up (Fig. 2G). CONCLUSION We evaluated the impact of Anti-RTX-Abs in a prospective study considering a large cohort of SDNS patients who received additional rituximab in case of relapse after a single infusion (375 mg/m2). According to the literature, we reported the development of Anti-RTX-Abs after a single infusion, which seems to persist for limited time. However, in contrast to previous findings, the development of Anti-RTX-Abs does not represent an unfavourable factor, which may limit the efficacy and the safety of further infusions. The prospective design of our study, in contrast to previous ones, represents one of the major strength of the present work. Moreover, Anti-RTX-Abs did not affect total and memory B-cell reconstitution following rituximab treatment.

Risk-adapted chemoimmunotherapy using brentuximab vedotin and rituximab in children, adolescents, and young adults with newly diagnosed Hodgkin’s lymphoma: a phase II, non-randomized controlled trial

BackgroundCure rates for Hodgkin’s lymphoma are excellent, but excess short-term and long-term morbidities from treatment remain a concern. Immunotherapy targeting both tumor antigens and the immunosuppressive tumor microenvironment in children,...

New and Old Anti-CD20 Monoclonal Antibodies for Nephrotic Syndrome. Where We Are?

Nephrotic proteinuria is the hallmark of several glomerulonephritis determined by different pathogenetic mechanisms, including autoimmune, degenerative and inflammatory. Some conditions such as Minimal Change Nephropathy (MCN) and Focal Segmental Glomerulosclerosis (FSGS) are of uncertain pathogenesis. Chimeric anti-CD20 monoclonal antibodies have been used with success in a part of proteinuric conditions while some are resistant. New human and humanized monoclonal anti-CD 20 antibodies offer some advantages based on stronger effects on CD20 cell subtypes and have been already administered in hematology and oncology areas as substitutes of chimeric molecules. Here, we revised the literature on the use of human and humanized anti-CD 20 monoclonal antibodies in different proteinuric conditions, resulting effective in those conditions resistant to rituximab. Literature on the use of human anti-CD 20 monoclonal antibodies in different proteinuric diseases is mainly limited to ofatumumab, with several protocols and doses. Studies already performed with ofatumumab given in standard doses of 1,500 mg 1.73m2 suggest no superiority compared to rituximab in children and young adults with steroid dependent nephrotic syndrome. Ofatumumab given in very high doses (300 mg/1.73m2 followed by five infusion 2,000 mg/1.73 m2) seems more effective in patients who are not responsive to common therapies. The question of dose remains unresolved and the literature is not concordant on positive effects of high dose ofatumumab in patients with FSGS prior and after renal transplantation. Obinutuzumab may offer some advantages. In the unique study performed in patients with multidrug dependent nephrotic syndrome reporting positive effects, obinutuzumab was associated with the anti-CD38 monoclonal antibody daratumumab proposing the unexplored frontier of combined therapies. Obinutuzumab represent an evolution also in the treatment of autoimmune glomerulonephritis, such as membranous nephrotahy and lupus nephritis. Results of randomized trials, now in progress, are awaited to add new possibilities in those cases that are resistant to other drugs. The aim of the present review is to open a discussion among nephrologists, with the hope to achieve shared approaches in terms of type of antibodies and doses in the different proteinuric renal conditions.

Anti-rituximab antibodies affect pharmacokinetics and pharmacodynamics of rituximab in children with immune-mediated diseases.

Rituximab (RTX) is a chimeric monoclonal CD20-antibody. Lack of efficacy has been suggested to be related to the presence of anti-drug antibodies (ADA). The aims of this study were to determine if ADA impact the pharmacokinetics (PK) and pharmacodynamics (PD) of RTX in children, whether the formation of ADA differs between various immune-mediated diseases and if it is related to the occurrence of infusion-related reactions (IRR). All children <18 years who had received RTX treatment in our centre between December 2006 and February 2020 with known ADA/RTX-levels, were retrospectively included. The presence of ADA was defined as a titre >8 AU/ml. Of twenty-six children treated with RTX for various immune-mediated diseases, six patients were ADA-positive (23.1%). In all ADA-positive patients, RTX concentrations were undetectable in contrast to ADA-negative patients (median RTX concentration 3.1 μg/ml; IQR 0.57-12.0; p<0.001). Failure of B cell depletion was found in 5/6 ADA-positive and 1/19 ADA-negative patients (p=0.003). In SLE-patients, 50.0% (n=4/8) had developed RTX-ADA. Severe anaphylaxis (n=3) occurred only in the ADA-positive group. In our cohort of paediatric patients, undetectable RTX concentrations were found in ADA-positive patients, indicative that these ADA have a PK impact. RTX-ADA also seem to affect the PD, as in the majority of these patients, B cell depletion failed. ADA were most present in SLE-patients and anaphylactic reactions occurred only in ADA-positive patients. With this knowledge, a change of drug might be considered in the presence of RTX-ADA.

Anti-Rituximab Antibodies in Idiopathic Nephrotic Children Treated with Rituximab: A Prospective Single Centre Study

Corticosteroids have been the main treatment of nephrotic syndrome (NS) for decades however many patients fail to respond. In such children, alternative immunosuppressive medications such as rituximab is used to maintain remission of NS. However, antibodies to rituximab develops during treatment reduces its efficacy. Therefore, this study aimed to measure anti-rituximab antibody (ARA) levels and efficacy of rituximab in children treated for NS. This prospective observational study was conducted among children with difficult to treat nephrotic syndrome. After baseline assessment, patients received single dose of intravenous infusion of 375 mg/m² rituximab. ARA levels were determined at base line, 3-month, 6-month, and 12-month interval. Thirty-four patients with a mean age of 7 years were evaluated in this study. During follow up visits five patients developed ARA; two patients detected ARA of 23.7 IU/ µL at 3-month, one patient had ARA level of 53.2 IU/µL at 6-month and during last follow up visit (at 12 month) two patients had mean ARA level of 24.1 IU/µL. The number of relapses per person year before rituximab was 1.5 (Incidence density) which changed to 0.14 per person year after the rituximab administration in the study subjects. Twenty-Nine patients became relapse-free during rituximab treatment. Out of five patients with ARA, one had relapse during follow up. There was no major adverse effect observed during and post-rituximab therapy. In conclusion, the study demonstrated ARA levels in few patients who were treated with rituximab having sustained clinical outcomes without any major adverse events.

Efficacy of rituximab in autism spectrum disorders associated with hereditary folate malabsorption with signs of antineuronal autoimmunity

Background. One of the key advances in psychiatry is an elucidation of the association of hereditary folate malabsorption (HFM) with autistic spectrum disorders (ASD), the evidence for which is based on the results of 5 meta-analyses of randomized controlled trials. It is shown that in such cases the antineuronal autoimmune reaction is an important mechanism of encephalopathy formation. The purpose of the study was to investigate the efficacy of rituximab in children with HFM-associated ASD who showed serological signs of antineuronal autoimmunity to expand the current arsenal of neuroprotective therapy in immunodependent encephalopathy in such cases. Materials and methods. Medical data of 138 children aged 3 to 8 years with HFM and ASD (97 boys and 41 girls) were analyzed. Parents of 62 of 81 patients with signs of antineuronal autoimmunity agreed to rituximab immunotherapy at a dose of 375 mg/m2 of body surface area per month for 3–9 months (study group, SG). Relatives of the other 19 patients with a similar distribution of antineuronal autoantibodies refused treatment (control group, CG). The dynamics of the mental state of children during immunotherapy was assessed by the ABC scale. For statistical analysis, we calculated the parametric Student’s t-test with the confidence probability p and the non-parametric criterion — the number of signs Z by U.V. Urbach, as well as the odds ratio (OR) and 95% confidence interval (95% CI). Results. Rituximab treatment resulted in a progressive decrease in serum antineuronal autoantibodies concentration in patients with ASD associated with HFM, with a more pronounced effect in the production of autoantibodies to neuronal potassium channels compared to autoantibodies to the GADA with complete elimination of the seropositivity after a 9-month course of immunotherapy in 92 % of cases. The phenomenon of rituximab-induced elimination of serum antineuronal autoantibodies is associated with the effect of neuroprotection, which was confirmed by the normalization of previously elevated serum concentrations of laboratory biomarkers of NSE cerebral damage (OR = 17.875; 95% CI = 4.738–67.436 at Ab to GADA and 41.800; 7.257–240.778 at Ab to potassium channels) and S-100 protein (9.750; 2.707–35.113 and 18.333; 3.462–97.083, respectively). In parallel, there was a progressive improvement in all indicators of the mental status of children with ASD on the ABC scale with a latency period of about 2 months (p &lt; 0.05: Z &lt; Z0.05). Conclusions. Immunotherapy with rituximab by eliminating the serological signs of antineuronal autoimmunity realizes the effect of neuroprotection, reducing the severity of all major clinical signs of ASD in children with HFM.

Rituximab treatment for difficult-to-treat nephrotic syndrome in children: a multicenter, retrospective study

Background/aimThis study aimed to evaluate the efficacy of rituximab in children with difficult-to-treat nephrotic syndrome, considering the type of disease (steroid-sensitive or –resistant) and the dosing regimen.Materials and methodsThis multicenter retrospective study enrolled children with difficult-to-treat nephrotic syndrome on rituximab treatment from 13 centers. The patients were classified based on low (single dose of 375 mg/m2) or high (2-4 doses of 375 mg/m2) initial dose of rituximab and the steroid response. Clinical outcomes were compared.ResultsData from 42 children [20 steroid-sensitive (frequent relapsing / steroid-dependent) and 22 steroid-resistant nephrotic syndrome, aged 1.9–17.3 years] were analyzed. Eleven patients with steroid-sensitive nephrotic syndrome (55%) had a relapse following initial rituximab therapy, with the mean time to first relapse of 8.4 ± 5.2 months. Complete remission was achieved in 41% and 36% of steroid-resistant patients, with the median remission time of 3.65 months. At Year 2, eight patients in steroid-sensitive group (40%) and four in steroid-resistant group (18%) were drug-free. Total cumulative doses of rituximab were higher in steroid-resistant group (p = 001). Relapse rates and time to first relapse in steroid-sensitive group or remission rates in steroid-resistant group did not differ between the low and high initial dose groups. ConclusionThe current study reveals that rituximab therapy may provide a lower relapse rate and prolonged relapse-free survival in the steroid-sensitive group, increased remission rates in the steroid-resistant group, and a significant number of drug-free patients in both groups. The optimal regimen for initial treatment and maintenance needs to be determined.

Rituximab use in pediatric systemic lupus erythematosus: Indications, efficacy and safety in an Indian cohort.

Introduction: Children with systemic lupus erythematosus have a more challenging and difficult course as compared to their adult counterparts. Today, the aim of therapy for any child with lupus is to keep the child in a state of sustained remission with minimal or no use of steroids. This laudable goal is often difficult to achieve for the child with lupus. In addition to the use of disease modifying agents, sometimes in combination, Rituximab (RTX) is also used as an off-label indication to manage such patients.Objectives: To study the use, efficacy and safety of RTX in a cohort of patients with pediatric lupus followed at a single tertiary level center in Northern India.Methods: This paper is a retrospective review looking at the use of RTX in children with systemic lupus at a tertiary level pediatric rheumatology center in North India over a period of seventeen years. This paper describes the indications, use, efficacy and safety of RTX in childhood systemic lupus erythematosus.Results: RTX was used in 17 of 225 pediatric lupus patients (7.5%), with the most common indication being resistant renal disease (53%). Significant improvement was seen in all domains studied: The mean SLEDAI was 16.25 prior to RTX and reduced to 1.43 six months after the RTX (p value 0.001), steroid use dropped from 100% pre- RTX to 33% at 2 years, there was a sustained reduction in proteinuria in the patients with nephritis from a mean urine spot protein creatinine ratio of 3.1 pre RTX to 0.4 at one year post RTX (p= .006). Finally, 82% of the children had no flare during the follow up (median 24 months). No patient had any adverse event.Conclusions: This study confirms that RTX is very effective in childhood lupus and can be safely used even in a country with a very high burden of infectious diseases. This data adds to the scarce literature in this area from the developing world.