Meta-analysis on the efficacy and safety of rituximab versus tacrolimus for nephrotic syndrome in the paediatric age group
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PROVIDER: S-EPMC10768748 | biostudies-literature | 2023 Oct
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Project description:IntroductionIn the Rituximab for Relapse Prevention in Nephrotic Syndrome (RITURNS) trial, we demonstrated superior efficacy of single-course rituximab over maintenance tacrolimus in preventing relapses in children with steroid dependent nephrotic syndrome (SDNS) during a 1-year observation. Here we present the long-term outcomes of all 117 trial completers, who were followed up for another 2 years.MethodsRelapsing patients in the rituximab arm received a second course of rituximab, either with (n = 44) or without mycophenolate mofetil (MMF) cotreatment (n = 15). In the tacrolimus arm, second line rituximab monotherapy was initiated after relapses (n = 32) or electively (n = 24).ResultsAll 12-month relapse-free patients in the rituximab arm relapsed in the second postexposure year, resulting in similar median relapse-free survival times in the 2 trial arms (62 vs. 59 weeks). Second line rituximab in the tacrolimus arm was less effective than first-line therapy in patients switched to rituximab following a relapse (relapse-free survival 55 vs. 63 weeks, P < 0.01). B-cell counts 6 months post-rituximab predicted relapse risk both for first and second line therapy. MMF cotreatment yielded much improved 2-year relapse-free survival as compared to rituximab monotherapy (67% vs. 9%, P < 0.0001). Higher grade 2 adverse event rates were observed post-rituximab versus on tacrolimus (0.87 vs. 0.53 per year).ConclusionThe superior therapeutic effect of rituximab in SDNS vanishes during the second year post-exposure. Rituximab appears to yield longer remission when applied as first line as compared to second line therapy. Maintenance MMF following rituximab induces long-term disease remission.
| S-EPMC10403658 | biostudies-literature
Project description:BackgroundRituximab and tacrolimus are therapies reserved for patients with frequently relapsing or steroid-dependent nephrotic syndrome who have failed conventional steroid-sparing agents. Given their toxicities, demonstrating non-inferiority of rituximab to tacrolimus may enable choice between these medications.MethodsThis investigator-initiated, single-center, open-label, pilot randomized controlled trial examined the non-inferiority of two doses of intravenous (IV) rituximab given one-week apart to oral therapy with tacrolimus (1:1 allocation), in maintaining sustained remission over 12 months follow-up, in patients with difficult-to-treat steroid-sensitive nephrotic syndrome, defined as frequently relapsing or steroid-dependent disease that had failed ≥ 2 steroid-sparing strategies. Secondary outcomes included frequency of relapses, proportion with frequent relapses, time to relapse and frequent relapses, and adverse events (CTRI/2018/11/016342).ResultsBaseline characteristics were comparable for 41 patients randomized to receive rituximab (n = 21) or tacrolimus (n = 20). While 55% of patients in each limb were in sustained remission at 1 year, non-inferiority of rituximab to tacrolimus was not demonstrated (mean difference 0%; 95% CI - 30.8%, 30.8%; non-inferiority limit - 20%; P = 0.50). Frequent relapses were more common in patients administered rituximab compared to tacrolimus (risk difference 30%, 95% CI 7.0, 53.0, P = 0.023). Both groups showed similar reductions in relapse rates and prednisolone use. Common adverse events were infusion-related with rituximab and gastrointestinal symptoms with tacrolimus.ConclusionsTherapy with rituximab was not shown to be non-inferior to 12-months treatment with tacrolimus in maintaining remission in patients with difficult-to-treat steroid-sensitive nephrotic syndrome. Frequent relapses were more common with rituximab. While effective, both agents require close monitoring for adverse events. A higher resolution version of the Graphical abstract is available as Supplementary information.
| S-EPMC8919684 | biostudies-literature
Project description:ImportanceCalcineurin inhibitors are an established first-line corticosteroid-sparing therapy for patients with corticosteroid-dependent nephrotic syndrome (CDNS), whereas B-lymphocyte-depleting therapy is mostly used as a rescue for calcineurin inhibitor-resistant cases. The positive efficacy and safety profile of rituximab raises the question of whether it could be used as a first-line alternative to calcineurin inhibitor therapy.ObjectiveTo compare the efficacy of rituximab and tacrolimus in maintaining relapse-free survival among children with CDNS.Design, setting, and participantsA parallel-arm, open-label, randomized clinical trial was performed from May 8, 2015, to September 20, 2016, with 1-year follow-up in a single-center, tertiary care unit. A total of 176 consecutive children aged 3 to 16 years with CDNS not previously treated with corticosteroid-sparing agents were screened for eligibility.InterventionsThe children received either tacrolimus (along with tapering alternate-day prednisolone) for 12 months or a single course of rituximab (2 infusions of 375 mg/m2).Main outcomes and measuresTwelve-month relapse-free survival in the intention-to-treat population.ResultsOf the 176 children screened for eligibility, 120 were randomized and all but 3 patients completed 1 year of follow-up. The groups were comparable, with mean (SD) age of 7.2 (2.8) years, 32 boys (53.3%) in each group, mean (SD) disease duration of 2.5 (1.5) years and 2.3 (1.7) in the tacrolimus and rituximab groups, respectively, disease duration less than 1 year among 15 children (25.0%) in each group, median (interquartile range) of 4 (3-5) relapses in each group, and mean (SD) cumulative prednisolone dose of 246 (48) mg/kg and 239 (52) mg/kg in the prestudy year in the tacrolimus and rituximab groups, respectively. Rituximab therapy was associated with a higher 12-month relapse-free survival rate than tacrolimus (54 [90.0%] vs 38 [63.3%] children; P < .001; odds ratio, 5.21; 95% CI, 1.93-14.07). Among the patients who experienced relapse, median time to first relapse was 40 weeks in the rituximab group and 29 weeks in the tacrolimus group. Only 2 patients in the rituximab group had more than 1 relapse during the study period compared with 10 patients in the tacrolimus group. The cumulative corticosteroid dose during the 12-month study period was lower with rituximab compared with tacrolimus (mean [SD], 25.8 [27.8] vs 86.3 [58.0] mg/kg). Although both treatments were well tolerated, mild to moderate infections were twice as common in the tacrolimus group (26 [43.3%] vs 13 [21.7%] events).Conclusions and relevanceIn children with CDNS, rituximab appears to be more effective than tacrolimus in maintaining disease remission and minimizing corticosteroid exposure and, given its good tolerability and lack of nephrotoxic effects, may be considered as first-line corticosteroid-sparing therapy.Trial registrationClinicalTrials.gov Identifier: NCT02438982; Clinical Trial Registry of India: CTRI/2014/01/004355.
| S-EPMC6142920 | biostudies-literature
Project description:Rituximab is considered to be a promising drug for treating childhood refractory nephrotic syndrome. However, the efficacy and safety of rituximab in treating childhood refractory nephrotic syndrome remain inconclusive. This meta-analysis aimed to investigate the efficacy and safety of rituximab treatment compared with other immunosuppressive agents in children with refractory nephrotic syndrome. Three randomized controlled trials and two comparative control studies were included in our analysis. The included studies were of moderately high quality. Compared with other immunotherapies, rituximab therapy significantly improved relapse-free survival (hazard ratio = 0.49, 95% confidence interval [CI], 0.26-0.92, P = 0.03). Rituximab also achieved a higher rate of complete remission (risk ratio,1.62; 95% CI, 0.92 to 2.84, P = 0.09) and reduced the occurrence of proteinuria (mean difference = -0.25, 95% CI = -0.29 to -0.21, P < 0.00001); however, a more targeted rituximab treatment did not significantly increase serum albumin levels and did not significantly reduce adverse events. Rituximab might be a promising treatment for childhood refractory nephrotic syndrome; however, the long-term effects and cost-effectiveness of rituximab treatment were not fully assessed, and there were limited studies that evaluated the clinical benefits of a concurrent infusion of rituximab plus a steroid compared with an infusion of rituximab only. Additional studies are required to address these issues.
| S-EPMC4314653 | biostudies-other
Project description:BackgroundNephrotic syndrome is a disorder characterized by proteinuria, hypoalbuminemia and dyslipidemia. Low-dose alternate-day steroid regimen is the standard of care. In case of relapse or significant adverse events, steroid-sparing agents may be used. This analysis was aimed at assessing the efficacy and safety of rituximab for the treatment of children with nephrotic syndrome.ResultsFour studies were included in the final meta-analysis. The end-point of our analysis was the percentage of patients in remission at 6 months. Pooled data from the four studies favours the use of rituximab (RR 5.25, 95 % CI: 3.05-9.06; p < 0.0001). As regards the safety data, rituximab has a limited number of adverse effects, the most common of which occur during the infusions.ConclusionsIn Italy, the off-label use of drugs is regulated by Law 648/96. In our opinion, there are three scientific requirements to merit a conditional national reimbursement for rituximab in nephrotic syndrome: 1. favourable clinical efficacy and safety data; 2. no available alternatives; 3. outcome data collecting by AIFA through prescribers. In conclusion, our results report a significant incremental benefit of adding rituximab to corticosteroid and/or calcineurin inhibitors for the treatment of nephrotic syndrome.
| S-EPMC4943005 | biostudies-literature
Project description:IntroductionGuidelines for the treatment of steroid-dependent nephrotic syndrome (SDNS) and frequently relapsing nephrotic syndrome (FRNS) are lacking. Given the substantial impact of SDNS/FRNS on quality of life, strategies aiming to provide long-term remission while minimising treatment side effects are needed. Several studies confirm that rituximab is effective in preventing early relapses in SDNS/FRNS; however, the long-term relapse rate remains high (~70% at 2 years). This trial will assess the association of intravenous immunoglobulins (IVIgs) to rituximab in patients with SDNS/FRNS and inform clinicians on whether IVIg's immunomodulatory properties can alter the course of the disease and reduce the use of immunosuppressive drugs and their side effects.Methods and analysisWe conduct an open-label multicentre, randomised, parallel group in a 1:1 ratio, controlled, superiority trial to assess the safety and efficacy of a single infusion of rituximab followed by IVIg compared with rituximab alone in childhood-onset FRNS/SDNS. The primary outcome is the occurrence of first relapse within 24 months. Patients are allocated to receive either rituximab alone (375 mg/m²) or rituximab followed by IVIg, which includes an initial Ig dose of 2 g/kg, followed by 1.5 g/kg injections once a month for the following 5 months (maximum dose: 100 g).Ethics and disseminationThe study has been approved by the ethics committee (Comité de Protection des Personnes) of Ouest I and authorised by the French drug regulatory agency (Agence Nationale de Sécurité du Médicament et des Produits de Santé). Results of the primary study and the secondary aims will be disseminated through peer-reviewed publications.Trial registration numberNCT03560011.
| S-EPMC7513594 | biostudies-literature
Project description:IntroductionRituximab (RTX) effectively prevents relapses in patients with complicated steroid-sensitive nephrotic syndrome (SSNS). The 1-year relapse-free survival rate is approximately 30% in children after the first episode of SSNS treated with standardised corticosteroids. Whether the benefits of RTX extend to the first relapse are unknown. The efficacy and safety of RTX in the first episode of paediatric idiopathic nephrotic syndrome (RTXFIRPedINS) trial (NCT04783675) will assess its effect on the risk of subsequent relapse.Methods and analysisRTXFIRPedINS is an open-label, single-arm, multicentre trial targeting patients aged 1-18 years with a first episode of SSNS. All patients will receive standardised corticosteroid treatment for 12 weeks. A sample size of 44 patients provides 80% power to detect a 20% increase in the 1-year relapse-free rate, assuming a dropout rate of 10%. After obtaining informed consent and screening, eligible patients will be treated with a single intravenous infusion of 375 mg/m2 RTX within 1 week after achieving remission. Trimethoprim-sulfamethoxazole will be administered for 3 months after RTX administration to prevent Pneumocystis carinii infection. The follow-up period will be 1 year. The primary outcome is the 1-year relapse-free survival rate after RTX infusion. The secondary study outcomes are the number of days from the infusion of RTX to the occurrence of the first relapse, 6-month relapse-free survival rate, the B cell recovery time and treatment-related adverse events. Immunological factors will be studied as predictors of response.Ethics and disseminationThis trial was approved by the Ethics Committee of the Children's Hospital of Fudan University and seven local ethics committees. We will publish our study results in peer-reviewed journals and present them at international scientific meetings.Trial registration numberNCT04783675.
| S-EPMC9562314 | biostudies-literature
Project description:BackgroundLong-term outcomes after multiple courses of rituximab among children with frequently relapsing, steroid-dependent nephrotic syndrome (FRSDNS) are unknown.MethodsA retrospective cohort study at 16 pediatric nephrology centers from ten countries in Asia, Europe, and North America included children with FRSDNS who received two or more courses of rituximab. Primary outcomes were relapse-free survival and adverse events.ResultsA total of 346 children (age, 9.8 years; IQR, 6.6-13.5 years; 73% boys) received 1149 courses of rituximab. A total of 145, 83, 50, 28, 22, and 18 children received two, three, four, five, six, and seven or more courses, respectively. Median (IQR) follow-up was 5.9 (4.3-7.7) years. Relapse-free survival differed by treatment courses (clustered log-rank test P<0.001). Compared with the first course (10.0 months; 95% CI, 9.0 to 10.7 months), relapse-free period and relapse risk progressively improved after subsequent courses (12.0-16.0 months; HRadj, 0.03-0.13; 95% CI, 0.01 to 0.18; P<0.001). The duration of B-cell depletion remained similar with repeated treatments (6.1 months; 95% CI, 6.0 to 6.3 months). Adverse events were mostly mild; the most common adverse events were hypogammaglobulinemia (50.9%), infection (4.5%), and neutropenia (3.7%). Side effects did not increase with more treatment courses nor a higher cumulative dose. Only 78 of the 353 episodes of hypogammaglobulinemia were clinically significant. Younger age at presentation (2.8 versus 3.3 years; P=0.05), age at first rituximab treatment (8.0 versus 10.0 years; P=0.01), and history of steroid resistance (28% versus 18%; P=0.01) were associated with significant hypogammaglobulinemia. All 53 infective episodes resolved, except for one patient with hepatitis B infection and another with EBV infection. There were 42 episodes of neutropenia, associated with history of steroid resistance (30% versus 20%; P=0.04). Upon last follow-up, 332 children (96%) had normal kidney function.ConclusionsChildren receiving repeated courses of rituximab for FRSDNS experience an improving clinical response. Side effects appear acceptable, but significant complications can occur. These findings support repeated rituximab use in FRSDNS.
| S-EPMC9161790 | biostudies-literature
Project description:BackgroundThe anti-CD20 monoclonal antibody rituximab (RTX) has been proposed as a rescue therapy for difficult-to-treat nephrotic syndrome (NS). We conducted a clinical trial to evaluate the efficacy and safety of RTX in children with difficult-to-treat NS dependent on or resistant to steroids and calcineurin inhibitors (CNIs).MethodsA multicenter open-label trial was performed at 8 major pediatric nephrology centers in Korea. The investigation consisted of a randomized controlled trial for steroid- and CNI-dependent NS (DDNS; randomization into the RTX group and the control group, at a ratio of 2:1) and a single-arm study of steroid and CNI-resistant NS (DRNS). DDNS patients in the RTX group and DRNS patients received a single dose of intravenous RTX (375 mg/m of body surface area) for B-cell depletion. A second RTX dose was administered at week 2 if the first dose failed to achieve depletion of CD19(+) cells. The primary endpoint was rate of maintaining remission at 6 months after treatment for DDNS and rate of remission achievement for DRNS.ResultsSixty-one children with DDNS were enrolled while in remission and randomized to the control group (21 patients) or the RTX group (40 patients). At 6 months after treatment, the remission rates were 74.3% in the RTX group and 31.3% in the control group (P = .003). The mean duration of remission maintenance was significantly higher in the RTX group than in the control group (9.0 vs 2.9 months, P = .004). Of the 23 patients with DRNS enrolled in the single-arm study and treated with RTX, 9 (39.1%) achieved partial or complete remission within 6 months. Depletion of B cells occurred in all patients with RTX therapy. Thirty patients (50.8% of 59 patients analyzed) experienced mild and transient infusion reaction during RTX administration, and most adverse events were mild.ConclusionsRTX administration was safe and effective in patients with difficult-to-treat NS. One or 2 doses of RTX may be sufficient to deplete B cells and achieve better control of pediatric NS.
| S-EPMC6257685 | biostudies-literature
Project description:Nephrotic syndrome affects both children and adults. Idiopathic nephrotic syndrome is reported to be one of the most frequent renal pathologies in childhood. Nephrotic children are at high risk for severe pneumococcal infections as one of the life-threatening complications of nephrotic syndrome due to involvement of the immunosuppressive regimen and the acquired immune deficiency induced by nephrotic syndrome including decreased plasma IgG and low complement system components. Aiming to prevent pneumococcal infection is of paramount importance especially in this era of ever-increasing pneumococcal resistance to penicillins and cephalosporins. The pneumococcal vaccines currently available are inactivated vaccines-the two main forms in use are polysaccharide vaccines and conjugated vaccines. However, the data supporting the use of these vaccines and to guide the timing and dosage recommendations is still limited for nephrotic children. Thus, this review discusses the evidences of immunogenicity and safety profile of both vaccinations on nephrotic patients as well as the effect of nephrotic syndrome treatment on vaccine seroresponses.
| S-EPMC6700369 | biostudies-literature