COVID-19 in Children with Nephrotic Syndrome on Anti-CD20 Chronic Immunosuppression.
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ABSTRACT:
SUBMITTER: Angeletti A
PROVIDER: S-EPMC7536764 | biostudies-literature | 2020 Oct
REPOSITORIES: biostudies-literature
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COVID-19 in Children with Nephrotic Syndrome on Anti-CD20 Chronic Immunosuppression.
Angeletti Andrea A Drovandi Stefania S Sanguineri Francesca F Santaniello Maria M Ferrando Giulia G Forno Roberto R Cipresso Gaia G Caridi Gianluca G Riella Leonardo V LV Cravedi Paolo P Ghiggeri Gian Marco GM
Clinical journal of the American Society of Nephrology : CJASN 20200710 10
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Project description:Rituximab, a chimeric anti-CD20 monoclonal antibody originally licensed for lymphoma, is emerging as a novel steroid-sparing agent for idiopathic nephrotic syndrome in children. The potential use of anti-CD20 monoclonal antibodies in idiopathic nephrotic syndrome has contributed to shifting the view of podocytopathies from T cell-mediated to more complex immunomediated disorders that can benefit from targeting B cells and other mediators of the early immune response. Clinical data on the use of rituximab also have implications on disease management and classification. In this review, we present results of clinical studies that support rituximab as an effective steroid-sparing agent in steroid-dependent idiopathic nephrotic syndrome. Recent randomized controlled trials suggest that potential benefits of rituximab therapy in steroid-dependent forms of idiopathic nephrotic syndrome vary depending on whether children are dependent on steroids alone or on both steroids and calcineurin inhibitors, with greater probabilities to achieve drug-free remission in the former group. Multiple-drug dependence may identify a different disease state with different prognosis and treatment options. Insufficient data are available on optimal use of rituximab as a maintenance steroid-sparing agent in these steroid-sensitive forms of the disease, including how often and for how long rituximab infusions should be repeated to maximize expected benefits and minimize potential harms. Finally, one randomized controlled trial in children with steroid-resistant idiopathic nephrotic syndrome yielded negative results. New anti-CD20 antibodies are under study in this patient population.
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Project description:BackgroundThe chimeric anti-CD20 monoclonal antibody rituximab is effective in steroid-dependent and calcineurin inhibitor-dependent forms of nephrotic syndrome, but many patients relapse at 1 year. Because ofatumumab, a fully human anti-CD20 monoclonal antibody, has a more extended binding site and higher affinity to CD20 compared with rituximab, it might offer superior efficacy in these patients.MethodsWe designed a single-center randomized clinical trial to compare the long-term efficacy of ofatumumab versus rituximab in children and young adults with nephrotic syndrome maintained in remission with prednisone and calcineurin inhibitors. We randomized 140 children and young adults (aged 2-24 years) to receive intravenous ofatumumab (1.50 mg/1.73 m2) or rituximab (375 mg/m2). After infusions, oral drugs were tapered and withdrawn within 60 days. The primary outcome was relapse at 1 year, which was analyzed following the intent-to-treat principle. The secondary endpoint was relapse within 24 months from infusion, on the basis of urine dipstick and confirmed by a urine protein-to-creatinine ratio <200.ResultsAt 12 months, 37 of 70 (53%) participants who received ofatumumab experienced relapse versus 36 of 70 (51%) who received rituximab (odds ratio [OR], 1.06; 95% confidence interval [95% CI], 0.55 to 2.06). At 24 months, 53 of 70 (76%) participants who received ofatumumab experienced relapse, versus 46 of 70 (66%) who received rituximab (OR, 1.6; 95% CI, 0.8 to 3.3). The two groups exhibited comparable B cell subpopulation reconstitution and did not differ in adverse events.ConclusionsA single dose of ofatumumab was not superior to a single dose of rituximab in maintaining remission in children with steroid-dependent and calcineurin inhibitor-dependent nephrotic syndrome.Clinical trial registration numbersClinicalTrials.gov (NCT02394119) and https://www.clinicaltrialsregister.eu/ctr-search/search (2015-000624-28).
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Project description: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.
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Project description:AimsAnti-CD20 antibodies are increasingly being used to treat idiopathic nephrotic syndrome (INS) in children. While they may allow steroid and calcineurin inhibitor withdrawal, repeated infusions of anti-CD20 antibodies are often required to maintain remission. Data on their potential toxicity in INS are needed, to consider repeated infusions.MethodsWe investigated the side effects associated with the use of rituximab (a chimeric antibody; 130 patients) and ofatumumab (a humanized antibody; 37 patients) in children with INS (steroid-dependent and steroid/calcineurin inhibitor-dependent disease) treated at a national referral centre over a 9-year period (400 treatments; follow-up 1-9 years).ResultsInfusion reactions were mainly absent in children with steroid-dependent disease. Rash, dyspnoea, fever, cough and itchy throat (5% and 18% following rituximab and ofatumumab infusion, respectively) were resolved by using premedication with salbutamol. Other short-term reactions (up to 3 months), including arthritis (2%) and lung injury (1%), were more common with rituximab. Infections were observed 3-9 months following infusion, were similarly common in the two groups and resolved with targeted therapies [antibiotic, fluconazole, immunoglobulins (Igs), etc.]. The number of circulating CD19/20 cells fell to 0 at month 1 and were reconstituted at month 3; circulating IgG antibodies remained within the normal range for 1 year. Tetanus and hepatitis B virus immunization was not modified by either treatment; Epstein-Barr virus and John Cunningham virus activation markers were occasionally observed.ConclusionOverall, the toxicity of anti-CD20 monoclonal antibodies was limited to post-infusion side effects in children with more complex disease. The relatively safe profile of anti-CD20 antibodies supports their use as steroid-sparing agents in children with INS.
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