Immunologic effects of rituximab on the human spleen in immune thrombocytopenia.
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ABSTRACT:
SUBMITTER: Audia S
PROVIDER: S-EPMC3204911 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundRituximab has been widely used off-label as a second line treatment for children with immune thrombocytopenia (ITP). However, its role in the management of pediatric ITP requires clarification. To understand and interpret the available evidence, we conducted a systematic review to assess the efficacy and safety of rituximab for children with ITP.Methodology/principal findingsWe searched MEDLINE, EMBASE, Cochrane Library, CBM, CNKI, abstract databases of American Society of Hematology, American Society of Clinical Oncology and Pediatric Academic Society. Clinical studies published in full text or abstract only in any language that met predefined inclusion criteria were eligible. Efficacy analysis was restricted to studies enrolling 5 or more patients. Safety was evaluated from all studies that reported data of toxicity. 14 studies (323 patients) were included for efficacy assessment in children with primary ITP. The pooled complete response (platelet count ? 100 × 10(9)/L) and response (platelet count ? 30 × 10(9)/L) rate after rituximab treatment were 39% (95% CI, 30% to 49%) and 68% (95%CI, 58% to 77%), respectively, with median response duration of 12.8 month. 4 studies (29 patients) were included for efficacy assessment in children with secondary ITP. 11 (64.7%) of 17 patients associated with Evans syndrome achieved response. All 6 patients with systemic lupus erythematosus associated ITP and all 6 patients with autoimmune lymphoproliferative syndrome associated ITP achieved response. 91 patients experienced 108 adverse events associated with rituximab, among that, 91 (84.3%) were mild to moderate, and no death was reported.Conclusions/significanceRandomized controlled studies on effect of rituximab for children with ITP are urgently needed, although a series of uncontrolled studies found that rituximab resulted in a good platelet count response both in children with primary and children secondary ITP. Most adverse events associated with rituximab were mild to moderate, and no death was reported.
| S-EPMC3364261 | biostudies-literature
Project description:The interactions of antibodies with myeloid Fc? receptors and the complement system are regulated by an Asn297-linked glycan in the Fc portion of IgG. Alterations of serum IgG-Fc glycosylation have been reported in various autoimmune diseases, and correlate with treatment response and disease activity. We hypothesized that IgG-Fc glycosylation is altered in immune thrombocytopenia (ITP) and associates with response to anti-CD20 monoclonal antibody treatment (rituximab). IgG-Fc glycosylation was analyzed by liquid chromatography-mass spectrometry. We found that IgG-Fc glycosylation was identical between refractory ITP patients (HOVON64 trial; N?=?108) and healthy controls (N?=?120). Two months after rituximab treatment, we observed a shift in Fc glycosylation, with a mean 1.7% reduction in galactosylation for IgG1 and IgG4 and a mean 1.5% increase for bisection in IgG1, IgG2/3 and IgG4 (adjusted p?<?1.7?×?10-3 and p?<?2?×?10-4, respectively). Neither baseline nor longitudinal changes in IgG-Fc glycosylation after rituximab were associated with clinical treatment response. We conclude that IgG-Fc glycosylation in refractory ITP is similar to healthy controls and does not predict treatment responses to rituximab. The observed changes two months after treatment suggest that rituximab may influence total serum IgG-Fc glycosylation. Overall, our study suggests that the pathophysiology of refractory ITP may differ from other autoimmune diseases.
| S-EPMC7033207 | biostudies-literature
Project description:BackgroundRituximab is a monoclonal anti-CD20 antibody used as a second-line treatment for immune thrombocytopenia (ITP). As additional treatments for ITP emerge, identifying the most appropriate patients and optimal timing for rituximab are important but challenging without established predictors of response to therapy.ObjectivesThe purpose of this study was to describe demographic, clinical, and laboratory characteristics of pediatric and adult patients with ITP to identify differences in evaluation before rituximab administration and correlates of platelet response.MethodsThis is a retrospective cohort study describing the characteristics of patients with ITP treated with rituximab from 2010 to 2020 at two academic tertiary care centers.ResultsA total of 64 patients met criteria for inclusion. Complete rituximab response (56%) was not significantly different between children (58%, n = 24) and adults (55%, n = 40). Response rate was similar in those with primary versus secondary ITP (53% vs 62%). Among patients treated with rituximab, Evans Syndrome was more common in children than adults (42% vs 18%). Immunologic labs assessed before rituximab varied by age and were more commonly evaluated in children (lymphocyte subsets 88% vs 22%). Immunologic markers, including antinuclear antibody, direct antiglobulin testing, immunoglobulin levels, and lymphocyte subsets, did not predict response to rituximab in pediatric or adult patients with ITP.ConclusionsPre-rituximab immunologic evaluation varied significantly between adults and children, which could represent institution-specific practice patterns or a more general practice difference. If the latter, underlying immunodeficiency in adults with ITP may be underrecognized. Standardized guidance for pre-rituximab immunologic evaluation is needed.
| S-EPMC8385184 | biostudies-literature
Project description:B-cell depletion may impair vaccine responses and increase infection risk in patients with immune thrombocytopenia (ITP). We investigated the effects of rituximab on antibody and cellular responses to Streptococcus pneumoniae polysaccharide and Haemophilus influenzae type b (Hib) vaccines in ITP patients. Of 60 patients in the main trial, 24 patients received both vaccines 6 months after rituximab (n = 17) or placebo (n = 7). Among 20 evaluable patients, 3 of 14 (21%) in the rituximab group and 4 of 6 (67%) in the placebo group achieved a fourfold increase in anti-pneumococcal antibodies (P = .12). For anti-Hib antibodies, 4 of 14 (29%) and 5 of 6 (83%), respectively, achieved a fourfold increase (P < .05). Fewer patients in the rituximab group demonstrated Hib killing (2 of 14 [14%], 5 of 6 [83%], P < .05). Three of 14 rituximab-treated patients failed to respond to vaccines by any criteria. After vaccinations, preplasma cell blasts and interferon-?-secreting T cells were reduced in rituximab-treated patients. Antibody responses were impaired for at least 6 months after rituximab. Cellular immunity was reduced in parallel with depleted B-cell pools. These findings have implications for the timing of vaccinations and the mechanism of infection after rituximab in ITP patients.
| S-EPMC3773242 | biostudies-literature
Project description:This paper prospectively evaluates the long-term follow-up [mean ± standard deviation (SD) duration: 89.7±19.4 months] data of 15 patients (13 females and 2 males) with refractory symptomatic immune thrombocytopenia (ITP) treated with rituximab.Rituximab was administered at 375 mg/m2 weekly for a total of 4 doses. Complete response (CR) was defined as a platelet count of ≥100,000/mm3 and partial response (PR) as a platelet count of ≥30,000/mm3 but less than 100,000/mm3. Early response (ER) and late response (LR) were defined as response within 42 days and after 42 days of initiation of rituximab therapy, respectively. Sustained response (SR) was defined as response lasting for at least 6 months.Mean age (±SD) at the start of rituximab was 46.6±11.3 years. Mean platelet count (±SD) prior to rituximab treatment was 17,400±8878/mm3. The mean time (±SD) between rituximab therapy and response to rituximab in early responders and late responders was 1.8±1.3 weeks and 10±2.8 weeks, respectively. Mean durations (±SD) of ER and LR were 51±47.2 months and 6±4.2 months, respectively. Seven of the 15 patients (46.7%) showed an initial response to rituximab (5 ER and 2 LR). The rate of SR over 6 months was 26.7% (4/15). Among the responders to rituximab, 3 (3/7, 42.9%) maintained their response 1 year after rituximab treatment and 2 (2/7, 28.6%) had ongoing response 5 years after initiation of rituximab. Two of the 7 patients (28.6%) still maintained their response 98 months after initiation of rituximab. All 5 initial responders with subsequent relapse achieved response from subsequent treatment modalities (3 CR, 2 PR).Our data confirm, over a long period of observation, that rituximab is safe and effective in the management of patients with chronic refractory primary ITP.
| S-EPMC5451692 | biostudies-other
Project description:We report the case of a young woman who developed, 3 years after stopping Rituximab (RTX) prescribed for immune thrombocytopenia (ITP), a severe immunodeficiency leading to fatal pulmonary Epstein-Barr virus-positive diffuse large B-cell lymphoma. Genetic analysis led us to identify four missense mutations known to affect immune-deficiency-associated genes (FAS-ligand (FASL) gene (p.G167R); perforin-1 (PRF1 (p.R55C) gene; the Bloom syndrome RecQ-Like helicase (BLM) gene and the Moesin (MSN) (p.A122T) gene). The heterozygous mutation in the FASL gene, not present in the Genome Aggregation Database or ClinVar database, could suggest atypical Autoimmune LymphoProliferative Syndrome and its role in this patient's immunodepression is discussed. This observation strengthens the role of FASL gene mutation in severe clinical phenotypes of primary immune deficiency and raises new questions about the genetic background of ITP occurring in young people in a context of immunodeficiency.
| S-EPMC6949674 | biostudies-literature
Project description:The use of rituximab for the treatment of immune thrombocytopenia was greeted enthusiastically: it led to up to 60% response rates, making it, nearly 20 years ago, the main alternative to splenectomy, with far fewer side effects. However, long-term follow-up data showed that only 20-30% of patients maintained the remission. No significant changes have been registered using different dose schedules and timing of administration, while the combination with other drugs seemed promising. Higher response rates have been observed in young women before the chronic phase, but apart from that, other clinical factors or biomarkers predictive of response are still lacking. In this review we examine the historical and current role of rituximab in the management of immune thrombocytopenia, 20 years after its first use for the treatment of autoimmune diseases.
| S-EPMC6545833 | biostudies-literature
Project description:Rituximab (RTX), an antibody targeting CD20, is widely used as a first-line therapeutic strategy in B cell-mediated autoimmune diseases. However, a large proportion of patients either do not respond to the treatment or relapse during B cell reconstitution. Here, we characterize the cellular basis responsible for disease relapse in secondary lymphoid organs in humans, taking advantage of the opportunity offered by therapeutic splenectomy in patients with relapsing immune thrombocytopenia. By analyzing the B and plasma cell immunoglobulin gene repertoire at bulk and antigen-specific single-cell level, we demonstrate that relapses are associated with two responses coexisting in germinal centers and involving preexisting mutated memory B cells that survived RTX treatment and naive B cells generated upon reconstitution of the B cell compartment. To identify distinctive characteristics of the memory B cells that escaped RTX-mediated depletion, we analyzed RTX refractory patients who did not respond to treatment at the time of B cell depletion. We identified, by single-cell RNA sequencing (scRNA-seq) analysis, a population of quiescent splenic memory B cells that present a unique, yet reversible, RTX-shaped phenotype characterized by down-modulation of B cell-specific factors and expression of prosurvival genes. Our results clearly demonstrate that these RTX-resistant autoreactive memory B cells reactivate as RTX is cleared and give rise to plasma cells and further germinal center reactions. Their continued surface expression of CD19 makes them efficient targets for current anti-CD19 therapies. This study thus identifies a pathogenic contributor to autoimmune diseases that can be targeted by available therapeutic agents.
| S-EPMC7610758 | biostudies-literature
Project description:BackgroundRituximab has been frequently used as a second-line treatment for patients with immune thrombocytopenia (ITP). The optimal dose and course of rituximab are uncertain.MethodsA comprehensive search for randomized controlled trials reporting the use of low-dose (100 mg) or standard-dose (375 mg/m2) rituximab in ITP treatment was conducted. Meta-analyses were performed on CRR (complete response rate), ORR (overall response rate), PRR (partial response rate), SRR (sustained response rate), infection rate, SB (significant bleeding) rate, and SAE (serious adverse event) rate.ResultsA total of 12 studies were included, comprising 869 patients. Compared to the control group, rituximab treatment resulted in an obvious increase in CRR (P < 0.00001), ORR (P < 0.0001), and SRR at month 6 and 12 (P = 0.0007, P = 0.0003), without increasing the infection rate (P = 0.12) and SAE rate (P = 0.11). No significant differences in CRR (RR 1.61 vs. 1.42, P = 0.45), ORR (RR 1.26 vs. 1.49, P = 0.28), PRR (RR 1.25 vs. 1.00, P = 0.11), SRR at month 12 (RR 2.00 vs. RR 1.64, P = 0.54), infection rate (RR 0.85 vs. 1.46, P = 0.36), and SB rate (RR 0.14 vs. 1.19, P = 0.17) were found in subgroups of low dose and standard dose.ConclusionRituximab was effective and safe for adult patients with ITP. A low-dose rituximab regimen might be an effective alternative to the standard-dose regimen in ITP, as it showed similar CRR, ORR, and SRR at month 12 and was relatively safer with a lower cost.
| S-EPMC8514896 | biostudies-literature
Project description:Vitamin D is responsible for regulation of calcium and phosphate metabolism and maintaining a healthy mineralized skeleton. It is also known as an immunomodulatory hormone. Experimental studies have shown that 1,25-dihydroxyvitamin D, the active form of vitamin D, exerts immunologic activities on multiple components of the innate and adaptive immune system as well as endothelial membrane stability. Association between low levels of serum 25-hydroxyvitamin D and increased risk of developing several immune-related diseases and disorders, including psoriasis, type 1 diabetes, multiple sclerosis, rheumatoid arthritis, tuberculosis, sepsis, respiratory infection, and COVID-19, has been observed. Accordingly, a number of clinical trials aiming to determine the efficacy of administration of vitamin D and its metabolites for treatment of these diseases have been conducted with variable outcomes. Interestingly, recent evidence suggests that some individuals might benefit from vitamin D more or less than others as high inter-individual difference in broad gene expression in human peripheral blood mononuclear cells in response to vitamin D supplementation has been observed. Although it is still debatable what level of serum 25-hydroxyvitamin D is optimal, it is advisable to increase vitamin D intake and have sensible sunlight exposure to maintain serum 25-hydroxyvitamin D at least 30 ng/mL (75 nmol/L), and preferably at 40-60 ng/mL (100-150 nmol/L) to achieve the optimal overall health benefits of vitamin D.
| S-EPMC7400911 | biostudies-literature