First Administration Of Rituximab Research Articles

Эффективность ритуксимаба в терапии системного ювенильного идиопатического артрита

Эффективность ритуксимаба в терапии системного ювенильного идиопатического артрита

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.

Monitoring of the Complement System Status in Patients With B-Cell Malignancies Treated With Rituximab.

Rituximab is a pioneering anti-CD20 monoclonal antibody that became the first-line drug used in immunotherapy of B-cell malignancies over the last twenty years. Rituximab activates the complement system in vitro, but there is an ongoing debate on the exact role of this effector mechanism in therapeutic effect. Results of both in vitro and in vivo studies are model-dependent and preclude clear clinical conclusions. Additional confounding factors like complement inhibition by tumor cells, loss of target antigen and complement depletion due to excessively applied immunotherapeutics, intrapersonal variability in the concentration of main complement components and differences in tumor burden all suggest that a personalized approach is the best strategy for optimization of rituximab dosage and therapeutic schedule. Herein we critically review the existing knowledge in support of such concept and present original data on markers of complement activation, complement consumption, and rituximab accumulation in plasma of patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphomas (NHL). The increase of markers such as C4d and terminal complement complex (TCC) suggest the strongest complement activation after the first administration of rituximab, but not indicative of clinical outcome in patients receiving rituximab in combination with chemotherapy. Both ELISA and complement-dependent cytotoxicity (CDC) functional assay showed that a substantial number of patients accumulate rituximab to the extent that consecutive infusions do not improve the cytotoxic capacity of their sera. Our data suggest that individual assessment of CDC activity and rituximab concentration in plasma may support clinicians’ decisions on further drug infusions, or instead prescribing a therapy with anti-CD20 antibodies like obinutuzumab that more efficiently activate effector mechanisms other than complement.

Rituximab in children with steroid-dependent nephrotic syndrome: experience of a tertiary center and review of the literature

Objectives: Rituximab (RTX) is a new treatment option in children with difficult-to-treat steroid-dependent nephrotic syndrome (SDNS). We evaluated the experience of our tertiary center and reviewed the current literature.Methods: This is a retrospective single-center study evaluating the efficacy and safety of RTX in children with difficult-to-treat SDNS. Age at diagnosis, type and duration of immunosuppression, age at administration, dose of RTX, possible adverse events, number of relapses, duration of remission, and B-cell count after administration of RTX were analyzed.Results: Nine children with a median age at diagnosis of nephrotic syndrome of 4.75 (range 1.33–11.33) years and a median age at administration of RTX of 16.08 (range 3.33–19.25) years were included. Before administration of RTX they had a median number of relapses per year of 1.70 (range 0.82–4.80). At last follow-up (median 2.75 years, range 0.58–3.92), a reduction in the number of relapses per year to 0.26 (range 0–2.18) was noted, despite cessation or lowering the dose of immunosuppressive therapy. Four patients achieved complete remission after the first administration of RTX, four more patients after subsequent doses of RTX. No severe adverse events were noted.Conclusion: RTX was an effective and safe therapeutic option in our cohort of children with difficult-to-treat SDNS, resulting in a significant reduction of yearly relapses in the absence of severe adverse events and facilitating the reduction of other immunosuppressive medication.

Positive experience of the usage of Rituximab in management of refractory myasthenia gravis in Russia

A subset of patients (15 to 20%) with myasthenia gravis (MG) remains refractory to standard types of treatment. Analysis of efficiency of rituximab, a chimeric monoclonal antibody to surface antigen of B lymphocytes (CD20), in 16 patients suffering from refractory MG was performed. In all cases, the drug was injected weekly and intravenously in the dosage of 375 mg/m2, for 4 weeks. All patients were dependent on intake of corticosteroids and cyclosporin. During rituximab therapy, the gradation of MG has significantly changed, being transformed from severe forms (IV and V MGFA class) into moderate and mild forms (III, II, and I MGFA class). Improvement of the clinical state included cease of myasthenic exacerbation, increased respiratory muscle strength; significant reduction of dosages (and even canceling) of basic pathogenetic and symptomatic treatment. Complete remission with cancellation of basic therapy was recorded in 4 (25 %) of patients within 2-year period. However, 2 of them manifested with aggravation of MG after the first course of rituximab, in 9 and 24 months, correspondingly, which required resumption of corticosteroid therapy and repeating of courses of rituximab, with positive result. In 9 (56.25 %) cases, pharmacological remission was recorded; in 3 (18.75 %) cases, there was a significant improvement of initially severe forms. In all patients rituximab therapy lead to the clinical improvement: prior to completion of the course, after the 1st and the 2nd infusion - in 12 (75 %) patients; 1 to 3 weeks after completion of the course – in 4 (25 %) patients. Maximal improvement was registered in 1 to 12 month after completion of the course of rituximab intake (at the terms of 4. ± 2.0 months). There were the following stages of basic therapy cancellation: during first 1 to 3 months of rituximab treatment, pyridostigmine and cyclosporine were cancelled; corticosteroids were dropped off gradually, according to the clinical status of patients. Increased sensitivity to steroids, even in small dosages, was recorded. Infusion reactions were dose-related and most frequently occurred during first administration of rituximab and were eliminated with slowing down of the infusion rate. Infusion reactions and side effects were absent in the course of postinfusion period in 5 (31.25 %) and 8 (50 %) patients, correspondingly.

Use of whole-blood transcriptomic profiling to highlight several pathophysiologic pathways associated with response to rituximab in patients with rheumatoid arthritis: data from a randomized, controlled, open-label trial.

To identify a molecular signature that could be predictive of the clinical response to rituximab (RTX) and elucidate the transcriptomic changes after RTX therapy in patients with rheumatoid arthritis (RA), with the use of whole-blood transcriptomic profiling. A microarray assay of the whole human genome was performed using RNA from peripheral blood samples obtained before the first cycle of RTX from 68 patients with RA in the SMART study. The transcriptomic profile was also assessed 24 weeks after the first administration of RTX (among 24 nonresponders and 44 responders, according to the European League Against Rheumatism response criteria at week 24). Ingenuity Interactive Pathways Analysis was used to identify molecular pathways that were modified by RTX therapy according to the clinical response. Quantitative polymerase chain reaction was performed to confirm the microarray results. In total, 198 genes showed significant baseline differential expression between patient groups according to their subsequent response to RTX (good or moderate responder versus nonresponder). This molecular signature could be reduced to 143 genes, which allowed for correctly classifying 89% of the patients by their EULAR response status at week 24, with 93% identification of responders and 100% identification of nonresponders. The signature for response featured up-regulation of inflammatory genes centered on NF-κB, including IL33 and STAT5A, and down-regulation of the interferon pathway. As expected, at week 24 post-RTX therapy, genes involved in the development and functions of B cells were the genes most strongly down-regulated, without any difference between the 2 groups. Whole-blood transcriptomic analyses may accurately identify patients with RA who will not respond to RTX therapy. These findings could open new perspectives on the clinical management of RA.

Impact of rituximab on height and weight in children with refractory steroid-dependent nephrotic syndrome

Children with steroid-dependent nephrotic syndrome (SDNS) often suffer from serious adverse events, including growth retardation and obesity. Rituximab (RTX) is a promising therapeutic option to overcome steroid dependency. We have examined the impact of RTX on growth and obesity in children with SDNS. Thirteen pediatric patients with SDNS who were refractory despite treatment with multiple immunosuppressive agents received RTX infusions. Mean follow-up was 2.3 years from the first administration of RTX. Improvement in the height and obesity indexes from prior to the initial RTX infusion through to the last visit was assessed. After RTX, the number of relapses [2.8 (before RTX) vs. 0.8/year (after RTX); p = 0.0008] and the prednisolone dose (287.9 vs. 70.7 mg/kg/year, respectively; p = 0.0002) were significantly decreased. Marked improvement in the height standard deviation score (SDS) was achieved by ten of the 13 patients (77 %) [n = 13; -1.6 (before RTX) vs. -0.8 SDS (after RTX); p = 0.03]. Notably, the height SDS of seven of the eight patients whose height was less than average at the first RTX improved from -2.6 to -1.4 SDS with RTX therapy. At the same time, the obesity index of 12 of the 13 patients (92 %) significantly improved (n = 13; 16.9 vs. 3.1 %; p = 0.004). Therapy with RTX may contribute to an improvement in the growth and obesity indexes in some patients suffering from severe side effects of steroids.

RITUXIMAB TREATMENT FOR INTERSTITIAL LUNG INJURY IN SCLERODERMA SYSTEMATICA

Objective: to study the efficiency and tolerance of rituximab (RTM) treatment in patients with scleroderma systematica (SDS) with interstitial lung injury (ILI). Subjects and methods. The trial included 27 patients (26 women and 1 man) (mean age 45.7±13.0 years), with diffuse (n=13) and circumscribed (n = 14) forms and a disease duration of > 5 years in 63%. All the patients underwent chest computed tomography; examination of external respiratory function, including forced vital capacity (FVC) and diffusing capacity of the lung (DCL), as well as echocardiographic study. The efficiency of the treatment was evaluated from changes in FVC, skin score, and disease activity index. The indicators were compared prior to the treatment and one year after the first administration of RTM. The latter was injected with premedication (125–500 mg of methylprednisolone intravenously) 500–1000 mg per administration. The mean dose of RTM was low and amounted to 1.3 g per year. Results. As estimated by the physician, good, satisfactory, no effects were seen in 81.5, 14.8, and 3.7% of the patients, respectively. There was a significant increase in mean FVC one year after the first administration of RTM and a reduction in the total activity of the disease, including skin syndrome. DCL was substantially unchanged in the entire group. In the diffuse and circumscribed forms of the disease, FVC increased significantly and to the same extent. A clinically significant increase in FVC (by 11%) was achieved in patients with a disease duration of ≤5 years and mild lung injury. In people with a more than 5-year disease duration, FVC was initially decreased to a greater extent and the treatment-induced increase was only 3.7%. A significant and permanent decline in peripheral blood B lymphocytes was noted when both the standard dose (2 g) of RTM and its lower doses (0.5–1 g) were administered. RTM treatment was well tolerated, but complicated by mild intercurrent infections in 11% of cases within the first 2 months after RTM administration. Conclusion. The findings substantiate the indications for RTM use primarily in the early stage of the disease. The admittedly low doses of RTM have an inadequate effect if the disease is long-lasting. Further study of dosage regimens for RTM is required within the framework of controlled trials.

Infusion Rate Escalation Study of Rituximab in Patients with CD20+ B-Cell Lymphomas: A Single Institution Analysis in Japan

Background. To determine the maximum tolerable infusion rate of rituximab, and investigate the safety and feasibility of rapid infusion of rituximab for patients with CD20 positive B-cell lymphomas (CD20+NHL). Patients and Methods. 18 patients with CD20+NHL were registered. This study had six cohorts of administration rate of rituximab. The median age was 56 years (range, 38–79), and five of 18 patients were male. Two patients (11%) with diffuse large B-cell lymphoma were receiving R-CHOP therapy, two (11%) with indolent lymphoma were receiving R-CVP therapy, and 14 (78%) with indolent lymphoma were receiving rituximab as maintenance therapy. Results. A total of 88 cycles of rituximab was administered. Rapid infusion of rituximab was well tolerated, with only one grade 3 leukocytepenia and one grade 4 neutropenia. Four patients (22%) developed grade 1 infusion-related toxicities at the first administration of rituximab. No patient with severe drug-related events was observed. Conclusions. We determined that the maximum tolerable infusion rate of rituximab is 300 mL/h (under 700 mg/h), and confirmed that administration of over 60 minutes is safe and feasible. We recommend rapid administration of rituximab for practice setting in patients with CD20+NHL being treated with rituximab or rituximab-containing chemotherapy. (Clinical trial no. JFCR2009-1027).

Rituximab Used Successfully in the Treatment of Anti-NMDA Receptor Encephalitis

We report the case of a young woman with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, without tumor, who was successfully treated with rituximab. Because conventional immunotherapy, including corticosteroids, immunoglobulin (IVIg), and plasma exchange showed little improvement in our patient, we introduced another treatment using rituximab. A week after the first administration of rituximab, her symptoms improved gradually and significantly. This case provides in vivo evidence that rituximab is an effective agent for treating anti-NMDAR encephalitis, even in those cases where conventional immunotherapies have been ineffective. Rituximab should be regarded as a beneficial therapeutic agent for this disease.

Rituximab for Peripheral Ulcerative Keratitis With Wegener Granulomatosis

To demonstrate the effectiveness of Rituximab in the management of peripheral ulcerative keratitis (PUK) associated with Wegener granulomatosis (WG). A 50-year-old female with WG, confirmed by skin biopsy and positive anti-neutrophil cytoplasmic antibodies 3 years prior, was presented with a corneoscleral granulomatous mass that affected the superior limbus and with vasculitic PUK in the right eye. The mass was treated daily with oral prednisone (1 mg.kg-1.d-1) in conjunction with weekly maintenance treatment of 10 mg of methotrexate. After 2 months of treatment, the volume of the nodular granulomatous lesion decreased. However, the PUK and corneal thinning persisted, which presented a risk for corneal perforation. Subsequently, two 1000-mg infusions of rituximab were administered at weekly intervals. One week after the first administration of rituximab, we observed persistence of corneal thinning, flattening of the nodular lesion, and disappearance of the necrotic foci. After the second rituximab treatment, the patient exhibited no signs of corneal perforation and we further observed total epithelialization of the PUK. No systemic side effects were seen. After 2 months, no nodular lesion was observed, although conjunctival epithelialization from the previous PUK remained. Weekly methotrexate and 10 mg of prednisone per day were maintained. Rituximab seems to offer therapeutic promise in the treatment of refractory PUK associated with WG. Rituximab may be the elective treatment for severe anterior ocular inflammation associated with risk for corneal perforation, as a result of WG.

Infusion Speed-Escalation Trial To Give Full-Dose Rituximab in One Hour without Steroids Pre-Medication.

The first administration of rituximab can cause important side effects due to cytokine release into the blood. It is therefore recommended to administer it over 4–6 hours. According to the manufacturer subsequent doses can be given in approximately 3 hours, but this is demanding for the patient (pt) and facilities and resources-consuming. A Canadian study has recently shown that rituximab can be given safely over 90 minutes from the second administration in combination with CHOP, provided that steroids and chemotherapy are administered before the antibody. We are conducting an infusion speed-escalation trial to verify if rituximab can be given in one hour without steroids pre-medication, in pts having received at least two previous doses of rituximab (with or without chemotherapy) in the previous 3 months. Further inclusion criteria include a normal cardiac function as evaluated by ECG and echocardiography. Cohorts of 3 patients are assigned to receive rituximab at a given initial infusion speed, to be increased by 100 mg /hour every 30 minutes. All receive standard anti-hystamine and paracetamol pre-medication. At every subsequent rituximab administration the initial speed is increased by 100 mg/h (intra-patient speed-escalation). If a pt experiences serious adverse events (SAE), then 6 pts are treated in the same cohort, in case of SAE in 2 of them the trial is discontinued. In each new cohort the initial speed is 100 mg/hr higher than in the previous cohort. Pts are monitored every 15 minutes for symptoms, blood pressure and hearth rate, hourly for temperature and an ECG is performed after treatment. For patients receiving chemo-immunotherapy, rituximab is given first and chemotherapy only later on the same day. Fifteen pts have so far been included (14 evaluable), with the first 4 cohorts complete. Median age was 60 (range 41–76), lymphoma type was diffuse large cell (8 pts), follicular (4 pts) and other indolent (3 pts). Two patients were treated with single agent rituximab and 12 in combination with chemotherapy. The median time from the last rituximab to inclusion in the study was 3 weeks (range 1–11). Overall, 3 cycles were given at a starting infusion speed of 200 mg/hr, 7 cycles at 300 mg/hr, 11 cycles at 400 mg/hr, 11 cycles at 500 mg/hr, 8 cycles at 600 mg/hr and 7 cycles at 700 mg/hr. The latter schedule allowed the administration of the whole prescribed drug in one hour. All pts tolerated the increased-speed infusion without major side effects. The blood pressure dropped by a median 10–15% of baseline, without symptoms and without significant differences between cohorts. The highest blood pressure drops were of respectively 25% and 29% without symptoms and spontaneously resolving within 15 minutes. There was no variation in the hearth frequency and no elevation of body temperature above 37°C. No relevant ECG changes were seen. We conclude that rituximab can be given in one hour without steroids pre-medication in pts who have already received at least two previous rituximab doses. The study is ongoing to evaluate the maximum infusion speed and will further explore if the latter is applicable from the second infusion on.

Tolerability and safety of rituximab (MabThera ®)

Rituximab, a human/mouse chimeric anti-CD20 antibody, has become part of standard therapy for patients with CD20-expressing B-cell lymphoma, and is currently under investigation for other indications including autoimmune diseases, in particular rheumatoid arthritis (RA). Its characteristic tolerability profile was established soon after clinical testing began and compares favourably with chemotherapy. The majority of patients experience mild to moderate infusion-related reactions (IRRs) during the first administration of rituximab, but the incidence decreases markedly with subsequent infusions. Current data suggest that the type of adverse events in patients with RA are similar to those in lymphoma, but that adverse events related to the rituximab infusions are less severe and less frequent. Rituximab induces a rapid depletion of normal CD20-expressing B-cells in the peripheral blood, and levels remain low or undetectable for 2-6 months before returning to pretreatment levels, generally within 12 months. Serum immunoglobulin levels remain largely stable, although a reduction in IgM has been described. T-cells are unaffected by rituximab and consequently opportunistic infections rarely occur in association with rituximab therapy. When used in combination with a variety of chemotherapeutic regimens, rituximab does not add to the toxicity of chemotherapy, with the exception of a higher rate of neutropenia. However, this does not translate into a higher infection rate. Over 540,000 patients worldwide have now received rituximab and serious adverse reactions have occurred in a small minority of patients, but for the great majority of patients, rituximab is safe and well tolerated.

Long-term complete remission of severe pemphigus vulgaris with monoclonal anti-CD20 antibody therapy and immunophenotype correlations

Long-term complete remission of severe pemphigus vulgaris with monoclonal anti-CD20 antibody therapy and immunophenotype correlations

Complement activation plays a key role in the side-effects of rituximab treatment.

Treatment with rituximab, a chimaeric anti-CD20 monoclonal antibody, can be associated with moderate to severe first-dose side-effects, notably in patients with high numbers of circulating tumour cells. The aim of this study was to elucidate the mechanism of these side-effects. At multiple early time points during the first infusion of rituximab, complement activation products (C3b/c and C4b/c) and cytokines [tumour necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6) and IL-8] were measured in five relapsed low-grade non-Hodgkin's lymphoma (NHL) patients. Infusion of rituximab induced rapid complement activation, preceding the release of TNF-alpha, IL-6 and IL-8. Although the study group was small, the level of complement activation appeared to be correlated both with the number of circulating B cells prior to the infusion (r = 0.85; P = 0.07) and with the severity of the side-effects. We conclude that complement plays a pivotal role in the pathogenesis of side-effects of rituximab treatment. As complement activation can not be prevented by corticosteroids, it might be relevant to study the possible role of complement inhibitors during the first administration of rituximab.