Dataset Information

Pharmacodynamics of rituximab on B lymphocytes in paediatric patients with autoimmune diseases.

ABSTRACT:

Aims

Rituximab is a chimeric IgG-1 monoclonal antibody that depletes B cells, aiding in the treatment of several conditions including autoimmune diseases. It is not licensed for use in children. This study aimed to quantify the B cell-related pharmacodynamics of rituximab in children with autoimmune disease.

Methods

Routine electronic health record data were collected at a large paediatric tertiary hospital in London, UK. Dosing protocols were either 2 × 750 mg/m² intravenous infusions of rituximab on days 1 and 15, or 4 × 375 mg/m² infusions on days 1, 8, 15 and 22. Rituximab pharmacokinetics (PK) were not measured but CD19+ lymphocyte counts were taken before and after rituximab treatment. A dose-response model was constructed describing the life cycle of CD19+ lymphocytes, with rituximab assumed to increase the death rate. Rituximab effect was assumed to decay by first-order kinetics.

Results

In total, 258 measurements of CD19+ lymphocyte counts were collected from 39 children with 8 autoimmune diseases. The elimination rate constant (% relative standard error) of rituximab effect decay was 0.036 (22.7%) days^-1 and CD19+ turnover was 0.02 (41%) days^-1 corresponding to half-lives of 19 and 35 days respectively. Rituximab increased CD19+ death rate 35-fold, with methotrexate and cyclophosphamide associated with further increases. Simulations suggested that a single infusion of 750 mg/m² provides similar 6-month suppression of CD19+ lymphocytes to current dosing.

Conclusions

Rituximab pharmacodynamics (PD) in paediatric autoimmune diseases has been described. Compared with rituximab alone, the additional effect of methotrexate or cyclophosphamide was statistically significant but small.

SUBMITTER: Pan S

PROVIDER: S-EPMC6624401 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Publications

Pharmacodynamics of rituximab on B lymphocytes in paediatric patients with autoimmune diseases.

Pan Shan S Yu Huixin H Surti Ayesha A Cheng Iek I Marks Stephen D SD Brogan Paul A PA Eleftheriou Despina D Standing Joseph F JF

British journal of clinical pharmacology 20190620 8

<h4>Aims</h4>Rituximab is a chimeric IgG-1 monoclonal antibody that depletes B cells, aiding in the treatment of several conditions including autoimmune diseases. It is not licensed for use in children. This study aimed to quantify the B cell-related pharmacodynamics of rituximab in children with autoimmune disease.<h4>Methods</h4>Routine electronic health record data were collected at a large paediatric tertiary hospital in London, UK. Dosing protocols were either 2 × 750 mg/m<sup>2</sup> intra ...[more]

PMID: 31026092

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Project description:INTRODUCTION: Evidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin's lymphoma in a real-life clinical setting. METHODS: Patients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators. RESULTS: A total of 370 patients (299 patient-years) with various autoimmune diseases (23.0% with systemic lupus erythematosus, 15.7% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3% of patients showed no response, 45.1% showed a partial response and 41.6% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physician's visual analogue scale; mean improvement from baseline of 12.1 mm). CONCLUSIONS: Data from this registry indicate that rituximab is a commonly employed, well-tolerated therapy with potential beneficial effects in standard of care-refractory autoimmune diseases, and support the results from other open-label, uncontrolled studies.

Project description:SARS-CoV-2 infection is more severe in patients undergoing rituximab (RTX) treatment. Humoral response to vaccination is severely impaired in patients already treated with RTX, but data on antibody persistence in patients initiating RTX are lacking. We evaluated the impact of RTX initiation on humoral response to SARS-CoV-2 vaccination in previously vaccinated patients with immune-mediated inflammatory diseases. We performed a retrospective, multicenter study evaluating the evolution of anti-spike antibodies and breakthrough infections after initiation of RTX in previously vaccinated patients with protective levels of anti-SARS-CoV-2 antibodies. Threshold for anti-S antibodies positivity and protection were 30 and 264 BAU/mL, respectively. We included 31 previously vaccinated patients initiating RTX (21 female, median age 57 years). At first RTX infusion, 12 (39%) patients had received 2 doses of vaccine, 15 (48%) had received 3 doses, and 4 (13%) had received 4 doses. The most frequent underlying diseases were ANCA-associated vasculitis (29%) and rheumatoid arthritis (23%). Median anti-S antibody titers at RTX initiation, 3 months, and 6 months were 1620 (589-2080), 1055 (467-2080), and 407 (186-659) BAU/mL, respectively. Overall, antibody titers waned by almost two-fold at 3 months and four-fold at 6 months. Median antibody titers were significantly higher in patients who received ≥3 doses compared to those who received only 2 doses. Three patients developed SARS-CoV-2 infection without any severe symptom. Anti-SARS-CoV-2 antibody titers in previously vaccinated patients decline after RTX initiation similarly to general population. Specific monitoring is useful to anticipate prophylactic strategies. Key Points • Anti-SARS-CoV-2 antibody titers in previously vaccinated patients decline after rituximab initiation similarly to the general population. • The number of dose of vaccine before rituximab initiation is associated with higher antibody titers at month 3. • Monitoring antibody levels is mandatory to initiate prophylactic strategies in this population.

Project description:BackgroundRecent studies have reported that similar to other IgG4 autoimmune diseases, such as muscle-specific kinase antibody-associated myasthenia gravis, most anti-neurofascin-155 (anti-NF155) nodopathies respond well to rituximab treatment, regardless of the dosage. However, there are still a few patients for which rituximab is ineffective for unknown reasons. Currently, there are no studies on the mechanism of ineffective treatment with rituximab.MethodsA 33-year-old Chinese man presenting with numbness, tremor, and muscle weakness for 4 years was recruited for this study. Anti-NF155 antibodies were identified by cell-based assay and confirmed by immunofluorescence assay on teased fibers. The anti-NF155 immunoglobulin (IgG) subclasses were also detected by immunofluorescence assay. Anti-rituximab antibodies (ARAs) were quantitatively analyzed using enzyme-linked immunosorbent assay (ELISA), and peripheral B cell counts were determined by flow cytometry.ResultsThe patient exhibited anti-NF155 IgG4-antibody positivity. After the first round of rituximab infusion, the patient showed stratified outcomes with improvements in numbness, muscle weakness and ambulation. However, after three rounds of rituximab infusion, the patient's symptoms deteriorated, and the numbness, tremor and muscle weakness returned. No obvious improvement was found after plasma exchange and another round of rituximab treatment. 14 days after the last treatment with rituximab, ARAs were detected. And the titers gradually decreased on day 28 and 60 but remained higher than normal. Peripheral CD19+ B cell counts were less than 1% within the 2-month period following the final rituximab administration.ConclusionsIn this study, ARAs presented in a patient with anti-NF155 nodopathy undergoing rituximab treatment and showed an unfavorable impact on rituximab efficacy. This is the first case to report the occurrence of ARAs in patients with anti-NF155 antibodies. We suggest that ARAs should be tested early during the initial intervention, especially in patients who respond poorly to rituximab treatment. In addition, we believe it is necessary to investigate the association between ARAs and B cell counts, their effect on clinical efficacy, and their potential adverse reactions in a larger cohort of patients with anti-NF155 nodopathy.

Dataset Information

Pharmacodynamics of rituximab on B lymphocytes in paediatric patients with autoimmune diseases.

Aims

Methods

Results

Conclusions

Publications

Pharmacodynamics of rituximab on B lymphocytes in paediatric patients with autoimmune diseases.

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