Repeated low-dose rituximab treatment based on the assessment of circulating B cells in patients with refractory myasthenia gravis

Background: The objective of this study was to evaluate the efficacy and safety of repeated low-dose rituximab treatment guided by monitoring circulating CD19+ B cells in patients with refractory myasthenia gravis (MG). Methods: Patients with refractory MG who had received rituximab treatment at two teaching hospitals between September 2013 and January 2017 were reviewed retrospectively. The treatment protocol consisted of an induction treatment with low-dose rituximab (375 mg/m2 twice with a 2-week interval), followed by retreatment (375 mg/m2 once). Retreatment was based on either circulating CD19+ B-cell repopulation or clinical relapse. Outcome measures included the MG Foundation of America (MGFA) clinical classification and postintervention status, prednisolone dose, CD19+ B-cell counts, clinical relapse, and adverse effects. Results: Of 17 patients, 11 (65%) achieved the primary endpoint, defined as the minimal manifestation or better status with prednisolone ⩽5 mg/day, after median 7.6 months (range, 2–17 months) following rituximab treatment. Over a median follow up of 24 months (range, 7–49 months), a total of 30 retreatments were undertaken due to clinical relapse without B-cell repopulation ( n = 6), on the basis of B-cell repopulation alone ( n = 16) and both ( n = 8). B-cell recovery appeared to be in parallel with clinical relapse on the group level, although the individual-level association appeared to be modest, with B-cell repopulation observed only at 57% (8/14) of clinical relapses. Conclusions: The repeated low-dose rituximab treatment based on the assessment of circulating B-cell depletion could be a cost-effective therapeutic option for refractory MG. Further studies are needed to verify the potentially better cost-effectiveness of low-dose rituximab, and to identify biomarkers that help optimize treatment in MG patients.

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Monitoring B-cell repopulation after depletion therapy in neurologic patients

Neurology Neuroimmunology & Neuroinflammation ◽

10.1212/nxi.0000000000000463 ◽

2018 ◽

Vol 5 (4) ◽

pp. e463 ◽

Cited By ~ 27

Author(s):

Erik Ellwardt ◽

Lea Ellwardt ◽

Stefan Bittner ◽

Frauke Zipp

Keyword(s):

B Cells ◽

B Cell ◽

Cell Depletion ◽

Close Monitoring ◽

B Cell Depletion ◽

Cell Recovery ◽

Cell Counts ◽

White Blood Cell Counts ◽

Anti Cd20 ◽

Cell Repopulation

ObjectiveTo determine the factors that influence B-cell repopulation after B-cell depletion therapy in neurologic patients and derive recommendations for monitoring and dosing of patients.MethodsIn this study, we determined the association of body surface area (BSA; calculated by body weight and height with the Dubois formula), sex, pretreatment therapy, age, CSF data, and white blood cell counts with the risk and timing of B-cell repopulation, defined as 1% CD19+ cells (of total lymphocytes), following 87 B cell–depleting anti-CD20 treatment cycles of 45 neurologic patients (28 women; mean age ± SD, 44.5 ± 15.0 years).ResultsPatients with a larger BSA had a higher probability to reach 1% CD19+ cells than those with a smaller BSA (p < 0.05) following B-cell depletion therapy, although those patients had received BSA-adapted doses of rituximab (375 mg/m2). Sex, pretreatment, age, CSF data, or absolute lymphocyte and leukocyte counts during treatment did not significantly influence CD19+ B-cell recovery in the fully adjusted models. Intraindividual B-cell recovery in patients with several treatment cycles did not consistently change over time.ConclusionsB-cell repopulation after depletion therapy displays both high inter- and intra-individual variance. Our data indicate that a larger BSA is associated with faster repopulation of B cells, even when treatment is adapted to the BSA. A reason is the routinely used Dubois formula, underestimating a large BSA. In these patients, there is a need for a higher therapy dose. Because B-cell count–dependent therapy regimes are considered to reduce adverse events, B-cell monitoring will stay highly relevant. Patients' BSA should thus be determined using the Mosteller formula, and close monitoring should be done to avoid resurgent B cells and disease activity.

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Thymoma complicated with myasthenia gravis and Good syndrome – a therapeutic conundrum: a case report

Journal of Medical Case Reports ◽

10.1186/s13256-019-2289-z ◽

2019 ◽

Vol 13 (1) ◽

Author(s):

Shiran Paranavitane ◽

Sumana Handagala ◽

Rajiva De Silva ◽

Thashi Chang

Keyword(s):

Myasthenia Gravis ◽

B Cell ◽

Low Dose ◽

Acetylcholinesterase Inhibitors ◽

Intravenous Immunoglobulins ◽

Myasthenic Crisis ◽

Left Hemithorax ◽

Case Presentation ◽

Cell Counts ◽

Good Syndrome

Abstract Background Thymomas are known to be associated with myasthenia gravis and Good syndrome. Good syndrome is the association of thymoma with combined B cell and T cell immunodeficiency. The combination of all three diseases has not been reported. We discuss the therapeutic dilemma of immunosuppression in such a case. Case presentation A 27-year-old Sinhalese man was evaluated for persistent cough which was associated with pleuritic chest pain and was found to have pleural-based lesions in his left hemithorax. Further evaluation confirmed these lesions to be implants from a thymoma. He subsequently developed myasthenia gravis and impending myasthenic crisis precipitated by pneumonia. He was found to have hypogammaglobulinemia with low B cell counts, confirming a diagnosis of Good syndrome. Treatment with intravenously administered broad-spectrum antibiotics, acetylcholinesterase inhibitors, orally administered glucocorticoids, plasma exchange, and intravenous immunoglobulin led to clinical improvement. He subsequently underwent thymectomy and debulking of the tumor and was maintained on regular intravenous immunoglobulins combined with low-dose prednisolone. Conclusions Regular intravenous immunoglobulins combined with low-dose immunosuppression in addition to thymectomy appear to be safe when myasthenia gravis occurs in association with Good syndrome.

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OP0057 A PERSONALISED RITUXIMAB RETREATMENT APPROACH BASED ON CLINICAL AND B-CELL BIOMARKERS IN ANCA-ASSOCIATED VASCULITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.2193 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 30.1-30

Author(s):

J. Arnold ◽

E. Vital ◽

S. Dass ◽

A. Aslam ◽

A. Rawstron ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Cox Regression ◽

Multivariable Analysis ◽

Complete Response ◽

Clinical Relapse ◽

Research Support ◽

Anca Associated Vasculitis ◽

Time To Relapse ◽

Cell Repopulation

Background:Time-to-relapse after rituximab for ANCA-associated vasculitis (AAV) is variable and optimal retreatment strategy has been unclear. We previously showed that repopulation of naïve B-cells at 6 months predicts sustained response [1].Objectives:In AAV following rituximab induction, to evaluate clinical and B-cell predictors of relapse in order to develop a retreatment algorithm.Methods:An observational study was conducted in 60 rituximab-treated AAV patients followed for over 10 years. Complete response (CR) was defined as Birmingham Vasculitis Activity Score v3.0 = 0. Retreatment was given on clinical relapse, defined as new features or worsening of persistent disease (not by biomarker status). Peripheral B-cell subsets were measured using highly sensitive flow cytometry. Predictors were tested using multivariable Cox-Regression.Results:Median times-to-retreatment for rituximab cycles 1-5 were 87, 71, 65, 59 and 86 weeks. Over 417 patient-years follow-up, 137 relapses occurred in 50 patients; 16 (in 14 patients) were major (renal=7, neurological=4, ENT=3 and respiratory=2). The major-relapse rate was 3.8/100 patient-years. In multivariable analysis, concomitant immunosuppressant [HR 0.48 (95% CI 0.24–0.94)], achieving CR [0.24 (0.12–0.50)] and naïve B-cell repopulation at 6 months [0.43 (0.22–0.84)] were associated with longer time-to-relapse. Higher baseline memory B-cells [1.01 (1.00–1.02)] were associated with a shorter time-to-relapse. AUROC for prediction of time-to-relapse was greater if guided by naïve B-cell repopulation than if ANCA and/or CD19+ return at 6 months had been used, 0.82 and 0.52 respectively.Conclusion:These data suggest that all patients should receive concomitant oral immunosuppressant. Those with incomplete response or with absent naïve B-cells should be retreated at 6 months. Patients with complete response and naïve repopulation at 6 months should not receive fixed retreatment. This algorithm could reduce hypogammaglobulinaemia due to unnecessary retreatment.Figure 1.A personalised retreatment algorithm for rituximab in ANCA-associated vasculitisReferences:[1]Md Yusof et al. Annals of rheumatic diseases (2015) PMID: 25854586.Disclosure of Interests:Jack Arnold: None declared, Edward Vital Speakers bureau: Roche, GSK and AstraZeneca, Consultant of: Roche, GSK and AstraZeneca, Grant/research support from: Roche, GSK and AstraZeneca, Shouvik Dass Speakers bureau: Roche and GSK, Aamir Aslam: None declared, Andrew Rawstron: None declared, Sinisa Savic: None declared, Paul Emery Speakers bureau: BMS, Abbott, Pfizer, MSD, Novartis, Roche and UCB, Consultant of: BMS, Abbott, Pfizer, MSD, Novartis, Roche and UCB, Grant/research support from: Abbott, BMS, Pfizer, MSD and Roche., Md Yuzaiful Md Yusof: None declared

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Determining the best window for BNT162b2 mRNA vaccination for SARS-CoV-2 in patients with multiple sclerosis receiving anti-CD20 therapy

Multiple Sclerosis Journal - Experimental Translational and Clinical ◽

10.1177/20552173211062142 ◽

2021 ◽

Vol 7 (4) ◽

pp. 205521732110621

Author(s):

Audrey Rico ◽

Laetitia Ninove ◽

Adil Maarouf ◽

Clémence Boutiere ◽

Pierre Durozard ◽

...

Keyword(s):

Multiple Sclerosis ◽

B Cells ◽

B Cell ◽

Serologic Response ◽

Cell Counts ◽

Anti Cd20 ◽

Cell Proportion ◽

Cell Repopulation

We studied the serologic response to the BNT162b2 mRNA vaccine at four weeks after the second dose in patients with RRMS treated with rituximab with extended-interval dosing ( n = 26). At four weeks, 73% of patients were seropositive. No patient without B cells at the first dose ( n = 4) was seropositive. Four of seven (57%) patients with B-cell proportion >0% and ≤5% were seropositive. All patients with B-cell proportion >5% ( n = 15) were seropositive. In all patients, quantitative ELISA measures after vaccination were correlated with B-cell counts measured before vaccination. In patients receiving rituximab, seropositivity after BNT162b2 mRNA vaccination emerged only after B-cell repopulation.

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CD19 Cell Count at Baseline Predicts B Cell Repopulation at 6 and 12 Months in Multiple Sclerosis Patients Treated with Ocrelizumab

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18158163 ◽

2021 ◽

Vol 18 (15) ◽

pp. 8163

Author(s):

Gianmarco Abbadessa ◽

Giuseppina Miele ◽

Paola Cavalla ◽

Paola Valentino ◽

Girolama Alessandra Marfia ◽

...

Keyword(s):

B Cell ◽

Cell Count ◽

Considerable Proportion ◽

Cell Counts ◽

Time Scheduling ◽

Magnetic Resonance Imaging Mri ◽

Multiple Sclerosis Patients ◽

Kinetics Of ◽

Cell Repopulation

Background: The kinetics of B cell repopulation in MS patients treated with Ocrelizumab is highly variable, suggesting that a fixed dosage and time scheduling might be not optimal. We aimed to investigate whether B cell repopulation kinetics influences clinical and radiological outcomes and whether circulating immune asset at baseline affects B cell repopulation kinetics. Methods: 218 MS patients treated with Ocrelizumab were included. Every six months we collected data on clinical and magnetic resonance imaging (MRI) activity and lymphocyte subsets at baseline. According to B cell counts at six and twelve months, we identified two groups of patients, those with fast repopulation rate (FR) and those with slow repopulation rate (SR). Results: A significant reduction in clinical and radiological activity was found. One hundred fifty-five patients had complete data and received at least three treatment cycles (twelve-month follow-up). After six months, the FR patients were 41/155 (26.45%) and 10/41 (29.27%) remained non-depleted after twelve months. FR patients showed a significantly higher percentage of active MRI scan at twelve months (17.39% vs. 2.53%; p = 0,008). Furthermore, FR patients had a higher baseline B cell count compared to patients with an SR (p = 0.02 and p = 0.002, at the six- and twelve-month follow-ups, respectively). Conclusion: A considerable proportion of MS patients did not achieve a complete CD19 cell depletion and these patients had a higher baseline CD19 cell count. These findings, together with the higher MRI activity found in FR patients, suggest that the Ocrelizumab dosage could be tailored depending on CD19 cell counts at baseline in order to achieve complete disease control in all patients.

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Dose-dependent Pharmacological Response to Rituximab in the Treatment of Antineutrophil Cytoplasmic Antibody-Associated Vasculiti

The Journal of Rheumatology ◽

10.3899/jrheum.210361 ◽

2021 ◽

pp. jrheum.210361

Author(s):

Jason M. Springer ◽

Ryan S. Funk

Keyword(s):

B Cell ◽

Antineutrophil Cytoplasmic Antibody ◽

High Dose ◽

Dosing Regimen ◽

Dosing Interval ◽

Cell Counts ◽

Pharmacological Response ◽

Trough Concentrations ◽

Cell Repopulation ◽

Trough Plasma

Objective Rituximab (RTX) is effective in induction and maintenance of remission in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). However, uncertainty remains regarding the optimal maintenance dosing regimen. This work evaluates the relationship between variability in RTX dosing and pharmacological response in AAV. Methods A prospective cohort of AAV patients (n=28) with either GPA (n=23) or MPA (n=5) receiving maintenance RTX therapy were followed in a single tertiary care academic medical center over a 2-year period. Patient demographics, RTX dosing information, and trough plasma RTX levels were collected along with laboratory measures of pharmacologic response, including B-cell counts and ANCA titers. Results RTX dosing information from 94 infusions with 59 trough samples were collected with a mean±SD dose of 640±221 mg, dosing interval of 210±88 days, and trough plasma RTX concentration of 622±548 ng/mL. RTX trough concentrations were associated with RTX dose (ρ=0.60, p<0.0001) and dosing interval (ρ=-0.55, p<0.0001). RTX dosing intensity (mg/d) was associated with RTX trough concentrations (ρ=0.57, p<0.0001). Higher dosing intensities were associated with undetectable B-cell repopulation (p<0.0001), but not negative ANCA titers (p=0.6). Stratification of dosing intensities based on the standard dosing regimen of 500 mg every six months (2.4 to 3.3 mg/d) demonstrated that this regimen was associated with B-cell repopulation in 8 of 17 doses (47%) compared to 0 of 23 doses (0%) with the high-dose regimen (>3.3 mg/d) (p<0.0001). Conclusion RTX maintenance dosing of 500 mg every six months may be inadequate to maintain B-cell depletion in the treatment of AAV.

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Bone Marrow Lymphoid Niche Adaptation to Mature B Cell Neoplasms

Frontiers in Immunology ◽

10.3389/fimmu.2021.784691 ◽

2021 ◽

Vol 12 ◽

Author(s):

Erwan Dumontet ◽

Stéphane J. C. Mancini ◽

Karin Tarte

Keyword(s):

Bone Marrow ◽

B Cells ◽

B Cell ◽

Tumor Cells ◽

Stromal Cells ◽

Therapeutic Option ◽

B Cell Lymphoma ◽

Lymphocytic Leukemia ◽

Niche Adaptation ◽

Functional Features

B-cell non-Hodgkin lymphoma (B-NHL) evolution and treatment are complicated by a high prevalence of relapses primarily due to the ability of malignant B cells to interact with tumor-supportive lymph node (LN) and bone marrow (BM) microenvironments. In particular, progressive alterations of BM stromal cells sustain the survival, proliferation, and drug resistance of tumor B cells during diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia (CLL). The current review describes how the crosstalk between BM stromal cells and lymphoma tumor cells triggers the establishment of the tumor supportive niche. DLBCL, FL, and CLL display distinct patterns of BM involvement, but in each case tumor-infiltrating stromal cells, corresponding to cancer-associated fibroblasts, exhibit specific phenotypic and functional features promoting the recruitment, adhesion, and survival of tumor cells. Tumor cell-derived extracellular vesicles have been recently proposed as playing a central role in triggering initial induction of tumor-supportive niches, notably within the BM. Finally, the disruption of the BM stroma reprogramming emerges as a promising therapeutic option in B-cell lymphomas. Targeting the crosstalk between BM stromal cells and malignant B cells, either through the inhibition of stroma-derived B-cell growth factors or through the mobilization of clonal B cells outside their supportive BM niche, should in particular be further evaluated as a way to avoid relapses by abrogating resistance niches.

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SO056THE CLINICAL AND IMMUNOLOGICAL IMPACT OF LOW DOSE RITUXIMAB IN CLINICAL NEPHROLOGY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa139.so056 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Sunu Alex

Keyword(s):

B Cells ◽

B Cell ◽

Low Dose ◽

Cost Effective ◽

Transplant Recipients ◽

Kidney Transplant Recipients ◽

Cell Percentage ◽

Steroid Dependent ◽

One Year

Abstract Background and Aims Currently, the dose of rituximab used in nephrology practice is mostly extrapolated from the dose used in lymphoproliferative disorders. It is possible that a lesser dose may suffice when treating a non-neoplastic disorder. We conducted this study to study the clinical response and CD19 B cell suppression with a single dose of 100mg rituximab in nephrology practice Method This was a single center prospective study of role of 100mg rituximab as initial dose in steroid dependent (SDNS), frequently relapsing nephrotic syndrome (FRNS), idiopathic membranous nephropathy (MN) and high immunologic risk kidney transplantation with subsequent doses based on CD19 B cell reconstitution. Results Following 100mg rituximab in 42 patients, CD19 B cell percentage decreased from 16.3+7.6 to 0.3±0.3, 1.9±1.7 and 4.0±4.5 by 30, 90 and 180 days respectively. At 30th day, 40(95.2%) had CD19 B cell count <1%. Of the 30 patients with SDNS and FRNS followed up for one year, 29(96.7%) went into remission at day 30. Remission was sustained in 23(76.6%) at day 180 and 21(70%) at 1 year. There was significant decrease [P <0.001] in the dose of steroids needed to maintain remission at 180 days following rituximab (0.27±0.02mg/Kg to 0.02±0.00mg/Kg). Of the five patients with MN, four patients achieved remission by 6 months. Remission was sustained in three patients by 1 year. Of the 7 kidney transplant recipients, 2 had antibody mediated rejections though CD19 B cells were suppressed even at one year. Conclusion Low dose of 100 mg rituximab is sufficient to deplete CD19 B cells for up to 90days and is effective in inducing remission in SDNS and FRNS and MN. Targeting subsequent doses depending on CD19 B cell reconstitution may prevent relapses, limit toxicity and be cost effective.

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Clinical Response and Pattern of B cell Suppression with Single Low Dose Rituximab in Nephrology

Kidney360 ◽

10.34067/kid.0000072020 ◽

2020 ◽

Vol 1 (5) ◽

pp. 359-367

Author(s):

Jacob George ◽

Sunu Alex ◽

E.T. Arun Thomas ◽

Noble Gracious ◽

Nalanda S. Vineetha ◽

...

Keyword(s):

Nephrotic Syndrome ◽

B Cells ◽

B Cell ◽

Clinical Response ◽

Low Dose ◽

Clinical Status ◽

Transplant Recipients ◽

Kidney Transplant Recipients ◽

Cell Percentage ◽

Steroid Dependent

BackgroundThere is no consensus regarding dose and frequency of rituximab in nephrology with extrapolation of doses used in treating lymphoproliferative disorders. There are no guidelines on targeting initial and subsequent doses on the basis of CD19+ B cells.MethodsInitially, 100 mg rituximab was given to 42 adults with steroid-dependent nephrotic syndrome (SDNS) and frequently relapsing nephrotic syndrome (FRNS), idiopathic membranous nephropathy (MN), and high-immunologic-risk kidney transplantation. Absolute and percentage levels of CD19 B cells and clinical status were assessed at baseline, days 30, 90, and 180, and at 1 year. Subsequent doses of rituximab were on the basis of CD19 B cell reconstitution and clinical response.ResultsCD19 B cell percentage decreased from 16.3 ± 7.6 to 0.3 ± 0.3 (P≤0.001), 1.9 ± 1.7 (P≤0.001), and 4.0 ± 4.5 (P=0.005) by 30, 90, and 180 days, respectively. Suppression of CD19 B cell count below 1% at days 30, 90, and 180 was seen in 40 of 42 (95.2%), 18 of 42 (42.9%), and 7 of 42 (16.7%) patients, respectively. Of 30 with SDNS and FRNS followed up for 1 year, 29 (96.7%) went into remission at day 30. Remission was sustained in 23 (76.6%) at day 180 and 21 (70%) at 1 year. There was a significant decrease (P<0.001) in the dose of steroids needed to maintain remission at 180 days after rituximab (0.27 ± 0.02 mg/kg to 0.02 ± 0.00 mg/kg). CD19 B cell percentage at 90 days correlated with relapse (P=0.001; odds ratio 1.42; 95% confidence interval, 1.25 to 2.57). Eighteen (60%) required an additional dose. Of five with MN, four achieved remission by 6 months, which was sustained in three by 1 year. Of the seven kidney transplant recipients, two had antibody-mediated rejections, although CD19 B cells were suppressed even at 1 year.ConclusionsLow-dose rituximab induces sustained depletion of CD19 B cells for up to 90 days. Its role in preventing relapses in SDNS, FRNS, MN, and rejection needs further study.

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Investigating the importance of B cells and antibodies during Trichuris muris infection using the IgMi mouse

Journal of Molecular Medicine ◽

10.1007/s00109-020-01954-3 ◽

2020 ◽

Vol 98 (9) ◽

pp. 1301-1317

Author(s):

Rinal Sahputra ◽

Emma A Murphy ◽

Ruth Forman ◽

Iris Mair ◽

Muhammad Z. H. Fadlullah ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Post Infection ◽

Cell Biology ◽

Low Dose ◽

Cell Function ◽

Intestinal Inflammation ◽

High Dose ◽

List Type ◽

Trichuris Muris

Abstract The IgMi mouse has normal B cell development; its B cells express an IgM B cell receptor but cannot class switch or secrete antibody. Thus, the IgMi mouse offers a model system by which to dissect out antibody-dependent and antibody-independent B cell function. Here, we provide the first detailed characterisation of the IgMi mouse post-Trichuris muris (T. muris) infection, describing expulsion phenotype, cytokine production, gut pathology and changes in T regulatory cells, T follicular helper cells and germinal centre B cells, in addition to RNA sequencing (RNA seq) analyses of wild-type littermates (WT) and mutant B cells prior to and post infection. IgMi mice were susceptible to a high-dose infection, with reduced Th2 cytokines and elevated B cell-derived IL-10 in mesenteric lymph nodes (MLN) compared to controls. A low-dose infection regime revealed IgMi mice to have significantly more apoptotic cells in the gut compared to WT mice, but no change in intestinal inflammation. IL-10 levels were again elevated. Collectively, this study showcases the potential of the IgMi mouse as a tool for understanding B cell biology and suggests that the B cell plays both antibody-dependent and antibody-independent roles post high- and low-dose T. muris infection. Key messages During a high-dose T. muris infection, B cells are important in maintaining the Th1/Th2 balance in the MLN through an antibody-independent mechanism. High levels of IL-10 in the MLN early post-infection, and the presence of IL-10-producing B cells, correlates with susceptibility to T. muris infection. B cells maintain gut homeostasis during chronic T. muris infection via an antibody-dependent mechanism.

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