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

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

scholarly journals P207 A proposal for individually tailored rituximab treatment based on clinical and B-cell biomarkers for remission maintenance in ANCA associated vasculitis

Rheumatology ◽  
2021 ◽  
Vol 60 (Supplement_1) ◽  
Author(s):  
Jack E Arnold ◽  
Edward M J Vital ◽  
Shouvik Dass ◽  
Aamir Aslam ◽  
Andy C Rawstron ◽  
...  
Keyword(s):  
B Cells ◽  
Complete Remission ◽  
B Cell ◽  
Multivariable Analysis ◽  
Research Support ◽  
P Values ◽  
Final Model ◽  
Time To Relapse ◽  
Cell Repopulation ◽  
Relapse Rates

Abstract Background/Aims  Time-to-relapse after rituximab for ANCA vasculitis is variable and optimal retreatment strategy is unclear. We previously showed that repopulation of naïve B-cells at 6 months predicts sustained response. Our objective was to evaluate clinical and B-cell predictors for relapse in multivariable analysis to develop a retreatment algorithm. Methods  An observational study was conducted in 60 rituximab-treated AAV patients over 10-years. Complete response was defined as a Birmingham Vasculitis Activity Score (BVAS) v3.0=0. Repeat rituximab cycles were given on clinical relapse. Naïve, memory B-cells and plasmablasts were measured using highly sensitive flow cytometry. Clinical and B cell predictors were analysed in multivariable analysis (MVA) to develop a retreatment algorithm. Results  Patients were: 33/60 (55%) male, mean(SD) age 51(19), 39/60 (65%) received concomitant immunosuppressants and 54/60 (90%) had prior therapy with cyclophosphamide. Median times to retreatment for 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 lungs=2). The major-relapse rate was 3.8/100 patient-years. Results of MVA are shown in the table. With naïve B-cell repopulation at 6 months, relapse rates at 12 and 18 months were 5% and 16%, versus 45% and 59% without naïve repopulation (p < 0.001). Relapse rates at 18 and 24 months were 17% and 54% with naïve repopulation at 12 months versus and 29% and 71% without (p = 0.045). AUROC for time-to-relapse was greater if retreatment was guided by naïve B-cell repopulation than if ANCA and/or CD19+ return was used at 6 months, 0.82 and 0.52 respectively. Conclusion  These results suggest the following: (i) all patients should receive an oral immunosuppressant; (ii) patients with incomplete remission should be retreated at 6 months; (iii) patients with complete remission but absent naïve B cells at 6 months should be retreated at 6 months; (iv) patients with complete remission and naïve B-cell return may not be appropriate for fixed retreatment. For this last group monitoring of clinical symptoms and B-cells may be effective and future work will address this further. This algorithm could avoid hypogammaglobulinaemia due to unnecessary retreatment. P207 Table 1:Factors associated with time-to-relapse to first cycle rituximabRisk FactorsUnivariable analysisHR (95% CI); p-values(with multiple imputation)Multivariable analysis (MVA)HR (95% CI); p-values(with multiple imputation)Age, per 10 years (BL)1.01 (0.86 – 1.17); p = 0.954Not included in MVAFemale (BL)1.15 (0.65 – 2.02); p = 0.629Not included in MVADisease duration, years (BL)1.06 (0.98 – 1.15); p = 0.160Included in MVA but removed from final model as p < 0.20Concomitant immunosuppressant (BL)0.69 (0.39 – 1.22); p = 0.2050.48 (0.24 – 0.94); p = 0.034Positive ANCA immunofluorescence (BL)0.89 (0.46 – 1.71); p = 0.725Not included in MVAPositive anti-PR3/anti-MPO (BL)0.57 (0.31 – 1.06); p = 0.077Included in MVA but removed from final model as p < 0.20CRP, mg/L (BL)1.00 (0.99 – 1.01); p = 0.456Not included in MVABVAS 3.0 per point score (BL)0.99 (0.94 – 1.05); p = 0.763Included in MVA but removed from final model as p < 0.20VDI per point score (BL)1.14 (0.87 – 1.50); p = 0.353Not included in MVANaïve B-cells, x 10 9/L* (BL)1.00 (1.00 – 1.01); p = 0.797Not included in MVAMemory B-cells, x 10 9/L* (BL)1.01 (1.00 – 1.02); p = 0.0401.01 (1.00 – 1.02); p = 0.045Plasmablasts, x 10 9/L* (BL)1.04 (0.94 – 1.16); p = 0.459Not included in MVAComplete depletion at 6 Weeks post-RTX0.90 (0.50 – 1.61); p = 0.721Not included in MVAComplete Response (26Wk)0.34 (0.19 – 0.61); p < 0.0010.24 (0.12 – 0.50); p < 0.001Positive ANCA immunofluorescence (26Wk)0.99 (0.56 – 1.75); p = 0.962Not included in MVAPositive anti-PR3/anti-MPO (26Wk)0.79 (0.44 – 1.42); p = 0.426Not included in MVACRP, mg/L (26Wk)0.99 (0.97 – 1.02); p = 0.618Not included in MVANaïve B-cell repopulation (26Wk)0.38 (0.19 – 0.76); p = 0.0060.43 (0.22 – 0.84); p = 0.013Memory B-cell repopulation (26Wk)0.45 (0.20 – 0.99); p = 0.046Included in MVA but removed from final model as p < 0.20Plasmablast cell repopulation (26Wk)1.14 (0.61 – 2.13); p = 0.675Not included in MVABL = baseline, 26Wk = 26 weeks. Disclosure  J.E. Arnold: None. E.M.J. Vital: Honoraria; Roche, GSK, AstraZeneca. S. Dass: Honoraria; Roche, GSK. A. Aslam: None. A.C. Rawstron: None. S. Savic: Honoraria; Novartis, Swedish Orphan Biovitrum, Sire. Grants/research support; Novartis, Swedish Orphan Biovitrum, Octapharma, CSL Behring. P. Emery: Consultancies; BMS, Abbott, Pfizer, MSD, Novartis, Roche, UCB. Grants/research support; Abbott, BMS, Pfizer, MSD, Roche. M. Md Yusof: None.

scholarly journals THU0040 PROTEINASE 3-REACTIVE B CELL RECONSTITUTION AFTER TREATMENT WITH RITUXIMAB FOR ANCA-ASSOCIATED VASCULITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 233.1-233
Author(s):  
A. Berti ◽  
S. Hillion ◽  
A. Hummel ◽  
E. Carmona ◽  
T. Peikert ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
B Cells ◽  
B Cell ◽  
Peripheral Blood ◽  
Proteinase 3 ◽  
Research Support ◽  
Color Flow ◽  
Anca Associated Vasculitis ◽  
Cell Repopulation

Background:Proteinase 3 (PR3)-reactive B cells are present in PR3-ANCA-associated vasculitis (AAV) at levels higher than healthy controls.Objectives:To evaluate the dynamics of the PR3-reactive B cell repopulation in patients with PR3-AAV after treatment with rituximab, and to analyze possible associations between these immunological changes and long-lasting remissions.Methods:We analyzed all available frozen peripheral blood mononuclear cells (n=148) from 23 randomly-selected PR3-AAV patients who participated in the RAVE trial and achieved complete remission (BVAS=0, prednisone=0) after treatment with rituximab.We measured PR3-reactive B cells and the relative subsets by a multi-color flow cytometry panel including CD19, IgD, CD27, CD38, CD24, and a biotinylated PR3 revealed by fluorescent streptavidin. The clinical data of the trial were correlated with flow-cytometry data.Results:10/23 (43%) patients relapsed during the follow up, 8/10 relapses were severe. At baseline, clinical features, PR3-ANCA levels, % of total PR3-reactive B cells and PR3-reactive B cell subsets were similar between relapsers and non-relapsers. All patients were followed until the end of the trial, for a mean of 44 months (25-75%IQR 31-54), without difference in follow-up time between relapsers and non-relapsers (p=0.98).The majority of patients had B cell repopulation at 12 (range 12-24) months after rituximab. At the time of B cell repopulation, transitional (CD19+CD24+CD38+) and naïve (CD19+CD27+IgD-) B cells were higher compared to baseline, while total plasmablasts (PB) were unchanged, and mature B cells significantly decreased in both relapsers and non relapsers. PR3-reactive B cells reappeared in all the patients, and the % of PR3-reactive of B cells were higher at the B cell repopulation visit compared to baseline (5.82% vs 4.25%, p<0.05), while total B cells were lower (66/μL vs 151/μL, p<0.01), regardless of future relapse.Within PR3-reactive B cells, only the % of PB (CD19+CD27+CD38+PR3+) were higher in relapsers vs. non-relapsers (median [25-75%IQR]; 1.95% [1.315-3.845] vs 0.84% [0.05-1.66], p=0.022) and severe relapsers vs non-severe relapsers (2.165% [1.66-4.315] vs 0.84% [0.1-1.74], p=0.015). Time-to-relapse and time-to severe-relapse were significantly shorter in patients with circulating PR3-PB higher than the median value of the cohort (1.6%) during B cell reconstitution (Figure 1A-B).Conclusion:In PR3-AAV, during B cell reconstitution after rituximab, the total fraction of PR3-B cells increases, due to the expansion of the transitional and naïve B cell compartments. Circulating PR3-PB within PR3-B cells are enriched in the peripheral blood of relapsing and severely relapsing patients compared to non-relapsing patients. Higher levels of PR3-PB after rituximab during B cell reappearance significantly increased the risk of subsequent relapse and severe relapse.References:[1]Cornec D, Berti A, Hummel A, et al. J Autoimmun. 2017Disclosure of Interests:Alvise Berti: None declared, Sophie Hillion: None declared, Amber Hummel: None declared, Eva Carmona: None declared, Tobias Peikert: None declared, Carol Langford: None declared, Peter A. Merkel: None declared, Paul Monach: None declared, Philip Seo: None declared, Robert Spiera Grant/research support from: Roche-Genetech, GSK, Boehringer Ingelheim, Chemocentryx, Corbus, Forbius, Sanofi, Inflarx, Consultant of: Roche-Genetech, GSK, CSL Behring, Sanofi, Janssen, Chemocentryx, Forbius, Mistubishi Tanabe, E. William St. Clair: None declared, Fernando Fervenza: None declared, Kristina Harris: None declared, John H. Stone Grant/research support from: Roche, Consultant of: Roche, Jacques-Olivier Pers: None declared, Ulrich Specks: None declared, Divi Cornec: None declared

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

2019 ◽  
Vol 12 ◽  
pp. 175628641987118 ◽  
Author(s):  
Kyomin Choi ◽  
Yoon-Ho Hong ◽  
So-Hyun Ahn ◽  
Seol-Hee Baek ◽  
Jun-Soon Kim ◽  
...  
Keyword(s):  
B Cells ◽  
Myasthenia Gravis ◽  
B Cell ◽  
Low Dose ◽  
Therapeutic Option ◽  
Treatment Protocol ◽  
Induction Treatment ◽  
Clinical Relapse ◽  
Cell Counts ◽  
Cell Repopulation

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.

scholarly journals Proteinase-3-anti-neutrophil cytoplasmic antibodies (PR3-ANCAs) predict relapses in ANCA–associated vasculitis patients after rituximab

2020 ◽  
Author(s):  
Laura S van Dam ◽  
Ebru Dirikgil ◽  
Edwin W Bredewold ◽  
Argho Ray ◽  
Jaap A Bakker ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Organ Damage ◽  
Cell Depletion ◽  
Remission Induction ◽  
Proteinase 3 ◽  
B Cell Depletion ◽  
Anca Associated Vasculitis ◽  
Therapeutic Decision Making ◽  
Cell Repopulation

Abstract Background The primary challenge of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) patient care is the early detection of relapses to prevent organ damage and increase survival. Potential biomarkers for relapses are ANCA and B cells, but their predictive value is a matter of debate. Therefore this study investigated how ANCA and B-cell status related to relapses in AAV patients treated with rituximab (RTX) as remission induction (RI). Methods This single-centre cohort study identified 110 ANCA-positive AAV patients treated with RTX between 2006 and 2018. Serial ANCA, CD19+ B-cell status and relapses were assessed &gt;2 years. Results Patients (31/110) relapsed within 2 years after RTX RI treatment. Patients who achieved and maintained PR3-ANCA negativity (n = 29) had few relapses (3%), while persistent proteinase 3 (PR3)-ANCA positivity (n = 49) and reappearance of PR3-ANCAs (n = 10) associated significantly with more relapses (37%, P = 0.002 and 50%, P = 0.002). Patients with incomplete B-cell depletion (n = 11) had significantly more relapses (54%) as compared with patients with B-cell depletion [n = 76 (26%), P = 0.02]. Also, patients with repopulation of B cells (n = 58) had significantly more relapses (41%) as compared with patients without B-cell repopulation [n = 27 (15%), P = 0.03]. Overall, the absence of PR3- or myeloperoxidase (MPO)-ANCA positivity was highly predictive for remaining relapse-free. In PR3-ANCA-positive patients, 96% of the relapses occurred with persistent or reappearance of PR3-ANCAs and 81% with B-cell repopulation. In MPO-ANCA-positive patients, all relapses were restricted to patients with persistent MPO-ANCAs and B-cell repopulation. Conclusions Upon RI treatment with RTX in AAV patients, ANCA and B-cell status were predictive of the majority of relapses and specifically their absence strongly predicted a relapse-free status. Therefore the implementation of ANCA and B-cell monitoring could guide therapeutic decision-making to prevent relapses in AAV patients treated with RTX.

AB0144 STRATIFICATION OF PATIENTS WITH PRIMARY SJÖGREN’S SYNDROME BY MEASURING B-CELL HEALTH

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1372-1373
Author(s):  
G. M. Verstappen ◽  
J. C. Tempany ◽  
H. Cheon ◽  
A. Farchione ◽  
S. Downie-Doyle ◽  
...  
Keyword(s):  
Cell Division ◽  
Cell Differentiation ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
B Cell Differentiation ◽  
Research Support ◽  
Differentiation Capacity ◽  
Cell Responses ◽  
Healthy Donors

Background:Primary Sjögren’s syndrome (pSS) is a heterogeneous immune disorder with broad clinical phenotypes that can arise from a large number of genetic, hormonal, and environmental causes. B-cell hyperactivity is considered to be a pathogenic hallmark of pSS. However, whether B-cell hyperactivity in pSS patients is a result of polygenic, B cell-intrinsic factors, extrinsic factors, or both, is unclear. Despite controversies about the efficacy of rituximab, new B-cell targeting therapies are under investigation with promising early results. However, for such therapies to be successful, the etiology of B-cell hyperactivity in pSS needs to be clarified at the individual patient level.Objectives:To measure naïve B-cell function in pSS patients and healthy donors using quantitative immunology.Methods:We have developed standardised, quantitative functional assays of B-cell responses that measure division, death, differentiation and isotype switching, to reveal the innate programming of B cells in response to T-independent and dependent stimuli. This novel pipeline to measure B-cell health was developed to reveal the sum total of polygenic defects and underlying B-cell dysfunction at an individual level. For the current study, 25 pSS patients, fulfilling 2016 ACR-EULAR criteria, and 15 age-and gender-matched healthy donors were recruited. Standardized quantitative assays were used to directly measure B cell division, death and differentiation in response to T cell-independent (anti-Ig + CpG) and T-cell dependent (CD40L + IL-21) stimuli. Naïve B cells (IgD+CD27-) were sorted from peripheral blood mononuclear cells and were labeled with Cell Trace Violet at day 0 to track cell division until day 6. B cell differentiation was measured at day 5.Results:Application of our standardized assays, and accompanying parametric models, allowed us to study B cell-intrinsic defects in pSS patients to a range of stimuli. Strikingly, we demonstrated a hyperresponse of naïve B cells to combined B cell receptor (BCR) and Toll-like receptor (TLR)-9 stimulation in pSS patients. This hyperresponse was revealed by an increased mean division number (MDN) at day 5 in pSS patients compared with healthy donors (p=0.021). A higher MDN in pSS patients was observed at the cohort level and was likely attributed to an increased division burst (division destiny) time. The MDN upon BCR/TLR-9 stimulation correlated with serum IgG levels (rs=0.52; p=0.011). No difference in MDN of naïve B cells after T cell-dependent stimulation was observed between pSS patients and healthy donors. B cell differentiation capacity (e.g., plasmablast formation and isotype switching) after T cell-dependent stimulation was also assessed. At the cohort level, no difference in differentiation capacity between groups was observed, although some pSS patients showed higher plasmablast frequencies than healthy donors.Conclusion:Here, we demonstrate defects in B-cell responses both at the cohort level, as well as individual signatures of defective responses. Personalized profiles of B cell health in pSS patients reveal a group of hyperresponsive patients, specifically to combined BCR/TLR stimulation. These patients may benefit most from B-cell targeted therapies. Future studies will address whether profiles of B cell health might serve additional roles, such as prediction of disease trajectories, and thus accelerate early intervention and access to precision therapies.Disclosure of Interests:Gwenny M. Verstappen: None declared, Jessica Catherine Tempany: None declared, HoChan Cheon: None declared, Anthony Farchione: None declared, Sarah Downie-Doyle: None declared, Maureen Rischmueller Consultant of: Abbvie, Bristol-Meyer-Squibb, Celgene, Glaxo Smith Kline, Hospira, Janssen Cilag, MSD, Novartis, Pfizer, Roche, Sanofi, UCB, Ken R. Duffy: None declared, Frans G.M. Kroese Grant/research support from: Unrestricted grant from Bristol-Myers Squibb, Consultant of: Consultant for Bristol-Myers Squibb, Speakers bureau: Speaker for Bristol-Myers Squibb, Roche and Janssen-Cilag, Hendrika Bootsma Grant/research support from: Unrestricted grants from Bristol-Myers Squibb and Roche, Consultant of: Consultant for Bristol-Myers Squibb, Roche, Novartis, Medimmune, Union Chimique Belge, Speakers bureau: Speaker for Bristol-Myers Squibb and Novartis., Philip D. Hodgkin Grant/research support from: Medimmune, Vanessa L. Bryant Grant/research support from: CSL

A reservoir of rituximab-resistant splenic memory B cells contributes to relapses after B-cell depletion therapy

2019 ◽  
Author(s):  
Etienne Crickx ◽  
Pascal Chappert ◽  
Sandra Weller ◽  
Aurélien Sokal ◽  
Imane Azzaoui ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Plasma Cells ◽  
Complete Response ◽  
Memory B Cells ◽  
Chain Gene ◽  
Gene Repertoire ◽  
Heavy Chain Gene ◽  
Immunoglobulin Heavy Chain Gene ◽  
Pathogenic Antibodies

AbstractImmune thrombocytopenia (ITP) is an autoimmune disease mediated by pathogenic antibodies directed against platelet antigens, including GPIIbIIIa. Taking advantage of spleen samples obtained from ITP patients, we characterized by multiples approaches the onset of disease relapses occurring after an initial complete response to rituximab. Analysis of splenic B cell immunoglobulin heavy chain gene repertoire at bulk level and from single anti-GPIIbIIIa B cells revealed that germinal centers were fueled by B cells originating from the ongoing lymphopoiesis, but also by rituximab-resistant memory B cells, both giving rise to anti-GPIIbIIIa plasma cells. We identified a population of splenic memory B cells that resisted rituximab through acquisition of a unique phenotype and contributed to relapses, providing a new target in B cell mediated autoimmune diseases.

Sarcomatoid urothelial carcinoma (SUC): A single-institution experience of oncologic outcomes and recurrence patterns.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 465-465
Author(s):  
Leonidas Nikolaos Diamantopoulos ◽  
Rishi Robert Sekar ◽  
Ali Raza Khaki ◽  
Brian Winters ◽  
Funda Vakar-Lopez ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Cox Regression ◽  
Multivariable Analysis ◽  
Complete Response ◽  
Oncologic Outcomes ◽  
Time To Recurrence ◽  
Treatment Data ◽  
Recurrence Patterns ◽  
Fluid Collections ◽  
Cystic Masses

465 Background: SUC is a rare histology with aggressive behavior. We evaluated outcomes and recurrence patterns of patients (pts) with SUC, in comparison with conventional urothelial carcinoma (CUC). Methods: We retrospectively assessed our radical cystectomy (RC) database to identify pts with cT2-4 SUC (any %) or CUC, at RC or transurethral resection specimens. Clinicopathologic/treatment data were captured and compared with t and χ2 tests, as appropriate. Overall survival (OS; diagnosis to death) and recurrence-free survival (RFS; RC to recurrence or death) were estimated (KM method). Significant factors in univariable (UVA) Cox regression for OS were included in multivariable analysis (MVA). Results: We identified 38 consecutive pts with cT2-4 SUC and 287 with CUC (2003-2018); 17 (45%) and 162 (56%) received neoadjuvant chemotherapy (NAC). The primary non-mesenchymal component was urothelial in all SUC cases. SUC had higher rates of pT3/4 (66% vs. 35%, p < .001) but comparable rates of pN+ disease (26% vs. 20%, p = .38). Complete response (ypT0N0) after NAC was lower for SUC (6% vs. 35%, p = .02). Median follow-up was 73.6 months (95%CI 62.6 – 84.7). Median RFS and OS was inferior among pts with SUC (9.4 vs 109.8 months, p < .001, 19.7 vs. 130.4 months, p < .001 respectively). On MVA, SUC was independently associated with worse OS ( Table). Of 17 (45%) pts with SUC who recurred post-RC, 5 presented with abdomino-pelvic cystic masses, with an average time to recurrence < 5 months. Conclusions: SUC was associated with high rates of extravesical spread at RC and worse NAC response, RFS and OS, vs. CUC. Development of abdomino-pelvic fluid collections should raise suspicion of recurrence among pts with this histology. [Table: see text]

B-cell-activating factor receptor expression on naive and memory B cells: relationship with relapse in patients with rheumatoid arthritis following B-cell depletion therapy

2010 ◽  
Vol 69 (12) ◽  
pp. 2181-2188 ◽  
Author(s):  
Inmaculada de la Torre ◽  
Rita A Moura ◽  
Maria J Leandro ◽  
Jonathan Edwards ◽  
Geraldine Cambridge
Keyword(s):  
Rheumatoid Arthritis ◽  
B Cells ◽  
B Cell ◽  
Memory B Cells ◽  
Receptor Expression ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
B Cell Activating Factor ◽  
Significant Difference ◽  
Cell Repopulation

ObjectivesTo examine the expression of B-cell-activating factor receptor (BAFF-R) on naive CD27− and memory CD27+ B cells in normal individuals and patients with rheumatoid arthritis (RA) undergoing B-cell depletion therapy with rituximab.Patients and MethodsBAFF-R expression on B-cell subsets was determined in normal controls (NC; n=11), active patients with RA pre-rituximab (pre-RX; n=15), relapsing patients either concordant for B-cell repopulation (C-R, n=13) or discordant, with relapse more than 3 months after repopulation (D-R, n=11) and patients in remission over 3 months postrepopulation (discordant non-relapsing (D-NR), n=5). Serum BAFF was measured by ELISA and analysed using Mann–Whitney.ResultsThere was no significant difference between NC, pre-RX and D-NR patients in %BAFF-R-positive B cells or mean fluorescence intensity (MFI) in naive and memory B cells. Relapsing patients had significantly lower MFI and %BAFF-R-positive cells in both naive and memory compartments from NC and pre-RX (C-R and D-R; p<0.01). BAFF levels in pre-RX patients were within the normal range and did not correlate with BAFF-R expression in any patient group. D-NR patients had relatively lower proportions of pre and postswitch CD27+ B cells than pre-RX patients (D-NR vs pre-RX; p<0.05 for both) and also lower numbers of postswitch B cells than D-R patients (D-NR vs D-R, p<0.05).ConclusionBAFF-R expression was significantly reduced on both naive and memory B cells in patients at relapse, regardless of the relationship with B-cell repopulation or serum BAFF levels. Re-establishment of active disease was also associated with an increase in class-switch recombination. Factors responsible for lower levels of BAFF-R may relate to altered thresholds for autoreactive B-cell generation at relapse in patients with RA.

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