Preserved T-cell Response in anti-CD20 Treated Multiple Sclerosis Patients Following SARS-CoV-2 Vaccination

The SARS-CoV-2 pandemic has tremendous implications for the management of patients with autoimmune conditions such as multiple sclerosis (MS) under immune therapies targeting CD20+ B cells (aCD20). We here investigated humoral and cellular immune responses, including neutralization against SARS-CoV-2 WT and delta variant and T cell responses of aCD20-treated MS patients following SARS-CoV-2 vaccination compared to healthy controls. aCD20-treated MS patients had lower anti-SARS-CoV-2-Spike titers, which correlated with B-cell repopulation. Sera of aCD20 treated patients had reduced capacity to neutralize WT and delta pseudoviruses in vitro. On the contrary, aCD20 treated patients elicited higher frequencies of CD3+ T cells, Th1 cells, Th2 cells, Tc1 cells and CD8+IFN-γ+IL-2+ cells. In summary, aCD20 treated patients have a reduced humoral immune response, depending on B cell repopulation, in accordance with a shift of cellular immune response to a stronger Th1, Th2 and Tc1 phenotype, suggesting strong cellular protection against SARS-CoV-2.

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

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.

CD19 B cell repopulation after ocrelizumab, alemtuzumab and cladribine: Implications for SARS-CoV-2 vaccinations in multiple sclerosis

BACKGROUND: CD20 depletion is a highly-effective treatment for relapsing multiple sclerosis that maintains B cells at low levels through six monthly dosing of 600mg ocrelizumab. This dosing schedule is associated with inhibition of seroconversion following SARS-CoV-2 vaccination, in contrast to the high levels of seroconversion following treatment with alemtuzumab and cladribine tablets. A number of emerging reports suggest that repopulation of 1-3% B cells facilitates seroconversion after CD20-depletion. The frequency of this occurring following repeated ocrelizumab treatment, after other DMT, and after treatment cessation is largely unknown. METHODS: Relapse data, lymphocyte and CD19 B cell numbers were extracted from phase II ocrelizumab extension study (NCT00676715) data supplied by the manufacturer via the Vivli Inc, trial data-request portal. Repopulation data of oral cladribine from the phase III CLARITY study (NCT00213135) was supplied by the European Medicines Agency; and the alemtuzumab phase III CARE-MS I (NCT00530348) and CARE-MS II (NCT00548405) trial data were supplied by the manufacturer via the clinicalstudydatarequest.com portal. RESULTS: Only 3-5% of people with MS exhibit 1% B cells at 6 months after the last infusion following 3-4 cycles of ocrelizumab, compared to 50-55% at 9 months, and 85-90% at 12 months. During this time relapses occurred at consistent disease breakthrough rates compared to people during standard therapy. In contrast most people (90-100%) exhibited more than 1% B cells during treatment with either cladribine or alemtuzumab. CONCLUSIONS. Few people repopulate peripheral B cells with standard ocrelizumab dosing, however an extending the dosing interval by 3-6 months may allow many more people to potentially seroconvert in the relative absence of excess relapse-activity. Most people demonstrate B cell repletion within 3 months of the last treatment of alemtuzumab and cladribine. This may help protect against severe COVID-19.

Rituximab Induction and Maintenance in ANCA-Associated Vasculitis: State of the Art and Future Perspectives

Antineutrophil cytoplasmatic antibody (ANCA)-associated vasculitis (AAV) is a group of rare autoimmune diseases characterized by inflammation of the vascular wall. The pathogenesis of AAV is strongly associated with B cell-derived ANCAs; thus, Rituximab (RTX) has become a promising drug in the induction and maintenance treatment of AAV. The purpose of this review is to describe the efficacy and safety of RTX in the induction of remission and maintenance therapy of AAV. Herein, we summarize the randomized controlled trials that have contributed to the refinement of the use of RTX in AAV in the past decades. RTX has been proven to be effective both in new-onset disease and in relapsing disease. Although the optimal duration of AAV maintenance therapy remains unknown, the ANCAs and the B-cell repopulation may offer support for the administration of further RTX cycles (or not). The safety of RTX is comparable with cyclophosphamide, with the advantage of a low risk of malignancy and no concern for fertility. In conclusion, RTX now plays an important role in the induction and maintenance therapy of AAV. Optimizing RTX-based treatment strategies in AAV is one of the main goals of the current research in AAV.

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

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.

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

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.

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

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