Background B-cell-depleting therapies increase the risk of morbidity and mortality due to COVID-19. Evidence-based SARS-CoV-2 vaccination strategies for patients on B-cell-depleting therapies are scarce. We aimed to investigate humoral and cell-mediated immune responses to SARS-CoV-2 mRNA-based vaccines in patients receiving CD20-targeted B-cell-depleting agents for autoimmune disease, malignancy, or transplantation. Methods The RituxiVac study was an investigator-initiated, single-centre, open-label study done at the Bern University Hospital (Bern, Switzerland). Patients with a treatment history of anti-CD20-depleting agents (rituximab or ocrelizumab) and with no previous history of SARS-CoV-2 infection were enrolled between April 26 and June 30, 2021, for analysis of humoral and cell-mediated immune responses (by interferon-γ [IFNγ] release assay) at least 4 weeks after completing vaccination against SARS-CoV-2. Healthy controls without a history of SARS-CoV-2 infection were also enrolled at least 4 weeks after completing vaccination against SARS-CoV-2. All study participants received two doses of either the Pfizer–BioNTech BNT162b2 vaccine or the Moderna mRNA-1273 vaccine. The primary outcome was the proportion of patients with a history of anti-CD20 treatment who showed a humoral immune response against the SARS-CoV-2 spike protein in comparison with immunocompetent controls. Prespecified secondary endpoints were the effect of anti-CD20 therapy (including time since last treatment and cumulative dose) on humoral or cell-mediated immune responses to SARS-CoV-2 vaccination, and biomarkers of immunocompetence. This study is registered with ClinicalTrials.gov , NCT04877496 . Findings The final study population comprised 96 patients and 29 immunocompetent controls. The median age of patients was 67 years (IQR 57–72) and of controls was 54 years (45–62), and 51 (53%) of 96 patients and 19 (66%) of 29 controls were female. The median time since last anti-CD20 treatment was 1·07 years (IQR 0·48–2·55) and the median cumulative dose of an anti-CD20 depleting agent was 2·80 g (1·50–5·00). Anti-spike IgG antibodies were detected in 47 (49%) of 96 patients 1·79 months (IQR 1·16–2·48) after the second vaccine dose compared to 29 (100%) of 29 controls 1·81 months (1·17–2·48) after the second vaccine dose (p<0·001). SARS-CoV-2-specific IFNγ release was detected in 13 (20%) of 66 patients and 21 (75%) of 28 of healthy controls (p<0·001). Only nine (14%) of 66 patients were double positive for anti-SARS-CoV-2 spike IgG and cell-mediated responses, compared with 21 (75%) of 28 healthy controls (p<0·001). Time since last anti-CD20 therapy (>7·6 months; positive predictive value 0·78), peripheral CD19 + cell count (>27 cells per μL; positive predictive value 0·70), and CD4 + lymphocyte count (>653 cells per μL; positive predictive value 0·71) were ...

Background and aimsReliable prognostic markers based on biopsy specimens of colorectal cancer (CRC) are currently missing. We hypothesize that assessment of T-cell infiltration in biopsies of CRC may predict patient survival and TNM-stage before surgery.MethodsPre-operative biopsies and matched resection specimens from 130 CRC patients treated from 2002-2011 were included in this study. Whole tissue sections of biopsy material and primary tumors were immunostained for pancytokeratin and CD8 or CD45RO. Stromal (s) and intraepithelial (i) T-cell infiltrates were analyzed for prediction of patient survival as well as clinical and pathological TNM-stage of the primary tumor.ResultsCD8 T-cell infiltration in the preoperative biopsy was significantly associated with favorable overall survival (CD8i p = 0.0026; CD8s p = 0.0053) in patients with primary CRC independently of TNM-stage and postoperative therapy (HR [CD8i] = 0.55 (95% CI: 0.36-0.82), p = 0.0038; HR [CD8s] = 0.72 (95% CI: 0.57-0.9), p = 0.0049). High numbers of CD8i in the biopsy predicted earlier pT-stage (p < 0.0001) as well as absence of nodal metastasis (p = 0.0015), tumor deposits (p = 0.0117), lymphatic (p = 0.008) and venous invasion (p = 0.0433) in the primary tumor. Infiltration by CD45ROs cells was independently associated with longer survival (HR = 0.76 (95% CI: 0.61-0.96), p = 0.0231) and predicted absence of venous invasion (p = 0.0025). CD8 counts were positively correlated between biopsies and the primary tumor (r = 0.42; p < 0.0001) and were reproducible between observers (ICC [CD8i] = 0.95, ICC [CD8s] = 0.75). For CD45RO, reproducibility was poor to moderate (ICC [CD45i] = 0.16, ICC [CD45s] = 0.49) and correlation with immune infiltration in the primary tumor was fair and non-significant (r[CD45s] = 0.16; p = 0.2864). For both markers, no significant relationship was observed with radiographic T-stage, N-stage or M-stage, indicating that assessment of T-cells in biopsy material can add additional information to clinical staging in the pre-operative setting.ConclusionsT-cell infiltration in pre-operative biopsy specimens of CRC is an independent favorable prognostic factor and strongly correlates with absence of nodal metastasis in the resection specimen. Quantification of CD8i is highly reproducible and allows superior prediction of clinicopathological features as compared to CD45RO. The assessment of CD8i infiltration in biopsies is recommended for prospective investigation.

BackgroundThe majority of patients with B-cell-depleting therapies show compromised vaccination-induced immune responses. Herein, we report on the trajectories of anti-SARS-CoV-2 immune responses in patients of the RituxiVac study compared with healthy volunteers and investigate the immunogenicity of a third vaccination in previously humoral non-responding patients.MethodsWe investigated the humoral and cell-mediated immune response after SARS-CoV-2 messanger RNA vaccination in patients with a history with anti-CD20 therapies. Coprimary outcomes were antispike and SARS-CoV-2-stimulated interferon-γ concentrations in vaccine responders 4.3 months (median; IQR: 3.6–4.8 months) after first evaluation, and humoral and cell-mediated immunity (CMI) after a third vaccine dose in previous humoral non-responders. Immunity decay rates were compared using analysis of covariance in linear regression.Results5.6 months (IQR: 5.1–6.7) after the second vaccination, we detected antispike IgG in 88% (29/33) and CMI in 44% (14/32) of patients with a humoral response after two-dose vaccination compared with 92% (24/26) healthy volunteers with antispike IgG and 69% (11/16) with CMI 6.8 months after the second vaccination (IQR: 6.0–7.1). Decay rates of antibody concentrations were comparable between patients and controls (p=0.70). In two-dose non-responders, a third SARS-CoV-2 vaccine elicited humoral responses in 19% (6/32) and CMI in 32% (10/31) participants.ConclusionThis study reveals comparable immunity decay rates between patients with anti-CD20 treatments and healthy volunteers, but inefficient humoral or CMI after a third SARS-CoV-2 vaccine in most two-dose humoral non-responders calling for individually tailored vaccination strategies in this population.Trial registration numberNCT04877496; ClinicalTrials.gov number.

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Objectives Giant cell arteritis (GCA) may lead to vision loss. To what extent tocilizumab (TCZ) is able to prevent vision loss is unknown. The aim was to analyze the occurrence of vision loss in a large GCA cohort treated with TCZ. Methods In this observational monocentric study, GCA patients treated with TCZ between the years 2010 and 2018 were studied. Demographic, clinical, and laboratory data were analyzed. Results A total of 186 patients were included (62% female); 109 (59%) fulfilled the American College of Rheumatology (ACR) criteria, in 123 (66%) patients, large vessel vasculitis was diagnosed by magnetic resonance-angiography (MRA). Cumulative duration of TCZ treatment was 224 years, median treatment duration was 11.1 (IQR 5.6–17.9) months. Glucocorticoids (GC) were tapered over a median of 5.8 (IQR 3.0–8.5) months. At baseline, visual symptoms were present in 70 (38%) and vision loss in 21 (11%) patients. Patients with vision loss at baseline were older (p = 0.032), had a lower C-reactive protein (p = 0.002), and showed a negative association with MRA of the aorta (p = 0.006). Two patients (1.1%) developed vision loss, both at the initiation of TCZ treatment. Conclusion Our data show a very low incidence of vision loss in TCZ-treated patient. The two cases of AION occurred at the initiation of therapy, they support the hypothesis that advanced, and established structural changes of arteries are key factors for this accident. Whether a shorter duration of concomitant GC treatment is risky regarding vision loss needs to be studied.

Neutrophils are no longer considered to be a highly differentiated and uniform population whose functions are solely confined to antimicrobial activities. This former restricted view of neutrophils as fixed effectors and that lack of plasticity was partly due to their characteristic short lifespan in circulation and very low transcriptional activity. 1-3 However, there has been increasing appreciation of the plasticity of neutrophils with the ongoing categorization of their subsets, including myeloid-derived suppressor cells and lowdensity neutrophils. Newly recognized neutrophil functions include the ability to communicate and modulate with almost all immune

Background:Two randomised controlled trials [1, 2] demonstrated a glucocorticoid (GC)-sparing effect of tocilizumab (TCZ) of at least 50%. Long-term GC treatment leads invariably to numerous side effects, particularly in elderly giant cell arteritis (GCA) patients.Objectives:The GUSTO (GCA treatment with ultra-short GC and TCZ) trial was set up to evaluate the efficacy and safety of TCZ-monotherapy after ultra-short GC treatment in new-onset GCA.Methods:Eighteen patients with newly diagnosed GCA were enrolled in this investigator-initiated, single-arm, single-center, open-label clinical trial with Simon’s two stage design (NCT03745586). Patients received 500 mg methylprednisolone intravenously for 3 consecutive days. Thereafter, GC treatment was discontinued and TCZ (8 mg/kg body-weight) was administered intravenously, followed by weekly subcutaneous TCZ injections (162 mg) from day 10 until week 52. The primary endpoint was defined as the proportion of patients who achieved remission within 31 days and showed no relapse at week 24; the secondary endpoint included the proportion of patients with complete relapse-free remission of disease at week 52. Remission was defined as disappearance of GCA symptoms, whereas partial remission included the presence of mild symptoms (defined as non-ischemic with NRS<5/10, reported as mild, not occurring on most days of the week). An interim analysis of the primary endpoint was performed after the first 12 patients reached the primary endpoint.Results:At baseline there were 12/18 female patients, and the median age was 71 (range 64-78) years. Overall, 15/18 had cranial symptoms (10/18 had jaw claudication, 6/18 had visual symptoms), 10/18 suffered from polymyalgia rheumatica (PMR)-symptoms, 16/18 had positive cranial ultrasound, and 13/18 had positive histopathology.At interim analysis, only 25% (3/12) of patients achieved remission within 31 days and stayed relapse-free up to week 24. Thus, the null hypothesis that the proportion of responders would be smaller than 40% (p=0.92) was not rejected. Of the 18 patients recruited at the time of interim analysis, 14 achieved remission within 24 weeks (mean duration 11.1 (95% CI 8.3-13.9) weeks) and 13 showed no relapses up to 52 weeks (72%, 95% CI 47-90%). Overall, 3/18 patients were non-responders (2/3 with persistent cranial symptoms including one new-onset of an anterior ischemic optic neuropathy (AION); 1/3 with persistent PMR symptoms) and started on rescue GC-treatment, and 2/18 discontinued the study due to an adverse event (hepatopathy and diverticulitis, respectively; 1/2 after induction of remission).Figure 1 demonstrates remission status over time.Conclusion:After a 3-days pulse of methylprednisolone, ensuing TCZ monotherapy induced and maintained remission until week 52 in 13/18 patients. The data add an important piece of evidence regarding the potency of blocking the interleukin-6 pathway in GCA and suggest that a substantial reduction of concomitant GC treatment in TCZ-treated GCA patients is feasible.References:[1]Villiger, P.M., et al., Tocilizumab for induction and maintenance of remission in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet, 2016. 387(10031): p. 1921-7.[2]Stone, J.H., et al., Trial of Tocilizumab in Giant-Cell Arteritis. N Engl J Med, 2017. 377(4): p. 317-328.Figure 1.Disease status of patients at each visit (Day 10 - week 52, n=18).Disclosure of Interests:Lisa Christ Shareholder of: F. Hoffmann-La Roche, Grant/research support from: Gilead Sciences; F. Hoffmann-La Roche; Pfizer, Luca Seitz: None declared, Godehard Scholz: None declared, Adela-Cristina Sarbu: None declared, Jennifer Amsler: None declared, Lukas Bütikofer: None declared, Christoph Tappeiner: None declared, Florian Kollert Shareholder of: Roche, Consultant of: Yes (Actelion, BMS, Boehringer-Ingelheim, Pfizer), Grant/research support from: Yes (Gilead, Pfizer), Employee of: Yes, I am currently employed by Roche and previously by Novartis, Stephan Reichenbach: None declared, Peter Villiger Speakers bureau: Roche, MSD, Abbvie, Pfizer, Novartis, Grünenthal, Celgene, Sanofi, Chugai, Consultant of: Roche, MSD, Abbvie, Pfizer, Novartis, Celgene, Sanofi, Grant/research support from: Roche, MSD, Abbvie

BackgroundMorbidity and mortality of COVID-19 is increased in patients with B-cell depleting therapies, the majority of which also show compromised vaccination-induced immune responses. Herein, we report on the trajectories of anti-SARS-CoV-2 antibodies in patients from the original RituxiVac study compared to healthy volunteers and investigate the immunogenicity of a third vaccination in previously non-responding patients.MethodsA follow-up evaluation was performed in volunteers and patients from the RituxiVac Study (NCT04877496), which investigated the humoral and cell-mediated immune response after SARS-CoV-2 mRNA vaccination in patients with a history with anti-CD20 depleting therapies (rituximab or ocrelizumab). The current population included 33 patients and 26 healthy volunteers with initial humoral vaccine response and 32 non-responding patients. Primary outcome was anti-SARS-CoV-2 antibody trajectories in vaccine responders 4.3 months (median; interquartile range [IQR]: 3.6 – 4.8 months) after first evaluation and humoral responses after a third vaccine dose in previous non-responders. Antibody decay rates were compared using analysis of covariance in linear regression.ResultsIn patients with detectable anti-spike IgG antibodies after two-dose vaccination, circulating anti-spike IgG persisted in 88% (29/33) of patients 5.6 months after the second vaccination (median; IQR: 5.1-6.7) compared to 92% (24/26) of healthy volunteers 6.8 months after the second dose (IQR: 6.0-7.1) (p=0.7). Antibody decay rates were comparable between patients and controls with −0.54 signal/cut-off (s/c) units per month (IQR −0.72 to −0.45) and −0.60 s/c units per month (IQR: −0.88 to −0.44), p=0.70. Two-dose responders with loss of circulating antibodies at follow-up (n=4/33, 12%) had lower initial antibody concentrations (p<0.01). Biomarkers for immunocompetence, including CD3, CD4 or CD19 cell count at baseline did not predict anti-spike IgG persistence. In two-dose non-responders, a third dose of mRNA vaccine against SARS-CoV-2 elicited humoral response with detectable anti-spike IgG antibodies in 19% (6/32) participants. No clinical parameters nor biomarkers of immunocompetence predicted humoral response after a third vaccine dose.ConclusionThe present study reveals comparable antibody reduction rates between patients with CD20-depleting treatment history and healthy volunteers, but inefficient humoral responses to a third dose of SARS-CoV-2 mRNA vaccines in the majority of two-dose non-responders. There is a need for individually tailored vaccination strategies in immunocompromised patients that could be stratified by B cell counts and initial level of antibody titers. (Funded by Bern University Hospital, ClinicalTrials.gov number, NCT04877496)