SARS-CoV-2 INFECTIONS AMONG 275 PATIENTS WITH TIXAGEVIMAB/ CILGAVIMAB PROPHYLAXIS

Background: At the end of 2021, concomitantly with the beginning of Omicron variant circulation, pre-exposure prophylaxis with the dual monoclonal long-acting monoclonal antibodies tixagevimab/cilgavimab became available in France to protect patients non-responding or non-eligible to SARS-CoV-2 vaccination at risk of severe COVID-19. Method(s): This study included patients who received tixagevimab/cilgavimab for pre-exposure prophylaxis independently of vaccination status or previous SARS-CoV-2 infection. This prophylaxis strategy was implemented at the Bichat-Claude Bernard University Hospital, Paris since December 2021 Last date of follow-up was November 1st, 2022. Incident SARS-CoV-2 infections were detected based on positive RT-PCR result and/or anti-nucleocapsid antibodies seroconversion. Severe COVID-19 was defined as an infection leading to an hospitalization requiring oxygenotherapy and/or high dose corticotherapy. Result(s): Among the 275 patients who received a tixagevimab/cilgavimab preexposure prophylaxis, 55% (n=153) were solid organ transplant recipients (50% lung, 46% kidney, 4% heart transplants), 42% (n=116) had an autoimmune disease, and 3% (n=6) had other indications. 51% (n=141) of all patients received rituximab. No severe adverse event of tixagevimab/cilgavimab was observed. Incident SARS-CoV-2 infection was diagnosed in 67 patients (24%). Among them, 59% (n=40) were solid organ transplant recipients, 36% (n=24) had an autoimmune disease and overall 52% had received rituximab. For the 56 patients whose infection date was available, the median delay between the last infusion of tixagevimab/cilgavimab and SARS-CoV-2 infection was 62 days (IQR=[30-97]). During the study period, 57% of incident infections occurred between December 17th, 2021 and May 31st, 2022, when BA.1 and BA.2 were the major Omicron sublineages in France, and 43% between June 1st, 2022 and November 2022 1st, a period during which BA.4 and BA.5 were predominant in France. Severe COVID-19 occurred in 6 patients out of 67 (9%);5 were solid organ transplant recipients and 3 received rituximab. No death due to COVID-19 was reported. Conclusion(s): Overall, 76% of patients receiving pre-exposure prophylaxis with tixagevimab/cilgavimab had no incident SARS-CoV-2 infection during the study period. Severe COVID-19 was observed in 9% of infected patients. These results suggest a potential protective effect in-vivo of tixagevimab/cilgavimab during the study period despite the circulation of different Omicron sublineages.

Impact du vaccin ARNm BNT162b2 anti-SARS-CoV-2 sur la production d'interféron alpha et l'auto-immunité cellulaire au cours du lupus érythémateux systémique : le projet COVALUS

Alors que la vaccination anti-SARS-CoV-2 est devenue un enjeu important de la prise en charge des patients atteints de maladies auto-immunes systémiques telles que le lupus érythémateux systémique (LES), nous manquons de données sur l'impact de la vaccination par ARN messager sur l'auto-immunité. Notre objectif était de décrire l'impact de la vaccination par ARNm sur la production d'interféron alpha et l'auto-immunité cellulaire au cours du lupus. Nous avons réalisé une étude prospective, observationnelle, monocentrique au cours de laquelle nous avons inclus des patients atteints de LES, éligibles à la vaccination anti-SARS-CoV-2 par le vaccin BNT162b2 selon les recommandations françaises alors en vigueur. Nous avons secondairement exclu les patients non-naïfs vis-à-vis de l'infection par le SARS-CoV-2 à T0 et les patients sous mycophénolate, azathioprine ou rituximab. Les patients étaient évalués juste avant la première dose, puis à 1 mois (M1), à 3 mois (M3) et à 6 mois (M6) de leur première dose. En plus du suivi clinicobiologique habituel de la maladie, nous avons évalué la production d'IFN-alpha par les cellules dendritiques plasmacytoïdes (pDCs) en cytométrie de flux. Nous avons également quantifié l'auto-immunité T en mesurant la proportion de cellules T activées (CD154+ CD69+) après stimulation des cellules sanguines mononucléées périphériques (PBMCs) par des antigènes nucléaires (U1-RNP, histones, SS-A, SS-B). Trente-six patients lupiques et 11 contrôles sains ont été inclus. Les patients lupiques étaient majoritairement des femmes (31/36, 81 %) d'un âge médian de 44 [36–50] ans. Nous avons observé une augmentation significative de la proportion de pDCs produisant spontanément de l'IFN-alpha à M1 (1,27 % [0,6–2,6]) et M3 (1,25 % [0,87–1,83]) comparativement à T0 (0,64 [0,27–1,09] %, respectivement p < 0,001 et p < 0,01) chez les lupiques. Nous avons observé une augmentation similaire dans le groupe contrôle, mais uniquement à M1 (1,46 [0,95–2,12] %) comparativement à T0 (0,25 [0,12–0,47] %, p < 0,02). Par ailleurs, les pDCs des patients lupiques exprimaient à leur surface plus de marqueurs d'activation CD86 et HLA-DR à M3 que à T0. Concernant la proportion de cellules T auto-réactives des patients lupiques, nous avons observé, qu'après une hausse non significative entre T0 et M1, les cellules auto-réactives diminuaient significativement dans le temps (coefficient β d l'effet fixe associé au temps dans le modèle linéaire à effet mixte = −0,00067, p = 0,015). Nous n'avons pas observé une telle tendance chez les contrôles. Au cours du suivi, nous avons observé 2 poussées cliniques de la maladie. À l'exception de ces patients, nous n'avons pas constaté de modification significative du SLEDAI, du taux d'anti-dsDNA, de C3 ou de C4 dans la cohorte. Chez les patients lupiques, la vaccination anti-SARS-CoV-2 par ARNm entraîne (1) une augmentation modeste infra-clinique de la production spontanée d'IFN-alpha par les pDCs et (2) une diminution des cellules T auto-réactives spécifiques des antigènes nucléaires. (French) [ FROM AUTHOR]

Efficacy and safety of the anti-SARS-CoV-2 BNT162b2 vaccine among SLE patients: the covalus project

PurposeVaccination in patients with autoimmune disease like systemic lupus erythematosus (SLE) raises a special concern because its impact on autoimmunity remains partially unknown. While clinical data from large cohort are reassuring [1], very little has been described on the post vaccination immune system reaction. Besides, long-term efficacy of the vaccine, especially regarding T-cell response has not been evaluated in detail.MethodsWe conducted a prospective observational study that included all the adult SLE patients vaccinated by the BNT162b2 anti-SARS-CoV-2 vaccine in a single tertiary medical center in Paris. We evaluated the efficacy and the safety of the vaccine just before the first dose and then one month (M1), three months (M3) and six months (M6) later. Apart from the standard clinical and biological follow-up, we measured, at each time, the proportion of plasmacytoid dendritic cells (PDCs) producing interferon-α (IFN-α) using intracellular flow cytometry staining. We quantified the activation of autoimmune T cells at each visit by stimulating the peripheral blood mononuclear cells (PBMCs) with nuclear antigens and quantifying the proportion of activated (CD154+ CD69+) among non-naïve (CD45-RA -) CD4 T cells. We also evaluated the anti-SARS-CoV-2 T cell response by an Interferon Gamma Release Assay (IGRA) test.ResultsWe included 57 SLE patients and 11 healthy volunteers (HV) vaccinated by the BNT162b2 vaccine according to the French national recommendations. SLE patients were mostly female (49/57, 86.0%) with a median [IQR] age of 44.0 [38.1–50.8] years and a time since SLE diagnosis of 10.8 [4.2–19-8] years. Their treatment regimen was heterogeneous: 47/57 (82.5%) received hydroxychloroquine;35 (61.4%) steroids, and 10 (17.5%) were on another immunosuppressive drug (mycophenolate mofetil, azathioprine or rituximab). We observed only one clinical SLE flare during the post vaccination follow-up. Except for this patient, we observed no modification in the anti-dsDNA titer among SLE patients. At M3 compared to T0, we observed more PDCs producing INF-α in the SLE group: 1.17% [0.72–1.77] vs 0.68% [0.34–1.18], p=0.002 but not in the HV group. The proportion of non-naïve CD4 T cells activated (CD154+ CD69+) by the nuclear antigens did not change after vaccination. Regarding the T cell response, we observed that 71% of the SLE patients had a positive IGRA test at M3, whereas at M6, only 36% of them had a positive IGRA test. The antiviral T cell response correlated well with the humoral response: there was no patient with negative anti-Spike serology and positive IGRA and 78% of patients with a positive serology had a positive IGRA test.ConclusionWe observed that BNT162b2 vaccine had a mild impact on innate and adaptative immunity on SLE patients. The antiviral T cell response was well correlated to the humoral anti-Spike response and decreased significantly from M3 to M6.

Tolérance de la vaccination contre le SRAS-CoV-2 chez les patients atteints de maladies rhumatologiques inflammatoires/auto-immunes : résultats du registre EULAR-COVAX chez 5121 patients

Introduction Les patients atteints de maladies musculosquelettiques inflammatoires/auto-immunes (I-RMD) n’ont pas été inclus dans les études de tolérance des vaccins contre le SARS-CoV-2 et sont souvent inquiets quant à la tolérance de la vaccination. Notre objectif est d’étudier la tolérance des vaccins contre le SARS-CoV-2 chez les patients atteints de maladies musculosquelettiques inflammatoires/auto-immunes (I-RMD). Patients et méthodes Pour cela, nous avons créé avec l’EULAR un registre international de cas rapportés par les médecins rhumatologues et internistes de patients atteints d’I-RMD et de RMD non inflammatoire (NI-RMD) vaccinés contre le SARS-CoV-2. Du 5 février 2021 au 27 juillet 2021, nous avons recueilli des données sur la démographie, la vaccination, le diagnostic de RMD, l’activité de la maladie, les traitements immunomodulateurs/immunosuppresseurs, les poussées, les événements indésirables (EI) et les infections COVID-19 chez les patients vaccinés. Les données ont été analysées de manière descriptive. Résultats L’étude a inclus 5121 participants de 30 pays, la majorité de France (40 %), Italie (16 %) et Portugal (14 %), 90 % avec des I-RMD (n=4604, 68 % de femmes, âge moyen 60,5 ans) et 10 % avec des NI-RMD (n=517), 77 % de femmes, âge moyen 71,4 ans. La polyarthrite rhumatoïde (33 %), les connectivites (18 %), les spondyloarthrites (11 %), le rhumatisme psoriaqique (10 %) et les vascularites (12 %) étaient les diagnostics les plus fréquents ;54 % des patients ont reçu des traitements de fond synthétiques conventionnels (csDMARD), 42 % des DMARD biologiques ou ciblés et 35 % des immunosuppresseurs. La plupart des patients ont reçu le vaccin Pfizer/BioNTech (70 %), 17 % AstraZeneca/Oxford et 8 % Moderna. Une infection COVID post-vaccination a été signalée dans 0,7 à 1,1 % des cas, selon le statut vaccinal (entièrement/partiellement vacciné) et le groupe RMD. Des poussées d’I-RMD ont été signalées dans 4,4 % des cas (0,6 % de poussées sévères), dont 1,5 % ont entraîné des changements de médicaments. Des EI ont été signalés dans 37 % des cas (37 % I-RMD, 40 % NI-RMD), des EI sévères dans 0,4 % des cas, très divers et avec une fréquence comparable et même inférieure à celle observée chez les patients atteints de NI-RMD (1,1 %). Discussion La tolérance au vaccin n’était pas différente entre les groupes I-RMD et NI-RMD. Dans les essais cliniques de vaccins à ARN contre le SRAS-CoV-2 dans la population générale, les taux d’EI graves étaient très semblables à ceux de notre étude, allant de 0,4 % à 0,6 % dans le groupe vacciné et de 0,5 % à 0,6 % dans le groupe témoin, ce qui suggère que ces EI graves ne sont pas nécessairement liés au vaccin. Conclusion Il s’agit de la plus grande étude de la tolérance des vaccins anti-SRAS-CoV-2 chez près de 5000 patients atteints de maladies inflammatoires/auto-immunes rhumatologiques. Le profil de sécurité des vaccins contre le SRAS-CoV-2 chez les patients atteints d’I-RMD était rassurant, et comparable à celui des patients atteints de NI-RMD. La majorité des patients ont bien toléré leur vaccination, avec de rares poussée d’I-RMD et de très rares EI sévères probablement non liés à la vaccination. Ces résultats devraient rassurer les rhumatologues et les personnes vaccinées, et favoriser la confiance dans la sécurité du vaccin COVID-19 chez les patients atteints de I-RMD.

COVID-19 vaccine safety in patients with rheumatic and musculoskeletal disease

Background: The consequences of the COVID-19 outbreak are unprecedented and have been felt by everyone around the world, including people with rheumatic and musculoskeletal diseases (RMDs). With the development of vaccines, the future is becoming brighter. Vaccines are a key pillar of public health and have been proven to prevent many serious diseases. However, vaccination also raises questions, especially for patients with inflammatory RMDs and/or treated with drugs that influence their immune system. Objectives: Our aim was to collect safety data among RMD patients receiving COVID-19 vaccines. Methods: The EULAR COVID-19 Vaccination (COVAX) Registry is an observational registry launched on 5 February 2021. Data are entered voluntarily by clinicians or associated healthcare staff;patients are eligible for inclusion if they have an RMD and have been vaccinated against SARS-CoV-2. Descriptive statistics are presented. Results: As of 27 April 2021, 1519 patients were reported to the registry. The majority were female (68%) and above the age of 60 (57%). Mean age was 63 years (SD 16), ranging from 15 to 97 years. A total of 28 countries contributed to the registry, with France (60%) and Italy (13%) as the highest contributors. The majority (91%) had inflammatory RMDs. Inflammatory joint diseases accounted for 51% of cases, connective tissue diseases 19%, vasculitis 16%, other immune mediated inflammatory diseases 4%, and non-inflammatory/mechanical RMDs 9%. The most frequent individual diagnoses were rheumatoid arthritis (30%), axial spondyloarthritis (8%), psoriatic arthritis (8%), systemic lupus erythematosus (SLE, 7%) and polymyalgia rheumatica (6%). At the time of vaccination, 45% were taking conventional synthetic DMARDs, 36% biological DMARDs, 31% systemic glucocorticoids, 6% other immunosuppressants (azathioprine;mycophenolate;cyclosporine;cyclophosphamide;tacrolimus), and 3% targeted synthetic DMARDs. The most frequent individual DMARDs were methotrexate (29%), TNF-inhibitors (18%), antimalarials (10%) and rituximab (6%). The vaccines administered were: 78% Pfizer, 16% AstraZeneca, 5% Moderna and 1% other/unknown;66% of cases received two doses and 34% one dose. Mean time from 1st and 2nd dose to case report was 41 days (SD 26) and 26 days (SD 23), respectively. COVID-19 diagnosis after vaccination was reported in 1% (18/1519) of cases. Mean time from first vaccination until COVID-19 diagnosis was 24 days (SD 17). Disease flares were reported by 5% (73/1375) of patients with inflammatory RMDs, with 1.2% (17/1375) classified as severe flares. Mean time from closest vaccination date to inflammatory RMD flare was 5 days (SD 5). The most common flare types were arthritis (35/1375=2.5%), arthralgia (29/1375=2.1%), cutaneous flare (11/1375=0.8%) and increase in fatigue (11/1375=0.8%). Potential vaccine side effects were reported by 31% of patients (467/1519). The majority were typical early adverse events within 7 days of vaccination, namely pain at the site of injection (281/1519=19%), fatigue (171/1519=11%) and headache (103/1519=7%). Organ/system adverse events were reported by 2% (33/1519) but only 0.1% (2/1519) reported severe adverse events, namely a case of hemiparesis in a patient with systemic sclerosis/ SLE overlap syndrome (ongoing at the time of reporting), and a case of giant cell arteritis in a patient with osteoarthritis (recovered/resolved without sequelae). Conclusion: The safety profiles for COVID-19 vaccines in RMD patients was reassuring. Most adverse events were the same as in the general population, they were non-serious and involved short term local and systemic symptoms. The overwhelming majority of patients tolerated their vaccination well with rare reports of inflammatory RMD flare (5%;1.2% severe) and very rare reports of severe adverse events (0.1%). These initial findings should provide reassurance to rheumatologists and vaccine recipients, and promote confidence in COVID-19 vaccine safety in RMD patients, namely those with inflammatory RMDs and/or taking treatments that influence their immune system.