French Vasculitis Study Group recommendations for the management of COVID-19 vaccination and prophylaxis in patients with systemic vasculitis



## English version
Following the publication of the French recommendations for the management of systemic necrotizing vasculitides [bib_ref] French recommendations for the management of systemic necrotizing vasculitides (polyarteritis nodosa and..., Terrier [/bib_ref] and of the French Vasculitis Study Group (FVSG) recommendations on the use of immunosuppressants and biotherapies for remission induction and maintenance of anti-neutrophil cytoplasmic antibody (ANCA)associated vasculitides [bib_ref] ANCA-associated vasculitides: recommendations of the French Vasculitis Study Group on the use..., Terrier [/bib_ref] , the SARS-CoV-2 pandemic requires updates according to data published in the literature.
There are ongoing discussions regarding the timing of SARS-CoV-2 vaccination of patients with chronic inflammatory diseases. It has been reported that patients who received rituximab (RTX) treatment and who no longer have detectable peripheral B cells in their blood are not able to build up an antibody response after SARS-CoV-2 vaccination whereas those with detectable B cells can mount antibody responses [bib_ref] SARS-CoV-2 vaccination in rituximab-treated patients: b cells promote humoral immune responses in..., Mrak [/bib_ref]. These data were confirmed by prospective study cohorts of patients with chronic inflammatory diseases who developed gradual recovery of antibody response to vaccination 9 months after treatment with RTX [bib_ref] Effect of immunosuppression on the immunogenicity of mRNA vaccines to SARS-CoV-2: a..., Deepak [/bib_ref] [bib_ref] Immunogenicity and safety of the BNT162b2 mRNA COVID-19 vaccine in adult patients..., Furer [/bib_ref]. Delaying RTX treatment, especially in case of maintenance treatment, may thus be justified in patients with stable disease until peripheral B cells repopulate to allow development of neutralizing antibodies in response to vaccination.
To help clinicians put this data into clinical practice, the Scientific Council of the FVSG adopted a set of recommendations for the management of SARS-CoV-2 vaccination and prophylaxis in patients with systemic vasculitis.
First, vaccination against the SARS-CoV-2 is strongly recommended in patients with vasculitis of any type (including ANCA-associated vasculitis). Severely immunocompromised patients are at very high risk for severe forms of COVID-19. Immunosuppressive treatments can affect vaccine response and induce a defect in the production of neutralizing antibodies and/or alter T lymphocyte response (even if the latter is not routinely assessed). In addition, vaccineinduced vasculitis flare is very rare and could be adequately diagnosed with close monitoring and managed.
Second, among patients on immunosuppressive therapy, those receiving RTX treatment are more likely to experience a severe form of COVID-19 [bib_ref] Factors associated with COVID-19-related death in people with rheumatic diseases: results from..., Strangfeld [/bib_ref] [bib_ref] Immunotherapies and COVID-19 mortality: a multidisciplinary open data analysis based on FDA's..., Pistor [/bib_ref] and have a lower probability of developing a protective antibody titers, especially when they have no detectable B lymphocytes at the time of vaccination [bib_ref] SARS-CoV-2 vaccination in rituximab-treated patients: b cells promote humoral immune responses in..., Mrak [/bib_ref] [bib_ref] Effect of immunosuppression on the immunogenicity of mRNA vaccines to SARS-CoV-2: a..., Deepak [/bib_ref]. On the other hand, the probability of developing an anti-SARS-CoV-2 humoral immune response in the course of RTX treatment is greater if the vaccination Available online at ScienceDirect www.sciencedirect.com is carried out after B-lymphocytes repopulation. For these reasons, the systematic injection of a 3rd dose of vaccine is recommended in patients on immunosuppressants to complete initial vaccination schedule, at least 4 weeks after the second dose, or as soon as possible for people who have already exceeded this time. The FVSG recommends a case-by-case discussion of delaying the first RTX infusion as part of induction therapy or spacing infusions as part of maintenance therapy, depending on the degree of clinical emergency, susceptibility to severe SARS-CoV-2 infection, anti-S protein antibody levels, and B cell count. Third, in a patient receiving RTX who does not have a sufficient antibody response after 3 doses of vaccine, the T lymphocyte response appears to be preserved [bib_ref] SARS-CoV-2 vaccination in rituximab-treated patients: b cells promote humoral immune responses in..., Mrak [/bib_ref] and probably provides some protection (even if it remains difficult to correlate with a potential clinical benefit), and the effectiveness of the vaccine booster (from 3 months after the 3rd dose) remains unclear. However, its realization seems important to discuss, ideally at the time of B-cell repopulation if it is possible to postpone the RTX infusion (especially in the case of maintenance treatments).
Fourth, in all cases, monitoring of the antibody response is essential to identify patients with no or insufficient antibody response, potentially eligible for cocktails of monoclonal antibodies directed against SARS-CoV-2 for pre-or post-exposure prophylaxis.
Fifth, the FVSG encourages vaccination of the family and professional circle [bib_ref] Association Between Risk of COVID-19 infection in nonimmune individuals and COVID-19 immunity..., Nordstr Om [/bib_ref] , adherence to barrier measures and urgent contact with the patient's physician in case of: (i) documented infection (positive PCR) to consider administration of a monoclonal antibody cocktail for curative purposes within 5 days after first signs of SARS-CoV-2 infection, (ii) contact with a patient with COVID-19 for administration of monoclonal antibodies for post-exposure prophylaxis, and (iii) in the near future for primary prophylaxis prior to any contact at risk, in the absence of a sufficient SARS-CoV-2 antibody response [9]. An antibody threshold of anti-spike antibodies less than 264 BAU/ml (Binding Antibodies Unit/mL) is considered insufficient to protect effectively and represent a threshold below which immunocompromised patients could be eligible for monoclonal antibodies for primary prophylaxis (i.e., prior to any contact with a COVID-19 positive patient or prior to any infection) [bib_ref] Correlates of protection against symptomatic and asymptomatic SARS-CoV-2 infection, Feng [/bib_ref]. In severe form of vasculitis, induction therapy should not be delayed and pre-exposure prophylaxis may be considered from the beginning if there is a high incidence of SARS-CoV-2 infections over the period even though evidence awaits validation by further studies. Finally, patients without antibody response after three doses of vaccine who develop severe SARS-CoV-2 infection requiring oxygen therapy may benefit high dose casirivimab-imdevimab curative treatment.
Recommendations developed by the FVSG are intended to inform particular patterns of practice and not to dictate the care of a particular patient, with the ultimate determination regarding its application to be made by the physician in light of each patient's individual circumstances and preferences. Due to the rapidly expanding information and evolving evidence related to COVID-19, which may lead to modification of some guidance statements over time, it is anticipated that updated versions of this recommendation will have to be published.

## French version
Suite a la publication des recommandations francaises sur la prise en charge des vascularites syst emiques n ecrosantes [bib_ref] French recommendations for the management of systemic necrotizing vasculitides (polyarteritis nodosa and..., Terrier [/bib_ref] et du Groupe Francais d'Etude des Vascularites (GFEV) sur l'utilisation des immunosuppresseurs et bioth erapies en traitement d'induction et d'entretien des vascularites associ ees aux ANCA [bib_ref] ANCA-associated vasculitides: recommendations of the French Vasculitis Study Group on the use..., Terrier [/bib_ref] , la situation epid emique actuelle impose l'actualisation de ces propositions pour prendre en compte les donn ees les plus r ecentes de la litt erature.
Le moment le plus opportun pour la vaccination contre le coronavirus SARS-CoV-2 des patients atteints de maladie inflammatoire syst emique reste discut e. Il a et e rapport e que les patients trait es par rituximab (RTX) ne d eveloppaient pas d'anticorps apr es vaccination SARS-CoV-2 en l'absence de cellules B p eriph eriques d etectables au moment de la vaccination, au contraire de ceux ayant une repopulation lymphocytaire B [bib_ref] SARS-CoV-2 vaccination in rituximab-treated patients: b cells promote humoral immune responses in..., Mrak [/bib_ref]. Ces donn ees ont et e valid ees par des etudes prospectives de cohorte de patients atteints de maladie inflammatoire chronique, qui ont pr esent e une r eponse vaccinale humorale r eapparaissant progressivement 9 mois apr es vaccination [bib_ref] Effect of immunosuppression on the immunogenicity of mRNA vaccines to SARS-CoV-2: a..., Deepak [/bib_ref] [bib_ref] Immunogenicity and safety of the BNT162b2 mRNA COVID-19 vaccine in adult patients..., Furer [/bib_ref]. Le report d'une perfusion de RTX peut ainsi se justifier, particuli erement dans le cas d'un traitement d'entretien chez un patient avec vascularite stable, jusqu' a la repopulation lymphocytaire B pour permettre le d eveloppement d'anticorps neutralisants en r eponse a la vaccination.
Pour aider les cliniciens a mettre en pratique ces donn ees, le Conseil Scientifique du GFEV propose des recommandations sur la vaccination et la prophylaxie contre l'infection SARS-CoV-2 chez les patients atteints de vascularite syst emique.
La vaccination contre le SARS-CoV-2 est fortement recommand ee chez les patients atteints de vascularite, quel que soit leur type (dont les vascularites associ ees aux ANCA). Les personnes s ev erement immunod eprim ees sont a tr es haut risque de formes graves de la COVID-19. Les traitements immunosuppresseurs peuvent impacter la r eponse vaccinale et induire un d efaut de production d'anticorps neutralisants et/ou alt erer la r eponse lymphocytaire T (meme si cette derni ere ne se mesure pas en routine). De plus, les pouss ees evolutives de vascularite sont exceptionnelles apr es une telle vaccination et peuventetre ais ement diagnostiqu ees lors d'un suivi rapproch e et control ees.
Au sein des personnes sous traitement immunosuppresseur, les patients recevant du RTX ont une probabilit e plus importante de pr esenter une forme s ev ere d'infection COVID-19 [bib_ref] Factors associated with COVID-19-related death in people with rheumatic diseases: results from..., Strangfeld [/bib_ref] [bib_ref] Immunotherapies and COVID-19 mortality: a multidisciplinary open data analysis based on FDA's..., Pistor [/bib_ref] et moindre de d evelopper une r eponse vaccinale satisfaisante, d'autant plus que leurs lymphocytes B ne sont pas d etectables au moment de la vaccination [bib_ref] SARS-CoV-2 vaccination in rituximab-treated patients: b cells promote humoral immune responses in..., Mrak [/bib_ref] [bib_ref] Effect of immunosuppression on the immunogenicity of mRNA vaccines to SARS-CoV-2: a..., Deepak [/bib_ref]. En revanche, la probabilit e de d evelopper une r eponse anticorps anti-SARS-CoV-2 apr es RTX est plus importante si la vaccination est r ealis ee apr es repopulation lymphocytaire B. Pour ces raisons, l'injection syst ematique d'une 3 eme dose de vaccin est recommand ee chez les patients sous immunosuppresseurs, 4 semaines apr es la deuxi eme dose, ou d es que possible quand ce d elai est d epass e. Le Conseil Scientifique du GFEV conseille de discuter, au cas par cas, la conduite a tenir concernant un eventuel recul d'une premi ere perfusion de RTX (dans le cadre d'un traitement d'induction) ou un eventuel espacement des perfusions (dans le cas d'un traitement d'entretien), selon le degr e d'urgence clinique, les facteurs de susceptibilit e a une forme s ev ere d'infection SARS-CoV-2, le taux d'anticorps dirig es contre la prot eine S et le taux des lymphocytes B.
Chez un patient recevant du RTX mais ne pr esentant pas de r eponse anticorps suffisante apr es 3 doses de vaccin, la r eponse lymphocytaire T semble pr eserv ee [bib_ref] SARS-CoV-2 vaccination in rituximab-treated patients: b cells promote humoral immune responses in..., Mrak [/bib_ref] et procure probablement une certaine protection, -meme s'il est impossible de l' evaluer pr ecis ement -, et l'efficacit e du rappel vaccinal (d es 3 mois apr es la 3 eme dose) n'est pas d emontr ee. N eanmoins, sa r ealisation semble importante a discuter, id ealement au moment de la reconstitution lymphocytaire B s'il est envisageable de d ecaler la perfusion de RTX (notamment dans le cas des traitements d'entretien).
Dans tous les cas, la surveillance de la r eponse anticorps est indispensable pour identifier les patients n'ayant pas de r eponse anticorps ou une r eponse anticorps insuffisante, qui sont potentiellement eligibles aux anticorps monoclonaux dirig es contre le SARS-CoV-2, en prophylaxie pr e-ou post-exposition. On incitera egalement a la vaccination de l'entourage [bib_ref] Association Between Risk of COVID-19 infection in nonimmune individuals and COVID-19 immunity..., Nordstr Om [/bib_ref] , au respect des mesures barri eres et a la prise de contact en urgence avec le m edecin suivant le patient en cas 1/ d'infection document ee (PCR+) pour discuter l'administration d'un traitement par anticorps monoclonaux a vis ee curative dans les 5 jours suivant les premiers signes de l'infection SARS-CoV-2, 2/ de contact avec un patient ayant la COVID-19, pour l'administration d'anticorps monoclonaux en prophylaxie post-exposition, et 3/ tr es prochainement en prophylaxie primaire avant tout contact a risque, en l'absence de r eponse vaccinale suffisante . Un seuil d'anticorps inf erieur a 264 BAU (Binding Antibodies Unit)/ml est jug e insuffisant pour prot eger efficacement, et repr esente le seuil au-dessous duquel les patients immunod eprim es seront eligibles aux anticorps monoclonaux en prophylaxie primaire (c'est a dire avant tout contact avec un patient positif pour la COVID-19 ou avant toute infection) [9,10]. En cas de forme s ev ere de vascularite, le traitement d'induction ne doit pasetre retard e et une prophylaxie pr e-exposition pourraitetre envisag ee d'embl ee en cas d'incidence elev ee des infections sur la p eriode, meme si cette attitude devraetre valid ee. Enfin un patient, sans r eponse anticorps vaccinale apr es 3 doses de vaccin, qui d eveloppe une infection SARS-CoV-2 s ev ere n ecessitant une oxyg enoth erapie, peut b en eficier d'un traitement curatif a forte dose par l'association casirivimab-imdevimab.
Ces recommandations elabor ees par le Conseil Scientifique du GFEV sont destin ees a proposer des attitudes pratiques et non a dicter les soins d'un patient particulier, la d ecision finale concernant leur application devantetre prise par le m edecin apr es prise en compte des circonstances individuelles et des pr ef erences de chaque patient. En raison de l'accroissement rapide de l'information et de l' evolution des preuves relatives a la COVID-19, qui peuvent conduire a des modifications des pratiques au fil du temps, il est probable que des versions actualis ees de cette recommandation devrontetre publi ees.

## Declaration of competing interest
All authors have been coinvestigators in academic studies for which rituximab was provided by Roche. There are no other conflicts of interest.