domain: sde sdv

text:
F Clarac

Z Campos

O Marquis

The extended osteoderm shield in Paleosuchus sp

Keywords: Crocodylia, Dwarfism, Heat Transfer, Diet, Niche Crocodylia, Nanisme, Transferts de chaleur, Régime alimentaire, Niche

Les crocodiliens nains (i.e. Osteolaemus sp. et Paleosuchus sp.) ont tous la particularité de vivre dans les forêts équatoriales et de présenter un bouclier d'ostéodermes qui s'étend au-delà de la zone dorsale (qui est comprise entre le crâne et la symphyse des crêtes caudales). Notre étude compare la répartition de l'ornementation osseuse et la porosité entre les ostéodermes dorsaux et les ostéodermes non-dorsaux au sein du bouclier d'ostéodermes d'un caïman nain de Cuvier (Paleosuchus palpebrosus). Sachant que ces deux critères constituent des indicateurs du degré de vascularisation du bouclier dermique, nous avons alors estimé la répartition du réseau vasculaire au sein du bouclier d'ostéodermes de P.palpebrosus. Nos résultats montrent que l'ornementation et la porosité sont nettement plus prononcées au niveau des ostéodermes qui composent la partie dorsale du bouclier.

L'interprétation de nos résultats permet d'établir que les ostéodermes dorsaux peuvent être impliqués dans les transferts de chaleur via les vaisseaux sanguins superficiels dans le cas où ils sont artificiellement exposés à une lampe chauffante dans des conditions de captivité ; il est cependant peu probable que ce phénomène se produise sous la canopée de la forêt équatoriale où l'exposition au soleil est peu accessible. Nous supposons donc que les ostéodermes des crocodiliens nains auraient principalement pour rôle de constituer une source de calcium labile qui permettrait d'amortir les variations de régime alimentaire qui sont liées aux différentes niches de la forêt équatoriale (i.e. les ruisseaux, les mares, les sols humides, les cavernes).

Introduction

The crocodylian osteoderms are bony plates that grow within the post-cranial dermis during the posthatching development [START_REF] Vickaryous | Development of the dermal skeleton in Alligator mississippiensis (Archosauria, Crocodylia) with comments on the homology of osteoderms[END_REF]. These bones are formed through direct osseous metaplasia [START_REF] Dubansky | Natural development of dermal ectopic bone in the American alligator (Alligator mississippiensis) resembles heterotopic ossification disorders in humans[END_REF] and are further remodelled by the combination of cyclic osteoclastic bone resorption and osteoblastic growth [START_REF] Klein | Skeletochronology and isotopic analysis of a captive individual of Alligator mississippiensis Daudin, 1802[END_REF][START_REF] De Buffrénil | Morphogenesis of bone ornamentation in extant and extinct crocodilians[END_REF]. Both the primary growth [START_REF] Dubansky | Natural development of dermal ectopic bone in the American alligator (Alligator mississippiensis) resembles heterotopic ossification disorders in humans[END_REF]) and the secondary remodelling [START_REF] De Buffrénil | Differentiation and growth of bone ornamentation in vertebrates: A comparative histological study among the Crocodylomorpha[END_REF] rely on a local network of blood vessels that interconnect within both the bone internal cavities and the ornamental pits [START_REF] Clarac | Vascularization in ornamented osteoderms: physiological implications in ectothermy and amphibious lifestyle in the crocodylomorphs?[END_REF]. The crocodylian osteoderms thus gather the skin blood vessels and therefore shelter the dermal blood flow within a skin that is elsewhere poorly vascularized [START_REF] Clarac | Vascularization in ornamented osteoderms: physiological implications in ectothermy and amphibious lifestyle in the crocodylomorphs?[END_REF]. It has been hypothesized that these cutaneous vessels drive the heat exchanges between the skin and the external environment when basking [START_REF] Seidel | The osteoderms of the American alligator and their functional significance[END_REF][START_REF] Farlow | Internal vascularity of the dermal plates of Stegosaurus (Ornithischia, Thyreophora)[END_REF]) via the control of both the vasodilation [START_REF] Grigg | The role of the cardiovascular system in thermoregulation of Crocodylus johnstoni[END_REF] and of the heart beat rate [START_REF] Seebacher | Integration of autonomic and local mechanisms in regulating cardiovascular responses to heating and cooling in a reptile (Crocodylus porosus)[END_REF][START_REF] Seebacher | Redistribution of blood within the body is important for thermoregulation in an ectothermic vertebrate (Crocodylus porosus)[END_REF]. A recent experimental study on Crocodylus niloticus (Crocodylidae) and Alligator sinensis (Alligatoridae) sub-adult specimens [START_REF] Clarac | The crocodylian skull and osteoderms: a functional exaptation to ectothermy?[END_REF] has indeed proved that the dorsal shield shows higher thermal variations than the flanks that are deprived of osteoderms [START_REF] Trutnau | Crocodilians: Their Natural History & Captive Husbandry[END_REF][START_REF] Kiladze | Lateral osteoderms of the Nile crocodile Crocodylus niloticus[END_REF]. Nevertheless, other authors repeated this experimental protocol on Paleosuchus palpebrosus (Alligatoridae; Veenstra & Broeckoven 2022) and showed similar results although this species has the particularity to present osteoderms along the flanks, the limbs, the sides of the tail and the belly within both sub-adult and adult specimens [START_REF] Magnusson | Paleosuchus palpebrosus. Catalogue of American amphibians and reptiles[END_REF]). However, both experiments relied on infrared images that only record the superficial skin temperature. This type of data may indeed be highly influenced by the temperature variation that is relative to the close dermis blood vessels that are housed by the osteoderm ornamental pits [START_REF] Clarac | Vascularization in ornamented osteoderms: physiological implications in ectothermy and amphibious lifestyle in the crocodylomorphs?[END_REF]. Therefore, in order to discuss the role of the osteoderms in heat transfers via the gathering of the skin vasculature, here we have sampled and compared a full set of osteoderms that come from a Paleosuchus palpebrosus adult specimen. We have localized and quantified the relative expression of bone ornamentation on both the dorsal keeled osteoderms and the lateral osteoderms that are present on the flanks, the tail sides, the limbs and the ventral side. We further calculated the bone porosity on a representative sub-sample in order to compute a proxy to the global osteoderm vascularization both with and without bone ornamentation [START_REF] Clarac | Vascularization in ornamented osteoderms: physiological implications in ectothermy and amphibious lifestyle in the crocodylomorphs?[END_REF]. Beside the full-body extension of the osteoderm shield, Paleosuchus palpebrosus also shares the peculiarity both to be a dwarf species that lives in an equatorial forest (Amazon basin ;[START_REF] Trutnau | Crocodilians: Their Natural History & Captive Husbandry[END_REF][START_REF] Campos | Geographic variation in colour and spot patterns in Dwarf Caiman, Paleosuchus palpebrosus (Cuvier, 1807) in Brazil[END_REF] [START_REF] Diefenbach | Thermal Preferences and Thermoregulation in Caiman crocodilus[END_REF], 29-33°C in Crocodylus johnstoni Seebacher & Grigg 1997, 25-35°C in Crocodylus porosus Seebacher et al. 1999). Here we discuss if the P.palpebrosus osteoderm microanatomy might consist of a good proxy to understand the peculiarity of the equatorial dwarf species thermoregulation process (i.e. Paleosuchus palpebrosus, Paleosuchus trigonatus, Osteolaemus tetraspis) in comparison with larger genera that occupy open environments such as Crocodylus, Alligator, Caiman [START_REF] Trutnau | Crocodilians: Their Natural History & Captive Husbandry[END_REF]. Indeed, the equatorial forest dwarf species live under the canopy and may have a minor use of the osteoderm in heat transfer as they both possess a low body temperature [START_REF] Campos | Thermal relations of dwarf caiman, Paleosuchus palpebrosus, in a hillside stream: Evidence for an unusual thermal niche among crocodilians[END_REF] and live in a rather thermally stable ecosystem that leaves poor exposure opportunities. Besides, previous studies have revealed that the equatorial dwarf genera (i.e. Osteolamus and Paleosuchus) have populations that show a cryptic behavior by living in caves [START_REF] Shirley | Diet and body condition of cavedwelling dwarf crocodiles (Osteolaemus tetraspis, Cope 1861) in Gabon[END_REF][START_REF] Lemaire | Habitat use and behaviour of Schneider's dwarf caiman (Paleosuchus trigonatus Schneider 1801) in the Nouragues reserve. French Guiana[END_REF], streams [START_REF] Magnusson | The ecology of a cryptic predator, Paleosuchus trigonatus, in a Tropical rainforest[END_REF], digging pools [START_REF] Riley | African dwarf crocodiles in the Likouala swamp forests of the Congo basin: habitat, density, and nesting[END_REF][START_REF] Riley | Diet and lung parasites of swamp forest dwarf crocodiles (Osteolaemus tetraspis osborni) in the Northern Congo Republic[END_REF] or dwelling under fallen trunks [START_REF] Lemaire | Habitat use and behaviour of Schneider's dwarf caiman (Paleosuchus trigonatus Schneider 1801) in the Nouragues reserve. French Guiana[END_REF]. These scenarios involve a poor sun exposure and therefore no significant basking behavior [START_REF] Medem | The crocodilian genus Paleosuchus[END_REF][START_REF] Magnusson | The ecology of a cryptic predator, Paleosuchus trigonatus, in a Tropical rainforest[END_REF] which could potentially involve heat transfer via the osteoderm shield [START_REF] Seidel | The osteoderms of the American alligator and their functional significance[END_REF][START_REF] Farlow | Internal vascularity of the dermal plates of Stegosaurus (Ornithischia, Thyreophora)[END_REF]. In this case, osteoderms might instead be involved as a calcium reservoir which would play a role in: 1) male-male contests and reproductive needs in females [START_REF] Hutton | Age determination of living Nile crocodiles from the cortical stratification of bone[END_REF][START_REF] Dacke | Alligator osteoderms as a source of labile calcium for eggshell formation[END_REF][START_REF] Broeckhoven | Osteoderms as calcium reservoirs: Insights from the lizard Ouroborus cataphractus[END_REF]; 2)

Transferring the calcium to both the axial skeleton and the teeth to further preserve the most vital functions when exposed to deficiencies that are due to the diet variations [START_REF] Klein | Skeletochronology and isotopic analysis of a captive individual of Alligator mississippiensis Daudin, 1802[END_REF]) which relate to the various habitat food resources (e.g. cave, jungle floor, streams; [START_REF] Magnusson | Diets of Amazonian crocodilians[END_REF].

Within this function, both the number of osteoderms and their degree of mineralization are relevant parameters; nevertheless, the osteoderm relative location on the body has no significant importance unlike when involved in heat transfer during basking periods.

Materials and Methods

We have studied a full dry skeleton of a Paleosuchus palpebrosus adult male specimen that is present in the comparative anatomy collections of the Muséum National d'Histoire Naturelle (RA 2022.0064).

This animal used to live in captivity at the Parc Zoologique de Paris within a vivarium that included both a 26°c water with a controlled quality and a beach that allowed access to both heat and UVb for an optimal vitamin D3 production. The specimen was weekly fed with dead fishes or rodents and died at the age of 23 years old in 2022. We have assessed that its full set of osteoderms is composed of 1184 units which we divided in two samples: 1) the large osteoderms that come from the dorsal area between the skull and the caudal crest symphysis, which all possess a high keel, a concave shape and an imbrication surface (n = 123; Table 1); 2) the osteoderms that come from the other parts of the body (flank, belly, limbs, tail), which never possess the combination of all these above criteria (n = 1061; Table 1). Within both samples we assessed the expression of bone ornamentation which we ranked according to three states of character (smooth, shallow, deep). We then sub-sampled a set of 6 osteoderms within each sample in order to perform one mid-line transversal cross-section per osteoderm. We further calculated the bone porosity as a proxy to the osteoderm vascularization since the relative size of both the internal cavities and of the ornamental pits is proportional to their content in blood vessels [START_REF] Clarac | Vascularization in ornamented osteoderms: physiological implications in ectothermy and amphibious lifestyle in the crocodylomorphs?[END_REF]. To do so, we took a picture of each cross section and rendered them binary in black and white with Photo Affinity 1.10.5 (Serif Europe Ltd. The Software Centre Wilford Industrial Estate Nottingham NG11 7EP) so that the bone matrix appears in black and the empty cavities appear in white. We included the open space that is consequent to the ornamental pit excavation into the white area by artificially connecting the top of the crests with a virtual black line (as in [START_REF] Clarac | The evolution of dermal shield vascularization in Testudinata and Pseudosuchia: phylogenetic constraints versus ecophysiological adaptations[END_REF]; using Affinity Designer 1.10.5; Serif Europe Ltd. The Software Centre Wilford Industrial Estate Nottingham NG11 7EP). We then measured the relative area that is occupied by the pits and cavities over the full cross-section envelope using Image J (version 1.53t, Wayne Rasband and Contributors National Institutes of Health, USA). Once we obtained the raw data, we proceeded to comparisons via non-parametric statistical tests (Mann-Whitney).

Paleosuchus

Results

The differential expression of bone ornamentation on the osteoderm shield

The crocodylian osteoderm ornamentation is composed of a pattern of repetitive excavated pits that are separated by ridges [START_REF] De Buffrénil | Morphogenesis of bone ornamentation in extant and extinct crocodilians[END_REF][START_REF] Clarac | Bone Ornamentation: deciphering the functional meaning of an enigmatic feature[END_REF]). Here we can observe that these pits are systematically deep on the dorsal part of both the trunk and the neck (Fig 1, Table 1). Among the osteoderms which come from the flanks, the tail, the belly and the limbs; only 3.7% (n = 39) are deeply pitted, 15.1% (n = 161) show shallow pits and 81.1 % (n = 861) are deprived of ornamentation (Fig 1,

Table 1).

Microanatomical comparative analyses

Within our cross-section subsample that is composed of 12 osteoderms, the osteoderm porosity varies between 0.04 and 0.16 with a mean value of 0.071 and a median value of 0.06 (Table 2, Fig. 2,3). Within the dorsal osteoderms, which compose half of the cross-section subsample (Cat. 1; n = 6), the porosity varies between 0.06 and 0.16 with a mean value of 0.09 and a median value of 0.085 (Table 2, Fig 2A,3A). Within the non-dorsal osteoderms, which compose the second half of the cross-section subsample (Cat. 2; n =6), the porosity varies between 0.08 and 0.054 with a mean value of 0.053 and a median value of 0.05 (Table 2,Fig 2B,3A). The Mann-Whitney test shows a significant difference between the median porosity of the dorsal osteoderms (Cat. 1) and the median porosity of the nondorsal osteoderms (Cat. 2; Table 3A) which plots a lower median value (median Cat. 2 = 0.05 < median

Cat. 1 = 0.085). We have compared the full dataset (Cat. 1&2; n =12) with a previous dataset that is composed of an interspecific sample which includes both extant and extinct pseudosuchian species that lived during the Triassic and later periods [START_REF] Clarac | The evolution of dermal shield vascularization in Testudinata and Pseudosuchia: phylogenetic constraints versus ecophysiological adaptations[END_REF]. Within this previous study, the sample was split in two sub-samples: 1) the terrestrial taxa which lived during the Mesozoic; 2) the semi-aquatic taxa that appeared at the lower-Jurassic and who present some descendants that are still present in the extant nature (i.e. Crocodylia; [START_REF] Benton | The phylogeny and classification of the tetrapods, Volume 1. Amphibians, Reptiles, and Birds[END_REF]). Here we have added a new dataset as a third subsample (Table 2; n = 12) in order to perform statistical comparisons via two-sampled non-parametric tests (i.e. Mann-Whitney). This test revealed that the median porosity is significantly different between P. palpebrosus and the other semi-aquatic forms whereas it is not with the terrestrial forms (Table 3B; Fig 3B). The test also revealed a significant difference of the median porosity between the semi-aquatic and the terrestrial forms (

Discussion

The role of bone ornamentation in the crocodylian heat transfers

Previous works led to assess that the expression of bone ornamentation consists of a good proxy to infer a terrestrial or a semi-aquatic lifestyle among extinct crocodylomorphs, allowing to discuss habitat preferences during their evolution [START_REF] Clarac | The evolution of bone ornamentation in Pseudosuchia: morphological constraints versus ecological adaptation[END_REF]Pochat-Cotilloux et al. 2023). These two independent studies indeed revealed that the pits which compose the bone ornamentation are more deeply excavated on both the cranial dermal bones and the osteoderms within the semi-aquatic forms.

The assessment of this morphological pattern led to argue that the expression of bone ornamentation relates to an adaptation to the semi-aquatic ambush predator lifestyle through two essential functions: 1) bone acidosis buffering during long term apnea [START_REF] Jackson | Lactate sequestration by osteoderms of the broad-nose caiman, Caiman latirostris, following capture and forced submergence[END_REF][START_REF] Janis | Palaeophysiology of pH regulation in tetrapods[END_REF]; 2) heat transfer when basking [START_REF] Seidel | The osteoderms of the American alligator and their functional significance[END_REF][START_REF] Farlow | Internal vascularity of the dermal plates of Stegosaurus (Ornithischia, Thyreophora)[END_REF][START_REF] Clarac | The crocodylian skull and osteoderms: a functional exaptation to ectothermy?[END_REF]. Both functions rely on the fact that the ornamental pits house cutaneous blood vessels, which can either be involved in heat transfer during both emerged and floating periods or in binding blood lactate to dermal bone calcium in order to reduce plasma acidity during long-term apnea [START_REF] Jackson | Acid-base balance during hypoxic hypometabolism: selected vertebrate strategies[END_REF]. Although the functional relation between bone ornamentation and the bone acidosis buffering is still conjectural, the relation between heat transfer and osteoderm ornamentation has been indirectly revealed through the acquisition of infrared data in parallel with locating the skin blood vessel clusters on an albino Alligator mississippiensis sub-adult specimen [START_REF] Clarac | The crocodylian skull and osteoderms: a functional exaptation to ectothermy?[END_REF]. Nevertheless, this previous founding does not mean that this role is exclusive but may rather be instead an exaptation in extant species that commonly bask in open environments. Here we show that the pits which compose the bone ornamentation in Paleosuchus palpebrosus are deeply excavated on the dorsal part of both the trunk and the neck in comparison to the other body parts where the pits are either shallow or absent (i.e. the flanks, tail, belly and limbs; Fig1, Table 1). According to this new result, the distribution of bone ornamentation in the adult Paleosuchus palpebrosus shows a significant match with the surface temperature gradient when basking [START_REF] Veenstra | Revisiting the thermoregulation hypothesis of osteoderms: a study of the crocodilian Paleosuchus palpebrosus (Crocodilia: Alligatoridae)[END_REF]. This correlation may be explained by the fact that the superficial skin vessels are housed in the ornamental pits and therefore influence the superficial temperature that has been measured with infrared cameras in previous studies [START_REF] Farlow | Internal vascularity of the dermal plates of Stegosaurus (Ornithischia, Thyreophora)[END_REF][START_REF] Clarac | The crocodylian skull and osteoderms: a functional exaptation to ectothermy?[END_REF][START_REF] Veenstra | Revisiting the thermoregulation hypothesis of osteoderms: a study of the crocodilian Paleosuchus palpebrosus (Crocodilia: Alligatoridae)[END_REF]. In this regard, our results also reveal that the resulting porosity is higher on the dorsal ornamented osteoderm than on the nondorsal osteoderms (Fig. 3A, Table 3A), which means that bone ornamentation increases the osteoderm global vascularization over the dorsal shield. The studies that were proposed by [START_REF] Clarac | The crocodylian skull and osteoderms: a functional exaptation to ectothermy?[END_REF] and [START_REF] Veenstra | Revisiting the thermoregulation hypothesis of osteoderms: a study of the crocodilian Paleosuchus palpebrosus (Crocodilia: Alligatoridae)[END_REF] were both conducted under experimental conditions and are likely to have indirectly revealed the functionality of the crocodylian osteoderm ornamentation in heat transfer. Nevertheless, this statement does not mean that bone ornamentation is systematically involved in such an adaptative function within all species and in all ecosystems (as discussed further below). Regarding the potential influence of the relative thickness variation of the superficial betakeratin layer over the body (as raised by [START_REF] Veenstra | Revisiting the thermoregulation hypothesis of osteoderms: a study of the crocodilian Paleosuchus palpebrosus (Crocodilia: Alligatoridae)[END_REF], further investigations need to be proceeded in order to draw any conclusion. Nonetheless, it might not be the most relevant parameter that explains the surface temperature display since the expression of scale keratin has proved to have no significant influence on heat transfers in snakes (Licht & Bennet 1972).

Fig. 3: Boxplots of the osteoderm porosity resuming the mean, the quartiles, the minimum and the maximum values. A. Intraspecimen sample (Paleosuchus palpebrosus); B. Interspecific comparison, abbreviations: S.aquatic : semi-aquatic (« Terrestrial forms» and « S.aquatic forms » both represent taxa that lived during the Jurassic and later periods, the data were previously published in [START_REF] Clarac | The evolution of dermal shield vascularization in Testudinata and Pseudosuchia: phylogenetic constraints versus ecophysiological adaptations[END_REF] The peculiarity of the equatorial forest dwarf species Even though Paleosuchus palpebrosus shows a well-ornamented dorsal shield, which has been evidenced to perform heat transfer in experimental forced conditions [START_REF] Veenstra | Revisiting the thermoregulation hypothesis of osteoderms: a study of the crocodilian Paleosuchus palpebrosus (Crocodilia: Alligatoridae)[END_REF], it is nevertheless possible that this anatomical feature has a poor implication in heat transfer within the natural environment because the internal body temperature of Paleosuchus palpebrosus ranges only between 20°C and 25°C [START_REF] Campos | Thermal relations of dwarf caiman, Paleosuchus palpebrosus, in a hillside stream: Evidence for an unusual thermal niche among crocodilians[END_REF] whereas the optimal body temperature of the crocodylians that live in open environments do all show higher values (e.g. 23-36°C in Caiman crocodilus [START_REF] Diefenbach | Thermal Preferences and Thermoregulation in Caiman crocodilus[END_REF], 29-33°C in Crocodylus johnstoni Seebacher & Grigg 1997, 25-35°C in Crocodylus porosus [START_REF] Seebacher | Crocodiles as dinosaurs: behavioural thermoregulation in very large ectotherms leads to high and stable body temperatures[END_REF]. These data suggest that Paleosuchus palpebrosus may not naturally show any basking behavior because it does not need to increase its inner temperature, which scores within the air temperature variation range of the equatorial forest (e.g. 22-28°C in Guyana [START_REF] Gregory | Air chemistry over the tropical forest of Guyana[END_REF]20-30°C in Congo Likoko et al. 2019). Even if some data are still missing regarding Paleosuchus trigonatus, it would be rather expected that they share similar characteristics in term of thermal behavior regarding its extreme close morphological and ecological resemblance with Paleosuchus palpebrosus [START_REF] Trutnau | Crocodilians: Their Natural History & Captive Husbandry[END_REF]. Even though, the expression of a deeply excavated ornamentation is almost exclusive to the dorsal shield in Paleosuchus palpebrosus, it is nevertheless to be noted that these osteoderms possess a global porosity that remains quite low in comparison with other semi-aquatic species; they would be instead definitely comparable to extinct forms that used to occupy a variety of terrestrial habitats (e.g. early crocodylomorphs [START_REF] Irmis | Early Crocodylomorpha[END_REF], notosuchians Hill 2010[START_REF] Martin | A Sebecosuchian in a Middle Eocene Karst with comments on the dorsal shield in Crocodylomorpha[END_REF]Fig 3B). Even though the results that were obtained by Veenstra & Broeckhoven (2022) on P. palpebrosus would rather lead to refute the role of the non-dorsal osteoderms in heat transfer, it is nonetheless possible that these bony plates might still play a role in other physiological functions such as bone acidosis buffering during long term apnea [START_REF] Jackson | Lactate sequestration by osteoderms of the broad-nose caiman, Caiman latirostris, following capture and forced submergence[END_REF] and in phosphorous-calcic regulations [START_REF] Hutton | Age determination of living Nile crocodiles from the cortical stratification of bone[END_REF][START_REF] Klein | Skeletochronology and isotopic analysis of a captive individual of Alligator mississippiensis Daudin, 1802[END_REF][START_REF] Dacke | Alligator osteoderms as a source of labile calcium for eggshell formation[END_REF][START_REF] Broeckhoven | Osteoderms as calcium reservoirs: Insights from the lizard Ouroborus cataphractus[END_REF]. Indeed, this last function might be especially relevant to both Paleosuchus sp. and Osteolaemus sp. because these two taxa share a similar cluster of forest habitats within one same ecosystem (i.e. streams; [START_REF] Magnusson | The ecology of a cryptic predator, Paleosuchus trigonatus, in a Tropical rainforest[END_REF], pools [START_REF] Riley | African dwarf crocodiles in the Likouala swamp forests of the Congo basin: habitat, density, and nesting[END_REF][START_REF] Riley | Diet and lung parasites of swamp forest dwarf crocodiles (Osteolaemus tetraspis osborni) in the Northern Congo Republic[END_REF], jungle floor [START_REF] Lemaire | Habitat use and behaviour of Schneider's dwarf caiman (Paleosuchus trigonatus Schneider 1801) in the Nouragues reserve. French Guiana[END_REF], caves [START_REF] Shirley | Diet and body condition of cavedwelling dwarf crocodiles (Osteolaemus tetraspis, Cope 1861) in Gabon[END_REF][START_REF] Lemaire | Habitat use and behaviour of Schneider's dwarf caiman (Paleosuchus trigonatus Schneider 1801) in the Nouragues reserve. French Guiana[END_REF]Fig.4). This cluster may include diet variations between niches and therefore imply deficiencies that are tributary to a narrow specific set of preys (e.g. the low calcium content in some invertebrates). The dwarf crocodylian extensive osteoderm shield would therefore consist of a labile resource of calcium that would allow the accommodation to a set of various niches. We hypothesize that the extensive nature of the osteoderm shield could come together with dwarfism in crocodylians since a small size facilitates access to equatorial forest narrow habitats (i.e. streams, excavated pools, jungle floors, caves) that may content a specific set of preys [START_REF] Magnusson | Diets of Amazonian crocodilians[END_REF]. Despite their small size, the extant dwarf crocodylian species are still apex predators so it seems unlikely that the osteoderm shield has a protective role against predators [START_REF] Trutnau | Crocodilians: Their Natural History & Captive Husbandry[END_REF]. This assumption is reinforced by the fact that the juveniles have not grown any osteoderm yet (Veenstra & Broeckoven 2022) although they make easy prey for a diversity of predators [START_REF] Somaweera | The role of predation in shaping crocodilian natural history[END_REF]. Regarding bone ornamentation, a previous biomechanical study has shown that the excavation of the ornamental pits would be rather detrimental to the osteoderm resistance (Clarac et al. 2019), it is therefore also unlikely that bone ornamentation has a functional implication in protection against external threats (whether they come from predator attacks or intraspecific competition).

Conclusion

We assume that the extensive osteoderm shield in the extant dwarf crocodylian species would result from a "trade-off" between the body growth and the synthesis of a resorbable calcium storage which allows to buffer the calcium deficiency that depends on the food resources that are available among the various niches which compose the equatorial ecosystem (i.e. streams, excavated pools, jungle floors, caves). However, before drawing any global relation which we could apply to the study of extinct species (e.g. Simosuchus clarki, Hill 2010; Diplocynodon sp. Massone & Böhme 2022), we believe that this hypothesis shall at least be confronted to a similar analysis which would integrate both the intraspecific and interspecific variability among Paleosuchus sp. and Osteolaemus sp.

Fig. 2 :

 2 Fig. 1: Diagram of the ornamental pit repartition on the osteoderm shield of Paleosuchus palpebrosus. In red: the deeply pitted osteoderms; in yellow: the shallow pitted osteoderms; in green: the non-ornamented osteoderms; In blue circle: a deeply pitted dorsal osteoderm. Scale bar: 1 cm (photo by François-Gilles Grandin)

Fig. 4 :

 4 Fig. 4: A, B. Natural environment of Paleosuchus trigonatus in French Guiana (photo by Jérémy Lemaire). C. Paleosuchus palpebrosus specimens in captivity at the Parc Zoologique de Paris (photo by François-Gilles Grandin)

  and to possess a lower body temperature (20-26°C; Campos & Magnusson 2013) than the crocodylians that live in open environments (e.g. 23-36°C in Caiman crocodilus

Table 1 :

 1 Number of osteoderms and repartition of bone ornamentation in Paleosuchus palpebrosus(AC 2022.0064)

			Ornamentation
	palpebrosus	Deep	Shallow Absent Total
	(AC 2022.0064)
	Dorsal	123	0	0	123
	osteoderms
	Non-dorsal	39	161	861	1061
	osteoderms

Table 2 :

 2 Variation of the osteoderm porosity in Paleosuchus palpebrosus (AC 2022.0064).

Abbreviations: Min: minimum value; Max: maximum value; Cat. : Category

Table 3B

 3B The second and the third percentile show a narrower range in P. palpebrosus than either in the terrestrial forms or in the semi-aquatic interspecific group (Fig3B).

	sample (Med = 0.175). A
				Paleosuchus palpebrosus
	Mann-Whitney test	(AC 2022.0064)
				Cat. 2 ; n =6
	Paleosuchus palpebrosus
	(AC 2022.0064)
	Cat. 1 ; n = 6
				Porosity
	Dorsal osteoderms (Cat. 1; n = 6)	0.16	0.058	0.094	0.056	0.076	0.090
	Statistic summary (Cat. 1)	Min 0.06	25 percentile 0.06	Mean 0.09	Median 0.085	75 percentile 0.1075	Max 0.16
	Non-dorsal osteoderms (Cat. 2; n = 6)	0.08	0.041	0.060	0.039	0.054	0.054
	Statistic summary (Cat. 2)	Min 0.04	25 percentile 0.04	Mean 0.053	Median 0.05	75 percentile 0.065	Max 0.08
	Total sample	Min	25 percentile	Mean	Median	75 percentile	Max
	Statistic summary (n= 12)	0.04	0.05	0.071	0.06	0.0875	0.16

, Fig 3B)

. The median value is indeed lower in both the terrestrial forms (Median = 0.05) and in P. palpebrosus (Median = 0.06) than in the semi-aquatic interspecific

Acknowledgments

We thank Dr. Salvador Bailon for giving us access to the Collections d'Anatomie Comparée at the Muséum National d'Histoire Naturelle (Paris, France). We also send our thankful regards to Hayat Lamrous (lab technician at Sorbonne Université) for performing the histological cross sections. We finally wish to acknowledge Dr. Jéremy Martin and Dr. Stéphane Hua for reviewing this article and help us improve its content. This research project was supported by the ANR-22-CE02-0015-01_MACHER which was obtained by Dr. Alan Pradel (Assistant Professor at the Muséum National d'Histoire Naturelle).


Jacques Morel

Infection prevention and vaccination in the rheumatic diseases

Keywords:

j-morel@chu-montpellier.fr --

a b s t r a c t

Patients with chronic inflammatory rheumatisms (CIR) have a higher risk of infections compared to healthy subjects. Viral and bacterial pneumonia are the most frequent infections observed in CIR with targeted disease modifying anti-rheumatic drugs (DMARDs). Moreover, drugs used to treat CIR (especially biologic and synthetic targeted DMARDs) increase the risk of infection and expose CIR patients to opportunistic infections such as tuberculosis reactivation. To limit the risk of infection, the risk-benefit ratio should be evaluated for each patient based on their characteristics and comorbidities. To prevent infections, an initial pre-treatment work-up must be performed, especially before the initiation of conventional synthetic DMARDs or biological and synthetic targeted DMARDs. This pretreatment assessment includes the case history, laboratory and radiology findings as well. The physician must make sure a patient's vaccinations are up-to-date. The vaccines recommended for patients with CIR being treated with conventional synthetic DMARDs, bDMARDs, tsDMARDs and/or steroids should be given. Patient education is also very important. During workshops, they learn how to manage their drug treatments in at-risk situations and learn which symptoms require treatment discontinuation.

Infection risk for CIR: influenza, pneumococcus, COVID-19 and opportunistic infections (tuberculosis, shingles, etc.).

Patients living with chronic inflammatory rheumatisms (CIR)have a higher risk of contracting a serious infection, which is defined as hospitalization, intravenous antibiotic therapy or death related to the infection. In a study done before biologics were avail-able, subjects with rheumatoid arthritis (RA) had a higher risk of developing a serious infection compared to subjects who did not have RA and were paired on age and sex [START_REF] Doran | Frequency of infection in patients with rheumatoid arthritis compared with controls: a population-based study[END_REF]. The most common infectionsseptic arthritis and osteomyelitiswere likely due the number of joint injections being performed at that time. The next most common were skin and soft tissue infections, followed by pneumonia. Based on randomized, placebo-controlled studies, a Cochrane review showed that the risk of developing a serious infection increased with nine biologics for all indications (except HIV/AIDS) [START_REF] Singh | Adverse effects of biologics: a network metaanalysis and Cochrane overview[END_REF]. This increased risk was significant for RA. Viral or bacterial pneumonia have become the most frequent infections in CIR [START_REF] Furer | Incidence and prevalence of vaccine preventable infections in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD): a systemic literature review informing the 2019update of the EULAR recommendations for vaccination in adult patients with AIIRD[END_REF].

In the general population, seasonal influenza affects between 5and 10% of adults [START_REF] Furer | Incidence and prevalence of vaccine preventable infections in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD): a systemic literature review informing the 2019update of the EULAR recommendations for vaccination in adult patients with AIIRD[END_REF]. Every year, 1 in 10 non-vaccinated adults con-tract the flu and half of them have symptoms. An American study showed that the incidence of flu is higher in patients with RA than E-mail address: j-morel@chu-montpellier.fr in control subjects. The risks of flu-related complications such as pneumonia or cardiovascular events (myocardial infarction, stroke)are 2.75 times higher in RA than in healthy individuals [START_REF] Blumentals | Rheumatoid arthritis and the incidence of influenza and influenza-related complications: a retrospective cohort study[END_REF]. Complications most often occur in those 70 years or older. The impact of treatments on the risk for contracting the flu is more controversial, with some studies showing a higher incidence in those receiving TNF inhibitors while other studies did not find such an increase with DMARDs or biologics [START_REF] Furer | Incidence and prevalence of vaccine preventable infections in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD): a systemic literature review informing the 2019update of the EULAR recommendations for vaccination in adult patients with AIIRD[END_REF].

Pneumococcal

pneumonia and invasive infections (septicemia, meningitis, arthritis/osteomyelitis) are also more frequent inpatients suffering from autoimmune diseases (including RA) than in healthy subjects with an incidence rate ratio (IRR) of 4.4 (3.8-5.2)and 2.5 (2.4-2.5), respectively. For pneumococcal pneumonia, the risk is highest in adults 18 to 49 years of age [START_REF] Furer | Incidence and prevalence of vaccine preventable infections in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD): a systemic literature review informing the 2019update of the EULAR recommendations for vaccination in adult patients with AIIRD[END_REF].

Infection risk with targeted therapies

When biologics targeting tumor necrosis factor  (TNF ) were first introduced, clinicians were faced with an increase in the incidence of infections, often bronchopulmonary in origin. Along with infections due to classical microorganisms, opportunistic infections occurred: tuberculosis and other mycobacterial infections, and even legionellosis, pneumocystis, histoplasmosis, shingles, etc. [START_REF] Tubach | Risk of tuberculosis is higher with anti-tumor necrosis factor monoclonal antibody therapy than with solubletumor necrosis factor receptor therapy: the three-year prospective French research axed on tolerance of biotherapies registry[END_REF][START_REF] Salmon-Ceron | Drug-specific risk of non-tuberculosis opportunistic infections in patients receiving anti-TNF therapy reported to the 3-year prospective French RATIO registry[END_REF]. Tuberculosis was initially described in patients treated by infliximab and then reported with all TNF inhibitors, including etanercept [START_REF] Tubach | Risk of tuberculosis is higher with anti-tumor necrosis factor monoclonal antibody therapy than with solubletumor necrosis factor receptor therapy: the three-year prospective French research axed on tolerance of biotherapies registry[END_REF]. This tuberculosis can be particularly severe and difficult to diagnose, with a higher frequency of extrapulmonary forms (more than 50% of cases). For non-tuberculosis opportunistic infections, a higher risk was observed with monoclonal antibodies than with etanercept [START_REF] Salmon-Ceron | Drug-specific risk of non-tuberculosis opportunistic infections in patients receiving anti-TNF therapy reported to the 3-year prospective French RATIO registry[END_REF]. Systematic screening for latent tuberculosis, with the prescription of prophylactic antibiotics in case of a positive test, has led to a reduction in the risk of tuberculosis reactivation to the same level as RA patients not receiving a bio-logic [START_REF] Rutherford | Opportunistic infections in rheumatoid arthritis patients exposed to biologic therapy: results from the British Society for rheumatology biologics register for rheumatoid arthritis[END_REF]. Beyond tuberculosis, there is a higher risk of developing a serious infection when receiving a targeted therapy than when receiving conventional treatments. Based on registers of patients with RA and treated with biologics, the incidence of serious infections was between 2 and 6 per 100 patient-years (PY) depending on which targeted therapy was studied, while it was 1.5 to 1.8 per100 PY for traditional DMARDs such as methotrexate (MTX) [START_REF] Gottenberg | Comparative effectiveness of rituximab, abatacept, and tocilizumab in adults with rheumatoid arthritis and inadequate response to TNF inhibitors: prospective cohort study[END_REF][START_REF] Zink | Evaluation of the RABBIT risk score for serious infections[END_REF].A Cochrane meta-analysis of safety data from the pivotal trials of various biologics showed a fairly similar risk of serious infection between patients given biologics (all indications pooled) and those treated with non-biologic DMARDS, except for certolizumab and anakinra, which had a significantly higher risk [START_REF] Singh | Adverse effects of biologics: a network metaanalysis and Cochrane overview[END_REF]. JAK (janus activated kinase) inhibitors are the first drugs in a new therapeutic class. Four JAKi have received European marketing approval: baricitinib (an inhibitor of JAK1 and 2), tofacitinib (an inhibitor of JAK1 and 3), up adacitinib and filgotinib (preferentially inhibit JAK1). This selectivity is based on in vitro pharmacological data whose clinical impact has not yet been demonstrated. The follow-up is longest with tofacitinib, with data from 6194 RA patients included in 17 phase I to III trials, with an exposure period of 19,406 PY [START_REF] Cohen | Long-term safety of tofacitinib for the treatment of rheumatoid arthritis up to 8.5 years: integrated analysis of data from the global clinical trials[END_REF]. The rate of serious infection was calculated at 2.7/100 PY (2.5-3) for all doses combined. This data is not very different to that observed with TNF inhibitors. Opportunistic infections were also described in these trials, with an incidence rate for tuberculosis infections of 0.21/100 PY (0.14-0.40)and a rate of non-tuberculosis opportunistic infections of 0.25(0.18-0.36) [START_REF] Winthrop | Tuberculosis and other opportunistic infections in tofacitinib-treated patients with rheumatoid arthritis[END_REF]. However, the incidence rate of infections due to varicella and herpes zoster presenting as shingles (sometimes disseminated) is higher than with traditional DMARDs (4/100 PY) [START_REF] Winthrop | Herpes zoster and to facitinib: clinical outcomes and the risk of concomitant therapy[END_REF]. The occurrence of shingles has also been observed with other JAKi.

Infection risk with corticosteroid therapy

While the risk of infection with targeted therapy is now well known, that of corticosteroid therapy is often under estimated, especially with low doses (5 mg/day or less). Dixon et al. studied the risk of developing a serious infection based on the dose and duration of exposure to oral glucocorticoid therapy [START_REF] Dixon | Immediate and delayed impact of oral glucocorticoid therapy on risk of serious infection in older patients with rheumatoid arthritis: a nested casecontrol analysis[END_REF]. A daily corticosteroid dose of 5 mg for 3 years increases the risk of developing a serious infection by 2-fold relative to a subject not receiving corticosteroids. A dosage of 30 mg/day for3 months increases the risk nearly 5-fold of developing a serious infection. The dose and duration of oral glucocorticoid therapy must be taken into consideration for treatment decisions because, in the end, a targeted therapy can be less risky than corticosteroids, especially if discontinuation is achieved because of this treatment.

In patients with CIR, the risk of developing a severe COVID-19 infection is related more to comorbidities and the treatments used than to the disease, in the absence of interstitial pneumonia. High-dose and long-term corticosteroids and DMARDs that target the lymphocytes such as mycophenolate mofetil, cyclophosphamide, rituximab are associated with severe COVID-19 infections, along with a worse response to vaccinations againstSARS-Cov2 [START_REF]FAI2R/SFR/SNFMI/SOFREMIP/CRI/IMIDIATE consortium and contributors. Severity of COVID-19 and survival in patients with rheumatic and inflammatory diseases: data from the French RMD COVID-19 cohort of 694 patients[END_REF].

Infection prevention in CIR

The first recommendation to provide to patients and referring physicians is that, in cases of patent infection, targeted therapies (biologics and JAKi) must be stopped. In certain high-risk scenarios, it is recommended to stop targeted therapies in a timeframe corresponding to 2 or even 5 half-lives. This means that the time frame for stopping differs depending on the molecule. How-ever, it may be possible to reduce this time frame. In fact, in RA patients receiving infliximab, stop timing ≤ 4 weeks before joint replacement surgery was sufficient to limit the risk of infection or flare-ups [START_REF] George | Perioperative timing of infliximab and the risk of serious infection after elective hip and knee arthroplasty[END_REF]. An excessively long stoppage of the targeted therapy may be complicated by a flare-up of the CIR, with a need to resort to glucocorticoids. This might expose patients to a higher risk of developing a serious infection than the one associated with the targeted therapy. Beyond the regular adaptation of CIR treatments based on disease activity level, preventative measures can be suggested to reduce the risk of developing a serious infection. It is crucial to perform a pre-treatment work-up before a DMARD is initiated and even more, before starting a targeted biological or synthetic therapy, to limit infection-related complications [START_REF] Furst | Updated consensus statement on bio-logical agents for the treatment of rheumatic diseases, 2011[END_REF].The case history and clinical examination will be used to evaluate the overall risk by looking for factors that contribute to infections such as comorbidities (diabetes, diverticulosis, respiratory conditions, chronic wounds, recurrent infections such as herpes, shingles, urinary/bronchial/sinus infections) and the presence of foreign materials (joint implants, long-term urinary catheter). The context will determine whether a targeted therapy should be used and which molecule to prescribe. Serious and uncontrolled infections (septicemia, opportunistic infections) in scenarios where there is a high-risk of bacterial infection (recent prosthetic joint infection, long-term urinary catheter) are contraindications to the initiation of a targeted therapy. Except for rituximab, testing for latent tuberculosis infection (LTI) should be done before starting a biologic or JAKi, in accordance with the recommendations of the French Health Products Safety Agency (AFSSAPS): Tubertest®with5 units, or in vitro Quanti FERON Gold®test or T-Spot-TB®plusa lung X-ray. In case of LTI, a 9-month course of isoniazid (INH)monotherapy or 3month regimen of INH plus rifampicin should be considered; the targeted therapy can be started 3 weeks after the antibiotics are initiated. A Spanish study showed that since this routine screening was implemented, there has been an 80% decrease in the incidence of LTI reactivation in RA patients receiving TNF inhibitors, bringing the rate in line with RA patients who were not receiving TNF inhibitors (0.09 cases per 100 patients versus 0.564before screening) [START_REF] Carmona | Effectiveness of recommendations to prevent reactivation of latent tuberculosis infection in patients treated with tumor necrosis factor antagonists[END_REF].

Blood tests for the hepatitis B and C viruses (HBV, HCV) and HIV are done before starting a DMARD. These tests are repeated depending on the individual risk and the results of previous tests, especially for HBV and if the last test was more than5 years prior. In cases of an active viral infection (HBV, HCV,HIV), the input of a specialist (hepatologist, infectious disease) will be required before any treatment decision is made. A complete blood count test is done to look for neutropenia or lymphopenia that may contribute to the development of certain infections. Other laboratory or morphological examinations will be requested depending on the clinical context and sometimes, the molecule administered. Thus, below-normal immunoglobulin G (IgG) levels have been associated with a higher risk of developing a serious infection in patients being treated with rituximab. Levels below6 g/L of IgG were associated with a higher risk of serious infection [START_REF] Gottenberg | Risk factors for severe infections inpatients with rheumatoid arthritis treated with rituximab in the autoimmunity and rituximab registry[END_REF]. In patients being treated with rituximab who have IgG < 6 g/L, one should consider rotation to another biologic or at least increased surveillance if the rituximab is continued. In case of recurrent infections in patients with low IgG and/or IgM, a change in treatment should be considered and treatment with2 immunoglobulins should be discussed with an infectious disease physician.

Additional morphological examinations such as a lung CT scan, sinus X-ray or panoramic dental X-ray and specialist opinion are requested, depending on the situation. In the ideal scenario, this screening and prevention assessment would be done at the onset of CIR and then regularly during the follow-up. This specific work-up could help to better evaluate the risk of infection and better prevent it by investigating all the elements that contribute to this risk. In France, certain rheumatology departments are already offering thisto patients with CIR.

Vaccination

Vaccination is another means to prevent infections. The updated vaccinations recommended for the general population must be pro-posed to all patients with CIR, especially before starting a DMARD. We have to make sure that the patient's standard vaccines are up to date, and if needed, catch-up on the immunization schedule, ideally before treatment starts [START_REF] Morel | Vaccinations in adults with chronic inflammatory joint disease: immunization schedule and recommendations for patients taking synthetic or biological disease-modifying anti-rheumatic drugs[END_REF] (Fig. 1). A booster vaccine against diphtheria, tetanus and polio is recommended every 10 years. A booster of the whooping cough vaccine is recommended once in adulthood, while maintaining a 10-year interval from the prior dose.

Along with these typical vaccines in the immunization schedule, two others are specifically recommended. The one against the seasonal flu (every year) and the one against pneumococcus, whose immunization program has been simplified given the new recommendations for the pneumococcal 13-valent conjugate vaccine PCV13 (Prevenar13®) in adults. For patients with RA, pneumococcal immunization was previously done only using the 23-valent polysaccharide vaccine, PPSV23 (Pneumovax®). The newly recommended immunization program consists of the PCV13vaccine followed by the PPSV23 vaccine 8 weeks later. This strategy, called "prime/boost", helps to induce an initial thymus-dependent response that subsequently amplifies the later response to the polysaccharide vaccine that helps to expand the serotype coverage. In patients with CIR who are being treated with drugs that modulate immunity, it is recommended to provide a booster 5 years after the PCV13/PPSV23 program. In fact, the first observational study done in patients with RA and ankylosing spondylitis showed that,1.5 years after vaccination with the 7-valent PCV, the percentage of patients with persistent antibody response against the pneumococcal 23F and 6B serotypes was significantly reduced when they were receiving MTX, TNF inhibitors or TNF inhibitors plus MTX [START_REF] Kapetanovic | Persistence of antibody response 1.5 years after vaccination using 7-valent pneumococcal conjugate vaccine in patients with arthritis treated with different anti-rheumatic drugs[END_REF].Thus, it is recommended to provide a booster dose with the PPSV23(Pneumovax®) 5 years after PCV13/PPSV23 immunization. Vaccination against the seasonal flu and against pneumococcal disease can be done on the same day at two different injection sites. These two vaccines are well tolerated in patients who have CIR, like in the general population.

The immune response to vaccination may not be optimal depending on the treatments [START_REF] Hua | Effect of methotrexate, anti-tumor necrosis factor _, and rituximab on the immune response to influenza and pneumococcal vaccines in patients with rheumatoid arthritis: a systematic review and meta-analysis[END_REF]. Patients receiving MTX and leflunomide had a worse immune response to the influenza and pneumococcal vaccines, based on antibody titers. A study of vaccine strategies has shown that temporary discontinuation for 2 weeks following the influenza vaccine will significantly improve the humoral immune response without having more flare-ups [START_REF] Park | Effect of methotrexate discontinuation on efficacy of seasonal influenza vaccination in patients with rheumatoid arthritis: a randomised clinical trial[END_REF]. Thus, one should consider whether the CIR activity will allow MTX to be suspended for 2 weeks after the vaccines. For rituximab, all studies showed worse vaccine protection in the months following the infusions. Thus, it is recommended to administer the vaccines; if possible, after the 4th month that follows the last rituximab infusion. For abatacept, a reduction in humoral response is observed that is greater for the conjugate vaccine than the polysaccharide vaccine. While we do not yet have enough data to provide clear recommendations, a suspension, like for MTX, could probably improve the vaccine response.

When an inert varicella zoster virus vaccine is available, it could be recommended for patients treated with JAKi and also when a biologic is initiated [START_REF] Lal | Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults[END_REF]. Other vaccines are given on a case-by-case basis, depending on the situation, like travel to certain countries. Live (attenuated) vaccines are contraindicated with the treatments used for CIR. Thus, DMARDs should be suspended 3 months before a patient receives a live vaccine. The vaccines in question are those against the Bacille Calmette-Guérin (BCG), the MMR (Mumps, Measles, Rubella) vaccine, yellow fever vaccine, chickenpox vaccine, and oral poliovirus vaccines.

COVID-19 vaccines

The first vaccines approved in Europe were the messenger RNA (mRNA) vaccines BNT162b or Comirnaty®(Pfizer/BioNTech) and the mRNA 1273 or Spikevax®(NIH/Moderna) [START_REF] Baden | Efficacy and safety of the mRNA-1273SARS-CoV-2 vaccine[END_REF][START_REF] Polack | Safety and efficacy of the BNT162b2 mRNACovid-19 vaccine[END_REF]. These two mRNA vaccines are given as two intramuscular doses 1 month apart. Two liveattenuated adenovirus DNA vaccines are avail-able: the one developed by Oxford University and Astra-Zeneca(ChAdOx1/Vaxzevria®) in which two doses are given 28 days apart, and the one developed by Janssen (Ad26.COV2-S) that requires only one injection [START_REF] Ramasamy | Safety and immunogenicity ofChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in[END_REF][START_REF] Sadoff | 4youngand old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial[END_REF]. The NVX-CoV2373 vaccine (Nuvaxovid®) uses more traditional technology by administration of the spike protein, like vaccines against whooping cough or HBV [START_REF] Heath | Safety and efficacy of NVX-CoV2373 Covid-19 vaccine[END_REF]. The vaccine is given as two doses 3 weeks apart for the primary vaccine series. Persons who received only a single dose of a vaccine, no matter which one, and who refuse or cannot get a second dose of the same vaccine, can complete their primary vaccination with Nuvaxovid®. Although others will be available as more phase 3clinical trials are completed, mRNA vaccines have gradually taken over due to their wide availability, effectiveness and safety. In fact, deaths related to blood clots happened with DNA vaccines [START_REF] Sánchez Van Kammen | Frequency of thrombo-cytopenia and platelet factor 4/Heparin antibodies in patients with cerebral venous sinus thrombosis prior to the COVID-19 pandemic[END_REF].Even if these events were extremely rare, they stuck in the minds of the general population, which no longer wanted to receive this type of vaccine. The large-scale availability of mRNA vaccines now allows every person to be vaccinated.

Vaccination is recommended for patients with CIR given the risk of developing a more severe form, especially when receiving treatments that modulate humoral or cell-mediated immunity such as MTX, rituximab, abatacept and long-term corticosteroid therapy. In the end, after receiving an mRNA vaccine, the humoral response observed in those receiving immuno modulatory therapy is close to that observed with other vaccines. Treatments against cytokines and the JAKi have little effect on the humoral response to vaccines, while treatments that target lymphocytes (MTX, rituximab, abatacept, mycophenolate mofetil) are associated with a worse response [START_REF] Furer | Immunogenicity and safety of the BNT162b2mRNA COVID-19 vaccine in adult patients with autoimmune inflammatory rheumatic diseases and in the general population: a multicentre study[END_REF]. In practice, there is no contraindication to COVID-19 vaccination in patients with CIR. This vaccination must be done as soon as possible. The tolerance to mRNA vaccines in patients with CIR differs little to that in healthy subjects, with the risk of flare-ups being comparable to other vaccines. There is no consensus on treatment discontinuation: EULAR recommends continuing treatments [START_REF] Furer | update of EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases[END_REF] while the American College of Rheumatology recommends a temporary discontinuation of MTX and JAKi treatments (7 days after vaccine) and abatacept (7 days before and 7 days after) [START_REF] Curtis | American college of rheumatology guidance for COVID-19 vaccination in patients with rheumatic and musculoskeletal diseases: version 3[END_REF].These treatment stoppages can only improve the vaccine response measured as antibody titers against the spike (anti-S) proteins ofSARS-CoV-2. However, it can only be considered if the disease activity allows it and if it does not delay vaccine administration. Rituximab considerably weakens the antibody response of mRNA vaccines. For this reason, a 3rd dose is recommended 1 month after the 2nd dose. The last dose of the SARS-CoV2 vaccine should be given 2 to 4 weeks before the next rituximab cycle, if the disease activity allows it. The level of antibody titers against anti-S proteins that provides protection against a severe form of has not yet been defined. However, at titer of 260 BAU (Binding Antibody Unit) or higher is an accepted threshold to aim for after a full immunization program. If the immune response is not adequate, monoclonal antibodies can be administered for pre-exposure prophylaxis [START_REF] Kaplon | Antibodies to watch in 2021[END_REF]. Association of nirmatrelvir/ritonavir should be administrated within the five days following the first symptoms of COVID-19.

Educating patients about their disease is also a good means to prevent complications by emphasizing the risks of infection when undergoing treatment, the behaviors to adopt as a function of the circumstance of infection risk or even warning symptoms such as fever or weight loss [START_REF] Piperno | Efficiency of an education program on the safety knowledge and skills of patients with rheumatoid arthritis treated by biologics[END_REF]. Various treatment education programs aimed at patients who have RA and workshops on the management of biological treatments with information about the rules that should lead to treatment discontinuation are available. The impact of patient education is still difficult to evaluate but the exchanges between healthcare professionals and patients in these programs are a supplemental tool for reducing the risks related to the disease and the treatments used. To summarize, infections are complications, sometimes serious, of the treatments used for CIR. Preventing these infections requires an exhaustive assessment of the infection risks and update of the vaccinations recommended for immunocompromised patients receiving biologic therapy and/or corticosteroids. Educating the patient on how to react to high-risk situations (stopping the treatment at the right time) and regular monitoring of these patients by the referring physician and rheumatologist are cornerstones of this infection prevention. Disclosure of interest Jacques Morel received less than D 10,000 in fees from Abbvie, Amgen, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Frésenius, Galapagos, Glaxo Smith Kline, Janssen, Lilly, Médac, Novartis, Pfizer, Sandoz. Jacques Morel received a research grant from BMSand Pfizer.