Jérôme Avouac
email: jerome.avouac@aphp.fr.

Olivier Fogel

Sophie Hecquet

Claire Daien

Ismail Elalamy

Fabien Picard

Clément Prati

Jean Hugues Salmon

Marie-Elise Truchetet

Jérémie Sellam

Anna Molto

Recommendations for assessing the risk of cardiovascular disease and venous thromboembolism before the initiation of targeted therapies for chronic inflammatory rheumatic diseases

Keywords: Cardiovascular disease, Chronic inflammatory rheumatic diseases, JAK inhibitors, Recommendations, Targeted therapies, Venous thromboembolism

Background:

Patients with rheumatoid arthritis (RA) and other chronic inflammatory rheumatic disorders have increased risk of cardiovascular disease (CVD) and venous thromboembolism (VTE) compared with the general population. Moreover, recent data have raised concerns around a possible increased risk of major CV events (MACE) and VTE in patients treated with JAK inhibitors (JAKi). In October 2022, the PRAC has recommended measures to minimize the risk of serious side effects, including CV conditions and VTE, associated with all approved in chronic inflammatory diseases.

Objective:

To provide an adequate and feasible strategy to evaluate, at the individual level, the risk of CVD and VTE in patients with chronic inflammatory rheumatic diseases.

Methods:

A multidisciplinary steering committee comprised 11 members including rheumatologists, a cardiologist, a hematologist expert in thrombophilia and fellows. Systematic literature searches were performed and evidence was categorized according to standard guidelines. The evidence was discussed and summarized by the experts in the course of a consensus finding and voting process.

Results:

Three overarching principles were defined. First, there is a higher risk of MACE and VTE in patients with chronic inflammatory rheumatic diseases compared with the general population. Second, the rheumatologist has a central role in the evaluation of the risk of CVD and VTE in patient with chronic inflammatory rheumatic diseases. Third, the risk of MACE and VTE should be regularly assessed in patients with chronic inflammatory rheumatic diseases, particularly before initiating targeted therapies. Eleven recommendations were defined to prevent potentially life-threatening complications of CVD and VTE in patients with chronic inflammatory rheumatic diseases, providing practical assessment of CVD and VTE before considering the prescription of targeted therapies, and especially JAKi.

Conclusion:

These practical recommendations based on expert opinion and scientific evidence provide consensus for the prevention and the assessment of CVD and VTE.

Introduction

Cardiovascular disease (CVD) and venous thromboembolism (VTE) risk in patients with rheumatoid arthritis (RA) and other chronic inflammatory rheumatic diseases, in particular axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA), is substantially elevated compared with the general population. For RA, the magnitude of the excess risk of CVD is comparable to that reported in patients with diabetes mellitus [START_REF] Van Halm | Rheumatoid arthritis versus diabetes as a risk factor for cardiovascular disease: a cross-sectional study, the CARRE Investigation[END_REF], and there is a 2-fold increase risk of VTE in RA compared to the general population [START_REF] Hu | Venous thromboembolism risk in rheumatoid arthritis patients: a systematic review and updated meta-analysis[END_REF]. Thus, a proactive and targeted CVD and VTE risk management is mandatory. The EULAR task force was convened to critically appraise existing evidence on CVD risk in patients with chronic inflammatory rheumatic diseases in 2009, leading to the formulation of 10 recommendations, which were updated in 2015/2016 [START_REF] Agca | EULAR recommendations for cardio-vascular disease risk management in patients with rheumatoid arthritis other forms of inflammatory joint disorders: 2015/2016 update[END_REF].However, these recommendations did not consider the risk of VTE and were elaborated prior to the launch of Janus Kinase inhibitors (JAKi), which have been added to the therapeutic arsenal for chronic inflammatory rheumatic disorders in 2017 in France. Currently, 4 JAKi are available in France in chronic inflammatory rheumatic diseases (tofacitinib, baricitinib, upadacitinib and filgotinib).

The ORAL Surveillance study has raised concerns about a possible increased risk of major cardiovascular events (MACE) and VTE in tofacitinib-treated patients in a specific population of RA patients with age > 50 years and at least one additional CV risk factor [START_REF] Ytterberg | Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis[END_REF]. Moreover, early real-life data have also suggested a higher venous and arterial thromboembolic risk with baricitinib [START_REF] Montastruc | Comparison of major cardiovascular and thromboembolic events in safety reports between rheumatoid arthritis patients treated with JAK inhibitors versus anti-TNF: results from VigiBase[END_REF][START_REF] Gouverneur | JAK inhibitors and risk of major cardiovascular events or venous thromboembolism: a self-controlled case series study[END_REF]. These data conducted to successive alerts from the European Medicines Agency (EMA) and the US Food and Drug Administration(FDA) between 2019 and 2022.

In 2019, the EMA's pharmacovigilance risk assessment commit-tee (PRAC) has concluded that tofacitinib could increase the risk of VTE in patients who are already at high risk. As a result, the agency recommended that tofacitinib should be used with caution in all patients at high risk of VTE [7]. In 2021, the FDA released a document and warning on CVD and VTE risks of tofacitinib in comparison with TNF-inhibitors, based on the analyses of ORAL Surveillance [8]. The full data were then published in early 2022 [START_REF] Ytterberg | Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis[END_REF].

In October 2022, the PRAC has recommended measures to minimize the risk of serious side effects associated with JAKi used totreat several chronic inflammatory disorders. These side effects include CV conditions, blood clots, cancer and serious infections. The committee recommended that these medications should be used in the following patients only if no suitable treatment alternatives are available: those aged 65 years or above, those at increased risk of major cardiovascular problems (such as heart attack or stroke), those who smoke or have done so for a long time in the past and those at increased risk of cancer. The committee also recommended using JAKi with caution in patients with risk factors for VTE.

The PRAC has also concluded that these safety findings apply to all approved uses of JAKi in chronic inflammatory diseases, including RA, axSpA and PsA. However, it is important to note that the PRAC has not modified the indications, the recommended dosages or the line of treatment of JAKi. The PRAC conclusions urgently require an adequate and feasible strategy to evaluate, at the individual level, the risk of CVD and VTE in patients with chronic inflammatory rheumatic diseases before considering the use of JAKi. To this end, the aim of this Evidence-Based Guideline is to summarize available evidence and to provide practical recommendations agreed by consensus regarding the prevention and the assessment of CVD and VTE at the initiation of targeted therapies and especially JAKi.2.

Methods

The recommendations were conducted on behalf of the French Society of Rheumatology and followed the 2014 EULAR Standardized Operating Procedures (SOPs) [START_REF] Van Der Heijde | update of the EULAR standardised operating procedures for EULAR-endorsed recommendations[END_REF].

Following approval by the French Society of Rheumatology, the convenor (JA) set up a steering committee which included a methodologist (AM), and two fellows (OF, SH) who conducted the systematic literature reviews (SLRs).

Subsequently, the remaining task force members were invited, making a total of 11 participants, including 9 rheumatologists, one cardiologist and one hematologist expert in thrombophilia.

The steering committee defined the research questions of the SLRs. Under the guidance of the methodologist, the two fellows performed two SLRs. The first focused on the risk of MACE upon all available JAKi (SH) in chronic inflammatory rheumatic diseases. The second addressed the prevalence and the risk factors associated with VTE, in and beyond the scope of all available JAKi, in chronic inflammatory rheumatic diseases (OF). These SLRs included studies published from 2011 until 2022 for MACE, without time limit for VTE and are published separately. The results of the SLRs were discussed with the steering committee first and the task force afterwards.

At the task force meeting in October 2022, the SLRs were first presented, and their findings discussed. In addition to the evidence from the SLRs, expert opinion was considered when formulating overarching principles and recommendations. Recommendations were edited according to the comments made, followed by a formal voting using anonymized polls. Consensus was reached if ≥ 75%of the members voted in favor of the recommendations in the first(or ≥ 67% and ≥ 50% in a second and third) round. Finally, each taskforce member anonymously indicated his or her level of agreement (LoA) through an online survey (numerical rating scale ranging from 0 = "do not agree at all" to 10 = "fully agree"). The mean of the LoA were presented. The draft of the manuscript was sent to all task force members for review. The final manuscript was approved by all authors and the French Society of Rheumatology executive board.

Results

The results of the SLRs will not be presented here in detail but are presented in respective parallel publications. However, if pertinent for the explanation of the results, parts of these data will be mentioned.

Overarching principles

The task force defined three overarching principles of CVD and VTE risk management in chronic inflammatory rheumatic diseases (Table 1)

.4.1. The risk of CVD and VTE is higher in patients with chronic inflammatory rheumatic diseases compared with the general population, in particular in patients with RA Increased CVD risk is now clearly acknowledged in RA with a risk of myocardial infarction (MI) in RA being found to be approximately 70% higher than in the general population [START_REF] Agca | EULAR recommendations for cardio-vascular disease risk management in patients with rheumatoid arthritis other forms of inflammatory joint disorders: 2015/2016 update[END_REF]. Since the publication of the first EULAR recommendations in 2009 for CVD risk management in patients with RA, the evidence for an enhanced CVD risk has markedly increased [START_REF] Agca | EULAR recommendations for cardio-vascular disease risk management in patients with rheumatoid arthritis other forms of inflammatory joint disorders: 2015/2016 update[END_REF][START_REF] Avouac | Mortality profile of patients with rheumatoid arthritis in France and its change in 10 years[END_REF]. It was reported in a large Danish cohort study that the risk of MI in RA patients is comparable to the risk of patients with diabetes [START_REF] Lindhardsen | The risk of myocardial infarction in rheumatoid arthritis and diabetes mellitus: a Danish nationwide cohort study[END_REF]. New evidence strengthens the notion that the excess risk of CVD morbidity and mortality in RA patients is linked to both traditional and RA-related CVD risk factors including inflammation, extra-articular manifestations or anticitrullinated protein antibody positivity [START_REF] Solomon | Explaining the cardiovascular risk associated with rheumatoid arthritis: traditional risk factors versus markers of rheumatoid arthritis severity[END_REF]. Compared with controls, patients with axSpA and PsA have an increased risk of vascular death and CVD events, influenced by greater prevalence of CVD risk factors as well as increased arterial stiffness [START_REF] Brophy | No increased rate of acute myocardial infarction or stroke among patients with ankylosing spondylitis-a retrospective cohort study using routine data[END_REF].

Likewise, recent evidence has highlighted the increased risk of VTE in chronic inflammatory rheumatic diseases compared to healthy controls, and particularly in RA [START_REF] Ketfi | Risk of venous thromboembolism in rheumatoid arthritis[END_REF]. A recent metaanalysis of 10 observational studies has reported a risk of VTE in RA estimated by an odds ratio (OR) of 2.23 (95% confidence interval [CI] 1.79-2.77). The OR for deep vein thrombosis (DVT) and pulmonary embolism (PE) were 2.25 (95%CI 1.70-2.98) and2.15 (95%CI 1.39-3.49), respectively [START_REF] Hu | Venous thromboembolism risk in rheumatoid arthritis patients: a systematic review and updated meta-analysis[END_REF]. Similar to the general population, the risk of VTE in RA is increased in several at risk situations including hospitalization, surgery, and neoplasia (corresponding to 60% of provoked VTE) [START_REF] Kim | Risk of venous thromboembolism in patients with rheumatoid arthritis[END_REF][START_REF] Holmqvist | Risk of venous thromboembolism inpatients with rheumatoid arthritis and association with disease duration and hospitalization[END_REF]. Several general (age, male sex, obesity, comorbidities) and disease-specific (disease activity, corticosteroids) VTE risk factors have been identified in RA patients [START_REF] Kim | Risk of venous thromboembolism in patients with rheumatoid arthritis[END_REF][START_REF] Chung | Rheumatoid arthritis increases the risk of deep vein thrombosis and pulmonary thromboembolism: a nationwide cohort study[END_REF][START_REF] Li | The risk and trend of pulmonary embolism and deep vein thrombosis in rheumatoid arthritis: a general population-based study[END_REF][START_REF] Molander | Risk of venous thromboembolism in rheumatoid arthritis, and its association with disease activity: a nationwide cohort study from Sweden[END_REF][START_REF] Ozen | Risk factors for venous thromboembolism and atherosclerotic cardiovascular disease: do they differ in patients with rheumatoid arthritis?[END_REF][START_REF] Yoshimura | Disease activity as a risk factor for venous thromboembolism in rheumatoid arthritis analysed using time-averaged DAS28CRP: a nested case-control study[END_REF][START_REF] Choi | The risk of pulmonary embolism and deep vein thrombosis in rheumatoid arthritis: a UK population-based outpatient cohort study[END_REF]. The risk of VTE seems also significantly increased in axSpA compared to the general population, but with a less extent than in RA [START_REF] Li | The risk and trend of pulmonary embolism and deep vein thrombosis in rheumatoid arthritis: a general population-based study[END_REF][START_REF] Eriksson | Is ankylosing spondylitis a risk factor for cardiovascular disease, and how do these risks compare with those in rheumatoid arthritis?[END_REF][START_REF] Ramagopalan | Risk of venous thromboembolism in people admitted to hospital with selected immune-mediated diseases: record-linkage study[END_REF][START_REF] Zoller | Autoimmune diseases and venous thromboembolism: a review of the literature[END_REF][START_REF] Avina-Zubieta | Risk of venous thromboembolism in ankylosing spondylitis: a general population-based study[END_REF]. No increased risk of VTE has been reported in PsA [START_REF] Damian | The incidence and risk factors for venous thromboembolic events in patients with psoriasis and psoriatic arthritis[END_REF][START_REF] Gazitt | The association between psoriatic arthritis and venous thromboembolism: a population-based cohort study[END_REF][START_REF] Galloway | Risk of venous thromboembolism in immune mediated inflammatory diseases: a UK matched cohort study[END_REF][START_REF] Ogdie | Risk of incident liver disease in patients with psoriasis, psoriatic arthritis, and rheumatoid arthritis: a population-based study[END_REF][START_REF] Bengtsson | Are ankylosing spondylitis, psoriatic arthritis and undifferentiated spondyloarthritis associated with an increased risk of cardiovascular events? A prospective nationwide population-based cohort study[END_REF]. Patients with chronic inflammatory rheumatic disorders do not seem to present an over-risk of inherited thrombophilia [START_REF] Regeczy | Hypercoagulability in various autoimmune diseases: no association with factor V Leiden mutation[END_REF].

The rheumatologist has a central role in the evaluation of CVD and venous thromboembolic risks in patient with RA and other chronic inflammatory rheumatic diseases, with the use of validated tools

The task force therefore recommends that the treating rheumatologist has a central role in this evaluation, as stated in the EULAR recommendations. Indeed, several issues regarding CVD and VTE risk prevention plainly fall within the scope of practice of all rheumatologists.

Achieving optimal disease control of rheumatic disease activity is an important treatment objective from a CVD/VTE standpoint and minimizing the use of corticosteroids and NSAIDs are some specific recommendations that rheumatologists could adopt to lower CV and VTE risk. The responsibility for CVD and VTE risk management should be defined locally given that different specialists may intervene to take over these complications. Moreover, CVD and VTE risk management may include health care professionals other than rheumatologists. In clinical practice, it is not always clear who is taking responsibility for CVD and VTE risk evaluation and management in patients with chronic inflammatory rheumatic disorders.

If the rheumatologist performs the risk assessment, he should use validated tools to provide the most reliable and accurate possible evaluation. Among the available tools, the 2021 recommendations from the European Society of Cardiology (ESC) have proposed the SCORE2 and the SCORE2-Older Persons (SCORE2-OP) risk scales to estimate 10-year fatal and nonfatal CVD risks (https://u-prevent.com/calculators) [START_REF] Visseren | ESC Guidelines on cardiovascular disease prevention in clinical practice[END_REF]. The SCORE2 is a new algorithm derived, calibrated and validated to predict the 10-year risk of a first CV event in European populations. It is an important advance in addressing some of the limitations of SCORE algorithm. It is an updated model based on individual international data from 13 million people with no initial CV history from more than 50 prospective cohort studies and national registries in European countries, in whom 60,000 incident CV events were recorded during the observation period (SCORE2 2021). This formidable effort was conducted in 3 steps:

•the model was derived from 677,684 participants from 45 cohorts without CV history recruited between 1990 and 2009;

•second, sexand age-specific regional multipliers were deter-mined for conversion of CV mortality rates to incidence rates involving nearly 10.8 million individuals with 731,265 CV events recorded during follow-up;

•finally, external validation of the risk models was performed using data from 1,133,181 individuals without a history of CV or diabetes in 25 prospective studies from 15 European countries.

SCORE2 has several improvements over the original SCORE model because it is based on more contemporary and representative data on CV events in Europe and also accounts for the impact of competing risks unrelated to CV events. The recalibration of SCORE2 to four European regions with different levels of CVD risk improves risk stratification. Most importantly, SCORE2 pro-vides estimates for both fatal and nonfatal CV events, which is an improvement over calculators that predict only fatal events. Consideration of fatal events alone may underestimate the total burden of CV events, which in recent decades has shifted toward nonfatal events, particularly in younger subjects. To improve the accuracy of risk prediction in adults older than 70 years, the new SCORE2-OP model, was derived from the Cohort of Norway (CONOR) study with 28,503 participants from a low-risk region, recalibrated for4 geographic regions, and validated in 338,615 persons from different regions (SCORE2-OP 2021). The main advantage of this model is that it considers sex-specific competing risk and inter-actions between age and risk factors. SCORE2-OP illustrates the broad distribution of 10-year CV risk in the elderly, emphasizing the need for accurate risk prediction to guide treatment decisions in this age group. The high and very high CVD risk categories based on SCORE2 and SCORE2-OP are provided in the Table 2. However, the suboptimal performance of risk scores used in general population when applied to patients with chronic inflammatory rheumatic disorders has to be recognized, leading to under estimation of CV risk in these populations. Thus, given the important gap sin knowledge still existing regarding the approach to CV risk stratification in clinical practice and the need of using disease-specific risk prediction models, there is clearly a need for new relevant and feasible methods to predict CV risk in RA. In the absence of validated tools, this risk stratification of CVD risk can be performed according to patient categories (atherosclerotic cardiovascular disease[ASCVD]diabetes, familial hypercholesterolemia, chronic kidney disease) as presented in Table 2. This stratification ensures flexibility for CVD evaluation since it gives to the clinician the possibility to use the SCORE or to refer to patient categories.

Regarding the risk of VTE, different thrombosis risk assessment models (RAMs) have been developed for specific clinical scenarios [START_REF] Spyropoulos | The use of weighted and scored risk assessment models for venous thromboembolism[END_REF], including the Caprini RAM for the use in patients undergoing surgery, the Padua prediction score, the IMPROVE risk score or the GENEVA risk score for non-surgical inpatients who are acutely ill [START_REF] Gould | Prevention of VTE in non-orthopedic surgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guide-lines[END_REF][START_REF] Barbar | A risk assessment model for the identification of hospitalized medical patients at risk for venous thrombo-embolism: the Padua Prediction Score[END_REF][START_REF] Spyropoulos | Predictive and associative models to identify hospitalized medical patients at risk for VTE[END_REF]. Notably, most of these RAMs do not include chronic inflammatory rheumatic diseases as a risk factor.

Unfortunately, there is no specific and validated screening tools for the assessment of the overall risk of VTE in patients with chronic inflammatory rheumatic diseases. Development of validated tools is imperative to enable correct assessment of the risk of thrombosis and to adequately implement tailored prophylactic measures in different clinical scenarios. In the absence of validated tools, the herein recommendations propose in Table 3 the list of risk factors to identify patients at risk of VTE.

The risk of MACE and VTE should be regularly assessed in patients with chronic inflammatory rheumatic diseases particularly before initiating targeted therapies

CVD risk assessment is recommended for all patients with RA, axSpA or PsA at least once every 5 years, which is in line with the latest ESC guidelines [START_REF] Visseren | ESC Guidelines on cardiovascular disease prevention in clinical practice[END_REF], so that lifestyle advice and CVD preventive treatment can be initiated when indicated. Currently, there is no evidence that annual CVD risk assessment compared with 5-yearrisk assessment leads to a more significant reduction in CVD mortality or morbidity in patients with chronic inflammatory rheumatic diseases [START_REF] Agca | EULAR recommendations for cardio-vascular disease risk management in patients with rheumatoid arthritis other forms of inflammatory joint disorders: 2015/2016 update[END_REF].

Risk factors for VTE, including in particular older age (≥ 65years), history of VTE, obesity and ongoing malignancy (Table 3) should be assessed in all patients with chronic inflammatory rheumatic diseases. Several of these risk factors are transient (Table 3) and need a continuous re-evaluation especially when the clinically condition changes (such as flare, hospitalization, surgery discharge and so on). CVD and VTE risk evaluation should be reconsidered at the initiation of targeted therapies, which may modify the risk of CVD or VTE, so that clinicians can act accordingly [START_REF] Ytterberg | Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis[END_REF][START_REF] Solomon | Reducing cardiovascular risk with immunomodulators: a randomised active comparator trial among patients with rheumatoid arthritis[END_REF][START_REF] Charles-Schoeman | Risk of major adverse cardiovascular events with tofacitinib versus tumour necrosis factor inhibitors inpatients with rheumatoid arthritis with or without a history of atherosclerotic cardiovascular disease: a post hoc analysis from ORAL Surveillance[END_REF][START_REF] Giles | Cardiovascular safety of tocilizumab versus etanercept in rheumatoid arthritis: a randomized controlled trial[END_REF].

Recommendations

The task force defined 11 recommendations of CVD and VTE risk management in chronic inflammatory rheumatic diseases. The list of the recommendations, including the level of agreement based on voting by the task force, is shown in Table 1. The recommendations follow a logical sequence and they are not listed in sequence of importance. All recommendations are discussed in detail below.

Disease activity should be controlled optimally in order to lower the risk of MACE and VTE in patients with chronic inflammatory rheumatic disorders. Remission (or alternatively low disease activity) should be the therapeutic target

The EULAR recommendations for CVD risk management have emphasized the importance of control of disease activity to lower CVD risk, and the association between higher cumulative inflammatory burden and increased risk of MACE in RA [START_REF] Agca | EULAR recommendations for cardio-vascular disease risk management in patients with rheumatoid arthritis other forms of inflammatory joint disorders: 2015/2016 update[END_REF]. They have highlighted that reducing inflammation is crucial in RA for CVD risk management. Treatment should aim at reaching a target of sustained remission or, alternatively, low disease activity in every patient, as stated by the EULAR recommendations [START_REF] Smolen | EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update[END_REF].Conventional synthetic disease-modifying anti-rheumatic drugs(csDMARDs), in particular methotrexate (MTX), as well as bio-logical DMARDs (bDMARDs), such as the TNF inhibitors (TNFi),are often associated with a significant reduction in CVD risk inpatients with RA [START_REF] Agca | EULAR recommendations for cardio-vascular disease risk management in patients with rheumatoid arthritis other forms of inflammatory joint disorders: 2015/2016 update[END_REF]. A recent manuscript has reported that the addition of either a TNFi or triple therapy (MTX, sulfasalazine and hydroxychloroquine) resulted in important improvements in vascular inflammation [START_REF] Solomon | Reducing cardiovascular risk with immunomodulators: a randomised active comparator trial among patients with rheumatoid arthritis[END_REF]. Reduction of disease activity after treatment with tocilizumab or rituximab (RTX) showed a beneficial effect on surrogate markers of CVD [START_REF] Agca | EULAR recommendations for cardio-vascular disease risk management in patients with rheumatoid arthritis other forms of inflammatory joint disorders: 2015/2016 update[END_REF]. The balance between JAKi-induced inflammation reduction and the risk of CVD is more difficult to apprehend because of the results of ORAL Surveillance. This was a large worldwide, multicenter, prospective, phase 3B/4,randomized, open-label, non-inferiority safety endpoint study, comparing the safety of tofacitinib (5 or 10 mg × 2/day) to TNF inhibitors (adalimumab in the US, etanercept in the rest of the world).Patients included had RA and inadequate response to MTX. At time of inclusion, patients were to be at least 50-years-old with at least one additional CV risk factor. A higher number of MACE were observed with tofacitinib compared to TNF  inhibitors (98/2911, 3.4% vs.37/1451, 2.5%) and the non-inferiority of tofacitinib was not shown [START_REF] Ytterberg | Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis[END_REF]. It is important to remind that:

•ORAL Surveillance included patients with RA having other risk factors that impact absolute risk of MACE, and this CVD-risk enriched population likely reflected a spectrum of CVD risk;

•tofacitinib was compared to TNFi which are associated with CVD reduction;

•the difference of MACE was formally observed in patients with ASCVD, and to a lesser extent in patients with only CV risk factors.

In addition, the potential effect on CVD of MTX, which was given in combination to tofacitinib or TNFi, was not evaluated.

For both axSpA and PsA, evidence for the association between inflammation and an enhanced CVD risk is less abundant compared with RA. In view of shared pathogenic mechanisms, it is plausible that decreasing the inflammatory burden in axSpA and PsA will also have favorable effects on the CVD risk in these patients. Therefore, control of disease activity, as is routinely recommended, is expected to lower CVD risk for both axSpA and PsA [START_REF] Wendling | French Society for Rheumatology(SFR) recommendations on the everyday management of patients with spondyloarthritis, including psoriatic arthritis[END_REF].Disease activity has also been identified as a risk factor for VTE in patients with RA [START_REF] Molander | Risk of venous thromboembolism in rheumatoid arthritis, and its association with disease activity: a nationwide cohort study from Sweden[END_REF][START_REF] Ozen | Risk factors for venous thromboembolism and atherosclerotic cardiovascular disease: do they differ in patients with rheumatoid arthritis?[END_REF] (see OP1).

Disease activity should be regarded as a modifiable risk factor for VTE in RA, and aggressive control of inflammation might reduce the risk of thrombosis in RA patients. TNFi may have the potential to reduce the risk of VTE by halting inflammation [START_REF] Schaefer | TNF inhibitors are associated with a reduced risk of venous thromboembolism compared to csDMARDs in RA patients[END_REF]. However, some RA therapies might have an intrinsic prothrombotic effect that could tilt the balance towards an increased risk of VTE. Indeed, corticosteroids and JAKi can be associated with an increased risk of VTE, especially in patients with risk factors of VTE [START_REF] Molander | Venous thromboembolism with JAK inhibitors and other immune-modulatory drugs: a Swedish comparative safety study among patients with rheumatoid arthritis[END_REF][START_REF] Dong | Thromboembolic events in Janus kinase inhibitors: a pharmacovigilance study from 2012 to 2021 based on the Food and Drug Administration's Adverse Event Reporting System[END_REF]. No data are available yet regarding the beneficial effect of inflammation reduction for the risk of VTE in axSpA or PsA.

Smoking cessation should be encouraged to reduce the risk of MACE and VTE

Smoking is a known risk factor for arterial and venous events per se [START_REF] Galloway | Risk of venous thromboembolism in immune mediated inflammatory diseases: a UK matched cohort study[END_REF][START_REF] Mahmoodi | Association of traditional cardiovascular risk factors with venous thromboembolism: an individual participant data metaanalysis of prospective studies[END_REF] and can also increase the risk of these events further through disease activity, given that smoking is associated with more aggressive disease in chronic inflammatory rheumatic disorders.

Stopping smoking is potentially the most effective of all preventive measures, with substantial reductions in (repeat) MIs or death [START_REF] Anthonisen | The effects of a smoking cessation intervention on 14.5-year mortality: a randomized clinical trial[END_REF]. Lifetime gains in CVD-free years are substantial at all ages, and benefits would be obviously even more substantial if other complications from smoking were accounted for. Quitting must be encouraged in all smokers and patients should be directed towards the locally defined evidence-based smoking cessation programmes, even if they have failed previously. Moreover, passive smoking should be avoided as much as possible.

Other lifestyle interventions such as healthy diet, weight loss and regular exercise should be encouraged [START_REF] Daien | Dietary recommendations of the French Society for Rheumatology for patients with chronic inflammatory rheumatic diseases[END_REF] There is accumulating data showing that exercise therapy has beneficial CVD effects in patients with chronic inflammatory rheumatic diseases [START_REF] Wendling | French Society for Rheumatology(SFR) recommendations on the everyday management of patients with spondyloarthritis, including psoriatic arthritis[END_REF][START_REF] Metsios | Individualised exercise improves endothelial function in patients with rheumatoidarthritis[END_REF][START_REF] Lemmey | Effects of high-intensity resistance training in patients with rheumatoid arthritis: a randomized controlled trial[END_REF].The Mediterranean diet, characterized by a high consumption of fruit, vegetables, legumes and cereals, including olive oil or vegetable oil is the primary source of fat intake and containing less red meat and more fish compared with common Western diets, has been shown to be associated with a reduced incidence of major CVD events in the general population [START_REF] Estruch | Mediterranean diet for primary prevention of cardiovascular disease[END_REF].

NSAID and corticosteroid exposure should be minimized to reduce the risk of MACE and VTE

NSAIDs and corticosteroids are commonly used for the treatment of chronic inflammatory rheumatic diseases and these agents effectively lower disease activity and inflammation. However, both treatment options have been associated with an increased risk of MACE and VTE [START_REF] Agca | EULAR recommendations for cardio-vascular disease risk management in patients with rheumatoid arthritis other forms of inflammatory joint disorders: 2015/2016 update[END_REF][START_REF] Ozen | Risk factors for venous thromboembolism and atherosclerotic cardiovascular disease: do they differ in patients with rheumatoid arthritis?[END_REF]. The CV risk of corticosteroids is now well established in chronic inflammatory rheumatic disorders, especially RA. In a recent study from the National Databank for Rheumatic Disease in US (FORWARD), the use of corticosteroids was also independently associated with an increased risk factor for unprovoked VTE (adjusted hazard ratio, HR, 1.99, 95% CI 1.66-2.40) [START_REF] Ozen | Risk factors for venous thromboembolism and atherosclerotic cardiovascular disease: do they differ in patients with rheumatoid arthritis?[END_REF]. As these medications are often indispensable in tackling disease activity in patients with chronic inflammatory rheumatic disorders, their use should be evaluated on an individual patient level in accordance with treatment-specific recommendations.

In the presence of atherosclerotic cardiovascular disease, the rheumatologist should ensure that a specialized follow-up is ongoing

Multidimensional prevention is crucial for short-and long-term outcomes in patients with coronary artery disease (CAD),cerebrovascular disease or lower extremity artery disease (LEAD)considering the high risk of new CV event. According to the latest ESC guidelines, several therapeutic measures are strongly recommended in this population. This includes daily aspirin in patients with a previous myocardial infraction or revascularization, clopidogrel daily in addition to aspirin for 6 months following coronary stenting in patients with chronic coronary syndromes, ACE inhibitors, beta-blockers among others in patients with left ventricular dysfunction and oral lipid lowering treatments [START_REF] Visseren | ESC Guidelines on cardiovascular disease prevention in clinical practice[END_REF]. Interventions for cerebrovascular diseases depend on the type of event, i.e., ischaemic or haemorrhagic. In patients with ischaemic stroke or transient ischaemic attack (TIA), prevention with antithrombotics is recommended. Use of an antiplatelet is recommended for patients with non-cardioembolic ischaemic stroke or TIA, and use of anticoagulants is recommended in patients with cardioembolic ischaemic stroke or TIA. Patients with lower extremity artery disease (LEAD) require lifestyle improvement, i.e., (smoking cessation, exercise and healthy diet) together with drug intervention, including platelet inhibitors [START_REF] Visseren | ESC Guidelines on cardiovascular disease prevention in clinical practice[END_REF]. Additionally, knowledge of local guidelines for management of hypertension, dyslipidemia and diabetes mellitus is needed to recognize thresholds and targets in order to tailor treatment in this specific high-risk population. These tasks may be beyond the scope of practice of the typical rheumatologist and a specialized follow-up is mandatory. Indeed, advances CV risk management using imaging and laboratory tests is required, as well as the optimization of lifestyle factors, hypertension and dyslipidemia and the investigation and management of cardiac-related symptoms. Thus, the rheumatologist should ensure that CVD risk assessment and management is being performed regularly, should record who is performing it (general practitioner, specialist) and should make sure that the patient is aware of the need for regular risk assessment, in coordination with primary care physicians.

A suitable therapeutic alternative to JAKi should be considered in patients with history of ASCVD or VTE

The part of the recommendation related to patients with ASCVD (i.e., history of coronary artery disease, cerebrovascular disease or peripheral artery disease) follows the statement form the PRAC, which indicated that JAKi should be used in patients with increased risk of major CV problems (such as heart attack or stroke) only if no suitable treatment alternatives are available [52]. Further, the PRAC has suggested that doses of JAKi should be reduced in some patient groups who may be at risk of cardiovascular problems. A recent post-hoc analysis of ORAL Surveillance showed an increased risk of MACE with tofacitinib 5 mg and 10 mg two times per day versus TNFi that was primarily observed in patients with a history of ASCVD at baseline. In patients without history of ASCVD but with CV risk factors, there did not appear to be a detectable difference in risk of MACE with tofacitinib 5 mg two times per day or the combined to facitinib doses versus TNFi [START_REF] Charles-Schoeman | Risk of major adverse cardiovascular events with tofacitinib versus tumour necrosis factor inhibitors inpatients with rheumatoid arthritis with or without a history of atherosclerotic cardiovascular disease: a post hoc analysis from ORAL Surveillance[END_REF]. A large observational study that used US claims data to assess risk of CV outcomes (composite of hospitalization for MI or stroke) with tofacitinib versus TNFi in patients with RA (Safety of TofAcitinib in Routine care patients with Rheumatoid Arthritis; STAR-RA) was recently published [START_REF] Khosrow-Khavar | Tofacitinib and risk of cardiovascular outcomes: results from the Safety of TofAcitinib in Routine care patients with Rheumatoid Arthritis (STAR-RA) study[END_REF]. Evidence for an increased risk of CV events with tofacitinib was not identified in this real-world cohort. However, STAR-RA also prespecified sub-group analyses of patients with or without previous ASCVD. These results were consistent with those of ORAL Surveillance; risk of CV events appeared to be increased with tofacitinib versus TNFi inpatients with, but not in those without, pre-existing ASCVD (HR1.27, 95% CI 0.95-1.70).

In the RA integrated report of baricitinib safety data, the incidence ratio of positively adjudicated MACE was 0.5/100patients-year [START_REF] Taylor | Safety of baricitinib for the treatment of rheumatoid arthritis over a median of 4.6 and up to 9.3 years of treat-ment: final results from long-term extension study and integrated database[END_REF]. Patients in this analysis had a mean age at base-line of 53 years and 79% were female. No specific analysis has been performed in the subgroup of patients with ASCVD. However, of the1780 patients (54.8% of the study population) with at least one CV risk factor, the IR of MACE was 0.70/100 patients-year and among those aged 50 years or older with at least one additional CV risk factor (n = 1325), the IR of MACE was 0.77/100 PYR. IRs for stroke, MI and CV death were 0.3/100 patients-year, 0.2/100 patients-year and 0.1/100 patients-year, respectively, in the all baricitinib dataset [START_REF] Taylor | Safety of baricitinib for the treatment of rheumatoid arthritis over a median of 4.6 and up to 9.3 years of treat-ment: final results from long-term extension study and integrated database[END_REF].

In the Upadacitinib Clinical Trial Programs in RA, PsA, and axSpA, 4298 patients received ≥ 1 dose of upadacitinib 15 mg,40-50% of patients had 2 or more CV risk factors, and the proportion of patients ≥ 65 years ranged from 6 to 23% [START_REF] Charles-Schoeman | MACE and VTE across upadacitinib clinical trial programs in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis [abstract[END_REF]. Factors potentially associated with MACE occurrence in patients with RA receiving upadacitinib 15 mg included in particular age ≥ 65 years and ASCVD [START_REF] Charles-Schoeman | MACE and VTE across upadacitinib clinical trial programs in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis [abstract[END_REF]. Taken together, these findings emphasize the importance of rheumatologists assessing medical history of ASCVD (Fig. 1), when considering tofacitinib or other JAKi as a treatment for patients with RA and other chronic inflammatory rheumatic diseases.

The PRAC also recommended using JAKi with caution in patients with risk factors for VTE, with possible dose reduction in this group of patients given the results of ORAL Surveillance suggesting a dose effect of tofacitinib for the risk of VTE, but without suggesting the use of a suitable alternative. Previous VTE is a major risk factor for the occurrence of new venous thromboembolic events [START_REF] Barbar | A risk assessment model for the identification of hospitalized medical patients at risk for venous thrombo-embolism: the Padua Prediction Score[END_REF][START_REF] Kanjee | Should you treat this acutely ill medical in patient with venous thromboembolism chemoprophylaxis? Grand rounds discussion from Beth Israel Deaconess Medical Center[END_REF]. In ORAL Surveillance and in the upadacitinib development program, across the treatment groups, VTE incidence ratios were higher in patients with vs. without a history of VTE [START_REF] Charles-Schoeman | MACE and VTE across upadacitinib clinical trial programs in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis [abstract[END_REF][START_REF] Charles-Schoeman | The risk of venous thromboembolic events in patients with RA aged ≥ 50 years with ≥ 1 cardiovascular risk factor: results from a phase 3b/4 randomized safety study of tofacitinib vs .tnf inhibitors[END_REF]. Thus, the taskforce has considered that previous VTE is a foremost risk factor that justifies considering a suitable alternative to JAKi (Fig. 1).

A suitable therapeutic alternative to JAKi should be considered in patients aged ≥ 65 years

This recommendation follows the PRAC, who recommended that JAKi should be used in patients aged 65 years or above only if no suitable treatment alternatives are available [52] (Fig. 1). This statement is based on the results of ORAL Surveillance study, which showed that the increased risk of MACE and VTE with to facitinibvs. TNFi was more pronounced in patients aged ≥ 65 years than in patients aged < 65 years [START_REF] Ytterberg | Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis[END_REF][START_REF] Charles-Schoeman | The risk of venous thromboembolic events in patients with RA aged ≥ 50 years with ≥ 1 cardiovascular risk factor: results from a phase 3b/4 randomized safety study of tofacitinib vs .tnf inhibitors[END_REF]. Moreover, patients with a his-tory of ASCVD were more likely to be ≥ 65 years [START_REF] Charles-Schoeman | Risk of major adverse cardiovascular events with tofacitinib versus tumour necrosis factor inhibitors inpatients with rheumatoid arthritis with or without a history of atherosclerotic cardiovascular disease: a post hoc analysis from ORAL Surveillance[END_REF]. These data were also observed in other JAKi. In the long-term baricitinib clinical trial dataset (n = 3770 patients, i.e.; 14,744 patient-years), the risk of MACE and VTE was more pronounced in patients ≥ 65 years or with risk factors (ASCVD, diabetes mellitus, hypertension, smoking, malignancy, low HDL, BMI > 30, severe mobility impairment(IR = 0.70 vs. 0.05 for MACE and 0.66 vs. 0.05 for VTE) [START_REF] Taylor | Safety of baricitinib for the treatment of rheumatoid arthritis over a median of 4.6 and up to 9.3 years of treat-ment: final results from long-term extension study and integrated database[END_REF]. The analysis of the safety profile of upadacitinib over 15,000 patient-years across the different indications has also revealed an increased incidence of MACE in RA and PsA patients ≥ 65 years (RA: 1.0 95% CI0.6-1.7 vs. 0.3 95% CI 0.2-0.4; PsA: 0.4 95% CI 0.0-2.2 vs. 0.2 95% CI0.1-0.6) [START_REF] Burmester | Safety profile of upadacitinib over15,000 patient-years across rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and atopic dermatitis[END_REF]. Data from the phase 2, phase 3 and LTE trials of filgotinib revealed that the EAIRs of adjudicated MACE and VTE were higher in patients aged ≥ 65 years [START_REF] Buch | Exploratory analysis of filgotinib safety data in patients with moderately to severely active RA and an increased risk of cardiovascular events: data from phase 2 and 3 clinical trials[END_REF].

A suitable therapeutic alternative to JAKi should be considered in patients at very high or high CVD risk or with major VTE risk factors

In the population < 65 years and without ASCVD or previous VTE, major CVD and VTE risk factors should be actively assessed in patients with chronic inflammatory rheumatic diseases before a prescription of JAKi should be considered (Fig. 1).

The detection of major CV risk factors should lead to consider other therapeutic classes and a reduction of JAKi doses, as stated by the PRAC [52]. The task force has considered patients at very high or high CVD risk according to the last ESC guidelines as a population of major CV risk that should avoid JAKi in case of sui-table therapeutic alternative [START_REF] Visseren | ESC Guidelines on cardiovascular disease prevention in clinical practice[END_REF]. This risk stratification of CVD risk can be performed according to patient categories (ASCVD, diabetes, familial hypercholesterolemia, chronic kidney disease) or according to the SCORE2/SCORE2-OP risk scores, as presented in Table 2 [START_REF] Visseren | ESC Guidelines on cardiovascular disease prevention in clinical practice[END_REF]. In addition to Oral Surveillance, the importance of CV risk factors in tofacitinib-treated patients has been highlighted by the STAR-RA study, which included a cohort that mirrored ORAL Surveillance inclusion and exclusion criteria (randomized controlled trial [RCT]-duplicate cohort). The primary outcome of the RCT-duplicate cohort aligned with the increased risk of MACE with tofacitinib versus TNFi observed in ORAL Surveillance (i.e., approximately 25% relative risk increase with tofacitinib 5 mg two times per day vs. TNFi) [START_REF] Ytterberg | Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis[END_REF][START_REF] Khosrow-Khavar | Tofacitinib and risk of cardiovascular outcomes: results from the Safety of TofAcitinib in Routine care patients with Rheumatoid Arthritis (STAR-RA) study[END_REF]. In the baricitinib, upadacitinib and filgotinib development programmes, the CVD-induced mortality and non-fatal MI occurred in patients at very high or high CVD risk [START_REF] Burmester | Safety profile of upadacitinib over15,000 patient-years across rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and atopic dermatitis[END_REF][START_REF] Genovese | Baricitinib in patients with refractory rheumatoid arthritis[END_REF][START_REF] Fleischmann | Upadacitinib versus placebo or adalimumab in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a phase III, double-blind, randomized controlled trial[END_REF][START_REF] Fleischmann | Long-term safety and efficacy of upadacitinib or adalimumab in patients with rheumatoid arthritis: results through3 years from the SELECT-COMPARE study[END_REF][START_REF] Smolen | Upadacitinib as monotherapy in patients with active rheumatoid arthritis and inadequate response to methotrexate (SELECT-MONOTHERAPY): a randomised, placebo-controlled, double-blind phase 3 study[END_REF][START_REF] Genovese | Safety and efficacy of upadacitinib in patients with active rheumatoid arthritis refractory to biologic disease-modifying antirheumatic drugs (SELECT-BEYOND): a double-blind, randomised controlled phase 3 trial[END_REF][START_REF] Buch | Outcomes of filgotinib in patients with RA aged ≥ 65 years: a post hoc subgroup analysis of phase 2 and 3 clinical trials and ongoing long-term extensions[END_REF].

The task force has also provided a definition of major VTE risk factors (Table 3). As previously stated above, age ≥ 65 years and previous VTE are recognized major VTE risk factors, which have been placed as priority risk factors in our risk assessment algorithm. Neoplasia and inherited thrombophilia are specific conditions that are usually known from patients and clinicians. Obesity is another major VTE risk factor that must be investigated prior to the use of JAKi. Obesity has been identified in the development programmes of the four JAKi in RA as a risk factor for VTE [START_REF] Charles-Schoeman | The risk of venous thromboembolic events in patients with RA aged ≥ 50 years with ≥ 1 cardiovascular risk factor: results from a phase 3b/4 randomized safety study of tofacitinib vs .tnf inhibitors[END_REF][START_REF] Fleischmann | Long-term safety and efficacy of upadacitinib or adalimumab in patients with rheumatoid arthritis: results through3 years from the SELECT-COMPARE study[END_REF][START_REF] Mease | Incidence of venous and arterial thromboembolic events reported in the tofacitinib rheumatoid arthritis, psoriasis and psoriatic arthritis development programmes and from real-world data[END_REF][START_REF] Fitton | Real-world single centre use of JAK inhibitors across the rheumatoid arthritis pathway[END_REF]. These data emphasize again the need of weight management in patients with inflammatory rheumatic diseases.

Other risk factors have been identified from the extensive literature review (Table 3), but do not represent, on their own, a contraindication to the use of JAKi. The combination of risk factors may increase the risk of VTE and should also be taken in consideration. Increased vigilance is also required with regard to transient VTE risk factors that are also listed in Table3.

In the above situations, if no suitable treatment alternatives are available, the use of JAKi should be conditional on a collegial decision

This recommendation, based on expert opinion, was elaborated in order not to leave the rheumatologist alone to manage a difficult situation. A collegial decision among rheumatologists allows a synthesis of the different risk factors for each patient with a personalized approach. It also allows a discussion and synthesis of specialized opinions gathered from cardiologists, neurologist, vascular physician, hemostasis and/or thrombosis specialist in order to put the risk into perspective. It also allows a formal validation of the decision and the mention in the medical file of "the absence of suitable alternative to JAKi". The meaning of "no suitable alter-native" has not been precisely defined but may correspond to the previous use of all other possible of authorized classes of targeted therapies.

Following this collegial decision, the task force feels that the rheumatologists will be more comfortable to have a concerted and thoughtful discussion with the patient for a shared decision-making. The group is fully aware of the constraints induced by this proposal. These procedures may evolve and be simplified in case of future reassuring data on JAKi.

In patients at very high and high CV risk, if no suitable treatment alternatives are available, the use of JAKi should also be conditional to approval of the referent cardiologist

To ensure the correct implementation of this recommendation, it will be important to clearly define the nature of the approval that will be sought from the cardiologist. Asking for confirmation of the use of a JAKi because of a complex cardiovascular situation may not result in productive advice since the cardiologist may not know the class of JAKi or be aware of the potential risks of CVD of this class. The approval must be directed towards the stability of the ASCVD and the potential risk of a new event that will preclude the use of a JAKi. Indeed, the prescription of a JAKi should be considered in a patient with the most stable CVD possible. To address this issue, the cardiologist may therefore proceed to advanced CV risk stratification using imaging and laboratory tests, optimize control of hypertension and dyslipidemia and investigate and manage possible cardiac-related symptoms. It would also be important to check the control of an associated diabetes mellitus [START_REF] Avouac | Influence of inflammatory and non-inflammatory rheumatic disorders on the clinical and biological profile oftype-2 diabetes[END_REF].

If the cardiologist considers that the risk factors are controlled enough and that the prescription of a JAKi is validated following a collegial decision among rheumatologists, the nature and frequency of the cardiological follow-up will have to be specified, adapted and personalized.

In patients with previous VTE, if no suitable treatment alternatives are available, the use of JAKi should also be conditional on an expert advice

The risk of recurrent VTE is complex situation in which there is no clear recommendation. This risk is lowered by anticoagulation, with a large effect in the initial phase following the venous thromboembolic event, and with a smaller effect in terms of secondary prevention of recurrence when extended anticoagulation is performed [START_REF] Fahrni | Assessing the risk of recurrent venous thromboembolism-a practical approach[END_REF]. On the other hand, extended anticoagulation is associated with an increased risk of major bleeding and thus leads to increased morbidity and mortality. Therefore, it is necessary to assess the risk of recurrence for VTE on an individual basis, and a recommendation for secondary prophylaxis should be specifically based on risk calculation of recurrence of VTE and bleeding, which falls beyond the scope of practice of all rheumatologists. Indeed, estimating the risk of recurrent VTE is complex and requires consideration of relevant risk factors for recurrent VTE, especially the presence of intrinsic risk factors that are known to promote recurrence. For this rea-son, the task force considered that the use of JAKi in patients with previous VTE should be conditioned to an expert opinion. After an individualized assessment of the risk factors for VTE ,a collegial decision among rheumatologists should be made to the feasibility of introducing an additional potential risk factor for VTE and, if it is considered as possible, whether the use of JAKi should be used at reduced dose and/or combined with thromboprophylaxis, the modalities of which should be determined. Many medical specialties are likely to manage VTE (internal medicine, vascular medicine, hematologist, pulmonologist. . .) and it is very important that the rheumatologist identifies a local referent for VTE within its health care structure.

Thromboprophylaxis should be considered for patients at major risk of VTE in presence of transient risk factors

In accordance with current guidelines on the presence of VTE during hospitalization, patients with chronic inflammatory rheumatic diseases should receive pharmacological thromboprophylaxis during the inpatient period, regardless of the cause of hospitalization [70]. In particular, RA patients hospitalized fora disease flare may be particularly at risk of VTE, especially if they receive high dose of corticosteroids (Table 2). An extended duration of thromboprophylaxis beyond hospital discharge is not routinely recommended in patients with chronic inflammatory rheumatic diseases. However, surgical and orthopaedic research have shown that the risk of VTE can remain elevated even after hospital discharge [START_REF] Felder | Prolonged thromboprophylaxis with low molecular weight heparin for abdominal or pelvic surgery[END_REF][START_REF] Forster | Anticoagulants (extended duration) for prevention of venous thromboembolism following total hip or knee replacement or hip fracture repair[END_REF], and a subgroup of patients may benefit from an extended duration of VTE prophylaxis [START_REF] Vedovati | A randomized study on 1-week versus4week prophylaxis for venous thromboembolism after laparoscopic surgery for colorectal cancer[END_REF].

RA disease activity is a known risk factor for VTE [START_REF] Molander | Risk of venous thromboembolism in rheumatoid arthritis, and its association with disease activity: a nationwide cohort study from Sweden[END_REF][START_REF] Ozen | Risk factors for venous thromboembolism and atherosclerotic cardiovascular disease: do they differ in patients with rheumatoid arthritis?[END_REF]. Most RA flares occur in an ambulatory setting but given that the thresholds for hospitalization due to RA flares differ worldwide, the proportions of inpatients and outpatients with RA having a VTE event may vary. Given that the absolute risk of VTE remains low in outpatients with active RA, the use of thromboprophylaxis is not recommended in the absence of risk factors. On the other hand, outpatients with major VTE risk factors and at least a transient risk factor, including RA flare (Table 3), might be at particular risk of VTE and could benefit from thromboprophylaxis until the transient provoking factor disappears. There is a paucity of evidence regarding thromboprophylaxis in patients with RA, and this issue should be considered on a case-bycase basis. Guidelines recommend pharmacological over mechanical thromboprophylaxis, given that the former may be more effective in the prevention of PE and symptomatic VTE [70,[START_REF] Fleming | The American Society of Colon and Rectal Surgeons Clinical Practice Guideline for the prevention of venous thromboembolic disease in colorectal surgery[END_REF]. The preferred methods of prophylaxis are low molecular weight heparin (LMWH) or fondaparinux over unfractioned heparin (UFH) [70].

Discussion

The ultimate goal of this consensus was to give multidisciplinary practical recommendations to prevent potentially life-threatening complications of MACE and VTE in patients with chronic inflammatory rheumatic diseases, following the communication of the PRAC. This consensus led to the development of a series of overarching principles and recommendations supported by available evidence regarding the background risk of MACE and VTE in patients with chronic inflammatory rheumatic diseases. Additionally, whenever appropriate consensus recommendations for the prevention of MACE and VTE were made (Table 1), as well as and the assessment of CVD and VTE at the initiation of targeted therapies, especially JAKi (Fig. 1). These recommendations may evolve according to new results obtained on JAKi in current practice, in particular with the help of registries, and thus, should be updated. Until now, most of publications that followed ORAL Surveillance did not firmly confirm the link between JAKi and MACE, whereas several concerns remain on the risk of VTE [START_REF] Molander | Venous thromboembolism with JAK inhibitors and other immune-modulatory drugs: a Swedish comparative safety study among patients with rheumatoid arthritis[END_REF][START_REF] Khosrow-Khavar | Tofacitinib and risk of cardiovascular outcomes: results from the Safety of TofAcitinib in Routine care patients with Rheumatoid Arthritis (STAR-RA) study[END_REF][START_REF] Salinas | Evaluation of VTE, MACE, and serious infections among patients with RA treated with baricitinib compared to TNFi :a multidatabase study of patients in routine care using disease registries and claims databases[END_REF]. The acceptability of these recommendations should be further evaluated by rheumatologists and patients, as well as their future dissemination among the medical community and patients.

Treatment strategies of established MACE or VTE in patients with chronic inflammatory rheumatic diseases were beyond the scope of this consensus, and physicians should refer to available guidelines.

Further evidence is needed regarding the drug-related risk of MACE and VTE with JAKi. Several questions remain unsolved and would deserve dedicated studies. They are listed in the research agenda (Table 4). It will be important to determine which mechanisms lead to the MACE and VTE events seen with JAKi, and particularly tofacitinib and baricitinib in clinical practice. Then, real life data are mandatory to confirm whether these risks maybe extended to JAK-1 more selective agents upadacitinib and filgotinib. It is important to consider that longterm follow-up data that will be obtained for upadacitinib and filgotinib will be influenced by the different recommendations and warnings, meaning that any risk reduction with these drugs might not be related to drugs themselves but to better management of JAKi.

The majority of available evidence was obtained in RA and how high is the CVD and VTE risk in patients with AS or PsA treated with JAKi is not known. One important issue will be the management of at-risk patients with ongoing therapy with JAKi, as well as the potential value of JAKi dose reduction and the combination of JAKi with methotrexate to decrease the risk of MACE and VTE. In addition to real life studies specifically designed to address these important issues, the development of specific risk assessment tools for MACE and VTE in patients with chronic inflammatory rheumatic diseases are warranted, as they might influence management in some clinical scenarios.

Disclosure of interest

JA: honoraria from Pfizer, Bristol Myers Squibb, UCB, Roche, Nor-dic, Novartis, Sanofi, Boehringer, Abbvie, Chugai, Galapagos, Biogen, Fresenius Kabi, Sandoz, AstraZeneca. Research grants: Pfizer, Bristol Myers Squibb, Fresenius Kabi, Novartis, Nordic Pharma, Galapagos. OF: honoraria from Galapagos, Abbvie, MSD, Novartis, BMS, UCB. Research grants: Cellgene.SH: honoraria from BMS.CD: honoraria from Abbvie, Biogen, BMS, Fresenius-Kiabi, Galapagos, MSD, Novartis, Pfizer, Sandoz, UCB.IE: honoraria from Afric-Phar, Amanys Pharma, Bayer Healthcare, Boehringer-Ingelheim, Bristol Myers Squibb, Galapagos, Gedeon Richter, Leo-Pharma, Pfizer, Recordati, Sanofi, Viatris .FP: honoraria from Alliance BMS-Pfizer, Astra Zeneca, Bayer, BBraun, Biotronik, Boston Scientific, Sanofi and Servier. CP: honoraria from Abbvie, Amgen, BMS, Fresenius, Galapagos, Janssen, Lilly, Novartis, Pfizer, Sandoz, UCB.JHS: honoraria from AbbVie, BMS, Galapagos, Lilly, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi, UCB, Viatris. MET: honoraria from Pfizer, Galapagos, Roche, UCB, Lilly, MSD, Medac, Nordic, BMS, Roche, Abbvie, UCB, Lilly, BMS, SOBI, Werfen. Research grants from Pfizer, Galapagos.JS: honoraria from Roche, Chugai, Pfizer, BMS, MSD, Abbvie, Sandoz, Hospira, Janssen, Novartis, Fresenius Kabi, Sanofi Genzyme, Galapagos, research grants from Roche, Pfizer, MSD, Schwa Medico, BMS.AM: honoraria from Abbvie, Janssen, Lilly, Merck, BMS, Novartis, UCB.

Funding

None.


Un Physicien

Jean-Christophe Pain
email: jean-christophe.pain@cea.fr

Aimé Cotton

Aimé Cotton fait partie des grands savants de la première moitié du vingtième siècle. Continuateur de l'oeuvre de Michael Faraday et Pieter Zeeman en magnétooptique, il est le pionnier de l'optique moléculaire. Ses grandes qualités d'expérimentateur lui ont permis, grâce à des méthodes optiques, de révéler l'anisotropie et les propriétés de symétrie des molécules. Aimé Cotton s'avéra également un enseignant hors pair qui savait transmettre aux jeunes sa passion de la recherche en ponctuant systématiquement ses cours d'expériences originales. Il était aussi un profond humaniste qui a su, par sa générosité et sa simplicité, inspirer la sympathie de ses collègues et amis et l'admiration de ses nombreux étudiants.

LES DEBUTS DU PROFESSEUR COTTON

Aimé Cotton est né à Bourg-en-Bresse, à l'Ecole Normale d'Instituteurs, le 9 Octobre 1869. Son père, Eugène Cotton, fils d'agriculteur du Jura, prépare seul le concours d'entrée à l'Ecole Normale. Il est reçu et enseigne au Collège de Nantua. Après avoir passé avec succès le baccalauréat, il est nommé professeur de Mathématiques à l'Ecole Normale puis au lycée de Bourg-en-Bresse. Ayant perdu sa femme en 1872 à la naissance de son troisième enfant, il doit élever seul sa fille Marie et ses deux fils Aimé et Emile. Marie Cotton est reçue à l'Ecole Normale Supérieure de Sèvres et enseigne au lycée de Bourg puis au lycée Fénelon à Paris. Son frère Emile entre à l'Ecole Normale Supérieure de la rue d'Ülm et devient professeur de Mathématiques à la Faculté des Sciences de Grenoble. Enfin, Aimé Cotton fait ses études secondaires au lycée de Bourg-en-Bresse et sa classe de Mathématiques spéciales au lycée Blaise Pascal de Clermont-Ferrand. Il est admis à l'Ecole Normale Supérieure en 1889. Il commence par une année de service militaire puis quatre ans d'études à la rue d'Ülm de 1890 à 1893 où il côtoie d'autres grands savants comme Paul Langevin, Jean Perrin, Pierre Weiss ou Pierre Curie. En 1893, il obtient l'Agrégation de sciences physiques et commence sa thèse au laboratoire de physique de la rue d'Ülm. Aimé Cotton découvre alors le dichroïsme circulaire : il montre que les corps colorés qui possèdent la propriété de polarisation rotatoire [START_REF] Rosmorduc | La polarisation rotatoire naturelle, de la structure de la lumière à celle des molécules[END_REF] (comme la liqueur de Fehling) présentent dans la région spectrale où se trouvent leurs bandes d'absorption, une absorption inégale pour les deux vibrations circulaires de sens inverses. En 1896, il soutient sa thèse « Recherches sur l'absorption et la dispersion de la lumière par les milieux doués de pouvoir rotatoire », et il est nommé Maître de conférences à l'Université de Toulouse. En 1900, il est rappelé à Paris pour succéder à Jules Violle (voir annexe) comme Maître de conférences à l'Ecole Normale Supérieure de Saint-Cloud : « C'est en empruntant des pièces à de vieux appareils ou en transportant dans les poches de son pardessus des ressources imprévues qu'il dote ses cours d'expériences inédites et de grande qualité. Il veut ainsi montrer à ses élèves tout l'intérêt d'une belle expérience de cours dans la compréhension de la physique mais aussi la beauté plastique de la recherche ». Ses premiers travaux de recherche, dans le prolongement de sa thèse, concernent alors les propriétés électro-optiques des cristaux et des liquides, dont la propagation de la lumière polarisée dans les milieux matériels absorbants. Il découvre la dispersion rotatoire anormale : cette découverte et celle du dichroïsme circulaire apporteront de nouveaux moyens d'investigation des configurations moléculaires.

Aimé Cotton (1869-1951).

DES OBSERVATIONS RELATIVES A l'EFFET ZEEMAN AU DICHROISME CIRCULAIRE

A cette époque, il commence une collaboration avec Pierre Weiss pour approfondir l'étude de l'effet Zeeman (découvert en 1896) de diverses raies spectrales. Pour cela, il met au point la balance qui porte son nom pour mesurer avec précision l'intensité du champ magnétique appliqué à la source lumineuse [START_REF] Cotton Aimé | Appareil pour la mesure de l'intensité des champs magnétiques[END_REF][START_REF] Cotton Aimé | Appareil pour la mesure de l'intensité des champs magnétiques[END_REF]. Du dédoublement Zeeman des raies bleues du zinc, Cotton et Weiss tirent une valeur numérique du rapport de la charge à la masse de l'électron (magnéton de Bohr) : e/m = 1,767.107 10 11 C/kg en 1907. Cette valeur est la plus précise mesurée à l'époque.

Pendant plusieurs années [START_REF] Rosmorduc | présentée en vue de l'obtention du doctorat de troisième cycle d'histoire des sciences[END_REF], les expériences d'Aimé Cotton sont consacrées à des observations qualitatives, sans spectroscope, de divers phénomènes accompagnant l'effet Zeeman. Il envisage surtout cet effet dans ses rapports avec l'absorption de la lumière. La loi de Kirchhoff, telle qu'il l'énonce en 1899, est la suivante : « Parmi les radiations qu'un corps absorbe se trouvent en premier lieu celles qui ont la période des radiations émises par le corps à la température où il se trouve ». Aimé Cotton utilise deux flammes A et B colorées par le sodium. Autour de ces flammes, à l'extérieur de la partie lumineuse, une gaine de quelques millimètres d'épaisseur qui est encore chaude, renferme le sodium libre. En vertu de la loi de Kirchhoff, cette gaine absorbe la lumière des raies D du sodium. La flamme A est observée à travers la flamme B ; pour que l'expérience réussisse, la flamme A est peu chargée en sodium et donne des raies d'émission étroites (comme une étude spectroscopique directe permettrait de le constater). Dans ces conditions, les bords de la flamme B absorbent la lumière émise par la flamme A et apparaissent noirs. Les raies d'absorption du sodium données par la gaine sont très étroites. De ce fait, si la présence d'un champ magnétique modifie tant soit peu la période vibratoire de la lumière émise par A, l'absorption est supprimée et les bords noirs de la flamme B disparaissent [START_REF] Cotton Aimé | Procédé simple pour constater le changement de période de la lumière du sodium dans un champ magnétique[END_REF]. Ce procédé permet donc d'observer facilement le phénomène de Zeeman [START_REF] Zeeman | On the Influence of Magnetism on the Nature of the Light Emitted by a Substance[END_REF].

Aimé Cotton est ultérieurement appelé à rédiger, pour le volume des constantes publié par la société française de physique, le chapitre concernant les mesures faites sur le phénomène de Zeeman (spectres de gaz). Il utilise, bien sûr, ses propres résultats ainsi que ceux des nombreux physiciens ayant travaillé sur le sujet, critiquant d'ailleurs parfois certains d'entre eux, en particulier au sujet d'insuffisances de précision dans la mesure des champs magnétiques.

Cherchant toujours à relier la dispersion et l'absorption optique, Aimé Cotton s'intéresse au phénomène de polarisation rotatoire magnétique (effet Faraday) au voisinage des raies d'absorption des corps colorés. C'est avec deux de ses élèves qu'il parvient à mettre en évidence le dichroïsme circulaire magnétique. Balance de Cotton.

LA BIREFRINGENCE MAGNETIQUE ET L'EFFET COTTON-MOUTON

LES TRAVAUX DE GUERRE SYSTEME DE DETECTION POUR L'ARTILLERIE

En 1914, n'étant pas mobilisable à cause de son âge, Aimé Cotton décide de mettre ses connaissances de physicien au service de la défense nationale. Il se heurte à certaines difficultés pour faire admettre sa participation, comme le prouvent des notes publiées en août 1940. Finalement, une commission, dirigée par Paul Painlevé, est créée dans le cadre du service de la recherche scientifique pour la défense nationale ; Aimé Cotton y trouve sa place aux cotés d'un certain nombre de ses collègues. Il commence par se préoccuper des canons de 75 mm et étudie l'influence de la température, de la pression et du vent sur leurs tirs ; mais l'essentiel de son travail consiste en la mise au point, avec son ami Pierre Weiss, d'une méthode de repérage des canons ennemis par le son. Les stations de repérage Cotton-Weiss [START_REF]les caractéristiques techniques du système Cotton-Weiss, daté du 25[END_REF][START_REF] Schiavon | Itinéraires de la précision. Géodésiens, artilleurs, savants et fabricants d'instruments en France, 1870-1930[END_REF] se développent sur le front et des collègues ou élèves d'Aimé Cotton comme Jean Cabannes (successeur de Cotton à la tête du laboratoire des recherches physiques de la Sorbonne après son départ à la retraite en 1941) y sont affectés.

Un canon émet deux sons : l'un du à l'onde de bouche, l'autre à l'onde de choc. La première est due à l'expansion brusque des gaz à la bouche du canon, la seconde aux phénomènes accompagnant le déplacement du projectile dans l'air. La méthode Cotton-Weiss envisage le repérage par l'onde de bouche et, dans le cas ou cela n'est pas possible, utilise les seules données fournies par l'onde de choc. Le matériel utilisé est portatif et à lecture directe. Il comprend : deux rupteurs, appareils sensibles au son, placés aux extrémités d'une courte base de 200 à 300 mètres, une boîte de mesure comprenant deux relais commandés par les deux rupteurs et un fluxmètre. Quand l'onde sonore atteint le premier rupteur, le relais se déclenche et l'aiguille du fluxmètre se déplace ; quand l'onde sonore atteint le second rupteur, le relais correspondant se déclenche et l'aiguille du fluxmètre s'immobilise. Du déplacement de l'aiguille est déduite la direction du canon sans autre correction que celle du vent.

LES CHAMPS MAGNETIQUES INTENSES

En 1920, Aimé Cotton est nommé professeur de physique théorique et de physique céleste à la Sorbonne. En 1922, il devient également professeur de physique générale à la Sorbonne (succédant à Gabriel Lippmann). Anatole Leduc, Eugène Bloch, Georges Bruhat (dont il a encadré le travail de thèse sur le dichroïsme circulaire et la dispersion rotatoire une dizaine d'années plus tôt), Pierre Auger [START_REF] Briand Jean-Pierre | Pierre Auger et la physique atomique[END_REF][START_REF] Hardouin | Comparaison de leurs contributions à l'effet Auger[END_REF], François Croze et Pierre Jacquinot (dont il a présidé le jury de thèse intitulée « Recherches sur le phénomène de Zeeman dans les champs magnétiques intenses » soutenue le 20 mai 1937) lui succèdent à la chaire de physique théorique et physique céleste. En 1923 il entre à l'Académie des Sciences comme successeur de Jules Violle (Aimé Cotton 32 voix, Charles Fabry 28 voix, Henri Abraham 1 voix). Il faut attendre 1924 pour que commence la construction du grand électro-aimant installé dans le laboratoire du Service des Recherches et Inventions à Bellevue près de Paris (futur laboratoire Aimé Cotton) [START_REF] Shinn Terry | The Bellevue grand electro-aimant, 1900-1940: birth of a researchtechnology community[END_REF]. La puissance de cet électro-aimant est de 100 kW (400 A sous 240 V) et permet d'obtenir des champs magnétiques intenses (jusqu'à 7 T). En 1928, les premières expériences sur l'instrument commencent, et une installation de liquéfacteurs pour l'obtention de très basses températures vient compléter l'appareil.

Le grand électro-aimant de Bellevue.

NAISSANCE DU LABORATOIRE AIME COTTON

Autour de l'électro-aimant installé à Bellevue se crée donc un laboratoire nommé d'abord "Laboratoire annexe du Laboratoire des recherches physiques de la Sorbonne" [START_REF] Entretiens | au laboratoire Aimé Cotton, avril-mai[END_REF]

LA METHODE SCIENTIFIQUE

Entre 1903 et 1906, une très curieuse affaire agite le monde scientifique français. Le physicien René Blondlot (1845-1923), professeur à la faculté des Sciences de Nancy et qui a déjà une oeuvre scientifique importante, annonce le 3 février 1903 qu'il a découvert une nouvelle espèce de radiations, baptisés « Rayons N » en l'honneur de sa ville [START_REF] Rosmorduc | Une erreur scientifique au début du siècle : Les Rayons N[END_REF][START_REF] De | Les rayons N du professeur René Prosper Blondlot[END_REF][START_REF] Nye Mary | Science in the Provinces: Scientific Communities and Provincial Leadership in France, 1860-1930[END_REF]. Au cours de la période 1903-1906, pas moins de 120 scientifiques confirmés publièrent près de 300 articles sur le sujet, notamment sur les caractéristiques de ces rayons. D'abord intéressés, beaucoup de scientifiques français deviennent sceptiques devant les résultats annoncés. Pendant 3 ans, partisans et adversaires des rayons N s'affrontent. La détection des rayons N est assurée, selon René Blondlot, par une petite étincelle produite par un excitateur et dont les rayons augmenteraient la luminosité. L'observation est faite sur des écrans fluorescents. Aimé Cotton pense que la variation de l'étincelle est due à un déplacement de l'écran et sa supposition est corroborée par le fait que le retrait de la lampe supposée générer les rayons N ne produit aucune modification de l'étincelle. En outre, Aimé Cotton considère que si le développement est effectué par quelqu'un sachant d'avance de quel côté l'impression doit être la plus intense, cela peut fausser le résultat ; il demande en conséquence que cette opération soit menée par quelqu'un de non informé, ce qui lui est refusé. Aimé Cotton en conclut donc à la non-validité des expériences faites par le Nancéen. Le philosophe des sciences Pierre Thuillier , entre autres, s'est longuement penché sur les différentes causes qui peuvent expliquer de tels égarements dans un domaine pourtant réputé pour le caractère rationnel de ses méthodes et objectifs [START_REF] Thuillier Pierre | La triste histoire des rayons N[END_REF]. On peut invoquer plusieurs raisons comme l'autorité que confère un poste dans une université et l'engouement généralisé pour certaines problématiques comme le rayonnement à la toute fin du 19 ème siècle. Pierre Thuillier évoque également des causes dites « internes au savoir » : si les protocoles de l'expérience menée ne sont pas clairement énoncés, si la rigueur du protocole n'est pas précisée, si l'interprétation est empreinte de subjectivité, si les variations observées ne sont pas significatives, etc. L'attitude et la démarche de Blondlot tombent dans plusieurs de ces écueils. En examinant attentivement l'enchaînement des processus, on constate que l'origine de l'affaire est la crédibilité indiscutable d'un scientifique qui prétend avoir mis en évidence un phénomène physique nouveau. Il est ensuite relayé par nombreux autres scientifiques, de plusieurs disciplines différentes, qui adhèrent à cette idée qui devient, dès lors, en quelque sorte, une vérité absolue. Ensuite les corps constitués prennent le train en marche, dont les Académies des Sciences étayées par les journaux spécialisés qui font leur une avec ces « découvertes » soutenues par des « experts scientifiques »… De là on aboutit à un « consensus » ; il n'y a pas de débat scientifique digne de ce nom jusqu'à ce que les faits prouvent que tout le monde s'est fourvoyé. Blondlot persiste malgré les défections de plus en plus nombreuses et s'enferme dans une attitude monomaniaque souvent observée chez les savants contrariés ou déçus par leurs résultats. Son échec n'empêche pas les autorités universitaires et politiques de l'élever, par la suite, au grade d'officier de la légion d'honneur et de le couvrir d'honneurs et de félicitations.

Le professeur René Blondlot et un extrait d'article relatif aux rayons « N ».

Aimé Cotton n'est pas un théoricien ; il sait cependant, à de multiples reprises, manipuler l'outil théorique, élaboré par d'autres, ou par lui-même, dans certains cas. A propos du rôle joué par les hypothèses théoriques de Lorentz dans la découverte de Zeeman : « Elle (la découverte) montre quels grands services l'emploi judicieux de théories peut rendre à l'observateur ; elle est elle-même un des cas très rares ou, pour un fait important et très nouveau, la théorie a précédé et aidé largement l'expérience ».

Aimé Cotton se caractérise donc par la primauté de l'expérience, ce que résume admirablement Louis de Broglie : « Savant méticuleux et prudent, d'une honnêteté intellectuelle absolue, vous avez toujours avancé avec sécurité sur les terrains nouveaux que vous exploriez. Vous avez ainsi fourni à vos élèves et à tous ceux qui suivaient vos travaux le bel exemple de ce que peut réaliser une grande habileté expérimentale quand elle est mise au service d'un esprit clair guidé par de scrupuleuses méthodes ». L'esprit expérimental d'Aimé Cotton se double, en effet, d'une grande honnêteté et aussi d'une vigoureuse persévérance alliée à une grande minutie.

L'ENGAGEMENT POLITIQUE

Aimé Cotton se trouve très tôt confronté à l'application de sa passion pour la justice puisque, en 1894, éclate l'affaire Dreyfus. La première prise de position en faveur de Dreyfus se situe pendant son séjour à Toulouse.

De son attitude dans la période de crise qui suit la guerre de 1914-1918, on retient qu'il reste « très méfiant à l'égard de la politique menée envers l'Allemagne, ainsi que des positions dites pacifistes intégrales. Il craint la renaissance du militarisme prussien… ».On retient aussi sa prise de position publique en faveur des syndicalistes Ferdinando Nicola Sacco et Bartolomeo Vanzetti condamnés à mort et exécutés aux USA malgré une campagne mondiale de protestation. Il apporte son aide à la jeune république espagnole. Pour améliorer son niveau scientifique, l'Espagne invite et accueille des scientifiques de renom : Aimé Cotton, Albert Einstein, Charles Fabry, Paul Langevin, Tullio Levi-Civita, Jean Perrin, Siegbahn, Ernest Sommerfeld, Pierre Weiss, Pieter Zeeman, etc.

CONCLUSION

Si les trois axes de ses travaux de recherche concernent le dichroïsme circulaire, la biréfringence magnétique et l'effet Faraday, ils ne sont pas les seuls ; Aimé Cotton a apporté une contribution importante à l'effet Zeeman, proposé la première solution au problème de la synthèse asymétrique et réalisé, avec l'électroaimant de Bellevue et son laboratoire, un des premiers ensembles modernes de recherche en physique [START_REF] Kastler | Le centenaire de la naissance d'Aimé Cotton[END_REF][START_REF] Aimé | OEuvres Scientifiques[END_REF]. Toute sa vie il s'est préoccupé des progrès et de la diffusion de l'Esperanto dans un souci de meilleure compréhension entre les hommes et particulièrement entre les savants : « …pour que les hommes de différents pays puissent mieux se comprendre, par suite mieux se connaître et mieux s'entendre les uns les autres ». Ses engagements anti-fascistes pendant la guerre d'Espagne ou contre la trahison de Munich et de la Tchécoslovaquie l'ont conduit à être arrêté par les Allemands et emprisonné. Aimé Cotton était un homme aux grandes qualités de caractère [START_REF] Cotton Eugénie | L'optique Et La Magnéto-Optique[END_REF] et a accompli une oeuvre scientifique remarquable.

REMERCIEMENTS

L'auteur tient à exprimer sa profonde gratitude à monsieur Jean Rosmorduc, ancien professeur émérite d'histoire des sciences à l'Université de Bretagne Occidentale, pour son aide précieuse.

ANNEXE :

Effet Zeeman : perturbation des niveaux d'énergie des électrons d'un atome sous l'action d'un champ magnétique, qui se traduit par une modification du spectre de raies d'émission du corps considéré. En analysant le spectre de raies émises par de la vapeur de sodium, Zeeman s'aperçoit, en 1896, que certaines d'entre elles sont démultipliées lorsque l'ampoule contenant la vapeur est placée dans un champ magnétique. En l'absence de champ magnétique, l'énergie d'un électron dans un atome ne dépend pas de l'orientation de son moment cinétique (seule la norme du vecteur intervient dans l'expression de l'énergie de l'électron, ce qui traduit les propriétés d'isotropie de l'espace, c'est-à-dire l'invariance du système par rotation). Il n'en est plus de même lorsque l'atome se trouve placé dans un champ magnétique : le vecteur moment cinétique s'oriente dans une direction privilégiée, l'invariance du système par rotation autour de lui-même n'est plus vérifiée, et l'énergie de l'électron dépend alors de l'angle entre le champ magnétique et le moment cinétique.

Jules Violle : Physicien français (1841-1923) : Il fait ses études à l'Ecole Normale Supérieure de Paris, et passe en 1870 sa thèse de doctorat ès sciences, portant sur la mesure de l'équivalent mécanique de la calorie, en utilisant l'élévation de température produite par les courants de Foucault induits dans une masse métallique en mouvement dans un champ magnétique. Ses recherches concernent principalement la radiométrie, la photométrie et la calorimétrie. En 1881, il propose un étalon d'intensité lumineuse indépendant des propriétés de l'émetteur de lumière (Etalon Violle), correspondant à la lumière émise par 1 cm 2 de platine en fusion (l'unité SI est le candela (Cd) : 1 violle = 20,17 Cd). Jules Violle perfectionne et invente plusieurs appareils de mesure du rayonnement, dont un actinomètre. En 1882, il invente encore le calorimètre à refroidissement, principe de base de certaines bouteilles isolantes. On lui doit également une théorie de la formation des geysers, des recherches sur l'origine de la grêle, et les moyens de la combattre. Il est par ailleurs l'un des premiers à proposer l'exploration de l'atmosphère par ballons-sondes. Il est enfin l'un des fondateurs de l'Institut d'Optique Théorique et Appliquée, et de l'Ecole Supérieure d'Optique.

L'effet Faraday est un effet magnéto-optique découvert par Michael Faraday en 1845. Il concerne l'interaction entre la lumière et un champ magnétique : la polarisation de la lumière effectue une rotation proportionnelle à la composante du champ magnétique le long de la direction de propagation de la lumière. En décomposant la polarisation de la lumière en deux polarisations circulaires tournant en sens contraires, ces deux composantes se propagent à des vitesses différentes, donnant ainsi un pouvoir rotatoire au matériau. Un rayon lumineux pénétrant dans le matériau avec une polarisation rectiligne ressort avec une polarisation orientée différemment. L'effet Faraday permet de mesurer le pouvoir rotatoire des substances ou détecter un champ magnétique.

On appelle dispersion rotatoire la variation en fonction de la longueur d'onde de l'angle de rotation caractérisant le pouvoir rotatoire d'une substance optiquement active. Dans le cas où le milieu est absorbant, on parle de dispersion anormale, et les deux vibrations circulaires composant la vibration rectiligne incidente peuvent être inégalement absorbées. A la sortie du milieu ces deux vibrations circulaires d'amplitudes inégales ont pour résultante une vibration elliptique. On dit qu'un matériau présente un dichroïsme circulaire s'il absorbe différemment la lumière selon que sa polarisation est circulaire droite ou circulaire gauche. Cette propriété, découverte par Aimé Cotton en 1896, concerne plutôt les liquides et les solutions du fait de la structure des molécules.

L'AUTEUR

Jean-Christophe PAIN, Physicien, chercheur au Commissariat à l'Energie Atomique.

  En parallèle, il travaille avec son camarade de promotion Henri Mouton, biologiste à l'Institut Pasteur sur les propriétés des solutions colloïdales. Il met au point la technique d'observation ultramicroscopique (1905) pour visualiser des particules colloïdales individuelles d'hydroxyde ferrique et constate que ces particules s'orientent sous l'action d'un champ magnétique. La solution présente alors une biréfringence magnétique intense (effet Cotton-Mouton) avec un axe optique parallèle aux lignes de champ (1907). En 1910, ils mettent en évidence ce phénomène de biréfringence magnétique dans un liquide pur : le nitrobenzène (déjà connu pour sa forte biréfringence électrique). Ils vont poursuivre ensemble pendant de longues années l'étude de ce phénomène sur un grand nombre de liquides en faisant varier des paramètres physiques comme l'intensité du champ appliqué, la température ou la longueur d'onde de la lumière utilisée. Très vite, Aimé Cotton se rend compte qu'il lui faut des champs magnétiques de plus en plus intenses et sur de plus grands volumes pour étudier cet effet très faible pour certaines substances. Il monte alors un projet d'électro-aimant puissant d'envergure nationale et réussit à intéresser l'Académie des Sciences. Mais la guerre de 1914 vient couper court à ce projet. En 1913, Aimé Cotton épouse Eugénie Feytis, agrégée-préparatrice à l'Ecole Normale Supérieure de Jeunes Filles de Sèvres, école dont elle assumera plus tard la direction. La même année, il remplace Jean Perrin dans cette même école pour préparer les jeunes étudiantes à l'agrégation. Plus tard, c'est aux efforts conjugués des époux Cotton que les Sévriennes doivent la création d'un laboratoire d'enseignement expérimental et le rattachement de l'Ecole Normale Supérieure féminine à l'enseignement supérieur. Aimé et Eugénie Cotton vont avoir trois enfants : Eugène Cotton qui poursuit une carrière de Physicien nucléaire au Commissariat à l'Energie Atomique, Minnie qui meurt à l'âge de neuf ans d'une grave appendicite et Jeannette qui épouse Pierre Manigault, biologiste travaillant à l'Institut Pasteur.

  . Cette expérience d'un instrument d'intérêt national s'avère très fructueuse. De nombreuses équipes venues du monde entier vont se succéder sur l'électro-aimant pour obtenir des résultats scientifiques remarquables. Le laboratoire compte sept ou huit permanents, et des chercheurs extérieurs viennent y travailler. Salomon Rosenblum, un physicien déjà connu à l'époque, sollicite, après son expérience positive sur l'électro-aimant (découverte en 1929 de la structure fine des rayons alpha du thorium C), l'aide d'Aimé Cotton pour la construction d'un aimant permanent. Alfred Kastler et Louis Leprince-Ringuet (à l'origine de la construction d'une chambre de Wilson pour rayons cosmiques qui apermis d'évaluer pour la première fois la masse du méson) s'y rendent régulièrement [13], ainsi qu'un jeune collaborateur très brillant (mort prématurément) de Pierre Auger, Paul Ehrenfest, le fils d'un physicien néerlandais. Les chercheurs permanents ont du mal à organiser le calendrier de leurs propres expériences. Le Professeur Fritz Simon d'Oxford est un réfugié juif ayant fui l'Allemagne nazie. Il est déjà bien intégré en Angleterre et se rend en 1936 au laboratoire avec l'un de ses collaborateurs, Nicholas Kurti, un réfugié hongrois également implanté en Angleterre. Ils mènent, avec un chercheur permanent du laboratoire, Paul Lainé, de belles expériences sur les très basses températures (alun de fer). C'est à Bellevue, vers 1936-37, qu'est obtenu un record de basse température par le procédé de « démagnétisation adiabatique » (ou encore « désaimantation adiabatique ») qui nécessite l'usage d'un électro-aimant. L'antiferromagnétisme prédit par Louis Néel est aussi découvert expérimentalement à cette époque par un autre chercheur de Bellevue : Henri Bizette. L'électro-aimant obtient donc de très beaux succès. Petit à petit, cette activité concentrée sur les basses températures se révèle très fructueuse. Aimé Cotton pense alors qu'il faut modifier la vocation du laboratoire, tout au moins son nom, pour l'appeler « Laboratoire de l'électro-aimant et des basses températures ». Il devient ensuite « Laboratoire des basses températures », puis « Laboratoire des basses températures et des champs magnétiques intenses ». On veut donner au laboratoire un nom qui évoque le type de recherches qui y sont menées et non l'outil avec lequel celles-ci sont effectuées. Il s'appelle ensuite « Laboratoire de magnétisme et de magnéto-optique ». Il enchaîne les appellations jusqu'à ce qu'en 1951, après la mort d'Aimé Cotton, Pierre Jacquinot en devienne le Directeur (il en était déjà le sousdirecteur) et propose qu'on l'appelle désormais « Laboratoire Aimé Cotton ». Les activités qui y sont menées ne justifient plus ni le nom de « basses températures », ni celui d' « électro-aimant ». Il doit lutter pour faire accepter l'appellation, car le CNRS n'a encore jamais baptisé un laboratoire du nom d'un homme (il le fera par la suite à de nombreuses reprises). Les directeurs successifs après P. Jacquinot sont : Robert Chabbal (1962-1969), Serge Feneuille (1978-1981), Sylvain Liberman (1981-1988), Catherine Bréchignac (1989-1996), Christian Colliex (1996-2001) et Pierre Pillet (2002-). Le laboratoire Aimé Cotton à l'université d'Orsay.

  Dès 1936, Aimé Cotton proteste contre la montée du fascisme en Europe. En 1941, alors qu'il prend sa retraite de professeur et continue à venir travailler au laboratoire de Bellevue, il est arrêté par les allemands et passe un mois et demi en prison à Fresnes. Madame Cotton s'oppose au projet d'Alfred Kastler et Pierre Jacquinot de prendre, à Fresnes, la place de son mari. L'événement émeut profondément le monde universitaire. Cela n'empêche pas Aimé Cotton de reprendre, après sa libération, sa place à Bellevue et même d'aller, sans se cacher, avec Charles Fabry, rendre visite à Troyes à Paul Langevin qui y est assigné à résidence. Il sera de nouveau arrêté en 1942 avec son fils Eugène dont, fort heureusement, les Allemands ignorent les activités résistantes à Lyon. On lui décernera la Rosette de la résistance. Son jubilé est organisé en 1948 par ses élèves en son honneur et son successeur à la Sorbonne déclare: « Le souvenir de vos belles leçons ne s'est pas estompé. La logique et la clarté des exposés, l'élégance des présentations ont marqué de nombreuses générations de Normaliens. Jamais les digressions théoriques ne masquaient le fait expérimental. Aujourd'hui encore, mon cours d'Optique n'est que le développement des idées que vous avez semées ». Aimé Cotton meurt le 16 Avril 1951 à Sèvres épuisé par une trachéite grave et des problèmes circulatoires. Même s'il a consacre presque toute son existence à son travail scientifique, Aimé Cotton ne négligeait pas sa vie familiale qui s'écoulait doucement dans son pavillon à Sèvres. Dans la maison de famille à Dhuys dans l'Ain, non loin de Bourg, il retrouvait son frère Emile, avec qui il partait chasser et se promener dans les montagnes.