Dr Léo Plaçais
email: leoplacais@gmail.com

Stéphane Dalle

Olivier Dereure

Sabiha Trabelsi

Sophie Dalac

Delphine Legoupil

Henri Montaudié

Jean-Philippe Philippe Arnault

Julie De

Julie De Quatrebarbes

Philippe Saiag

Florence Brunet-Possenti

Thierry Lesimple

Eve Maubec

François Aubin

Florence Granel-Brocard

Jean-Jacques Grob

Pierre-Emmanuel Stoebner

Clara Allayous

Bastien Oriano

Caroline Dutriaux

Laurent Mortier

Céleste Lebbe

SDalle, OD Lp

OD, ST Sdalle

Risk of irAEs in patients with autoimmune diseases treated by immune checkpoint inhibitors for stage III or IV melanoma: results from a matched case-control study

niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

INTRODUCTION

Immune checkpoint inhibitors (ICIs) are one of the major therapeutic advances in oncology in the past 10 years. Since their first approval in metastatic melanoma [START_REF] Robert | Ipilimumab plus dacarbazine for previously untreated metastatic melanoma[END_REF] and non-small cell lung cancer (NSCLC), [START_REF] Garon | Pembrolizumab for the treatment of non-small-cell lung cancer[END_REF] ICI indications have broadened and now extend to more than 50 different cancer types. [START_REF] Robert | A decade of immune-checkpoint inhibitors in cancer therapy[END_REF] The most prescribed ICIs are anti-PD-1/PD-L1 (programmed cell death protein 1/programmed cell death ligand 1) agents, and their prescription is likely to increase with up to 2975 active clinical trials of September 2019. [START_REF] Yu | Trends in clinical development for PD-1/PD-L1 inhibitors[END_REF] ICI restore anticancer immunity by targeting tumour-driven expression of immune checkpoints to mount an effective antitumoral immune response. However, as these pathways are physiologically involved in the downregulation of T cell responses and act as gatekeepers to prevent excessive T-cell activation, ICIs subsequently expose to the risk of T-cell-driven autoimmunity. [START_REF] Ramos-Casals | Immune-Related adverse events of checkpoint inhibitors[END_REF] ICIs' side effects include a large range of autoimmune manifestations (immune-related adverse events, referred to as irAEs), [START_REF] Postow | Immune-Related adverse events associated with immune checkpoint blockade[END_REF] estimated to occur in 54%-76% of the patients. [START_REF] Xu | Comparative safety of immune checkpoint inhibitors in cancer: systematic review and network meta-analysis[END_REF] Management depends on the severity

WHAT IS ALREADY KNOWN ON THIS TOPIC

⇒ Patients with pre-existing autoimmune diseases (pAID) are thought to be at greater risk of immune-related adverse events (irAEs), but previously published data are discordant. ⇒ Precise quantification of this risk, independently of the other known risk-factors of irAEs is lacking.

WHAT THIS STUDY ADDS

⇒ -Patients with pAID had a higher risk of developing both all-grade and grade ≥3 irAEs, but also of multiple irAEs, occurring in a shorter time than controls, but contrasting with a better overall survival at 24 months. Subsetting pAID into clinical subgroups highlighted distinct associations with organ-specific irAEs. Autoimmunity grade: while most CTCAE (Common Terminology Criteria for Adverse Events) grade 1 irAEs do not require therapeutic intervention; grade 2 irAEs may require ICI temporary interruption and patients with grade ≥3 should receive corticosteroids. [START_REF] Ramos-Casals | Immune-Related adverse events of checkpoint inhibitors[END_REF] Lethal irAEs occur in 0.3%-1.3% of cases, [START_REF] Wang | Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis[END_REF] and symptoms may persist after ICI cessation and cause long-term sequelae. 9 10 Thus, identifying patients at higher risk of developing irAEs is crucial to early diagnosis and improved care Autoimmune diseases (AIDs) are frequent, with an estimated prevalence of 4.5%, [START_REF] Hayter | Updated assessment of the prevalence, spectrum and case definition of autoimmune disease[END_REF] and co-occurrence with cancer is not uncommon, as recent studies reported a 14%-25% frequency of pre-existing AID (pAID) in 210 509 patients with lung cancer, [START_REF] Khan | Prevalence of autoimmune disease among patients with lung cancer: implications for immunotherapy treatment options[END_REF] and of 1.6% in 311 patients treated by anti-PD-1 agents. [START_REF] Dupont | The prognostic impact of immune-related adverse events during anti-PD1 treatment in melanoma and non-small-cell lung cancer: a real-life retrospective study[END_REF] As irAEs often mimic AID manifestations, [START_REF] Allenbach | Immune checkpoint inhibitorinduced myositis, the earliest and most lethal complication among rheumatic and musculoskeletal toxicities[END_REF][START_REF] Terrier | Risk of scleroderma according to the type of immune checkpoint inhibitors[END_REF][START_REF] Calabrese | Rheumatic immune-related adverse events from cancer immunotherapy[END_REF][START_REF] Collins | Inflammatory gastrointestinal diseases associated with PD-1 blockade antibodies[END_REF] patients with pAID were thought to be at higher risk of irAEs and excluded from the first clinical trials of ICI. [START_REF] Herbst | Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial[END_REF][START_REF] Brahmer | Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer[END_REF][START_REF] Reck | Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer[END_REF] Several studies described the safety and oncological outcomes of ICI therapy in patients with pAID. Overall, they reported a frequency of pAID flare of 23%-47%, a frequency of irAEs of 29%-44% and a frequency of grades 3-4 irAEs of 10%-44%. Most pAID flares and irAEs were managed by corticosteroid therapy, leading the authors to conclude that ICI therapy in pAID patients was safe but required close monitoring. [START_REF] Menzies | Anti-Pd-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab[END_REF][START_REF] Danlos | Safety and efficacy of anti-programmed death 1 antibodies in patients with cancer and pre-existing autoimmune or inflammatory disease[END_REF][START_REF] Leonardi | Safety of programmed death-1 pathway inhibitors among patients with non-small-cell lung cancer and preexisting autoimmune disorders[END_REF][START_REF] Gutzmer | Programmed cell death protein-1 (PD-1) inhibitor therapy in patients with advanced melanoma and preexisting autoimmunity or ipilimumab-triggered autoimmunity[END_REF][START_REF] Tison | Safety and efficacy of immune checkpoint inhibitors in patients with cancer and preexisting autoimmune disease: a nationwide, multicenter cohort study[END_REF] In a recent study published by Tison et al, [START_REF] Tison | Safety and efficacy of immune checkpoint inhibitors in patients with cancer and preexisting autoimmune disease: a nationwide, multicenter cohort study[END_REF] of 112 patients with pAID treated by ICI, 71% presented with an immune toxicity (pAID flare, irAE or both), and ICI was permanently withdrawn for 21%. Moreover, treatment of immune toxicities with immunosuppressive drugs was associated with a lower progression-free survival. In contrast, in a recent study from a prospective Dutch nationwide melanoma registry, the incidence of grade ≥3 irAEs did not differ between 415 patients with pAID and controls. [START_REF] Van Der Kooij | Safety and Efficacy of Checkpoint Inhibition in Patients With Melanoma and Preexisting Autoimmune Disease : A Cohort Study[END_REF] These results pinpoint the need for a precise evaluation of the risk of irAEs in patients with pAID.

We present the results of a large case-control matched study of patients included in a prospective cohort, evaluating the risk of irAEs among patients with pAID compared with patients without pAID matched for irAEs' risk factors and disease stage.

Study design

This study was conducted using the French multicentric prospective and longitudinal cohort MelBase (registered NCT02828202), which is dedicated to the prospective follow-up in 26 participating centres of adults with unresectable stage III or IV melanoma at the time of declaration of metastasis. MelBase prospectively records data regarding oncological progression and survival, treatment introduction and discontinuation, adverse events, and their management, as well as demographic data including age, sex and medical history. Inclusion criteria require an age of over 18 years old, the availability of a tumour sample for histological confirmation of advanced primary melanoma (unresectable stage III or stage IV) and the absence of prior systemic treatment other than adjuvant treatment. Additional data regarding baseline immunosuppressive therapy and pAID flares in cases were collected retrospectively through a questionnaire sent to all recruiting centres.

Cases and controls

Cases were defined as patients treated by anti-PD-1 and/or anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) antibodies for metastatic melanoma with a history of AID prior to immunotherapy, prospectively recorded at inclusion and were referred to as pAID. Specifically, during the inclusion process of the MelBase cohort, the dermato-oncologist in charge of the patient declared if his/her patient had an history of an AID (detailed in the online supplemental annex). For most of these patients, the decision of initiating an ICI therapy was taken collegially by multidisciplinary boards specialised in the management of immunotoxicities due to their history of AIDs and weighted while considering the diagnostic criteria and AID activity. All cases of pAID were centrally reviewed by the authors at the conception of the study.

Definitions and classification of irAEs

IrAEs were defined as an event or laboratory test abnormality, considered to be possibly, probably or certainly linked to the immunotherapy, following the WHO-UMC (WHO-Uppsala Monitoring Centre) causality assessment guidelines, and recorded prospectively during the follow-up. Severity was determined using the CTCAE v4.0. The clinical subtypes of irAEs were regrouped as follows: cardiovascular, endrocrinological, rheumatological, cutaneous, pulmonary, haematological, neurological, psychiatric, renal, ophthalmological, musculoskeletal and general symptoms.

Statistical analysis and case-control matching

Baseline demographic and disease characteristics were summarised as numbers and percentages for categorical variables, and as mean, SD, median, IQR and range for continuous variables, as appropriate. Case-control matching was performed on R statistical software V.4.0.4, on a 3-controls-for-1-case ratio, using the following criteria: age (by 2-year range classes), sex, immunotherapy regimen (anti-PD-1 monotherapy, anti-CTLA-4 monotherapy, or anti-PD-1 and anti-CTLA-4 associated therapy), number of previous therapeutic lines, baseline lactate dehydrogenase (LDH) values (by quartiles), existence of liver metastasis and of cerebral metastasis and number of metastasis (< or ≥3 sites).

Comparison of variable distribution between cases and controls was performed using either χ 2 , Fisher's exact test and Kruskal-Wallis's test when appropriate. Logistic regression was used to calculate OR of developing irAEs. Patients censored before 12 months were patients lost to follow-up (most commonly patients who had completed their follow-up). Missing data were handled by multiple imputation using chained equations. Twenty datasets were imputed and analysed separately, and results were then pooled into a final estimate. Survival analysis was performed using log-rank test and Kaplan-Meier method with associated 95% CI was used to generate survival curves and estimate overall survival and time-to-first-irAE. Data analyses were conducted using R statistical software V.4.0.4 and the R MICE (Multivariate Imputation by Chained Equations) package to address missing data (The R Foundation for Statistical Computing, Vienna, Austria). Statistical significance was set to p<0.05.

Patient's consent

The French Ethics Committee approved MelBase protocol (Comité de protection des personnes Ile-de-france XI, no 12027, 2012). MelBase is registered in the National Institute of Health clinical trials database (NCT02828202). Written informed consent was obtained from all patients.

Patient's and public involvement

None.

RESULTS

Patient's characteristics

One hundred and ten patients with pAID were identified among the 2227 patients included in the prospective cohort MelBase from March 2013 to October 2020, and matched with 330 controls, on a 1-case-for-3-controls ratio. The median duration of follow-up was 7.24 months (IQR (3.67-23.41)) for cases and 6.86 months (IQR (3.62-20.83)) (p=0.30) (online supplemental figure).

The mean age was 65 years old for cases and controls. There was no difference for the gender repartition, nor for the mean body mass index (table 1). Thirty-nine per cent of the cases harboured a BRAF mutation, and 41% of the controls (p=0.8). The proportion of patients with an ECOG (Eastern Cooperative Oncology Group) performance status score >1 was higher in cases than in controls (24% vs 14%, p=0.02) (table 1).

Seventy-eight per cent of the patients were treated by anti-PD-1 monotherapy (42% by nivolumab, 36% by pembrolizumab), 14% by anti-CTLA-4 monotherapy and 8% by the association of anti-PD-1 and anti-CTLA-4 therapy (combination therapy). Seventy-four per cent received ICI as first-line immunotherapy.

Pre-existing autoimmune diseases

Of the 110 cases, 47 (43%) had a history of autoimmune thyroiditis, 18 (16%) of psoriasis, 11 (10%) of rheumatoid arthritis, 8 (7%) of vitiligo, 3 (3%) of sarcoidosis, 3 of Raynaud disease, 3 of spondyloarthritis, 3 of multiple sclerosis, 2 (2%) of Crohn's disease, 2 of thrombopenic idiopathic purpura, 2 of giant cell arteritis, 2 of myasthenia, 1 (1%) of Guillain-Barré syndrome, 1 of systemic sclerosis, 1 of polymyositis, 1 of dermatomyositis, 1 of autoimmune hepatitis and 1 of IgA nephropathy. The median time from AID diagnosis to first ICI infusion was 103 months (IQR (37-241)). Seventy cases (63%) were treated for their pAID in the 3 months before ICI initiation, and 19 (17%) by immunosuppressive or immunomodulatory agents (13 by systemic corticosteroid therapy and 8 by methotrexate). We separated pAID into four subgroups: endocrinological pAID (autoimmune thyroiditis), cutaneous pAID (psoriasis and vitiligo), rheumatological pAID (rheumatoid arthritis and spondyloarthritis) and others. Endocrinological and cutaneous pAID were more often treated by anti-CTLA-4 monotherapy or combination therapy, and rheumatological and other pAID were more often treated by immunosuppressive agents at baseline (online supplemental table).

Autoimmunity

Risk of irAEs and severe irAEs

Overall, 72% of the 118 cases and 77% of the 354 controls presented with at least one irAE of all-grades, and 57% and 37% with at least one irAE of grade ≥3. There was no difference for the number of immunotherapy cures before irAEs between cases and controls (1.4 vs 1.3, p=0.1). The mean time from first infusion of immunotherapy to first irAEs was 4.5 months (SD 3.0) in the whole population, 4.8 months for cases and 4.3 months for controls (SD 2.8 and SD 2.6, respectively, p=0.12).

Cases had a higher risk of all-grade irAE occurrence (OR 1.91, 95% CI (1.56 to 2.27), p=0.03), along with a higher risk of grade ≥3 irAEs (OR 1.44, 95% CI (1.08 to 1.82), p=0.04) when compared with matched controls (figure 1). When considering only organ-specific irAEs (ie, after exclusion of general symptoms of irAEs), cases still had a higher risk of all-grade irAE occurrence (OR 2.26, 95% CI (1.22 to 4.39), p=0.03) and of grade ≥3 irAEs (OR 1.71, 95% CI (1.09 to 2.34), p=0.05).

The risk of multiple irAEs was also higher among cases (OR 1.46, 95% CI (1.15 to 2.67)) with a mean number of irAEs per patient of 7.2 (SD 1.2) versus 5.1 for controls (SD 1.1) (p=0.04, table 2). Both all-grade and grade ≥3 irAEs occurred earlier in cases (log-rank test, p=0.002 and p=0.01, respectively;

Risk of irAEs depending on the ICI regimen

The higher risk of all-grade irAEs in patients with pAID was consistent in patients treated by anti-PD-

Risk of irAEs and pAID flares among pAID subgroups

When considering pAID subgroups (online supplemental table), endocrinological pAID were associated with a higher risk of all-grade irAEs (OR 2.

Clinical subtypes of irAEs

The distribution of the clinical irAE subtypes did not differ between cases and controls, neither for all-grade irAEs nor for grade ≥3 irAEs (table 2). The most frequent grade ≥3 irAEs were digestive tract, endocrinological, haematological and pulmonary (table 2).

Distribution of irAE subtypes depending on pAID subgroup

We compared the distribution of the irAE clinical subtypes between patients with endocrinological, cutaneous, rheumatological and others pAID. The overall distribution of all-grade (but not grade ≥3) irAE clinical subtypes was significantly different between pAID subgroups (p=0.04) (table 3). Patients with rheumatological pAID had a higher frequency of gastrointestinal tract and rheumatological all-grade irAEs (p=0.04 and p<0.0001, respectively) as well as of severe irAEs (p=0.002).

Patients with endocrinological pAID had the higher frequency of all-grade neurological irAEs (p<0.0001) but not of severe neurological irAEs. Musculoskeletal irAEs were more frequent among patients with others pAID (p=0.02) (table 3).

Survival analysis

Cases had an increased overall survival when compared with controls (log-rank test, p=0.02; figure 3). However, many of the survival data were censored due to restricted follow-up duration. The estimated landmark overall survival at 24 months was 64.8% (IQR (56.2-74.7) for cases and 45.9% (IQR (40.4-52.1)) for controls. We compared cases treated with immunosuppressive agents or not and did not find a difference in survival (logrank test, p=0.68).

DISCUSSION

While previous studies reported a high risk of irAEs and/or AID flare in patients with pAID treated by ICI, this study is to our knowledge the first to compare these patients with matched controls for irAE risk factors and oncological status, in a prospective cohort of patients treated for metastatic melanoma. The strengths of our study are the prospective collection of data and the case-control design allowing for precise quantification of the risk of irAEs depending on the existence of a history of AID.

The main limitations are the absence of data on the irAEs' therapeutical management apart from checkpoint inhibitor therapy discontinuation, and the limited follow-up duration which might have underestimated the risk of delayed irAEs. Another potential limitation is the absence of a systematic set of diagnostic criteria fulfilment at the inclusion of a patient with pAID in the MelBase cohort. This could restrict the interpretation of our observations in small groups of complex AIDs. The theoretical risk of misclassification of a control as a case, despite central reviewing, would result in negative bias and thus does not prevent the extrapolation of our results.

In our study, patients with pAID had two times higher risk of developing both all-grade irAEs than controls, independently of

Autoimmunity

known risk factors of irAEs, such as age, sex, 27 28 the immunotherapy regimen [START_REF] Chen | A systematic review of immune-related adverse event reporting in clinical trials of immune checkpoint inhibitors[END_REF] and/or of disease status, such as the melanoma stage, the existence of hepatic or cerebral metastasis, the number of metastasis and the LDH values at baseline. 30 31 Additionally, there were no difference between cases and controls for the body mass index values. [START_REF] Eun | Risk factors for immune-related adverse events associated with anti-PD-1 pembrolizumab[END_REF] We were not able to perform a matching of the ECOG status because of a higher proportion of ECOG 0 patients among control candidates. Thus, cases were more often classified as ECOG >1 than controls, which could, however, have undermined our results, as low ECOG has been associated with an increased risk of irAEs and of multisystem irAEs. [START_REF] Cortellini | Clinical outcomes of patients with advanced cancer and pre-existing autoimmune diseases treated with Anti-Programmed death-1 immunotherapy: a real-world transverse study[END_REF] [START_REF] Shankar | Multisystem immune-related adverse events associated with immune checkpoint inhibitors for treatment of non-small cell lung cancer[END_REF] We also reported a higher risk of multiple irAEs, and a shorter time to both all-grade and grade ≥3 irAE onset in patients with pAID, as previously reported. [START_REF] Danlos | Safety and efficacy of anti-programmed death 1 antibodies in patients with cancer and pre-existing autoimmune or inflammatory disease[END_REF] The most frequently represented AID among cases were autoimmune thyroiditis, psoriasis, rheumatoid arthritis and vitiligo, in a relative proportion close to the one described in the general population. [START_REF] Cooper | The epidemiology of autoimmune diseases[END_REF] We regrouped the cases into four pAID subgroups based on their clinical expression, a choice that might not reflect common disease pathogenesis but rather help categorise patients in the real-world practice. Patients with endocrinological and others pAID had an increased risk of all-grade and grade ≥3 irAEs, but not patients with cutaneous or rheumatological pAIDs. This difference could be explained by the high proportion of immunosuppressive treatment at baseline in patients with rheumatological pAID or be the testament of physiopathological differences. Thirty per cent of the cases experienced a pAID flare during follow-up. As the pAID flares were all declared as irAEs, this might have overestimated the number of irAEs in caseshowever, they only represent a small fraction of the irAEs developed over follow-up in this group (n=794) and were the most frequent in patients with rheumatological irAEs, whose risk of irAEs was not increased when compared with controls in the subgroup analysis. Importantly, we noticed a difference in the clinical subtypes of all-grade irAEs depending on the subgroup of pAID, suggesting a predisposition for certain irAEs. These patterns of irAE clinical subtypes' susceptibility could help monitoring patients with pAID treated by ICI and improve the screening for irAEs in this population.

Both cases and controls presented with a rather high number of irAEs compared with previously published data. This might be explained by the systematic and prospective recording of all-grade irAEs and by the inclusion of general symptom irAEs, which were declared as linked to the immunotherapy but might also reflect cancer evolution. Importantly, after exclusion of general symptom irAEs, the ORs of developing all-grade and grade ≥3 irAEs in cases compared with controls were even greater. Despite of a higher risk of grade ≥3 irAEs, the proportion of lethal irAEs did not differ between cases and controls, and cases had an increased overall survival rate. This result could possibly be linked to the increased occurrence of multiple irAEs, which have reportedly been associated with increased survival in patients with NSCLC. [START_REF] Shankar | Multisystem immune-related adverse events associated with immune checkpoint inhibitors for treatment of non-small cell lung cancer[END_REF] Moreover, in patients treated for metastatic melanoma or NSCLC, the occurrence of irAEs seems to be associated with an increased oncological survival. 36 37 Our findings are in line with previously published data from retrospective case-series and prospective cohorts. Menzies et al were the first to address the risk of irAEs in patients with pAID and found an incidence of 29% of all-grade irAEs among 51 patients with pAID followed for a median of 4.7 months and a 8% ICI discontinuation rate. [START_REF] Menzies | Anti-Pd-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab[END_REF] Danlos et al reported a grade ≥2 irAE incidence of 44% over a 5.1-month period of follow-up, along with an ICI discontinuation rate of 11.1%, in 45 patients with pAID compared with 352 patients without pAID from the REISAMIC prospective registry. [START_REF] Danlos | Safety and efficacy of anti-programmed death 1 antibodies in patients with cancer and pre-existing autoimmune or inflammatory disease[END_REF] The higher incidence of allgrade irAEs in our study can be explained by the prospective design and systematic recording of all-grade irAEs, the differences in ICI regimen 6 38 and longer follow-up. In a large multicentric retrospective study, Cortellini et al found a 65.9% incidence of all-grade irAEs in 85 patients with pAID followed for a median of 14.7 months, along with an ICI discontinuation rate of 7%. [START_REF] Cortellini | Clinical outcomes of patients with advanced cancer and pre-existing autoimmune diseases treated with Anti-Programmed death-1 immunotherapy: a real-world transverse study[END_REF] Interestingly, both inactive and active pAID were associated with a higher risk of all-grade irAEs. Moreover, in accordance with our results, the risk of all-grade irAEs was greater in patients with endocrinological pAID and lower in patients with rheumatological pAID. In a large multicentric retrospective study, Tison et al reported a 71% incidence of all-grade irAEs and/or autoimmune flares in 112 patients with pAID followed for a median of 8 months. The ICI discontinuation rate (21%) was greater than in our study, possibly reflecting a higher proportion of potentially severe AIDs, such as inflammatory bowel disease. [START_REF] Tison | Safety and efficacy of immune checkpoint inhibitors in patients with cancer and preexisting autoimmune disease: a nationwide, multicenter cohort study[END_REF] Our results however contrast with those of a recent prospective cohort study published by Van der Koij et al, which did not find an increase in the risk of grade ≥3 irAEs among patients with pAID treated by checkpoint inhibitors for advanced melanoma, a difference possibly explained by the absence of a matched casecontrol design for irAEs risk factors and by the high proportion of patients with AID treated by corticosteroids at inclusion. [START_REF] Van Der Kooij | Safety and Efficacy of Checkpoint Inhibition in Patients With Melanoma and Preexisting Autoimmune Disease : A Cohort Study[END_REF] Overall, while our results pinpoint an increased risk of irAEs and severe irAEs in patients with pAID, we did not find an increased risk of lethal irAEs and reported an increased overall survival when compared with controls, further confirming they should be considered for ICI therapy. Patients with pAID should, however, be closely monitored for irAEs, which are more frequent and occur earlier. As the risk of irAEs differs depending on the nature of the pAID, specific guidelines for autoimmune flares and irAEs should be considered. [START_REF] Haanen | Autoimmune diseases and immune-checkpoint inhibitors for cancer therapy: review of the literature and personalized risk-based prevention strategy[END_REF] Ongoing clinical trials will provide valuable data to confirm the safety and efficacy of ICI in patients with pAID. [START_REF]clinicaltrials. gov. National cancer Institute (NCI): a phase Ib study of nivolumab in patients with autoimmune disorders and advanced malignancies (AIM-NIVO)[END_REF]

CONCLUSION

In this case-control study, the existence of a history of AID was associated with an increased risk of all-grade irAEs, severe irAEs and multiple irAEs, yet was associated with an increase in overall survival. Patients with a history of AID should be closely monitored during checkpoint inhibitor therapy.

Figure 1

 1 Figure1Risk of all-grade irAEs and risk of grade ≥3 irAEs in patients with pre-existing autoimmune diseases matched to controls. AID, autoimmune disease; irAEs, immune-related adverse events.

Figure 2

 2 Figure 2Cumulative incidence of all-grade irAE and grade ≥3 irAE among patients with pre-existing autoimmune diseases and matched controls. Cases: patients with pre-existing autoimmune disease, controls: patients without pre-existing autoimmune disease. The x axis represents the percentage of patients who developed 100% of their irAEs at a given follow-up time, represented on the y axis. Both cases and controls curves will reach a plateau at 1.0 at the end of follow-up. irAE, immune-related adverse event.

Table 1

 1 Cases and controls characteristics

	Age (years old, mean (SD)) >65 years old (no (%)) Gender (no (%)) Female Male Body mass index (kg/m 2 , mean (SD)) Melanoma stage M1a M1b M1c IIIB IIIC BRAF status (no (%)) Wild type Mutated LDH at baseline >1x ULN >2x ULN ECOG status at baseline 0-1 >1 Number of metastases (no (%)) <3 ≥3 Hepatic metastases Yes Cerebral metastases	Cases (N=110) 65 (14) n=65 (59) n=58 (53) n=52 (47) 26 (21) n=9 (8%) n=22 (20%) n=59 (54%) n=5 (5%) n=15 (14%) n=67 (61) n=43 (39) n=29 (26%) n=4 (4%) n=84 (76%) n=26 (24%) n=16 (15) n=94 (85) n=30 (27%)	Controls (N=330) 65 (18) n=195 (59) n=174 (53) n=156 (47) 25 (20) n=51 (15%) n=55 (17%) n=172 (52%) n=8 (2%) n=44 (13%) n=195 (59) n=135 (41) n=87 (26%) n=17 (5%) n=285 (86%) n=45 (14%) n=48 (15) n=282 (85) n=90 (27%)	P value 1 1 1 0.8 0.3 0.8 1 0.7 0.02* 1 1 1	Ann Rheum Dis: first published as 10.1136/ard-2022-222186 on 4 July 2022. Downloaded from
	Yes First-line immunotherapy Yes No Number of previous therapeutic lines 0	n=28 (25%) n=81 (74%) n=29 (26%) n=81 (74%)	n=84 (25%) n=243 (74%) n=87 (26%) n=243 (74%)	1 1	http://ard.bmj.com/
	1 ≥2 Immunotherapy regimen Anti-PD-1 monotherapy Pembrolizumab Nivolumab Anti-CTLA-4 monotherapy Anti-PD-1+anti-CTLA-4 combination * p<0.05 ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; PD-1, n=19 (17%) n=57 (17%) n=10 (9%) n=30 (9%) 1 n=86 (78%) n=258 (78%) n=40 (36%) n=120 (36%) n=46 (42%) n=138 (42%) n=15 (14%) n=45 (14%) n=9 (8%) n=27 (8%) programmed cell death protein 1; ULN, upper limit of normal.	on February 19, 2024 at Univ of Montpellier. Protected by copyright.

Table 2

 2 Characteristics of the irAEs presented by cases and controls

	Cases (N=110)	Controls (N=330)	P value

on February 19, 2024 at Univ of Montpellier. Protected by copyright. http://ard.bmj.com/ Ann Rheum Dis: first published as 10.1136/ard-2022-222186 on 4 July 2022. Downloaded from figure

2

). No difference was seen for irAEs-related mortality, and the proportion of patients requiring definitive immunotherapy cessation after irAEs was not higher in cases than in controls (7% vs 4%, p=0.30, table

2

). The existence of a baseline immunosuppressive therapy in cases was not associated with a significant protective effect on all-grade or grade ≥3 irAEs (OR 1.18, 95% CI (0.66 to 2.13), p=0.57 and OR 0.91, 95% CI (0.38 to 2.21), p=0.85, respectively).

Table 3

 3 Distribution of the clinical subtypes of irAEs depending on the subgroup of pre-existing autoimmune disease

	irAE subtype Median number of all-grade irAEs (IQR) Median number of grade 3+ irAEs (IQR) Endocrinological irAEs (no (%)) All-grade Grade 3+ Digestive tract irAEs (no(%)) All-grade Grade 3+ Cutaneous irAEs (no (%)) All-grade Grade 3+ Haematological irAEs (no (%) All-grade Grade 3+ Neurological irAEs (no (%)) All-grade Grade 3+ Pulmonary irAEs (no (%)) All-grade Grade 3+ Cardiovascular irAEs (no (%)) All-grade Grade 3+ Rheumatological irAEs* (no (%)) All-grade Grade 3+ Renal irAEs (no (%)) All-grade	Endocrinological AID 4.1 (0-13) 1 (0-1) 19 (5.2) 2 (5.6) 65 (17.9) 12 (33.3) 53 (14.6) 2 (5.6) 12 (3.3) 5 (13.9) 33 (9.1) 1 (2.8) 18 (4.9) 2 (5.6) 7 (1.9) 1 (2.8) 7 (1.9) 0 (0) 9 (2.)	Cutaneous AID 1.5 (0-8) 1 (0-1) 8 (5.4) 1 (3.8) 32 (21.8) 6 (23.1) 16 (10.9) 2 (7.7) 6 (4.1) 2 (7.7) 3 (2.0) 1 (3.8) 7 (4.8) 2 (7.7) 3 (2.0) 2 (7.7) 6 (4.1) 0 (0) 5 (3.4)	Rheumatological AID 3 (1-6) 1 (0-1) 6 (7.3) 1 (7.1) 22 (26.9) 4 (28.6) 7 (8.5) 0 (0) 8 (9.8) 0 (0) 0 (0) 0 (0) 1 (1.2) 1 (7.1) 0 (0) 0 (0) 8 (9.8) 2 (14.2) 1 (1.2)	Others AID 4(1-13) 2 (0-4) 15 (7.5) 8 (20.5) 47 (23.4) 10 (25.6) 18 (9.0) 3 (7.7) 7 (3.5) 1 (2.6) 11 (5.5) 1 (2.6) 7 (3.5) 3 (7.7) 6 (3.0) 1 (2.6) 0 (0) 0 (0) 2 (1.0)	P value for the distribution 0.04* 0.16 0.65 0.12 0.04* 0.83 0.16 0.86 0.09 0.21 <0.001* 1.0 0.47 1.0 0.50 0.67 <0.001* 0.002* 0.43	Ann Rheum Dis: first published as 10.1136/ard-2022-222186 on 4 July 2022. Downloaded from
	Grade 3+ Psychiatric irAEs (no (%)) All-grade Grade 3+ Musculoskeletal irAEs* (no (%)) All-grade Grade 3+ Ophthalmological irAEs (no (%)) All-grade Grade 3+ General symptom irAEs (no (%)) All-grade Grade 3+ *: p<0.05 *Rheumatological irAEs included arthralgia and arthritis. Musculoskeletal irAEs included myalgia, myositis, muscle weakness, CPK increase and bone pain. 2 (5.6) 2 (7.7) 0 (0) 1 (2.6) 0.69 3 (0.8) 4 (2.7) 1 (1.2) 7 (3.5) 0.09 1 (2.8) 1 (3.8) 1 (7.1) 2 (5.1) 0.92 5 (1.4) 4 (2.7) 1 (1.2) 12 (6.0) 0.02* 0 (0) 1 (3.8) 0 (0) 0 (0) 8 (2.2) 1 (0.7) 3 (3.7) 5 (2.5) 0.42 2 (5.6) 0 (0) 1 (7.1) 0 (0) 0.13 125 (34.3) 52 (35.4) 24 (29.3) 64 (31.8) 0.74 6 (16.7) 6 (23.1) 4 (28.6) 9 (23.1) 0.77 AID, autoimmune disease; irAEs, immune-related adverse events. 0.35	on February 19, 2024 at Univ of Montpellier. Protected by copyright. http://ard.bmj.com/

Plaçais L, et al. Ann Rheum Dis 2022;81:1445-1452. doi:10.1136/annrheumdis-2022-222186

Funding This study did not receive external funding, but the MelBase cohort is sponsored by the French National Cancer Institute and by BMS, MSD, Novartis and Roche.

Competing interests DL: fees from Novartis, BMS et MSD. PS: consulting fees from Roche, Novartis, BMS, Pierre FABRE, MSD. FB-P: consulting fees from BMS and Sanofi. TL: consulting fees from MSD, BMS, Pierre Fabre, Novartis. J-JG : consulting fees from MSD, Roche, Novartis, Amgen, Pierre-Fabre, Sanofi, Philogen, Merck, Pfizer. CA: grants from Amgen, BMS, Roche. LM: grants from BMS, Novartis, Roche, MSD, GSK, Pierre Fabre and consulting fees from BMS, Novartis, Roche, MSD, GSK, Pierre Fabre. CL: grants from BMS, MSD, Novartis, Sanofi, Pierre Fabre; consulting fees from BMS, MSD, Novartis, Amgen, Roche, Merck, Serono, Sanofi, Pierre Fabre and teaching fees from Roche, BMS, Novartis, Amgen, MSD.

Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.

Patient consent for publication Not required.

Ethics approval This study involves human participants and was approved by Comité de protection des personnes Ile-de-france XI, no 12027, 2012. Participants gave informed consent to participate in the study before taking part.

Provenance and peer review Not commissioned; externally peer reviewed.

Data availability statement Data will be available on request and acceptance of the MelBase cohort scientific board.

Supplemental material

This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

ORCID iDs

Léo Plaçais http://orcid.org/0000-0001-7345-9478 Florence Brunet-Possenti http://orcid.org/0000-0003-2100-2913


Clément Melin
email: clement.melin@cea.fr

Gilles Bernard-Michel
email: gilles.bernard-michel@cea.fr

Benjamin Cariteau
email: benjamin.cariteau@cea.fr

Philippe Fillion
email: philippe.fillion@cea.fr

METERO-V experimental set-up: presentation and first results. Uniform flows through a 8x34 PWR-type rod bundle with mixing grids at Reynolds number ranging from 800 to 70000: pressure loss measurements

    METERO-V experimental set-up: presentation and first results. Uniform flows through a 8x34 PWR-type rod bundle with mixing grids at Reynolds number ranging from 800 to 70000: pressure loss measurements

I. INTRODUCTION

Component scale and system-scale thermalhydraulics codes have 3D models to assess the 3D effects during several accidental scenarios such as Large Break, Intermediate Break, Small Break-LOCA, or low flow rate SLB (Steam Line Break). During these accidents, the flow is mainly vertical in the core but the heterogeneous power distribution may create crossflows. The models that represent these situations have been validated through several experimental programs such as UPTF, SCTF or CCTF facilities. Nevertheless, this experimental database do not cover all conditions in terms of flow inclination, Reynolds number or pitch-to-diameter ratio of a PWR core in the studied situations. METERO-V (V for vertical) program is part of the NEPTUNE project, including CEA, EDF, Framatome, and IRSN. This extended abstract is dedicated to introduce the METERO-V experimental facility and its instrumentation. Preliminary results of pressure drop measurements are also provided.

II. FACILITY DESCRIPTION

METERO-V is a 20 𝑚 3 water loop, the fluid used is softened water at ambient temperature. In the test section the maximum pressure is 2.7 bar and the temperature goes from 10 to 50 °C. The test section contains two unheated halves rod bundles. The experimental facility imposes the boundary conditions for each half rod bundle in terms of flow rate and temperature. Several flow regimes are achievable by METERO with Reynolds number from 800 to 70 000.

Fig. 1 : METERO-V schematic view

The design of METERO-V permits to perform flow rate dissymmetries. The flow rate in each leg is imposed thanks to the regulation valves and the flowmeters. Furthermore, METERO-V is also built to perform temperature dissymmetries. The cold leg is made up of a heat exchanger that can disperse up to 80 kW of energy, while the warm leg provides an 80 kW heating power input. The experimental setup can produce a temperature dissymmetry between the two rod bundles of up to 40 °C depending on the flow rate.

The temperature measurements are performed by PT100 probes. METERO-V is also capable to generate in the test section a two-phase flow due to the air injection at the bottom of the test section. All of these elements are displayed on the schematic view of the METERO-V thermalhydraulic loop (Fig. 1). The test section is rectangular with a dimension of 435x106x1789 mm. It is composed of two unheated halves rod bundles made of four mixing grids used in French PWR and 8x34 rods. The hydraulic diameter Dh of this geometry is 11.6 mm. The geometrical parameters of the test section geometry are listed on the Fig. 2.

Fig. 2 : Test section geometrical parameters

III. RESULTS

Nine pressure taps are available on each small side of the test section. Their localization allows the measurement of bare rod bundle pressure drop (DP-1 on Fig. 1) and mixing grid pressure drop (DP-2 on Fig. 1). Rosemount 2051C and 3051C are used to perform the pressure drops measurements. Their scale of measurements are ±620 mbar, ±62.2 mbar and ±7.3 mbar. The uncertainties associated to the instruments are listed in the Table I.

Considered negligible

From the data measured, the bare rod friction factor is deduced. The bare rod friction factor is defined as: The bare rod friction factor is compared to the Cheng and Todreas model [START_REF] Cheng | Hydrodynamic models and correlations for bare and wire-wrapped hexagonal rod bundles-bundle friction factors, sub-channel friction factors and mixing parameters[END_REF] and the Ma et al model [START_REF] Ma | Friction and local pressure loss characteristics of a 5 × 5 rod bundle with spacer grids[END_REF] from the literature. There is a good agreement with the models for the highest Reynolds numbers, but there is a difficulty to perform low Reynolds number measurements due to the small values of pressure drops encountered of around a few Pascal. The mixing grid pressure drops do not have absolute values due to the confidentiality of their geometry.

𝑓 = ∆𝑃 1 2 𝜌𝑣 2 𝐿 𝐷 ℎ (1)

IV. CONCLUSIONS

This extended abstract presented the preliminary results of the METERO-V experimental facility in terms of pressure drop measurements. The results showed a good agreement with the literature, further work needs to be done to improve the METERO-V model especially for laminar flows. Furthermore, the characterization of the velocity fields inside the rod bundle will be done with PIV for uniform and dissymmetrical velocity inlets.

  Proceedings of ICAPP 2023 23-27 April 2023 -Gyeongju, Korea Paper 2023233

Fig. 3 :

 3 Fig. 3 : Friction factor of the bare rod bundle region (left) and absolute grid pressure drop (right) against the Reynolds number

ACKNOWLEDGMENTS

METERO-V program is achieved in the framework of the NEPTUNE project, financially supported by CEA, EDF, Framatome and IRSN.


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