Les manifestations inflammatoires digestives sont fréquentes au cours des déficits immunitaires (jusqu’à 21 %). Leur physiopathologie est complexe et associe des anomalies immunitaires telles qu’une perte de tolérance, un déficit de sécrétion muqueuse en IgA, une réponse infectieuse altérée à un environnement anormal avec dysbiose, production d’endotoxine pro-inflammatoire, altérations épigénétiques ou épitranscriptomiques. L’ensemble conduirait à un état inflammatoire dérégulé du tractus gastro-intestinal et ainsi, à une entéropathie. Ces atteintes sont hétérogènes et peuvent se manifester non seulement sous la forme de maladies inflammatoires chroniques intestinales (MICI), mais aussi sous la forme d’une colite lymphocytaire, d’une entéropathie auto-immune, éosinophilique, voire, le plus souvent, d’une atteinte non spécifique. Leur présentation clinique, biologique et radiologique est souvent difficile à distinguer des entéropathies inflammatoires des sujets immunocompétents. Au niveau histologique, toutefois, plusieurs spécificités peuvent les différencier comme celle d’un aspect de réaction de greffon contre l’hôte avec présence de corps apoptotiques, ou d’une absence de plasmocytes muqueux. Il n’existe pas de traitement codifié ce qui conduit à proposer les traitements utilisés au cours des MICI des sujets immunocompétents avec cependant un moindre taux de réponse. Ces atteintes inflammatoires digestives sont associées à un surrisque de manifestations auto-immunes (cytopénies auto-immunes notamment). Enfin, elles sont également associées à un surrisque de mortalité liée aux complications de l’entéropathie mais aussi à ses traitements.

Sjögren’s Syndrome (SjS) has historically been associated with classical anti-Ro60/SSA, Ro52/SSA and La/SSB, however they are lacking in one third of the patients, which induces delays in diagnosis, and their disease-contributing role is debated. Here we have applied a SjS-tailored Systems Serology approach to a cohort of 58 SjS and 16 non-SjS sicca syndrome patients, and 40 healthy individuals, involving a multiplex assay measuring antibody isotype, subclass, Fc Receptor and complement engagement to 14 SjS-related autoantigens, an antibody-glycosylation profiling assay and a phagocytosis cell-based assay. Via a machine learning approach, we have identified unique autoantibody signatures, including classical and non-classical autoantigens-related features especially involving autoantigen-specific Fc Receptor binding, with apparent functional consequences. These findings provide interesting insights into the autoantibody responses in SjS, possibly paving the way for improved diagnostics, especially in difficult-to-diagnose patients (e.g., seronegative SjS and non-SjS sicca syndrome patients), and novel therapeutic options targeting autoantibody-specific Fc/Fc Receptor-related effector functions. This study reports that a Systems Serology approach, dedicated to the evaluation multiple Sjögren’s syndrome autoantibodies’ Fab and Fc related features, could possibly improve its diagnosis, and reveal novel pathogenic mechanisms. This study reports that a Systems Serology approach, dedicated to the evaluation multiple Sjögren’s syndrome autoantibodies’ Fab and Fc related features, could possibly improve its diagnosis, and reveal novel pathogenic mechanisms.

Adenosine deaminase 2 deficiency (DADA2) is an inborn error of immunity leading to systemic vasculitis, haematological manifestations, immune deficiency and/or autoimmunity. We report the case of a 26-year-old female with an initial diagnosis of systemic lupus erythematosus (SLE). However, atypical evolution patterns for SLE (hypogammaglobulinaemia, moderate B-cell lymphopenia, disappearance of anti-dsDNA) led to the identification of a homozygous class 5 missense variant of CECR1/ADA2, thus to a final diagnosis of DADA2. Strikingly, the patient was treated with anifrolumab (an anti-interferon alpha receptor 1 antibody) that rapidly induced clinical remission and significant corticosteroid tapering. Consistently, we show a lower type I interferon (IFN-I) score and a persistently low tumour necrosis factor α (TNFα) and IL-6 expression levels in whole blood cells of the patient during anifrolumab compared to anti-TNFα. Altogether, this case (1) illustrates the challenging diagnosis of DADA2 (SLE with hypogammaglobulinaemia) and (2) reinforces DADA2 as a disease at the border with type I interferonopathies. Besides, we report here, to our knowledge, the first description of a successful use of anifrolumab in DADA2, paving the way for further studies to validate this therapeutic approach.

BACKGROUND:Cardiovascular (CV) diseases are the leading cause of mortality in patients with systemic lupus erythematosus (SLE). While traditional risk factors inadequately assess CV risk, SLE-specific determinants remain elusive. We have conducted a study of CV outcomes in a cohort of SLE patients, aiming to facilitate individualized risk assessment. METHODS:The LESLY cohort comprised patients diagnosed with SLE at the University Hospital of Lyon between January 2002 and August 2020. CV events (CVE) were defined as myocardial ischemia or stroke. Complete-case multivariable analyses identified predictors of CV risk, among baseline SLE characteristics and traditional CV factors. The identified predictors were subsequently employed to develop machine learning models estimating CV risk in patients with SLE. The dataset was partitioned into training (80%, n = 699) and validation (20%, n = 175) sets. RESULTS:CVE occurred in 55 LESLY patients (6.3%), including 27 acute coronary syndromes and 25 ischemic strokes, over a mean follow-up of 8.8 ± 5.2 years. Antiphospholipid antibodies (HR = 3.51 [1.91-6.43], p < 0.001) and inaugural skin involvement (HR = 2.69 [1.25-5.77], p = 0.011) were the most potent predictors of CVE occurrence. Finally, an Elastic Net Penalized Cox model accurately predicted individualized CV risks in an internal validation cohort (C-index 0.791 [95% CI: 0.674-0.906]; Brier score 6.4% [95% CI: 3.7-9.8%]). CONCLUSION:This study corroborates the primacy of CVD in SLE, underscoring the predictive roles of inaugural skin involvement and antiphospholipid antibodies. These findings enabled the development of an exploratory risk stratification model that may inform clinical decision-making for cardiovascular risk management in SLE, pending external validation.

INTRODUCTION:Rituximab is used for treating autoimmune cytopenia and associated diseases including autoimmune haemolytic anaemia; immune thrombopenia, systemic lupus erythematosus and antiphospholipid syndrome. However, rituximab may induce acquired immune deficiency in some patients, particularly hypogammaglobulinemia (HG), whose risk factors remain poorly defined. PATIENTS AND METHODS:We conducted a retrospective multicentre study including patients with autoimmune cytopenia and related diseases who received at least one rituximab infusion to validate serum protein electrophoresis (SE) as a screening tool for HG and to assess its incidence, risk factors, and clinical outcomes. Univariate and multivariate Cox analysis were performed to characterize predictor of HG. RESULTS:Among 47 patients (391.89 person-years follow-up), Gammaglobulin evaluation on SE strongly correlated with IgG (ρ = 0.97, P=2.2×10-16). HG, defined as gammaglobulin levels <7g/L on SE after rituximab exposure, occurred in 14.9% of patients and was associated with a higher cumulative number of rituximab injections (median 11 vs. 1.5; P=0.033). All immunoglobulin isotypes declined after treatment, and severe infections were more frequent in HG patients. Although cumulative rituximab dose and corticosteroid exposure were associated with HG in univariate analysis, these findings were not confirmed in multivariate models. CONCLUSION:SE appears to be a reliable screening tool for HG, but larger studies are needed to clarify risk factors.

Inflammatory enteropathies are frequent in primary immune deficiencies (PID) (up to 21%). Their pathophysiology is complex and combines immune abnormalities (loss of tolerance, deficit in mucosal IgA secretion and altered infectious response) with an abnormal environment (dysbiosis, production of pro-inflammatory endotoxins, epigenetic and epitranscriptomic alterations). This leads to a deregulated inflammatory state of the gastrointestinal tract and thus to enteropathy. These conditions are heterogeneous and manifest not only as an inflammatory bowel disease but also as in lymphocytic, autoimmune, or eosinophilic colitis. Most of the time PID associated enteropathies remain unspecified. Their clinical, biological, and scannographic features are difficult to distinguish from enteropathies in immunocompetent patients. However, some histological specificities are described including graft-versus-host disease phenotype, with apoptotic bodies, and absence of mucosal plasma cells. There is no standardized treatment for this specific condition. Treatments of inflammatory bowel disease in immunocompetent patients are usually used, although refractory cases are more frequent. This entity is associated with an increased risk of autoimmune manifestations notably including autoimmune cytopenia. Finally, IBD in PID are associated with an increased risk of death related to the enteropathy and its treatments.

BACKGROUND:Cystic fibrosis transmembrane conductance regulator (CFTR) modulators, ivacaftor and lumacaftor/ivacaftor, were introduced in France in 2012 and 2015, respectively, and transformed treatment landscape. Real-world data on medication adherence to these treatments remains limited, although crucial for effectiveness. We evaluated 1-year and 2-year medication adherence (persistence and implementation) using linked data from the French Cystic Fibrosis Registry and the French National Health Data System (SNDS), and examined determinants. METHODS:We conducted a retrospective cohort study including all French cystic fibrosis patients aged 6 years and more, initiating ivacaftor or lumacaftor/ivacaftor between 2012 and 2020, and treated for at least 6 months. Medication adherence was measured as persistence (time to discontinuation fixed to 84-day gap) and implementation (continuous multiple-interval measure of medication availability version 7; CMA-7). It was calculated over 1-year and 2-year following treatment initiation. Determinants of non-persistence (treatment discontinuation) were identified using a Cox proportional hazards model. Determinants of optimal implementation (CMA7≥0.8) were assessed with multivariate logistic regressions. RESULTS:Among 1362 patients, 95 initiated ivacaftor and 1267 initiated lumacaftor/ivacaftor, with a mean age of 19 years and 53% male. Mean time to discontinuation was 653 ± 141 days. Proportion of patients with optimal implementation at 1 year and 2 years were 79% and 75%, respectively. Age <18 years, higher socio-economic level, higher number of cotherapies, and lower percent predicted forced expiratory volume in 1 s (ppFEV1%) were associated with better treatment implementation at both 1-year and 2-years. CONCLUSIONS:Most patients on CFTR modulators showed optimal implementation with persistence declining over time, potentially affecting long-term outcomes.

Objective To compare patients with SLE associated with either Evans syndrome (ES) or an isolated autoimmune cytopenia (immune thrombocytopenia (ITP) or autoimmune haemolytic anaemia (AIHA)).Methods Multicentre retrospective study including patients with SLE presenting with ITP, AIHA or ES of clinical significance (ie, requiring therapeutic intervention according to European Alliance of Associations for Rheumatology guidelines or clinician discretion). Clinical, laboratory and outcome data were compared between patients with ES and those with ITP or AIHA. Severe SLE flares were defined as flares with SLE Disease Activity Index ≥10.Results Among 95 patients with SLE included, 30 had ES, 43 ITP and 22 AIHA. The number of severe SLE flares per patient was higher in ES than in ITP (1.3 vs 0.4, p=0.0004) and patients with AIHA (0.4, p=0.006). Patients with ES had a higher incidence rate ratio (IRR) of severe SLE flares (IRR =3.03; 95% CI 1.50 to 6.41), which remained significant in inverse probability of treatment weighting analyses. At last follow-up, patients with ES presented higher rates of renal (36.7% vs 9.3%, p=0.007) and neurological (36.7% vs 11.6%, p=0.019) involvement than patients with ITP. Severe infections were more frequent in patients with ES than ITP (47% vs 23%, p=0.045), with a higher mean number of severe infections per patient (1.2 vs 0.5, p=0.04).Conclusion In patients with SLE, ES is associated with an increased risk of severe flares than isolated autoimmune cytopenia. These findings were consistent after adjustment for baseline imbalances, supporting ES as a high-risk SLE phenotype.

Background The 2020 pandemic highlighted that teleconsultation, thanks to the contribution of connected spirometry, could be a relevant tool for monitoring people with CF (pwCF). Currently, the clinical improvement and stability of pwCF treated with ETI make this monitoring method even more attractive. We evaluate the feasibility and changes in patient satisfaction and clinical status with a follow-up format alternating face-to-face consultations and teleconsultations for clinically stable adult pwCF treated with ETI for more than one year. Methods This was a prospective before-and-after study, the included patients were monitored every 3 months during the year of follow-up, alternating between face-to-face consultations and teleconsultations. Changes in patient satisfaction, clinical status, quality of life and number of requests to the CF center were evaluated. Results Forty-seven patients completed the follow-up period (out of the 50 included patients). The demographics of the cohort were as follows: male‒female ratio of 2:1, mean age at inclusion was 32 (8.7) years, mean FEV1% of 79% (18.5), mean BMI of 22.4Kg/m2 (2.6) and 80% presenting with chronic Pseudomonas bronchial colonization. 78% of teleconsultations were carried out without problems and only 4% had to be postponed due to technical problems. We reported no statistically significant differences in patient satisfaction, respiratory and nutritional status, or quality of life before and after this new strategy of follow-up. Conclusion Alternating follow-up was feasible and satisfactory for adult pwCF treated with ETI. If, larger studies are necessary, hybrid monitoring may play a key role in the management of cystic fibrosis in the years to come.

PROGNOSTIC IMPACT OF NEW TREATMENTS FOR CYSTIC FIBROSIS. The prognosis of cystic fibrosis has improved over the past 25 years, due to the introduction of widespread neonatal screening, a structured organization of care and advances in symptomatic treatments. The large use of CFTR protein modulators represents a new stage in the improvement of prognosis and median survival estimates. This is reflected in a steady increase in the adult patient population, an ageing population associated with the onset of metabolic and cardiovascular complications, and more frequent cancers, particularly gastrointestinal. As a result, current symptomatic treatments are being reduced and follow-up recommendations adapted to these new challenges. However, the treatment effect is merely suspensive, and its long-term efficacy and safety have yet to be assessed.

INTRODUCTION:The role of internal medicine departments in the management of chronic diseases in older patients with more comorbidities is a topical issue. METHODS:For each internal medicine department of the Lyon University Hospital (North, Centre and South Hospices Civils de Lyon Hospital Group), Programme de médicalisation des systèmes d'information (PMSI) activity report data were used, with the number of medical unit summary (RUM) and standardised discharge summary (RSS) stays for 4 consecutive years from 2018 to 2022. RESULTS:Activity increased in the three internal medicine departments in outpatient day hospital activity, the rest of the activity remained stable. The rate of admissions via emergency units was multiplied by 3, with an increase in discharges to rehabilitation services. The death rate doubled. The average age increased to 68, with an increase in the Charlson score comorbidity index to 2, independently of age, and in the percentage of stays with severity 3 and 4. CONCLUSION:Analysis of data on conventional inpatient care in internal medicine at Lyon University Hospital shows a major qualitative change, with older patients with more comorbidities and higher severity stay profiles, leading to an increase in the number of inpatient deaths, and greater use of rehabilitation units.

BACKGROUND:Systematic screening for cystic fibrosis related diabetes (CFRD) is recommended for all people living with cystic fibrosis (pwCF) from the age of 10. However, adhering to these guidelines is challenging given the cumbersome nature and potential side effects of the current test of reference, the Oral Glucose Tolerance Test (OGTT). Continuous glucose monitoring (CGM) could become an alternative to OGTT, thanks to its ease of use and to the extensive information it provides. METHODS:We present the baseline data from a prospective observational multicentric French and Canadian cohort. Concomitant OGTT, CGM and collection of clinical data were performed in adult pwCF. RESULTS:Complete data were available in 107 participants (73 with normal glucose tolerance, 24 with impaired glucose tolerance and 10 with cystic fibrosis related diabetes), of whom 63 % were treated with Elexacaftor/Tezacaftor/Ivacaftor. Glycated hemoglobin (HbA1c), time above 7.8mmol/L and time above 10mmol/L were lower in participants with normal glucose tolerance than in those with CFRD. Several CGM parameters associated more strongly with diagnosis of CFRD at OGTT than HbA1c (Area under the ROC curves: 0.88 for time above 10mmol/L and 0.87 for time above 7.8mmol/L, vs 0.61 for HbA1c). Spending more than 10 % of the time above 7.8mmol/L detected CFRD with 100 % sensitivity and 46% specificity. CONCLUSIONS:Certain CGM parameters correlated more closely with diagnosis of CFRD at OGTT than HbA1c in adult pwCF, with or without treatment by Elexacaftor/Tezacaftor/Ivacaftor. If future studies confirm these results prospectively, CGM could be used as a first step to screen for CFRD.

Haploinsufficiency of cytotoxic T-lymphocyte associated protein 4 (CTLA4), a known cause of inborn errors of immunity, can lead to autoimmunity, inflammation, neoplasia and infections. A previously undescribed CTLA4 variant was identified in a patient who presented with life-threatening cutaneous infection caused by Pseudomonas aeruginosa, severe VZV infection, and Evans syndrome. Our aim was to assess the pathogenicity of the previously undescribed c.379T > G variant in the CTLA4 gene and explore its phenotypic presentation in relatives. We employed genetic and protein-based in silico analyses to evaluate the potential role of the c.379T > G variant in the CTLA4 gene. We subsequently studied CTLA4 expression ex vivo, analyzed the clinical presentation of affected carriers and compared the biological status across affected individuals, healthy carriers and noncarriers. In silico analyses revealed that the c.379T > G mutation, which is located within the ligand binding area of CTLA4, is highly pathogenic. Its clinical manifestations, which are sometimes fatal, include multiple infections, autoimmunity, inflammation of the central nervous system, lymphoproliferation and thymoma with Good’s syndrome. Compared with its expression in healthy donors, the expression of CTLA4 following stimulation in memory regulatory T cells was decreased in affected individuals. Immunophenotyping revealed an increased proportion of immature and double-negative B cells in affected patients compared with their nonmutated relatives. Additionally, a reduction in naive T cells and an increase in CD4 + CD25-Foxp3 + cells were observed in carriers compared with controls. The c.379T > G variant of CTLA4, resulting in a p.Tyr127Asp substitution, is pathogenic and contributes to the development of a CTLA4 haploinsufficiency phenotype. This finding highlights the heterogeneous presentations of the disease, including oncological and neurological manifestations.

Introduction Le rôle des services de médecine interne dans la prise en charge des maladies chroniques chez des patients plus âgés avec plus de comorbidités est d’actualité. Méthodes Pour chaque service de médecine interne du CHU de Lyon (groupement hospitalier Nord, centre et Sud hospices civils de Lyon), les données de rapport d’activité Programme de médicalisation des systèmes d’information (PMSI) ont été utilisées, avec le nombre de séjours résumé d’unité médicale (RUM) et résumé de sortie standardisée (RSS) pendant 4 années consécutives de 2018 à 2022. Résultats L’activité globale augmentait dans les trois services de médecine interne sur l’activité ambulatoire d’hôpital de jour, alors qu’elle restait stable sur l’hospitalisation conventionnelle et diminuait en consultation. Le taux d’admission via les unités d’urgence était multiplié par 3 avec une augmentation des sorties vers les services de soins médicaux et réadaptation. Le taux de décès était multiplié par deux. L’âge moyen augmentait à 68 ans avec une augmentation de l’index de comorbidités du score de Charlson à 2 indépendamment de l’âge et du pourcentage de séjours de sévérité 3 et 4. Conclusion L’analyse des données de l’hospitalisation conventionnelle en médecine interne au CHU de Lyon montre un changement qualitatif important avec l’accueil de patients plus âgés, avec plus de comorbidités et avec des profils de séjour de sévérité plus élevés se traduisant par une augmentation du nombre de décès en hospitalisation, et un plus fort recours aux unités d’aval de SMR.

Highly effective modulator therapy (HEMT) is available to a broader range of people with cystic fibrosis (pwCF). It has significantly improved short-term clinical outcomes and has the potential to alter the natural history of this fatal genetic disease. If long-term follow-up observational data is required to ensure clinical benefits, it is obvious that it will also change the needs of pwCF and the roles and missions of healthcare professionals (HCPs) in CF centers and beyond. We will conduct a nationwide research program called 'HORIZON' to support the changes in the organization of CF care in the coming years. It has received the financial support of the French Ministry of Health in 2022. Our primary objective is to design a new model of care that respond to the new needs and missions of pwCF and HCPs in this era of rapid and profound changes due to HEMT. This research program is based on the intervention mapping method, in which we will conduct the first four steps to design and plan the implementation of a new model of care. The program will involve all stakeholders of the CF care network, including HCPs from CF care centers and outside, pwCF, their families, patient organizations, and experts in CF. It will combine quantitative and qualitative research approaches and rely on an 'action research' method. Anticipating and supporting the reorganization of CF care in France requires a robust research program to find the best model that meets the expectations of all key stakeholders.

Introduction The effects of cystic fibrosis (CF) on females’ sexuality have not been described. The aims of the present study were to describe and characterize sexual issues in females with CF. Methods We included adult (≥18 years) females with CF currently or previously in a sexual relationship from 11 adult CF centres in France. We collected quantitative data using a modified version of the self-administered Pelvic Incontinence Sexual Questionnaire IUGA-Revised (PISQ-IR). We performed one-to-one interviews using a semi-directive framework in volunteer females to further characterize the effects of CF on sexual life. We summarized answers to questionnaire as percentages and analysed interviews by theme according to discourse analysis method. Results Between November 2019 and July 2021, 212 females completed the PISQR-IR, of whom 15 were interviewed. Of the females who completed the questionnaire, 93.4% were concerned about the discomfort, pain, or unpleasantness they experienced during sexual intercourse. The most frequent cause of sexual difficulties was a lack of vaginal lubrication (78.8%), followed by pain (74.1%) and discomfort. Interviews revealed sexual lives that were uncomfortable or painful, unsatisfying or avoided for most females, with a strong impression of being sexually different, incompetent, and betrayed by their bodies in terms of sexual desire. Conclusion Sexual difficulties faced by females with CF are highly prevalent. Increasing awareness regarding sex life issues in females with CF appears necessary to improve their management by CF multidisciplinary teams.