Inès Elhani

Background: A20 haploinsufficiency (HA20) is an autoinflammatory disease driven by pathogenic variants in TNFAIP3 , which plays a crucial role in regulating immune responses. The clinical manifestations of HA20 resemble those of inflammatory bowel disease (IBD), with prominent gastrointestinal (GI) involvement. Given the well‐established association between gut microbiota alterations and IBD, this study aimed to describe the GI involvement of HA20 patients and to investigate their fecal microbiota using shotgun sequencing and metabolomics. Methods: This study included 16 HA20 patients and 22 healthy age and sex‐matched controls. GI clinical phenotype, liver imaging, and liver and GI tissue histology were assessed. Shotgun metagenomic sequencing was performed on fecal DNA. Fecal metabolomic profiling of bile acids, short‐chain fatty acids (SCFAs), and tryptophan metabolites was performed. Results: Liver imaging revealed chronic liver disease in 3/5 patients, showing as liver dysmorphia and portal hypertension. Histological analysis showed lymphoplasmocytic infiltrate of the GI tract and the liver. The fecal microbiota of HA20 patients was characterized by marked alterations, including a reduction in microbial diversity and an increase in the pro‐inflammatory bacterium Ruminococcus gnavus . Microbial bile acid deconjugation and desulfation were impaired. Additionally, tryptophan metabolism was altered, with a shift towards the kynurenine pathway. Conclusion: Our results show that HA20 is associated with gut microbiota alterations and significant disruptions in metabolic pathways, particularly involving bile acids. These alterations could contribute to the chronic inflammation observed in HA20. These findings highlight the role of the gut‐liver axis and of mucosal barrier dysfunction in HA20.

Les maladies auto-inflammatoires monogéniques sont des maladies génétiques causant une activation excessive de l'immunité innée. Elles se traduisent par des symptômes inflammatoires systémiques chroniques et/ou récurrents. Plusieurs de ces maladies sont caractérisées par une forte prévalence d'atteintes digestives et une association avec des maladies inflammatoires chroniques du tube digestif. C'est le cas de l'haploinsuffisance de A20 (HA20) dont les patients souffrent de douleurs abdominales et d'ulcérations digestives, de la fièvre Méditerranéenne familiale (FMF) qui est associée à des péritonites aseptiques, des cryopyrinopathies (CAPS) et du déficit en mévalonate kinase (MKD), qui sont associés à des douleurs abdominales. Les perturbations du microbiote intestinal, appelées dysbiose, sont associées à la survenue et au développement de maladies inflammatoires de l'intestin mais aussi de maladies systémiques. Les effets pro-inflammatoires peuvent être directs, découler d'une altération de la barrière intestinale, ou de la modulation de métabolites dérivés du microbiote intestinal, particulièrement les acides biliaires, les acides gras à chaines courtes, et les métabolites dérivés du tryptophane. L'objectif de ce travail était de décrire les atteintes digestives clinico-radiologiques et histologiques des patients atteint de HA20, et de décrire la composition du microbiote intestinal des patients atteints de HA20, de FMF, de CAPS et de MKD. Nos observations ont montré que les patients atteints de HA20 présentent une atteinte gastro-intestinale et hépatique inflammatoire aspécifique. Les patients présentaient une dysbiose caractérisée par une surreprésentation de R. gnavus, et une sous-représentation d'espèces bactériennes impliquées dans la production de butyrate et du maintien de la barrière digestive. Ces anomalies étaient associées à une altération du métabolisme des acides biliaires, un déficit d'absorption des acides gras à chaines courtes, et un engagement du tryptophane alimentaire vers la voie neurotoxique de la kynurénine. Chez les patients avec FMF, on observait également une dysbiose caractérisée par une diminution de bactéries anti-inflammatoires, particulièrement Streptococcus salivarius et Streptococcis vestibularis, ainsi qu'une diminution de bactériophages, suggérant un affaiblissement de la barrière intestinale. Contrairement au HA20 et à la FMF, les patients atteints de CAPS et MKD n'ont pas montré de dysbiose similaire. En conclusion, ces résultats soutiennent la participation d'une dysbiose et d'une altération des profils de métabolites dérivés du microbiote intestinal dans le HA20 et dans la FMF

Introduction: Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease. Colchicine is the first-line treatment, yet 5–10% of patients are resistant, increasing the risk of complications like amyloidosis. In 2023, Batu et al proposed the Turkish Paediatric Autoinflammatory Diseases (TURPAID) score to predict colchicine resistance in paediatric FMF at diagnosis. Its utility in broader populations is unknown. We assessed its performance in paediatric and adult FMF patients from the international Juvenile Inflammatory Rheumatism (JIR) cohort. Methods: We retrospectively analysed 236 genetically confirmed FMF patients treated with colchicine for ≥6 months. Patients were classified as colchicine-sensitive (CoS) or colchicine-resistant (CoR) based on the initiation of biologic therapy , which served as an operational definition of resistance, and matched for age and sex. The TURPAID score (range 0–4; resistance threshold ≥2) was retrospectively applied. Receiver operating characteristic (ROC) curves were used to assess predictive value. Results: A TURPAID score ≥2 was observed in 89% of paediatric and 76% of adult CoS patients. Mean scores were significantly higher in paediatric-onset FMF. ROC analysis showed poor discrimination in both paediatric and adult groups (area under the curve=0.6). Clinical features and attack patterns varied by age. The genetic component (1.5 points for MEFV exon 10 mutations) contributed to overclassification, reducing predictive accuracy. Conclusion: The TURPAID score did not effectively predict colchicine resistance in the JIR cohort. Its limited generalisability may stem from age-related differences, recall bias and excessive genetic weighting. Genetic results should be a prerequisite and not a determinant of colchicine resistance prediction scores in FMF.

Background: Although colchicine is the mainstay of familial Mediterranean fever (FMF) treatment, 5–10% of patients are considered to have colchicine resistance (CR). However, there is no globally agreed CR definition or indications for biological disease-modifying anti-rheumatic drugs (bDMARDs). Methods: A survey on ‘Biologics in Monogenic Autoinflammatory Diseases’, part of the ‘Clinical Practice Strategies’ (CLiPS) initiative, was conducted by a JIR cohort-initiated eCOST network among expert participants worldwide. Our primary aim was to provide a flowchart reflecting the different CR definitions and present data regarding bDMARD indications. The secondary aim was to determine how specific biases influence clinical approaches. We analysed the CliPS according to the experience levels of physicians, country-specific FMF prevalence, countries’ gross domestic product, bDMARD availability and reimbursement policies of the countries. Results: A total of 223 responses from 46 countries were included in the study. Almost half of the respondents (73/160, 45.6%) indicated that three to four attacks within the preceding 6 months were necessary for their CR definition. The most frequently used acute-phase reactant was C-reactive protein (157/164, 95.7%). Almost three-fourths of the respondents (74%, n=165) considered that supplementary factors, including complications of FMF, attack severity, elevated activity scores, patient-reported outcome and quality of life scales, influenced their CR definition. Conclusion: We present a novel flowchart describing physicians’ general attitudes and unique findings regarding management strategies for colchicine-resistant FMF and shifting trends influenced by epidemiological and socioeconomic factors.

Introduction Familial Mediterranean fever (FMF) is a genetic disease leading to recurrent episodes of inflammation. Two pathogenic variants are required for classical disease, but the disease can occur in heterozygous patients. Patients are treated continuously with colchicine to prevent amyloid A (AA) amyloidosis, including heterozygous patients who display a moderate form of FMF and rarely develop AA amyloidosis. The need for lifelong colchicine treatment in heterozygous FMF is therefore controversial. We aimed to characterise genotype-specific levels of inflammatory biomarkers, and to focus on heterozygous patients who discontinued colchicine. Methods All patients with FMF from the European databases AIDnet and JIRcohort who received colchicine during follow-up were included. Demographics, C reactive protein (CRP), serum amyloid A (SAA), S100A8/A9 and S100A12 levels, leucocyte and neutrophil counts were extracted. Visits were classified as active, subclinical or inactive according to symptoms, CRP and SAA levels. Results Data from 747 patients were extracted (233 homozygous, 201 compound heterozygous, 224 heterozygous patients, 49 heterozygous with one class III variant and 40 compound heterozygous with two class III variants). During active visits, all biomarker levels were higher compared with inactive visits (pConclusion S100A8/A9 and S100A12 proteins are biomarkers that can be used to assess disease activity. Heterozygous patients have lower levels of inflammatory biomarkers and some of them can sustainably discontinue colchicine treatment.

Background: Transitioning from pediatric to adult care is a critical step for individuals with autoinflammatory diseases, requiring effective programs to ensure continuity of care and disease management. Despite various recommendations, the effectiveness of transition programs, particularly in monogenic autoinflammatory diseases, remains understudied. Methods: A single-center medical records review study was conducted at the French National Reference Center for Adult Autoinflammatory Diseases in Tenon Hospital from 2017 to 2023. All patients who had consulted for the first time between the ages of 15 and 30 years and had received care for an autoinflammatory disease during childhood were included. The patients were classified according to whether they had undergone a transition, defined as either no transition, simple transition (referral letter), or joint transition (pediatrician and adult physician consultation). Results: One hundred eleven patients (median age, 18 years) were included. Patients who consulted without transition started adult follow-up and were followed up less regularly than those who underwent the transition process (p < 0.001 and p = 0.028). In patients with familial Mediterranean fever, the absence of a formal transition was associated with poorer disease control at baseline (p = 0.019). The type of transition did not impact disease control during follow-up. Conclusions: Participation in a transition program is associated with earlier and more regular follow-up in adulthood. Although transition type did not significantly impact disease control during follow-up in familial Mediterranean fever, the potential benefit of joint consultation extends beyond consultation frequency and disease outcomes, encompassing patient perspectives and self-management abilities. This study highlights the significance of collaborative transition programs in AIDs.