A large deletion in a non-coding regulatory region leads to NFKB1 haploinsufficiency in two adult siblings.

Mutations in NFkB pathway genes can cause inborn errors of immunity (IEI), with NFKB1 haploinsufficiency being a significant etiology for common variable immunodeficiency (CVID). Indeed, mutations in NFKB1 are found in 4 to 5% of in European and United States CVID cohorts, respectively; CVID representing almost » of IEI patients in European countries registries. This case study presents a 49-year-old patient with respiratory infections, chronic diarrhea, immune thrombocytopenia, hypogammaglobulinemia, and secondary lymphoma. Comprehensive genetic analysis, including high-throughput sequencing of 300 IEI-related genes and copy number variation analysis, identified a critical 2.6-kb deletion spanning the first untranslated exon and its upstream region. The region's importance was confirmed through genetic markers indicative of enhancers and promoters. The deletion was also found in the patient's brother, who displayed similar but milder symptoms. Functional analysis supported haploinsufficiency with reduced mRNA and protein expression in both patients. This case underscores the significance of copy number variation (CNV) analysis and targeting noncoding exons within custom gene panels, emphasizing the broader genomic approaches needed in medical genetics.

Chronological interplay, clinical features, and treatments among patients with cancer and primary Sjögren's syndrome.

OBJECTIVE: While the incidence and type of blood malignancies are well documented amid primary Sjögren's syndrome patients (pSS), data focusing on solid neoplasms are more conflicting. We aimed to describe clinical, pathological, and immunological characteristics of pSS patients with cancers, along with the chronological interplay between the two conditions. METHODS: Outcomes concerning both pSS and cancer were retrospectively collected from Montpellier University Hospital (tertiary center) between 2019 and 2020. pSS characteristics were compared to a control group of pSS patients without cancer. RESULTS: A total of 165 patients with pSS were included: 55 patients with cancer (52 female, mean age 58.4 ± 10.4 years at pSS diagnosis; mean follow-up 10.5 ± 10.1 years, 12 patients had multiple cancers) and 110 controls without cancer. Characteristics of pSS patients with cancers were different from controls mostly for lymphoma prognosis factors. Among the 70 cancers, we recorded 55 solid neoplasms (whom 27 breast cancers and 8 lung cancers, and 82% of adenocarcinomas), with no evidence of disease at the end of follow-up in 85% of them. Among the 15 recorded blood malignancies, ten were lymphomas with an excellent prognosis. Regarding chronological interplay between cancer and pSS, most cancers (43%) were diagnosed close (± 5 years) to pSS diagnosis. Breast cancers were diagnosed before or close to pSS diagnosis (mean delay - 1.8 ± 13.0 years), at an early stage, with only two relapses (no cancer-related death), while lung cancers were diagnosed late after. CONCLUSIONS: The tight chronological interplay between breast cancer and pSS and the intriguing pathological and immunological pattern of pSS in these patients suggest a hypothesis of immune control of cancer.

Comprehensive description of adult-onset Still's disease after COVID-19 vaccination.

Cases of adult-onset Still's disease (AOSD) have been reported after COVID-19 vaccination. Here we provide a comprehensive description and analysis of all cases of AOSD reported in the literature and in pharmacovigilance databases through April 2022. Disproportionality analyses of pharmacovigilance data were performed in order to further explore the association between vaccination and AOSD. We included 159 patients, 144 from the World Health Organization pharmacovigilance database and 15 from the literature. Detailed clinical characteristics were described for the cases from the literature and from the French pharmacovigilance database (n = 9). The cases of AOSD after COVID-19 vaccination concerned women in 52.2% of cases. The median age was 43.4 years. More than 80% of AOSD reports occurred during the first three weeks and concerned mostly the BNT162b2 mRNA vaccine. We identified 14.5% of disease flare with a median time-to-onset of AOSD flare-up significantly shorter than for the new onset form. More than 90% patients received steroids. Although all cases were considered serious and required hospitalization, most cases presented a favorable outcome (67.1%) with a good response to corticosteroid therapy with a mean time to recovery of 7.2 days. Disproportionality analyses suggested that AOSD was associated with COVID-19 vaccines as well as other vaccines. AOSD was nearly five times more frequently reported with COVID-19 vaccines than with all other drugs. Clinicians should be informed about the potential risk of AOSD onset or flare following COVID vaccines and the importance of its early detection to optimize its management.

Use of biologics to treat relapsing and/or refractory polyarteritis nodosa: data from a European collaborative study.

OBJECTIVES: To describe the effectiveness and safety of biologics for the treatment of relapsing and/or refractory polyarteritis nodosa (PAN). METHODS: A retrospective European collaborative study was conducted in patients with PAN who received biologics for relapsing and/or refractory disease. RESULTS: Forty-two patients with PAN received a total of 53 biologic courses, including TNF-α blockers in 15 cases, rituximab (RTX) in 18 cases, tocilizumab (TCZ) in 10 cases and other biologics in 10 cases. TNF-α blockers and TCZ were mainly used for refractory diseases whereas RTX was mainly initiated for relapsing disease. After a median follow-up of 29 (8-50) months, remission, partial response, treatment failure and treatment discontinuation due to severe adverse events occurred in, respectively, 40%, 13%, 40% and 7% of patients receiving TNF-α blockers, 50%, none, 30% and 20% of TCZ recipients, and 33%, 11%, 56% and none of the RTX recipients. No remission was noted in patients treated with other biologics. Severe adverse events were observed in 14 (28%) patients without significant differences between the three biologics, leading to early biologics discontinuation in only three cases. CONCLUSION: These results suggest that TCZ may be effective in relapsing and/or refractory PAN. Our data warrant further study to confirm these findings.

Mesenchymal stromal cells-derived extracellular vesicles alleviate systemic sclerosis via miR-29a-3p.

Systemic sclerosis (SSc) is a potentially lethal disease with no curative treatment. Mesenchymal stromal cells (MSCs) have proved efficacy in SSc but no data is available on MSC-derived extracellular vesicles (EVs) in this multi-organ fibrosis disease. Small size (ssEVs) and large size EVs (lsEVs) were isolated from murine MSCs or human adipose tissue-derived MSCs (ASCs). Control antagomiR (Ct) or antagomiR-29a-3p (A29a) were transfected in MSCs and ASCs before EV production. EVs were injected in the HOCl-induced SSc model at day 21 and euthanasized at day 42. We found that both ssEVs and lsEVs were effective to slow-down the course of the disease. All disease parameters improved in skin and lungs. Interestingly, down-regulating miR-29a-3p in MSCs totally abolished therapeutic efficacy. Besides, we demonstrated a similar efficacy of human ASC-EVs and importantly, EVs from A29a-transfected ASCs failed to improve skin fibrosis. We identified Dnmt3a, Pdgfrbb, Bcl2, Bcl-xl as target genes of miR-29a-3p whose regulation was associated with skin fibrosis improvement. Our study highlights the therapeutic role of miR-29a-3p in SSc and the importance of regulating methylation and apoptosis.

Extracellular Vesicles Are More Potent Than Adipose Mesenchymal Stromal Cells to Exert an Anti-Fibrotic Effect in an In Vitro Model of Systemic Sclerosis.

Systemic sclerosis (SSc) is a complex disorder resulting from dysregulated interactions between the three main pathophysiological axes: fibrosis, immune dysfunction, and vasculopathy, with no specific treatment available to date. Adipose tissue-derived mesenchymal stromal cells (ASCs) and their extracellular vesicles (EVs) have proved efficacy in pre-clinical murine models of SSc. However, their precise action mechanism is still not fully understood. Because of the lack of availability of fibroblasts isolated from SSc patients (SSc-Fb), our aim was to determine whether a TGFß1-induced model of human myofibroblasts (Tß-Fb) could reproduce the characteristics of SSc-Fb and be used to evaluate the anti-fibrotic function of ASCs and their EVs. We found out that Tß-Fb displayed the main morphological and molecular features of SSc-Fb, including the enlarged hypertrophic morphology and expression of several markers associated with the myofibroblastic phenotype. Using this model, we showed that ASCs were able to regulate the expression of most myofibroblastic markers on Tß-Fb and SSc-Fb, but only when pre-stimulated with TGFß1. Of interest, ASC-derived EVs were more effective than parental cells for improving the myofibroblastic phenotype. In conclusion, we provided evidence that Tß-Fb are a relevant model to mimic the main characteristics of SSc fibroblasts and investigate the mechanism of action of ASCs. We further reported that ASC-EVs are more effective than parental cells suggesting that the TGFß1-induced pro-fibrotic environment may alter the function of ASCs.

Zika virus infections in three travellers returning from South America and the Caribbean respectively, to Montpellier, France, December 2015 to January 2016.

We report three unrelated cases of Zika virus infection in patients returning from Martinique, Brazil and Colombia respectively, to Montpellier, France. They developed symptoms compatible with a mosquito-borne disease, and serological and molecular investigations indicated a recent Zika virus infection. Considering the recent warning for the likely teratogenicity of Zika virus and the presence of competent mosquito vectors in southern France, these cases highlight the need for awareness of physicians and laboratories in Europe.

Time to use the right classification to predict the severity of checkpoint inhibitor-induced liver injury, as assessed for causality using the updated RUCAM.

BACKGROUND AND AIMS: While immune checkpoint inhibitors (ICIs) are revolutionising cancer therapy, checkpoint inhibitor-induced liver injury is a significant immune-related side effect of this immunotherapy. This study focuses on the severity classifications and characteristics of patients with checkpoint inhibitor-induced hepatitis. METHODS: A retrospective analysis of patients with severe Checkpoint Inhibitor-induced hepatitis grade 3 and 4 according to the recommended Common Terminology Criteria for Adverse Events (CTCAE) classification was conducted. Data on clinicobiological characteristics, treatment and outcomes were collected from 3 university hospitals, and causality was assessed by using the updated Roussel Uclaf Causality Assessment Method. The severity of hepatitis was assessed using the Model for End-stage Liver Disease score, the Drug-Induced Liver Injury Network, and the Drug-Induced Liver Injury International Expert Working Group classifications. RESULTS: We retrospectively included 100 patients presenting various hepatitis patterns with a median time to onset of 20 days after checkpoint inhibitors. Severity grading varied significantly among the classifications used. A lower incidence of severe cases was observed when using the Drug-Induced Liver Injury classifications instead of the recommended CCTCAE classification, and this was correlated with outcomes. CONCLUSIONS: This retrospective study challenges the efficacy of the CTCAE classification in defining the severity of Checkpoint Inhibitor-induced hepatitis and suggests that the traditional hepatology-focused scores may be more relevant. The CTCAE classification is inconsistent and gives equal weight to jaundice and elevated transaminases, which leads to steroid overtreatment and limits the rechallenge of ICIs.

[Prerequisite and organisation of health-care pathways for Cell and Gene therapies, using Mesenchymal Stromal Cells (MSC) or Chimeric Antigen Receptor (CAR) T cells, in patients with autoimmune systemic diseases]. / Prérequis et organisation du parcours de soins en vue de l'utilisation d'une thérapie cellulaire ou génique par cellules stromales mésenchymateuses (CSM) ou par cellules T porteuses d'un récepteur antigénique chimérique (CAR-T cells) chez les patients avec maladies auto-immunes systémiques.

First-line treatments of autoimmune systemic diseases (ARD) are based on the use of various types of immunosuppressive or immunomodulatory drugs, either alone or in association, according to standardized reference protocols. Prolonged use of these drugs in severe or refractory ARD is associated with high morbidity and increased mortality. Innovative cell therapies represent a new promising approach for patients with ARDs, with the recent clinical use of: a) mesenchymal stromal cells (MSCs), based on their immunomodulatory, antifibrotic and pro-angiogenic properties and b) Chimeric Antigen Receptors (CAR) T cell therapies T lymphocytes, where genetically modified expression of a chimeric antigen receptor (CAR-T cells). Therapeutic use of MSC or CAR-T cells, remains indications of exception in patients with severe ARDs resistant to prior standard therapies with new prerequisite and organisation of health-care pathways as compared to traditional drugs, not only for the Cell and Gene Therapy (CGT) product definition and delivery process, but also for the patient clinical management before and after administration of the CGT product. The aim of this workshop under the auspices of the French Speaking Society of Bone Marrow and Cell transplantation (SFGM-TC) working group on autoimmune diseases (MATHEC) is to describe: a) the prerequisite for French hospitals to set-up the specific health-care pathways for MSC or CART therapy in ARDs patients, in accordance with regulatory and safety needs to perform academic or industry sponsored clinical trials, and b) the care-pathway for ARD patients treated with CGT, highlighting the importance of working in tandem between the ARD and the CAR-T cell specialist all along the indication, procedures and follow-up of ARDs. Patient safety considerations are central to guidance on patient selection to be validated collectively at the multidisciplinary team meeting (MDTM) based on recent (less than 3 months) thorough patient evaluation. MSC and CAR-T procedural aspects and follow-up are then carried out within appropriately experienced and SFGM-TC accredited centres in close collaboration with the ADs specialist.

Functional diversity of NLRP3 gain-of-function mutants associated with CAPS autoinflammation.

NLRP3-associated autoinflammatory disease is a heterogenous group of monogenic conditions caused by NLRP3 gain-of-function mutations. The poor functional characterization of most NLRP3 variants hinders diagnosis despite efficient anti-IL-1 treatments. Additionally, while NLRP3 is controlled by priming and activation signals, gain-of-functions have only been investigated in response to priming. Here, we characterize 34 NLRP3 variants in vitro, evaluating their activity upon induction, priming, and/or activation signals, and their sensitivity to four inhibitors. We highlight the functional diversity of the gain-of-function mutants and describe four groups based on the signals governing their activation, correlating partly with the symptom severity. We identify a new group of NLRP3 mutants responding to the activation signal without priming, associated with frequent misdiagnoses. Our results identify key NLRP3 residues controlling inflammasome activity and sensitivity to inhibitors, and antagonistic mechanisms with broader efficacy for therapeutic strategies. They provide new insights into NLRP3 activation, an explanatory mechanism for NLRP3-AID heterogeneity, and original tools for NLRP3-AID diagnosis and drug development.

Long-term home parenteral nutrition in systemic sclerosis-related intestinal failure is feasible but unveils occult cardiac disease.

OBJECTIVE: The aim of this study was to compare safety and efficacy of long-term home parenteral nutrition between patients with systemic sclerosis and intestinal failure (IF) and controls with IF from another etiology. METHODS: A retrospective study was conducted in a referral center for systemic sclerosis (SSc) in Montpellier, France. Patients followed between 1985 and 2020 with SSc-related IF were included and compared with control patients with IF from another etiology. The patients included had to be treated for ≥4 wk by home parenteral nutrition (HPN). Primary outcome was occurrence of HPN-related complications. Secondary outcomes included duration of parenteral nutrition, body mass index at 12 mo, and survival. RESULTS: Cumulative duration of HPN was 23 397 catheter days. HPN resulted in body mass index increase in both groups. There was no statistical difference regarding catheter-related bloodstream infections and thrombosis between the groups, despite use of immunosuppressive drugs and autologous hematopoietic stem cell transplantation in patients with SSc. However, the patients with SSc had significantly more HPN-related cardiac overload than the controls (P < 0.0001). Overloads occurred in SSc patients with and without cardiac disease, arguing for comprehensive hemodynamic screening in this condition. CONCLUSION: Long-term HPN in SSc-related IF is feasible but unveils occult cardiac disease.

Hemophagocytic Lymphohistiocytosis Associated with Immunological Checkpoint Inhibitors: A Pharmacovigilance Study.

BACKGROUND: Acquired hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially fatal condition characterized by hyperactivation of macrophages and cytotoxic lymphocytes, combining a series of non-specific clinical symptoms and laboratory disorders. Etiologies are multiple: infectious (mainly viral) but also oncologic, autoimmune or drug-induced. Immune checkpoint inhibitors (ICI) are recent anti-tumor agents associated with a novel profile of adverse events triggered by immune system over-activation. Here, we sought to provide a comprehensive description and analysis of HLH cases reported with ICI since 2014. METHODS: Disproportionality analyses were performed in order to further explore the association between ICI therapy and HLH. We selected 190 cases, 177 from the World Health Organization pharmacovigilance database and 13 from the literature. Detailed clinical characteristics were retrieved from the literature and from the French pharmacovigilance database. RESULTS: The cases of HLH reported with ICI concerned men in 65% of cases with a median age of 64 years. HLH occurred in an average of 102 days after the initiation of ICI treatment and mostly concerned nivolumab, pembrolizumab and nivolumab/ipilimumab combination. All cases were considered serious. Most cases presented a favorable outcome (58.4%); however, death was reported for 15.3% of patients. Disproportionality analyses showed that HLH was seven times more frequently reported with ICI therapy than with other drugs and three times more than with other antineoplastic agents. CONCLUSIONS: Clinicians should be aware of the potential risk of ICI-related HLH to improve the early diagnosis of this rare immune-related adverse event.

[Vaccination before and after autologous hematopoietic cell transplantation for autoimmune diseases: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (MATHEC-SFGM-TC)]. / Vaccinations avant et après greffe de cellules hématopoïétiques autologues chez les patients atteints de maladies auto-immunes : propositions du groupe Maladies Auto-immunes et Thérapie Cellulaire de la SFGM-TC.

The Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) organized the 12th workshop on hematopoietic stem cell transplantation clinical practices harmonization procedures on September 2021 in Lille, France. In the absence of specific national or international recommendation, the French working group for autologous stem Cell transplantation in Auto-immune Diseases (MATHEC) proposed guidances for vaccinations of patients undergoing autologous hematopoietic stem cell transplantation for autoimmune disease, including in the context of SARS-Cov-2 pandemic.

Clinical pattern of checkpoint inhibitor-induced liver injury in a multicentre cohort.

Background & Aims: Immune checkpoint inhibitors (ICIs) have changed the landscape of cancer therapy. Liver toxicity occurs in up to 25% of patients treated with ICIs. The aim of our study was to describe the different clinical patterns of ICI-induced hepatitis and to assess their outcome. Methods: We conducted a retrospective observational study of patients with checkpoint inhibitor-induced liver injury (CHILI) discussed in multidisciplinary meetings between December 2018 and March 2022 in three French centres specialised in ICI toxicity management (Montpellier, Toulouse, Lyon). The hepatitis clinical pattern was analysed by the ratio of serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) (R value = (ALT/ULN)/(ALP/ULN)) for characterisation as cholestatic (R ≤2), hepatocellular (R ≥5), or mixed (2