Autoinflammatory Research Articles

TNF inhibitors target a mevalonate metabolite/TRPM2/calcium signaling axis in neutrophils to dampen vasculitis in Behçet’s disease

TNF inhibitors have been used to treat autoimmune and autoinflammatory diseases. Here we report an unexpected mechanism underlying the therapeutic effects of TNF inhibitors in Behçet’s disease (BD), an autoimmune inflammatory disorder. Using serum metabolomics and peripheral immunocyte transcriptomics, we find that polymorphonuclear neutrophil (PMN) from patients with BD (BD-PMN) has dysregulated mevalonate pathway and subsequently increased farnesyl pyrophosphate (FPP) levels. Mechanistically, FPP induces TRPM2-calcium signaling for neutrophil extracellular trap (NET) and proinflammatory cytokine productions, leading to vascular endothelial inflammation and damage. TNF, but not IL-1β, IL-6, IL-18, or IFN-γ, upregulates TRPM2 expression on BD-PMN, while TNF inhibitors have opposite effects. Results from mice with PMN-specific FPP synthetase or TRPM2 deficiency show reduced experimental vasculitis. Meanwhile, analyses of public datasets correlate increased TRPM2 expressions with the clinical benefits of TNF inhibitors. Our results thus implicate FPP-TRPM2-TNF/NETs feedback loops for inflammation aggravation, and novel insights for TNF inhibitor therapies on BD.

Normalized Interferon Signatures and Clinical Improvements by IFNAR1 Blocking Antibody (Anifrolumab) in Patients with Type I Interferonopathies

PurposeA causal role of type-I interferons (IFN-I) in autoinflammatory type-I interferonopathies such as SAVI (STING–associated vasculopathy with onset in infancy) and CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures) is suggested by elevated expression of IFN-I stimulated genes (ISGs). Hitherto, the lack of specific inhibitors of IFN-I signaling has prevented the verification of a causal role for IFN-I in these conditions. Commonly used inhibitors of the JAK/STAT pathway exert broad effects on multiple signaling pathways leading to more general immunosuppression beyond IFN-I signaling.MethodsHere we show in four patients with SAVI and one patient with CANDLE syndrome that blockade of the IFNAR1 receptor (Anifrolumab) exerts an additive effect over JAK-inhibitor alone. In two patients with SAVI, monotherapy with Anifrolumab is sufficient to retain a suppressed IFN-I signature and clinical improvement.ResultsAnifrolumab normalizes IFN-I signature genes and relieves symptoms beyond what is typically achieved by a JAK-inhibitor (Baricitinib) alone in patients with type-I interferonopathies. In two patients Anifrolumab was used successfully as monotherapy. Addition of Anifrolumab enabled steroid tapering and cessation with reduced overall immunosuppression and lower risks of opportunistic infections and improved metabolic states and growth which is highly beneficial in these young patients.ConclusionThese results verify a causal role of IFN-I signaling in type-I Interferonopathies SAVI and CANDLE and suggests Anifrolumab as an important new treatment option in autoinflammatory diseases with elevated IFN-I induced gene expression.Genia Kretzschmar, Laura Piñero Páez, and Ziyang Tan are shared-first authors.Sara Alehashemi, AnnaCarin Horne, and Petter Brodin are co-senior author.

Investigating the impact of tocilizumab on serum cytokines concentrations in Japanese FMF patients: a sub-analysis of the NUH01FMF study

Familial Mediterranean Fever (FMF) is the most common hereditary autoinflammatory disease, characterized by recurrent fever, arthritis, rash, and serositis, and is caused by mutations in the MEFV gene coding for the pyrin protein. The primary treatment goal is to prevent acute attacks and minimize subclinical inflammation to avoid secondary amyloidosis with colchicine as the first-line treatment. However, 10-20% of patients are colchicine-resistant or intolerant. While the therapeutic potential of IL-6 inhibitors such as tocilizumab (TCZ) has been suggested, the detailed serum cytokine profiles after TCZ treatment in patients with FMF remain largely unexplored. This study focused on a sub-analysis of a clinical trial evaluating TCZ in patients with colchicine-resistant FMF (crFMF). We analyzed the serum cytokine profiles at 0, 2, 4, 8, 12, 16, 20, and 24 weeks in the TCZ and placebo groups. Our findings revealed a decrease in serum C-X-C motif chemokine ligand 1 and vascular endothelial growth factor levels in the TCZ group at week 4 compared to baseline, which persisted until week 24, indicating the potential of TCZ to manage crFMF by modulating specific inflammatory cytokines. Further research is required to confirm these findings and optimize the treatment strategies for FMF.

Evaluation of Children with Familial Mediterranean Fever in South-Eastern Region of Türkiye

Background: Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disorder commonly found in populations from the Mediterranean region, including Turks, Armenians, Arabs, and Jews. It is characterized by recurrent episodes of fever and inflammation, primarily affecting the peritoneum, pleura, and joints. Familial Mediterranean fever is caused by mutations in the MEFV gene, which encodes pyrin, a protein that regulates the inflammatory response. The most common mutations associated with FMF are M694V, M680I, and V726A. These mutations lead to the overproduction of interleukin-1β (IL-1β), triggering the inflammatory episodes that are the hallmark of the disease. Objectives: This study aims to explore the clinical implications of MEFV gene mutations in a cohort of patients diagnosed with FMF and treated with colchicine. The primary objective is to determine the frequency of various MEFV mutations in the patient cohort and examine their association with clinical presentations, such as symptom severity and response to treatment. Methods: A retrospective cohort of 302 patients diagnosed with FMF and undergoing colchicine treatment was examined. Demographic data, clinical symptoms, and genetic mutations were systematically collected and analyzed. Mutation analysis focused on identifying the most common MEFV variants and their potential influence on clinical outcomes. Consanguinity and family history were also considered for their role in FMF genetic predisposition. Results: The study included 157 females and 145 males, with a mean age of 142.60 ± 48.04 months at the time of analysis. The average age of diagnosis was 94 ± 42 months, with no significant differences between genders. Abdominal pain was the most common symptom (90.3%), followed by fever (69.0%) and arthralgia (42.3%). Consanguinity was reported in 35.1% of cases, mainly between first-degree cousins, and 24.5% had a family history of FMF. Genetic analysis revealed that the M694V mutation was the most common homozygous mutation (71.4%), followed by the E148Q mutation as the most frequent heterozygous mutation (37.5%). The compound heterozygous mutation M694V/E148Q was found in 20% of cases. A statistically significant association was found between arthritis and homozygous mutations (P = 0.001) as well as with the M694V mutation (P = 0.004). Homozygous M694V mutations were detected in 16.9% of patients. The findings underscore a strong correlation between the M694V mutation and the development of FMF. Despite the efficacy of colchicine in managing symptoms and preventing complications such as amyloidosis, some patients exhibited treatment resistance, particularly those with arthritis. Conclusions: This study highlights the significant role of MEFV gene mutations, particularly M694V, in the pathogenesis of FMF. It underscores the importance of early diagnosis and the potential for personalized treatment based on genetic findings. While the retrospective design of the study presents limitations, such as selection and information bias, the results provide valuable insights into the clinical and genetic dimensions of FMF. Future studies should build on these findings by using prospective designs and investigating the interaction between genetic and environmental factors in FMF. Expanding the scope of genetic analysis could also lead to the discovery of new mutations, enhancing our understanding of this complex disorder.

Three cases of autoinflammatory disease with novel NLRC4 mutations, and the first mutation reported in the CARD domain of NLRC4 associated with autoinflammatory infantile enterocolitis (AIFEC)

BackgroundGain of function (GOF) mutations in NOD-like receptor family CARD-containing 4 protein (NLRC4) gene induce a wide spectrum of autoinflammatory phenotypes. Currently, we categorize them into four groups: familial cold autoinflammatory syndrome (FCAS)4, autoinflammatory infantile enterocolitis (AIFEC), NLRC4-macrophage associated syndrome (MAS), and neonatal-onset multisystem inflammatory disease (NOMID). The rarity and complexity of the disease necessitate the description of new cases and a reexamination of our understanding of the condition.Case presentationsWe present three patients with NLRC4-GOF mutations and AIFEC phenotypes. The first patient is an infant girl with periodic fever, seizure, high inflammatory markers, and an episode of macrophage associated syndrome (MAS). History of recurrent fever episodes since childhood was reported in mother and maternal grandmother. A heterozygous mutation was found in CARD domain of NLRC4: c.A91C: p.Asn31His. The second patient is an adolescent boy with periodic fever, diarrhea, aphthous stomatitis, seizure, and central nervous system (CNS) vasculitis. A heterozygous mutation was found in NLRC4 gene: c.1202T > C. p. Val401Ala. The third patient is a child with chronic diarrhea and elevated inflammatory markers. We found a heterozygous mutation in NLRC4 gene: c.390delG: p.S132Afs*21. All mutations have been reported for the first time as NLRC4 mutations associated with autoinflammation. We introduced novel mutations in the CARD domain and between CARD and NBD domain in the first and third cases, respectively. All three children are under remission following treatment.ConclusionsNLRC4-GOF mutations can be associated with autoinflammation with diverse symptoms. Given the rarity of the disease and the possibility of new mutations being identified, the existence of a phenotype/genotype correlation has yet to be thoroughly investigated. The variety in manifestations and severity spectrum mandates a variety of treatments. Adalimumab has shown favorable outcomes in our AIFEC cases.

Overview of anti-inflammatory diets and their promising effects on non-communicable diseases.

An anti-inflammatory diet is characterised by incorporating foods with potential anti-inflammatory properties, including fruits, vegetables, whole grains, nuts, legumes, spices, herbs and plant-based protein. Concurrently, pro-inflammatory red and processed meat, refined carbohydrates and saturated fats are limited. This article explores the effects of an anti-inflammatory diet on non-communicable diseases (NCD), concentrating on the underlying mechanisms that connect systemic chronic inflammation, dietary choices and disease outcomes. Chronic inflammation is a pivotal contributor to the initiation and progression of NCD. This review provides an overview of the intricate pathways through which chronic inflammation influences the pathogenesis of conditions including obesity, type II diabetes mellitus, CVD, autoinflammatory diseases, cancer and cognitive disorders. Through a comprehensive synthesis of existing research, we aim to identify some bioactive compounds present in foods deemed anti-inflammatory, explore their capacity to modulate inflammatory pathways and, consequently, to prevent or manage NCD. The findings demonstrated herein contribute to an understanding of the interplay between nutrition, inflammation and chronic diseases, paving a way for future dietary recommendations and research regarding preventive or therapeutic strategies.

A new-disease-causing dominant-negative variant in CARD11 gene in a Chinese case with recurrent fever

Immunodeficiency 11B with atopic dermatitis (IMD11B, OMIM:617638) is rare primary immunodeficiency disease caused by germline dominant negative (DN) mutations in the CARD11 gene. Affected patients present with immune dysfunction, recurrent infections and atopic dermatitis. In this study, we sought to identify and characterize the genetic variant in one patient with periodic fever, recurrent infections, and eczema. Trio whole-exome sequencing (WES) was employed in this patient and her parents, and Sanger sequencing validated the potential pathogenic variant. In vitro functional study was performed to evaluate the pathogenicity of genetic variant identified. A very rare missense mutation (c.2324C > T, p.S775L) in CARD11 gene (NM_032415) was identified by WES in the patient but not her parents. Luciferase reporter assays and co-immunoprecipitation demonstrated mutation exerts a dominant-interfering effect on wild-type CARD11, inhibiting the activity of NF-κB. RNA sequencing analysis also confirmed that mutant CARD11 inhibited down-stream transcriptional activity of NF-κB. A review of literature doesn’t found significant genotype–phenotype correlation. We identified a vary rare DN CARD11 mutation, expanding the genetic and phenotypic spectrum of CARD11.

Features of Vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic mutation syndrome associated with the c.121A>C, p.(Met41Leu) UBA1 genetic variant: A systematic review

Abstract Introduction/Objective Vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic mutation (VEXAS) syndrome was first described in 2020. VEXAS is driven by a mutation in the UBA1 gene on hematopoietic progenitor cells that encodes the E1 ubiquitin-activating protein. Loss of this protein leads to various inflammatory clinical presentations ranging from dermatological, pulmonary, rheumatologic and hematologic. Many UBA1 variants have been identified. We did a systematic review focusing on a particular UBA1 variant gene mutation underlying this disease process. Methods/Case Report Databases were searched for articles discussing VEXAS syndrome until April 2024. Only case reports and case series in the English language were included. Data on patient demographics, clinical presentation, laboratory values, bone marrow findings, dermatologic presentation and skin biopsy findings were extracted. Results (if a Case Study enter NA) 332 articles discussing VEXAS syndrome were retrieved, of which 115 were case reports or case series. These were screened for patients carrying a p.Met41Leu UBA1 gene mutation and only the 25 patients with this genetic variant were ultimately included in our study. The average age was 68 years (59-81 years). 24/25 (96%) patients reported dermatologic symptoms ranging from erythema to urticarial eruptions to erythema multiforme. Fever was the second most common presenting complaint (76%) followed by arthritis (68%), chondritis (36%) and thromboembolic disease (28%). Macrocytic anemia was a common laboratory finding (65%). MDS was seen in 52% of the patients. All patients had hematopoietic progenitor cells with vacuoles. Sweet’s syndrome was the most common initial diagnosis (52%) as skin biopsies in most patients showed dermal edema and neutrophilic dermatoses/infiltration. Conclusion The c.121A>C, p.(Met41Leu) UBA1 variant is frequently related to cutaneous manifestations. In patients with clinical features of an inflammatory disorder with dermatological and hematologic abnormalities, testing for the p.Met41Leu UBA1 mutation might lead to an earlier diagnosis and prompt initiation of effective treatment.

Urticarial vasculitis

Purpose of review Urticarial vasculitis is a rare condition manifesting with a variety of clinical presentations ranging from skin limited lesions to life-threatening systemic illnesses. This review aims to highlight the recent findings on the etiology, diagnostic modalities, and therapeutic strategies and course of urticarial vasculitis. Recent findings In addition to well established triggers, urticarial vasculitis (UV) cases associated with severe acute respiratory syndrome coronavirus 2 (SARS-Cov2) disease and COVID-19 vaccines, vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome, and adenosine deaminase (ADA) deficiency have been reported. A clinical-dermoscopic model for differentiating urticarial vasculitis has been developed with purpuric patches and globules favoring UV diagnosis and thus diminishing the need for histopathology. The efficacy of treatment modalities has been reviewed, and antihistamines, systemic corticosteroids, omalizumab, cyclophosphamide, tocilizumab, anti-interleukin (IL)-1 agents, and rituximab were shown to have the highest success rates. Regarding the durability of remission, rituximab, dapsone, and MMF were related to long-lasting treatment free responses. The course of hypocomplementemic urticarial vasculitis was investigated in an epidemiological study, revealing 5- and 10-year survival rates of 92% and 83%, respectively. Chronic obstructive pulmonary disease, septicemia, and end-stage renal disease were identified as causes of mortality. Summary With the aid of dermoscopy, a noninvasive tool, differentiation from chronic spontaneous urticaria can be made, and the need for histopathological examination can be diminished. Although clear definitions and consensus criteria for performing disease severity are lacking, careful screening is needed to tailor the treatment on an individual basis. Emerging infections like SARS-CoV 2, vaccines, and autoinflammatory disorders like VEXAS syndrome and ADA deficiency are new associations. The optimal use of well established agents like systemic corticosteroids and immunomodulators are mainstay treatment modalities, whereas IL-1 inhibitors, omalizumab, rituximab and Janus Kinase inhibitors may represent viable alternatives in selected cases.

Somatic mutations in autoinflammatory and autoimmune disease.

Somatic mutations (also known as acquired mutations) are emerging as common, age-related processes that occur in all cells throughout the body. Somatic mutations are canonically linked to malignant processes but over the past decade have been increasingly causally connected to benign diseases including rheumatic conditions. Here we outline the contribution of somatic mutations to complex and monogenic immunological diseases with a detailed review of unique aspects associated with such causes. Somatic mutations can cause early- or late-onset rheumatic monogenic diseases but also contribute to the pathogenesis of complex inflammatory and immune-mediated diseases, affect disease progression and define new clinical subtypes. Although even variants with a low variant allele fraction can be pathogenic, clonal dynamics could lead to changes over time in the proportion of mutant cells, with possible phenotypic consequences for the individual. Thus, somatic mutagenesis and clonal expansion have relevant implications in genetic testing and counselling. On the basis of both increased recognition of somatic diseases in clinical practice and improved technical and bioinformatic processes, we hypothesize that there will be an ever-expanding list of somatic mutations in various genes leading to inflammatory conditions, particularly in late-onset disease.

Ruxolitinib-based regimen in children with autoimmune disease or autoinflammatory disease-related haemophagocytic lymphohistiocytosis.

For autoimmune disease (AD) and autoinflammatory disease (AID)-related haemophagocytic lymphohistiocytosis (HLH) (AD/AID-HLH), there is still a lack of standardized treatment. Glucocorticoids (GCs) are the main treatment currently; however, 37.9% to 61% of patients fail to achieve effective control of HLH, making it urgent to find novel treatment strategies. We conducted a retrospective, single-centre study examining ruxolitinib (RUX)-based regimen in children with AD/AID-HLH. Patients were first treated with RUX monotherapy, and additional treatments including methylprednisolone and etoposide were added sequentially when the disease could not be controlled. The study included 26 patients with a median follow-up of 23.9 months, of whom 15 had prior treatments. The overall response rate at week 8 with the RUX-based regimen was 96.2%, with 92.3% attaining complete response (CR) and 3.9% attaining partial response. The 2-year overall survival rate was 96.2% (95% CI, 80.4% to 99.9%). During RUX monotherapy, 46.1% of patients achieved CR as the best response, with a median first response time to RUX of 2 days. Additionally, 53.8% of patients required additional GCs and 23.1% required etoposide chemotherapy. All observed adverse events were manageable and acceptable. Overall, our study supports the efficacy and safety of the RUX-based regimen in children with AD/AID-HLH.

Adult-onset Still’s disease masquerading as acute coronary syndrome: a case report and review of the literature

IntroductionAdult-onset Still’s disease is a rare systemic autoinflammatory disease. We present a case of a young man with a constellation of symptoms and myopericarditis as a complication of this disease.CaseA 36-year-old Hispanic man with no significant past medical history developed a quotidian fever pattern following an upper respiratory tract infection. He initially presented with chest pain concerning for myocardial infarction and underwent cardiac catheterization, which revealed non-obstructive coronary artery disease. He was found to have myopericarditis, significant neutrophilic leukocytosis, and hyperferritinemia. He improved on high-dose corticosteroids but developed steroid-induced psychosis, and 4 months from symptom onset, he finally received tocilizumab, which eventually induced remission without adverse reactions.DiscussionAdult-onset Still’s disease should be considered in a patient with fevers of undetermined origin. Due to its multisystemic involvement, adult-onset Still’s disease is often a diagnosis arrived at after an extensive cardiac, hematologic, malignant, and infectious workup. Imaging, laboratory testing, and bone marrow biopsy were necessary to rule out alternative etiologies of this patient’s presentation. Steroids are the mainstay of treatment because they are easily affordable, although the high risk of adverse effects makes them less desirable. Interleukin-1 inhibitors (anakinra or canakinumab) and interleukin-6 inhibitor tocilizumab are the steroid-sparing biologic agents of choice but are cost-prohibitive.ConclusionAdult-onset Still’s disease should be considered in the differential diagnoses of fever of undetermined origin. Early identification and initiation of treatment are critical to faster recovery and prevention of progression to severe complications. Steroids remain the standard first-line therapy and should be followed by disease-modifying steroid sparing drugs. The social determinants of health may preclude their timely initiation and should alert providers of proactive ways to avoid further delays.

A case of revertant mosaic-like normal-looking spots in a patient with erythroderma with IL36RN and CARD14 heterozygous mutations.

An 89-year-old Japanese woman presented with erythroderma associated with significant scaling. A histological examination showed acanthosis with hyperkeratosis and hyperkeratinization of the hair follicles. Genetic analyses using DNA from the peripheral blood revealed heterozygous mutations in IL36RN (c.115+6T>C) and CARD14 c.2648G>A (p.Arg883His). Based on these findings, we diagnosed her with erythroderma attributable to autoinflammatory keratinization disease. She then developed more than 30 small, round, well-defined, spots on her back and extremities that appeared histologically normal. We suspected that these spots might be revertant mosaicism. Immunohistochemical staining with p65, which is a component of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), revealed nuclear staining in epidermal keratinocytes in erythematous lesions, but not in the normal-looking spots. However, mutations in IL36RN and CARD14 unexpectedly persisted in the epidermis and dermis of the normal-looking spots.

DNA-sensing pathways in health, autoinflammatory and autoimmune diseases.

Detection of microbial DNA is a primary means of host defense. In mammalian cells, DNA-sensing pathways induce robust anti-microbial responses and initiation of adaptive immunity, leading to the eventual clearance of the infectious agent. However, while conferring the advantage of broad detection capability, the sequence-independent recognition mechanisms of most DNA sensors pose a significant challenge for mammalian cells to maintain ignorance to self-DNA under homeostatic conditions. In this Review, we summarize the fundamentals of DNA-sensing pathways and the intricate regulatory networks that keep these pathways in check. In addition, we describe how regulatory restraints can be defective and underlie human autoinflammatory and autoimmune diseases. Further, we discuss therapies in development that limit inflammation fueled by self-DNA or inappropriate activation of DNA-sensing pathways.

Novel Serum Markers that Distinguish Behcet’s Disease from Idiopathic Recurrent Aphthous Stomatitis

ABSTRACT Background Behcet’s disease (BD) is a rare and recurrent autoinflammatory disorder characterized by systemic vasculitis, frequently manifested as recurrent aphthous stomatitis (RAS). We aim to identify specific serum proteins to discriminate between BD and idiopathicRAS. Method Peripheral blood was collected from 12 BD patients, 12 idiopathic RAS patients, and 21 healthy volunteers. The serum samples underwent Tandem Mass Tag-based mass spectrometry analysis. Differentially expressed proteins (DEPs) were identified for KEGG pathway enrichment, Gene Ontology (GO), and protein-protein interaction (PPI) analyses. ELISA was utilized to verify two BD-specific DEPs in another cohort consisting of 18 BD patients, 18 idiopathic RAS patients, and 18 controls. Results Compared with RAS serum, BD serum showed 242 DEPs. 49 proteins were differentially expressed in BD but not RAS serum compared to healthy controls. KEGG pathway and GO analyses revealed that DEPs in BD and RAS have similar biological functions and cellular distributions, featuring a significant association with pathways regulating blood coagulation and immune response. When comparing DEPs between BD and RAS, several keratins emerged as markers that distinguish RAS from BD. We also identified multiple DEPs in BD but not RAS patients. PPI analysis uncovered that lipoprotein metabolism regulators serve as hub proteins, indicating their potentially essential roles in BD pathology. In addition, ELISA results confirmed the elevated LRG1 and SOD3 levels in BD, but not RAS patients, compared to healthy donors. Conclusion Our data uncovered novel serum proteins that distinguish BD from RAS, which may potentially be useful in BD diagnosis and treatment.

Familial Mediterranean Fever in Pregnancy.

Though the incidence of familial Mediterranean fever (FMF) in pregnancy is rare, understanding the etiology and symptomatology of FMF is essential for obstetric treatment of patients with FMF. Familial Mediterranean fever is a hereditary periodic fever syndrome that has unique obstetric considerations. Familial Mediterranean fever is typically characterized by recurrent episodes of high-grade fevers, pleuritis/pericarditis, and arthritis lasting 1-3 days with complete recovery seen in between episodes. Familial Mediterranean fever is seen worldwide, but particularly in patients of Mediterranean descent. Its incidence varies across ethnicities. This article provides a comprehensive review of existing literature. It is well established that colchicine is safe and effective to use during pregnancy in patients with FMF to control and prevent flares. Although most pregnancies progress without negative outcomes, FMF has been shown in the literature to be associated with preterm birth and premature rupture of membranes. Its impact on increasing the rate of fetal growth restriction and hypertensive disorders is less understood. Additionally, FMF flares may be suppressed in pregnancy, whereas other sources report that flares are similar to those outside of pregnancy in terms of frequency, type of symptoms, and severity. Breastfeeding is safe in patients with FMF who are taking colchicine. Genetic counseling can be offered to patients with FMF, but in utero diagnostic testing is generally not pursued solely for the indication of FMF diagnosis in the fetus. Further investigation of the impact of FMF on pregnancy is needed for advancing our understanding of the condition and optimizing care for pregnant individuals with FMF.

Comparative analysis of rare periodic fever syndromes including the first Korean case of hyperimmunoglobulinemia D and periodic fever syndrome.

Comparative analysis of rare periodic fever syndromes including the first Korean case of hyperimmunoglobulinemia D and periodic fever syndrome.

Aspects cliniques des amyloses systémiques en 2024

The three most common varieties of systemic amyloidosis are transthyretin amyloidosis (ATTR), immunoglobulin amyloidosis (AL) and inflammatory amyloidosis (AA). There are two forms of transthyretin amyloidosis: the wild type, the most common, represents approximately 15% of heart diseases and the genetic, or "mutated" form, which is a rare disease and manifests mainly by peripheral neuropathy and heart disease. Major therapeutic advances have been made in recent years thanks to molecules that stabilize transthyretin and/or prevent its translation by destroying messenger RNA. Immunoglobulin amyloidosis (AL) is a hematological disease whose severity is due to the toxicity of immunoglobulin light chains forming amyloid deposits that are toxic to tissues, particularly the heart and kidneys. Treatments for immunoglobulin amyloidosis are increasingly effective, and target the plasma cell, leading to an overall improvement in the prognosis, with cardiac involvement being the most worrying condition. Inflammatory amyloidosis (AA) complicates chronic inflammatory diseases less often due to the effectiveness of anti-inflammatory biotherapies in inflammatory rheumatism, chronic inflammatory bowel diseases and genetic auto-inflammatory diseases. The causes of inflammatory amyloidosis are now more diverse with an increase in cases of unknown cause associated or not with obesity.

Cyclopeptide Inhibitors Target the N-Terminal Tail of STING and Alleviate Autoinflammation.

Cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway is a crucial component of innate immunity that plays a vital role in protecting against pathogen infections and cellular stress. However, aberrant activation of cGAS-STING pathway is related to inflammatory and autoimmune diseases. Here, we developed cyclopeptide STING inhibitors by cyclizing the N-terminal tail (NTT) of STING. These cyclopeptides selectively inhibited the activation of STING pathway in human or murine cell lines. Mechanistically, the inhibitors directly bound to STING, and subsequently blocked the aggregation and activation of STING. In addition, the optimal inhibitor STi-2 significantly suppressed proinflammatory cytokine production and systemic inflammation in Trex1-/- mice. Overall, our work facilitates the development of specific inhibitors of STING as potential therapies for cGAS-STING associated autoinflammatory diseases.

Efficacy and safety of targeted therapies in VEXAS syndrome: retrospective study from the FRENVEX

ObjectivesVacuoles, E1 enzyme, X-linked, autoinflammatory and somatic (VEXAS) syndrome is an adult-onset autoinflammatory disease associated with somatic ubiquitin-like modifier-activating enzyme 1 (UBA1) mutations. We aimed to evaluate the efficacy and...