Identification of an IL-1 receptor mutation driving autoinflammation directs IL-1-targeted drug design.

The interleukin 1 (IL-1) pathway signals through IL-1 receptor type 1 (IL-1R1) and emerges as a central mediator for systemic inflammation. Aberrant IL-1 signaling leads to a range of autoinflammatory diseases. Here, we identified a de novo missense variant in IL-1R1 (p.Lys131Glu) in a patient with chronic recurrent multifocal osteomyelitis (CRMO). Patient PBMCs showed strong inflammatory signatures, particularly in monocytes and neutrophils. The p.Lys131Glu substitution affected a critical positively charged amino acid, which disrupted the binding of the antagonist ligand, IL-1Ra, but not IL-1α or IL-1ß. This resulted in unopposed IL-1 signaling. Mice with a homologous mutation exhibited similar hyperinflammation and greater susceptibility to collagen antibody-induced arthritis, accompanied with pathological osteoclastogenesis. Leveraging the biology of the mutation, we designed an IL-1 therapeutic, which traps IL-1ß and IL-1α, but not IL-1Ra. Collectively, this work provides molecular insights and a potential drug for improved potency and specificity in treating IL-1-driven diseases.

ADAR RNA Modifications, the Epitranscriptome and Innate Immunity.

Modified bases act as marks on cellular RNAs so that they can be distinguished from foreign RNAs, reducing innate immune responses to endogenous RNA. In humans, mutations giving reduced levels of one base modification, adenosine-to-inosine deamination, cause a viral infection mimic syndrome, a congenital encephalitis with aberrant interferon induction. These Aicardi-Goutières syndrome 6 mutations affect adenosine deaminase acting on RNA 1 (ADAR1), which generates inosines in endogenous double-stranded (ds)RNA. The inosine base alters dsRNA structure to prevent aberrant activation of antiviral cytosolic helicase RIG-I-like receptors. We review how effects of inosines, ADARs, and other modified bases have been shown to be important in innate immunity and cancer.

Trappc1 intrinsically prevents ferroptosis of naive T cells to avoid spontaneous autoinflammatory disease in mice.

T lymphocytes are pivotal in adaptive immunity. The role of the trafficking protein particle complex (TRAPPC) in regulating T-cell development and homeostasis is unknown. Using CD4cre -Trappc1flox/flox (Trappc1 cKO) mice, we found that Trappc1 deficiency in T cells significantly decreased cell number of naive T cells in the periphery, whereas thymic T-cell development in Trappc1 cKO mice was identical as WT mice. In the culture assays and mouse models with adoptive transfer of the sorted WT (CD45.1+ CD45.2+ ) and Trappc1 cKO naive T cells (CD45.2+ ) to CD45.1+ syngeneic mice, Trappc1-deficient naive T cells showed significantly reduced survival ability compared with WT cells. RNA-seq and molecular studies showed that Trappc1 deficiency in naive T cells reduced protein transport from the endoplasmic reticulum to the Golgi apparatus, enhanced unfolded protein responses, increased P53 transcription, intracellular Ca2+ , Atf4-CHOP, oxidative phosphorylation, and lipid peroxide accumulation, and subsequently led to ferroptosis. Trappc1 deficiency in naive T cells increased ferroptosis-related damage-associated molecular pattern molecules like high mobility group box 1 or lipid oxidation products like prostaglandin E2, leukotriene B4, leukotriene C4, and leukotriene D4. Functionally, the culture supernatant of Trappc1 cKO naive T cells significantly promoted neutrophils to express inflammatory cytokines like TNFα and IL-6, which was rescued by lipid peroxidation inhibitor Acetylcysteine. Importantly, Trappc1 cKO mice spontaneously developed severe autoinflammatory disease 4 weeks after birth. Thus, intrinsic expression of Trappc1 in naive T cells plays an integral role in maintaining T-cell homeostasis to avoid proinflammatory naive T-cell death-caused autoinflammatory syndrome in mice. This study highlights the importance of the TRAPPC in T-cell biology.

Plonmarlimab, a novel anti-GM-CSF blocking antibody, ameliorates disease progression in the pre-clinical model of macrophage activation syndrome.

OBJECTIVES: We aimed to characterize and investigate the safety and efficacy of Plonmarlimab, a novel anti-granulocyte-macrophage colony-stimulating factor (anti-GM-CSF) neutralizing antibody, on the treatment of macrophage activation syndrome (MAS), a life-threatening systemic inflammatory disease, in pre-clinical models. METHODS: The binding affinity was evaluated using Biacore. The neutralizing activity was measured through the blockade of ligand-receptor interaction, inhibition of STAT5 phosphorylation and suppression of TF-1 cell proliferation. The efficacy of Plonmarlimab was evaluated in a humanized MAS model, which was established by engrafting human umbilical cord blood (UCB) cells into NOG-EXL mice. Additionally, the safety profile of Plonmarlimab was investigated in cynomolgus monkeys. RESULTS: At the molecular level, Plonmarlimab showed sub-nanomolar binding affinity with human GM-CSF and effectively blocked the binding of GM-CSF to its receptor. At the cellular level, Plonmarlimab dose-dependently inhibited intracellular STAT5 phosphorylation and suppressed GM-CSF-induced TF-1 proliferation. In the UCB-engrafted NOG-EXL MAS mouse model, Plonmarlimab treatment significantly ameliorated disease progression, demonstrated by the improvements in body weight loss, anaemia and some histopathological features. Furthermore, Plonmarlimab was well tolerated up to 150 mg/kg weekly in monkeys with no reported adverse effects. CONCLUSIONS: Plonmarlimab is a highly potent GM-CSF blocking antibody and has demonstrated promising efficacy in a pre-clinical MAS model with a favourable safety profile, supporting its clinical development.

Proteasome-Associated Syndromes: Updates on Genetics, Clinical Manifestations, Pathogenesis, and Treatment.

The ubiquitin-proteasome system (UPS) has a critical role in post-translational protein modification that is essential for the maintenance of all cellular functions, including immune responses. The proteasome complex is ubiquitously expressed and is responsible for degradation of short-lived structurally abnormal, misfolded and not-needed proteins that are targeted for degradation via ubiquitin conjugation. Over the last 14 years, an increasing number of human diseases have been linked to pathogenic variants in proteasome subunits and UPS regulators. Defects of the proteasome complex or its chaperons - which have a regulatory role in the assembly of the proteasome - disrupt protein clearance and cellular homeostasis, leading to immune dysregulation, severe inflammation, and neurodevelopmental disorders in humans. Proteasome-associated diseases have complex inheritance, including monogenic, digenic and oligogenic disorders and can be dominantly or recessively inherited. In this review, we summarize the current known genetic causes of proteasomal disease, and discuss the molecular pathogenesis of these conditions based on the function and cellular expression of mutated proteins in the proteasome complex.

The Complexity of Being A20: From Biological Functions to Genetic Associations.

A20, encoded by TNFAIP3, is a critical negative regulator of immune activation. A20 is a ubiquitin editing enzyme with multiple domains, each of which mediates or stabilizes a key ubiquitin modification. A20 targets diverse proteins that are involved in pleiotropic immunologic pathways. The complexity of A20-mediated immunomodulation is illustrated by the varied effects of A20 deletion in different cell types and disease models. Clinically, the importance of A20 is highlighted by its extensive associations with human disease. A20 germline variants are associated with a wide range of inflammatory diseases, while somatic mutations promote development of B cell lymphomas. More recently, the discovery of A20 haploinsufficiency (HA20) has provided real world evidence for the role of A20 in immune cell function. Originally described as an autosomal dominant form of Behcet's disease, HA20 is now considered a complex inborn error of immunity with a broad spectrum of immunologic and clinical phenotypes.

Clinical characteristics and heterogeneity of generalized pustular psoriasis: A comparative study in a large retrospective cohort.

Generalized pustular psoriasis (GPP) is a rare and potentially life-threatening skin disease and the clinical heterogeneity of which is largely unknown. Retrospective cohort analysis was conducted on hospitalized GPP patients between January 2010 and November 2022. A total of 416 patients with GPP and psoriasis vulgaris (PV) respectively were included, matched 1:1 by sex and age. The heterogeneity of GPP was stratified by PV history and age. Compared with PV, GPP was significantly associated with prolonged hospitalization (11.7 vs. 10.3 day, p < 0.001), elevated neutrophil lymphocyte ratio (NLR) (5.93 vs. 2.44, p < 0.001) and anemia (13.9% vs. 1.2%, p < 0.001). Moreover, GPP alone (without PV history) was a relatively severer subtype with higher temperature (37.6°C vs. 38.0°C, p = 0.002) and skin infections (5.2% vs. 11.4%, p = 0.019) than GPP with PV. For patients across different age, compared with juvenile patients, clinical features support a severer phenotype in middle-aged, including higher incidence of anaemia (7.5% vs. 16.0%, p = 0.023) and NLR score (3.83 vs. 6.88, p < 0.001). Interleukin-6 (r = 0.59), high density lipoprotein cholesterol (r = -0.56), albumin (r = -0.53) and C-reactive protein-to-albumin ratio (r = 0.49) were the most relevant markers of severity in GPP alone, GPP with PV, juvenile and middle-aged GPP, respectively. This retrospective cohort suggests that GPP is highly heterogeneous and GPP alone and middle-aged GPP exhibit severe disease phenotypes. More attention on the heterogeneity of this severe disease is warranted to meet the unmet needs and promote the individualized management of GPP.

Yao Syndrome: An Overview of Genotypic Associations, Clinical Manifestations, Diagnosis, and Treatment.

BACKGROUND: Yao syndrome (YAOS) is a rare systemic autoinflammatory disorder (AID) of the innate immune system. It was recently categorized as genetically transitional disease (GTD) and is associated with NOD2 variants located at multiple NOD2 gene loci. Unlike most other periodic fever syndromes, the estimated disease prevalence is 1-10/100,000 with a predominance for females and white adult population. In this review, we aimed to provide a detailed analysis of different aspects of this syndrome to help better understand the underlying pathogenesis and incorporate the current evidence-based medicine published to diagnose and manage these patients. SUMMARY: We conducted literature search on YAOS from 2011 to 2024 using PubMed, Embase, and Scopus databases. Thirty-two studies were included in our narrative review. A descriptive analysis was performed of both Yao and non-Yao authored records to embrace the syndrome reported from all investigators and assess differences and similarities. The most reported gene variant is the homozygous IVS8+158 followed by compound heterozygous IVS8+158 and R702W. Mean age of disease onset is between 36 and 42 years. The mean age of disease diagnosis is between 40 and 45 years with a variable disease duration. Fever is the most commonly reported symptom followed by musculoskeletal, gastrointestinal symptoms and dermatitis. On laboratory workup, patients have elevated levels of erythrocyte sedimentation rate, C-reactive protein, and serum ferritin with negative autoantibody workup. Arthritic symptoms in YAOS patients have a positive response to sulfasalazine and glucocorticoids, while nonsteroidal anti-inflammatory drugs and colchicine produce minimal response. Anti-IL1 and anti-IL6 agents (canakinumab, anakinra, and tocilizumab) are effective treatment modalities. KEY MESSAGES: The evolving concept and acceptance of GTD will hopefully further our understanding about this SAID and similar disorders. We suggest developing a registry of patients with YAOS to keep track of expanding data on this subject. It is important to understand various aspects of YAOS including genetic and environmental factors, differential diagnosis, clinical manifestations, laboratory findings, and treatment options available to diagnose and manage these patients appropriately and timely.

Identifying high-risk neurological phenotypes in adult-onset classic monogenic autoinflammatory diseases: when should neurologists consider testing?

BACKGROUND: Monogenic autoinflammatory disorders result in a diverse range of neurological symptoms in adults, often leading to diagnostic delays. Despite the significance of early detection for effective treatment, the neurological manifestations of these disorders remain inadequately recognized. METHODS: We conducted a systematic review searching Pubmed, Embase and Scopus for case reports and case series related to neurological manifestations in adult-onset monogenic autoinflammatory diseases. Selection criteria focused on the four most relevant adult-onset autoinflammatory diseases-deficiency of deaminase 2 (DADA2), tumor necrosis factor receptor associated periodic fever syndrome (TRAPS), cryopyrin associated periodic fever syndrome (CAPS), and familial mediterranean fever (FMF). We extracted clinical, laboratory and radiological features to propose the most common neurological phenotypes. RESULTS: From 276 records, 28 articles were included. The median patient age was 38, with neurological symptoms appearing after a median disease duration of 5 years. Headaches, cranial nerve dysfunction, seizures, and focal neurological deficits were prevalent. Predominant phenotypes included stroke for DADA2 patients, demyelinating lesions and meningitis for FMF, and meningitis for CAPS. TRAPS had insufficient data for adequate phenotype characterization. CONCLUSION: Neurologists should be proactive in diagnosing monogenic autoinflammatory diseases in young adults showcasing clinical and laboratory indications of inflammation, especially when symptoms align with recurrent or chronic meningitis, small vessel disease strokes, and demyelinating lesions.

Cigarette smoking and risk of adult-onset Still disease: a propensity score matching analysis.

BACKGROUND: Environmental factors play an important role in the pathogenesis of rheumatic diseases. Smoking is thought to be a risk factor for autoimmune rheumatic diseases. AIMS: The purpose of the present study was to assess the association between smoking and adult-onset Still disease (AOSD) and the effect of smoking on outcomes of this disease. METHODS: In this case-control study, patients with AOSD who met the Yamaguchi criteria, were older than 16 years at the disease onset and were in follow-up for at least 12 months were consecutively enrolled in the study. The outcome of AOSD was assessed by acquiring remission on treatment, remission off treatment, time to remission and rate of flare. The smoking status of participants was defined by direct or phone interviews. Individuals who had smoked daily for at least 6 months were defined as a smoker. We performed propensity score matching analyses by using four parameters, including age, sex, educational status and marital status. RESULTS: Propensity score matching resulted in 72 patients with AOSD and 216 matched controls. The number of ever smokers in the AOSD and control groups were 11 (15.3%) and 25 (11.6%) respectively. There was no significant increase in the risk of AOSD in multivariate analysis after adjustment for age, sex, marital status and educational level. There were no significant differences in the outcomes of AOSD between ever and never smokers. CONCLUSIONS: Smoking probably is not a risk factor for AOSD and did not affect the response to treatment.

Pulmonary manifestations, treatments and outcomes of IgG4-related disease-a systematic literature review.

Immunoglobulin G4-related disease (IgG4-RD) is a multisystem fibroinflammatory condition. A consistent feature of many cases is pulmonary infiltrates, or respiratory failure. This systematic literature review aims to summarise the pulmonary manifestations of IgG4-RD, including clinical outcomes and treatment. This review was registered on PROSPERO (CRD42023416410). Medline, Embase and Cochrane databases were searched for articles discussing IgG4-RD syndrome. Information was extracted on demographics, type and prevalence of pulmonary manifestations, treatment and clinical outcomes. Initially, after deduplication, 3123 articles were retrieved with 18 ultimately included. A pooled total of 724 patients with IgG4-RD were included, 68.6% male, mean age 59.4 years (SD 5.8) at disease onset. The most frequently described pulmonary manifestation was mediastinal lymphadenopathy (n = 186, 48.8%), followed by pulmonary nodules (n = 151, 39.6%) and broncho-vascular thickening (n = 85, 22.3%). Where treatment was reported, the majority of patients received glucocorticoids (n = 211, 93.4%). Other immunosuppressive therapy included cyclophosphamide (n = 31), azathioprine (n = 18), with mycophenolate mofetil (n = 6), rituximab (n = 6), methotrexate (n = 5) and other unspecified immunomodulators (50). Clinical outcomes were reported in 263 patients, where 196 patients had remission of their disease, 20 had relapse, 35 had stable disease, four had progression and eight patients died from complications of IgG4-RD. This systematic review summarises pulmonary manifestations, treatments and outcomes in patients with IgG4-RD. Pulmonary involvement in IgG4-RD is relatively common, leading to high levels of morbidity and mortality. Glucocorticoids remain the mainstay of treatment, but further work is required to explore the management of patients with pulmonary manifestations in association with IgG4-RD.

Autoinflammatory Diseases Due to Defects in Degradation or Transport of Intracellular Proteins.

The number of human inborn errors of immunity has now gone beyond 430. The responsible gene variants themselves are apparently the cause for the disorders, but the underlying molecular or cellular mechanisms for the pathogenesis are often unclear. In order to clarify the pathogenesis, the mutant mice carrying the gene variants are apparently useful and important. Extensive analysis of those mice should contribute to the clarification of novel immunoregulatory mechanisms or development of novel therapeutic maneuvers critical not only for the rare monogenic diseases themselves but also for related common polygenic diseases. We have recently generated novel model mice in which complicated manifestations of human inborn errors of immunity affecting degradation or transport of intracellular proteins were recapitulated. Here, we review outline of these disorders, mainly based on the phenotype of the mutant mice we have generated.

NLRP1-associated autoinflammatory disease with epithelial dyskeratosis.

Several gain-of-function variants in NLRP1 cause a distinctive autoinflammatory disease reported under different names featuring mainly skin and mucosal involvement and variable systemic signs. Here, we report a new case of NLRP1-associated autoinflammatory disease in a 6-year-old Peruvian girl, who presented with confluent hyperkeratotic plaques that drained purulent material with subsequent scarring. A c.3641C > G (p. Pro1214Arg) variant that has been previously been reported was found in NLRP1 and was not present in either parent. The term NLRP1-associated autoinflammatory disease with epithelial dyskeratosis (NADED) is proposed to encompass all reported cases, which have received different nomenclature so far.

SAMD9L autoinflammatory or ataxia pancytopenia disease mutations activate cell-autonomous translational repression.

Sterile α motif domain-containing protein 9-like (SAMD9L) is encoded by a hallmark interferon-induced gene with a role in controlling virus replication that is not well understood. Here, we analyze SAMD9L function from the perspective of human mutations causing neonatal-onset severe autoinflammatory disease. Whole-genome sequencing of two children with leukocytoclastic panniculitis, basal ganglia calcifications, raised blood inflammatory markers, neutrophilia, anemia, thrombocytopaenia, and almost no B cells revealed heterozygous de novo SAMD9L mutations, p.Asn885Thrfs*6 and p.Lys878Serfs*13. These frameshift mutations truncate the SAMD9L protein within a domain a region of homology to the nucleotide-binding and oligomerization domain (NOD) of APAF1, ∼80 amino acids C-terminal to the Walker B motif. Single-cell analysis of human cells expressing green fluorescent protein (GFP)-SAMD9L fusion proteins revealed that enforced expression of wild-type SAMD9L repressed translation of red fluorescent protein messenger RNA and globally repressed endogenous protein translation, cell autonomously and in proportion to the level of GFP-SAMD9L in each cell. The children's truncating mutations dramatically exaggerated translational repression even at low levels of GFP-SAMD9L per cell, as did a missense Arg986Cys mutation reported recurrently as causing ataxia pancytopenia syndrome. Autoinflammatory disease associated with SAMD9L truncating mutations appears to result from an interferon-induced translational repressor whose activity goes unchecked by the loss of C-terminal domains that may normally sense virus infection.

NLRP3 leucine-rich repeats control induced and spontaneous inflammasome activation in cryopyrin-associated periodic syndrome.

BACKGROUND: The cryopyrin-associated periodic syndromes (CAPS) comprise a group of rare autoinflammatory diseases caused by gain-of-function mutations in the NLRP3 gene. NLRP3 contains a leucine-rich repeats (LRR) domain with a highly conserved exonic organization that is subjected to extensive alternative splicing. Aberrant NLRP3 inflammasome assembly in CAPS causes chronic inflammation; however, the mechanisms regulating inflammasome function remain unclear. OBJECTIVE: We aimed to elucidate the mechanisms regulating NLRP3-mediated autoinflammation in human disease, characterizing the role of LRR in inflammasome activation. METHODS: We analyzed sequence read archive data to characterize the pattern of NLRP3 splicing in human monocytes and investigated the role of each LRR-coding exon in inflammasome regulation in genetically modified U937 cells representing CAPS and healthy conditions. RESULTS: We detected a range of NLRP3 splice variants in human primary cells and monocytic cell lines, including 2 yet-undescribed splice variants. We observe that lipopolysaccharides affect the abundance of certain splice variants, suggesting that they may regulate NLRP3 activation by affecting alternative splicing. We showed that exons 4, 5, 7, and 9 are essential for inflammasome function, both in the context of wild-type NLRP3 activation by the agonist molecule nigericin and in a model of CAPS-mediated NLRP3 inflammasome assembly. Moreover, the SGT1-NLRP3 interaction is decreased in nonfunctional variants, suggesting that alternative splicing may regulate the recruitment of proteins that facilitate inflammasome assembly. CONCLUSION: These findings demonstrate the contribution of the LRR domain in inflammasome function and suggest that navigating LRR exon usage within NLRP3 is sufficient to dampen inflammasome assembly in CAPS.

Cohort-driven variant burden analysis and pathogenicity identification in monogenic autoinflammatory disorders.

BACKGROUND: Nearly 50 pathogenic genes and hundreds of pathogenic variants have been identified in monogenic autoinflammatory diseases (AIDs). Nonetheless, there are still many genes for which the pathogenic mechanisms are poorly understood, and the pathogenicity of many candidate variants needs to be determined. OBJECTIVE: Monogenic AIDs are a group of rare genetic diseases characterized by inflammation as the phenotype. With the development of next-generation sequencing, pathogenic genes have been widely reported and used for clinical screening and diagnosis. The International Society for Systemic Autoinflammatory Diseases has recognized approximately 50 pathogenic genes and hundreds of related pathogenic variants in monogenic AIDs. We plan to investigate these pathogenic variants by conducting a variant burden analysis to determine whether or not there are consistent characteristics. METHODS: We performed a variant burden analysis on the Genome Aggregation Database cohort using the currently reported genetic variants in monogenic AIDs, analyzing the enrichment of allelic signatures and deleterious predictions at the variants. Allelic signatures were extracted from Genome Aggregation Database, and the deleterious predictions were extracted from existing tools. The features obtained from the variant burden analysis were applied to the Random Forest model to classify the pathogenicity of novel mutations. RESULTS: Functional enrichment and network analysis of AID pathogenic genes have hinted at the possible involvement of unsuspected signals. The variant burden analysis demonstrated that the pathogenicity of a variant could not be reliably classified using only its allele frequency and deleterious predictions. However, variants of varying classifications of pathogenicity exhibited strikingly different patterns of the allelic signature in the upstream and downstream regions surrounding the variants. Furthermore, the distribution of deleterious variants surrounding the variants in the cohort varied significantly across pathogenicity categories. Finally, the cohort-based features extracted from the alleles were applied to the prediction of pathogenicity in monogenic AIDs, achieving superior prediction performance compared with other tools. The cohort-based features have potential applications across a more extensive variety of disease categories. CONCLUSIONS: The pathogenicity of a variant can be effectively classified on the basis of variant frequency and deleterious prediction of the allele in the cohort, and this information can be used to improve the accuracy of the current classification of the pathogenicity of the variant.

Biologics and JAK inhibitors for the treatment of monogenic systemic autoinflammatory diseases in children.

Systemic autoinflammatory diseases (SAIDs) are caused by aberrant activation of 1 or more inflammatory pathways in an antigen-independent manner. Monogenic forms of SAIDs typically manifest during childhood, and early treatment is essential to minimize morbidity and mortality. On the basis of the mechanism of disease and the dominant cytokine(s) that propagates inflammation, monogenic SAIDs can be grouped into major categories including inflammasomopathies/disorders of IL-1, interferonopathies, and disorders of nuclear factor-κB and/or aberrant TNF activity. This classification scheme has direct therapeutic relevance given the availability of biologic agents and small-molecule inhibitors that specifically target these pathways. Here, we review the experience of using biologics that target IL-1 and TNF as well as using Janus kinase inhibitors for the treatment of monogenic SAIDs in pediatric patients. We provide an evidence-based guide for the use of these medications and discuss their mechanism of action, safety profile, and strategies for therapeutic monitoring.

Proteomic Profiling of Tears in Blau Syndrome Patients in Identification of Potential Disease Biomarkers.

Blau syndrome (BS) is a rare autoinflammatory granulomatosis characterized by granulomatous arthritis, uveitis, and dermatitis. Ocular complications are particularly severe in BS, significantly contributing to morbidity. This study aims to identify potential biomarkers for BS ocular degeneration through proteomic profiling of tear samples from affected patients. Seven subjects from the same family, including four carriers of the BS-associated NOD2 mutation (p.E383K), were recruited alongside healthy controls. Tear samples were collected using Schirmer strips and analyzed via mass spectrometry. A total of 387 proteins were identified, with significant differences in protein expression between BS patients, healthy familial subjects, and healthy controls. Key findings include the overexpression of alpha-2-macroglobulin (A2M) and immunoglobulin heavy constant gamma 4 (IGHG4) in BS patients. Bioinformatic analysis revealed that differentially expressed proteins are involved in acute-phase response, extracellular exosome formation, and protein binding. Notably, neutrophils' azurophilic granule components, as azurocidin (AZU1), myeloperoxidases (MPO), and defensins (DEFA3), were highly expressed in the most severely affected subject, suggesting a potential role of neutrophils in BS ocular severity. These proteins might be promising biomarkers for ocular involvement in BS, facilitating early detection and tailored treatment strategies.

Anakinra in idiopathic recurrent pericarditis: a comprehensive case series and literature review.

OBJECTIVE: Idiopathic recurrent pericarditis (IRP) is defined by recurring episodes of pericardial inflammation without a known cause. This study investigates the safety and efficacy of anakinra, an interleukin­1 inhibitor, as a successful therapy for IRP in cases resistant to conventional treatment. METHODS: A retrospective evaluation of patients treated at our autoinflammatory center between 2011 and 2023 was conducted. Patient files were examined for demographic, clinical, and treatment response data, including nonsteroid anti-inflammatory drugs (NSAIDs), corticosteroids, and colchicine. Monogenic autoinflammatory disease screening was performed for Mediterranean Fever (MEFV), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase (MVK), nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3), and nucleotide-binding oligomerization domain-containing protein 2 (NOD2). Patients who experienced multiple episodes of pericarditis were diagnosed with recurrent pericarditis. The study evaluated anakinra treatment in IRP patients unresponsive to conventional therapy. RESULTS: The study included 21 participants, 9 (42.9%) female and 12 (57.1%) male. The average age of the participants was 43.1 ± 16.5 years. The MEFV mutation analysis revealed that 2 (9.5%) had a mutation in exon 10 and 4 (19.0%) had one in exon 2. Out of the 16 cases, 15 successfully discontinued steroid treatment. Four patients (19.0%) experienced injection site reactions. C­reactive protein (CRP) levels were measured at an average of 196 ± 67.8 mg/l before and 2.6 ± 3.15 mg/l after anakinra treatment. CONCLUSION: In conclusion, the study adds to the growing evidence for the efficacy of interleukin-1 inhibitors, such as anakinra, as a promising treatment modality for IRP in cases resistant to conventional treatment.

An immunogenetic investigation of 30 autoimmune and autoinflammatory diseases and their links to psychiatric disorders in a nationwide sample.

Autoimmune and autoinflammatory diseases (AIIDs) involve a deficit in an individual's immune system function, whereby the immune reaction is directed against self-antigens. Many AIIDs have a strong genetic component, but they can also be triggered by environmental factors. AIIDs often have a highly negative impact on the individual's physical and mental wellbeing. Understanding the genetic underpinning of AIIDs is thus crucial both for diagnosis and for identifying individuals at high risk of an AIID and mental illness as a result thereof. The aim of the present study was to perform systematic statistical and genetic analyses to assess the role of human leukocyte antigen (HLA) alleles in 30 AIIDs and to study the links between AIIDs and psychiatric disorders. We leveraged the Danish iPSYCH Consortium sample comprising 65 534 individuals diagnosed with psychiatric disorders or selected as part of a random population sample, for whom we also had genetic data and diagnoses of AIIDs. We employed regression analysis to examine comorbidities between AIIDs and psychiatric disorders and associations between AIIDs and HLA alleles across seven HLA genes. Our comorbidity analyses showed that overall AIID and five specific AIIDs were associated with having a psychiatric diagnosis. Our genetic analyses found 81 significant associations between HLA alleles and AIIDs. Lastly, we show connections across AIIDs, psychiatric disorders and infection susceptibility through network analysis of significant HLA associations in these disease classes. Combined, our results include both novel associations as well as replications of previously reported associations in a large sample, and highlight the genetic and epidemiological links between AIIDs and psychiatric disorders.