Search Results (123)

Background: Familial Mediterranean Fever (FMF) is a chronic autoinflammatory disorder that is characterized by increased arterial stiffness and subtle cardiovascular dysfunction. Colchicine remains the mainstay of treatment and may provide vascular benefits that extend beyond its anti-inflammatory effects. However, the association between colchicine therapy and ventriculoarterial coupling (VAC), a hemodynamic marker of cardiovascular efficiency, has not been previously studied. Methods: In this cross-sectional study, 97 patients with FMF receiving colchicine therapy for at least one year and 81 colchicine-naive individuals without FMF were consecutively enrolled from a tertiary rheumatology outpatient clinic. The VAC was evaluated using the Chen method, calculated as the ratio of arterial elastance (Ea) to end-systolic elastance (Es), based on echocardiographic measurements and noninvasive brachial blood pressure. Correlation analyses and stepwise multivariate linear regression analyses were performed to identify independent predictors of VAC. Results: Patients with FMF demonstrated significantly lower VAC values compared to controls (1.23 ± 0.34 vs. 1.40 ± 0.57; p = 0.001). The colchicine dose was inversely correlated with VAC (r = −0.243; p = 0.001) and remained an independent predictor in multivariate analysis (β = −0.186, p = 0.018). Beta-blocker use was positively associated with VAC (β = 0.194, p = 0.014), whereas female sex showed a borderline inverse association. Conclusions: Colchicine use in patients with FMF was associated with more favorable VAC in a dose-dependent manner. These findings suggest that colchicine may exert cardiovascular effects beyond the control of inflammation. VAC may be a useful noninvasive marker for assessing vascular–ventricular interactions in FMF. Full article

Candidate Phyla Radiation bacteria are emerging members of the human microbiota, particularly in oral and gut environments. Saccharibacteria were previously identified in the gut microbiota of healthy individuals and women diagnosed with familial Mediterranean fever (FMF), a monogenic autoinflammatory disorder prevalent in the eastern Mediterranean region, including Armenia. This study aimed to assess the prevalence and diversity of Saccharibacteria spp. and its basebiont Schaalia odontolytica in FMF patients, explore gender differences, and evaluate the modulation potential of two locally produced probiotics: Lactobacillus acidophilus INMIA9602 Er317/402 (Narine^®, VITAMAX-E, Yerevan, Armenia) and Escherichia coli M-17 (Colibacteron^®, VITAMAX-E, Yerevan, Armenia). The abundance and behavior of saccharibacteria and S. odontolytica appear to vary depending on health status and sex. Placebo administration caused both quantitative and qualitative shifts, suggesting a possible interaction between Candidatus saccharibacteria spp. and Schaalia odontolytica, though the underlying biological significance remains to be clarified. Narine administration appeared to increase the abundance of Candidatus saccharibacteria operational taxonomic units (OTUs) in FMF women and S. odontolytica OTUs in FMF men, whereas Colibacteron selectively decreased certain OTUs, predominantly in FMF women. These findings underscore the need to further investigate saccharibacteria’s role in systemic inflammation and probiotic-mediated modulation of the gut microbiota. Full article

VEXAS syndrome (Vacuoles, E1-enzyme, X-linked, Autoinflammation, and Somatic) is a recently identified late-onset autoinflammatory disorder characterized by a unique interplay between hematological and inflammatory manifestations. It results from somatic mutations in the UBA1 gene, located on the short arm of the X chromosome. Initially, females were considered mere carriers, with the syndrome primarily affecting males over 50. However, recent evidence indicates that heterozygous females can exhibit symptoms as severe as those seen in hemizygous males. The disease manifests as systemic inflammation, macrocytic anemia, thrombocytopenia, chondritis, neutrophilic dermatoses, and steroid-dependent inflammatory symptoms. Due to its overlap with autoimmune and hematologic disorders such as relapsing polychondritis, Still’s disease, and myelodysplastic syndromes, misdiagnosis is common. At the molecular level, VEXAS syndrome is driven by impaired ubiquitination pathways, resulting in dysregulated immune responses and clonal hematopoiesis. A key diagnostic marker is the presence of cytoplasmic vacuoles in myeloid and erythroid precursors, though definitive diagnosis requires genetic testing for UBA1 mutations. Traditional immunosuppressants and TNF inhibitors are generally ineffective, while JAK inhibitors and IL-6 blockade provide partial symptom control. Azacitidine and decitabine have shown promise in reducing disease burden, but hematopoietic stem cell transplantation (HSCT) remains the only curative treatment, albeit with significant risks. This review provides a comprehensive analysis of VEXAS syndrome, examining its clinical features, differential diagnoses, diagnostic challenges, and treatment approaches, including both pharmacological and non-pharmacological strategies. By enhancing clinical awareness and optimizing therapeutic interventions, this article aims to bridge emerging genetic insights with practical patient management, ultimately improving outcomes for those affected by this complex and often life-threatening disease. Full article

Anticytokine autoantibodies (AAbs), particularly anti-interferon-gamma (anti-IFN-γ) AAbs, disrupt cytokine functions, leading to infections, autoimmune-like diseases, and conditions resembling interleukin-12 (IL-12)/IFN-γ pathway defects. Advances in genetic testing have clarified overlaps between autoinflammatory, autoimmune disorders, and primary immunodeficiencies but reveal complex phenotypes and pathways. While these insights deepen our understanding of immune mechanisms, they also complicate diagnosis and treatment, with limited options for IFN-γ deficiencies caused by genetic mutations. The adult-onset immunodeficiency with disseminated lymphadenitis due to nontuberculous mycobacteria (NTM) and other opportunistic infections has been linked to high levels of anti-IFN-γ AAbs. This syndrome, initially identified in HIV-negative Asian patients, frequently affects individuals of Asian descent and may be associated with specific human leukocyte antigen (HLA) alleles. The presence of neutralizing anti-IFN-γ AAbs impairs the IFN-γ-dependent immune response, likely contributing to the persistent NTM infection. This study underscores the potential for late-onset anti-IFN-γ AAb syndrome to manifest with disseminated NTM (dNTM) infections, highlights the importance of timely diagnosis and considers rituximab as a potential therapeutic option. Full article

A 29-year-old gentleman of African descent presented to the emergency department with a three month history of a rash affecting the trunk, upper limbs, and thighs. The patient was unsure of any triggers and denied any preceding illness, new medications, illicit drug use, or recent vaccinations. On examination, there was a widespread papulosquamous eruption characterised by scaly, hyperpigmented papules and plaques involving the trunk, upper arms, and upper thighs. A definitive diagnosis was established through a diagnostic skin biopsy of a fresh lesion. Full article

Background/Objectives: Hidradenitis suppurativa (HS) is a chronic autoinflammatory skin disease characterized by recurrent, painful, and persistently draining purulent lesions. Alterations in the composition of the microbiome may be associated with immune dysregulation and HS progression. The objective of this study was to investigate the correlations between the gut microbiome and HS. Methods: A total of 80 participants (40 HS patients and 40 healthy controls [HCs]) were included in this study. Each participant filled out a specially designed questionnaire, which included demographics, HS severity, physical characteristics, dietary habits, and gastrointestinal disorders. DNA isolation and sequencing of microbiota were performed from fecal samples collected from each participant. Results: No statistically significant difference was observed in the alpha diversity between the microbiota of HS and HC. Nevertheless, HS was found to significantly decrease the chances of, among others, Collinsella, Izemoplasmatales, Clostridia, Lachnospiraceae, eligens group, xylanophilum group, and Pseudoflavonifractor occurrence. Conversely, HS significantly increased the chances of Enterorhabdus, Senegalimassilia, Gastranaerophilales, Candidatus Stoquefichus, Erysipelatoclostridiaceae, Holdemanella, Solobacterium, Ruminiclostridium, [Eubacterium] fissicatena group, Angelakisella, Comamonas, and Enterobacter occurrence. The logistic regression analysis, performed separately for each genus, showed a significant influence of disease severity (based on the Hurley scale) on the chances of occurrence for the following genera: Chloroplast (OR = 5.778), Dielma (OR = 5.75), Eisenbergiella (OR = 5.75) and Paludicola (OR = 5.778). Conclusions: In conclusion, our study adds to the growing body of literature on the gut microbiome in HS and provides valuable insights into the specific alterations in microbial occurrence and abundance associated with the disease. Full article

Background and Clinical Significance: Chronic nonbacterial osteomyelitis (CNO) of the jaw is a rare autoinflammatory bone disorder that primarily affects children and adolescents. Diagnosing CNO of the mandible can be challenging due to its rarity, and the clinical and radiographic findings overlap with those of other bone disorders. Case Presentation: This case series retrospectively presents four female pediatric patients (9–12 years old) diagnosed with mandibular CNO. The patients were treated at King Abdulaziz University Dental Hospital, Jeddah, Saudi Arabia, between 2018 and 2024. Clinical features and radiographic and histopathological findings were evaluated. All cases had mandibular swelling and pain. Radiographic features consistently revealed mixed sclerotic and radiolucent lesions with bone expansion and periosteal reactions. Histopathological findings revealed viable bone interspersed with varying degrees of fibrous tissue. No evidence of bacterial colonies or inflammation was observed. This case series highlights the radiographic and histopathological features of CNO in the mandible of pediatric patients. The mixed radiographic features and variability of histopathological findings combined with the refractory nature of the lesions contribute to diagnostic complexity. Diagnostic challenges include differentiating CNO from other inflammatory and fibro-osseous conditions. The presence of recurrent episodes of pain, the formation of subperiosteal bone, periostitis, lysis of the cortical layer, expansion of the mandibular canal, and sterile bone biopsies with nonspecific inflammatory changes were related mainly to CNO. Conclusions: These findings underscore the need for increased awareness and a multidisciplinary approach for accurate diagnosis and management of CNO. Conservative management, particularly in dental cases, avoids prolonged unnecessary use of antibiotics, and the prescription of nonsteroidal anti-inflammatory drugs should be followed. Full article

VEXAS syndrome and Alzheimer’s disease (AD), though distinct in clinical manifestations, share overlapping pathophysiological mechanisms, including systemic inflammation, protein misfolding, and vascular dysfunction. VEXAS syndrome, a rare autoinflammatory disorder characterized by somatic UBA1 mutations, systemic inflammation, and hematologic abnormalities, presents primarily in older males. Meanwhile, AD, the leading cause of dementia, involves progressive neurodegeneration driven by amyloid-beta plaques, tau tangles, and chronic neuroinflammation. This article explores potential connections between the two conditions, focusing on inflammation, neurovascular changes and cellular stress. Systemic inflammation observed in VEXAS syndrome may potentiate neuroinflammatory processes in Alzheimer’s disease (AD), as circulating proinflammatory cytokines have the capacity to cross the blood–brain barrier (BBB), thereby inducing glial activation and promoting neuroinflammation. Additionally, coexisting vascular dysfunctions characteristic of both conditions may synergistically contribute to accelerated cognitive decline. Both conditions involve disruption of the ubiquitin–proteasome system, with UBA1 mutations being specific to VEXAS. Given the established role of UBA1 in maintaining neuronal homeostasis, investigating the overlapping and distinct molecular mechanisms may provide valuable insights into their pathophysiology. The review underscores the need for further research to elucidate these links and improve therapeutic strategies, especially for individuals affected by both disorders. Full article

Background: Ankylosing Spondylitis (AS) is a rare autoinflammatory disorder affecting 0.1–1.4% of the population, with increasing recognition over the past 20 years. Although the specific causes of AS remain unclear, the presence of the HLA-B27 gene is associated with increased risk, though only 1–5% of carriers develop the disease. Despite extensive research, no definitive lab tests exist, and many patients are diagnosed years after symptom onset. Methods: In the present study, in order to investigate the disease’s genetic background in correlation with autoimmune diseases, a metanalysis has been performed following PRISMA guidelines using Scopus and PubMed publications towards extracting single-nucleotide polymorphisms (SNPs) of high importance for the disease. Moreover, the polymorphisms have been annotated and analyzed using information from several databases, including PubMed, LitVar2, ClinVar, and Gene Ontology. Results: From 1940 screened titles and abstracts, 57,909 studies were selected, with 539 meeting the inclusion criteria. The genetic background of AS is described through 794 genetic variants, of which 76 SNPs are directly associated with AS (Classes A and B), predominantly located in intronic regions. ERAP1 and IL23R emerged as key genes implicated in AS, while chromosomes 1, 2, and 5 accumulated the most associated SNPs. Functional enrichment revealed strong associations with immune regulation and interleukin signaling pathways, particularly IL6 and IL10 signaling. IL-6 promotes inflammation in AS, while IL-10 tries to suppress it, acting as an anti-inflammatory cytokine. Of the 78 AS-related SNPs, 16 were unique to AS, while 66 were common to autoimmune diseases, especially rheumatoid arthritis (RA) and psoriasis (PsO), suggesting genetic overlap between these diseases. Conclusions: This study creates a comprehensive genetic map of AS-associated SNPs, highlighting key pathways and genetic overlap with autoimmune diseases. These findings contribute to understanding disease mechanisms and could guide therapeutic interventions, advancing precision medicine in AS management. Full article

Background: Germline alleles near genes encoding certain immune checkpoints (CTLA4, CD200) are associated with autoimmune/autoinflammatory disease and cancer, but in opposite ways. This motivates a systematic search for additional germline alleles with this pattern with the aim of identifying potential cancer immunotherapeutic targets using human genetics. Methods: Pairwise fixed effect cross-disorder meta-analyses combining genome-wide association studies (GWAS) for breast, prostate, ovarian and endometrial cancers (240,540 cases/317,000 controls) and seven autoimmune/autoinflammatory diseases (112,631 cases/895,386 controls) coupled with in silico follow-up. Results: Meta-analyses followed by linkage disequilibrium clumping identified 312 unique, independent lead variants with p < 5 × 10⁻⁸ associated with at least one of the cancer types at p < 10⁻³ and one of the autoimmune/autoinflammatory diseases at p < 10⁻³. At each lead variant, the allele that conferred autoimmune/autoinflammatory disease risk was protective for cancer. Mapping led variants to nearest genes as putative functional targets and focusing on immune-related genes implicated 32 genes. Tumor bulk RNA-Seq data highlighted that the tumor expression of 5/32 genes (IRF1, IKZF1, SPI1, SH2B3, LAT) was each strongly correlated (Spearman’s ρ > 0.5) with at least one intra-tumor T/myeloid cell infiltration marker (CD4, CD8A, CD11B, CD45) in every one of the cancer types. Tumor single-cell RNA-Seq data from all cancer types showed that the five genes were more likely to be expressed in intra-tumor immune versus malignant cells. The five lead SNPs corresponding to these genes were linked to them via the expression of quantitative trait locus mechanisms and at least one additional line of functional evidence. Proteins encoded by the genes were predicted to be druggable. Conclusions: We provide population-scale germline genetic and functional genomic evidence to support further evaluation of the proteins encoded by IRF1, IKZF1, SPI1, SH2B3 and LAT as possible targets for cancer immunotherapy. Full article

Background/objectives: Stimulator of Interferon Genes (STING)-associated vasculopathy with onset in infancy (SAVI) is a rare autoinflammatory disorder caused by gain-of-function mutations in the TMEM173 gene. These mutations result in chronic activation of the STING pathway and excessive type I interferon production, leading to systemic inflammation, vascular abnormalities, interstitial lung disease, and skin ulcerations. Janus kinase (JAK) inhibitors, including baricitinib, have shown promise in mitigating systemic and organ-specific manifestations. However, these inhibitors broadly suppress immune pathways, potentially increasing vulnerability to infections. Case presentation: This case report describes a 21-year-old woman with SAVI (due to a heterozygous TMEM173 mutation) who developed disseminated molluscum contagiosum (MC) while receiving baricitinib therapy. Laboratory results revealed lymphopenia, low CD4/CD8 ratio, and impaired immune cell activity, suggesting compromised antiviral immunity. Discussion: Despite SAVI’s association with excessive type I interferon signaling, this chronic hyperactivation may cause immune dysregulation, exhausting T cells and natural killer cells vital for viral defense. Furthermore, baricitinib suppresses interferon signaling via the JAK-STAT pathway, reducing inflammatory damage in SAVI but also impairing antiviral responses. Moreover, MC viruses evade host immune defenses by antagonizing STING and TANK-binding kinase 1-mediated interferon activation, further contributing to infection risk. This report is the first to document MC in a SAVI patient and highlights the rare complication of disseminated MC due to impaired type I interferon signaling and immune suppression from baricitinib therapy. This case underscores the need for vigilance regarding viral infections in SAVI patients treated with JAK inhibitors. Full article

Background/Objectives: Chronic non-bacterial osteomyelitis (CNO) is a rare autoinflammatory disease characterized by chronic sterile uni- or multifocal osteomyelitis. The treatment of CNO is mostly empirical and the outcome of the disease has not yet been standardized. The aims of this study were to correlate clinically active lesions with radiological signs of inflammation and to evaluate the outcomes in terms of symptoms and radiological signs with Whole Body Magnetic Resonance Imaging (WB-MRI) based on the treatment line used. Methods: A retrospective, observational cohort study of 20 CNO patients, recruited from a single tertiary center in southern Italy, was conducted. Patients included in the study were treated based on the “step-up” approach and were guided by the “treat-to-target” strategy as well as by the response to therapy. The outcome measure was stratified into four different groups, defined by a “Delphy consensus”, depending on the symptoms and the presence of bone lesions in WB-MRI, compared with the therapy carried out. Results: Pain was the most common presenting symptom of the disease. Only 15% of our patients reported long-term complications. WB-MRI was performed for each patient both at diagnosis and during follow-up. At onset, the site most affected by the disease was the tibia. All patients who reached a 5-year follow-up (30%, n = 6) achieved a complete disease remission. Conclusions: The standardized “step-up” treatment approach in our cohort proved effective in disease management with disease control or remission in nearly 90% of patients at one year from diagnosis. Full article

Periodic Fever, Aphthous Stomatitis, Pharyngitis and Adenitis (PFAPA) syndrome is an autoinflammatory disorder of unknown genetic etiology typically characterized by recurrent fever episodes, pharyngitis, aphthous stomatitis and cervical lymphadenitis. The syndrome runs a benign course with fever episodes recurring in regular intervals and usually resolves around adolescence, even though, for a subset of patients, it persists through adulthood. It is considered a condition of multifactorial etiology, a syndrome that is triggered by environmental factors in genetically predisposed individuals. Increasing evidence points towards a correlation between monogenic autoinflammatory syndromes and PFAPA syndrome both in pathogenesis and therapeutic approaches. In this review, we present an update of the current literature on PFAPA and focus on new data on genetics of PFAPA and the association of PFAPA with other autoinflammatory diseases. Full article

Inflammatory Bowel Disease (IBD) is a multifactorial gastrointestinal condition encompassing two major forms of intestinal inflammation: Crohn’s disease (CD) and ulcerative colitis (UC). Both conditions are linked to auto-inflammatory reactions and genetic predispositions. Various drug therapies and biological treatments proposed to reduce IBD-associated inflammation. We induced IBD in a mouse model by stimulating bowel inflammation with an oral dextran sodium sulfate (DSS) beverage. Our novel cell therapy approach for IBD involves intramuscular (IM) and intraperitoneal (IP) delivery of non-matched, expanded, potent xenogeneic fetal human mesenchymal stromal cells (f-hPSCs) in 2 × 10⁶ cell injections. This cell therapy has already been shown previously to induce pro-regenerative and anti-inflammatory effects in different systemic and local disorders, where the injected f-hPSCs were shown to respond to the stress of the host and secrete the adequate secretome in response to this stress. In the current study, the IP-injected f-hPSCs treatment of the DSS-induced IBD enhanced the regenerative processes of the damaged bowel and reduced the inflammatory process. This was associated with rapid regain of the mice’s weight and a decrease in inflammation-associated parameters, such as colon edema, bowel shortening, and a threefold increase in bowel mass, as estimated by increased colon weight and reduced length. This ratio best emphasized the induced inflammatory response associated with the decrease in the inflamed colon length with an increase in its mass. Although IM f-hPSCs delivery was somehow effective by a few parameters, the IP delivery produced a superior response. The IP f-hPSCs treated mice lost only ~15% of their weight at the peak of the IBD effect, compared to ~25% in untreated mice. A reduction in the inflammatory response of the gut was also indicated by a decrease in neutrophil infiltration, as assayed by a myeloperoxidase (MPO) assay. Additionally, a significant improvement in the histological score of the gut and faster recovery to 90% of its original size was observed. These findings suggest that f-hPSC treatments could serve as an effective and safe anti-inflammatory and pro-regenerative treatment for IBD. Full article

Familial Mediterranean fever (FMF) is an autoinflammatory genetic disorder characterized by recurrent fevers and inflammation of the serous membranes in the abdomen, lungs, and joints. Currently, the standard treatment of FMF includes colchicine, which is an alkaloid, derived from Colchicum autumnale. Colchicine’s efficacy in FMF is well-established as it is used both to prevent acute attacks and reduce the risk of long-term complications. However, despite these available treatments, 5–10% of patients exhibit resistance to the drug. It has been demonstrated that polymorphisms in several genes involved in inflammation can influence treatment outcomes and the risk of FMF complications like amyloidosis. Among them, some research focused on polymorphism affecting adenosine triphosphate (ATP)-binding cassette sub-family B member 1 (ABCB1) gene encoding for P-glycoprotein. P-glycoprotein is considered a key transporter protein as it regulates the absorption, distribution, and excretion of several drugs, including colchicine. In diseases like FMF, ABCB1 polymorphisms have been shown to affect the response to colchicine, potentially leading to treatment resistance or altered toxicity. Based on this evidence, this systematic review aims to analyze available evidence on ABCB1-mediated colchicine transport and its clinical implications in FMF, showing how relevant ABCB1 variants are in response to therapy. Full article