Search Results (327)

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

Gene therapy involves introducing genetic material into cells to treat or prevent disease and offers highly targeted and potentially curative approaches for both inherited and acquired conditions. The skin is an especially suitable organ for gene therapy due to its accessibility, ease of sampling, rapid cell turnover, and the possibility for localized treatment with minimal systemic exposure. Gene therapy is being actively explored across a range of dermatological conditions, including recessive dystrophic epidermolysis bullosa, ichthyosis, psoriasis, chronic wounds, and melanoma, with therapeutic strategies encompassing viral vectors, non-viral delivery systems, gene editing technologies, RNA-based treatments, and cell-based approaches. These diverse methods aim to correct genetic defects, modulate immune responses, promote tissue repair, or selectively target malignant cells. This review examines the advancements and potential of gene therapies in addressing complex skin diseases, providing hope for improved patient outcomes and long-term care. Full article

Gout, a metabolic and autoinflammatory disease, is the most common form of inflammatory arthritis worldwide. Hyperuricemia may result in monosodium urate (MSU) crystals forming and depositing in joints and surrounding tissues, triggering an autoinflammatory response. Effective urate-lowering therapies, as well as anti-inflammatory medications, are used to treat gout. Over the past few decades, new antihyperglycemic drug classes with different modes of action have been added to treat hyperglycemia in type 2 diabetes mellitus (T2DM). Two of these drug classes, sodium–glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), have reduced cardiovascular and renal events and mortality. Several clinical studies have demonstrated that SGLT2 inhibitors possess urate-lowering properties, which may be beneficial for treating gout patients, particularly those with comorbid T2DM. Regarding SGLT2 inhibitors, some researchers have suggested that their benefits are partly explained by their ability to reduce serum urate (SU) levels, probably through increased urinary uric acid excretion. The effect of GLP-1 RA on SU levels and urinary excretion of uric acid in humans is unclear. This paper reviews the mechanisms of action of SGLT2 inhibitors and GLP-1RA, both approved and in development. Additionally, it examines what is known about their structure–activity relationships, uricosuric effects, pharmacokinetic profiles, and adverse effects. Full article

Background: Deficiency of IL-36 Receptor Antagonist (DITRA) is a rare monogenic autoinflammatory disease, characterized by dysregulation of IL-36 signaling and phenotypically classified as a subtype of generalized pustular psoriasis. Objectives: This study aimed to explore the role of potentially coding and non-coding RNAs (ncRNAs) in the IL36RN interactome to identify putative pathogenic mechanisms, biomarkers, and therapeutic targets for DITRA. Methods: A systems biology approach was applied using the STRING database to construct the IL36RN protein–protein interaction network. Key ncRNA interactions were identified using RNAInter. The networks were visualized and analyzed with Cytoscape v3 and the CytoHubba plugin to identify central nodes and interaction hubs. Pathway enrichment analysis was then performed to determine the biological relevance of candidate ncRNAs and genes. Results: Analysis identified thirty-eight ncRNAs interacting with the IL36RN network, including six lncRNAs and thirty-two miRNAs. Of these, thirty-three were associated with key DITRA-related signaling pathways, while five remain to be validated. Additionally, seven protein-coding genes were highlighted, with three (TINCR, PLEKHA1, and HNF4A) directly implicated in biological pathways related to DITRA. Many of the identified ncRNAs have prior associations with immune-mediated diseases, including psoriasis, supporting their potential relevance in DITRA pathogenesis. Conclusions: This study provides novel insights into the ncRNA-mediated regulation of IL36RN and its network in the context of DITRA. The findings support the potential utility of specific ncRNAs and genes, such as TINCR, PLEKHA1, and HNF4A, as key genomic elements warrant further functional characterization to confirm their mechanistic roles and may inform biomarker discovery and targeted therapeutic development in DITRA. 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

Background: Actinic keratoses (AKs) are common pre-neoplastic lesions that may progress to cutaneous squamous cell carcinoma (cSCC). Photodynamic therapy (PDT) is an effective field-directed treatment for AK, but its impact on key biomarkers remains unclear. This study evaluates the clinical, dermatoscopic, and immunohistochemical effects of PDT on AK, with a focus on proliferation (Ki67, p53) and inflammation (COX-2) markers, to assess its efficacy in delaying carcinogenesis. Methods: In our prospective one-center study, we enrolled 31 patients with AK, with no history of previous AK treatment. They underwent three PDT sessions at four-week intervals, with follow-up eight weeks after the final session. Clinical, dermatoscopic, and immunohistochemical analyses of Ki67, p53, and COX-2 expression were performed before and after treatment. Results: Clinically, 54.8% of patients achieved complete lesion clearance, with no residual severe AK lesions. Ki67 and p53 immunoexpression significantly decreased post-PDT (p < 0.05), confirming its antiproliferative effect. COX-2 expression also declined significantly (p < 0.05), supporting PDT’s anti-inflammatory role. However, COX-2 remained stable or increased in 35.48% of cases, possibly due to inflammation-induced regeneration. There is a positive correlation between the reduction in Ki67, p53, and COX-2 immunoexpression and the decrease in AK severity (both according to Olsen grade and dermatoscopic grade). Conclusions: PDT effectively reduces AK severity, proliferation, and inflammation markers, potentially delaying carcinogenesis. However, residual biomarker expression suggests that additional treatment sessions or combination therapies may be necessary for complete lesion clearance. Further studies are required to optimize PDT protocols. Full article

The extensive research and studies conducted over the past decade have greatly improved our comprehension of the pathogenesis and risk factors associated with Spondyloarthritis (SpA). In addition, they have contributed to the advancement of novel therapeutic approaches. Although genetics still represents the primary risk factor for SpA, increasing evidence presented in this review suggests that environmental factors—such as air pollution, smoking, gut microbiota (GM), infections, and diet—also contribute to its pathogenesis. In detail, environmental particulate matters (PMs), which include ligands for the aryl hydrocarbon receptor—a cytosolic transcription factor responsive to toxic substances—facilitate the differentiation of T Helper 17 (Th17) cells, potentially exacerbating the autoinflammatory processes associated with SpA. Furthermore, smoking influences both the cellular and humoral aspects of the immune response, resulting in leukocytosis, impaired leukocyte functionality, and a decrease in various cytokines and soluble receptors, including interleukin (IL) 15, IL-1 receptor antagonist (IL-1Ra), IL-6, soluble IL-6 receptor (sIL-6R), as well as the vascular endothelial growth factor (VEGF) receptor. Studies have indicated that patients with SpA exhibit an increased prevalence of antibodies directed against a conserved epitope shared by the human leukocyte antigen B27 (HLA-B27)- and Klebsiella nitrogenase, in comparison to HLA-B27-positive controls. Additionally, current evidence regarding the GM suggests the presence of a gut–joint–skin axis, wherein the disruption of the mucosal barrier by specific bacterial species may enhance permeability to the gut-associated lymphoid tissue (GALT), resulting in localized inflammation mediated by Th1 and Th17 cells, as well as IL-17A. Finally, this review discusses the role of diet in shaping the microbial composition and its contribution to the pathogenesis of SpA. A comprehensive understanding of the mechanisms by which environmental factors influence the pathogenesis and progression of the disease could facilitate the development of novel personalized therapies targeting both external and internal environmental exposures, such as the gut microbial ecosystem. Full article

Macrophage activation syndrome (MAS) is a complex, life-threatening, hyperinflammatory condition occurring as a form of hemophagocytic lymphohistiocytosis (HLH), commonly associated with several autoimmune and autoinflammatory diseases, and certain infections such as Parvovirus B19 (P19V). The onset of systemic lupus erythematosus (SLE) presenting as MAS during pregnancy is uncommon, posing significant diagnostic and therapeutic challenges. We present a case of a 30-year-old woman at the 12th gestational week with fever, arthralgia, rash, cervical lymphadenopathy, cytopenia, and elevated liver enzyme. Bone marrow biopsy revealing hemophagocytosis, elevated ferritin and triglycerides, high interleukin-2, fever and cytopenia, confirmed the diagnosis of HLH. Further evaluation revealed the diagnosis of SLE. Treatment was initiated with intravenous immunoglobulin and corticosteroids. Given the deterioration in the patient’s clinical condition, a decision was made to terminate the pregnancy. She continued in the following months to receive SLE treatment with corticosteroids, cyclophosphamide, hydroxychloroquine, and later with mycophenolate mofetil due to the development of Class IV of lupus nephritis. P19V IgM antibodies were initially positive, later seroconverted to IgG, indicating that infection may have acted as a trigger for the onset of SLE and MAS development during pregnancy. The overlapping clinical features of P19V infection, SLE, and MAS pose significant diagnostic and therapeutic challenges. Early recognition and comprehensive diagnostic evaluation are crucial for the management of these conditions, especially during pregnancy, where both maternal outcomes are at risk. 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

Selenium (Se) is an essential micronutrient for antioxidant defense. Selenoproteins are involved in metabolic and signaling pathways of autoimmune and autoinflammatory diseases. Copper (Cu) and zinc (Zn) are integral components of key enzymes and regulatory proteins. Trace element (TE) dysregulations have potential relevance as disease biomarkers. In this study, we compare TE status and TE profiles between patients with axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA), and relate the results to markers of inflammation, remission, and healthy controls. Serum TE was measured using total reflection X-ray fluorescence. The Se transporter SELENOP and extracellular glutathione peroxidase (GPx3) were determined by ELISA and enzymatic assay, respectively. Both groups of patients (axSpA; n = 84, and PsA; n = 76) displayed TE deficiency compared to healthy European adults. Serum Cu, Se, Zn, SELENOP, and GPx3 levels were not different between the groups. The serum Cu and Cu-Zn ratio correlated positively with C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). An inverse correlation of serum Se, Zn, and SELENOP with CRP was observed in axSpA, but not in PsA. On average, all TE, including the inflammation-responsive Cu levels, were below reference ranges, indicating a TE deficiency in both groups. Increasing CRP was associated with low SELENOP levels, suggesting personalized Se substitution as indicated to maintain systemic Se supply and protect from ferroptotic cell loss under inflammatory conditions. 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 and Objectives: Canakinumab, a human recombinant monoclonal antibody against interleukin-1ß (IL-1ß), is indicated for the treatment of selected autoinflammatory periodic fever syndromes and rheumatic diseases. Data on its use during pregnancy remain limited and all are primarily derived from case reports. Although animal studies indicate no evidence of reproductive toxicity, the risk to the fetus or mother remains unknown. This study aims to provide more findings about this important topic. Methods: A retrospective analysis was conducted on three patients followed and treated in the National Center for Periodic Fever Syndromes. Although due to the small sample size, no general conclusions regarding the safety of canakinumab during pregnancy can be drawn. Results: Three maternal-exposed pregnancies were assessed, with no paternal exposure. Diagnoses included mevalonate kinase deficiency, familiar Mediterranean fever and TNF-receptor-associated periodic syndrome. All mothers were treated with canakinumab, and two of those continued the canakinumab treatment during the whole course of pregnancy. The diseases remained under full control during pregnancy, enabling conception in two cases where attempts prior to treatment were unsuccessful. The therapy led to disease control, a reduction in inflammation and subsequently successful conception. One patient underwent IVF repeatedly. All pregnancies resulted in three healthy infants, with no reported miscarriages during the canakinumab-exposed pregnancies, no complications during pregnancies and no serious infections in the newborns. The children had normal development, without any developmental delays or chronic illnesses. Conclusions: The current data, including our findings, indicate no harmful effects of canakinumab during pregnancy. However, because of the scarcity of data, the use of canakinumab during pregnancy should be carefully managed, and women who want to become pregnant should continue treatment only after a thorough benefit–risk evaluation. Full article

Background/Objectives: This study analyzes the impact of PFAPA syndrome (periodic fever, aphthous stomatitis, pharyngitis, and adenitis) on health-related quality of life (HRQoL) and the psychological functioning of children and adolescents aged 2 to 1 years. Methods: A cross-sectional descriptive study was conducted with 62 participants (31 males and 31 females) diagnosed with PFAPA. The Strengths and Difficulties Questionnaire (SDQ) and the Family Impact Module scale of Pediatric Quality of Life Inventory (PedsQL) were used to assess psychological functioning and HRQoL, respectively. Results: Participants exhibited predominantly low HRQoL, particularly in physical health and emotional functioning. School functioning was also affected. However, social functioning and family relationships showed more favorable scores. A positive correlation was observed between age and emotional symptoms. Family concern was the most significantly impacted aspect. Conclusions: PFAPA syndrome has a significant impact on the HRQoL of affected children and adolescents, particularly in physical and emotional aspects. A holistic approach is necessary for disease management, considering not only physical symptoms but also psychosocial and academic factors, as well as the impact on the family. Full article

Rheumatoid arthritis (RA) is a highly prevalent systemic autoimmune disease. Recently, natural small molecules have been explored as alternative therapeutic agents. Iris halophila Pall is the traditional herbal medicine, and it is rich in active ingredients with anti-inflammatory and immunomodulatory effects. In our previous study, LC-MS analysis revealed that piceatannol (PIC) is one of the primary active ingredients in the root of Iris tectorum. The purpose of this study was to explore the immunomodulatory effects of PIC on the maturation and function of dendritic cells, as well as on experimental arthritis induced by complete Freund’s adjuvant (CFA) and incomplete Freund’s adjuvant (IFA). Additionally, we aimed to probe into the potential mechanisms underlying the effects of PIC. We first verified the immunosuppressive effect of PIC using flow cytometry and an ELISA. The immunosuppressive mechanism of PIC on dendritic cells (DCs) was investigated through a joint analysis of network pharmacology and Western blotting. Our findings revealed that under Lipopolysaccharide (LPS)-induced inflammatory conditions, PIC could restrain the maturation and function of DCs (p < 0.001) and decrease the secretion of inflammatory cytokines (p < 0.001) compared to the LPS group. Furthermore, PIC suppressed the activation and polarization of CD4⁺ T cells, resulting in a decreased proportion of Th1 and Th17 cells (p < 0.001), ultimately improving the symptoms of CFA-induced arthritis in comparison to the model group. The PIC-induced shift in the T helper cell differentiation correlated with the secretion of polarizing cytokines from DCs in the AIA model. Mechanistically, PIC exerted its immunosuppressive function mainly by down-regulating the Mitogen-Activated Protein Kinase (MAPK) and Nuclear Factor kappa-B (NF-κB) signaling pathways. Collectively, these data unveil the anti-inflammatory mechanisms of a traditional medicine via the inhibition of the immune activation function of DCs in vivo and open up a therapeutic approach for autoinflammatory diseases. Full article