small molecules

2026-09-24 | The Role of Vitamin D in Noninfectious Uveitis: A Scoping Review with Transcriptomic and Bioinformatic Insights

Vitamin D deficiency has been linked to immune dysregulation and increased risk of autoimmune diseases, including noninfectious uveitis (NIU). This study synthesized evidence linking vitamin D metabolism-related genes and immune mechanisms to NIU and explored transcriptomic pathways potentially modulated by vitamin D signaling. A scoping review of clinical, genetic, and experimental studies evaluating vitamin D status, vitamin D-related polymorphisms, and immunological mechanisms in NIU was conducted following PRISMA-ScR guidelines. In parallel, transcriptomic data from the Gene Expression Omnibus were analyzed using Gene Set Enrichment Analysis to identify immune and inflammatory pathways enriched in NIU subtypes versus healthy controls, focusing on vitamin D signaling and innate immune activation. The review identified consistent associations between hypovitaminosis D and increased risk or severity of NIU across subtypes, including Behçet disease-associated uveitis and HLA-A29-positive birdshot chorioretinopathy. Genetic studies associated NIU susceptibility with polymorphisms in vitamin D metabolism and signaling genes, including DHCR7, GC/VDBP, CYP27B1, and VDR. Transcriptomic analysis revealed enrichment of innate immune and inflammatory pathways, including Toll-like receptor and MyD88-dependent signaling, tumor necrosis factor-related pathways, oxidative stress responses, and dysregulation of immunoregulatory mediators such as interleukin-10, particularly in immune-mediated NIU phenotypes. Integrating scoping review findings with transcriptomic analyses supports a multifactorial relationship between vitamin D status, genetic susceptibility, and immune pathway dysregulation in NIU. Although causality cannot be established, vitamin D deficiency may represent a potentially modifiable factor influencing innate and adaptive immune responses. Prospective and interventional studies are warranted to determine whether vitamin D supplementation can modify disease activity or clinical outcomes.

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2026-09-24 | The MHC-I-opathy architecture: immunogenetic and biomechanical determinants of disease expression.

Major histocompatibility complex class I molecule (MHC-I)-opathies were originally proposed to unify clinically heterogenous diseases such as spondyloarthritis, psoriasis and Behcet's disease, in which MHC class I genetics, endoplasmic reticulum aminopeptidase (ERAP)-dependent peptide processing, barrier dysfunction, mechanical stress and CD8 T‑cell responses intersect. In this review, we argue that this concept has become increasingly defined and should now be considered as a graded pathogenic framework. Within this model, type 17 MHC-I-opathies, including psoriasis and spondyloarthritis, are largely coupled to interleukin (IL)-23/IL-17-driven neutrophilic inflammation, whereas Takayasu arteritis may represent a type 1 MHC-I-opathy in which human leucocyte antigen B*52 (HLA-B*52)-associated antigen presentation converges with IL-12B, interferon gamma (IFNγ), tumour necrosis factor (TNF) and macrophage-driven granulomatous vascular inflammation. Disease expression is shaped not by MHC‑I carriage alone, but by the extent to which multiple genetic, environmental and tissue-specific layers align the HLA/ERAP-mediated peptide repertoire, barrier perturbation, microbiota- or tissue-derived antigenic pressure, biomechanical stress and adaptive CD8 T‑cell effector programmes. The more completely these layers converge, the more likely a disease or patient is to display the characteristic behaviour of an MHC-I-opathy, including earlier onset, recurrent tissue-localised inflammation, broader anatomical involvement and greater severity. This framework moves the field beyond susceptibility odds ratios toward phenotype stratification, prognostic prediction and rational selection of targeted therapies, including cytokine blockade, modulation of antigen presentation and approaches directed at pathogenic CD8 T‑cell repertoires.

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2026-09-15 | Repurposing Lenalidomide for Refractory Behcet's Disease: Systematic Review and Computational Pharmacology Insights for Rare Disease Therapy.

Lenalidomide is an immunomodulatory drug. Its repurposing for refractory Behcet's Disease is a promising strategy. Behcet's Disease is a rare and complex autoinflammatory condition. Current treatment options are limited. This study explored the drug's therapeutic potential using clinical and computational analyses. This study included a systematic review of clinical case reports. Computational methods included toxicological predictions, network pharmacology to screen common targets of lenalidomide and Behcet's Disease, and the construction of protein-protein interaction networks utilizing tools such as ProTox-3.0, ADMETlab 3.0, and Cytoscape. Additionally, molecular docking (AutoDock Vina) and molecular dynamics simulations (GROMACS) were used to assess binding and stability. Clinical data showed low-dose lenalidomide provided rapid symptom relief and appeared to be well tolerated. Computational toxicology revealed a complex, dose-dependent safety profile. Network analysis identified 63 common targets. Seven core genes were found, including IL6, TNF, and JAK1. These genes were enriched in immune pathways, particularly the JAK-STAT cascade. Molecular docking and dynamics confirmed stable binding to key targets like IL6 and JAK1. Lenalidomide appears potentially effective in Behcet's Disease. Its action likely involves multi-target regulation of core immune pathways. Multi-target regulation of the JAKSTAT and TNF signaling cascades directly addresses the core autoinflammatory pathology of Behcet's Disease. The concordance between clinical efficacy and computational findings highlights its repurposing potential. The findings also stress the importance of dose optimization for safety, generating a promising low-dose safety hypothesis. Lenalidomide is a viable repurposing candidate warranting further clinical investigation for refractory Behcet's Disease. This strategy provides a mechanistically supported treatment for this rare disease. Combining network pharmacology and molecular dynamics provides a robust preclinical rationale for repurposing lenalidomide in Behcet's Disease.

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2026-09-09 | Efficacy and safety of upadacitinib in anti-TNF-refractory intestinal Behçet's disease: a single-center retrospective study.

To evaluate the efficacy and safety of upadacitinib in patients with anti-TNF-refractory intestinal Behçet's disease (BD). We conducted a single-center retrospective study using data from a maintained BD registry at Peking Union Medical College Hospital between July 2024 and April 2026. Seventeen consecutive patients were included. Upadacitinib was initiated at a daily dose of 15 mg for all patients, with dose escalation to 30 mg in nine cases due to an inadequate response. The primary end point was a complete remission (CR) at month 6, defined by a composite disease activity index incorporating global gastrointestinal (GI) symptom score and endoscopic evaluation. Secondary endpoints included changes in disease activity index for intestinal Behçet's disease (DAIBD), inflammatory markers, glucocorticoid dosage and safety. At month 6, 50.0% (8/16) of patients who underwent endoscopy evaluation achieved CR based on the composite disease activity index. CR of global GI symptom score was observed in 76.5% (13/17) of patients and mucosal healing in 50% (8/16). Median DAIBD score decreased markedly from 55.0 (IQR 45.0-80.0) at baseline to 0.0 (IQR 0.0-10.0), accompanied by significant reductions in CRP and ESR. Upadacitinib demonstrated a glucocorticoid-sparing effect and was generally well tolerated. Upadacitinib represents a potential therapeutic option for patients with anti-TNF-refractory intestinal BD.

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2026-08-27 | Dexamethasone intravitreal implant (Ozurdex) monotherapy for uveitic macular edema secondary to non-infectious uveitis: a single-center retrospective cohort study.

Uveitic macular edema is a major cause of visual impairment in intermediate, posterior, and panuveitis. Local corticosteroid therapy can control posterior-segment inflammation while avoiding concomitant systemic corticosteroid exposure in selected patients. This study evaluated the anatomical, functional, pressure-related, and durability outcomes of the 0.7 mg dexamethasone intravitreal implant (Ozurdex) used as local monotherapy for macular edema secondary to non-infectious uveitis. This single-center retrospective cohort study included 21 patients (28 eyes) treated between September 2023 and April 2026. Etiologies were idiopathic uveitis in 18 patients and sarcoidosis, Behçet disease, and psoriatic arthritis in one patient each. All eyes were naïve to local ocular therapy for uveitic macular edema, and the dexamethasone implant was administered within 1 week of documented diagnosis. Patients receiving concomitant systemic corticosteroids or systemic immunomodulatory therapy during dexamethasone implant treatment were excluded. Outcomes included best-corrected visual acuity (BCVA), central retinal thickness (CRT), intraocular pressure (IOP), repeat implantation, cataract formation, and time to first treatment failure. Follow-up was assessed at approximately 1, 3, 6, 9, and 12 months. Thirty-three implants were administered in 28 eyes of 21 patients. Seven patients were treated bilaterally because macular edema involved both eyes; the remaining 14 were treated unilaterally because macular edema was present in only one eye. Twenty-five of 28 eyes met SUN criteria for active non-anterior uveitis at baseline. Mean CRT decreased from 407 µm at baseline to 334 µm at 1 month (p = 0.049), 310 µm at 6 months (p = 0.020), and 318 µm at 12 months (p = 0.009). Mean BCVA improved from 0.298 logMAR at baseline to 0.181 logMAR at 1 month (p = 0.023) and remained numerically better at 12 months (0.188 logMAR; p = 0.057). Mean IOP increased from 18.20 to 23.20 mmHg at 1 month (p = 0.001) and subsequently returned toward baseline. Three patients developed an IOP > 30 mmHg; all were controlled with topical IOP-lowering medication, and none required glaucoma laser or surgery. At 12 months, CRT, BCVA, and IOP data were available for 26 of 28 eyes (92.9%). Five eyes received a second dexamethasone implant, generally around 6 months after the first, for persistent or recurrent CME associated with clinically active uveitis. Three eyes developed cataract. Kaplan-Meier analysis estimated first-implant treatment success at 74% between 3 and 6 months and 42% after 9 months. In this selected real-world cohort, dexamethasone implant monotherapy was associated with significant anatomical improvement and early functional improvement, with high 12 month follow-up completeness. The initial implant provided a clinically useful but time-limited treatment effect, and repeat implantation was required in a subset of eyes. These findings support dexamethasone implant as a local treatment strategy for selected patients with uveitic macular edema while emphasizing the need for monitoring of ocular steroid-related adverse effects and individualized long-term inflammatory management.

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cell therapies

2026-08-14 | Case Report: Giant vulvar ulcer caused by Behcet's disease.

Behcet's disease (BD) is a chronic, multisystem autoimmune vasculitis that can cause severe genital ulcers. Giant vulvar ulcers (diameter ≥4 cm) secondary to BD pose significant therapeutic challenges due to their refractory nature, risk of functional impairment, and impact on fertility and aesthetic outcomes. A 19-year-old female presented with a left-sided vulvar ulcer that had persisted for over 4 months and worsened over the preceding 2 months. The patient was diagnosed with a female vulvar ulcer secondary to Behcet's disease and perineal soft tissue infection based on the 2014 International Criteria for Behcet's Disease (ICBD). The patient received intravenous glucocorticoid and antibiotic therapy, followed by pedicled skin flap transplantation, with adjuvant topical Shengji Yuyang ointment for wound care. Following systemic anti-inflammatory therapy, antibiotic treatment, and pedicled flap transplantation combined with topical Shengji Yuyang ointment, the ulcer healed completely within 6 weeks. At 5-month follow-up, no recurrence was observed. However, at month 6, after self-discontinuation of prednisone due to weight gain, a small recurrent ulcer developed, which resolved with topical corticosteroids and oral colchicine. Vulvar ulcers secondary to BD may initially appear mild, but if diagnosis and treatment are delayed, they can rapidly progress, leading to extensive tissue destruction and impairment of genital aesthetics and reproductive function. Early identification and intervention are essential. Pedicled flap transplantation, when combined with adequate preoperative wound preparation, can both accelerate ulcer healing and preserve the aesthetic and functional integrity of the affected area.

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2026-07-31 | Allogeneic haematopoietic stem cell transplantation for refractory perforating intestinal Behçet disease in a patient with aplastic anaemia: A case report.

Aplastic anemia (AA) rarely coexists with intestinal Behçet disease (iBD), and the post-partum period may further complicate its expression. Managing refractory iBD with recurrent perforation on a background of long-standing AA is challenging, and evidence on optimal treatment is limited. A 42-year-old woman with non-severe aplastic anemia (NSAA) diagnosed in 2005 (AA duration ≈ 20 years) developed recurrent fever, oral ulcers, and penetrating ulcers of the ileocaecum and terminal ileum shortly after cesarean delivery in June 2019, with one episode of vulvar ulceration. Histology showed transmural vasculitis with focal obliterative endarteritis, confirming iBD; HLA-B51 was negative. Pre-transplant marrow was markedly hypocellular without dysplasia, and karyotype (46,XX), flow cytometry, myelodysplastic syndrome/AML and myeloproliferative neoplasm gene panels, and paroxysmal nocturnal hemoglobinuria screening were all negative, supporting acquired AA rather than hypoplastic myelodysplastic syndrome. Despite corticosteroids, tacrolimus, tofacitinib, and tocilizumab, she sustained 2 intestinal perforations (May and September, 2023). As iBD was refractory and AA had progressed to very severe AA, she underwent human leukocyte antigen (HLA)-matched sibling peripheral-blood allogeneic hematopoietic stem cell transplantation (allo-HSCT) in June 2024 with fludarabine/busulfan/cyclophosphamide/ anti-thymocyte globulin conditioning. Neutrophil and platelet engraftment occurred around D+11 and D+15, with 100% donor chimerism at D+16 and no acute or chronic graft-versus-host disease; only transient, self-limiting cytomegalovirus (CMV) and Epstein-Barr virus DNAemia occurred, without CMV disease or post-transplant lymphoproliferative disorder. Blood counts recovered progressively, with hemoglobin 127 grams/L and platelets 118 × 109/L at the last follow-up (≈12 months), only mild residual cytopenia, transfusion independence, and sustained remission of iBD on maintenance immunosuppression. She then returned to work and was lost to follow-up. This case suggests that allo-HSCT may be an effective option for selected patients with AA and refractory iBD, achieving sustained remission of both the marrow failure and the intestinal disease. As this is a single case with limited follow-up (≈12 months), longer follow-up and additional cases are needed.

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2026-07-28 | Living Biodrugs and Their Derived Advanced Therapy Medicinal Products to Treat Autoimmune Pathologies

Autoimmune diseases are a broad group of disorders characterized by chronic inflammation and progressive tissue damage, driven by a combination of genetic, environmental, and immune factors. Conventional immunosuppressants and biologics usually only provide partial or temporary effects with risks of toxicity and relapses. On the other hand, mesenchymal stem cells (MSCs) have demonstrated strong immunomodulatory effects, including, but not limited to, suppression of T and B cell activation, induction of regulatory T cells, and conversion of pro-inflammatory M1 macrophages into reparative M2 macrophages. Such properties are mainly mediated by the secretome, a collection of bioactive molecules and extracellular vesicles (EVs, including exosomes), rather than by direct engraftment. Immunomodulatory MSC-derived exosomes (MSC-Exos) contain biomolecules that can enhance tissue repair and control immune responses. In preclinical studies, their efficacy was demonstrated on models of several autoimmune diseases. Furthermore, clinical trials have already reported better remission rates, reduced levels of inflammatory cytokines, and enhanced tissue repair. Compared with whole-cell MSC therapy, MSC-Exos offer superior safety, stability, and adjustability, with lower risks of tumorigenesis and immune rejection. However, significant challenges must be addressed before these treatments can be fully used clinically. This involves improving the consistency of production and testing methods, determining safe and effective doses, and ensuring long-term safety. Precision and power are expected to increase with current developments in bioengineering, priming techniques, and surface modifications. Moreover, the use of biomarkers in the future may help tailor treatments to patients. This review highlights MSC-Exos as an innovative cell-free therapy capable of managing both immune dysregulation and tissue injury, with a particular focus on its effects in Behçet&s;s disease, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and type 1 diabetes.

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2026-07-13 | Supplementary file 1_Two cases of probable Neuro-Behçet syndrome treated with autologous HSCT.pdf

Neuro-Behçet syndrome (NBS) is a rare but detrimental neurological manifestation of the Behçet syndrome (BS) – a chronic multisystemic inflammatory disease. NBS is frequently associated with brainstem and spinal cord lesions, often resulting in substantial neurological disability. Atypical clinical presentations can pose significant challenges for diagnosis and treatment of NBS. Here, we report the clinical course, treatment strategies and responses of two cases with probable NBS. Both cases presented with longitudinally extensive transverse myelitis and brainstem lesions and experienced recurrent relapses as well as disease progression resistant to multiple immunotherapies. Autologous hematopoietic stem cell transplantation (aHSCT) was without beneficial effect on the disease course in both cases. In summary, NBS or probable NBS should be considered in patients with myelitis and brainstem involvement with limited treatment response. These cases illustrate diagnostic challenges and limitations of current diagnostic criteria, while also underscoring the heterogeneity of disease presentation. Immune reset by aHSCT failed to confer clinical benefit as a rescue therapy in these two patients. Further studies are required to optimize therapeutic strategies for NBS.

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2026-06-27 | Variable vessel vasculitis of arteries and veins in VEXAS syndrome.

A man in his 50s receiving immunomodulatory therapy for presumed Behçet's disease presented with odynophagia and jaw pain. Three months earlier, he had developed deep vein thrombosis and extensive superficial phlebitis with transmural inflammation on histopathology. Imaging revealed carotid artery vasculitis and unilateral inflammation around the temporal vessels. Ultrasound demonstrated wall thickening of the right temporal vein with normal temporal arteries. Persistent systemic inflammation and bicytopenia prompted bone marrow examination revealing myelodysplastic syndrome. Detection of a somatic UBA1 mutation confirmed VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic). Glucocorticoids and interleukin-1 blockade were initiated. Due to severe cytopenia, the patient underwent allogeneic haematopoietic stem cell transplantation, resulting in clinical remission. VEXAS causes variable vessel vasculitis, affecting arteries and veins alike even without thrombosis. In older men with myelodysplasia or cytopenia, VEXAS should be considered in the differential of both venous and arterial vasculitis. Ultrasound may distinguish temporal phlebitis from giant cell arteritis.

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antibodies

2026-09-04 | From inflammation to rupture: advances in the pathogenesis of pseudoaneurysm formation in Vascular Behçet's Disease.

This narrative review aims to comprehensively synthesize recent advances in the immunopathological mechanisms and genetic landscape underlying pseudoaneurysm formation in Vascular Behçet's Disease (VBD). We integrate key discoveries from 2010 to 2026 regarding genetic susceptibility, immune cell dysregulation, inflammatory mediator networks, and structural deterioration of the vascular wall. Unlike previous reviews that primarily focused on clinical manifestations and descriptive observations, this article proposes a multilevel pathogenic cascade model linking genetic predisposition to full-thickness vascular wall destruction. We critically evaluate current consensus and controversies, identify unresolved knowledge gaps, and highlight potential strategies for early risk stratification and precision intervention. These insights may provide a theoretical framework for addressing the clinical challenges associated with the high rupture risk and recurrence rate of VBD-associated pseudoaneurysms. At the genetic level, the HLA-B51/ERAP1 axis establishes a fundamental susceptibility background, while non-HLA genes, including TNFAIP3, IL10, and CCR1, contribute to fine-tuning immune regulatory thresholds. At the cellular level, excessive neutrophil NETosis, activation of THBS1high macrophages, aberrant Th17 responses, and disruption of the Treg/effector T-cell balance collectively form a self-amplifying inflammatory network. Notably, THBS1high macrophages have been reported to provide single-cell-level evidence linking immune activation to aneurysm development by driving vascular smooth muscle cell (VSMC) phenotypic switching; however, this finding derives from a single-center exploratory study and awaits independent replication. At the inflammatory mediator level, TNF-α functions as a central driver that cooperates with matrix metalloproteinase (MMP)-mediated extracellular matrix degradation, JAK/STAT signaling, and the IL-23/IL-17 axis to establish a highly interconnected pro-inflammatory signaling network. At the vascular structural level, inflammation propagates from the adventitial vasa vasorum toward the inner vascular layers, accompanied by medial elastic fiber disruption and VSMC phenotypic transition, ultimately resulting in pseudoaneurysm formation. The YAP/TAZ mechanotransduction pathway further reinforces a vicious cycle between vascular expansion and inflammation. Current animal models, including herpes simplex virus (HSV)-induced models and HLA-B51 transgenic models, fail to consistently reproduce vascular phenotypes, representing a major barrier to mechanistic investigation. VBD-associated pseudoaneurysm represents a multilevel pathogenic cascade driven by the interaction of genetic susceptibility, immune cell amplification, inflammatory mediator networks, and progressive vascular wall degeneration. Integrated stratification based on immunological and genetic biomarkers may enable early identification of high-risk patients and facilitate individualized therapeutic strategies. Targeting the THBS1-macrophage axis and the NETs-IL-17A inflammatory circuit may represent a promising direction for precision intervention, although substantial translational barriers remain. Future studies should prioritize the development of vascular phenotype-relevant animal models, conduct dedicated genetic investigations focused on pseudoaneurysm susceptibility, and integrate multi-omics approaches to bridge mechanistic discoveries with clinical translation.

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2026-08-12 | Clinical Use of Interleukin-6 Blockade in Neuroimmunological Disorders.

Interleukin-6 (IL-6) is a multifunctional cytokine that plays a critical role in immune regulation, host defense, and tissue repair. Within the central nervous system (CNS), IL-6 contributes to both neuroprotection and neuroinflammation, depending on the signaling pathway involved; classic signaling, trans-signaling, or trans-presentation. Dysregulation of IL-6, particularly through sustained overexpression, disrupts the blood-brain barrier (BBB) integrity, promotes glial activation, and amplifies chronic inflammation, thereby contributing to the pathophysiology of numerous neurological disorders. This review aims to evaluate the role of IL-6 in neuroinflammatory processes and its clinical implications across a spectrum of neurological diseases. It focuses on the therapeutic potential and safety profile of IL-6 inhibitors, particularly tocilizumab and satralizumab. Key conditions discussed include neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein-associated disease (MOGAD), autoimmune encephalitis (AE), neuro-Behçet's disease (NBD), myasthenia gravis (MG), epilepsy, multiple sclerosis (MS), and Alzheimer's disease (AD). Clinical trials have demonstrated the efficacy of IL-6 receptor blockade in reducing relapse rates in NMOSD, leading to regulatory approvals. Promising off-label results have also been reported in treatment-resistant cases of MOGAD, epilepsy, and autoimmune conditions. However, IL-6 inhibition carries risks such as serious infections and paradoxical inflammatory reactions. Targeting the IL-6 pathway represents a significant advancement in neuroimmunology, offering new therapeutic opportunities for otherwise refractory conditions. Future research should focus on large-scale randomized controlled trials and the development of IL-6 inhibitors capable of crossing the BBB to enhance CNS-specific efficacy. Cost-related accessibility also remains a major challenge for broader clinical application.

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2026-07-26 | A systemic myeloid-driven Th1 hyper-response characterizes inflammatory oral ulceration.

Inflammatory oral ulcers (RAS, Behçet's oral lesions) severely impair quality of life. Local Th1 cytokine upregulation has been reported, yet systemic Th1 polarization, myeloid mediators and clinical correlations remain undefined. While apremilast and anti-TNF-α biologics aid systemic Behçet manifestations, no agents target isolated oral ulcers specifically. Thirty-five ulcer patients (22 RAS, 8 Behçet's with sole oral lesions, 5 traumatic) and 30 matched healthy controls were enrolled. We performed plasma cytokine arrays, PBMC flow cytometry, HOK epithelial functional assays, and correlated Th1 markers with the validated Oral Ulcer Severity Score (OUSS). Longitudinal Th1 changes after topical steroids were assessed in an open-label pilot cohort of 18 patients. Inflammatory ulcer patients showed a dominant systemic Th1 signature (elevated IFN-γ, TNF-α, IL-12; expanded T-bet+ CD4 + T cells), absent in traumatic ulcers and controls. Mild plasma IL-17 elevation lacked matching Th17 cell expansion or epithelial toxicity; Th2 markers were unaltered. Activated CD14 + monocytes drove IL-12 release. Combined IFN-γ/TNF-α synergistically damaged keratinocytes, while IL-4/IL-17 had no effect. T-bet + CD4 + T cells correlated with OUSS (r = 0.68, p < 0.0001), and IFN-γ correlated with ulcer size (r = 0.54, p < 0.01). Post-treatment OUSS dropped by 65%, accompanied by separate significant reductions in T-bet + cells (p < 0.05) and IFN-γ (p < 0.01). Limitations include small subgroups, no ulcer biopsy validation, and uncontrolled longitudinal data prone to spontaneous remission bias. Myeloid-initiated systemic Th1 hyperactivity is a lineage-dominant feature of inflammatory oral ulcers, driving epithelial injury and correlating with severity. Though causal inference is constrained by study limitations, the Th1 pathway represents a rational target for precision therapy.

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2026-07-09 | Impact of systemic autoimmune diseases in maternal, fetal and neonatal outcomes in Spain.

Pregnancy in autoimmune disease is increasingly feasible but carries heterogeneous maternal and perinatal risks beyond hypertensive disorders. We aimed to quantify disease-specific risks of maternal, fetal and neonatal outcomes across autoimmune diseases in a nationwide cohort, explicitly distinguishing primary vs secondary APS. We analyzed pregnancy-related hospitalizations in Spain (SNHDD, 2016-2022). Exposures were systemic lupus erythematosus (SLE), primary Sjögren syndrome (SjS), mixed connective tissue disease (MCTD), systemic sclerosis (SSc), sarcoidosis, Behçet disease, and antiphospholipid syndrome (APS) (primary/secondary). Outcomes included preeclampsia (PE), preeclampsia with severe features (PESC), composite maternal morbidity (cesarean delivery, postpartum hemorrhage, thrombosis, stroke, ICU admission), and composite fetal/neonatal morbidity-mortality (fetal distress, fetal growth restriction, preterm delivery, abruptio placentae, stillbirth, neonatal death). In 1,973 249 Spanish pregnancy hospitalizations, 5,727 involved autoimmune disease. Risks clustered by disease: SLE (PE OR 1.78; PESC 2.17; composite maternal 1.35; fetal/neonatal 1.16), primary APS (PE 1.50; PESC 1.88; maternal 1.66; fetal/neonatal 1.10), secondary APS (PE 2.61; PESC 3.47; maternal 1.94), and MCTD (PE 4.57; PESC 7.24) showed the strongest signals. SSc increased composite maternal (1.62) and fetal/neonatal (1.69) risk; SjS raised cesarean and selected fetal outcomes; Behçet disease mainly increased maternal thrombosis (9.31); and sarcoidosis showed no independent associations. Pregnancies affected by autoimmune disease exhibit distinct, disease-specific patterns of hypertensive, maternal, and fetal/neonatal risk, with the most consistently elevated risks observed in SLE, APS (especially secondary), and MCTD. These comparative estimates may support risk-stratified, guideline-concordant care and inform counseling, surveillance, and delivery planning, with explicit consideration of comorbidity burden.

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2026-07-09 | Integrative single-cell transcriptomics and mendelian randomization identifies BTN3A2 as a shared protective factor in Behçet's disease and inflammatory bowel disease.

Behçet's disease (BD) and inflammatory bowel disease (IBD) are immune-mediated chronic inflammatory disorders. Although they exhibit significant overlap in clinical manifestations and immunological features, whether they share molecular targets and pathogenic links remains unclear. This study aimed to explore the possible linking and shared treatment target between these two diseases. We analyzed scRNA-seq data from the peripheral blood of BD and IBD patients to delineate the immune cell landscape and identify key subsets via differential proportion analysis. Combining expression quantitative trait loci (eQTL) and genome-wide association study (GWAS) data, Mendelian Randomization (MR) analysis was performed to infer causal relationships between the key gene expressions in BD and IBD. Finally, validation was performed using the experimental autoimmune uveitis (EAU) mouse model, external datasets, and blood samples from BD uveitis patients. scRNA-seq analysis revealed a significant decrease in the proportion of CD4+ TEM_TH1-like cells in both BD and IBD. We identified 45 key signature genes within this subpopulation, among which the BTN3A2 gene was identified as a protective one in both BD and IBD. Co-localization analysis indicated spatial consistency between the BTN3A2 eQTL and BD GWAS signals. At the cellular functional level, BTN3A2+ and BTN3A2- CD4+ TEM_TH1-like cells exhibited distinct cell-cell communication networks and pathway enrichment characteristics. The interactions between BTN3A2+ and BTN3A2- cells were mediated by distinct signaling pathways in IBD and BD respectively. The EAU mouse model, which recapitulates BD-like ocular inflammation, was found for the first time to display IBD-like colonic pathological, including inflammatory infiltration, crypt dilation, goblet cell loss, and barrier disruption, accompanied by elevated IL-1β expression. Transcriptomic analysis using EAU mouse retina further revealed that the IBD pathway was one of the most significantly enriched disease-related pathways. Independent external datasets showed a significant downregulation of BTN3A2 at mRNA level in IBD, whereas downregulation of BTN3A2 at mRNA and protein levels was found in BD patients with uveitis. This study identifies BTN3A2 as a shared protective factor in BD and IBD and provides experimental evidence linking BD-associated ocular inflammation to intestinal pathology, establishing a new basis for comorbidity-targeted therapeutic strategies.

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proteins

2026-08-29 | Case Report: From idiopathic recurrent pericarditis to systemic Behçet's Disease: unmasking a unified IL-1-driven autoinflammatory phenotype.

Recurrent idiopathic recurrent pericarditis (RP) is increasingly recognized as an organ-specific autoinflammatory syndrome driven by the interleukin-1 (IL-1) axis. Behçet's Disease (BD), a systemic vasculitis, exhibits significant pathogenetic overlap with RP through IL-1 mediated hyperinflammation, particularly in phenotypes dominated by serositis. The clinical evolution of prolonged, seemingly idiopathic RP into overt, systemic BD upon the tapering of targeted therapy remains a critical, yet underreported, observation. A 42 years old female with corticosteroid-dependent, colchicine-resistant RP achieved complete and sustained clinical and biochemical remission using the IL-1 receptor antagonist, Anakinra, for almost 30 months, despite the tapering started after 18 months of continuous therapy with Anakinra, associated to colchicine and a quick tapering and withdrawal of corticosteroids. Following the elective tapering of Anakinra, the patient remained stable for three months with a dose of an injection of 100mg of Anakinra three times per week, before suffering a severe pericardial relapse concurrent with the systemic onset of systemic BD. The clinical condition observed fulfilled the International Criteria for Behçet's Disease (ICBD), featuring recurrent oral and genital ulcerations, erythema nodosum and a positive pathergy test. The immediate reinitiation of Anakinra (100mg daily) led to the rapid and complete resolution of both the pericardial inflammation and all systemic mucocutaneous manifestations. This case highlights a potential pathogenetic overlap between refractory RP and serositis-dominant BD phenotypes, suggesting that isolated RP may, in select cases, represent an early mono-organ precursor of a systemic autoinflammatory propensity. Furthermore, it provides clinical rationale for considering IL-1 blockade in serositis-dominant BD, though larger prospective studies are needed to confirm these findings.

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2026-06-22 | Type III interferons attenuates Th1/Th17 cell pathogenicity and regulates retinal pigment epithelium cells via NLRP1/NLRP3 signaling axis in autoimmune uveitis.

Accumulating data implicate Type III interferons (IFN-λs) in autoimmune disorders, prompting our exploration of their role in uveitis pathogenesis. Serum and peripheral blood mononuclear cells (PBMCs) from patients with active Vogt-Koyanagi-Harada (VKH) and active Behçet's disease (BD) were analyzed for IFN-λ expression by enzyme-linked immunosorbent assay and real-time quantitative PCR. Experimental autoimmune uveitis (EAU) was induced in IFNLR1-/- mice to evaluate disease severity, inflammatory responses, and blood-retinal barrier (BRB) integrity. RNA sequencing and bioinformatic analyses were performed to identify related genes and associated signaling pathways. IFN-λ levels were significantly elevated in active VKH and BD patients and effectively distinguished them from healthy controls. Compared with wild-type mice, IFNLR1-/- mice developed more severe EAU, characterized by increased Th1/Th17 responses, reduced Treg frequency, and disrupted blood-retinal barrier integrity, which was evidenced by decreased tight junction proteins ZO-1, Claudin-5, and Occludin. Both retinal pigment epithelium (RPE) cells from IFNLR1-/- mice and human primary retinal pigment epithelium (RPE) cells with silenced IFNLR1 secreted higher levels of interleukin (IL)-6, IL-8, IL-1β, and MCP-1, which were suppressed by recombinant IFN-λ1 and IFN-λ2. RNA sequencing revealed an enrichment of T-cell and NOD-like receptor signaling pathways in IFNLR1-/- EAU mice. Consistent with this transcriptional profile, the expression of NLRP3 and NLRP1 was upregulated in RPE cells. Knockdown of these inflammasomes reduced proinflammatory cytokine production and upregulated the tight junction proteins. These results suggest that IFN-λs may alleviate uveitis by targeting RPE cells, primarily through downregulation of NLRP1/NLRP3 inflammasome activity, thereby attenuating inflammatory responses and preserving BRB integrity.

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2026-04-27 | Mapping the peptide interaction fingerprint of the Behçet's disease-associated HLA-B∗51.

The strongest genetic risk factor for Behçet's disease, a relapsing inflammatory disorder marked by recurrent mucocutaneous ulcers and uveitis, is HLA-B∗51:01, a class I major histocompatibility complex (MHC class I) allele that presents intracellular peptides to CD8+ T cells. The molecular mechanisms linking the peptide preferences of this allele to dysregulated immunity remain unclear, limiting efforts to design peptide-based modulators of antigen presentation. Here, we define HLA-B∗51:01's peptide selection rules by mapping the "interaction fingerprint" of 36 self-peptides using an extensive set of all-atom molecular dynamics simulations. These uncovered a conserved hydrophobic-polar blueprint tuned by peptide length. In silico pulling experiments performed at high-speed atomic force microscopy-like loading rates suggest a three-tier hierarchy of mechanical resilience: 9-mers resist the highest forces, 8-mers exhibit intermediate resistance, and 10-/11-mers rupture most easily. Our comprehensive analysis provides an atomistic framework for understanding the molecular mechanisms underlying the HLA-B∗51:01 pathobiology and offers quantitative parameters to guide the design of therapeutic peptides or small molecules to modulate antigen presentation in Behçet's disease.

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2026-04-23 | Single-cell analysis highlights the role of CD4+ IFN-I-related T cells in Behcet's uveitis during Interferonα-2a therapy.

Behcet's disease (BD) involves multiple immune cells, but the mechanism by which interferon α-2a (IFNα-2a) exerts therapeutic effects on BD through immune cell modulation remains unclear. This study aimed to investigate the role of CD4 + IFN-I-related T cells in BD with active uveitis during IFNα-2a therapy. A single-cell atlas of peripheral blood mononuclear cells (PBMCs) was constructed from BD patients with active uveitis, post-4-month IFNα-2a therapy BD patients, active BD patients, and healthy controls (HCs) by integrating in-house and public scRNA-seq data. Bulk mRNA sequencing of CD4 + T cells from active BD patients and HCs was performed for validation. Cell-cell interaction, in vitro coculture, and inhibitor experiments were used to explore the underlying mechanisms. CD4 + IFN-I-related T cells (characterized by high interferon-related gene expression) were significantly decreased in active BD patients but restored after IFNα-2a therapy. The LLT1-CD161 interaction intensity between CD4 + IFN-I-related T cells and NK cells was reduced in active BD and recovered post-therapy. CD4 + IFN-I-related T cells inhibited NK cell activation and IFN-γ secretion via the CD161 receptor. IFNα-2a therapy reverses the decreased frequency of CD4 + IFN-I-related T cells in active BD, which in turn inhibits the inflammatory phenotype of NK cells through LLT1-CD161 interaction, providing new insights into the therapeutic mechanism of IFNα-2a in BD.

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2026-01-08 | Efficacy and safety of low-dose interleukin 2 for Behçet's syndrome: a randomized, placebo-controlled, double-blind, phase 2 clinical trial.

Behçet's syndrome (BS), a chronic vasculitis, leads to recurrent oral ulcers, severely impacting quality of life. Here we report the results of a randomized, double-blind, placebo-controlled trial (NCT04065672) to evaluate the efficacy and safety of low-dose interleukin-2 (LD-IL-2) in BS patients. 60 participants with active oral ulcers are randomly assigned to receive LD-IL-2 or placebo. The primary endpoint is the oral ulcer count at week 12. The LD-IL-2 group has significantly fewer oral ulcers than the placebo group (0.69 ± 1.05 vs. 1.57 ± 0.90, P = 0.001) with greater improvements in ulcer pain, disease activity, and quality of life. No infections or severe adverse events are observed in either group. LD-IL-2 expands regulatory T (Treg) cells and decreased the ratio of effector T cell to Treg cells. Thus, LD-IL-2 therapy might be an effective and safe treatment in BS patients and is associated with the modulation of CD4 + T cell populations.

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2025-08-12 | DNA 5-Hydroxymethylcytosine Landscape and Transcriptional Profile Highlight the TUBB4B-Mediated Th17/Th1/Treg Imbalance in Behçet's Uveitis.

Behçet's uveitis (BU) is an auto-inflammatory disease frequently with a poor prognosis. Here, we performed an integrated analysis of DNA 5-hydroxymethylcytosine (5-hmC) landscape and transcriptomic profiling in CD4+ T cells from active BU patients and healthy controls. We conducted an integrated analysis of DNA 5-hmC modifications and transcriptomic data from CD4+ T cells of active BU patients and healthy individuals. Publicly available single-cell RNA-sequencing data were analyzed to validate findings across cell clusters. Functional experiments were performed to assess the effects of TUBB4B on cytokine production and T-cell frequencies. Bioinformatics analyses identify 801 downregulated and 2489 upregulated differential hydroxymethylated genes, predominantly enriched in pathways related to pathogen defense and various immune responses. RNA sequencing reveals 958 downregulated and 572 upregulated genes, with significant enrichment in pathways related to bacterial infection. Integration of epigenetic and transcriptional data highlights 74 candidate genes and three genes including TUBB4B, SKI and ZFPM1 are validated to be downregulated in active BU patients. Further analysis of publicly available single-cell RNA-sequencing data reveals TUBB4B downregulation across multiple cell clusters, particularly in naïve CD4+ T cells. Functional experiments indicate that overexpressing TUBB4B could decrease the frequencies of IL-17+ and IFN-γ+ CD4+ T cells and reduce the production of IL-17 and IFN-γ, while upregulating the frequency of CD4+CD25+FOXP3+ T cells and enhancing secretion of IL-10. This study underscores the pivotal role of pathogen-induced immune dysregulation in BU development and identifies TUBB4B as a potential therapeutic target for the study on prevention and treatment of this disease.

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2025-05-01 | Comparative expression profiling of Portuguese and Turkish Behçet syndrome patients: Are we looking at the same Behçet?

Background: Behçet syndrome (BS) is a multisystemic inflammatory disorder with an obscure pathogenesis. Inconsistent, sometimes contrasting immunological findings observed in BS studies and considerable geographic variation in BS’s disease expression need explanation. This study compared the gene expression profiles of Portuguese and Turkish BS patients. Methods: Publicly available transcriptome datasets from Portuguese (GSE17114) and Turkish (GSE209567) BS cohorts were retrieved and analyzed. Behçet syndrome patients were grouped as mucocutaneous, ocular, and vascular. Differentially expressed genes (DEGs) were identified using p ≤ 0.05 and fold-changes (FC) ≥1.5 and ≥2. BRB-ArrayTools for class comparisons, Venny 2.1.0 for Venn diagram analyses, Cluster 3.0 and Java Treeview for clustering, and WebGestalt for functional enrichment analyses were used. Results: During the class comparison PB versus TB (PB: Portuguese and TB: Turkish BS patients), 8024 DEGs were documented with an FC ≥2. Venn diagram analysis showed no shared genes at the intersection PB versus PC ∩ TB versus TC (PC: Portuguese and TC: Turkish controls). Both populations demonstrated decreased anti-inflammatory gene expressions, albeit with distinct gene identities. A set of 20 genes including IFI27 successfully clustered PB & TB. No enriched gene ontology terms were shared during functional enrichment analyses. Conclusion: Significant molecular differences exist between Portuguese and Turkish BS patients. Decreased expression of anti-inflammatory genes (e.g., CD69 , CLEC12A , CLC ) is common in BS. The identities of these genes are different across populations. Pro-inflammatory genes (e.g., IFI27 ) may further enhance disease severity in BS. A forthcoming era of personalized therapeutics based on molecular profiles may be approaching for BS. Specifically, CD69 for Portuguese and CLEC12A , CLC , and IFI27 genes for Turkish BS patients, may prove to be promising drug targets for BS.

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2024-09-24 | Regulatory role of the lncRNAs MIAT and PVT1 in Behçet's disease through targeting miR-93-5p and miR-124-3p.

Noncoding RNAs play pivotal roles in the process of autoimmune diseases. However, the definite contributions of these molecules to Behçet's disease (BD) are still unknown. This study aimed to explore the clinical value of a novel competing endogenous (ce) RNA network in the pathogenesis of BD and to assess its use in primary diagnosis. Bioinformatic analysis was applied to construct a BD-related ceRNA network: lncRNA (MIAT and PVT1)-miRNA (miR-93-5p and miR-124-3p)-mRNA (SOD-2 and MICA). Blood was obtained from 70 BD patients and 30 healthy subjects, and the serum expression of the tested RNAs was estimated via quantitative real-time PCR (qPCR). Serum tumor necrosis factor-alpha (TNF-α) levels were also determined. The associations between these RNAs were further analyzed, and receiver operating characteristic (ROC) curve and logistic regression analyses were employed to validate their diagnostic and prognostic values. The expression levels of the lncRNAs PVT1 and miR-93-5p were significantly increased, whereas those of the lncRNAs MIAT and miR-124-3p, as well as those of the SOD-2 and MICA mRNAs, were significantly decreased in BD patients compared with controls. BD patients had significantly higher serum TNF-α levels than controls did. ROC curve analysis indicated that the selected RNAs could be candidate diagnostic biomarkers for BD. Moreover, the highest diagnostic efficiency was achieved with the combination of MIAT and miR-93-5p or PVT1 and miR-124-3p with either SOD-2 or MICA. Logistic regression analysis revealed that all RNA expression levels could be predictors for BD. Mechanistically, our research revealed a novel ceRNA network that is significantly disrupted in BD. The findings reported herein, highlight the noncoding RNA-molecular pathways underlying BD and identify potential targets for therapeutic intervention. These insights will likely be applicable for developing new strategies for the early diagnosis, management and risk assessment of BD as well as the design of novel preventive measures. Trial registration The protocol for the clinical studies was approved by Cairo University's Faculty of Pharmacy's Research Ethics Committee (approval number: BC 3590).

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2024-08-28 | Approaches based on miRNAs in Behçet's Disease: Unveiling pathogenic mechanisms, diagnostic strategies, and therapeutic applications.

Behçet's Disease (BD) is an intricate medical puzzle, captivating researchers with its enigmatic pathogenesis. This complex ailment, distinguished by recurrent mouth and genital lesions, eye irritation, and skin injuries, presents a substantial obstacle to therapeutic research. This review explores the complex interaction of microRNAs (miRNAs) with BD, highlighting their crucial involvement in the disease's pathophysiology. miRNAs, recognized for regulatory influence in diverse biological processes, hold a pivotal position in the molecular mechanisms of autoimmune diseases, such as BD. The exploration begins with examining miRNA biogenic pathways and functions, establishing a foundational understanding of their regulatory mechanisms. Shifting to the molecular landscape governing BD, the review highlights miRNA-mediated impacts on critical signaling pathways like Notch, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and protein kinase B (AKT)/mammalian target of rapamycin (mTOR), offering insights into intricate pathophysiological mechanisms. Dissecting the immunological landscape reveals the profound influence of miRNAs on BD, shedding light on the intricate modulation of immune responses and offering novel perspectives on disease etiology and progression. Beyond molecular intricacies, the review explores the clinical relevance of miRNAs in BD, emphasizing their potential as diagnostic and prognostic indicators. The discussion extends to the promising realm of miRNA-based therapeutic interventions, highlighting their potential in alleviating symptoms and altering disease progression. This comprehensive review, serving as a valuable resource for researchers, clinicians, and stakeholders, aims to decipher the intricate molecular tapestry of BD and explore the therapeutic potential of miRNAs.

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2024-06-18 | miR-141-3p attenuates RSL3-induced ferroptosis and intestinal epithelial-mesenchymal transition via directly inhabits ZEB1 in intestinal Behçet's syndrome.

The aims of this study were to investigate whether the ferroptosis is involved in intestinal Behçet's syndrome (IBS), and to identify if miR-141-3p could attenuate RAS-selective lethal 3 (RSL3)-induced ferroptosis and intestinal epithelial to mesenchymal transition (EMT) via directly inhabits zinc fnger E-box binding homeobox 1 (ZEB1). The expressions of ferroptosis-related proteins in the intestinal tissues of patients with IBS were investigated by immunohistochemistry and quantitative real-time PCR (qRT-PCR). Malondialdehyde (MDA) contents of the intestinal tissues and cells were detected. Serum from IBS patients and RSL3 were co-cultured with intestinal epithelial cells in vitro. In order to investigate whether RSL3-induced ferroptosis can be ameliorated by miR-141-3p, the intestinal epithelial cells were firstly stimulated with RSL3 and then incubated with miR-141-3p mimics. Western blot was used to measure the expression of EMT and ferroptosis-related proteins. Expression of GPX4 (22.51% ± 2.05%, 51.75% ± 3.47%, t =  - 7.77, p = 0.000) and xCT (17.49% ± 1.57%, 28.73% ± 1.75%, t =  - 4.38, p = 0.003) were significantly lower in intestinal mucosal tissues of patients with IBS compared with HC group. Compared with the HC samples, the IBS specimens had significantly higher MDA (t = 4.32, p = 0.01). Moreover, the relative mRNA levels of ferritin light chain (FTL) (t = 4.07, p = 0.02) and ferritin heavy chain (FTH) (t = 8.82, p = 0.001) in the intestinal tissues were significant higher in IBS patients than in HC group. Serum from IBS patients could induce intestinal epithelial cell ferroptosis in vitro. Moreover, miR-141-3p could attenuate intestinal epithelial cell ferroptosis-induced by RSL3 and intestinal EMT via targeting ZEB1 in vitro. Ferroptosis were induced in patients with IBS. Moreover, the serum from IBS patients could induce ferroptosis in vitro. miR-141-3p could attenuate intestinal epithelial cell ferroptosis and intestinal EMT via targeting ZEB1. Therefore, miR-141-3p may open new avenues for the treatment of IBS in the future. Key Points • Ferroptosis in IBS is first reported in this study. • In this study, we explored that the serum from IBS patients could induce ferroptosis in vitro and miR-141-3p could attenuate intestinal epithelial cell ferroptosis and intestinal EMT via targeting ZEB1.

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