遺伝性自己炎症疾患

Behçet's syndrome (BS) is a heterogeneous systemic vasculitis characterized by chronic inflammation and immune dysregulation. Growth differentiation factor-15 (GDF-15), a member of the transforming growth factor-β superfamily, has been implicated in chronic inflammatory and immune stress responses. This study aimed to evaluate serum GDF-15 levels in patients with BS and to investigate their relationship with disease activity and clinical parameters. This cross-sectional study included 49 patients diagnosed with BS according to International Study Group criteria, as well as a control group of 33 healthy individuals. Demographic characteristics, clinical features, laboratory parameters, treatments, and disease activity scores were recorded. Serum GDF-15 levels were measured using a commercial enzyme-linked immunosorbent assay. Statistical analyses were performed to compare groups and to evaluate associations between GDF-15 levels and clinical and laboratory variables. In the unadjusted comparison, serum GDF-15 levels were significantly higher in patients with BS than in controls (P = .016). However, GDF-15 levels were not associated with disease activity scores. In multivariable logistic regression adjusting for sex and BMI, GDF-15 was no longer an independent predictor of BS (adjusted P = .53), whereas sex (OR = 5.61, P = .006) and BMI (OR = 0.86, P = .024) remained independently associated with the group, indicating that the unadjusted GDF-15 difference largely reflects demographic confounding rather than a disease-specific effect. No significant correlations were observed between GDF-15 levels and classical acute-phase reactants. This study underscores the importance of recognizing negative biomarker findings to prevent overinterpretation of biomarker utility. Although serum GDF-15 levels were higher in patients with BS in the unadjusted comparison, this difference was no longer statistically significant after adjustment for sex and BMI. GDF-15 levels were also not associated with disease activity, limiting their utility as a disease-specific biomarker. Further longitudinal studies are needed.

AA amyloidosis is the most severe complication of familial Mediterranean fever (FMF). Why some patients develop amyloidosis while genotype-identical relatives remain unaffected is unknown. We assessed whether genetic counseling helps to identify at-risk relatives and whether inflammatory activity, rather than MEFV genotype, drives amyloidosis. We conducted a single-center comparative study (1998-2025) including 52 Algerian FMF probands with biopsy-proven AA amyloidosis and 30 first- or second-degree relatives with biallelic MEFV mutations who also had FMF but no amyloidosis. All underwent clinical, laboratory and MEFV genotyping (exons 2,3,5,10). Only individuals with two MEFV mutations (homozygous or compound heterozygous) were included. Multivariable logistic regression identified independent predictors of amyloidosis. The M694I/M694I genotype was equally frequent in both groups (71.2% vs. 66.7%, p = 0.67). In univariable analysis, it was not associated with amyloidosis (OR 1.23, 95% CI 0.48-3.16, p = 0.67). Independent drivers of amyloidosis were identified by multivariable logistic regression: attack duration > 72 h (adjusted odds ratio [aOR] 3.21, 95% CI 1.41-7.31, p = 0.006), attack interval < 3 months (aOR 4.12, 95% CI 1.77-9.58, p < 0.001), and baseline CRP > 100 mg/L (aOR 2.91, 95% CI 1.23-6.88, p = 0.014). Only 9.6% of amyloidosis patients achieved normalised CRP (< 5 mg/L) under colchicine, compared to 86.7% of relatives (p < 0.001). Strikingly, among amyloidosis patients who achieved CRP normalisation, 57.7% required 1.5 mg/day of colchicine and 7.7% required 2 mg/day, whereas 86.7% of amyloid-free relatives achieved normalisation with only 1 mg/day, highlighting the higher inflammatory burden in patients who develop amyloidosis despite carrying the same MEFV genotype. Genetic counseling allowed screening of 30 relatives without amyloidosis. Inflammation, not MEFV genotype, dictates AA amyloidosis in FMF. Genetic counseling is essential to identify at-risk relatives. Treatment should target complete CRP normalisation regardless of genotype.

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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. SUMMARY: 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.

OBJECTIVES: Systemic autoinflammatory diseases (SAIDs) arise from genetic defects in innate immunity, leading to dysregulated activation of inflammatory pathways, including interleukin (IL)-1, IL-6, TNF, and JAK/STAT. Clinical manifestations range from recurrent fever to severe complications such as encephalitis and AA amyloidosis. Management aims to control inflammation using immunosuppressive agents and targeted monotherapies (biologics or JAK inhibitors). Advanced combination therapy (ACT), defined as the use of biologics and/or JAK inhibitors in combination, has emerged as a strategy for refractory disease. METHODS: In this observational retrospective longitudinal cohort study, patients with SAIDs treated with ACT were included. Demographic, clinical, treatment, and safety data were collected. Treatment response was assessed using a composite outcome incorporating corticosteroid dose, C-reactive protein (CRP), and clinical improvement and categorized as non-response, partial response, or complete response. RESULTS: Thirty-eight patients (median age 30 years [range 4-76]) were included. The most common indications for ACT were pyogenic arthritis, pyoderma gangrenosum and acne (PAPA), mevalonate kinase deficiency (MKD), and undifferentiated SAIDs. Most patients had disease-related complications and were dependent on glucocorticoids and/or opioids to control inflammation and pain, respectively. Following multiple ACT trials, complete response was observed in 21 patients (55.3%), partial response in 12 (31.6%), and no response in 5 (13.1%). Overall, 65 ACT regimens were administered, most commonly combining IL-1 and TNF inhibitors. Thirty-nine regimens were discontinued because of lack of efficacy, secondary loss of response, or adverse events. At the final follow-up, 26 patients (68%) remained on ACT, with a median treatment duration of 60 months (range, 11-186). CONCLUSIONS: ACT offers significant clinical benefits for patients with difficult-to-treat SAIDs, though challenges such as secondary loss of efficacy and infection risks remain.

INTRODUCTION: Magnetic resonance imaging (MRI) is essential for diagnosing neuro-Behçet's disease (NBD). The classic MRI sign typically results from parenchymal NBD lesions in the thalamus, midbrain, and the internal capsule. It may also affect the spinal cord, bilateral basal ganglia, pons, and white matter. Despite its importance, a comprehensive quantitative synthesis of MRI characteristics differentiating NBD subtypes is still needed. This study aimed to compare specific MRI findings, such as brainstem atrophy, enhancing lesions, and anatomical distribution, in acute and chronic progressive parenchymal NBD, with potential implications for prognosis and long-term disease management. METHODS: This systematic review and meta-analysis was conducted according to the PRISMA 2020 guidelines. PubMed, Web of Science, and Scopus were searched from inception to August 2025. Retrospective studies assessing the MRI findings of parenchymal NBD were included. RESULTS: Seven retrospective studies (total n = 327) with parenchymal NBD met the inclusion criteria. The characteristic lesions showed that brainstem atrophy was significantly less in the acute NBD group than in the chronic progressive NBD group (OR = 0.03, 95% CI [0.01, 0.11], p < 0.00001). Contrast-enhancing lesions were significantly more frequent in acute parenchymal NBD, consistent with active inflammatory disease (OR = 2.58, 95% CI [1.04, 6.40], p = 0.04). However, the anatomical distribution of MRI lesions does not differ significantly between acute and chronic progressive NBD. No significant difference was observed between the mild-to-moderate and severe groups in the brainstem (OR = 0.42, p = 0.22) and thalamus (OR = 0.31, p = 0.12). CONCLUSION: Our analysis provides quantitative evidence for distinct MRI characteristics, such as differential brainstem atrophy and enhanced lesion incidence, which may inform NBD subtyping and have implications for prognosis and long-term disease management. However, this meta-analysis is limited by the retrospective nature of the included studies and their potential heterogeneity, necessitating further prospective research to confirm these findings. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD420251178483.