Kazushi Izawa

Background: In Japan, general medicine physicians (GMPs) may treat adult patients who have periodic fever associated with autoinflammatory diseases. However, little is known about the status of practice among GMPs in treating these patients. Although prescribing cimetidine is a therapeutic option for periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome, GMPs' prescribing behavior is uncertain. We aimed to investigate: (1) practice among GMPs in treating adult patients with periodic fever associated with autoinflammatory diseases; (2) prescription of cimetidine by GMPs for patients with periodic fever associated with autoinflammatory diseases in general. Methods: A nationwide cross‐sectional study was conducted using an anonymous online questionnaire in May and June 2025. Physicians who were affiliated with three general medicine‐related academic societies in Japan were selected. The questionnaire examined whether respondents had experience treating patients with periodic fever associated with autoinflammatory diseases, current cimetidine prescription practices, the number of patients by age, and respondents' characteristics. Descriptive statistical analysis was performed. Results: We analyzed data from 247 respondents. Of these, 181 respondents reported having experience treating periodic fever. Among respondents, 159 (87.8%) had experience treating familial Mediterranean fever, and more than half had experience treating Behçet's disease or PFAPA syndrome; 31 (17.1%) were currently prescribing cimetidine to 44 patients. Among patients, 32 (72.7%) were aged between 18 and 39 years. Colchicine and corticosteroids were the main concomitant and alternative medications related to cimetidine. Conclusions: The current results describe clinical practice profiles among Japanese GMPs treating adult patients with periodic fever associated with autoinflammatory diseases (250/250 words).

Mutations in the MEFV gene, which encodes pyrin, are associated with a spectrum of inflammatory conditions called pyrin-associated autoinflammatory diseases (PAADs). Of the 400 MEFV variants listed in the Infevers database, most are classified as variants of uncertain significance. Thus, genetic diagnosis of PAADs remains challenging, and the molecular mechanisms underlying pyrin activation remain poorly understood. Here, we used a cell-based pyroptosis assay to stratify 265 missense MEFV variants and identified previously uncharacterized pathogenic variants. We then characterized the interaction between the pyrin B30.2 domain and CDC42, a key regulator of pyrin intracellular trafficking and activation. We found that classical familial Mediterranean fever (FMF)–related variants bind tightly to CDC42 to induce pyrin hyperactivation, whereas certain non-FMF variants induce pyrin hyperactivation independently of CDC42, indicating involvement of multiple pathways in pyrin activation. Our approach provides a proof of concept for a genotype-first approach, which may advance our understanding of complex human diseases.

Heterozygous carboxyl-terminal variants in the RHO guanosine triphosphatase (GTPase) CDC42 are known to cause severe autoinflammatory syndromes. Here, we identified a heterozygous amino-terminal p.T43I (Thr ⁴³ →Ile) CDC42 variant in patients with autoinflammation and uncovered a molecular link between CDC42 and the inflammasome sensor pyrin, mutated in the hereditary autoinflammatory syndrome familial Mediterranean fever. We demonstrate that the region surrounding residue T43 of CDC42 interacts with the carboxyl-terminal B30.2 domain of pyrin and regulates its localization and activation. The p.T43I substitution strengthens the CDC42-pyrin interaction through additional van der Waals interactions, leading to increased pyrin inflammasome activation, as evidenced by increased ASC (apoptosis-associated speck-like protein containing a caspase activating and recruitment domain) speck formation, enhanced pyroptosis, and excessive interleukin-1β (IL-1β) and IL-18 production. These findings identify CDC42 as a pyrin ligand and provide critical insights into the role of the pyrin B30.2 domain in inflammasome activation, suggesting dual regulation of pyrin by two RHO family GTPases, RHOA and CDC42.

In this first randomized, placebo-controlled trial, thalidomide demonstrated potential efficacy and acceptable safety in patients aged 1 year or older with chronic granulomatous disease–related inflammatory bowel disease, suggesting potential as a therapeutic option without increasing the risk of infection.

Aim: Pediatric primary sclerosing cholangitis (PSC) is a rare progressive cholestatic liver disease that often presents diagnostic challenges owing to overlapping clinical and histological features with autoimmune hepatitis (AIH). We hypothesized that anti‐integrin αvβ6 autoantibodies may serve as a noninvasive biomarker to differentiate pediatric PSC from AIH and monitor disease activity. Methods: We retrospectively analyzed serum samples from 65 patients with pediatric‐onset PSC, 39 with AIH, and 66 controls. Anti‐integrin αvβ6 autoantibodies were quantified using enzyme‐linked immunosorbent assay. Functional activity of the autoantibodies was assessed using a solid‐phase fibronectin‐binding inhibition assay. Results: Anti‐integrin αvβ6 autoantibody levels were significantly higher in pediatric‐onset PSC than in AIH and controls. The sensitivity and specificity for distinguishing PSC were 63.9% (95% confidence interval [CI]: 51.4–74.8) and 97.1% (95% CI: 91.9–99.2), respectively. Higher levels were observed in PSC with inflammatory bowel disease than without ( p = 0.0069) and in PSC–AIH overlap compared with AIH alone ( p = 0.0018). In one case, rising autoantibody levels preceded the clinical transition from AIH to PSC–AIH overlap. Levels declined during remission and after liver transplantation; however, increased again upon recurrence. Functional assays demonstrated that autoantibodies from patients with pediatric‐onset PSC inhibited binding of integrin αvβ6 to fibronectin. Conclusions: Anti‐integrin αvβ6 autoantibodies may serve as a noninvasive clinically informative biomarker for distinguishing pediatric‐onset PSC from AIH and reflecting longitudinal changes in disease activity, including posttransplant recurrence. These findings support their potential clinical utility in the diagnosis and longitudinal assessment of pediatric‐onset PSC.

Stimulator of interferon genes (STING) is critical for the type I interferon responses to pathogen- or self-derived cytosolic DNA. STING signalling is terminated by ESCRT-driven lysosomal microautophagy. How STING is directly encapsulated by lysosomes has not yet been understood. Here we show that two lysosomal components, a phosphoinositide PI(3,5)P₂ and CHMP4B (a subunit of ESCRT-III subcomplex) are essential for STING encapsulation by lysosomes. Liposome sedimentation assay reveals that CHMP4B binds to PI(3,5)P₂. The forced recruitment of the catalytic core of Pikfyve (a lipid kinase generating PI(3,5)P₂) to early endosomes, recruits a fraction of CHMP4B to early endosomes. CHMP4B mutant, defective in the binding to PI(3,5)P₂, cannot restore the microautophagic degradation of STING or the resolution of the STING signalling in cells depleted of Chmp4b. Our results reveal a molecular mechanism that terminates innate immune signalling at the lysosomal membrane.

Objective: Cytokine storm syndrome (CSS), commonly associated with hemophagocytic lymphohistiocytosis (HLH), is a fatal hyperinflammatory syndrome. Differentiating the underlying diseases responsible for CSS is essential for timely therapeutic decisions. This study explored the clinical usefulness of serum cytokine profiling in distinguishing underlying diseases in patients with CSS. Methods: Serum samples were collected from 143 adult and pediatric patients with CSS and 22 healthy controls. The cohort included patients with various diagnoses of primary and secondary HLH and Kawasaki disease (KD)‐like hyperinflammatory syndromes. Serum levels of 48 cytokines were analyzed in 97 patients using a bead‐based multiplex immunoassay (Luminex assay). Serum levels of interferon alpha (IFN‐α), interleukin‐18 (IL‐18), IL‐6, CXCL9, and soluble tumor necrosis factor receptor II (sTNF‐RII) were measured in 165 participants using enzyme‐linked immunosorbent assay (ELISA). Results: Luminex assay categorized patients with CSS into five clusters based on serum cytokine patterns. ELISA revealed distinct cytokine patterns, wherein patients with histiocytic necrotizing lymphadenitis‐associated HLH and systemic lupus erythematosus‐associated macrophage activation syndrome (MAS) showed elevated IFN‐α; systemic juvenile idiopathic arthritis–associated and adult‐onset Still's disease–associated MAS, X‐linked inhibitor of apoptosis protein deficiency with HLH, and NLRC4‐associated autoinflammatory disorder exhibited higher IL‐18 levels. Additionally, KD shock syndrome had higher IL‐6 levels than the other groups. CXCL9 was significantly elevated in patients with virus‐associated HLH, familial HLH, malignant lymphoma‐associated HLH, and KD‐MAS. Multisystem inflammatory syndrome in children and toxic shock syndrome also showed moderate elevations of CXCL9 and IL‐6 levels. Conclusion: Serum cytokine profiling effectively differentiates CSS subtypes, facilitating better diagnosis and personalized treatment strategies based on specific disease backgrounds. image

Objective: Cryopyrin‐associated periodic syndrome (CAPS) is an autoinflammatory disease caused by gain‐of‐function mutations in NLRP3 . Although somatic NLRP3 mosaicism is increasingly recognized, it remains unclear how variant allele frequency (VAF) changes over time and whether age at disease onset reflects differences in somatic mutation dynamics. This study aimed to analyze the longitudinal VAF trends and their correlation with clonal hematopoiesis (CH) in patients with CAPS mosaicism. Methods: We analyzed NLRP3 VAF in blood and various tissues, including dried umbilical cord (DUC), using digital polymerase chain reaction and deep amplicon sequencing. Whole‐exome and single‐cell genome sequencing were performed to evaluate CH‐related mutations. Results: We included 15 patients with VAFs of 4.3% to 34.9%. In the 12 early‐onset cases, VAFs were generally consistent across various tissues and did not increase over time, including the DUC. Conversely, in the three late‐onset cases, VAFs were particularly high in myeloid cells. Notably, in one late‐onset case, no mutations were detected in DUC. After disease onset, VAFs exhibited a 2.9% to 10.6% and a 6.2% to 16.4% increase in the whole blood and neutrophils over 6.4 and 4.4 years, respectively, showing a clonal expansion of NLRP3 mutant cells. Single‐cell genome sequencing revealed frequent co‐occurrence of NLRP3 and TET2 mutations in the same cells, with a gradual increase in both VAFs over three years in one late‐onset case. Conclusion: In early‐onset cases, the VAFs were comparable across various tissues and did not increase over time. Mutations in late‐onset cases were enriched in myeloid cells, and VAFs were increased, suggesting a link to CH. image