Ryuta Nishikomori

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).

In Japanese infants aged ≤12 months at risk for severe RSV-associated lower respiratory tract infections who received two doses of nirsevimab 5–6 months apart, no safety concerns or anti-drug antibodies occurred. Nirsevimab serum concentrations were consistent with those previously demonstrated to be efficacious in healthy preterm and term infants.

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

Objectives: To assess the real-world safety and effectiveness of canakinumab, a monoclonal anti-interleukin-1β antibody, in patients with cryopyrin-associated periodic syndrome (CAPS) in a real-world setting in Japan. Methods: All patients with CAPS who received canakinumab treatment after drug approval in Japan were registered in a post-marketing all-patient surveillance with 2-year observation period and a follow-up period of up to 5 years. Results: Of 93 patients in the safety analysis set, the proportion of patients with any adverse drug reactions (ADRs) and any serious ADRs was 33.33% and 4.30%, respectively. The most common ADRs were infections and infestations (21.51%). Of 70 new and 18 continuing patients (roll-over from a previous clinical trial) in the effectiveness analysis set, the proportion of responders among new and continuing patients, who achieved both clinical and serological remissions, was 78.57% and 83.33%, respectively, at Week 24. Most responders remained without relapse after the remission until Week 104 (98.11% of new and 100% of continuing patients). Clinical symptoms related to auditory, joint, visual, renal, and central nervous system maintained or improved in the majority of patients. Conclusions: Canakinumab was well-tolerated and effective during long-term treatment for patients with CAPS in the real-world setting.

Objectives: Chronic nonbacterial osteomyelitis (CNO)/chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory disorder characterised by aseptic inflammation of bone tissue. The number of patients and the clinical picture of CNO/CRMO in Japan are unknown; therefore, we conducted the first nationwide epidemiological survey. Methods: In the primary survey, the number of patients diagnosed with CNO/CRMO between 2015 and 2019 in paediatrics, rheumatology, orthopaedic surgery and dermatology departments of various institutions was investigated. In the second survey, the clinical pictures of these patients were assessed. Results: The primary survey reported 289 patients, and the estimated number of patients nationwide was 434 (95% confidence interval, 367–501). The second survey analysed 205 patients. The median number of radiological bone lesions was three and the bone affected most frequently was the tibia. Tumour necrosis factor inhibitors showed higher efficacy and lower relapse rates than non-steroidal anti-inflammatory drugs or bisphosphonates. Cases that responded to tocilizumab and canakinumab were also reported. Earlier diagnosis was associated with higher rates of symptom- or drug-free status at the last follow-up visit. Conclusions: This is the first nationwide study in Japan, and one of the largest multi-centre studies worldwide, to provide comprehensive epidemiological data about CNO/CRMO.

Patients with autoimmune and autoinflammatory diseases experience difficult physical, mental, and social situations and have various unmet medical needs. To provide appropriate solutions for these patients, an accurate understanding of their unmet medical needs is necessary. Patient-reported outcomes (PROs) reflect the problems of patients and are highly likely to be useful in understanding patient needs. This article reviews established PRO measures from the perspective of determining those appropriate for identifying the unmet medical needs of patients with autoimmune and autoinflammatory diseases. To consider appropriate PRO measures, discussions were held by experts at the Ministry of Health, Labor and Welfare group meetings. The possibility of developing a method to collect PRO data electronically using information and communication technology was also considered. The experts proposed 28 measures, both disease-specific and non-disease-specific, as candidates. It was confirmed that linguistic validation was important and that measures obtained from adults and children could not be considered together. A migration from paper to digital PRO measures was not conducted due to the need for ensuring accuracy and the shortage of technical and financial support. Appropriate non-disease-specific PRO measures were considered to be the KINDL® and EQ-5D-Y for children and the SF-36v2® and EQ-5D™ for adults.

We aimed to gather real-world clinical evidence of detailed disease activity, treatments, remission rates, and adverse events (AEs) associated with vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome in a prospective study. Patients in Japan suspected of having VEXAS syndrome were enrolled in a registry study. A novel disease activity measure (VEXASCAF) assessing 11 symptoms associated with VEXAS syndrome was evaluated at enrolment and after 3 months. AEs, survival, CRP levels, and treatments were also recorded at enrolment and 3 months after enrolment. All exons of UBA1 were sequenced using a next-generation sequencer to determine the variant allele frequencies of pathogenic variants in the peripheral blood of all patients. Of the 55 registered patients, 30 patients were confirmed to have pathogenic variants of UBA1. All patients were male, with a median age of 73.5 years. VEXASCAF and CRP levels decreased significantly at 3 months post-enrolment, but the oral prednisolone dose did not change. Only two patients achieved complete remission according to FRENVEX at 3 months after enrolment. During the observation period of 6 months, 28 AEs were observed, including 3 deaths, 4 malignancies from two cases, 2 thromboses, and 13 infections (including 4 mycobacterial infections). Inflammation of the lung and cervical region (i.e. parotid and submandibular gland swelling, tonsillitis, cervical swelling, and pain) were the most common AEs. Patients with VEXAS syndrome required high-dose glucocorticoids to achieve remission, and complications—such as malignancy, thrombosis, and infection—occurred frequently within a short observation period.