Delayed global standardization and prefectural disparities in systematic lupus erythematosus treatment in Japan: a nationwide study using the National Database of Health Insurance Claims and Specific Health Checkups of Japan.

OBJECTIVES: To evaluate the status of the global standardization of, and prefectural differences in, systematic lupus erythematosus (SLE) treatments in Japan. METHODS: The Japanese National Database of Health Insurance Claims and Specific Health Checkups (NDB Japan) was used. A patient with SLE was defined as having a disease with ICD10 code M321 or M329 between April 2019 and March 2020, for which oral corticosteroids (OCS), immunosuppressive agents or biologic agents were prescribed at least once during a given month. SLE treatments were evaluated by treatment center type and prefecture. RESULTS: In total, 74,277 patients met the definition of SLE. The SLE prevalence was 60 per 100,000 (range: 47 - 102 per 100,000 by prefecture). Nationwide, 79.4% of the patients (range: 52.1% - 93.3% by prefecture) visited a specialized treatment center (STC); 37.4% (range: 26.4% - 51.3% by prefecture) received only OCS, with fewer of these patients visiting a STC than a non-STC (34.8% and 49.7%, p<0.001); and 21.4% (range: 10.7% - 35.0%) received HCQ, with more of these patients visiting a STC than a non-STC (23.0% and 13.5%; p<0.001). CONCLUSIONS: NDB Japan demonstrated delayed global standardization of, and prefectural disparity in, SLE treatments in Japan.

Nationwide epidemiological survey of juvenile idiopathic arthritis during transition to young adulthood in Japan using the National Database of Designated Incurable Diseases of Japan.

Objectives We aimed to assess the unmet medical needs of young adult patients with juvenile idiopathic arthritis by evaluating real-world treatment data. Methods We analyzed data on juvenile idiopathic arthritis in the 20-29 age group from the National Database of Designated Incurable Diseases of Japan, which records severe cases or those requiring high-cost medical care registered between April 2018 and March 2020. Results Overall, 322 patients with juvenile idiopathic arthritis transitioning to adulthood were included. A high frequency of methotrexate use was observed among all juvenile idiopathic arthritis subtypes. The frequency of methotrexate use at registration was significantly higher in patients with rheumatoid factor-positive polyarthritis and those with oligoarthritis or polyarthritis than in those with systemic arthritis. The historical use percentage of any biological disease-modifying antirheumatic drug was ≥85% for all juvenile idiopathic arthritis subtypes. The proportion of patients with ≥2 biological disease-modifying antirheumatic drug prescriptions was significantly higher in patients with rheumatoid factor-positive polyarthritis than in those with systemic arthritis. Conclusions High-cost drugs were necessary for many patients with juvenile idiopathic arthritis transitioning to young adulthood and registered in the database. Further studies on the medical interventions and support for these patients are needed.

Inherited CARD9 Deficiency Due to a Founder Effect in East Asia.

Autosomal recessive CARD9 deficiency can underly deep and superficial fungal diseases. We identified two Japanese patients, suffering from superficial and invasive Candida albicans diseases, carrying biallelic variants of CARD9. Both patients, in addition to another Japanese and two Korean patients who were previously reported, carried the c.820dup CARD9 variant, either in the homozygous (two patients) or heterozygous (three patients) state. The other CARD9 alleles were c.104G > A, c.1534C > T and c.1558del. The c.820dup CARD9 variant has thus been reported, in the homozygous or heterozygous state, in patients originating from China, Japan, or South Korea. The Japanese, Korean, and Chinese patients share a 10 Kb haplotype encompassing the c.820dup CARD9 variant. This variant thus originates from a common ancestor, estimated to have lived less than 4,000 years ago. While phaeohyphomycosis caused by Phialophora spp. was common in the Chinese patients, none of the five patients in our study displayed Phialophora spp.-induced disease. This difference between Chinese and our patients probably results from environmental factors. (161/250).

Lymphadenitis caused by Purpureocillium lilacinum in a patient with CARD9 deficiency.

We hereby make the first report of a case of mycosis caused by Purpureocillium lilacinum in CARD9 deficiency. A 40-year-old woman complained of lymph node swellings in the left cervical area. She also had chronic mucocutaneous candidiasis (CMC), and was found to have CARD9 deficiency. Lymphadenitis by P. lilacinum was confirmed. The diagnosis was difficult, as culturing the biopsy specimen at a cautiously selected temperature (25 °C) and genetic analysis were both required. Oral administration of voriconazole improved her lymphadenopathy.

In-depth proteomic analysis of juvenile dermatomyositis serum reveals protein expression associated with muscle-specific autoantibodies.

OBJECTIVES: The clinical symptoms and complications of JDM differ depending on the type of muscle-specific autoantibodies (MSAs) present. We aimed to identify protein expression profiles specific for MSAs that characterize various clinical features by comprehensively analyzing the proteins present in the serum of patients with JDM. METHODS: We analysed sera from patients with JDM that were positive for anti-melanoma differentiation-associated protein 5 (MDA5) antibodies (n = 5), anti-nuclear matrix protein 2 (NXP2) antibodies (n = 5) and anti-transcriptional intermediary factor 1 alpha or gamma subunit (TIF1-γ) antibodies (n = 5), and evaluated healthy controls (n = 5) via single-shot liquid chromatography-tandem mass spectrometry (MS) in data-independent acquisition mode, which is superior for comparative quantitative analysis. We identified different protein groups based on MSAs and performed pathway analysis to understand their characteristics. RESULTS: We detected 2413 proteins from serum MS analysis; 508 proteins were commonly altered in MSAs, including many myogenic enzymes and IFN-regulated proteins. Pathway analysis using the top 50 proteins that were upregulated in each MSA group revealed that the type I IFN and proteasome pathways were significantly upregulated in the anti-MDA5 antibody group alone. CONCLUSION: Although JDM serum contains many proteins commonly altered in MSAs, the pathways associated with clinical features of MSAs differ based on protein accumulation. In-depth serum protein profiles associated with MSAs may be useful for developing therapeutic target molecules and biomarkers.

Epidemiology conduction of paediatric rheumatic diseases based on the registry database of the Pediatric Rheumatology Association of Japan.

OBJECTIVES: Although epidemiological surveys of paediatric rheumatic diseases in Japan have been conducted, they were single surveys with no continuity. This is the first report of the Pediatric Rheumatology Association of Japan registry database, which was established to continuously collect data for paediatric rheumatic diseases. METHODS: Pediatric Rheumatology International Collaborate Unit Registry version 2 (PRICUREv2) is a registry database established by the Pediatric Rheumatology Association of Japan. The registry data were analysed for the age of onset, time to diagnosis, sex differences, seasonality, and other factors. RESULTS: Our data showed the same trend regarding rates of paediatric rheumatic diseases reported in Japan and other countries. The age of onset was lower in juvenile idiopathic arthritis (JIA) and juvenile dermatomyositis and higher in systemic lupus erythematosus and Sjögren's syndrome. The time to diagnosis was relatively short in JIA and systemic lupus erythematosus but longer in juvenile dermatomyositis and Sjögren's syndrome. Rheumatoid factor-positive polyarticular JIA showed a seasonality cluster with regard to onset. CONCLUSION: PRICUREv2 aided the retrieval and evaluation of current epidemiological information on patients with paediatric rheumatic diseases. It is expected that the data collection will be continued and will be useful for expanding research in Japan.

Social independence evaluation index for Japanese patients with childhood-onset chronic diseases.

Introduction: This study established an independent evaluation index for patients with childhood-onset chronic diseases in Japan. Methods: From November to December 2020, three Delphi rounds were conducted. Thirty-nine participants completed at least one survey. We asked them about targets of social independence for 10 types of activities (education/labor/finance/acquisition of necessities/housing/transportation/leisure/social relationship/intimate relationships/sexuality). The Delphi technique was to be repeated until a consensus of over 80% of participants was reached. Results: The targets chosen for measuring independence in patients with childhood-onset chronic diseases were as follows: "Graduation from high school," "Labor for livelihood (including temporary turnover)," "Financially independent (including temporary turnover, excluding students)," "Buy or rent a house and buy the daily necessities and get the public services you need to live," "Do housework alone," "Plan alone and use transportation to get around," "Participate in play/recreation/leisure activities on own initiative," "Engage in relationships with other people outside of a limited environment (home, school, office, hospital, etc.)," "Create and maintain intimate or romantic relationships between individuals (couples, lovers, sexual partners)," and "Use or know how to use contraceptives and how to prevent sexually transmitted diseases." Conclusions: We established an independent evaluation index for patients with childhood-onset chronic diseases in Japan through a three-round Delphi process. The assessment of social independence using our independent evaluation index may help plan for and provide appropriate support and assistance to these patients.

In-Depth Serum Proteomics by DIA-MS with In Silico Spectral Libraries Reveals Dynamics during the Active Phase of Systemic Juvenile Idiopathic Arthritis.

In serum proteomics using mass spectrometry, the number of detectable proteins is reduced due to high-abundance proteins, such as albumin. However, recently developed data-independent acquisition mass spectrometry (DIA-MS) proteomics technology has made it possible to remarkably improve the number of proteins in a serum analysis by removing high-abundance proteins. Using this technology, we analyzed sera from patients with systemic juvenile idiopathic arthritis (sJIA), a rare pediatric disease. As a result, we identified 2727 proteins with a wide dynamic range derived from various tissue leakages. We also selected 591 proteins that differed significantly in their active phases. These proteins were involved in many inflammatory processes, and we also identified immunoproteasomes, which were not previously found in serum, suggesting that they may be involved in the pathogenesis of sJIA. A detailed high-depth DIA-MS proteomic analysis of serum may be useful for understanding the pathogenesis of sJIA and may provide clues for the development of new biomarkers.

Phenotypes of atopic dermatitis up to 36 months of age by latent class analysis and associated factors in Japan.

BACKGROUND: Atopic dermatitis (AD) in early childhood is the first allergic manifestation in the atopic march. Recently, latent class analysis (LCA) has revealed the presence of AD subgroups in childhood. OBJECTIVE: This study aimed to elucidate different AD phenotypes up to 36 months of age and identify factors associated with a particular AD phenotype in early childhood. METHODS: Pediatric allergists or dermatologists examined children who visited local public health centers in Chiba or Yokohama city at 4, 18, and 36 months of age for regular health checkups between 2003 and 2005. LCA was used to identify AD subtypes on the basis of the course of skin symptoms and comorbidity of other allergic diseases. After LCA, the association between genetic and environmental factors and AD phenotypes was assessed. RESULTS: A total of 1,378 children who underwent the 3 checkups were included. Complete data were available for 515 children up to 36 months of age. Of 515 children, 183 were diagnosed with AD at least at one out of the 3 time points. The LCA model of these children with AD separated 4 AD phenotypes: early-persistent (EP), early-transient (ET), late-onset (LO), and variable (V). Antibiotic use by 4 months of age was significantly higher in EP group than in other 3 groups. Mother's allergy was significantly higher in EP and LO groups than in other 2 groups. Passive smoking at 18 months of age was higher in LO group than in other groups. Furthermore, >80% of V group was born in spring-summer. CONCLUSION: We identified 4 AD phenotypes using LCA on the basis of the onset/course of AD and comorbidity of other allergic diseases and also identified several factors related to the particular phenotypes, which may be useful markers for the prediction of prognosis of AD in early childhood.

Checklist for rapid assessment of independence in children with pediatric rheumatic diseases in transition to adult medical care.

OBJECTIVES: The Committee for Support of Transition to Adult Medical Care, Pediatric Rheumatology Association of Japan, has developed a checklist for patients with pediatric rheumatologic diseases to evaluate readiness for transition to adult medical care. METHODS: Using checklists for general pediatric chronic diseases developed by researchers at the Ministry of Health, Labour and Welfare, committee members discussed points for modification or addition specific to pediatric rheumatic diseases and pediatric rheumatism clinical practice. RESULTS: Three patient-assessment checklists based on patient age and understanding level and a parent-assessment checklist were developed. The checklist for junior high school students and above included a 'Health Education in Adolescence and Young Adulthood' section with items related to sexual knowledge and concerns. Also, items on oral medications and subcutaneous injections management in the 'Self-management of Daily Medical Care,' domain and next medical visits management were added. The checklist for junior high school students included 30 items in seven domains and can be completed within 10 minutes. The checklist was given to 28 children with pediatric rheumatic diseases aged 10 years and older and their mothers. CONCLUSION: The checklist was developed to share the challenges of independence during transition with patients and parents.

Transitioning from paediatric to adult rheumatological healthcare: English summary of the Japanese Transition Support Guide.

Issues related to transitioning from paediatric to adult healthcare are currently receiving international attention. In Japan, 1000 patients with childhood-onset chronic rheumatological diseases reach adulthood every year and require transition from care by paediatric to care by adult rheumatologists. Here, we propose a guide for the latter, wherein the adult caregiver poses the clinical questions about transitional support that they need to have answered, and the paediatric caregiver mainly compiles the plans for the transition. To formulate the guide, we sought comments from both the Japan College of Rheumatology and the Pediatric Rheumatology Association of Japan and obtained their approval. Here, we present the outcome of this consultation in the form of a Guide for Supporting Transitional Care, aiming to provide essential knowledge to physicians in the fields of adult internal medicine and orthopaedics who may be involved in treating patients with rheumatic disease during the transition from paediatric to adult care. The features of transitional support that are common for patients with various different rheumatic diseases are presented in this guide, with the aim of informing policy and strategies to deliver optimal outcomes in transitional care by non-paediatric rheumatologists.

A variant in human AIOLOS impairs adaptive immunity by interfering with IKAROS.

In the present study, we report a human-inherited, impaired, adaptive immunity disorder, which predominantly manifested as a B cell differentiation defect, caused by a heterozygous IKZF3 missense variant, resulting in a glycine-to-arginine replacement within the DNA-binding domain of the encoded AIOLOS protein. Using mice that bear the corresponding variant and recapitulate the B and T cell phenotypes, we show that the mutant AIOLOS homodimers and AIOLOS-IKAROS heterodimers did not bind the canonical AIOLOS-IKAROS DNA sequence. In addition, homodimers and heterodimers containing one mutant AIOLOS bound to genomic regions lacking both canonical motifs. However, the removal of the dimerization capacity from mutant AIOLOS restored B cell development. Hence, the adaptive immunity defect is caused by the AIOLOS variant hijacking IKAROS function. Heterodimeric interference is a new mechanism of autosomal dominance that causes inborn errors of immunity by impairing protein function via the mutation of its heterodimeric partner.

Dysregulation of the Intestinal Microbiome in Patients With Haploinsufficiency of A20.

INTRODUCTION: Haploinsufficiency of A20 (HA20) is a form of inborn errors of immunity (IEI). IEIs are genetically occurring diseases, some of which cause intestinal dysbiosis. Due to the dysregulation of regulatory T cells (Tregs) observed in patients with HA20, gut dysbiosis was associated with Tregs in intestinal lamina propria. METHODS: Stool samples were obtained from 16 patients with HA20 and 15 of their family members. Infant samples and/or samples with recent antibiotics use were excluded; hence, 26 samples from 13 patients and 13 family members were analyzed. The 16S sequencing process was conducted to assess the microbial composition of samples. Combined with clinical information, the relationship between the microbiome and the disease activity was statistically analyzed. RESULTS: The composition of gut microbiota in patients with HA20 was disturbed compared with that in healthy family members. Age, disease severity, and use of immunosuppressants corresponded to dysbiosis. However, other explanatory factors, such as abdominal symptoms and probiotic treatment, were not associated. The overall composition at the phylum level was stable, but some genera were significantly increased or decreased. Furthermore, among the seven operational taxonomic units (OTUs) that increased, two OTUs, Streptococcus mutans and Lactobacillus salivarius, considerably increased in patients with autoantibodies than those without autoantibodies. DISCUSSION: Detailed interaction on intestinal epithelium remains unknown; the relationship between the disease and stool composition change helps us understand the mechanism of an immunological reaction to microorganisms.

Clinical practice guidance for Sjögren's syndrome in pediatric patients (2018) - summarized and updated.

There are a considerable number of pediatric patients with Sjögren's syndrome (SS); however, SS is generally considered rare among children. Pediatric patients with SS report fewer sicca symptoms; therefore, many are under-diagnosed and cannot access appropriate medical management. Therefore, we propose a newly developed guidance for the diagnosis, treatment, and management of pediatric SS, including epidemiology, clinical features, and diagnostic examination methodology. The aim of this guidance was to standardize the medical care of pediatric SS in Japan, and we published the Japanese version by YODOSHA in 2018. This article is the English version, which is summarized and updated. This guidance will need to be revised in the near future as additional clinical data become available.