Background: Haploinsufficiency of A20 (HA20) is an immune dysregulation disorder caused by loss-of-function TNFAIP3 mutations. This international multicenter study aimed to delineate its clinical spectrum, genetic basis, and natural history. Methods: A cross-sectional, retrospective analysis was conducted in HA20 patients with pathogenic or likely pathogenic TNFAIP3 variants. Clinical, laboratory and treatment data were assessed. Clustering analysis was applied to evaluate clinical features and disease phenotypes. Patients were stratified by age (< 16 years vs ≥ 16 years), country of origin (China vs U.S.), and gender. Results: A total of 185 patients from 41 clinics across 7 countries were included (median onset 3.3 years). Common clinical features were mucocutaneous involvement (80.5%), recurrent fever (63.3%), gastrointestinal symptoms (58.6%), cytopenias (56.6%), arthritis/arthralgia (46.7%), and recurrent infections (35.5%). Compared with adults and patients from the U.S. cohort, intestinal ulcers were significantly more frequent in children and patients from the Chinese cohort (P = 0.002 and P < 0.0001, respectively), whereas uveitis was less common in these groups (P = 0.001 and P < 0.0001, respectively). Hierarchical clustering of clinical disease phenotypes based on Pearson distance identified two major clusters, an autoinflammation-predominant phenotype and an autoimmune-predominant phenotype. The autoinflammation-predominant phenotype was more common in children and patients from the Chinese cohort (P = 0.033 and P = 0.003, respectively). A total of 89 pathogenic TNFAIP3 mutations were identified, including 46 novel variants. Large deletions were associated with neurologic disease and developmental delay (P = 0.0054 and P = 0.0245, respectively); however, there were no clear association between disruptions of specific functional A20 domains and onset age or phenotype. Therapeutically, TNF and IL-1 inhibitors were effective in most patients, with thalidomide and JAK inhibitors used in refractory cases; 51.5% had achieved minimal disease activity at the most recent follow-up. Conclusions: HA20 is a common dominantly inherited immune dysregulation disorder with phenotypic heterogeneity and potential age-dependent evolution. This large international cohort highlights diagnostic and therapeutic strategies to advance evaluation and management of HA20. ### Competing Interest Statement WG and GY are employees of Chigene (Beijing) Translational Medical Research Center Co. Ltd and Beijing Quanpu Medical Laboratory Co., Ltd. DMS receives consulting fees from Sobi and grant support from Sobi and Eli Lilly. The others declare no competing interest. ### Funding Statement T.H. received grant 82302056 from the National Natural Science Foundation of China. Q.Z. received grants 82225022, 32141004 and 32321002 from the National Natural Science Foundation of China and 2024YFC2511002 from the National Key Research and Development Program of China. J.Y. received grant SZSM202411012 supported by Sanming Project of Medicine in Shenzhen. D.M.S. received grants by Jeffrey Modell Foundation, Eli Lilly, Sobi, Samuel and Emma Winters Foundation. J.W received grants 82394420, 82394423, 82402121 from the National Natural Science Foundation of China and grant 2023M733104 from China Postdoctoral Science Foundation. S.W. received grant 82402118 from the National Natural Science Foundation of China. L.G. received the grant LHDMY23H100005 from Joint Funds of the Zhejiang Provincial Natural Science Foundation of China. X.Y. received the grants 82394420, 82394424 and 82471844 from the National Natural Science Foundation of China, the Hundred-Talent Program of Zhejiang University, grant 2021R01012 from Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang and Key Technology Breakthrough Program of Ningbo Sci-Tech Innovation YONGJIANG 2035 (Grant No. 2024Z221). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee/IRB of Shenzhen Children's Hospital and University of Pittsburgh gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study and not in the manuscript are available upon reasonable request to the authors

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare immunodeficiency characterized by increased vulnerability to weakly virulent mycobacteria. However, its clinical and molecular spectrum, as well as its susceptibility to infections beyond mycobacteria, remains incompletely understood. To evaluate the clinical and genetic characteristics of MSMD patients, focusing on their susceptibility to mycobacteria, SARS-CoV-2 and endemic fungal infections. Thirteen MSMD patients underwent genetic analyses, immunological assays, and clinical evaluations. COVID-19 outcomes were documented. Pathological findings and mNGS confirmed Talaromyces marneffei infections. Following BCG vaccination, 92.3

ObjectiveJuvenile systemic sclerosis (jSSc) is a rare but serious rheumatic disease in children that significantly impacts growth and development. This study aimed to summarize the clinical characteristics and disease patterns of jSSc and to evaluate the treatment response over an 11-year period at our center.MethodsTwenty-one pediatric jSSc patients treated at our center from January 2015 to December 2025 were retrospectively analyzed. Classification was based on the 2013 American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) systemic sclerosis classification criteria. Overall disease severity and multiorgan activity were assessed using the Juvenile Systemic Sclerosis Severity Score (J4s; range 0–40), while skin involvement was specifically evaluated using the modified Rodnan skin score (mRSS; range 0–51). The median follow-up duration was 2.3 years (range 0.5–7.2 years). Paired t-tests and Wilcoxon signed-rank tests were used to compare pre- and posttreatment parameters, with p < 0.05 considered statistically significant.ResultsTwenty-one patients were enrolled. Skin sclerosis was the most common symptom (100.0%). Antinuclear antibody (ANA) was positive in 16 cases (76.2%), with anti-single-stranded DNA (anti-ssDNA) antibody being the most common specific antibody (23.8%), followed by anti-PM-Scl antibody (19.0%). Glucocorticoids and methotrexate were commonly used as initial therapies. After a median treatment duration of 24 months, overall disease severity (J4s) significantly decreased (5.94 ± 1.66 vs 2.67 ± 2.22, p = 0.003), and skin involvement (mRSS) also improved significantly (10.0 ± 9.21 vs 7.42 ± 8.26, p = 0.008). Fourteen patients received biologic agents, with 11 using tocilizumab. During the follow-up, no deaths or serious adverse events occurred.ConclusionsjSSc is a rare and severe multiorgan disease with unique autoantibody profiles in Chinese children. The J4s and mRSS serve as objective assessment tools for evaluating overall disease severity and skin involvement, respectively, and are effective in monitoring treatment response. Early diagnosis and individualized therapy, including the adjunctive use of tocilizumab, may improve clinical outcomes.

BackgroundSpondyloenchondrodysplasia with immune dysregulation (SPENCD) is a rare autosomal recessive disorder caused by biallelic ACP5 mutations and is characterized by skeletal dysplasia, neurological involvement, and immune dysregulation. According to the latest International Union of Immunological Societies (IUIS) classification, SPENCD is categorized as an inborn error of immunity within the autoinflammatory disorders spectrum; however, targeted therapeutic strategies for immune manifestations remain limited.MethodsWe conducted a multicenter study including five patients from India and from Chongqing and Tianjin, China. Whole-exome sequencing identified six ACP5 variants across the five patients, including four novel variants. The diagnosis of SPENCD was established based on the genetic findings in combination with characteristic clinical features and radiological manifestations. Three patients received treatment with Janus kinase (JAK) inhibitors. In one representative treated patient (Patient 1), immunological parameters before and after treatment were evaluated using flow cytometry and quantitative PCR.ResultsFour novel ACP5 variants were identified in this cohort. All three patients treated with tofacitinib (a JAK inhibitor) showed variable but overall clinical improvement. In one representative patient, immunological changes were observed after treatment, including a reduction in CD21low B cells and changes in T helper cell subsets.ConclusionThis study expands the spectrum of ACP5 mutations and provides clinical and immunological observations suggesting JAK inhibitor therapy may be considered for immune dysregulation in patients with SPENCD.

OBJECTIVES:To describe diagnostic framework classification, treatment patterns and outcomes in Kawasaki disease-associated macrophage activation syndrome (KD-MAS) using a single-centre cohort and a structured descriptive synthesis of published cases to inform hypothesis generation and future refinement of diagnostic and management strategies for KD-MAS. METHODS:We performed a retrospective single-centre cohort study. MAS was classified by haemophagocytic lymphohistiocytosis (HLH)-2004, HLH-2009 or 2016 systemic juvenile idiopathic arthritis (sJIA)-MAS criteria. Data were abstracted around a prespecified MAS window; severity was indexed by haemophagocytic syndrome diagnostic score (HScore) and the association between HScore and treatment escalation was assessed using Firth's logistic regression. In parallel, we conducted a literature review. RESULTS:In our centre, incidence was 0.6% (22/3786); mean age was 3.72 years; coronary involvement was 77.2%. The proportions of clinician-diagnosed KD-MAS cases fulfilling each framework were HLH-2004 14/22, HLH-2009 18/22 and 2016 sJIA-MAS 20/22; 11 met all three. Cytopenias, liver dysfunction and coagulopathy were frequent; management followed stepwise escalation from intravenous immunoglobulin (IVIG) or corticosteroid monotherapy to IVIG plus corticosteroids and, when required, to adjunct immunosuppressive/biologic therapy; similar patterns appeared in the literature. HScore was higher with intensified therapy than with standard therapy (median 274 vs 199; p=0.020). Each 10-point HScore increase was associated with higher odds of escalation (OR 1.44 univariable; 1.37 adjusted). CONCLUSION:The 2016 sJIA-MAS criteria demonstrate the highest proportion fulfilling criteria in our cohort for KD-MAS. Treatment in our cohort and in published cases generally reflected a stepwise, typically progressing from IVIG±glucocorticoids to adjunct immunosuppressants/biologics. Higher HScores co-occurred with escalation, suggesting they capture baseline severity; prospective multicentre studies are needed to test incremental value and risk-stratification thresholds.

IntroductionELF4 is an ETS family transcription factor involved in immune regulation, including antiviral responses and inflammatory signaling. Germline loss-of-function variants in ELF4 cause deficiency in ELF4, X-linked (DEX), a disorder characterized by recurrent mucocutaneous inflammation and variable immune abnormalities. To date, ELF4-related disease has been reported only in association with germline mutations. Here, we report a pediatric patient with autoinflammatory disease harboring a truncating ELF4 variant (c.239T>A, p.L80*).MethodsClinical and genetic evaluations were performed in the patient and his family. The ELF4 c.239T>A variant was assessed by Sanger sequencing in peripheral blood and buccal mucosa samples. ELF4 protein expression was examined in patient-derived cells and ectopic expression of wild-type and mutant ELF4 constructs in HEK293T cells by immunoblotting. Full-length single-cell RNA sequencing was performed on whole-blood leukocytes to compare mutant-assigned and wild-type-assigned immune cells within the same individual.ResultsAn ELF4 truncating variant (c.239T>A, p.L80*) was detected in peripheral blood but was not detected in parental blood samples or the patient’s buccal mucosa by Sanger sequencing. Given the limited sensitivity of Sanger sequencing, the developmental origin and tissue distribution of the variant could not be definitively determined. A reduced full-length ELF4 signal was observed in patient-derived PBMCs and in the p.L80* HEK293T overexpression system, together with impaired transcriptional activity in an IFN-β promoter reporter assay. Single-cell transcriptomic analysis identified cells with p.L80*-supporting transcripts across multiple immune lineages and suggested cell type-specific transcriptional alterations. Pathway analyses indicated reduced antiviral and interferon-related programs in mutant-assigned NK cells. Exploratory analysis of mutant-assigned CD16+ monocytes also suggested inflammation-related pathway alterations, although the limited number of allele-informative cells warrants cautious interpretation.ConclusionsELF4 is an ETS family transcription factor that plays an important role in immune regulation. Our study identifies a functionally impaired ELF4 p.L80* variant in a pediatric patient with autoinflammatory disease and provides preliminary evidence of cell type-specific transcriptional alterations associated with this variant.

ObjectivesComprehensive ultrasound effectively assesses synovitis in juvenile idiopathic arthritis (JIA) but is time-consuming. Existing simplified scores apply a uniform joint combination to all subtypes, overlooking the differences between the oligoarticular (oJIA) and polyarticular (pJIA) forms. We aimed to develop subtype-specific simplified ultrasound systems to improve clinical efficiency.MethodsIn this prospective study, 83 patients with active oJIA (n = 42) or pJIA (n = 41) underwent a standardized 68-joint grayscale and Power Doppler assessment. Subtype-specific models were constructed using data-driven stepwise selection to ensure 100% patient coverage. Primary endpoints were diagnostic performance for high disease activity (according to the Juvenile Arthritis Disease Activity Score-27, JADAS27) and numerical agreement.ResultsExamination time was reduced by approximately 67% (∼13 vs. 38.8 min). The oJIA model required 4 joint pairs (elbows, knees, ankles, MCP1); although its correlation with systemic activity was limited by localized disease, it showed excellent numerical agreement with the comprehensive score, supporting its use for monitoring. The pJIA model (6 joint pairs: elbows, wrists, hips, knees, PIP3, PIP5) showed superior diagnostic performance for high disease activity (AUC = 0.88) compared with the all-patient model (AUC = 0.67), and a strong correlation with JADAS27 (rs = 0.68, P < 0.001).ConclusionsSubtype-specific simplified ultrasound systems substantially reduce examination time while maintaining accuracy. The pJIA model effectively grades disease activity, whereas the oJIA model provides a reliable, efficient tool for longitudinal monitoring. This individualized approach optimizes workflow efficiency in pediatric rheumatology.

BackgroundRefractory juvenile idiopathic arthritis (JIA) remains difficult to manage, particularly in patients with persistent disease activity despite multiple conventional synthetic disease-modifying antirheumatic drugs and biologic agents. Telitacicept is a dual inhibitor of B-cell activating factor and a proliferation-inducing ligand, but its use in JIA has not been well described.Case presentationWe report three pediatric patients with refractory JIA treated with telitacicept. Case 1 was a 6-year-old girl with extended oligoarticular JIA who presented with recurrent swelling, pain, and limited motion of multiple joints, and elevated inflammatory markers after previous treatment with methotrexate, leflunomide, adalimumab, and intra-articular glucocorticoids. After switching to telitacicept combined with tofacitinib and methotrexate, joint symptoms and inflammatory markers improved, and an ACR70 response was achieved; clinical improvement was maintained during 12 months of follow-up. Case 2 was a 17-year-old boy with RF-positive polyarticular JIA and long-standing active disease involving the wrists and small joints of the hands. After telitacicept was added to background therapy, joint swelling resolved, inflammatory markers normalized, and ACR90 response was achieved during 9 months of follow-up. Case 3 was an 11-year-old boy with systemic JIA whose systemic manifestations had been controlled but who continued to have predominant polyarticular involvement. After telitacicept initiation, wrist swelling and inflammatory markers improved during the first 2 months, and an early ACR90 response was observed; however, relapse occurred at month 3 with recurrence of systemic symptoms, leading to discontinuation of telitacicept. No serious adverse events were observed. One patient developed a mild upper respiratory tract infection that resolved with symptomatic treatment.ConclusionThese cases provide preliminary clinical observations on telitacicept use in refractory JIA. BAFF/APRIL inhibition may warrant further investigation in selected patients with refractory JIA, particularly those with persistent articular involvement; however, prospective controlled studies are needed to evaluate efficacy and safety.

BackgroundGermline monoallelic gain-of-function (GOF) variants in NFKBIA, encoding IκBα, cause a rare immunodeficiency syndrome classically described as autosomal-dominant anhidrotic ectodermal dysplasia with immunodeficiency. However, the pathogenic spectrum of variants within the N-terminal hotspot and the extent to which distinct alleles converge on shared immunologic phenotypes are not fully defined.MethodsWe studied four unrelated patients with de novo heterozygous NFKBIA variants (p.G33D, p.M37R, p.M37K, p.D31H), including two novel alleles (p.G33D and p.D31H). Clinical and immunological phenotyping, T-cell and B-cell subset analysis, and CFSE-based lymphocyte proliferation assays were performed. Functional consequences were assessed by TNF-α-induced IκBα degradation in patient PBMCs and by NF-κB dual-luciferase reporter assays in HEK293T cells expressing wild-type or mutant IκBα. A comprehensive literature review of all previously reported NFKBIA GOF cases was performed.ResultsClinical severity ranged from recurrent sinopulmonary infections onset in adolescence to severe infantile multisystem disease with bacterial, fungal, and opportunistic infections. All patients exhibited ectodermal abnormalities, and one had autoantibodies. Despite marked clinical heterogeneity, all four patients showed a qualitatively convergent lymphocyte phenotype characterized by expanded naïve T-cell and B-cell compartments and reduced memory and effector subsets. PHA-induced CD4+ and CD8+ T-cell proliferation was preserved in P1 and P3, whereas anti-CD3/CD28-induced T-cell proliferation, assessed only in P3, was impaired, while B-cell proliferation was preserved in the tested patients. Patient PBMCs exhibited markedly delayed or minimal TNF-α-induced IκBα degradation, and all four mutant proteins more strongly suppressed TNF-α-induced NF-κB reporter activity compared to wild-type IκBα. Baseline expression of the IκBα-EGFP fusion proteins was comparable across wild-type and all four mutant constructs.ConclusionThese findings broaden the clinical and genotypic spectrum of N-terminal IκBα GOF disease, identify a consistent immune phenotype characterized by expanded naïve and contracted memory lymphocyte compartments, and support defective regulated IκBα degradation and impaired lymphocyte maturation as shared features of N-terminal IκBα GOF disease.

BACKGROUND:Haploinsufficiency of A20 (HA20) is an immune dysregulation disorder caused by loss-of-function TNFAIP3 mutations. This international multicenter study aimed to delineate its clinical spectrum, genetic basis, and natural history. METHODS:A cross-sectional retrospective analysis was conducted in HA20 patients with pathogenic or likely pathogenic TNFAIP3 variants. Clinical, laboratory, and treatment data were assessed. Clustering analysis was applied to evaluate clinical features and disease phenotypes. Patients were stratified by age (<16 years vs ≥16 years), country of origin (China vs United States), and sex. RESULTS:A total of 185 patients from 41 clinics across 7 countries were included (median age at onset, 3.3 years). Common clinical features were mucocutaneous involvement (80.5%), recurrent fever (63.3%), gastrointestinal symptoms (58.6%), cytopenia (56.6%), arthritis/arthralgia (46.7%), and recurrent infections (35.5%). Compared with adults and patients from the US cohort, intestinal ulcers were significantly more frequent in children and patients from the Chinese cohort (P = .002 and P < .0001, respectively), whereas uveitis was less common in these groups (P = .001 and P < .0001, respectively). Hierarchical clustering of clinical disease phenotypes based on Pearson distance identified two major clusters, an autoinflammation-predominant phenotype and an autoimmune-predominant phenotype. The autoinflammation-predominant phenotype was more common in children and patients from the Chinese cohort (P = .033 and .003, respectively). A total of 89 pathogenic TNFAIP3 mutations were identified, including 46 novel variants. Large deletions were associated with neurologic disease and developmental delay (P = .0054 and .0245, respectively); however, there were no clear associations between disruptions of specific functional A20 domains and age at onset or phenotype. Therapeutically, TNF and IL-1 inhibitors were effective in most patients, with thalidomide and JAK inhibitors provided in refractory cases; 51.5% had obtained minimal disease activity at most recent follow-up. CONCLUSIONS:HA20 is a common dominantly inherited immune dysregulation disorder with phenotypic heterogeneity and potential age-dependent evolution. This large international cohort highlights diagnostic and therapeutic strategies to advance evaluation and management of HA20.

Genome-wide association studies (GWAS) have pinpointed a multitude of risk loci associated with Juvenile Idiopathic Arthritis (JIA), but it is challenging to decipher novel plasma proteins. To address this, we applied an integrative omics pipeline to uncover novel proteins associated with JIA risk. In this research, we utilized an integrative omics method to identify new plasma proteins associated with JIA. Complementary results from an independent cohort were analyzed through Whole Genome Sequencing (WGS), single-cell RNA sequencing (scRNA-seq), and bulk RNA sequencing (bulk RNA-seq) at the Children's Hospital of Chongqing Medical University to validate the reliability of the identified novel proteins. Additionally, to assess the therapeutic potential of novel proteins, we performed Phe-WAS and conducted an extensive review of existing literature using PubMed and Web of Science. An integrative omics pipeline analysis identified ERAP2 as having putatively causal effects on JIA. In the fourth step of Summary-data-based Mendelian randomization analysis, we discovered that the SNP rs2927608 and rs2910686 can regulate the expression of the ERAP2 gene, thereby regulating the protein content of both ERAP2 and ERAP1. WGS analysis also detected two potentially pathogenic mutations on ERAP2 in sJIA patients. ScRNA-seq reveals that ERAP2 expression is significantly elevated in patients with sJIA compared to normal and other subtypes, particularly in monocytes. Bulk RNA-seq with ROC analysis demonstrating significant diagnostic power (AUC = 0.86, 95

This retrospective observational study aimed to evaluate the effectiveness and hepatoprotective effects of combination therapy with tocilizumab (TCZ) and total glycosides of peony (TGP) in treating systemic juvenile idiopathic arthritis (sJIA). Among the 119 sJIA patients enrolled, 49 received TCZ combined with TGP (study group) and 70 received TCZ not combined with TGP (control group). We compared clinical characteristics, 5 liver function indices (alanine aminotransferase [ALT]/aspartate aminotransferase [AST]/alkaline phosphatase/γ-glutamyltransferase/total bilirubin), transaminase (ALT/AST) Kaplan-Meier curves, and inflammatory indices between the groups. The study group showed significantly lower rates of abnormal ALT, AST, alkaline phosphatase, and γ-glutamyltransferase levels (P < .05). Among patients with abnormal liver function indices, transaminase abnormalities were the most common (87.50%), particularly after the first TCZ administration (44.64%). Analysis of Kaplan-Meier curves for transaminases for different treatment durations indicated significantly lower abnormal rates (ALT/AST > 1 and 3 × upper limit of normal) in the study group (P < .05). The Cox regression model and forest plot identified the group with the highest risk ratio (study group vs control group, hazard ratio = 3.985, 95% confidence interval: 1.997-7.952) as an independent risk factor for transaminase abnormalities. A comparison of therapeutic outcomes revealed a more obvious decrease in the number of patients with abnormal inflammation indices in the study group before and after treatment. Moreover, the erythrocyte sedimentation rate value in the study group at the last follow-up significantly lower than that in the control group (P < .05). The combination of TCZ and TGP effectively reduced inflammation and lowered the incidence of liver injury, suggesting it may be the preferred combination therapy for sJIA.

The study aimed to analyze the single-cell transcriptomes of immune cells in juvenile idiopathic arthritis (JIA) patients to understand the cellular heterogeneity within the immune system. Peripheral blood samples from fourteen JIA patients and four healthy individuals were subjected to single-cell RNA sequencing. Various subtypes of JIA were included in the patient cohort. Functional analyses, such as pseudotime trajectories and cell communication studies, were conducted to uncover immune cell changes in JIA patients. Results showed disrupted interferon and acute inflammatory responses in most cell types of JIA patients, with particularly intense responses in systemic JIA (sJIA) patients versus non-sJIA patients. Pseudotime analysis of CD4+ T, CD8+ T, B, and myeloid cells revealed that the functions of each cytokine production, cytotoxicity, and the processing and presentation of antigens were progressively strengthened, while the regulation of nuclear factor kappa B (NF-κB)-related pathways was weaker in CD4+ T and CD8+ T cells than in non-JIA. Reclustering analysis of myeloid cells highlighted interferon-related functions predominantly in non-classical monocytes of sJIA patients. Additionally, cell communication analysis identified unique ligand-receptor pairs in sJIA, suggesting potential roles in disease progression. In conclusion, interferon disorders are evident across various immune cell types in JIA patients, with stronger responses observed in sJIA patients. The ligand-receptor pairs involving migration inhibitory factor (MIF) and CXCR7/CD44 may contribute to differing joint symptoms between sJIA and non-sJIA patients. Moreover, non-classical monocytes and the CXCR2 receptor in MIF signaling may play crucial roles in sJIA progression.

BackgroundUNC13D deficiency is the most common form of familial hemophagocytic lymphohistiocytosis (FHL) in Asia. Hypogammaglobulinemia is a rare phenotype observed in both patients with FHL3 and sporadic hemophagocytic lymphohistiocytosis (HLH). Our observations suggest that UNC13D deficiency with hypogammaglobulinemia presents a distinct clinical phenotype compared to other HLH patients. This finding provides valuable clinical insights and may contribute to a more comprehensive understanding of the disease, highlighting the need for further investigation into its genetic and clinical characteristics.MethodsWe retrospectively analyzed the clinical features of five patients with UNC13D deficiency with hypogammaglobulinemia at our center, along with a literature review. The clinical findings were then compared with those of sporadic HLH patients presenting with hypogammaglobulinemia.ResultsAll patients experienced respiratory infections, with two patients showing recurrent episodes. Seizures were observed in 75% of the patients. HLH-related biomarkers were present in all patients. The four patients who did not undergo allogeneic hematopoietic stem cell transplantation (HSCT), all died. Eight variant sites were identified, with 25% located in exon 9 and another 25% in exon 20. The majority (66.67%) of the variants were found in the region responsible for interaction with RAB27α. UNC13D deficiency with hypogammaglobulinemia was associated with a higher frequency of respiratory manifestations, neurological involvement, and an increased mortality rate.ConclusionsOur study presents the first comprehensive description of the clinical features of UNC13D deficiency with hypogammaglobulinemia. Patients with this condition tend to exhibit more severe clinical manifestations and a poorer prognosis. Allogeneic HSCT may help mitigate immune dysregulation.

Background:Management of juvenile idiopathic arthritis (JIA) relies heavily on long-term pharmacotherapy, yet an increasing number of case reports suggest that some drugs may themselves precipitate or worsen the disease. But systematic methods for detecting these safety signals in pediatric cohorts are still lacking. Methods:We screened 10,012,438 reports from the FAERS database using four disproportionality algorithms (ROR, PRR, EBGM, and BCPNN) to identify potential drug and JIA associations. Three complementary machine learning models were developed, including DMPNN, GCN, and SVM, trained on molecular descriptors, chemical fingerprints, and structural graphs to stratify high-risk compounds. Toxicogenomic profiles were generated using ProTox-3.0, and drug-disease target overlap and pathway enrichment were assessed using the CTD and GeneCards databases. External validation relied on our own newly generated transcriptomic data: (i) our newly generated bulk RNA-seq dataset from 47 individuals (39 JIA patients and 8 controls) and (ii) a multi-center single-cell RNA-seq compendium that combined 21 in-house PBMC profiles obtained at four Chinese pediatric hospitals with 9 publicly available systemic juvenile idiopathic arthritis (sJIA) samples. Two of the in-house sJIA patients were sampled longitudinally, before and one month after IL-6-receptor-inhibitor therapy permitting assessment of treatment-induced transcriptomic shifts. Drug-signature activity was quantified with single-sample GSEA for the bulk data and AddModuleScore for the single-cell data. Results:We identified drugs with consistent positive signals across all four FAERS-based disproportionality algorithms. Machine learning models (DMPNN, GCN, SVM) independently confirmed 23 high-risk compounds, with 22 overlapping across all models and predicted risk scores >0.60. Among these, lansoprazole and aripiprazole showed strong signals in both pharmacovigilance and DMPNN predictions. Further toxicogenomic analysis revealed immune toxicity patterns overlapping with JIA-related gene targets and pathways. Notably, bulk RNA-seq and single-cell RNA-seq validation demonstrated that lansoprazole signatures were significantly enriched in monocyte from sJIA patients. This multi-level convergence supports the hypothesis that certain non-antirheumatic drugs may aggravate JIA-like inflammation, particularly within the systemic subtype. Conclusions:In this study, we identify lansoprazole as a likely instigator of systemic juvenile idiopathic arthritis, underscoring that proton-pump inhibitors should be used judiciously in children at autoimmune risk and providing a generalizable playbook for rare-disease pharmacovigilance.

Objective:Systemic juvenile idiopathic arthritis (sJIA) and reactive arthritis (ReA) share overlapping clinical features, posing diagnostic challenges. Early differentiation is critical for treatment decisions but lacks reliable biomarkers. This study aims to identify simple clinical indicators and develop a clinical prediction model to distinguish sJIA from ReA. Methods:This study retrospectively included clinical data of 397 sJIA patients and 290 ReA patients who attended the Children's Hospital of Chongqing Medical University from 2016-2024. Key predictors were identified by ANOVA, chi-square tests, univariate logistic regression, multivariate logistic regression, and stepwise analysis. The diagnostic model was established and validated by performing ROC analysis. Furthermore, we additionally included data from 20 sJIA and 20 ReA patients from two other centers to validate the above results. Results:A total of 19 statistically different clinical indicators were identified by ANOVA and chi-square tests. These indicators were included in univariate and multivariate logistic regression analyses, lower albumin levels and significantly higher levels of gamma-glutamyl transferase (GGT) were found in sJIA patients compared to ReA in both the training and validation sets (p values were all < 0.05). In a stepwise analysis of age, gender, inflammatory cells (lymphocytes, monocytes) and inflammatory markers, it was found that albumin and GGT were still effective in differentiating between the two diseases. Clinical prediction models were developed using albumin and GGT, with AUCs of 0.842 (training) and 0.849 (validation), showing excellent diagnostic effect. These indicators also demonstrated good diagnostic efficacy in cohorts from two other centers. Conclusion:Albumin and GGT are important clinical indicators for differentiating sJIA from ReA. The albumin-GGT prediction model provides a simple, clinically feasible tool to reduce diagnostic uncertainty.

Mutations in the ELANE gene, which encodes neutrophil elastase, are known to cause cyclic neutropenia (CyN) and severe congenital neutropenia (SCN). Currently, targeting ELANE for insertion-deletion to trigger nonsense-mediated mRNA decay (NMD) may be a simple and universal method to treat SCN caused by ELANE mutations. Here, we present a patient with a heterozygous out-of-frame frameshift variant (-2 frame indel) in exon 4 of the ELANE gene. The patient underwent whole exome sequencing during hospitalization for acute parotitis and bronchitis, and found a variant in ELANE, c.581_588del AGGCCGGC (p.Q194Rfs*93), inherited from the father. The father of the patient, without neutropenia, did not present any clinically significant symptoms and showed no evidence of somatic mosaicism. During the subsequent three-year follow-up period, the patient did not experience any other major infections, and neutrophil counts remained consistently within the normal range. More importantly, bone marrow cytology indicated mild granulocytic hypoplasia without evidence of maturation arrest. This case provides clinical evidence supporting the notion that late exon frameshift -2 frame indel insertions can inhibit mRNA translation efficiency and prevent the production of mutant proteins, thereby promoting neutrophil maturation. It also bolsters the ongoing development of gene therapy for ELANE-related diseases.

Immunoglobulin A vasculitis (IgAV) is the most common cause of systemic vasculitis in childhood. Due to the continued use of the disease name “anaphylactoid purpura” in China, several misunderstandings have arisen in clinical practice and treatment regimens differ widely. In addition, new research and evidence-based data have grown. The Subspecialty Group of Immunology, Society of Pediatrics, Chinese Medical Association and the Chinese Alliance of Pediatric Rheumatic and Immunologic Diseases initiated an update of guidelines for the diagnosis and management of childhood IgAV. The aim therefore was to provide agreed consensus recommendations for diagnosis and treatment for children with IgAV. This study utilized the Delphi technique to develop an evidence-based expert consensus for childhood IgAV. We conducted a systematic literature review to retrieve evidence, which was graded using GRADE (Grading of Recommendations Assessment, Development, and Evaluation) criteria. Two rounds of Delphi voting and a consensus meeting involving 23 experts were conducted. Recommendations were accepted when ≥ 75

Objective:This study evaluated the diagnostic accuracy of the 2012 SLICC and 2019 EULAR/ACR criteria in Chinese cSLE patients and aimed to develop an optimized classification schema based on the 2019 EULAR/ACR criteria, specifically tailored for cSLE. Methods:Data from cSLE and control cases were extracted from the CAPRID database. Gold-standard diagnosis were established by consensus among 43 rheumatologists (≥80% agreement). From 1,390 consensus cases, a random selection of 1,045 cases (512 cSLE/533 non-cSLE) were allocated to derivation (n=522) and validation (n=523) cohorts. The 2012 SLICC and 2019 EULAR/ACR criteria were evaluated in the total cohort. Multiple optimization schemes were then developed through LASSO regression with expert consultation in the derivation cohort. All potential optimization schemes underwent validation in the validation cohort, from which the optimal scheme was selected and further evaluated in an ANA-positive subgroup. Results:The 2012 SLICC criteria demonstrated sensitivity of 96.7% and specificity of 96.5%, while the 2019 EULAR/ACR criteria had sensitivity of 95.3% and specificity of 97.8%, with an optimal total score threshold of 10. When both the non-scarring alopecia and arthritis criteria were removed alongside the redefined urinary protein criterion, specificity significantly improved to 99.3% (P < 0.05), while sensitivity remained unaffected at 94.1% (P = 0.210). In the ANA-positive cohort, the optimized integrated scheme significantly improved specificity (97.7% vs. 86.4%, P = 0.012) while maintaining comparable sensitivity (96.2% vs. 97.8%, P = 0.138). Conclusion:Both criteria performed well in Chinese cSLE patients. Optimizing the 2019 EULAR/ACR criteria by removing alopecia and arthritis criteria and modifying the urinary protein criterion enhanced specificity without compromising sensitivity.