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

This cohort study reports the long-term clinical outcomes of the use of intermittent intravenous methylprednisolone pulse therapy combined with mycophenolate mofetil for patients with juvenile dermatomyositis.

Systemic juvenile idiopathic arthritis (sJIA) is an autoinflammatory disorder that impacts children aged ≤ 16 years. This study evaluated the efficacy and safety of firsekibart, a fully human anti-IL-1β monoclonal antibody, in children with active sJIA. This multicenter, randomized, open-label, active-controlled phase 2 study (NCT05925452) enrolled participants aged 2– < 18 years with active sJIA across 14 sites in China. Participants were randomized (1:1:1) to firsekibart 3.0 mg/kg or 4.0 mg/kg subcutaneously every 4 weeks, or tocilizumab intravenously every 2 weeks, for 24 weeks. The primary endpoint was modified JIA American College of Rheumatology Pediatric criteria (ACR Pedi) 30 response at day 28. Secondary endpoints included ACR Pedi 30/50/70/90 responses, corticosteroid tapering, immunogenicity, and safety. Fifty participants were randomized (firsekibart 3.0 mg/kg: n = 17; 4.0 mg/kg: n = 16; tocilizumab: n = 17). At day 28, ACR Pedi 30 response rates were 94.1

Lymphocyte activation gene 3 (LAG3) has become an important immune checkpoint receptor, which plays a crucial role in regulating the immune response. The immunoregulatory function of LAG3 is achieved through complex receptor-ligand interactions, structure-function relationships, and unique signaling pathways. The role of LAG3 in cancers has been widely explored, and drugs targeting LAG3 are constantly emerging, demonstrating promising application prospects. In autoimmune diseases, downregulation of LAG3 leads to the breakdown of immune tolerance and excessive immune activation. In this review, we begin with the mechanisms by which LAG3 exerts its immunosuppressive function and its role in the immune system, focusing on the role of LAG3 in autoimmune diseases and recent research progress.

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.

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

Glucocorticoids (GCs) are potent anti-inflammatory and immunosuppressant medications and remain the cornerstone of systemic lupus erythematosus (SLE) therapy. However, ongoing exposure to GCs has the potential to elicit multiple adverse effects. Considering the irreplaceability of GCs in SLE therapy, it is important to explore the optimal regimen of GCs. Here, we compared the long-term efficacy and safety of pulsed and oral GC therapy in a lupus-prone mouse model. Mice were grouped using a randomized block design. We monitored survival rates, proteinuria, serum autoantibodies, and complement 3 (C3) levels up to 28 weeks of age, and assessed renal damage, bone quality, lipid deposition in the liver and marrow, glucose metabolic parameters, and levels of hormones of the hypothalamic-pituitary-adrenal (HPA) axis. Finally, we explored the mechanisms underlying the superior efficacy of the pulse regimen over oral prednisone regimen. We found that both GC regimens alleviated the poor survival rate, proteinuria, and glomerulonephritis, while also reducing serum autoantibodies and increasing the level of C3. The pulsed GC regimen showed less resistance to insulin, less suppression of the HPA axis, less bone loss, and less bone marrow fat deposition than the oral GC regimen. Additionally, GC-induced leucine zipper (GILZ) was significantly overexpressed in the GC pulse group. These results suggest that the GC pulse regimen ameliorated symptoms in lupus-prone mice, with fewer side effects, which may be related to GILZ overexpression. Our findings offer a potentially promising GC treatment option for SLE.

Background This study investigates the clinical characteristics and outcomes of pediatric patients with rheumatic diseases infected with COVID-19 in China. Methods We conducted a retrospective analysis of pediatric patients with rheumatic diseases who contracted COVID-19. Data were collected via a comprehensive questionnaire with a 14-day follow-up. Multivariable logistic regression was used to assess severe outcomes, and network analyses evaluated symptom correlations. Results A total of 1070 cases were collected. Fever (88.05%) and cough (62.75%) were the most common symptoms. Cough, nasal congestion, and runny nose exhibited a stronger correlation with each other. A higher incidence of fever reduced the incidence of two single symptoms (nasal congestion [r = -0.833], runny nose [r = -0.762]). Vaccinated children showed a shorter time to negative COVID-19 conversion (7.21 days vs. 7.63 days, p < 0.05) and lower hospitalization rates (p = 0.025). Prolonged symptom duration was associated with older age (OR: 1.07 [1.04-1.11]; p < 0.001) and systemic lupus erythematosus (OR: 1.47 [1.01-2.12]; p = 0.046). Conclusions Pediatric patients with rheumatic diseases exhibited a wide range of clinical symptoms after COVID-19 infection. The infection generally did not lead to severe outcomes in this study. COVID-19 vaccination was associated with reduced hospitalization risk and expediting the time to negativity for virus. Impacts This manuscript demonstrates a comprehensive analysis of the clinical characteristics and outcomes of COVID-19 infection in pediatric patients with rheumatic diseases in China. It provides critical insights into the specific challenges faced by this vulnerable population and offers practical recommendations for improving patient management during periods of increased infectious risk.

Objective The aim of this study is to identify whether low lupus disease activity status (LLDAS) and clinical remission (CR) of belimumab plus standard of care (SoC) therapy are achievable goals in childhood-onset SLE (cSLE).Methods This multicentre, one arm pre-post intervention study was conducted at 15 centres in China. The primary end point was to describe the proportion of patients who achieved LLDAS and CR after 3, 6 and 12 months after treatment with belimumab plus SoC therapy. A multiple regression model was used to impute missing data. A Poisson regression model was used to calculate the effect of belimumab treatment on the reduced risk of serious diseases and the incidence of new damage.Result A total of 193 (92.2% female) with active cSLE from 15 centres were included. At 3, 6 and 12 months, the proportion of LLDAS (CR) was 12.4% (1.0%), 25.6% (4.5%) and 70.3% (29.7%), respectively. The mean SELENA-SLEDAI score decreased from 11.0 at baseline to 3.7, 2.9 and 1.7 at 3, 6 and 12 months. At baseline, all patients received steroids at a mean (s.d.) prednisone equivalent dose of 31.0 (18.2) mg/day, which decreased to 19.4 (10.8) mg/day at month 3, 12.6 (7.2) mg/day at month 6 and 6.7 (5.3) mg/day at month 12. The symptoms and immunological indicators were also significantly improved.Conclusion This is the first and largest sample size prospective clinical intervention study of cSLE patients treated with belimumab in China. LLDAS and CR were attainable treat-to-target of belimumab plus SoC therapy in cSLE.

Given the limited tocilizumab (TCZ) treatment data for systemic juvenile idiopathic arthritis (sJIA) in China, we evaluated the long-term efficacy and safety of TCZ in Chinese patients with sJIA. In this multicentre, interventional Phase IV study, patients with sJIA and inadequate clinical response to non-steroidal anti-inflammatory drugs/corticosteroids received TCZ infusions every 2 weeks based on body weight (< 30 kg, 12 mg/kg; ≥ 30 kg, 8 mg/kg), over a 52-week open-label period and an 8-week safety follow-up period. The primary endpoint was the proportion of patients with a JIA American College of Rheumatology (ACR) 30 response and absence of fever at Week 12. Sixty-two patients were enrolled and treated (12-mg/kg group, 34; 8-mg/kg group, 28). At Week 12, 87.1

BACKGROUND:Lupus nephritis is a rare immunological disorder. Genetic factors are considered important in its causation. We aim to systematically investigate the rare pathogenic gene variants in patients with lupus nephritis. METHODS:Whole-exome sequencing was used to screen pathogenic gene variants in 1886 probands with lupus nephritis. Variants were interpreted on the basis of known pathogenic variants or the American College of Medical Genetics and Genomics guidelines and studied by functional analysis, including RNA sequencing, quantitative PCR, cytometric bead array, and Western blotting. RESULTS:Mendelian form of lupus nephritis was confirmed in 71 probands, involving 63 variants in 39 pathogenic genes. The detection yield was 4%. The pathogenic genes enriched in nuclear factor kappa-B (NF-κB), type I interferon, phosphatidylinositol-3-kinase/serine/threonine kinase Akt (PI3K/AKT), Ras GTPase/mitogen-activated protein kinase (RAS/MAPK), and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways. Clinical manifestation patterns were diverse among different signaling pathways. More than 50% of the pathogenic gene variants were reported to be associated with lupus or lupus nephritis for the first time. The identified pathogenic gene variants of lupus nephritis overlapped with those of autoinflammatory and immunodeficiency diseases. Inflammatory signatures, such as cytokine levels of IL-6, IL-8, IL-1 β , IFN α , IFN γ , and IP10 in serum and transcriptional levels of interferon-stimulated genes in blood, were significantly higher in patients with pathogenic gene variants compared with controls. The overall survival rate of patients with pathogenic gene variants was lower than those without pathogenic gene variants. CONCLUSIONS:A small fraction of patients with lupus nephritis had identifiable pathogenic gene variants, primarily in NF-κB, type I interferon, PI3K/AKT, JAK/STAT, RAS/MAPK, and complement pathways.

Objective The clinical characteristics of children with Behçet's disease like trisomy 8 (T8-BD) diagnosed and treated in multi-centers were summarized, so as to improve the understanding and treatment ability of clinicians. Methods Clinical data of children with T8-BD who were hospitalized in the First Hospital of Jilin University, Children's Hospital of Fudan University and Peking Union Medical College Hospital from January 2016 to June 2022 were retrospectively collected, and then based on the literature, to summarize their general data, symptoms and signs, auxiliary examination results, and treatment and prognosis. Results A total of 6 children with T8-BD hospitalized in the First Hospital of Jilin University, Children's Hospital of Fudan University and Peking Union Medical College Hospital and 13 children with T8-BD recorded in 10 literature reports were included. Among the 19 children with T8-BD, there were 4 males (21.1%) and 15 females (78.9%). The median age of onset was 8 years (range: 0-16 years). The main clinical manifestations were oral ulcer (94.7%), vulvar ulcer (57.9%) and fever (57.9%, including 4 cases with periodic fever-like manifestations). There were 14 cases (73.7%) of malignant hematologic diseases, 9 cases (47.4%) of digestive tract lesions, 7 cases (36.8%) of skin lesions, and 1 case (5.3%) of cerebrospinal fluid pressure elevation. There were 7 cases (36.8%) of abnormal development, including 5 cases of developmental delay, 3 cases of deep folds, 3 cases of joint deformity, 1 case of special facial appearance, 1 case of intellectual impairment, and 1 case of agenesis of corpus callosum. Auxiliary examination showed hemocytopenia in 11 cases (57.9%); C-reactive protein increase in 11 cases (57.9%), and erythrocyte sedimentation rate increase in 9 cases (47.4%). In terms of treatment, 11 cases (57.9%) were treated with glucocorticoid, 9 cases (47.4%) with traditional immunosuppressant, 6 cases (31.6%) with biological agents, 6 cases (31.6%) with hematopoietic stem cell transplantation and 3 cases (15.8%) with chemical agents. In terms of prognosis, 4 cases (21.1%) died, all of which were complicated with hematologic malignancies. Conclusions The common clinical symptoms of T8-BD are oral ulcers, vulvar ulcers and fever, which can be combined with digestive tract lesions, skin lesions, hematologic malignancies and developmental abnormalities. However, some children are accompanied by other atypical manifestations at the onset of the disease, to which clinicians should pay attention to identify. Overall, the prognosis of children with T8-BD is reasonable, but patients with hematologic malignancies have poor response to immunosuppressive therapy and increased risk of death.

Objective To investigate the clinical features and treatment outcomes of chronic non-bacterial osteomyelitis (CNO) from five tertiary pediatric rheumatology services in China and provide possible treatment options for clinicians. Methods In this multicenter, retrospective study, pediatric patients diagnosed with CNO in Children's Hospital of Fudan University, Peking Union Medical College Hospital, Children's Hospital of Nanjing Medical University, Children's Hospital of Chongqing Medical University and the First Hospital of Jilin University from March 2014 to August 2022 were included. According to the treatment plan, the patients were divided into nonsteroidal anti-inflammatory drugs (NSAID) group, traditional disease modifying anti-rheumatic drugs (DMARD) group, tumor necrosis factor inhibitor (TNF-i) group, bisphosphonate group, and bisphosphonate+TNF-i group, and physician global assessment score was used to evaluate the efficacy. Results Retrospective data analysis showed that the disease was more common in boy sthan girls(31 vs. 27), and the average age at onset of symptoms was 8.5±3.4 years, the mean age of diagnosis was 9.8±3.2 years, and the Median follow-up was 10.9(5.0, 30.1) months. A total of 46 cases (79.3%) were diagnosed in the last 3 years. Bone pain and / or arthralgia was the predominant symptom in 54(93.1%) patients followed by fever in 31(53.4%) patients. Raised inflammatory markers (ESR and CRP) were present in 87.9% and 77.6% of the patients. The most frequently affected bones were lower limb bones, including 42 cases of femur and 41 cases of tibia; 3 patients had compression fractures of the vertebrae at the time of diagnosis. Bone biopsy was conducted in 33 cases, and subacute or chronic osteomyelitis manifested with inflammatory cells infiltration were detected. The remission rate was not statistically different between treatment groups (P=0.562), with the remission rate at 11 months in the bisphosphonate+TNF-i group being 60.0%, 55.6% and 33.3% in the NSAID and DMARD groups respectively; 66.7% and 52.4% in the NSAID and TNF-i groups respectively at 12 months. A total of 40 patients were followed up for ≥6 months, with the remission rate of 81.3%. Conclusions Our multicenter study describes the features and outcomes of CNO patients in China. The characteristics of CNO children from multiple centers in China were lack of specificity. Bone pain and/or arthralgia were the main clinical symptoms, accompanied by fever, normal white blood cells, and raised inflammatory markers (CRP and/or ESR). Although anti-inflammatory treatment regimens were different, the efficacy of the treatment groups was similar. Anti-inflammatory therapy is currently the first choice.

Objective The clinical characteristics of children with Beh?et’s disease like trisomy 8（T8-BD） diagnosed and treated in multi-centers were summarized, so as to improve the understanding and treatment ability of clinicians. Methods Clinical data of children with T8-BD who were hospitalized in the First Hospital of Jilin University, Children’s Hospital of Fudan University and Peking Union Medical College Hospital from January 2016 to June 2022 were retrospectively collected, and then based on the literature, to summarize their general data, symptoms and signs, auxiliary examination results, and treatment and prognosis. Results A total of 6 children with T8-BD hospitalized in the First Hospital of Jilin University, Children’s Hospital of Fudan University and Peking Union Medical College Hospital and 13 children with T8-BD recorded in 10 literature reports were included. Among the 19 children with T8-BD, there were 4 males（21.1%） and 15 females（78.9%）. The median age of onset was 8 years（range: 0-16 years）. The main clinical manifestations were oral ulcer（94.7%）, vulvar ulcer（57.9%） and fever（57.9%,including 4 cases with periodic fever-like manifestations）. There were 14 cases（73.7%） of malignant hematologic diseases, 9 cases（47.4%） of digestive tract lesions, 7 cases（36.8%） of skin lesions, and 1 case（5.3%） of cerebrospinal fluid pressure elevation. There were 7 cases（36.8%） of abnormal development, including 5 cases of developmental delay, 3 cases of deep folds, 3 cases of joint deformity, 1 case of special facial appearance, 1 case of intellectual impairment, and 1 case of agenesis of corpus callosum. Auxiliary examination showed hemocytopenia in 11 cases（57.9%）; C-reactive protein increase in 11 cases（57.9%）, and erythrocyte sedimentation rate increase in 9 cases（47.4%）. In terms of treatment, 11 cases（57.9%） were treated with glucocorticoid, 9 cases（47.4%） with traditional immunosuppressant, 6 cases（31.6%） with biological agents, 6 cases（31.6%） with hematopoietic stem cell transplantation and 3 cases（15.8%） with chemical agents. In terms of prognosis, 4 cases（21.1%） died, all of which were complicated with hematologic malignancies. Conclusions The common clinical symptoms of T8-BD are oral ulcers, vulvar ulcers and fever, which can be combined with digestive tract lesions, skin lesions, hematologic malignancies and developmental abnormalities. However, some children are accompanied by other atypical manifestations at the onset of the disease, to which clinicians should pay attention to identify. Overall, the prognosis of children with T8-BD is reasonable, but patients with hematologic malignancies have poor response to immunosuppressive therapy and increased risk of death.

Childhood-onset systemic lupus erythematosus (cSLE) is an autoimmune disease that results in significant damage and often needs more aggressive treatment. Compared to adult-onset SLE, cSLE has a stronger genetic background and more prevalent elevated type I Interferon expression. The management of cSLE is more challenging because the disease itself and treatment can affect physical, psychological and emotional growth and development. High dose oral glucocorticoid (GC) has become the rule for treating moderate to severe cSLE activity. However, GC-related side effects and potential toxicities are problems that cannot be ignored. Recent studies have suggested that GC pulse therapy can achieve disease remission rapidly and reduce GC-related side effects with a reduction in oral prednisone doses. This article reviews characteristics, including pathogenesis and manifestations of cSLE, and summarized the existing evidence on GC therapy, especially on GC pulse therapy in cSLE, followed by our proposal for GC therapy according to the clinical effects and pathogenesis.

Purpose Deficiency of adenosine deaminase 2 (DADA2), an autosomal recessive autoinflammatory disorder caused by biallelic loss-of-function variants in adenosine deaminase 2 (ADA2), has not been systemically investigated in Chinese population yet. We aim to further characterize DADA2 cases in China. Methods A retrospective analysis of patients with DADA2 identified through whole exome sequencing (WES) at seventeen rheumatology centers across China was conducted. Clinical characteristics, laboratory findings, genotype, and treatment response were analyzed. Results Thirty patients with DADA2 were enrolled between January 2015 and December 2021. Adenosine deaminase 2 enzymatic activity was low in all tested cases to confirm pathogenicity. Median age of disease presentation was 4.3 years and the median age at diagnosis was 7.8 years. All but one patient presented during childhood and two subjects died from complications of their disease. The patients most commonly presented with systemic inflammation (92.9%), vasculitis (86.7%), and hypogammaglobinemia (73.3%) while one patient presented with bone marrow failure (BMF) with variable cytopenia. Twenty-three (76.7%) patients were treated with TNF inhibitors (TNFi), while two (6.7%) underwent hematopoietic stem cell transplantation (HSCT). They all achieved clinical remission. A total of thirty-nine ADA2 causative variants were identified, six of which were novel. Conclusion To establish early diagnosis and improve clinical outcomes, genetic screening and/or testing of ADA2 enzymatic activity should be performed in patients with suspected clinical features. TNFi is considered as first line treatment for those with vascular phenotypes. HSCT may be beneficial for those with hematological disease or in those who are refractory to TNFi.

Juvenile idiopathic arthritis (JIA) is a genetically heterogeneous group of connective tissue diseases that are commonly characterized by chronic joint synovial inflammation with unknown etiology in childhood.It is cu-rrently incurable and the main therapeutic goal is to achieve clinical remission.The drugs currently used to treat JIA mainly include non-steroid anti-inflammatory drugs, glucocorticoid, disease modifying antirheumatic drugs, and biological agents.In this article, recent advances in the understanding of JIA treatment and related clinical research were reviewed, in an attempt to provide prospects for the future direction of drug development and treatment concepts.

Abstract Background: This study aimed to investigate the clinical effectivity of intravenous methylprednisolone repeated intermittent pulse combined with mycophenolate mofetil in the treatment of newly diagnosed juvenile dermatomyositis and to review the literatures. Methods: Reviewed the clinical data of 12 juvenile dermatomyositis patients, from January 2014 to January 2017, hospitalized and treated with intravenous methylprednisolone repeated intermittent pulse combined with mycophenolate mofetil. Results: A total of 12 patients were enrolled, and their overall treatment response rate was 100%. After treatment, all patients showed significant improvement in cutaneous performance and children myositis assessment scores. The median recovery time of muscle enzyme and children myositis assessment scores were 1.8 months and 19.6 months, respectively. During the intravenous methylprednisolone repeated intermittent pulse treatment, the body weight percentile was higher than that before treatment, blood pressure and intraocular pressure were transiently increased, and the level of serum lipids, glucose and calcium showed no significant changes. During the maintenance treatment period, the height percentile was increased when compared to those before treatment, while the weight percentile, blood pressure and intraocular pressure of the patients showed no significant changes. Two patients with recurrence were followed up for more than 3 years after corticosteroid re-withdrawal, and no relapse was seen till now. Conclusion: Intravenous methylprednisolone repeated intermittent pulse combined with mycophenolate mofetil showed positive outcomes and good safety index in juvenile dermatomyositis patients. It is likely considered to be a promising treatment strategy for juvenile dermatomyositis. Trial registration: ClinicalTnals, ID：NCT05509140. Registered 18 August 2022 - Retrospectively registered, https://register.clinicaltrials.gov/prs/app/action/LogoutUser?uid=U00052MF&ts=12&cx=mcg5gj.

ABSTRACT Background Heterozygous loss-of-function mutations in the tumour necrosis factor alpha induced protein 3 (TNFAIP3) gene cause an early-onset auto-inflammatory disease named haploinsufficiency of A20 (HA20). Here we describe three unrelated patients with autoimmune lupus nephritis (LN) phenotypes carrying three novel mutations in the TNFAIP3 gene. Methods Whole-exome sequencing (WES) was used to identify the causative mutations in three biopsy-proven LN patients. Sanger sequencing and quantitative polymerase chain reaction (qPCR) were used to validate the mutations identified by WES. RNA sequencing, qPCR and cytometric bead array was used to detect inflammatory signatures in the patients. Results The patients predominantly presented with an autoimmune phenotype, including autoimmune haemolytic anaemia, multipositive autoantibodies and LN. Additionally, novel phenotypes of allergy and pericardial effusion were first reported. WES identified three novel heterozygous mutations in the TNFAIP3 gene, including a novel splicing mutation located in the canonical splicing site (c.634+2T>C) resulting in an intron 4 insertion containing a premature stop codon, a de novo novel copy number variation (exon 7–8 deletion) and a novel nonsense mutation c.1300_1301delinsTA causing a premature stop codon. We further identified hyperactivation signatures of nuclear factor- kappa B and type I IFN signalling and overproduction of pro-inflammatory cytokines in the blood. This report expanded the phenotype to a later age, as two girls were diagnosed at age 3 years and one man at age 29 years. Conclusions Kidney involvement may be the main feature of the clinical spectrum of HA20, even in adults. Genetic screening should be considered for early-onset LN patients.