Janus kinase inhibitor, tofacitinib, in refractory juvenile dermatomyositis: a retrospective multi-central study in China.

OBJECTIVES: Juvenile dermatomyositis (JDM) is a chronic autoimmune disease. Some patients remain in an active state even though they were administrated with a combination of corticosteroid and methotrexate. Existing research has suggested that interferon and Janus kinase played an important role in pathogenesis. Existing research has suggested the efficacy of JAK inhibitors (JAKi). Our retrospective study aimed to investigate the efficacy of tofacitinib in refractory JDM patients. METHODS: A total of eighty-eight patients in China who had been diagnosed with JDM and subjected to tofacitinib therapy for over 3 months were retrospectively analyzed. Skin and muscle manifestations were assessed using the Cutaneous Assessment Tool-binary method (CAT-BM), Childhood Myositis Assessment Scale (CMAS), and kinase. Pulmonary function was assessed using a high-resolution CT (computerized tomography) scan and pulmonary symptoms. All patients were subjected to regular follow-up, and core measures were assessed every 3 months after initiation. Furthermore, the data were analyzed using the Wilcoxon single test, Mann-Whitney U test, and chi-square test. RESULTS: Compared with the baseline data, skin and muscle manifestations were found significantly improved during the respective follow-up visit. At the most recent follow-up, nearly 50% of patients achieved a clinical complete response and six patients received tofacitinib monotherapy. Sixty percent of patients suffering from interstitial lung disease well recovered on high-resolution CT. Seventy-five percent of patients showed a reduction in the size or number of calcinosis, and 25% of patients showed completely resolved calcinosis. CONCLUSION: In this study, the result suggested that tofacitinib therapy exerted a certain effect on skin manifestations, muscle manifestations, interstitial lung disease (ILD), calcinosis, as well as downgrade of medication. In-depth research should be conducted to focus on the correlation between the pathogenesis of JDM and JAKi.

Age-related differences in clinical and laboratory characteristics of childhood-onset systemic lupus erythematosus: Pre-puberal-onset SLE is prone to delayed diagnosis.

OBJECTIVE: This study aimed to analyze age-specific characteristics of childhood-onset systemic lupus erythematosus (cSLE) at a health center in China. METHODS: The children with SLE were grouped based on age at disease-onset: pre-pubertal (≤7 years), peri-pubertal (8-13 years), and adolescence (14-18 years). The retrospective study included patients with cSLE diagnosed at the Beijing Children's Hospital between 2013 and 2021. RESULTS: A total of 675 females and 178 males were eligible for inclusion in this study. Among them, 160 patients were diagnosed during pre-puberty, 635 during peri-puberty, and 58 during adolescence. The female-to-male ratio of pre-pubertal, peri-pubertal, and adolescent diagnosis was 3.5: 1, 3.6: 1, and 7.28:1, respectively. The median time from onset to diagnosis during the pre-puberal period was 3.0 (IQR 1.0-24.0 months), which was longer than that during the peri-puberal period (1.4; IQR 0.7-4) months and adolescence (1.0; IQR 0.4-2) months (p = <.0001). The proportion of LN in patients diagnosed during the peri-puberal period (304, 46.6%) and during adolescence (27, 47.9%) was higher than that of patients diagnosed during the pre-puberal period (59, 36.9%) (p = .044). 46 (28.8%), 233 (36.7%), and 32 (55.2%) of children diagnosed during the pre-pubertal period, peri-pubertal period, and adolescence, respectively, suffered from leukopenia. CONCLUSION: The proportion of renal involvement and leukopenia in the pre-pubertal group was lower than that of the pubertal group and adolescent group. More importantly, the younger the age of the patient, the more likely the diagnosis to be delayed.

Lipid profiles in patients with juvenile idiopathic arthritis: a systematic literature review and meta-analysis.

OBJECTIVE: The purpose of this study was to comprehensively evaluate the lipid profiles in patients with juvenile idiopathic arthritis (JIA). METHODS: The literature and relevant reviews were searched for published clinical studies on the relationship between JIA and blood lipid levels. The Newcastle-Ottawa scale (NOS) was applied to evaluate the risk and methodological value of the included case‒control and cohort studies. Standardized mean differences (SMDs) and 95% confidence intervals were derived for all variables with adequate unprocessed data. This meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. RESULTS: In total, 16 studies were incorporated through screening. The analysis findings revealed that the levels of very low-density lipoprotein cholesterol [SMD=-0.411, 95% CI (-0.774~-0.048), P = 0.026], high-density lipoprotein cholesterol [SMD=-0.528, 95% CI (-0.976~-0.079), P = 0.021], and apolipoprotein A1 [SMD=-1.050, 95% CI (-1.452~-0.647), P = 0.000] in JIA patients were statistically lower than those observed in healthy controls. The level of low-density lipoprotein cholesterol [SMD = 0.202, 95% CI (0.003 ~ 0.400), P = 0.046] was significantly higher in JIA patients than in healthy controls. In JIA patients, body mass index [SMD=-0.189, 95% CI (-0.690 ~ 0.311), P = 0.459], high-density lipoprotein [SMD =-1.235, 95% CI (-2.845 ~ 0.374), P = 0.133), low-density lipoprotein [SMD = 0.616, 95% CI (-0.813 ~ 2.046), P = 0.398), triglycerides (SMD = 0.278, 95% CI (-0.182 ~ 0.738), P = 0.236], total cholesterol [SMD=-0.073, 95% CI (-0.438 ~ 0.293), P = 0.696] and apolipoprotein B levels [SMD = 0.226, 95% CI (-0.133 ~ 0.585), P = 0.217] were not significantly different from those in healthy controls. CONCLUSIONS: The outcomes of this meta-analysis suggest that dyslipidemia is common in JIA patients compared to healthy controls. Patients with JIA have a significantly increased risk of atherosclerosis and cardiovascular disease later in life.

A systematic review and meta-analysis of environmental factors associated with juvenile idiopathic arthritis.

OBJECTIVES: Juvenile idiopathic arthritis (JIA) is the most common pediatric rheumatic disease, thought to be influenced by both genetics and the environment. Identifying environmental factors associated with disease risk will improve knowledge of disease mechanisms and ultimately benefit patients. This review aimed to collate and synthesize the current evidence of environmental factors associated with JIA. METHODS: MEDLINE (Ovid), EMBASE (Ovid), Cumulative Index of Nursing and Related Health Literature (EBSCOhost), science network (WOS, Clarivate Analytics), Chinese National Knowledge Infrastructure, and Chinese Biological Medical Database were systematically searched. Study quality was rated using the Newcastle-Ottawa Scale. Pooled estimates for each environmental factor were generated using a random-effects, inverse-variance method, where possible. The remaining environmental factors were synthesized in narrative form. RESULTS: This review includes environmental factors from 23 studies (6 cohorts and 17 case-control studies). Cesarean section delivery was associated with increased JIA risk (pooled relative risk [RR] 1.103, 95% CI 1.033-1.177). Conversely, maternal smoking of more than 20 cigarettes/day (pooled RR 0.650, 95% CI 0.431-0.981) and gestational smoking (pooled RR0.634, 95% CI 0.452-0.890) were associated with decreased JIA risk. CONCLUSION: This review identifies several environmental factors associated with JIA and demonstrates the huge breadth of environmental research. We also highlight the challenges of combining data collected over this period due to limited study comparability, evolution in healthcare and social practices, and changing environment, which warrant consideration when planning future studies.

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At the end of 2022, the World Health Organization reported an increase in group A Streptococcus (GAS) infections, such as scarlet fever, in multiple countries. The outbreak primarily affected children under 10 years old, and the number of deaths was higher than anticipated, causing international concern. This paper reviews the current state of the GAS disease outbreak, its causes, and response measures. The authors aim to draw attention from clinical workers in China and increase their awareness and vigilance regarding this epidemic. Healthcare workers should be aware of the potential epidemiological changes in infectious diseases that may arise after the optimization of control measures for coronavirus disease 2019 to ensure children's health.

Clinical characteristics of 1020 childhood-onset systemic lupus erythematosus: data from a health centre in China.

OBJECTIVES: Childhood-onset systemic lupus erythematosus (cSLE) is a multisystem autoimmune disease characterised and presents partially differently from adults. A large cSLE cohort study is lacking in China. The present study aimed to determine the clinical characteristics in a large population of patients with cSLE, and compare with adult-onset SLE (aSLE) in an SLE cohort of China. METHODS: The retrospective study included patients with cSLE diagnosed at the Beijing Children's hospital between July 2006 and October 2020. All patients met at least 4 of ACR classification criteria for SLE. In addition, data including demographic, clinical and serologic data were collected. Our data were compared with other cSLE cohorts and Chinese aSLE cohorts. RESULTS: A total of 1020 patients were included in this study, comprising 808 female and 212 male patients (female to male ratio, 3.8:1). The mean age at diagnosis of lupus was 11.1 years (range 1.0-17.2). It took on average 6 months (range 0.1-132) from first symptoms to cSLE diagnosis and over 12 months in 12% of patients. The most common primary manifestations at onset were rash (37.2%), fever (33.4%), nephropathy (14.2%) and arthritis (13.6%). The most common clinical manifestations were rash (67.9%) and fever (57.5%). 59.4% of patients had haematological involvement, 46.0% had lupus nephritis, 33.2% had arthritis. cSLE was more active and associated with more inflammation than aSLE patients. CONCLUSIONS: This study is a large single-centre study on cSLE from China and clarifies the clinical phenotype and autoantibody spectrum of cSLE. The clinical manifestations and autoantibody spectrum of cSLE are diverse, with regional and populational differences.

Early onset is an indication of the severity of DADA2 disease.

OBJECTIVE: To find indicators of disease severity and factors of early remission in patients with deficiency of adenosine deaminase 2 (DADA2). METHODS: We enrolled six DADA2 patients from six families. Direct sequencing of adenosine deaminase 2 gene (ADA2) was performed by Sanger analysis. A literature review was conducted for articles regarding paediatric DADA2. RESULTS: We found that more organs were involved in early-onset (≤1 year of age) than in late-onset (>1 year of age) DADA2 patients had high level inflammatory responses, such as elevated ESR, SF, serum amyloid A and CRP. Disease severity was not significantly different from missense and frameshift mutation. Early administration of TNF inhibitor might result in better remission and reduce recurrence. In the literature, four articles describing 51 paediatric DADA2 patients were identified. We also found that fever, stroke, peripheral nervous system involvement, hypogammaglobulinaemia and hypertension were more frequent in early onset DADA2 patients. CONCLUSION: Early-onset DADA2 may be more severe. Early administration of TNF inhibitor can effectively reduce recurrence and quickly alleviate the disease.

SAMHD1 associates with inflammation and vasculitis in paediatric-onset systemic lupus erythematosus.

OBJECTIVES: In this study, we aimed to explore the expression of the Aicardi-Goutières syndrome (AGS) mutant gene SAMHD1 in paediatric-onset systemic lupus erythematosus (pSLE), its correlations with clinical and laboratory parameters, and the relationship between its expression and the type 1 interferon (IFN) signalling pathway. METHODS: Peripheral blood from 98 pSLE patients and 44 gender and age-matched healthy individuals were examined. Gene expression levels of SAMDH1 and interferon-stimulated genes (ISGs; MxA, IRF3 and IRF7) were evaluated using real-time RT-PCR assays. RESULTS: SAMHD1 levels in pSLE patients were significantly increased compared to those in healthy donors (p<0.001). SAMHD1 was associated with serum ferritin (r=0.221, p=0.042) in pSLE patients. SAMHD1 levels were significantly increased (p<0.05) in pSLE patients with butterfly erythema, alopecia, and photosensitivity. SAMHD1 was positively correlated with MxA, IRF3 and IRF7 levels, indicating that SAMHD1 was associated with the type 1 IFN signalling pathway. CONCLUSIONS: SAMHD1 was significantly increased and correlated with MxA, IRF3 and IRF7 in pSLE patients.

Research progress in drug therapy of juvenile idiopathic arthritis.

BACKGROUND: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children. With the gradual expansion of the incidence of JIA in the population, the pathogenesis and treatment of JIA were further explored and analyzed, and JIA has achieved some success in drug therapy. DATA SOURCES: A systemic literature search was conducted on PubMed, Cochrane Library, EMBASE, ISI Web of Science, the US National Institutes of Health Ongoing Trials Register, and the EU Clinical Trials Register. Through the searching of clinical trials of JIA in recent years, we summarized the progress of the clinical treatment of JIA. RESULTS: The main treatment drugs for JIA include non-steroidal anti-inflammatory drugs, glucocorticoids, disease-modifying antirheumatic drugs and biological agents. So far, a variety of biological agents targeting the cytokines and receptors involved in its pathogenesis have been gradually approved for JIA in many countries. The application of biological agents in JIA showed good efficacy and safety, bringing unprecedented experience to children and adolescents with JIA. CONCLUSIONS: The potential and advantages of biologic agents in the treatment of JIA are significant, and the application of biologic agents in the treatment of JIA will be more and more common.

International Consensus for the Dosing of Corticosteroids in Childhood-Onset Systemic Lupus Erythematosus With Proliferative Lupus Nephritis.

OBJECTIVE: To develop a standardized steroid dosing regimen (SSR) for physicians treating childhood-onset systemic lupus erythematosus (SLE) complicated by lupus nephritis (LN), using consensus formation methodology. METHODS: Parameters influencing corticosteroid (CS) dosing were identified (step 1). Data from children with proliferative LN were used to generate patient profiles (step 2). Physicians rated changes in renal and extrarenal childhood-onset SLE activity between 2 consecutive visits and proposed CS dosing (step 3). The SSR was developed using patient profile ratings (step 4), with refinements achieved in a physician focus group (step 5). A second type of patient profile describing the course of childhood-onset SLE for ≥4 months since kidney biopsy was rated to validate the SSR-recommended oral and intravenous (IV) CS dosages (step 6). Patient profile adjudication was based on majority ratings for both renal and extrarenal disease courses, and consensus level was set at 80%. RESULTS: Degree of proteinuria, estimated glomerular filtration rate, changes in renal and extrarenal disease activity, and time since kidney biopsy influenced CS dosing (steps 1 and 2). Considering these parameters in 5,056 patient profile ratings from 103 raters, and renal and extrarenal course definitions, CS dosing rules of the SSR were developed (steps 3-5). Validation of the SSR for up to 6 months post-kidney biopsy was achieved with 1,838 patient profile ratings from 60 raters who achieved consensus for oral and IV CS dosage in accordance with the SSR (step 6). CONCLUSION: The SSR represents an international consensus on CS dosing for use in patients with childhood-onset SLE and proliferative LN. The SSR is anticipated to be used for clinical care and to standardize CS dosage during clinical trials.

Machine learning for screening and predicting the risk of anti-MDA5 antibody in juvenile dermatomyositis children.

Objective: The anti-MDA5 (anti-melanoma differentiation associated gene 5) antibody is often associated with a poor prognosis in juvenile dermatomyositis (JDM) patients. In many developing countries, there is limited ability to access myositis- specific antibodies due to financial and technological issues, especially in remote regions. This study was performed to develop a prediction model for screening anti-MDA5 antibodies in JDM patients with commonly available clinical findings. Methods: A cross-sectional study was undertaken with 152 patients enrolled from the inpatient wards of Beijing Children's Hospital between June 2018 and September 2021. Stepwise logistic regression, least absolute shrinkage and selection operator (LASSO) regression, and the random forest (RF) method were used to fit the model. Model discrimination, calibration, and decision curve analysis were performed for validation. Results: The final prediction model included eight clinical variables (gender, fever, alopecia, periungual telangiectasia, digital ulcer, interstitial lung disease, arthritis/arthralgia, and Gottron sign) and four auxiliary results (WBC, CK, CKMB, and ALB). An anti-MDA5 antibody risk probability-predictive nomogram was established with an AUC of 0.975 predicted by the random forest algorithm. The model was internally validated by Harrell's concordance index (0.904), the Brier score (0.052), and a 500 bootstrapped satisfactory calibration curve. According to the net benefit and predicted probability thresholds of decision curve analysis, the established model showed a significantly higher net benefit than the traditional logistic regression model. Conclusion: We developed a prediction model using routine clinical assessments to screen for JDM patients likely to be anti-MDA5 positive. This new tool may effectively predict the detection of anti-MDA5 in these patients using a non-invasive and efficient way.

miR-1968-5p is involved in the pathogenesis of lupus nephritis of NZBWF1 mice by targeting csf1.

OBJECTIVE: Lupus nephritis is one of the most common and severe systemic lupus erythematosus complications. However, the pathogenesis of lupus nephritis is still poorly understood. Increasing evidence has shown that microRNAs (miRNAs) are extensively involved in the pathophysiology of autoimmune diseases. NZBWF1 is the classical mouse model of lupus nephritis. The present study aimed to investigate the expression profiling of mRNA and miRNAs of NZBWF1 mice with lupus nephritis using microarray, and explored the potential molecular mechanism of miRNA. METHODS: miRNA and mRNA microarrays were performed to identify miRNA and mRNA expression changes between pre-diseased (8-week-old) NZBWF1 mice and diseased NZBWF1 mice with lupus nephritis (28-week-old). Quantitative polymerase chain reaction (qPCR) validated these results. The target of miRNA was confirmed through a dual-luciferase reporter and stimulated mesangial cells experiment. RESULTS: The combined miRNA and mRNA analysis identified 43 differentially expressed miRNAs and 1796 differentially expressed mRNAs between pre-disease (8-week-old) (n = 4) and diseased (28-week-old) NZBWF1 mice. We found that miR-1968-5p was significantly decreased, and csf1 mRNA was significantly increased in lupus nephritis mouse and verified by RT-PCR. csf1 has been demonstrated to play important roles in SLE. Bioinformatics analysis predicted that the csf1 was a potential target gene of miR-1968-5p. A dual-luciferase reporter assay confirmed the target binding. In cell experiments, overexpression or knockdown of miR resulted in a decrease or increase of csf1 expression, respectively. CONCLUSION: These results suggest that miR-1968-5p may be involved in the pathogenesis of lupus nephritis of NZBWF1 mice by targeting csf1.

Clinical characteristics of cerebral venous sinus thrombosis in childhood-onset systemic lupus erythematosus patients: a single-centre study from China.

OBJECTIVES: Cerebral venous sinus thrombosis (CVST) is a rare complication of childhood-onset SLE (cSLE) and is potentially fatal to the patient. In order to better define the characteristics of CVST in cSLE, we analysed a single-centre study of cSLE presenting with CVST. METHODS: Clinical characteristics and laboratory findings of cSLE patients complicated with CVST from January 2006 to December 2019 were analysed through this retrospective, single-centre study. RESULTS: A total of 1395 records of cSLE patients were reviewed. Five patients (0.36%) had CVST. Headache (80%) was the most frequent symptom. The transverse sinus (45%) was the most frequent location of thrombus, followed by the sigmoid sinus (27%). The SLE disease activity index (SLEDAI) at the time of CVST was 11±3. The D-dimer was elevated in all 5 cases, only one patient was positive for ACL and anti-ß2GP-I IgM. All the patients underwent MRV screen to confirm the diagnosis. All the patients had a favourable outcome after receiving glucocorticoid and immunosuppressant treatment, as well as anticoagulant therapy. CONCLUSIONS: CVST is relatively rare in cSLE and tends to occur in active lupus patients. Severe and persistent headache is an index of CVST. Early diagnosis and more intensive therapy for SLE, combined with anticoagulation therapy, could significantly improve the prognosis of CVST in cSLE.

Mariana serpentinite mud volcanism exhumes subducted seamount materials: implications for the origin of life.

The subduction of seamounts and ridge features at convergent plate boundaries plays an important role in the deformation of the overriding plate and influences geochemical cycling and associated biological processes. Active serpentinization of forearc mantle and serpentinite mud volcanism on the Mariana forearc (between the trench and active volcanic arc) provides windows on subduction processes.  Here, we present (1) the first observation of an extensive exposure of an undeformed Cretaceous seamount currently being subducted at the Mariana Trench inner slope; (2) vertical deformation of the forearc region related to subduction of Pacific Plate seamounts and thickened crust; (3) recovered Ocean Drilling Program and International Ocean Discovery Program cores of serpentinite mudflows that confirm exhumation of various Pacific Plate lithologies, including subducted reef limestone; (4) petrologic, geochemical and paleontological data from the cores that show that Pacific Plate seamount exhumation covers greater spatial and temporal extents; (5) the inference that microbial communities associated with serpentinite mud volcanism may also be exhumed from the subducted plate seafloor and/or seamounts; and (6) the implications for effects of these processes with regard to evolution of life. This article is part of a discussion meeting issue 'Serpentine in the Earth system'.

Analysis of clinical manifestations and treatment in 26 children with fibrodysplasia ossificans progressiva in China.

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is a rare and disabling heritable connective tissue disease that is difficult to treat. This study seeks to explore the clinical characteristics, clinical manifestations, treatment and prognosis of FOP to provide a clinical basis for its early diagnosis and treatment. METHODS: Twenty-six children with FOP were retrospectively analyzed in terms of their onset, clinical manifestations, auxiliary examinations and treatment. RESULTS: Among the 26 cases, the youngest age of manifestation of mass was 8 days after birth, and the average age was 3 years and 2 months. The peak age was 2-5 years old. Inflammatory mass and toe-finger deformity are the main early clinical manifestations of the disease. These inflammatory masses often lead to hard osteogenic deposits that initially mainly involve the central axis, such as the neck (22/26, 84.6%), back (20/26, 76.9%), and head (13/26, 50%). Toe-finger deformity mainly manifests as symmetrical great toe deformity, or short and deformed thumb and little finger. The diagnosis of FOP requires typical clinical manifestations or ACVR1 gene detection. The main therapeutic drugs for FOP include glucocorticoids and non-steroidal anti-inflammatory drugs. Although not compliant with the recommended medical management of FOP, in our clinical practice children with uncontrollable illness could be treated using a variety of immunosuppressive agents in combination. CONCLUSIONS: FOP is a rare autosomal dominant heritable disease. The main clinical manifestations observed in this study were recurrent inflammatory mass and toe-finger deformity. If the diagnosis and treatment are not performed in a timely manner, serious complications are likely to affect the prognosis. Therefore, early diagnosis and active treatment should be performed.

Glucocorticoids pharmacology and their application in the treatment of childhood-onset systemic lupus erythematosus.

Glucocorticoids are potent anti-inflammatory and immunosuppressant medications and remain the mainstay of systemic lupus erythematosus (SLE) therapy. The potency of a specific glucocorticoid, i.e., the dose of glucocorticoid that is required to produce a specific effect, is dependent on its pharmacokinetic (PK) and pharmacodynamic (PD) properties. In this review, we summarize the PK/PD properties of commonly used glucocorticoids in an attempt to better delineate their role in the management of children with childhood-onset SLE (cSLE). We also address glucocorticoid side effects as these play a major role when deciding on the dose, frequency, and duration of use. A better understanding of the pharmacology of glucocorticoids appears useful to achieve improved outcomes in the management of cSLE.