Type I interferon pathway in pediatric systemic lupus erythematosus.

BACKGROUND: The role of type I interferon (IFN-I) signaling in systemic lupus erythematosus (SLE) has been well established. However, unanswered questions remain regarding the applicability of these findings to pediatric-onset SLE. The aim of this review is to provide an overview of the novel discoveries on IFN-I signaling in pediatric-onset SLE. DATA SOURCES: A literature search was conducted in the PubMed database using the following keywords: "pediatric systemic lupus erythematosus" and "type I interferon". RESULTS: IFN-I signaling is increased in pediatric SLE, largely due to the presence of plasmacytoid dendritic cells and pathways such as cyclic GMP-AMP synthase-stimulator of interferon genes-TANK-binding kinase 1 and Toll-like receptor (TLR)4/TLR9. Neutrophil extracellular traps and oxidative DNA damage further stimulate IFN-I production. Genetic variants in IFN-I-related genes, such as IFN-regulatory factor 5 and tyrosine kinase 2, are linked to SLE susceptibility in pediatric patients. In addition, type I interferonopathies, characterized by sustained IFN-I activation, can mimic SLE symptoms and are thus important to distinguish. Studies on interferonopathies also contribute to exploring the pathogenesis of SLE. Measuring IFN-I activation is crucial for SLE diagnosis and stratification. Both IFN-stimulated gene expression and serum IFN-α2 levels are common indicators. Flow cytometry markers such as CD169 and galectin-9 are promising alternatives. Anti-IFN therapies, such as sifalimumab and anifrolumab, show promise in adult patients with SLE, but their efficacy in pediatric patients requires further investigation. Janus kinase inhibitors are another treatment option for severe pediatric SLE patients. CONCLUSIONS: This review presents an overview of the IFN-I pathway in pediatric SLE. Understanding the intricate relationship between IFN-I and pediatric SLE may help to identify potential diagnostic markers and targeted therapies, paving the way for improved patient care and outcomes.

Development of spontaneous recurrent seizures accompanied with increased rates of interictal spikes and decreased hippocampal delta and theta activities following extended kindling in mice.

Interictal epileptiform discharges refer to aberrant brain electrographic signals between seizures and feature intermittent interictal spikes (ISs), sharp waves, and/or abnormal rhythms. Recognition of these epileptiform activities by electroencephalographic (EEG) examinations greatly aids epilepsy diagnosis and localization of the seizure onset zone. ISs are a major form of interictal epileptiform discharges recognized in animal models of epilepsy. Progressive changes in IS waveforms, IS rates, and/or associated fast ripple oscillations have been shown to precede the development of spontaneous recurrent seizures (SRS) in various animal models. IS expressions in the kindling model of epilepsy have been demonstrated but IS changes during the course of SRS development in extended kindled animals remain to be detailed. We hence addressed this issue using a mouse model of kindling-induced SRS. Adult C57 black mice received twice daily hippocampal stimulations until SRS occurrence, with 24-h EEG monitoring performed following 50, 80, and ≥ 100 stimulations and after observation of SRS. In the stimulated hippocampus, increases in spontaneous ISs rates, but not in IS waveforms nor IS-associated fast ripples, along with decreased frequencies of hippocampal delta and theta rhythms, were observed before SRS onset. Comparable increases in IS rates were further observed in the unstimulated hippocampus, piriform cortex, and entorhinal cortex, but not in the unstimulated parietal cortex and dorsomedial thalamus. These data provide original evidence suggesting that increases in hippocampal IS rates, together with reductions in hippocampal delta and theta rhythms are closely associated with development of SRS in a rodent kindling model.

Screening and Identification of the Biomarkers Applied for the Evaluation of Acute and Chronic Thermal Tolerance Ability in Largemouth Bass (Micropterus salmoides).

Affected by the continuously rising temperature, thermal stress leads to a delinked growth rate and resistance to stress in cultured largemouth bass (Micropterus salmoides, LMB) in China. Identification of LMB with better thermal resistance will benefit the breeding of new varieties. However, there has been limited reporting on the evaluation to identify LMB with better thermal resistance. LMB consists of the northern LMB (Micropterus salmoides salmoides, NLMB) and the Florida LMB (Micropterus salmoides floridanus, FLMB). Due to their different geographical distributions, it has been suggested that FLMB exhibit better thermal resistance compared to NLMB. In this study, NLMB and FLMB were subjected to thermal stress for 3 h (acute) and 60 d (chronic) at 33 °C, respectively. Subsequently, the variations of 12 candidate biomarkers between NLMB and FLMB were analyzed. Exposure to acute thermal stress significantly increased plasma cortisol, blood glucose, and lactate levels; activities of superoxide dismutase (SOD), glutathione peroxidase (GPX), catalase (CAT), glucose kinase (GK), pyruvate kinase (PK), lactate dehydrogenase (LDH), and glucose 6 phosphatase (G6Pase); and the expressions of hsp70 and hsp90 in both NLMB and FLMB (p < 0.05). Compared to NLMB, FLMB exhibited a lower plasma cortisol level and a higher expression of hsp90 under acute thermal stress (p < 0.05). Exposure to chronic thermal stress significantly increased plasma cortisol and blood glucose levels, as well as activities of GK, PK, LDH, and G6Pase, as well as expressions of hsp70 and hsp90 in both NLMB and FLMB (p < 0.05). Additionally, FLMB showed a lower expression of hsp70 compared to NLMB (p < 0.05). In conclusion, our results showed that LMB with lower plasma cortisol level and higher expression of hsp90 under acute thermal stress, as well as lower expression of hsp70 under chronic thermal stress were suggested to have better thermal resistance. Our study provides valuable information for identifying and breeding LMB varieties with better thermal resistance in the future.

Expression characteristics of the cyp19a1b aromatase gene and its response to 17ß-estradiol treatment in largemouth bass (Micropterus salmoides).

To investigate the regulatory role of the cyp19a1b aromatase gene in the sexual differentiation of largemouth bass (Micropterus salmoides, LMB), we obtained the full-length cDNA sequence of cyp19a1b using rapid amplification of cDNA ends technique. Tissue expression characteristics and feedback with 17-ß-estradiol (E2) were determined using quantitative real-time PCR (qRT-PCR), while gonad development was assessed through histological section observations. The cDNA sequence of LMB cyp19a1b was found to be1950 base pairs (bp) in length, including a 5' untranslated region of 145 bp, a 3' untranslated region of 278 bp, and an open reading frame encoding a protein consisting of 1527 bp that encoded 508 amino acids. The qRT-PCR results indicated that cyp19a1b abundantly expressed in the brain, followed by the gonads, and its expression in the ovaries was significantly higher than that observed in the testes (P < 0.05). After feeding fish with E2 for 30 days, the expression of cyp19a1b in the pseudo-female gonads (XY-F) was significantly higher than that in males (XY-M) (P < 0.05), whereas expression did not differ significantly between XX-F and XY-F fish (P > 0.05). Although the expression of cyp19a1b in XY-F and XX-F fish was not significantly different after 60 days (P>0.05), both exhibited significantly higher levels than that of XY-M fish (P<0.05). Histological sections analysis showed the presence of oogonia in both XY-F and XX-F fish at 30 days, while spermatogonia were observed in XY-M fish. At 60 days, primary oocytes were abundantly observed in both XY-F and XX-F fish, while a few spermatogonia were visible in XY-M fish. At 90 days, the histological sections' results showed that a large number of oocytes were visible in XY-F and XX-F fish. Additionally, the gonads of XY-M fish contained numerous spermatocytes. These results suggest that cyp19a1b plays a pivotal role in the development of ovaries and nervous system development in LMB.

Phenotype of Takayasu-like vasculitis and cardiopathy in patients with Blau syndrome.

OBJECTIVES: We aimed to determine the prevalence of cardiovascular involvement in our Blau syndrome (BS) cohort and provide detailed analysis of their cardiovascular manifestations and outcome. We also tried to find out the risk factors for developing cardiovascular involvement. METHODS: Clinical manifestations, laboratory findings, and treatments were reviewed. Clinical features were compared between children with cardiovascular involvement and those without angiocardiopathy. RESULTS: A total of 38 BS children were eligible for final analysis. Among them, 13 (34.2%) developed Takayasu-like vasculitis and/or cardiopathy. Compared with those without angiocardiopathy, recurrent fever was more frequent in BS patients with cardiovascular involvement (p < 0.001). What is more, tumor necrosis factor alpha antagonists (anti-TNF) were more urgently needed in children with cardiovascular involvement (p = 0.015). BS patients with cardiovascular involvement include 4 with Takayasu-like vasculitis and 9 with cardiopathy. The onset of cardiovascular manifestations ranged from 0.75 to 18.5 years of age, with most cases occurring before school period. Symptoms were elusive and lacked specificity, such as dizziness, short of breath, and edema. Some patients were even identified because of the unexpected hypertension during follow-up. Cardiopathy and vasculitis occurred in patients with different genotypes. Imaging changes were discovered before the presentation of the typical triad in 3/4 patients with Takayasu-like vasculitis. Three children developed left ventricular dysfunction with decreased left ventricular ejection fraction. Combination of glucocorticoids and methotrexate with anti-TNF agents is a common treatment option for these BS patients. In the cohort, BS-related cardiovascular involvement was controlled well, with cardiac structural and functional abnormalities completely recovered and slower progression of vasculitis lesions. CONCLUSION: Cardiovascular manifestations is not rare in BS patients. Because of its insidious onset, a systematic and comprehensive assessment of cardiovascular involvement should be performed in newly diagnosed patients with BS. Aggressive initiation of anti-TNF agents may be beneficial to improve the prognosis. Key Points • About 34.2% patients with Blau syndrome developed Takayasu-like vasculitis and/or cardiopathy. • Compared with those without angiocardiopathy, recurrent fever and application of anti-TNF agents were more frequent in BS patients with cardiovascular involvement (p < 0.001, p = 0.015) • Regular assessment of cardiovascular involvement is extremely necessary because of its insidious onset.

Lipids and sudden sensorineural hearing loss: A bidirectional two-sample Mendelian randomization analysis.

OBJECTIVE: While numerous observational studies have indicated an association between lipids and Sudden Sensorineural Hearing Loss (SSNHL), it remains uncertain whether dyslipidemia serves as a causal risk factor for SSNHL. Our objective is to elucidate the potential causal relationship between lipid levels and SSNHL through Mendelian randomization analysis. METHODS: The primary and secondary lipid data used in this study were sourced from the UK Biobank (UKBB) and the Global Lipid Genetics Consortium results (GLGC), respectively. These datasets were obtained from large, publicly available genome-wide association studies (GWAS). The outcome data for sudden sensorineural hearing loss (SSNHL) were acquired from the Finnegan Biobank, consisting of 1491 cases and 196,592 controls. Subsequently, both single-variable Mendelian randomization (SVMR) and multivariate Mendelian randomization (MVMR) methods were employed to evaluate the causal relationship between lipids and the occurrence of SSNHL. RESULTS: Among the primary lipid data, SVMR analysis showed a significant correlation between high density lipoprotein cholesterol (HDL-C) (OR: 0.822, 95 %CI: 0.694-0.974, p = 0.023) and SSNHL, and triglycerides (TG) (OR: 0.997, 95 %CI: 0.836-1.188, p = 0.975), low density lipoprotein cholesterol (LDL-C) (OR: 1.067, 95 %CI: 0.861-1.322, p = 0.552) did not correlate with SSNHL. In the secondary lipid data, SVMR analysis showed that HDL-C (OR: 0.987, 95 %CI: 0.805-1.210, p = 0.903), TG (OR: 0.991, 95 %CI: 0.787-1.246, p = 0.937) and LDL-C (OR: 1.092, 95 % CI: 0.926-1.287, p = 0.294) did not correlate with SSNHL. MVMR analysis of the primary lipid data showed that HDL-cholesterol (OR: 0.755, 95 % CI: 0.596-0.956, p = 0.019) was significantly associated with SSNHL, while TG (OR: 0.808, 95 %CI: 0.611-1.068, p = 0.134) and LDL-C (OR: 1.146, 95 %CI: 0.869-1.511, p = 0.333) did not correlate with SSNHL, consistent with the results of SVMR. Inverse MR results showed that SSNHL did not correlate with TG (OR: 0.999, 95 %CI: 0.997-1.001, p = 0.835), HDL-C (OR: 1.001, 95 %CI: 0.998-1.003), LDL-C (OR: 0.999, 95 %CI: 0.997-1.002, p = 0.863). CONCLUSIONS: Mendelian randomization (MR) results suggest that decreased serum HDL-C levels are an independent risk factor for SSNHL. Monitoring and focusing on lipid levels may be of value in the prevention and treatment of SSNHL.

High-risk groups of neonatal lupus erythematosus in term infants: a birth cohort study.

This study aims to analyze the clinical characteristics and risk factors of high-risk groups of neonatal lupus erythematosus (NLE) in term infants. High-risk groups of NLE infants whose mothers were positive for anti-SSA, anti-SSB or anti-U1RNP antibodies during pregnancy were enrolled. They were born between February 2013 and February 2020, with a gestational age not less than 37 weeks. We analyzed their clinical data from birth to 24 months after birth. A total of 105 patients in the NLE high-risk group were included. Among them, 30 patients were diagnosed with NLE (NLE group), and 75 patients were not (non-NLE group). The affected systems of the NLE group included the dermal (13.3%), hepatic (76.0%), and hematological systems (43.3%). Hepatic involvement, anemia and thrombocytopenia did not emerge until 60 days, 41 days and 22 days after birth, respectively, in some cases. Systemic involvement could be cured within 3 to 12 months after birth. The clearance time of specific autoantibodies was 12 months after birth. There was no significant difference in the clinical characteristics of babies and their mothers between the two groups, neither in the positive rate nor in the clearance time of specific autoantibodies. CONCLUSION: After standardized prenatal health care, there is still a high risk of dermal, hepatic, or hematological system involvement for high-risk groups of NLE. There are no specific indicators for the prediction of whether babies will develop NLE. All of these patients need to be followed up closely within one year after birth. WHAT IS KNOWN: • Neonatal lupus erythematosus (NLEs) can affect the cardiac, dermal, hepatic, and hematological systems of infants. WHAT IS NEW: • After standardized prenatal health care employing good multidepartment cooperation in our center, no neonates had cardiac block in this study. However, dermal, hepatic, and hematological system involvement of NLE can still gradually appear (as long as 60 days after birth in some cases) during follow-up, and some of these conditions are serious and require timely and active intervention. No single factor has been found to predict whether offspring at high-risk of NLE whose mothers are positive for anti-SSA, SSB and/or RNP will develop NLE.

The role of intraoperative neurophysiological monitoring in intramedullary spinal cord tumor surgery.

Intramedullary tumors are a class of central nervous system tumors with an incidence of 2 to 4%. As they are located very deep and frequently cause postoperative neurological complications, surgical resection is difficult. In recent years, many surgeons have performed electrophysiological monitoring to effectively reduce the occurrence of postoperative neurological complications. Modern electrophysiological monitoring technology has advanced considerably, leading to the development of many monitoring methods, such as SSEPs, MEPs, DCM, and EMG, to monitor intramedullary tumors. However, electrophysiological monitoring in tumor resection is still being studied. In this article, we discussed the different monitoring methods and their role in monitoring intramedullary tumors by reviewing previous studies. Intratumorally tumors need to be monitored for a summary of the condition of the patient. Only by using various monitoring methods flexibly and through clear communication between surgeons and neurophysiological experts can good decisions be made during surgery and positive surgical results be achieved.

Integrated transcriptomic and proteomic analyses reveal the mechanism of easy acceptance of artificial pelleted diets during food habit domestication in Largemouth bass (Micropterus salmoides).

Acceptance of artificial pelleted diets contributes to increasing the cultured areas and output of carnivorous fish. However, the mechanism of acceptance of artificial pelleted diets remains largely unknown. In this study, the easy acceptance of artificial pelleted diets (EAD) group and the not easy acceptance of artificial pelleted diets (NAD) group of Largemouth bass (Micropterus salmoides) were divided based on the ratios of stomach weight/body weight (SB) after 0.5 h feeding, which was bigger than 18% in the EAD group and ranged from 8 to 12% in the NAD group. Through transcriptome and proteome sequencing, a total of 2463 differentially expressed genes (DEGs) and 230 differentially expressed proteins (DEPs) were identified, respectively. Integrated analyses of transcriptome and proteome data revealed that 152 DEPs were matched with the corresponding DEGs (named co-DEGs-DEPs), and 54 co-DEGs-DEPs were enriched in 16 KEGG pathways, including the metabolic pathways, steroid biosynthesis, fatty acid biosynthesis, etc. Furthermore, 3 terpenoid backbone biosynthesis-related genes (Hmgcr, Hmgcs, and Fdps) in metabolic pathways, 10 steroid biosynthesis-related genes (Fdft1, Sqle, Lss, Cyp51a1, Tm7sf2, Nsdhl, Hsd17b7, Dhcr24, Sc5d, and Dhcr7), and 3 fatty acid biosynthesis-related genes (Acaca, Fasn, and Ascl) were all up-regulated in the EAD group, suggesting that the lipid metabolism pathway and steroid biosynthesis pathway play important roles in early food habit domestication in Largemouth bass. In addition, the detection results of randomly selected 15 DEGs and 15 DEPs indicated that both transcriptome and proteome results in the study were reliable. Our study provides useful information for further research on the mechanisms of food habit domestication in fish.

Tocilizumab reduces the unmanageable inflammatory reaction of a patient with Aicardi-Goutières syndrome type 7 during treatment with ruxolitinib.

BACKGROUND: Aicardi-Goutières syndrome (AGS) is a rare hereditary early-onset encephalopathy characterized by upregulation of the type I interferon pathway, poorly responsive to conventional immunosuppression. CASE PRESENTATION: We describe a 7-year-old Chinese boy who developed symptoms at the age of 6 months. He presented with a chilblain-like rash, leukopenia, neutropenia, elevated liver enzymesgrowth retardation, microcephaly, elevated acute phase reactants, intracranial calcification and leukodystrophy. At the age of 3 years old, whole-exome sequencing confirmed a de novo heterozygous gain-of-function mutation, c.1016 C > A (p.Ala339Asp), in the IFIH1 gene, and he was diagnosed with AGS7. He was treated with ruxolitinib accompanied by steroids and thalidomide for about four years. The rash, hematological manifestations, and the liver function were all improved, but the erythrocyte sedimentation rate remained consistently elevated until the addition of tocilizumab, a monoclonal antibody against interleukin 6. CONCLUSIONS: Ruxolitinib was not successful in suppressing the inflammatory process, and tocilizumab produced highly encouraging results in reducing the inflammatory reaction of AGS. The study makes a significant contribution to the literature because we may found a potential alternative therapeutic option for AGS.

Efficacy and safety of thalidomide in children with monogenic autoinflammatory diseases: a single-center, real-world-evidence study.

BACKGROUND: Monogenic autoinflammatory diseases (AIDs) are rare inflammatory diseases caused by genetic variants. The pathogenesis is complex and treatment options are limited. This study aimed to describe the safety and efficacy of thalidomide in the treatment of monogenic AIDs. METHODS: This was a single-center, single-arm, real-world study. From September 2016 to August 2021, patients with monogenic AIDs who met the inclusion and exclusion criteria were given thalidomide for 12 months. There was a 3-month run-in period before dosing. The efficacy and adverse events were evaluated and recorded every 3 months. After 3 and 12 months of thalidomide treatment, clinical manifestations, disease activity score, inflammatory markers, and background medication adjustments were compared with baseline for efficacy analyses. RESULTS: A total of 16 patients entered this study, including 3 with Aicardi-Goutières syndrome (AGS), 4 Blau syndrome, 2 chronic infantile neurologic cutaneous articular syndrome (CINCA), 2 A20 haploinsufficiency (HA20), 1 adenosine deaminase 2 deficiency(DADA2), 1 familial Mediterranean fever (FMF),1 tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), 1 PLCγ2-associated antibody deficiency and immune dysregulation (PLAID), and 1 stimulator of interferon genes-associated vasculopathy with onset in infancy(SAVI). The efficacy rate in the 16 patients after 3-month and 12-month thalidomide treatment in patients was 56.3%. Twelve patients completed the study, the fever improved in all of them, rash improved in 7 patients, and 5 patients stopped using glucocorticoids or other immunosuppressive agents. C-reactive protein was normal in 8 patients and erythrocyte sedimentation rate was normal in 11 patients. Anorexia and nausea occurred in 2 cases, with no other reported drug-related adverse reactions. CONCLUSION: The largest cohort of monogenic AIDs with the treatment of thalidomide demonstrated that thalidomide can help reduce disease activity and inflammation, reduce the dosage of glucocorticoids, and improve clinical outcomes. Thalidomide is relatively safe in monogenic AIDs.

A dominant pathogenic MEFV mutation causes atypical pyrin-associated periodic syndromes.

Pyrin, a protein encoded by the MEFV gene, plays a vital role in innate immunity by sensing modifications in Rho GTPase and assembling the pyrin inflammasome, which in turn activates downstream immune responses. We identified a novel and de novo MEFV p.E583A dominant variant in 3 patients from the same family; the variant was distinct from the previously reported S242 and E244 sites. These patients exhibited a phenotype that diverged from those resulting from classical MEFV gene mutations, characterized by the absence of recurrent fever but the presence of recurrent chest and abdominal pain. Colchicine effectively controlled the phenotype, and the mutation was found to induce pyrin inflammasome assembly and activation in patients' peripheral blood mononuclear cells (PBMCs) and cell lines. Mechanistically, truncation experiments revealed that the E583A variant affected the autoinhibitory structure of pyrin. Our study offers insights into the mechanisms underlying pyrin inflammasome activation.

Evaluation of belimumab in treatment of Chinese childhood-onset systemic lupus erythematosus: a prospective analysis from multicenter study.

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 centers 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: 193 (92.2% female) with active cSLE from 15 centers 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 (SD) 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.

Application of cementoplasty in patients with symptomatic benign osteopathy disease.

BACKGROUND: The optimal treatment for some symptomatic, benign osteopathy lesions is yet to be identified. PURPOSE: To investigate the clinical efficiency of cementoplasty in managing symptomatic, benign osteopathy. MATERIAL AND METHODS: Between June 2006 and January 2020, we retrospectively enrolled 31 patients (10 men, 21 women; mean age = 46.5 ± 16.6 years; age range = 20-85 years), accounting for 34 treatment sites, who underwent percutaneous osteoplasty (14 treatment sites) and percutaneous vertebroplasty (20 treatment sites) with digital subtraction angiography (DSA) or DSA combined with computed tomography (CT). All the participants experienced different degrees of clinical symptoms with benign osteopathy lesions. The technical success of the procedure and occurrence of complications were recorded. Follow-up examinations were conducted to assess the treatment outcome using the MacNab criteria. RESULTS: All the participants had a diagnosis of benign osteopathy lesions before or after the cementoplasty. Surgery was successfully completed in all patients. Cement distributions were diffuse and homogeneous, with the complication of cement leakage occurring in 17.6% (6 of 34) of the lesions. The leakage occurred in the intervertebral disc (n = 1), the intra-articular space (n = 1), and the surrounding soft tissue (n = 4). Analysis of the treatment outcome using the MacNab criteria revealed that all patients showed improvement in their clinical symptoms to some extent and in the quality of life. CONCLUSION: Cementoplasty is an effective treatment for symptomatic, benign osteopathy, with the advantage of favorable clinical outcomes, and low complication rate.

The effect of antinuclear antibody titre and its variation on outcomes in children with primary immune thrombocytopenia.

Antinuclear antibody (ANA) can be positive in children with primary immune thrombocytopenia (ITP), but the effect of ANA titre and its variation on outcomes of children with primary ITP remains unclear. Here, we conducted a single-centre retrospective cohort study of children with primary ITP at the Peking Union Medical College Hospital in China. A total of 324 children with primary ITP included in this study were followed for a median time of 25 months. In this cohort, 39.2% had an ANA titre of 1:160 or higher. Results from a generalized estimating equation model revealed that patients with higher ANA titres had lower platelet counts at onset but a higher recovery rate of subsequent platelet counts. Results from Cox regression models adjusted for potential confounders revealed that patients with ANA titres of 1:160 or more were more likely to develop to autoimmune disease (AID) than those without, and the risk of AID development increased with the rise of ANA titres (p value for trend less than 0.001). These data highlight the predictive value of ANA titre for platelet counts and the risk of AID development in children with primary ITP.

Clinical phenotypes and prognosis of cytomegalovirus infection in the pediatric systemic lupus erythematosus: a longitudinal analysis.

BACKGROUND: Cytomegalovirus (CMV) plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). However, it is not clear whether the anti-CMV treatment has an impact on the prognosis of SLE patients with CMV infection. We aimed to analyze the clinical characteristics and prognosis of CMV infection in pediatric SLE (pSLE) and to evaluate the effect of anti-CMV treatment on pSLE outcome. METHODS: A retrospective study including 146 pSLE from 2012 to 2021 was conducted. CMV-positive and CMV-negative groups were compared by univariate analysis and stepwise logistic multiple regression to analyze the clinical characteristics of CMV infection in pSLE. Generalized estimating equations (GEE) were used to model the longitudinal dynamics of pSLE disease activity with or without CMV infection and anti-CMV treatment. RESULTS: The CMV infection rate was 74.7% (109/146) in this pSLE cohort. CMV-positive pSLE patients were more likely to present positive anti-dsDNA antibody, hypocomplementemia, high SLEDAI-2K score and musculoskeletal involvement (P < 0.05). Survival analysis showed that CMV-positive pSLE patients were more prone to disease flare and poorer outcomes. GEE modeling indicated that CMV phosphoprotein 65 (pp65) titers were positively correlated with SLEDAI-2K, and anti-CMV treatment could better reduce pSLE activity than non-treatment (P < 0.05). CONCLUSIONS: CMV infection is highly prevalent among pSLE patients. Positive anti-dsDNA antibody, hypocomplementemia, high SLEDAI-2K score and musculoskeletal involvement were significant clinical clues indicating CMV infections in pSLE. CMV infection is correlated with higher disease activity and poorer outcome. Anti-CMV treatment can reduce disease activity and flares.

A Cohort Study on Deficiency of ADA2 from China.

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.

Unique mutation spectrum of progressive pseudorheumatoid dysplasia in the Chinese population: a retrospective genotype-phenotype analysis of 105 patients.

BACKGROUND: Progressive pseudorheumatoid dysplasia (PPRD) is a rare genetic disease with autosomal recessive inheritance. There was a lack of genotype-phenotype correlation data from the Chinese population. This study aimed to identify the genotype and phenotype characteristics of Chinese PPRD patients and to conduct a genotype-phenotype analysis of Chinese PPRD patients. METHODS: Genetic analysis was performed for suspected PPRD patients from Peking Union Medical College Hospital. Medical records were collected from the electronic medical record system and patient-held portable health records. Published Chinese PPRD cases were gathered from both international and Chinese local databases. We collected demographic information, genetic variants, clinical manifestations, and imaging characteristics for further analysis. RESULTS: We included 105 Chinese PPRD patients in the current study. Thirty-three variants, including nine novels and five hotspot variants, were identified, with 26/33 (79%) variants exclusively seen in the Chinese population. Chinese PPRD patients share a phenotype similar to that in international reports. Joint involvement may progress with age (R2 = 0.2541). Long bone shortening and severe deformities occur in three patients with biallelic null variants, of which at least one variant is located in exon 2. Among hotspot variants, c.624dupA (p.C209Mfs*21) were associated with later onset and more involved joints. Elbow joints were more likely to be affected in patients carrying c.624dupA (p.C209Mfs*21) and c.866dupA (p.S209Efs*13). Shoulder joints are more likely to be involved in patients with biallelic null variants (P = 0.027). CONCLUSIONS: Chinese PPRD patients share a unique mutation spectrum. Among the five hotspot variants, c.624dupA is associated with later onset of disease, more extensive joint involvement, and a tendency to affect elbow joints. Biallelic null variants with at least one variant in exon 2 could be a likely cause of long bone shortening and severe deformities.