Autoinflammatory syndromes mimicking Behçet's disease with gastrointestinal involvement: a retrospective analysis.

OBJECTIVES: This retrospective study aimed to investigate the clinical characteristics and genetic findings in paediatric patients with gastrointestinal involvement in Behçet's disease (BD), elucidating the spectrum of autoinflammatory syndromes mimicking BD in this young population. METHODS: Fifty paediatric patients diagnosed with BD between January 2016 and December 2022, including 24 (48%) with gastrointestinal involvement, underwent comprehensive analysis. Clinical presentations, laboratory examinations, gastrointestinal endoscopy, and genetic tests were conducted, with patients stratified based on genetic results for rigorous comparative clinical analysis. RESULTS: The cohort, with a median age of disease onset at 4.0 years, predominantly manifested with recurrent oral ulcers (100%). Gastrointestinal symptoms were prevalent in 83.3%, with abdominal pain (70%) and haematochezia (16.7%) being notable. Endoscopic evaluations unveiled lesions primarily in the terminal ileum and ileocecal region, with diverse ulcers across various anatomical sites. While 70.8% initially met ICBD criteria, only 41.6% fulfilled new paediatric classification criteria. Genetic analysis in 18 patients unveiled pathogenic variants in 7, with the genetic-positive group exhibiting earlier onset and more atypical symptoms. Noteworthy cases included X-linked deficiency in ELF4, A20 haploinsufficiency, and Majeed syndrome, with two cases revealing chromosomal abnormalities such as trisomy 8 syndrome. Comparative analysis underscored earlier disease onset, heightened inflammatory markers, and distinctive gastrointestinal lesions in the genetic-positive cohort. CONCLUSIONS: Identification of monogenic diseases and chromosomal abnormalities resembling BD underscores the imperative of precise diagnosis for tailored treatment and genetic counselling. Expanding genetic screening initiatives holds promise for enhancing our comprehension of the genetic landscape associated with BD.

Juvenile dermatomyositis with central nervous system involvement: two case reports from a retrospective single-center cohort, with literature review.

Background: Juvenile dermatomyositis (JDM) is a systemic autoimmune disease primarily involving the muscles and skin; it can also affect the central nervous system (CNS). The relevant literature provides limited information regarding the characteristics of JDM with CNS involvement. Method: We reviewed patients with JDM who were hospitalized at our center between January 2016 and August 2023, with a focus on those with CNS involvement. The aim was to provide detailed case reports on these patients, and to summarize the relevant literature about the characteristics of similar cases. Results: Among 193 hospitalized patients with JDM, two (1.03%) had CNS involvement. Two patients, a 5.5-year-old girl and an 11-year-old boy, were admitted with severe proximal muscle weakness and seizures, and presented with active cutaneous vasculitis. Both were ultimately diagnosed with JDM, with CNS involvement. Both patients had confirmed presence of anti-NXP2 antibody through myositis-specific antibody analysis. Additionally, they all exhibited hyperferritinemia and thrombocytopenia. Salvage therapies like intravenous methylprednisolone (IVMP) pulse therapy and/or plasma exchange were administered successfully. At final follow-up, both patients had achieved complete clinical response and full neurological recovery. Our literature review identified nine similar case studies. CNS involvement usually occurred within the first 10 months of the disease course, and most of these patients had fatal outcomes, with a mortality rate of 66.6% (6/9). Including the two patients described herein, the median age for disease onset is 10.5 years (range 4-17 years), and the male: female ratio is 6:5. Seizures are the most common neurological symptom, accompanied by active cutaneous vasculitis. The brain biopsies showed two distinct pathological presentations: one was central nervous system vasculitis, and the other was cerebral macrophage activation syndrome. Conclusions: CNS involvement is a rare but life-threatening JDM complication. Herein, our cases and the literature indicate that it typically occurs within the first 10 months of the disease course and manifests as seizures, often accompanied by active cutaneous vasculitis, with fatal outcomes. Timely implementation of salvage therapies, like IVMP pulse therapy and plasma exchange, may significantly impact patient outcomes.

Monogenic autoinflammatory disease-associated cardiac damage.

INTRODUCTION: Autoinflammatory diseases (AIDs) constitute several disorders that are characterized by the presence of recurrent episodes of unprovoked inflammation due to dysregulated innate immune system in the absence of autoantibodies or infections. Most of them have a strong genetic background, with mutations in single genes involved in inflammation referred to monogenic AIDs. In this article, we will review the cardiac manifestations in various monogenic AIDs. AREAS COVERED: Various cardiac manifestations can be seen in various monogenic AIDs, including pericarditis, valvular diseases, coronary diseases, cardiomyopathies, and pulmonary hypertension, especially in Familial Mediterranean fever (FMF). EXPERT COMMENTARY: Monogenic AIDs can manifest a variety of cardiac lesions, the most common of which is pericardial effusion, which may be local pericardial inflammation secondary to systemic inflammatory responses. While, the pathogenesis and incidence are still unclear. More research is still needed to explore the relationship between monogenic AIDs and cardiac damage for better understanding these diseases.

Mitochondrial Dynamics of Podocyte in Various International Society of Nephrology/Renal Pathology Society Class Lupus Nephritis Patients.

Morphological changes of podocyte mitochondria are observed in patients with mitochondrial cytopathy and nephrotic syndrome. However, whether mitochondrial dynamics involved in podocyte in lupus nephritis (LN) is still not clear. This study aims to investigate the associations between mitochondrial morphology and podocyte lesions and laboratory and pathological features in LN. The foot process width (FPW) and mitochondrial morphology were observed through electron microscope. Then the associations between mitochondrial morphology and podocyte lesions and laboratory features were explored in various International Society of Nephrology/Renal Pathology Society class LN patients. Foot process effacement and excessive mitochondria fission in podocyte were observed and proteinuria was positively correlated with FPW. Mitochondria area, circumference, and aspect ratio were negatively correlated with BUN, and 24h-UTP positively correlated with Alb. At the same time, Alb was negatively correlated with form factor. FPW, form factor, surface density, and numerical density on area were positively correlated with 24h-UTP. Excessive mitochondrial fission is associated with podocyte damage and proteinuria, whereas the mechanism still needs to be explored.

Identification of a circRNA-miRNA-mRNA network to explore the effects of circRNAs on pathogenesis and treatment of systemic lupus erythematosus.

OBJECTIVES: Systemic lupus erythematosus (SLE) is an autoimmune disease characterised by immune inflammation. It involves multiple organs. Many studies have demonstrated that circRNAs are closely associated with SLE. Nonetheless, the potential mechanism by which circRNAs impacts SLE is not fully understood. The aim of this study was to explore the regulatory roles of circRNAs, the key genes and pathways governing the pathophysiological processes of SLE, and to screen therapeutic agents. METHODS: The sequencing data of circRNA, miRNA and mRNA were obtained from Gene Expression Omnibus (GEO) datasets. Candidates were identified to construct a circRNA-miRNA-mRNA network based on circRNA-miRNA interactions and miRNA-mRNA interactions. Gene functional enrichments were performed on the DAVID database. Protein-protein interaction (PPI) network was constructed by STRING database and visualised in Cytoscape software. The hub genes were explored by the MCODE plugin app. The Connectivity Map L1000 platform was used to identify potential agents. RESULTS: A total of 1093 differentially expressed circRNAs (DEcircRNAs), 42 differentially expressed miRNAs (DEmiRNAs) and 1431 differentially expressed mRNAs (DEmRNAs) were identified. We integrated 3 overlapped circRNAs, 13 miRNAs and 352 target mRNAs into a circRNA-miRNA-mRNA network. We next identified 44 hub genes based on the PPI network. KEGG pathway analysis revealed that the DEGs were mainly associated with MAPK signalling pathway. In addition, we discovered several chemicals as potential treatment options for SLE. CONCLUSIONS: Through this bioinformatics analysis, we suggest a regulatory role for circRNAs in the pathogenesis and treatment of SLE from the view of a competitive endogenous RNA (ceRNA) network.

Symptomatic femoral head necrosis in patients with rheumatoid arthritis: A retrospective case-control study.

OBJECTIVE: We conducted a retrospective case-control study to investigate the risk factors for osteonecrosis of the femoral head (ONFH) in rheumatoid arthritis (RA) patients. METHODS: The clinical data of patients diagnosed with RA at Fujian Provincial Hospital from January 2013 to December 2020 were retrospectively collected and evaluated. Twenty-two patients with ONFH were identified. Eighty-eight age-, sex-, and disease duration-matched RA patients without symptomatic ONFH were randomly selected as controls in a ratio of 1:4. Logistic regression analysis was used to analyze the risk factors. RESULTS: The anticardiolipin (ACL)-immunoglobulin G (IgG) concentration, clinical disease activity index, simplified disease activity index, incidence of hyperlipidemia in the case group were higher than those in the control group. Multivariate logistic regression analysis did not find the independent risk factor in ONFH patients with RA. CONCLUSION: The pathogenesis of ONFH in RA is related to many factors such as ACL IgG, disease activity index, and hyperlipidemia. While, we went to great lengths to explore the relationship between antiphospholipid antibodies and ONFH, but it plays a very small role.

Relationship between osteonecrosis and antiphospholipid antibodies in patients with systemic lupus erythematosus: a systematic review protocol.

INTRODUCTION: Osteonecrosis (ON) is characterised by the destruction of the normal blood supply to the bone tissue. ON is the main cause of disability in patients with systemic lupus erythematosus (SLE). Studies have reported the existence of many risk factors for SLE complicated by ON, including the use of high-dose glucocorticoids and high disease activity. The correlation between antiphospholipid antibodies (aPLs) and ON in SLE has been controversial. We aim to conduct a systematic review of the literature related to SLE, aseptic ON and aPLs, to provide a reference for the clinical screening of high-risk patients and for early prevention. METHODS AND ANALYSIS: The following six databases will be searched: MEDLINE/PubMed, Embase, Web of Science, Chinese Biomedical Literature Database, Wan-Fang Database and China National Knowledge Infrastructure. The database searches will not be restricted by date. Case-control studies, cohort studies or observational studies that compare aPLs between SLE patients with and without ON will be considered eligible. Articles published in English and Chinese will be included. Two researchers will independently perform the processes of study selection, data extraction and study quality assessment. The Newcastle-Ottawa Quality Assessment Scale will be used to assess the quality of the retrieved studies. A meta-analysis will be performed after screening the studies. Data will be analysed using ORs for dichotomous data. ETHICS AND DISSEMINATION: Ethical approval is not required because this systematic review will use published data. The systematic review will be electronically disseminated through a peer-reviewed publication or conference presentations. PROSPERO REGISTRATION NUMBER: CRD42020209637.

Five years follow-up of juvenile lupus nephritis: a single-center retrospective cohort study.

BACKGROUND: We analyze the clinical manifestations and 5 years of follow-up outcomes of children with lupus nephritis (LN) and provide a reference for clinicians. METHODS: The clinical data of children diagnosed with LN (n=62) from January 2012-2015 were collected and analyzed. RESULTS: The median age at the diagnosis was 12.0 years. The female to male ratio was 3.4:1. The most prevalent clinical features were mucocutaneous involvement and hematological involvement. Renal biopsy was performed on 38 patients. Class IV and class V were the most common findings. The lupus activity was improved markedly after 3 months treatment. The rate of survival was 98.3% in 5 years. The most common side effects of corticosteroid and other immunosuppressive agent drug treatment were corticosteroid-related hypertension and high intraocular pressure. The rate of cataracts, osteoporotic fracture, and visual field defects increased as the treatment progressed. Especially, the incidence of visual field defects in children is higher than adults. CONCLUSIONS: The LN children showed a good prognosis. During the follow-up process, the adverse drug reactions, such as hormone-related hypertension and ocular hypertension, especially the visual field defects caused by hydroxychloroquine, cannot be excluded. However, multicenter long term follow-up studies are essential to substantiate the current data.

Single-Center Overview of Pediatric Monogenic Autoinflammatory Diseases in the Past Decade: A Summary and Beyond.

Objective: Monogenic autoinflammatory diseases (AIDs) are inborn disorders caused by innate immunity dysregulation and characterized by robust autoinflammation. We aimed to present the phenotypes and genotypes of Chinese pediatric monogenic AID patients. Methods: A total of 288 pediatric patients clinically suspected to have monogenic AIDs at the Department of Pediatrics of Peking Union Medical College Hospital between November 2008 and May 2019 were genotyped by Sanger sequencing, and/or gene panel sequencing and/or whole exome sequencing. Final definite diagnoses were made when the phenotypes and genotypes were mutually verified. Results: Of the 288 patients, 79 (27.4%) were diagnosed with 18 kinds of monogenic AIDs, including 33 patients with inflammasomopathies, 38 patients with non-inflammasome related conditions, and eight patients with type 1 interferonopathies. Main clinical features were skin disorders (76%), musculoskeletal problems (66%), fever (62%), growth retardation (33%), gastrointestinal tract abnormalities (25%), central nervous system abnormalities (15%), eye disorders (16%), ear problems (9%), and cardiopulmonary disorders (8%). The causative genes were ACP5, ADA2, ADAR1, IFIH1, LPIN2, MEFV, MVK, NLRC4, NLRP3, NLRP12, NOD2, PLCG2, PSMB8, PSTPIP1, TMEM173, TNFAIP3, TNFRSF1A, and TREX1. Conclusions: The present study summarized both clinical and genetic characteristics of 18 kinds of monogenic AIDs found in the largest pediatric AID center over the past decade, with fever, skin problems, and musculoskeletal system disorders being the most prevalent clinical features. Many of the mutations were newly discovered. This is by far the first and largest monogenic AID report in Chinese pediatric population and also a catalog of the phenotypic and genotypic features among these patients.

The association of MEFV gene mutations with the disease risk and severity of systemic juvenile idiopathic arthritis.

BACKGROUND: Systemic juvenile idiopathic arthritis (sJIA) has many clinical features overlapping with familial Mediterranean fever (FMF), which is caused by mutations in MEFV gene. And FMF patients were easily misdiagnosed as sJIA in China. So we speculate that MEFV is critical genetic background for sJIA and influences patients' severity. In this study, we aim to figure out whether MEFV mutations are risk factor for the occurrence of sJIA and to study the association of MEFV mutations with disease severity of sJIA patients. METHODS: The present study includes 57 sJIA children and 2573 healthy controls. Odd ratio with 95% confidence interval based on allelic frequency of MEFV mutations or variants was used to evaluate their contribution to sJIA susceptibility. Meta-analysis was then performed to reach comprehensive conclusion. All included sJIA patients were grouped by presence and number of MEFV mutations. Clinical data and indicators of disease severity were compared among different groups. Multiple linear regression method was used to find out whether the number of MEFV variants is associated with the severity of sJIA. Kaplan-Meier curves and log rank test were used to estimate the probability of the first relapse. RESULTS: The MEFV mutations of our subjects predominantly existed in exons 2 and 3. No significant difference was found in allelic frequency between sJIA children and healthy controls. Meta-analysis demonstrated that p.M694V/I was a risk factor for sJIA (pooled OR: 7.13, 95% CI: 3.01-16.89). The relative period of activity was significantly lower in the one mutation group than those with more than one mutation (p = 0.0194). However, no relevance was found in multiple linear regression models. CONCLUSIONS: The mutation p.M694V/I in MEFV might be a risk factor for sJIA. SJIA patients carrying more than one heterozygous mutation in MEFV tend to be more severe than those containing only one, but studies in other cohort of patients need to be performed to validate it.

Characterization of microbiota in systemic-onset juvenile idiopathic arthritis with different disease severities.

BACKGROUND: Systemic-onset juvenile idiopathic arthritis (SoJIA) is one of most serious subtypes of juvenile idiopathic arthritis. Although the pathogenesis of SoJIA remains unclear, several studies have suggested a correlation between gut dysbiosis and JIA. Further understanding of the intestinal microbiome may help to establish alternative ways to treat, or even prevent, the disease. AIM: To explore alterations in fecal microbiota profiles in SoJIA patients and to evaluate the correlations between microbiota and clinical parameters. METHODS: We conducted an observational single-center study at the Pediatric Department of Peking Union Medical College Hospital. Children who were diagnosed with SoJIA at our institution and followed for a minimum period of six months after diagnosis were recruited for the study. Healthy children were recruited as a control group (HS group) during the same period. Clinical data and stool samples were collected from SoJIA patients when they visited the hospital. RESULTS: The SoJIA group included 17 active and 15 inactive consecutively recruited children; the control group consisted of 32 children. Firmicutes and Bacteroidetes were the two most abundant phyla among the total sample of SoJIA children and controls. There was a significant difference among the three groups in observed species, which was the highest in the Active-SoJIA group, followed by the Inactive-SoJIA group and then HS group (Active-SoJIA vs HS: P = 0.000; and Inactive-SoJIA vs HS: P = 0.005). We observed a lower Firmicutes/Bacteroidetes ratio in SoJIA patients (3.28 ± 4.47 in Active-SoJIA, 5.36 ± 8.39 in Inactive-SoJIA, and 5.67 ± 3.92 in HS). We also observed decreased abundances of Ruminococcaceae (14.9% in Active-SoJIA, 17.3% in Inactive-SoJIA, and 22.8% in HS; Active-SoJIA vs HS: P = 0.005) and Faecalibacterium (5.1% in Active-SoJIA, 9.9% in Inactive-SoJIA, and 13.0% in HS; Active-SoJIA vs HS: P = 0.000) in SoJIA compared with HS. By contrast, the abundance of Bacteroidaceae was the highest in the Active-SoJIA group, followed by the Inactive-SoJIA and HS groups (16.5% in Active-SoJIA, 12.8% in Inactive-SoJIA, and 9.7% in HS; Active-SoJIA vs HS: P = 0.03). The Spearman correlation analysis revealed a negative correlation between Proteobacteria or Enterobacteriaceae and juvenile arthritis disease activity score on 27 joints (JADAS-27). CONCLUSION: The composition of the intestinal microbiota is different in SoJIA patients compared with healthy children. The dysbiosis presents partial restoration in inactive status patients.

[Clinical features and TTC21B genotype of a child with nephronophthisis type 12].

Nephronophthisis (NPHP) is a group of autosomal recessive tubulointerstitial cystic kidney disorders. This article reports a case of NPHP type 12 caused by TTC21B mutations. The girl had an insidious onset, with moderate proteinuria, renal dysfunction, stage 2 hypertension, situs inversus, and short phalanges when she visited the hospital for the first time at the age of 3 years and 6 months. The renal lesions progressed to end-stage renal disease (ESRD) before she was 4 years old. Urine protein electrophoresis showed glomerular proteinuria. There were significant increases in urinary ß2-microglobulin and α1-microglobulin. Gene detection revealed two compound heterozygous mutations, c.1552T>C (p.C518R) and c.752T>G (p.M251R), in the TTC21B gene, which came from her father and mother respectively. The c.752T>G mutation was a novel mutation. It is concluded that besides typical tubular changes of NPHP, marked glomerular damage is also observed in patients with TTC21B gene mutations.

Overproduction of Mitochondrial Fission Proteins in Membranous Nephropathy in Children.

BACKGROUND/AIMS: The molecules involved in nephrotic syndrome (NS) have not been fully clarified. Mitochondrial fission proteins are found to be involved in podocyte injury in vitro. Increased glomerular expression of mitochondrial fission proteins was found in adriamycin nephropathy in our previous study. Whether or not mitochondrial fission proteins are involved in podocyte injury in NS is not clear. This study explored the glomerular expression and possible pathological significance of mitochondrial fission-associated proteins, including dynamin-related protein 1 (Drp1) and mitochondrial fission protein 1 (Fis1), in children with NS. METHODS: Eighteen children with primary NS, including 6 with minimal change disease, 6 with focal segmental glomerulosclerosis, 6 with membranous nephropathy, 6 children with isolated haematuria and 3 normal controls were included. The glomerular expression of Drp1, phospho-Drp1 (Ser616) and Fis1, urinary protein measurements, and podocyte mitochondrial density under electron microscopy were investigated and compared. RESULTS: Glomerular expression of Drp1, phospho-Drp1 (Ser616) and Fis1 was mainly increased in children with NS with membranous nephropathy. No relationship was found between glomerular expression of Drp1, phospho-Drp1 (Ser616) and Fis1 and podocyte mitochondrial density or urinary protein measurements. CONCLUSION: Glomerular overproduction of Drp1, phospho-Drp1 (Ser 616) and Fis1 occurred mainly in children with membranous nephropathy. The pathological significance deserves further investigation.

IP3R-Grp75-VDAC1-MCU calcium regulation axis antagonists protect podocytes from apoptosis and decrease proteinuria in an Adriamycin nephropathy rat model.

BACKGROUND: The mechanism of podocyte apoptosis is not fully understood. In addition, the role of the inositol 1,4,5-triphosphate receptor (IP3R)/glucose-regulated protein 75 (Grp75)/voltage-dependent anion channel 1 (VDAC1)/mitochondrial calcium uniporter (MCU) calcium regulation axis, which is located at sites of endoplasmic reticulum (ER) mitochondria coupling, in the mechanism of podocyte apoptosis is unclear. This study aimed to understand the roles of this axis in podocyte apoptosis and explore potential targets for podocyte protection. METHODS: The expression of IP3R, Grp75, VDAC1, and MCU and mitochondrial Ca2+ were analyzed during Adriamycin- or angiotensin II-induced apoptosis in cultured mouse podocytes. The interaction between IP3R, Grp75, and VDAC1 was investigated using co-immunoprecipitation experiments. The effects of IP3R, Grp75, and MCU agonists and antagonists on mitochondrial Ca2+ and apoptosis were investigated in cultured podocytes. The podocyte-protective effects of an MCU inhibitor were further investigated in rats with Adriamycin-induced nephropathy. RESULTS: Increased expression of IP3R, Grp75, VDAC1 and MCU, enhanced interaction among the IP3R-Grp75-VDAC1 complex, mitochondrial Ca2+ overload, and increased active caspase-3 levels were confirmed during Adriamycin- or angiotensin II-induced mouse podocyte apoptosis. Agonists of this axis facilitated mitochondrial Ca2+ overload and podocyte apoptosis, whereas specific antagonists against IP3R, Grp75, or MCU prevented mitochondrial Ca2+ overload and podocyte apoptosis. A specific MCU inhibitor prevented Adriamycin-induced proteinuria and podocyte foot process effacement in rats. CONCLUSIONS: This study identified a novel pathway in which the IP3R-Grp75-VDAC1-MCU calcium regulation axis mediated podocyte apoptosis by facilitating mitochondrial Ca2+ overload. Antagonists that inhibit Ca2+ transfer from ER to mitochondria protected mouse podocytes from apoptosis. An MCU inhibitor protected podocytes and decreased proteinuria in rats with Adriamycin-induced nephropathy. Therefore, antagonists to this pathway have promise as novel podocyte-protective drugs.