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Biomedicines Jun 2024T cell activation is critical for an effective immune response against pathogens. However, dysregulation contributes to the pathogenesis of autoimmune diseases,...
T cell activation is critical for an effective immune response against pathogens. However, dysregulation contributes to the pathogenesis of autoimmune diseases, including Juvenile Idiopathic Arthritis (JIA). The molecular mechanisms underlying T cell activation are still incompletely understood. T cell activation promotes the acetylation of histone 3 at Lysine 27 (H3K27ac) at enhancer and promoter regions of proinflammatory cytokines, thereby increasing the expression of these genes which is essential for T cell function. Co-activators E1A binding protein P300 (P300) and CREB binding protein (CBP), collectively known as P300/CBP, are essential to facilitate H3K27 acetylation. Presently, the role of P300/CBP in human CD4+ T cells activation remains incompletely understood. To assess the function of P300/CBP in T cell activation and autoimmune disease, we utilized iCBP112, a selective inhibitor of P300/CBP, in T cells obtained from healthy controls and JIA patients. Treatment with iCBP112 suppressed T cell activation and cytokine signaling pathways, leading to reduced expression of many proinflammatory cytokines, including IL-2, IFN-γ, IL-4, and IL-17A. Moreover, P300/CBP inhibition in T cells derived from the inflamed synovium of JIA patients resulted in decreased expression of similar pathways and preferentially suppressed the expression of disease-associated genes. This study underscores the regulatory role of P300/CBP in regulating gene expression during T cell activation while offering potential insights into the pathogenesis of autoimmune diseases. Our findings indicate that P300/CBP inhibition could potentially be leveraged for the treatment of autoimmune diseases such as JIA in the future.
PubMed: 38927552
DOI: 10.3390/biomedicines12061344 -
International Journal of Rheumatic... Jun 2024Mixed connective tissue disease (MCTD) is a rare entity in children. There is a paucity of studies on juvenile-onset MCTD (jMCTD) worldwide especially from Southeast...
INTRODUCTION
Mixed connective tissue disease (MCTD) is a rare entity in children. There is a paucity of studies on juvenile-onset MCTD (jMCTD) worldwide especially from Southeast Asia.
OBJECTIVES
To describe clinical and laboratory features of jMCTD diagnosed at pediatric rheumatology centers across India.
METHODS
A predesigned detailed case proforma in an excel format was prepared and was sent to all the Pediatric Rheumatology centers in India. Eleven centers provided the clinical and laboratory data of their jMCTD patients, which was then compiled and analyzed in detail.
RESULTS
Thirty-one jMCTD patients from 11 centers were included in the study. Our cohort had 27 females and four male patients over 12 months (August 2021 to July 2022). The median age at presentation was 12 years (range 5-18 years) and the median duration of symptoms was 24 months at diagnosis (range 2-96 months). The common features included arthritis (90%), malar rash (70.9%), and Raynaud's phenomenon (70.9%). At a mean follow-up of 43 months (range 1-168 months), 45% of them were in remission. There were two deaths reported, due to macrophage activation syndrome and sepsis respectively.
CONCLUSION
We present the largest multicenter experience on jMCTD from the Indian subcontinent. The study's findings serve as a crucial stepping stone toward unraveling the complexities of jMCTD and improving patient care and management strategies.
Topics: Humans; Child; Male; Female; Mixed Connective Tissue Disease; India; Adolescent; Child, Preschool; Treatment Outcome; Age of Onset; Immunosuppressive Agents; Antirheumatic Agents; Retrospective Studies; Time Factors; Remission Induction
PubMed: 38925615
DOI: 10.1111/1756-185X.15243 -
Arthritis & Rheumatology (Hoboken, N.J.) Jun 2024To report safety and efficacy of CD19-targeting CAR T cells in a child with refractory juvenile dermatomyositis (JDM).
OBJECTIVES
To report safety and efficacy of CD19-targeting CAR T cells in a child with refractory juvenile dermatomyositis (JDM).
PATIENTS AND METHODS
We describe the case of a 12-year-old Caucasian boy with severe, chronically active JDM, refractory to multiple immunosuppressive treatment lines, including B-cell depletion with rituximab. The patient received a single infusion of fresh, autologous, second-generation anti-CD19 CAR T-cell product (lentiviral vector) manufactured on the Prodigy device (1x10 CAR T cells/kg), after lymphodepletion with cyclophosphamide (1000 mg/m over 2 days) and fludarabine (90 mg/m over 3 days). Immunosuppressive and glucocorticoid treatment were withdrawn before leukapheresis and CAR T-cell infusion.
RESULTS
Before anti-CD19 CAR T-cell therapy, the patient had persistent severe skin and muscular disease activity. CAR T cells expanded significantly (peak at day 7, 32.69 cells/μL). Complete B-cell depletion was documented on day 5 in blood and at week 2 in bone marrow. The patient presented fever as part of mild cytokine release syndrome (G1), transient anemia (G2) and neutropenia (G4). Neither infection nor neurotoxicity were observed. Laboratory tests, MRI imaging, Physician's Global Assessment of disease activity (PGA), Childhood Myositis Assessment Scale (CMAS) and Cutaneous Assessment Tool for myositis (CAT) were performed at baseline and follow-up to assess treatment response, showing remarkable progressive improvement that persists over time, even after B-cell recovery.
CONCLUSIONS
This JDM patient with severe chronic disease, refractory to multiple treatments, achieved sustained B-cell depletion and ongoing immunosuppressive drug-free clinical and radiological improvement eight months after a single infusion of anti-CD19 CAR T cells.
PubMed: 38924652
DOI: 10.1002/art.42933 -
Arthritis Research & Therapy Jun 2024Juvenile idiopathic arthritis (JIA) comprises a heterogeneous group of conditions that can cause marked disability and diminished quality of life. Data on predictors of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Juvenile idiopathic arthritis (JIA) comprises a heterogeneous group of conditions that can cause marked disability and diminished quality of life. Data on predictors of clinical response are insufficient to guide selection of the appropriate biologic agent for individual patients. This study aimed to investigate the propensity of S100A8/9 and S100A12 as predictive biomarkers of abatacept response in polyarticular-course juvenile idiopathic arthritis (pJIA).
METHODS
Data from a phase 3 trial (NCT01844518) of subcutaneous abatacept in patients with active pJIA (n = 219) were used in this exploratory analysis. Association between biomarker levels at baseline and improvements in JIA-American College of Rheumatology (ACR) criteria responses or baseline disease activity (measured by Juvenile Arthritis Disease Activity Score in 27 joints using C-reactive protein [JADAS27-CRP]) were assessed. Biomarker level changes from baseline to month 4 were assessed for disease outcome prediction up to 21 months.
RESULTS
At baseline, 158 patients had available biomarker samples. Lower baseline S100A8/9 levels (≤ 3295 ng/mL) were associated with greater odds of achieving JIA-ACR90 (odds ratio [OR]: 2.54 [95% confidence interval (CI): 1.25-5.18]), JIA-ACR100 (OR: 3.72 [95% CI: 1.48-9.37]), JIA-ACR inactive disease (ID; OR: 4.25 [95% CI: 2.03-8.92]), JADAS27-CRP ID (OR: 2.34 [95% CI: 1.02-5.39]) at month 4, and JIA-ACR ID (OR: 3.01 [95% CI: 1.57-5.78]) at month 16. Lower baseline S100A12 levels (≤ 176 ng/mL) were associated with greater odds of achieving JIA-ACR90 (OR: 2.52 [95% CI: 1.23-5.13]), JIA-ACR100 (OR: 3.68 [95% CI: 1.46-9.28]), JIA-ACR ID (OR: 3.66 [95% CI: 1.76-7.61]), JIA-ACR90 (OR: 2.03 [95% CI: 1.07-3.87]), JIA-ACR100 (OR: 2.14 [95% CI: 1.10-4.17]), and JIA-ACR ID (OR: 4.22 [95% CI: 2.15-8.29]) at month 16. From baseline to month 4, decreases in S100A8/9 and S100A12 generally exceeded 50% among JIA-ACR90/100/ID responders.
CONCLUSION
Lower baseline levels of S100A8/9 and S100A12 proteins predicted better response to abatacept treatment than higher levels and may serve as early predictive biomarkers in pJIA. Decreases in these biomarker levels may also predict longer-term response to abatacept in pJIA.
Topics: Humans; Abatacept; Arthritis, Juvenile; Male; Female; Child; Biomarkers; Antirheumatic Agents; Calgranulin B; Adolescent; Treatment Outcome; Child, Preschool; Calgranulin A; S100A12 Protein; S100 Proteins
PubMed: 38918871
DOI: 10.1186/s13075-024-03347-0 -
Reumatismo Jun 2024The indices to measure disease activity of chronic arthritis in adulthood and childhood are different. Therefore, assessing the status of the disease in young patients...
OBJECTIVE
The indices to measure disease activity of chronic arthritis in adulthood and childhood are different. Therefore, assessing the status of the disease in young patients with juvenile idiopathic arthritis (JIA) can be tricky, especially when the transition to adult care is ongoing. The aim of our study was to assess the level of correlation between adult and juvenile scores in the measurement of disease activity in JIA patients during transitional care.
METHODS
We estimated the disease activity by using the Juvenile Arthritis Disease Activity Score 71 (JADAS71), clinical JADAS, adult Disease Activity Score (DAS28), Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI) in JIA patients in transitional care. We enrolled patients older than 16 years at the time of the first transition visit, and disease activity was assessed at baseline and 12 months. Regression analyses were carried out to estimate the level of agreement among the different indices.
RESULTS
We recruited 26 patients with JIA; 11 patients were polyarticular (42.3%) and 15 patients were oligoarticular (53.1%). The mean age at diagnosis was 7.7±3.9 years and the age at the first evaluation was 20.9±3.7 years. The correlation between JADAS71 and DAS28 was r2=0.69, r2=0.86 between JADAS71 and SDAI, and r2=0.81 between JADAS71 and CDAI.
CONCLUSIONS
SDAI and JADAS71 showed the best correlation, but a few patients were not captured at the same level of disease activity. New prospective studies with a larger number of patients will be needed in this field.
Topics: Humans; Arthritis, Juvenile; Female; Male; Severity of Illness Index; Transition to Adult Care; Child; Adolescent; Young Adult; Adult
PubMed: 38916167
DOI: 10.4081/reumatismo.2024.1638 -
Pediatric Investigation Jun 2024Systemic lupus erythematosus (SLE) is a diffuse connective tissue disease with complex clinical manifestations and prolonged course. The early diagnosis and condition...
IMPORTANCE
Systemic lupus erythematosus (SLE) is a diffuse connective tissue disease with complex clinical manifestations and prolonged course. The early diagnosis and condition monitoring of SLE are crucial to disease prognosis.
OBJECTIVE
To assess the diagnostic value of long noncoding RNA (lncRNA) nuclear enriched abundant transcript 1 (NEAT1) in childhood-onset SLE (cSLE).
METHODS
Fifty-seven children diagnosed with SLE, 40 children diagnosed with juvenile idiopathic arthritis (JIA), and 40 healthy children were included. Peripheral blood samples from each patient were collected. A quantitative polymerase chain reaction was used to confirm the expression of lncNEAT1_1 and lncNEAT1_2 in peripheral blood. Associations among parameters were analyzed using the Mann-Whitney test or independent sample -test.
RESULTS
The expression of both lncNEAT1_1 and lncNEAT1_2 in patients with cSLE were significantly higher than that of healthy control and patients with JIA. Receiver operating characteristic curves revealed an area under the curve (AUC) of 0.633 (95% confidence interval [CI], 0.524-0.742; = 0.024) for lncNEAT1_1. The AUC of lncNEAT1_2 was 0.812 (95% CI, 0.727-0.897; < 0.0001) to discriminate individuals with cSLE from health control and children with JIA with a sensitivity of 0.622 and a specificity of 0.925. Moreover, lncNEAT1_2 expression was higher in patients with cSLE presenting with fever, lupus nephritis, elevated erythrocyte sedimentation rate, active disease activity, and decreased C3 level, compared with those without these conditions. However, no similar correlation was observed for lncNEAT1_1.
INTERPRETATION
The expression of lncNEAT1_2 was significantly elevated in children with SLE, especially those with fever, renal involvement, and low C3 levels. These findings suggest that lncNEAT1_2 may represent a potential biomarker for cSLE.
PubMed: 38910848
DOI: 10.1002/ped4.12413 -
Archivos de La Sociedad Espanola de... Jun 2024Epithelial inclusion cysts (EIC) are a rare ocular disease and its physiopathology is not well-known. They consist on growths of ocular surface epithelial cells inside...
Epithelial inclusion cysts (EIC) are a rare ocular disease and its physiopathology is not well-known. They consist on growths of ocular surface epithelial cells inside the anterior segment of the eye in the form of a cyst. To date several cases have been published in the literature, none of them related to glaucoma surgery. We describe two cases of EIC after glaucoma devices implantation. An 86 year-old male patient with primary open angle glaucoma develop an EIC in right eye three years after removal of PRESERFLO™ MicroShunt (Santen, Osaka, Japan) and a 9 year-old female patient with glaucoma secondary to uveitis for juvenile idiopathic arthritis develops an EIC under the tube of an Ahmed valve implant during postoperative period. EIC develop after ocular penetrating wounds and an inflammatory stimulus. They are benign proliferations, follow-up is necessary to detect space complications early, so less mutilating surgery is needed for removal.
PubMed: 38909890
DOI: 10.1016/j.oftale.2024.05.012 -
Journal of Nippon Medical School =... Jun 2024Mixed connective tissue disease (MCTD) is characterized by mixed features of systemic lupus erythematosus, systemic sclerosis, and polymyositis/dermatomyositis and is...
Mixed connective tissue disease (MCTD) is characterized by mixed features of systemic lupus erythematosus, systemic sclerosis, and polymyositis/dermatomyositis and is rare in children. Here, we report a case of MCTD in a 10-year-old girl who presented at our hospital with arthralgia, Raynaud's phenomenon, and fatigue. Blood tests were positive for anti-U1-ribonucleoprotein (RNP) antibodies and for rheumatoid factors (RFs) IgG-RF and anti-galactose-deficient IgG. Levels of myogenic enzymes and hypergammaglobulinemia were elevated. Macrophages were prominent in bone marrow, with scattered phagocytic macrophages. MCTD was diagnosed based on the patient's symptoms and laboratory findings. Methylprednisolone pulse therapy combined with oral tacrolimus was administered, which led to resolution of symptoms. Three months after pulse therapy, arthralgia worsened and methotrexate was administered. Arthralgia improved but did not resolve. Magnetic resonance imaging performed to investigate the hip pain revealed a mature ovarian teratoma, which was surgically removed. Because the pain persisted and interfered with her daily life, she was treated with tocilizumab for joint pain relief, which decreased the pain level. Tocilizumab is a candidate for additional treatment of juvenile idiopathic arthritis-like arthritis associated with childhood-onset MCTD.
PubMed: 38897945
DOI: 10.1272/jnms.JNMS.2025_92-303 -
Asian Journal of Surgery Jun 2024
PubMed: 38897832
DOI: 10.1016/j.asjsur.2024.05.197 -
Rheumatology (Oxford, England) Jun 2024
PubMed: 38897666
DOI: 10.1093/rheumatology/keae329