Effectiveness of tumor necrosis factor inhibitors in children with enthesitis-related arthritis: a single-center retrospective analysis.

Objective: In children with enthesitis-related arthritis (ERA), the hip and sacroiliac joint function might be impaired if not properly treated. We sought to evaluate the effectiveness of anti-tumor necrosis factor-α (TNF-α) therapy using the inflammatory indicators, Juvenile Arthritis Disease Activity Score 27 (JADAS27) and magnetic resonance imaging (MRI). Methods: We conducted a single-center retrospective study of 134 patients with ERA. We evaluated the effect of anti-TNF therapy on the inflammatory indicators, active joint count, MRI quantitative score, and JADAS27 over 18 months. We used the Spondyloarthritis Research Consortium of Canada (SPARCC) and the Hip Inflammation MRI Scoring System (HIMRISS) scoring systems for hip and sacroiliac joints scoring. Results: The average age of onset of children with ERA was 11.62 ± 1.95 years, and they were treated with disease-modifying antirheumatic drugs (DMARDs) combined with biologics (n = 87, 64.93%). There were no differences in HLA-B27 positivity between the biologics and non-biologics treatment groups [66 (49.25%) vs. 68 (50.75%), P > 0.05]. Children who received anti-TNF (71 received etanercept, 13 adalimumab, 2 golimumab, and 1 infliximab) therapy improved significantly. Children with ERA used DMARDs and biologics at baseline (Group A) were followed up to 18 months, and their active joint count (4.29 ± 1.99 vs. 0.76 ± 1.33, P = 0.000), JADAS27 (13.70 ± 4.80 vs. 4.53 ± 4.52, P = 0.000) and MRI quantitative scores (P = 0.001) were significantly lower than those at baseline. Some of the patients (n = 13, 9.70%) were treated with DMARDs at the onset of the disease, but did not show significant improvement (Group B). After 6-18 months of switching to anti-TNF therapy, related indicators of the children were significantly lower than at baseline and 1 month (P < 0.013). At 18 months, a total of 33 patients (n = 74, 44.59%) in Group A and 7 (n = 13, 53.85%) in Group B reached inactive state. Conclusion: Eighteen months after diagnosis, anti-TNF therapy was found to be effective in children diagnosed with ERA. MRI is important for the early diagnosis of juvenile idiopathic arthritis. TNF-α inhibitors can significantly improve the clinical manifestations of sacroiliac joint and hip involvement in patients with ERA. Overall, the real-world study provides more evidence for precision diagnosis and treatment for other hospitals, families and patients.

Case report: A STAT1 gain-of-function mutation causes a syndrome of combined immunodeficiency, autoimmunity and pure red cell aplasia.

Inherited autosomal dominant gain-of-function (GOF) mutations of signal transducer and activator of transcription 1 (STAT1) cause a wide range of symptoms affecting multiple systems, including chronic mucocutaneous candidiasis (CMC), infections, and autoimmune disorders. We describe a rare case of STAT1 mutation with recurrent CMC, lung infections, and anemia. According to the whole-exome sequencing (WES), the patient was genetically mutated in STAT1 GOF (c.854A>G, p.Q285R), and bone marrow biopsy suggested pure red cell aplasia (PRCA). As a functional verification, STAT1 levels and phosphorylation (p-STAT1) of peripheral blood mononuclear cells (PBMCs) following IFN-γ stimulation in STAT1 GOF patient was higher than in the healthy control. Combination therapy of blood transfusion, antimicrobials, intravenous immunoglobulin, methylprednisolone, and the Janus Kinase (JAK) specific inhibitor ruxolitinib was used during treatment of patients. The patient also received a hematopoietic stem cell transplant (HSCT) to help with infections and anemia. This is the first reported case of STAT1 GOF disease complicated with PRCA. This complication might be attributed to immune disorders caused by STAT1 GOF. Furthermore, ruxolitinib may be a viable therapeutic option before HSCT to improve disease management.

Identifying a novel KLF2/lncRNA SNHG12/miR-494-3p/RAD23B axis in Spare Nerve Injury-induced neuropathic pain.

Spinal cord injury (SCI) is a devastating condition for patients, affecting nearly 2.5 million people globally. Multiple side effects of SCI have resulted in a terrible life experience for SCI patients, of which neuropathic pain has attracted the most scientific interest. Even though many efforts have been made to attenuate or eliminate neuropathic pain induced by SCI, the outcomes for patients are still poor. Therefore, identifying novel diagnosis or therapeutic targets of SCI-induced neuropathic pain is urgently needed. Recently, multiple functions of long non-coding RNA (lncRNA) have been elucidated, including those in SCI-induced neuropathic pain. In this study, lncRNA small nucleolar RNA host gene 12 (SNHG12) was found to be upregulated in the dorsal root ganglion (DRGs) of rats with spare nerve injury (SNI). By constructing SCI rat models, we found that lncRNA SNHG12 expression was increased in the DRGs, and mainly distributed in the cytoplasm of PC12 cells. Paw withdrawal threshold (PWT), paw withdrawal latency (PWL), and enzyme linked immunosorbent assay (ELISA) results indicated that lncRNA SNHG12 knockdown attenuated SNI-induced neuropathic pain, and decreased the expression levels of interleukin (IL)-1ß, IL-6, and tumour necrosis factor α (TNF-α) in the DRGs. Bioinformatics analysis, RNA pull-down, chromatin immunoprecipitation (ChIP), and luciferase reporter gene assays showed that lncRNA SNHG12 regulates the RAD23 homologue B, nucleotide excision repair protein (RAD23B) expression, through targeting micro RNA (miR)-494-3p. Furthermore, the study indicated that Kruppel-Like Factor 2 (KLF2) could regulate lncRNA SNHG12 expression in PC12 cells. This study identified a novel KLF2/lncRNA SNHG12/miR-494-3p/RAD23B axis in SNI-induced neuropathic pain, which might provide a new insight for developing novel diagnosis, or therapeutic targets of SCI-induced neuropathic pain in the future.

Platelet-Derived Microparticles: A New Index of Monitoring Platelet Activation and Inflammation in Kawasaki Disease.

OBJECTIVE: To investigate the dynamic changes of platelet-derived microparticles (PDMP) in Kawasaki disease (KD) and its clinical significance and to study its relationship with intravenous immunoglobulin (IVIG) resistance, inflammatory indicators and aspirin treatment in children with KD. METHODS: Twenty children with KD were enrolled as the experimental group, while 20 age- and gender-matched children with common febrile disease were included in the control group. Blood samples were drawn before and 7-10 d after IVIG infusion and thereafter at 1, 2, and 3 mo after the onset of KD to estimate the PDMP concentrations by enzyme linked immunosorbent assay (ELISA). C-reactive protein (hs-CRP), erythrocyte sedimentation rate (ESR), procalcitonin (PCT), and cytokines [Interleukin-6 (IL-6), Tumor necrosis factor-α (TNF-α), and Soluble interleukin-2 (sIL-2R)] were also measured. RESULTS: The level of PDMP in KD children before IVIG was significantly higher than that in controls (P < 0.0001). The PDMP level in KD children decreased significantly at 7 to 10 d after IVIG (P < 0.0001) and then decreased to the lowest level in the course of 1 to 2 mo. Some children's PDMP level rebounded in the course of 3 mo (P = 0.047). In addition, the mean level of PDMP in IVIG-resistant children was higher than that in IVIG-effective children; however, there was no significant difference between the two groups (P = 0.1945). Furthermore, PDMP was positively correlated with hs-CRP, IL-6, and sIL-2R levels, but no correlation was observed with ESR, PCT, and TNF-α levels. CONCLUSIONS: PDMP can be used as an index to monitor inflammation in children at the acute stage of KD. And the duration of platelet activation in KD is individualized.

IRF5 is elevated in childhood-onset SLE and regulated by histone acetyltransferase and histone deacetylase inhibitors.

Interferon regulatory factor 5 (IRF5) plays a critical role in the induction of type I interferon, proinflammatory cytokines and chemokines, and participates in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). However, the relationship between IRF5 and childhood-onset SLE remains elusive. In the present study, we demonstrated that levels of mRNA expression of IRF5, IFN-α, and Sp1 were significantly increased in childhood-onset SLE, as seen on quantitative real-time PCR, and the expression of Sp1 and IFN-α was positively correlated with IRF5. In addition to being used as antitumor drugs, a number of histone deacetylase inhibitors (HDACi) display potent anti-inflammatory properties; however, their effects on IRF5 expression remain unclear. In this study, we identified that HDACi trichostatin A (TSA) and histone acetyltransferase (HAT)-p300 downregulated IRF5 promoter activity, mRNA expression, and protein level, whereas the HAT-p300/CBP-associated factor had no effect. Moreover, TSA inhibited the production of TNF-α and IL-6 in differentiated THP-1cells. Furthermore, chromatin immunoprecipitation assays revealed that TSA inhibited DNA binding of Sp1, RNA polymerase II, HDAC3, and p300 to the core promoter region of IRF5. Our results suggest that HDACi may have therapeutic potential in patients with autoimmune diseases such as SLE through repression of IRF5 expression.

Pancytopenia as an early indicator for Stevens-Johnson syndrome complicated with hemophagocytic lymphohistiocytosis: a case report.

BACKGROUND: Stevens-Johnson syndrome (SJS) is a severe skin and mucosal bullous disease. When complicated with Hemophagocytic lymphohistiocytosis (HLH), the condition is especially life-threatening. CASE PRESENTATION: Here we report the case of a 4-year-old boy suffering from SJS with extensive erythema multiforme and bulla. Despite active intervention and supportive care, the boy experienced increased skin lesions and a higher fever. Meanwhile, decreases in white blood cell count and hemoglobin were observed. Hyperferritinemia, increased soluble CD25 level, decreased NK cell activity and hemophagocytosis in the boy's bone marrow confirmed the diagnosis of HLH. After high-dose intravenous immunoglobulin and methylprednisone pulse therapy, the boy was discharged in good condition. CONCLUSION: Simultaneous occurrence of HLH and SJS is very uncommon and the condition is life-threatening. Pancytopenia can be a precocious indicator and enables to start a prompt diagnosis and treatment.

SOD1 overexpression in paraventricular nucleus improves post-infarct myocardial remodeling and ventricular function.

Excessive sympathetic activation contributes to the progression of chronic heart failure. Reactive oxygen species in paraventricular nucleus (PVN) play an important role in the enhanced sympathetic outflow. This study was designed to determine whether superoxide dismutase 1 (SOD1) overexpression in the PVN attenuated the sympathetic activation and cardiac dysfunction in rats after an episode of myocardial infarction (MI). Adenoviral vectors containing human SOD1 (Ad-SOD) or null adenoviral vectors (Ad-null) were immediately microinjected into the PVN of rats with coronary artery ligation or sham operation. At the eighth week, the SOD1 protein level and activity in the PVN increased while the superoxide anions in the PVN decreased in Ad-SOD rats. The SOD1 overexpression in the PVN prevented the increases in left ventricular end-diastolic pressure and volume, and the decreases in ejection fraction and peak velocities of contraction in MI rats. In addition, there was an attenuation of renal sympathetic nerve activity, cardiac sympathetic afferent reflex and plasma norepinephrine level in MI rats. Furthermore, the SOD1 overexpression in the PVN reduced cardiomyocyte size, collagen deposition and the TUNEL-positive cardiomyocytes in MI rats. These results indicate that the SOD1 overexpression in the PVN attenuates the excessive sympathetic activation, myocardial remodeling, cardiomyocyte apoptosis and ventricular dysfunction in MI rats.

Responses of neurons in paraventricular nucleus to activation of cardiac afferents and acute myocardial ischaemia in rats.

Stimulation of cardiac sympathetic afferents increases sympathetic outflow and blood pressure. Chemicals released during myocardial ischaemia activate cardiac afferents. This study was to determine the responses of neurons in paraventricular nucleus (PVN) to the cardiac afferent activation caused by exogenous chemicals or myocardial ischaemia using an extracellular single-unit recording method. Rats were anaesthetized and underwent bilateral cervical vagal denervation (VD) and carotid and aortic baroreceptor denervation (BD). In 196 spontaneously active neurons in parvicellular PVN, 60 (30.6%), 36 (18.4%) and 91 (46.4%) neurons were respectively sensitive, mildly sensitive and insensitive to capsaicin, while nine (4.6%) neurons showed inhibitory responses to capsaicin. Epicardial application of capsaicin activated capsaicin-sensitive neurons in the PVN and increased mean arterial pressure. These neurons were also sensitive to exogenous bradykinin, adenosine and H(2)O(2). The neuron response is not secondary to a capsaicin-induced increase in mean arterial pressure because a similar degree of pressor response induced by aortic coarctation did not increase the neuron activity. Compared with intact rats, VD or BD or combined VD and BD increased the response of capsaicin-sensitive neurons to epicardial application of capsaicin, while stimulation of vagal afferents inhibited the response. Myocardial ischaemia caused increases in the activity of capsaicin-sensitive neurons and renal sympathetic nerve activity. The results indicate that chemical stimulation of cardiac sympathetic afferents activates capsaicin-sensitive neurons in parvicellular PVN, which is inhibited by the afferent activities of vagi and arterial baroreceptors. Acute myocardial ischaemia activates capsaicin-sensitive neurons in PVN and enhances sympathetic outflow.