Central Nervous System Demyelination Related to Tumour Necrosis Factor Alpha Inhibitor

Background An association between tumour necrosis factor alpha (TNF-α) inhibitors exposure and central nervous system (CNS) demyelinating disorders has been postulated but is poorly understood. Objectives Describe the clinical spectrum and progress of a cohort of patients who developed demyelinating disorder following exposure to TNF-α inhibitor. Methods Retrospective chart review of patients who presented to a single neurologist in Western Australia between May 2003 and July 2020. Results 7 patients (6 females and 1 male) were identified. Mean age was 49.1 years. Mean follow-up time was 2.9 years. Mean interval between commencement of TNF-α inhibitor and onset of demyelinating event was 3 years. The spectrum of demyelinating events included transverse myelitis ( N = 3), acute brainstem syndrome ( N = 1) and optic neuritis ( N = 1). 2 patients had an atypical presentation but had MRI findings which unequivocally showed demyelinating changes. 2 patients had a monophasic event while the other 5 patients were diagnosed to have multiple sclerosis. All symptomatic patients with multiple sclerosis were started on disease modifying therapy and remained relapse free during follow-up. Conclusion Exposure to TNF-α inhibitor appears to increase the risk of demyelinating event. Whether TNFα inhibition directly results in CNS demyelination or trigger demyelination in susceptible individuals requires further research.

594 Impact of admission hyperglycaemia on heart failure events and mortality in patients with Takotsubo syndrome at long-term follow-up: data from the high-Glucotako investigators

Aims As known, Takotsubo Syndrome (TTS) can occur during stressful events that result in sympathetic overactivity. No studies have investigated the sympathetic activity and long-term prognosis in patients with TTS and admission hyperglycaemia vs. normoglycaemia. Moreover, whether hyperglycaemia may serve as a metabolic trigger to unbalance the sympathetic system axis as well as through over-inflammation is not fully understood. To investigate admission hyperglycaemia effects on the sympathetic system and long-term prognosis in Takotsubo syndrome (TTS). Methods and results In this multicentre study, we screened 4783 patients undergoing coronary angiography within the first 72 h of hospitalization for suspected acute coronary syndrome between January 2015 and January 2018. All enrolled patients met the InterTAK diagnostic criteria proposed in the European Society of Cardiology position statement for the diagnosis of TTS. Exclusion criteria encompassed patients with previous myocardial infarction, TTS events, or chronic kidney or liver disease. Patients with TTS were divided into those with hyperglycaemia vs. those with normoglycaemia according to a cutoff admission blood glucose value of 140 mg/dl. Sympathetic activity was assayed by blood values of norepinephrine and 123I-labelled metaiodobenzylguanidine (MIBG) cardiac scintigraphy with late heart-to-mediastinum ratio (H/Mlate) and washout rate (WR), performed in 30 patients who did not present any contraindication to the examination, evaluated at baseline and at follow-up. Similarly, systemic inflammatory markers [C-reactive protein (CRP), white blood cell count (leukocytes and neutrophils), tumour necrosis factor-alpha (TNF-a)] and B-type natriuretic peptide (BNP) were assessed. Prespecified endpoints [heart failure (HF) and all-cause deaths] were assessed at long-term follow-up (12 and 24 months). At hospitalization, TTS patients with hyperglycaemia (N = 28) vs. those with normoglycaemia (M = 48) had significantly higher levels of inflammatory markers and B-type natriuretic peptide and lower left ventricular ejection fraction. Admission glucose values were correlated with norepinephrine levels (R2 = 0.39; P = 0.001). In 30 patients with TTS, 123I-MIBG cardiac scintigraphy showed lower late heart-to-mediastinum ratio values in the acute phase (P < 0.001) and at follow-up (P < 0.001) in those with hyperglycaemia. Patients with hyperglycaemia had higher rates of HF (P < 0.001) and death events (P < 0.05) after 24 months. In multivariate Cox regression analysis, hyperglycaemia (P = 0.008), tumour necrosis factor-alpha (P = 0.001), and norepinephrine (P = 0.035) were independent predictors of HF events. Conclusions Patients with TTS and hyperglycaemia exhibit sympathetic overactivity with a hyperglycaemia-mediated proinflammatory pathway, which could determine a worse prognosis during follow-up.

A cluster analysis of patients with axial spondyloarthritis using tumour necrosis factor alpha inhibitors based on clinical characteristics

Background This study aimed to classify the distinct group of patients with axial spondyloarthritis (SpA) on tumour necrosis factor alpha inhibitors (TNFi) according to the baseline characteristics using a clustering algorithm. Methods The clinical characteristics and demographic data of patients with axial SpA included in the Korean College of Rheumatology Biologics and Targeted Therapy registry were investigated. The patterns of disease manifestations were examined using divisive hierarchical cluster analysis. After clustering, we compared the clinical characteristics of patients and the drug survival of TNFi between the classified groups. Results A total of 1042 patients were analysed. The cluster analysis classified patients into two groups: axial group predominantly showing isolated axial manifestations (n = 828) and extra-axial group more frequently showing extra-axial symptoms (n = 214). Almost all extra-axial symptoms (peripheral arthritis, enthesitis, uveitis, and psoriasis) were more frequently observed in the extra-axial group than in the axial group. Moreover, patients in the extra-axial group had shorter disease duration, later disease onset, and higher disease activity than those in the axial group. The disease activity was comparable between the two groups after 1 year of treatment with TNFi. Interestingly, the extra-axial group had a lower drug survival with TNFi than the axial group (p = 0.001). Conclusions Cluster analysis of patients with axial SpA using TNFi classified two distinct clinical phenotypes. These clusters had different TNFi drug survival, clinical characteristics, and disease activity.

New therapeutic approaches in hidradenitis suppurativa

Complex multifactorial pathogenesis of hidradenitis suppurativa eventually results in chronic inflammation of the apocrine gland-bearing areas of the skin. However, the pathogenesis is not fully understood, there are many immune cells and inflammatory pathways of which role is clearly defined in the last years in HS, such as interleukin 1β (IL-1β), tumour necrosis factor alpha (TNFα), IL-17, IL-12 and IL-23. These pathways provide multiple targets for medical treatment. Currently, only adalimumab is licenced in HS, but the numerous ongoing clinical trials promise huge potential therapeutic options in this debilitating disease.

Effect of DNA Methylation on LPS-Induced Expression of Tumour Necrosis Factor Alpha (TNF-α) in Bovine Mammary Epithelial Cells

Background: Cow mastitis is a major disease that affects dairy industry worldwide. Although the inflammatory response induced by lipopolysaccharide (LPS) in bovine mammary epithelial cells (BMECs) is similar to the response to pathogenic bacteria, the underlying regulatory mechanisms remain unclear. This study aimed to clarify the effect of DNA methylation on LPS-induced expression of tumour necrosis factor alpha (TNF-α) in BMECs. Methods: The mammary epithelial cells were treated with LPS and DNA methylation inhibition 5-Aza-2’-deoxycytodine (5Aza). Expression of TNF-α, IL-6, BNBD-5, DNA methyltransferases (DNMT1, DNMT2, DNMT3A and DNMT3B) and DNA methylation at TNF-α regions, were analyzed using quantitative realtime PCR (qRT-PCR), Elisa and bisulfite sequencing PCR (BSP). Result: Our results showed that LPS significantly increased the expression of inflammatory factors, including interleukin-6 (IL-6), bovine neutrophil beta-defensins (BNBD-5) and TNF-α. Further, we observed that the DNA methylation inhibitor, 5-Aza-2'-deoxycytosine (5-Aza), enhanced LPS-induced TNF-α mRNA expression. In addition, we found that LPS treatment significantly decreased the methylation levels of specific CpG sites in the TNF-α promoter (at -245 and -323) and inhibited the expression of DNA methyl transferases (DNMT1, DNMT2, DNMT3A and DNMT3B). Our results indicate that LPS promotes the expression of TNF-α in BMECs by inhibiting DNA methylation in the gene promoter region.