Use of biologics for inflammatory bowel disease in Hong Kong: consensus statement

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Downregulation in IFNGR1 Increases Suspectiblity to Mycobacterium Avium Subspecies Paratuberculosis Infection in Crohn\u27s Disease

BACKGROUND: Crohn\u27s disease (CD) is an inflammatory bowel disease (IBD) and has been associated with Mycobacterium avium subspecies paratuberculosis (MAP). MAP has been detected in stool, tissue and blood samples from patients with CD. Gamma interferon (γ-IFN) is an inflammatory cytokine that plays a crucial role in killing intracellular pathogens like MAP, and its receptor (IFNGR1) mutations cause immunodeficiency and severe disseminated mycobacterial infections. The role of MAP in association with IFNGR1 mutation in CD patients have not been investigated. METHODS: In this study, we investigated blood samples of 79 human subjects for MAP infection in association with IFNGR1 gene dysfunction. Samples were divided into 22 CD, 6 Ulcerative colitis (UC), 32 normal healthy and 19 non-inflammatory bowel disease (NIBD). Five variants of IFNGR1 single nucleotide polymorphisms (SNP) were investigated using Taqman Genotyping assay, then IFNGR1 expression measured by RT-PCR and serum IFNGR1 and γ-IFN levels were measured using ELISA. MAP infection was detected using nested PCR. RESULTS: Among 28 IBD patients, 4/6 (66.67%) of UC and 18/22 (81.82%) of CD are tested positive for at least one SNP homozygous minor form compared to 21.88% and 47.37%% in 32 healthy and 19 NIBD (P \u3c 0.05). IFNGR1 gene expression was downregulated 1.4-fold in IBD patients (P =0.07) and 1.7-fold downregulated in MAP positive IBD patients compared to MAP negative IBD patients (P=0.06). Serum IFNGR1 protein levels were downregulated 1.53-fold in IBD patients compared to normal, and 1.4-fold downregulated in MAP positive IBD patients compared to MAP negative IBD patients. MAP infection is more common in rs2234711 SNP positive patients (5/7 =71.42%) (P \u3c 0.05). Serum γ-IFN levels were not elevated in both groups. CONCLUSION: IFNGR1 SNP\u27s, MAP infection and IFNGR1 downregulation were found in higher incidence in IBD, suggesting role of IFNGR1 in susceptibility of MAP infection in IBD patients

SAR Studies on the Inhibitors for the Treatment of Inflammatory Diseases

School of Molecular Sciences(Chemistry)Inflammation is defensive host response that occurs from infection and injury and the inflammatory process is the pivotal physiological response of our body and essential part of the human physiology. Due to the mechanistic relationship between chronic diseases and inflammation, a better understanding for the molecular mechanism of chronic inflammation could attenuate cellular inflammation pathways. Under inflammatory pathways, the impetus of proinflammatory mediators usually caused by the increased expression of transcriptional factors which is also a potential targets in the development of novel and effective anti-inflammatory therapeutics. Among others, we are interested in the Nuclear Factor Kappa-B (NF-??B) which is reported as a major mediator that regulates inflammatory gene expression and also decrease the prevalence of inflammation responses. To suppress the inflammatory activity, inhibitors that could selectively target this protein are needed. We therefore, chose the natural product cerulenin which has been studied widely because of its antifungal and antibacterial properties, for designing inhibitors. In light of the interesting inhibitory properties displayed by cerulenin for fatty acid synthase (FASN), we were keen to explore the possible binding mode of this natural product with a view to design various derivatives that would be amicable to synthetic manipulation in order to enable SAR studies. Potent analogues of cerulenin, with various chain lengths and substitutions, are synthesized and evaluated for their ability to inhibit NF-??B enhanceosome. Taken together, by identifying target protein with constructed inhibitors derived from cerulenin might give revolutionary effect on discovering new therapeutic agents.ope

Crohn's Disease

In this book, several important points regarding Crohn's disease are discussed. In the first section, we focus on etiopathogeny of Crohn's disease and the recent advances in our overall understanding of the disease - specifically, the role of the gut epithelium, alterations of the epithelial crypts, and the roles of the different cytokines in the pathophysiology of Crohn's disease. In the second section, a diagnosis of Crohn's disease is discussed. Another particular area of focus is in the diagnosis of intestinal tuberculosis, and the role of mycobacterium avium in Crohn's disease. In the third and final section, the management of Crohn's disease is discussed, with a focus on recent evidence-based medicine recommendations

Immune-Mediated Skin Reactions Induced by Recombinant Antibodies and Other TNF-Alpha Inhibitors

Biologic agents that act by inhibiting tumour necrosis factor alpha (TNF-alpha) have become a breakthrough treatment for chronic inflammatory diseases. This highly effective treatment has surprisingly brought us new adverse effects that we had not encountered before the age of biologics. Immune-mediated reactions are a group of adverse effects with not clearly understood etiopathogenesis. It turns out that TNF-alpha inhibitors are able to disrupt the cytokine cascade in genetically predisposed individuals. Some of the theories assume a cross reaction and overproduction of interferon (INF) alpha, while others put an emphasis on dysregulation of cytokines, in particular interleukin (IL)-17. Similarly, debatable is the role of the reactions mentioned in the etiopathogenesis, the production of antibodies against biologics and the production of antinuclear antibodies. The most common immune-mediated skin reactions are psoriasis and psoriasiform reactions, lupus-like syndrome, sarcoidosis, alopecia areata, vasculitis and lichenoid reactions. Less common reactions described in our paper include pyoderma gangrenosum and morphea. Most of these reactions belong to the so-called paradoxical reactions. Paradoxical psoriasis is an adverse effect, represented by occurrence of a disease caused by the therapeutic class of drugs normally used to cure or improve symptoms of such disease

Inhibitors of Tumoral Necrosis Factor Alpha in Inflammatory Bowel Disease

The treatment of inflammatory bowel disease (IBD) has undergone a major paradigm shift in the last two decades with the introduction of biological drugs. Tumoral necrosis factor (TNF) antagonists were the first monoclonal antibodies available for treatment of IBD. New emerging concepts as early initiation of treatment during the “opportunity window,” and “treat to target” with a tight control strategy have contributed to optimum utilization of these drugs allowing better long-term outcomes for treated patients. This chapter aims to review all current pivotal data regarding efficacy and safety of infliximab, adalimumab, certolizumab pegol, and golimumab, as long as real life experience with these agents. Comparative efficacy among anti-TNF agents and the role of therapeutic drug monitoring in the management of IBD will also be discussed. Last, the authors present future perspectives with the drugs and position anti-TNF agents as viable therapeutic options in the current IBD therapeutic armamentarium

Antimicrobial treatment with the fixed-dose antibiotic combination RHB-104 for Mycobacterium avium subspecies paratuberculosis in Crohn\u2019s disease: pharmacological and clinical implications

Introduction: Crohn\u2019s disease (CD) is an inflammatory bowel disease of unknown etiology. However, increasing evidence suggests Mycobacterium avium subspecies paratuberculosis (MAP) as a putative causative agent: 1) MAP is the etiological agent of Johne\u2019s disease, a granulomatous enteritis affecting ruminants, which shares clinical and pathological features with CD; 2) MAP has been detected in tissues and blood samples from CD patients; 3) case reports have documented a favorable therapeutic response to anti-MAP antibiotics. Area covered: This review provides an appraisal of current information on MAP characteristics, diagnostic methodologies and emerging drug treatments. The authors focus on RHB-104, a novel oral formulation containing a fixed-dose combination of clarithromycin, clofazimine and rifabutin, endowed with synergistic inhibitory activity on MAP strains isolated from CD patients. Expert opinion: Based on encouraging in vitro data, RHB-104 has entered recently the clinical phase of its development, and is being investigated in a randomized, placebo-controlled phase III trial aimed at evaluating its efficacy and safety in CD. Provided that the overall clinical development will support the suitability of RHB-104 for inducing disease remission in CD patients with documented MAP infection, this novel antibiotic combination will likely take a relevant position in the therapeutic armamentarium for CD management

Comparative analysis of adverse events between infliximab and adalimumab in Crohn's disease management: a Brazilian single-centre experience

AbstractIntroductionData is scarce regarding adverse events (AE) of biological therapy used in the management of Crohn's Disease (CD) among Brazilian patients.ObjectivesTo analyse AE prevalence and profile in patients with CD treated with Infliximab (IFX) or Adalimumab (ADA) and to verify whether there are differences between the two drugs.MethodRetrospective observational single-centre study of CD patients on biological therapy. Variables analysed: Demographic data, Montreal classification, biological agent adminis- tered, treatment duration, presence and type of AE and the need for treatment interruption.ResultsForty-nine patients were analysed, 25 treated with ADA and 24 with IFX. The groups were homogeneous in relation to the variables studied. The average follow-up period for the group treated with ADA was 19.3 months and 21.8 months for the IFX group (p = 0.585). Overall, 40% (n = 10) of patients taking ADA had AE compared with 50% (n = 12) of IFX users (p = 0.571). There was a tendency towards higher incidence of cutaneous and infusion reac- tions in the IFX group and higher incidence of infections in the ADA treated group, although without significant difference.ConclusionsNo difference was found in the AE prevalence and profile between ADA and IFX CD patients in the population studied

EuroGuiDerm Guideline on the systemic treatment of Psoriasis vulgaris - Part 2 : specific clinical and comorbid situations

This evidence- and consensus-based guideline on the treatment of psoriasis vulgaris was developed following the EuroGuiDerm Guideline and Consensus Statement Development Manual. The second part of the guideline provides guidance for specific clinical and comorbid situations such as treating psoriasis vulgaris patient with concomitant psoriatic arthritis, concomitant inflammatory bowel disease, a history of malignancies or a history of depression or suicidal ideation. It further holds recommendations for concomitant diabetes, viral hepatitis, disease affecting the heart or the kidneys as well as concomitant neurological disease. Advice on how to screen for tuberculosis and recommendations on how to manage patients with a positive tuberculosis test result are given. It further covers treatment for pregnant women or patients with a wish for a child in the near future. Information on vaccination, immunogenicity and systemic treatment during the COVID-19 pandemic is also provided.Peer reviewe