Tumour necrosis factor‐alpha antagonists for treatment of paediatric Crohn’s disease
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ABSTRACT:
SUBMITTER: Gana J
PROVIDER: S-EPMC9139691 | biostudies-literature | 2022 Jan
REPOSITORIES: biostudies-literature
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Project description:Anti-tumour necrosis factor α (anti-TNFα) therapy is an established treatment in inflammatory bowel disease. However, this treatment is associated with high costs and the possibility of severe adverse events representing a true challenge for patients, clinicians and health care systems. Consequently, a crucial question is raised namely if therapy can be stopped once remission is achieved and if so, how and in whom. Additionally, in a real-life clinical setting, discontinuation may also be considered for other reasons such as the patient's preference, pregnancy, social reasons as moving to countries or continents with less access, or different local policy or reimbursement. In contrast to initiation of anti-TNFα therapy guidelines regarding stopping of this treatment are missing. As a result, the decision of discontinuation is still a challenging aspect in the use of anti-TNFα therapy. Currently this is typically based on an estimated, case-by-case, benefit-risk ratio. This editorial is intended to provide an overview of recent data on this topic and shed light on the proposed drug withdrawal strategies.
| S-EPMC4408449 | biostudies-literature
Project description:Folliculitis decalvans is a chronic inflammatory skin disease leading to scarring alopecia. Management of this disabling disease is difficult and no treatment is currently approved. Current knowledge regarding the pathogenesis of folliculitis decalvans suggests the benefit of using anti-tumour necrosis factor-α. This pilot study aimed to evaluate the clinical efficacy of anti-tumour necrosis factor-α for management of folliculitis decalvans. A single-centre retrospective pilot study included patients with refractory folliculitis decalvans treated by tumour necrosis factor-α inhibitors. An Investigator's Global Assessment (IGA) score was designed and validated to assess the efficacy of the therapy. Response to treatment was considered good to excellent when an IGA ≤ 2 was obtained at month 12. Eleven patients were included, with a mean time from diagnosis of folliculitis decalvans to the introduction of infliximab (n = 9) or adalimumab (n = 2) of 8.55 ± 1.26 years. Nine patients had failed on at least 2 lines of systemic therapies before starting anti-tumour necrosis factor-α. The median IGA score at baseline was 3. At the end of follow-up, 5 patients were considered responders. Overall, the safety profile of anti-tumour necrosis factor-α was good. The results suggest that the clinical benefit of anti-tumour necrosis factor-α is obtained after at least 6 months of treatment. However, further prospective studies are needed to confirm these results.
| S-EPMC10074284 | biostudies-literature
Project description:Huntington's disease (HD) is an inherited neurodegenerative disorder caused by the expansion of the CAG repeat in exon 1 of the huntingtin (HTT) gene, which results in a mutant protein with an extended polyglutamine tract. Inflammation occurs in both the brain and the periphery of HD patients and mouse models, with increases in brain and/or plasma levels of neurotoxic TNFα and several other proinflammatory cytokines. TNFα promotes the generation of many of these cytokines, such as IL6, which raises the possibility that TNFα is central to the inflammatory milieu associated with HD. A number of mouse studies have reported that the suppression of chronic immune activation during HD has beneficial consequences. Here, we investigated whether TNFα contributes to the peripheral inflammation that occurs in the R6/2 mouse model, and whether the in vivo blockade of TNFα, via etanercept treatment, can modify disease progression. We found that etanercept treatment normalised the elevated plasma levels of some cytokines. This did not modify the progression of certain behavioural measures, but slightly ameliorated brain weight loss, possibly related to a reduction in the elevated striatal level of soluble TNFα.
| S-EPMC6510744 | biostudies-literature
Project description:Tumour necrosis factor receptor type 2 (TNFR2, TNFRSF1B) is an essential receptor for various host-defence functions of tumour necrosis factor alpha (TNF). As part of studies to determine the structure of TNFR2, the formation, crystallization and preliminary X-ray diffraction analysis of the TNF-TNFR2 complex are described. The TNF-TNFR2 complex, which comprises one TNF trimer and three TNFR2 monomers, was confirmed and purified by size-exclusion chromatography. Crystals of the TNF-TNFR2 complex were obtained using polyethylene glycol 3350 as a precipitant. The crystal belonged to space group P2(1)2(1)2(1), with unit-cell parameters a = 74.5, b = 117.4, c = 246.8 A. Assuming the presence of two TNF-TNFR2 complexes in the asymmetric unit, the Matthews coefficient V(M) was 2.49 A(3) Da(-1) and the solvent content of the crystal was 50.7%. The crystal diffracted to 2.95 A resolution.
| S-EPMC2650442 | biostudies-literature
Project description:BackgroundA broad spectrum of adverse reactions associated with the use of tumor necrosis factor alpha (TNFα) antagonists has been recognized over the past years. Induction of scalp psoriasis is a less known undesirable consequence of the use of these drugs and is not well characterized.ObjectiveTo characterize TNFα inhibitors-induced psoriatic alopecia.MethodsWe studied 6 patients with TNF-inhibitor induced psoriatic alopecia and reviewed 28 patients with this condition reported in the literature to date.ResultsIn addition to severe scalp psoriasis, we report hair follicle pathologies ranging from alopecia areata to scarring alopecia. Prognosis was good, but discontinuation of TNFα inhibitors was required in more than half of the cases in order to achieve a favourable outcome.ConclusionTNFα inhibitors-associated psoriatic alopecia is rarely reported but requires a high index of suspicion and prompt diagnosis, as timely intervention may prevent irreversible damage.
| S-EPMC11361512 | biostudies-literature
Project description:ObjectivesThis case-controlled study aimed to identify the association of tumor necrosis factor (TNF)α-1031 and TNFβ+ 252 gene polymorphisms between chronic rhinosinusitis (CRS) and healthy controls. Another purpose of this study was to investigate the associations of these gene polymorphisms with factors related to CRS.MethodsAll deoxyribonucleic acid (DNA) samples were genotyped for TNFα-1031 and TNFβ+252 genes by mean of polymerase chain reaction (PCR) and restriction fragment length polymorphisms (RFLP). The statistical analysis were carried out using chi-square test or Fisher exact test to determine the associations of these gene polymorphisms in CRS. Multiple logistic regression was performed to evaluate the associations of these gene polymorphisms in CRS and its related risk factors.ResultsThe genotype and allele frequencies of TNFα-1031 and TNFβ+252 gene did not show any significant associations between CRS and healthy controls. However, a significantly statistical difference of TNFα-1031 was observed in CRS participants with atopy (P-value, 0.045; odds ratio, 3.66) but not in CRS with asthma or aspirin intolerance.ConclusionAlthough the presence of TNFα-1031 and TNFβ+252 gene polymorphisms did not render any significant associations between CRS and healthy control, this study suggests that TNFα-1031 gene polymorphisms in CRS patients with atopy may be associated with increase susceptibility towards CRS.
| S-EPMC5545697 | biostudies-literature
Project description:BackgroundThere are little data on positioning biologics in Crohn's disease (CD).AimsWe aimed to assess the comparative effectiveness and safety of ustekinumab vs tumour necrosis factor-alpha (anti-TNF) agents after first-line treatment with anti-TNF in CD.MethodsWe used Swedish nationwide registers to identify patients with CD, exposed to anti-TNF who initiated second-line biologic treatment with ustekinumab or second-line anti-TNF therapy. Nearest neighbour 1:1 propensity score matching (PSM) was used to balance the groups. The primary outcome was 3-year drug survival used as a proxy for effectiveness. Secondary outcomes included drug survival without hospital admission, CD-related surgery, antibiotics, hospitalization due to infection and exposure to corticosteroids.ResultsSome 312 patients remained after PSM. Drug survival at 3 years was 35% (95% CI 26-44%) in ustekinumab compared to 36% (95% CI 28-44%) in anti-TNF-treated patients (p = 0.72). No statistically significant differences were observed between the groups in 3-year survival without hospital admission (72% vs 70%, p = 0.99), surgery (87% vs 92%, p = 0.17), hospital admission due to infection (92% vs 92%, p = 0.31) or prescription of antibiotics (49% vs 50%, p = 0.56). The proportion of patients continuing second-line biologic therapy did not differ by reason for ending first-line anti-TNF (lack of response vs intolerance) or by type of first-line anti-TNF (adalimumab vs infliximab).ConclusionBased on data from Swedish routine care, no clinically relevant differences in effectiveness or safety of second-line ustekinumab vs anti-TNF treatment were observed in patients with CD with prior exposure to anti-TNF.
| S-EPMC10293383 | biostudies-literature
Project description:Tumour necrosis factor (TNF), an important proinflammatory cytokine, plays a role in the regulation of cell differentiation, proliferation and death, as well as in inflammation, innate and adaptive immune responses, and also implicated in a wide variety of human diseases. The presence of DNA sequence variations in regulatory region might interfere with transcription of TNF gene, influencing the circulating level of TNF and thus increases the susceptibility to human diseases (infectious, cancer, autoimmune, neurodegenerative and other diseases). In this review, we have comprehensively analysed various published case-control studies of different types of human diseases, in which TNF gene polymorphism played a role, and computationally predicted several single nucleotide polymorphisms (SNPs) lie in transcription factor-binding sites (TFBS) of transcription factors (TFs). It has been observed that TNF enhancer polymorphism is implicated in several diseases, and TNF rs1800629 and rs361525 SNPs are the most important in human disease susceptibility as these might influence the transcription of TNF gene. Thirty-two SNPs lies in TFBS of 20 TFs have been detected in the TNF upstream region. It has been found that TNF enhancer polymorphism influences the serum level of TNF in different human diseases and thus affects the susceptibility to diseases. The presence of DNA sequence variation in TNF gene causes the modification of transcriptional regulation and thus responsible for association of susceptibility/resistance with human diseases.
| S-EPMC7169614 | biostudies-literature
Project description:The activation of Wnt/beta-catenin signalling has an important function in gastrointestinal tumorigenesis. It has been suggested that the promotion of Wnt/beta-catenin activity beyond the threshold is important for carcinogenesis. We herein investigated the role of macrophages in the promotion of Wnt/beta-catenin activity in gastric tumorigenesis. We found beta-catenin nuclear accumulation in macrophage-infiltrated dysplastic mucosa of the K19-Wnt1 mouse stomach. Moreover, macrophage depletion in Apc(Delta716) mice resulted in the suppression of intestinal tumorigenesis. These results suggested the role of macrophages in the activation of Wnt/beta-catenin signalling, which thus leads to tumour development. Importantly, the conditioned medium of activated macrophages promoted Wnt/beta-catenin signalling in gastric cancer cells, which was suppressed by the inhibition of tumour necrosis factor (TNF)-alpha. Furthermore, treatment with TNF-alpha induced glycogen synthase kinase 3beta (GSK3beta) phosphorylation, which resulted in the stabilization of beta-catenin. We also found that Helicobacter infection in the K19-Wnt1 mouse stomach caused mucosal macrophage infiltration and nuclear beta-catenin accumulation. These results suggest that macrophage-derived TNF-alpha promotes Wnt/beta-catenin signalling through inhibition of GSK3beta, which may contribute to tumour development in the gastric mucosa.
| S-EPMC2413189 | biostudies-literature