Managing complex perianal disease after anti-TNF failure: Where to go next?
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ABSTRACT:
SUBMITTER: Yzet C
PROVIDER: S-EPMC8784625 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background and aimsMost patients with perianal Crohn's fistula receive medical treatment with anti-tumour necrosis factor [TNF], but the results of anti-TNF treatment have not been directly compared with chronic seton drainage or surgical closure. The aim of this study was to assess if chronic seton drainage for patients with perianal Crohn's disease fistulas would result in less re-interventions, compared with anti-TNF and compared with surgical closure.MethodsThis randomised trial was performed in 19 European centres. Patients with high perianal Crohn's fistulas with a single internal opening were randomly assigned to: i] chronic seton drainage for 1 year; ii] anti-TNF therapy for 1 year; and iii] surgical closure after 2 months under a short course anti-TNF. The primary outcome was the cumulative number of patients with fistula-related re-intervention[s] at 1.5 years. Patients declining randomisation due to a specific treatment preference were included in a parallel prospective PISA registry cohort.ResultsBetween September 14, 2013 and November 20, 2017, 44 of the 126 planned patients were randomised. The study was stopped by the data safety monitoring board because of futility. Seton treatment was associated with the highest re-intervention rate [10/15, versus 6/15 anti-TNF and 3/14 surgical closure patients, p = 0.02]. No substantial differences in perianal disease activity and quality of life between the three treatment groups were observed. Interestingly, in the PISA prospective registry, inferiority of chronic seton treatment was not observed for any outcome measure.ConclusionsThe results imply that chronic seton treatment should not be recommended as the sole treatment for perianal Crohn's fistulas.
| S-EPMC7476637 | biostudies-literature
Project description:Background: Perianal fistulising Crohn’s disease (pfCD) is a disabling phenotype of Crohn’s disease (CD) with suboptimal outcomes. We assessed neutrophil extracellular traps (NETs) in perianal fistulas and implicated their roles in pfCD healing. Methods: Patients with complex pfCD who developed preplaced seton drainage were recruited during the verified maintenance of remission in CD. Fistula tracts were sampled during definitive surgery plus seton removal. Patient demographics, CD classification, medication strategy, and healing of pfCD were recorded. RNA sequencing was applied for transcriptomic profile analysis. NETs components, including myeloperoxidase (MPO), neutrophil elastase (NE), and citrullinated histone H3 (CitH3), were identified using immunofluorescence. Serum infliximab (IFX), anti-IFX antibodies, and tissue levels of IFX, adalimumab (ADA), MPO and CitH3 were determined using enzyme-linked immunosorbent assays. Peptidyl arginine deiminase IV (PAD4), tumour necrosis factor (TNF)-α, and NE were detected using immunohistochemistry. Gene expression levels of PAD family members were assessed with qPCR. Results: Twenty-one patients were included, 15 of whom adopted IFX as maintenance treatment. RNA-seq revealed difference in neutrophil associated pathways between unhealed and healed fistulas. NETs components (MPO/NE/CitH3) were detectable in the fistulas and were parallel with the PAD4 levels. Eleven of 21 (52%) patients experienced complete healing of the pfCD 108 weeks post-operatively. Fistula NETs were significantly increased in patients with unhealed pfCD. Increased NETs were associated with abundant TNF-α production and the absence of IFX in fistulas. Conclusions: NETs exist in pfCD fistulas, which are associated with unhealed post-operative fistulas in pfCD, suggesting their prognostic roles in pfCD.
2023-10-07 | GSE215067 | GEO
Project description:About a third of patients with inflammatory bowel disease do not respond to anti-tumour necrosis factor (anti-TNF) therapy, which is challenging. To review the current data on the two main strategies when facing primary non-response to an anti-TNF agent in inflammatory bowel disease: changing to a second anti-TNF (switching) or to a drug with another mechanisms of action (swapping). We performed a bibliographic search to identify studies reporting on efficacy of any biologic treatment after primary anti-TNF non-response. The efficacy of a second anti-TNF is lower when the reason to withdraw the first one is primary failure. Nevertheless, switching to another anti-TNF even after primary failure may still be effective in some patients. Both vedolizumab and ustekinumab have generally been shown to be less effective in anti-TNF exposed patients. However, despite primary anti-TNF failure, patients may respond to vedolizumab or ustekinumab in a limited but considerable number of cases. The cause for swapping (primary vs. secondary anti-TNF failure) seems to have limited effect on vedolizumab efficacy. Primary anti-TNF non-response seems to be a clearer predictor of treatment failure for ustekinumab. Unfortunately, the two main strategies to treat specifically a patient with primary non-response to an anti-TNF agent-switching to a second anti-TNF or swapping for vedolizumab/ustekinumab-have not been properly compared. The data reviewed in the present study clearly emphasise the imperative need to carry out head-to-head randomised trials in patients exposed to anti-TNF agents in general, and specifically in those with primary non-response to these agents.
| S-EPMC8625924 | biostudies-literature
Project description:Anti-tumour necrosis factors (anti-TNFs) are established as first-line biological therapy for rheumatoid arthritis (RA) with over two decades of accumulated clinical experience. Anti-TNFs have well established efficacy/safety profiles along with additional benefits on various comorbidities. However, up to 40% of patients may respond inadequately to an initial anti-TNF treatment because of primary non-response, loss of response, or intolerance. Following inadequate response (IR) to anti-TNF treatment, clinicians can consider switching to an alternative anti-TNF (cycling) or to another class of targeted drug with a different mechanism of action, such as Janus kinase inhibitors, interleukin-6 receptor blockers, B-cell depletion agents, and co-stimulation inhibitors (swapping). While European League Against Rheumatism recommendations for pharmacotherapeutic management of RA, published in 2020, are widely regarded as helpful guides to clinical practice, they do not provide any clear recommendations on therapeutic choices following an IR to first-line anti-TNF. This suggests that both cycling and swapping treatment strategies are of equal value, but that the treating physician must take the patient’s individual characteristics into account. This article considers which patient characteristics influence clinical decision-making processes, including the reason for treatment failure, previous therapies, comorbidities, extra-articular manifestations, pregnancy, patient preference and cost-effectiveness, and what evidence is available to support decisions made by the physician.
| S-EPMC9386864 | biostudies-literature
Project description:BackgroundAnti-TNF medications are the first-line treatment for Crohn's Disease (CD), despite the fact that a significant portion of the population continues to be ineffectively treated. This research aims to discover accurate intervention targets for the follow-up of anti-TNF non-responders using bioinformatics technology.MethodsGSE16879, GSE111761, and GSE52746 retrieved from the GEO database. Unbiased differentially expressed genes (DEGs) were discovered utilizing the limma and RobustRankAggreg (RRA) tools. Then, we used weighted gene co-expression network analysis (WGCNA) to identify the module most strongly associated with non responders and subjected this module to Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analysis with overlapping genes of the DEGs. GSEA analysis applied to check the results of GO and KEGG. Using the Cytoscape program, the protein-protein interaction (PPI) network was constructed. The software's MCODE addon and CytoHubba addon was used to find the most important modules and the hub genes. Subsequently, we employed reverse transcription-polymerase chain reaction (RT-PCR) to confirm hub gene expression from mucosal biopsy specimens.ResultsThere were a total of 142 genes co-upregulated and 65 genes co-downregulated. According to the WGCNA analysis, 42 genes were duplicated inside the light cyan module. GO and KEGG enrichment analyses of overlapped genes in nonresponders demonstrated an increase in the expression of genes associated with inflammation and immune response, consistent with GSEA results. The PPI network was constructed using 41 protein nodes and 177 edges. After validation, 8 of the top 10 genes were verified to be differentially expressed.ConclusionOur investigation is the first to integrate three CD databases after the anti-TNF medication treatment. We identified IL1B, CCL4, CXCL1, CXCL10, CCL3, CSF3, TREM1, and IL1RN as potential therapeutic targets for patients whose anti-TNF treatment failed.
| S-EPMC10590116 | biostudies-literature
Project description:Patients with perianal fistulas are frequently treated by a knotted seton which is well-known for causing complaints. We aimed to assess the feasibility of the knotless SuperSeton and advantages with respect to perianal disease activity. In a prospective cohort study, we included all consecutive adult patients with a knotted seton in situ or a perianal fistula requiring new seton drainage. Primary endpoint was seton feasibility (maintenance of the connection for minimally three months). Secondary endpoints included improvement of the Perianal Disease Activity Index (PDAI), complications and re-interventions within three months of follow-up. PDAI scores of patients with a knotted seton were crossover compared to PDAI scores after knotless seton replacement. Sixty patients (42% male, mean age 42 (SD 13.15), 41 with Crohn's disease) were included between August 2016 and April 2018. Of 79 knotless setons, 69 (87.3%) stayed connected for ≥ 3 months. Overall, the knotless seton significantly decreased discharge (P = 0.001), pain (P < 0.001) and induration (P < 0.001) measured by the PDAI when compared to baseline. In patients with a knotted seton, replacement by the knotless seton significantly decreased discharge (P = 0.005) and pain (P < 0.001) measured by the PDAI. Furthermore, 71% of patients reported fewer cleaning problems compared to the knotted seton. Ten patients developed a perianal abscess, and five patients required a re-intervention. This study supports the feasibility of the knotless seton with promising short-term results. The knotless seton might be preferred over the knotted seton in terms of perianal disease activity.
| S-EPMC7541651 | biostudies-literature
Project description:Inflammatory bowel disease (IBD) affects young people of reproductive age. Therefore, a broad discussion is needed about the possible disease effects in pregnancy, as well as the risks of fetal exposure to the medications used, especially biological therapy. This study aimed to describe the management of 4 Crohn's disease patients who received anti-TNF therapy during pregnancy and present a literature review. We reported 4 cases composed of young women who became pregnant while receiving anti-TNF agents. The patients presented a satisfactory response to the clinical treatment and the pregnancies progressed without complications. We did not observe maternal or embryonic toxicity, or unfavorable outcomes. The available data point to inflammatory activity as the main risk factor for unfavorable gestational evolution to date, and showed anti-TNF therapy to be safe during pregnancy and breastfeeding. However, the benefits and risks must be discussed with the patient and management decisions should be taken on an individual basis.
| S-EPMC6244106 | biostudies-other
Project description:BACKGROUND/RATIONALE:
Treatment outcomes of patients with inflammatory bowel disease (IBD) have improved enormously during the past decade due to the use of anti-tumour necrosis factor (anti-TNF) therapy. As a result, 67 to 91% of paediatric patients and 66% of adult patients is still in sustained remission two years after the initiation of anti-TNF therapy. Prolonged use of anti-TNFs comes with disadvantages such as dose dependent susceptibility to infections and dermatological adverse effects. Preliminary, mostly uncontrolled studies suggest that dose reduction by dosing interval lengthening is a realistic option in a relevant proportion of patients with IBD, provided that intensive follow-up is applied.
OBJECTIVE:
To evaluate whether a faecal calprotectin (FC) guided strategy of anti-TNF dosing interval lengthening is non-inferior in maintaining remission in patients with IBD, compared with an unchanged dosing interval.
| 2359035 | ecrin-mdr-crc
Project description:Drug serum concentrations will be measured at several time-points for inflammatory disease patients treated with anti-TNF agents. The purpose is to determine which patients that will clinically benefit from either discontinue treatment, adjusting the dose, switch to another anti-TNF agent or a different class of medication.
| 2161631 | ecrin-mdr-crc
Project description:Infectious diseases are increasingly recognised to be a major threat to biodiversity. Disease management tools such as control of animal movements and vaccination can be used to mitigate the impact and spread of diseases in targeted species. They can reduce the risk of epidemics and in turn the risks of population decline and extinction. However, all species are embedded in communities and interactions between species can be complex, hence increasing the chance of survival of one species can have repercussions on the whole community structure. In this study, we use an example from the Serengeti ecosystem in Tanzania to explore how a vaccination campaign against Canine Distemper Virus (CDV) targeted at conserving the African lion (Panthera leo), could affect the viability of a coexisting threatened species, the cheetah (Acinonyx jubatus). Assuming that CDV plays a role in lion regulation, our results suggest that a vaccination programme, if successful, risks destabilising the simple two-species system considered, as simulations show that vaccination interventions could almost double the probability of extinction of an isolated cheetah population over the next 60 years. This work uses a simple example to illustrate how predictive modelling can be a useful tool in examining the consequence of vaccination interventions on non-target species. It also highlights the importance of carefully considering linkages between human-intervention, species viability and community structure when planning species-based conservation actions.
| S-EPMC3233597 | biostudies-other