Infliximab Treatment For Crohn's Disease Research Articles

P121 Characterisation of the miRNAome in Crohn’s Disease patients reveals transcriptomic changes associated with tissue composition and drug treatment

Abstract Background Gene regulation plays a major role in Crohn's Disease (CD) susceptibility and drug response. MicroRNA (miRNA)-mediated mechanisms tune gene expression at the post-transcriptional level. MiRNAs are 20-to-25-nt long non-coding RNAs that repress protein expression by direct inhibition or cleavage of the targets. Evaluating the miRNAome is emerging as a promising tool to clarify pathogenesis and identify promising biomarkers. We characterised the regulatory miRNAome across disease subtypes, gut tissue locations and infliximab treatment in CD. Methods We generated 120 transcriptomic profiles from terminal ileum and left colon biopsies from Hospital Universitario de la Princesa (Madrid). This cohort is composed of 10 patients with active endoscopy, 10 quiescent CD cases, and 10 controls (30 in total). In a balanced setting, half of the samples were incubated with infliximab for 18 hours at 37ºC and the rest with basal medium (Table 1). We carried out an exploratory analysis to gain insights into the determinants of miRNAome variability, including variance partition analyses and linear mixed modelling to detect significantly altered miRNAs. We also harnessed results from several publications including GSE16879 dataset to perform a comparative study with infliximab response signatures. Results Tissue location is the primary determinant of miRNA expression variability. The Variance Partition model identified 30 top miRNAs whose variability is maximised across regions. However, patient-specific effects also play a relevant role. We also identified 96 differentially expressed miRNAs between terminal ileum and left colon, with an overrepresentation of molecules involved in stress and developmental pathways (Fig.1). Among these, we find miR200s and miR429, that are associated with suppression of epithelial-mesenchymal transition and are up-regulated in colon more than in ileum. Down-regulation of miR196 is also shown in terminal ileum. Regarding the effects of infliximab treatment, we detected nine deregulated miRNAs which are associated with cellular response pathways. These include miR200s and miR192, which targets NOD2 and down-regulates NF-κB. Our results show an up-regulation of miR192 upon infliximab incubation (log2FC=2.37), which is associated with a reduction in TNFα expression and, consequently, with induced overexpression of miR192. We conclude that this miRNA is a potential target for therapy development. Conclusion In short, tissue location, and to a lesser extent disease subtype, are the main determinants of miRNAome in CD. A few treatment-responsive miRNAs like miR192 and miR200s are identified, in spite of detection challenges, emphasizing the need to improve our comprehension of the miRNA dynamics associated with drug response.

Fecal Microbiota Alterations Associated With Clinical and Endoscopic Response to Infliximab Therapy in Crohn's Disease.

Gut microbiota dysbiosis is associated with the occurrence and development of Crohn disease (CD). Currently, infliximab (IFX) is used more and more to treat CD; however, gut microbiota alterations during IFX therapy are variable and sometimes even contradictory. We longitudinally identified microbial changes during IFX therapy associated with the clinical and endoscopic response to IFX treatment in CD. Fecal-associated microbiota was analyzed using 16S sequencing in 49 patients with active CD who were prospectively recruited at baseline, week 6, and week 30, respectively. Moreover, a model trained on the gut microbiota alterations at week 6 was developed to investigate their potential to predict clinical and endoscopic responses to IFX therapy at weeks 14 and 30. Characteristics of fecal microbiota composition in patients with CD after IFX treatment displayed an increased diversity and richness, a significant gain in short-chain fatty acid -producing bacteria, and a loss of pathogenic bacteria. Furthermore, certain functional profiles of Kyoto Encyclopedia of Genes and Genomes pathways were predictably altered during the treatment period. Increased proportions of Lachnospiraceae and Blautia were associated with IFX efficacy; the combined increase of these taxa at week 6 showed 83.4% and 84.2% accuracy in predicting clinical response at weeks 14 and 30, respectively, with a predictive value of 89.1% in predicting endoscopic response at week 30. We found that IFX diminished CD-related gut microbial dysbiosis by modifying microbiota composition and function. Specifically, increased Lachnospiraceae and Blautia at week 6 are associated with the clinical and endoscopic response to IFX, providing potentially predictive biomarkers for IFX treatment decision-making.

Mucosal healing predicts long-term outcome of maintenance therapy with infliximab in Crohnʼs disease

Infliximab (IFX) treatment induces mucosal healing (MH) in patients with Crohn's disease (CD) but the impact of MH on the long-term outcome of IFX treatment in CD is still debated. We studied MH during long-term treatment with IFX in 214 CD patients. A total of 183 patients (85.5%) responded to induction therapy and 31 patients (14.5%) were primary nonresponders. They underwent lower gastrointestinal (GI) endoscopy within a median of 0.7 months (interquartile range [IQR] 0.1-6.8) prior to first IFX and after a median of 6.7 months (IQR 1.4-24.6) after start of IFX and were further analyzed. The relationship between the outcome of IFX treatment long-term and MH was studied. MH was observed in 67.8% of the 183 initial responders (n = 124), with 83 patients having complete healing (45.4%) and 41 having partial healing (22.4%). Scheduled IFX treatment from the start resulted in MH more frequently (76.9% MH rate) than episodic treatment (61.0% MH rate; P = 0.0222, odds ratio [OR] 2.14, 95% confidence interval [CI] 1.11-4.12). Concomitant treatment with corticosteroids (CS) had a negative impact on MH (37.9% in patients with CS versus 63.2% in patients without CS; P = 0.021, OR 0.36, 95% CI 0.16-0.80). MH was associated with a significantly lower need for major abdominal surgery (MAS) during long-term follow-up (14.1% of patients with MH needed MAS versus 38.4% of patients without MH; P < 0.0001). MH induced by long-term maintenance IFX treatment is associated with an improved long-term outcome of the disease especially with a lower need for major abdominal surgeries.

Occurrence of Plantar Pustular Psoriasis during Treatment with Infliximab

Pustular psoriasis is an uncommon form of psoriasis that often affects areas of the hands and feet. It typically manifests as small pustules that develop within erythematous areas of the palms and soles. Infliximab, a tumor necrosis factor inhibitor, can be used to treat pustular psoriasis. Infliximab can also be effective in the treatment of various other disorders, including plaque-type psoriasis, psoriatic arthritis, Crohn disease, rheumatoid arthritis, and ankylosing spondylitis. We present a case of a young woman developing pustular psoriasis for the first time despite being on infliximab treatment for Crohn disease. Infliximab has been successful in the treatment of pustular psoriasis. In rare cases, plaque psoriasis appears for the first time during infliximab treatment for other disorders, such as Crohn disease. Plantar pustular psoriasis occurring for the first time during infliximab treatment is an uncommon occurrence.

Interim evaluation of our experience with infliximab treatment in IBD

Introduction: Infliximab (IFX) became an accepted treatment modality in active luminal disease and for enterocutaneous fistulae in patients suffering from Crohn's disease (CD). Aims: Retrospective evaluation of our experience with IFX treatment from three different standpoints: (1) routine (standard and maintenance) IFX treatment in CD. (2) effects of initial (step-down) IFX therapy in CD, (3) possibilities of IFX treatment in ulcerative colitis (UC). Material and methods: (1) Standard and maintenance IFX treatment was introduced in 49 CD patients with fistulae or steroid-resistent cases. Indicators were: proven closure of fistulae, and changes in Crohn's disease activity index (CDAI). (2) Initial IFX treatment – as the start of „step down“ therapy – has been applied in four freshly discovered CD patients. Indicators were: changes in CDAI, further need of complementary drugs, clinical evaluation. (3) Evidence based results of IFX treatment in steroid dependent or resistant UC patients are still contradictory. IFX standard and maintenance treatment were initiated in 7 UC patients. Indicators were: decrease in steroid need, changes in Modified Truelove-Witts severity index (MTWSI). Results: (1) Fistulae closed in 13/16 (81%) of cases. CDAI decline was significant in every case, side effects developed in 2 cases, resulting in halting IFX therapy. (2) Newborn diagnosis of severe CD may lead to hard treatment decisions. Starting with initial IFX therapy seem to support the paradigma of “step-down“ therapy, all of our four cases showed significant improvement in clinical status, CDAI decreasing, and reduced need of complementary therapy. (3) Seven UC patients with extreme therapeutic involvement (very high steroid need, insufficient response to immunesuppressive drugs) were selected for IFX treatment trial. MTWSI responses were significant in 4/7 cases, while in all others steroid dose decrease or discontinuation were possible. Discussion: Without doubt, IFX seems to be the most spectacular medicine in recent years for patients with IBD. Cost-effectiveness must be re-evaluated by state health policy.

Complement activation in plasma before and after Infliximab treatment in Crohn disease

Background: Crohn disease is characterized by up‐regulated intestinal inflammation mainly caused by increased tumour necrosis factor alpha (TNF‐α) levels. However, the complement system (C) may also have a role in maintaining inflammation. Methods: Plasma from 26 patients with Crohn disease complicated by fistulizing ano‐rectal disease was collected before and after three Infliximab infusions (5 mg kg−1). Results: Before treatment, the C3‐activation capacities (C3‐AC) in plasma from patients with Crohn disease were comparable with values obtained from healthy controls. The classical C pathway‐mediated C3‐AC, mannan‐binding lectin C4‐AC, leucocyte count, C‐reactive protein concentration and Crohn Disease Activity Index decreased significantly 8 weeks after the first infusion of Infliximab (P < 0.04, Wilcoxon test). Conclusions: Before treatment, all three C pathways were within the normal range in plasma from patients with Crohn disease; the decrease observed in the classical pathway‐mediated C3‐AC after treatment with Infliximab reflects a general down‐regulation in immune activation.

Inflammatory Bowel Disease A Positive Response to Infliximab in Crohn Disease: Association with a Higher Systemic Inflammation Before Treatment But Not With -308 TNF Gene Polymorphism

Background: Two-thirds to three-fourths of patients with either refractory luminal or fistulizing Crohn disease respond to infliximab treatment. The ability or inability to respond seems to persist over time. Biological characteristics and/or genetic background can influence the response to treatment. The aim was to assess the value of C-reactive protein and TNF- α serum levels before treatment as well as the TNF -308 gene polymorphism in the prediction of response to infliximab treatment in Crohn disease. Methods: Two-hundred-and-twenty-six Crohn disease patients treated in the setting of an expanded access programme to infliximab in Belgium were studied. There were 136 refractory luminal diseases and 90 refractory fistulizing diseases. Luminal diseases were treated with one single infusion; fistulizing diseases with three infusions at weeks 0, 2 and 6. A clinical response to treatment was defined as either a Crohn disease activity index <150 (complete) or a drop of 70 points (partial) at week 4, for luminal disease, and as either complete fistula healing (complete) or a decrease of at least 50% of the number of draining fistulas on two consecutive visits between weeks 0 and 18, for fistulizing disease. CRP and serum TNF- α levels were measured at week 0 before treatment and were compared between responders and non-responders. Patients were genotyped for the-308 TNF gene polymorphism, and allelic as well as genotype frequencies were compared between responders and non-responders. Results: There were 73.2% responders (46.4% complete and 26.8% partial) and 26.8% non-responders. Response rates were similar in luminal and fistulizing diseases. CRP level before treatment was significantly higher in responders than in non-responders (16.8 mg/l (5-160) versus 9.6 mg/l (5-143); P = 0.02). Furthermore, response rate was significantly higher in patients with elevated CRP (>5 mg/l) than in patients with a normal CRP value (<5 mg/l) before treatment (76% versus 46%; P = 0.004; OR: 0.26 (0.11-0.63)). Allelic and genotype frequencies for-308 TNF gene polymorphism were not significantly different between responders and non-responders - with the exception of a slightly higher TNF2 frequency in nonresponders in luminal disease (22.1% versus 11.6%; P = 0.04). However, this was not associated with a significant difference in genotype frequencies. Conclusion: A positive clinical response to infliximab was associated with a higher CRP level before treatment in our population of Crohn disease patients, but there was no relevant association with-308 TNF gene polymorphism. We therefore suggest that CRP level may help to identify better candidates for infliximab treatment.

Pharmacogenetic association between the TNF receptor 2 genotype and response to infliximab treatment in Crohn disease

Pharmacogenetic association between the TNF receptor 2 genotype and response to infliximab treatment in Crohn disease

Pharmacogenetic association between the TNF receptor 2 genotype and response to infliximab treatment in Crohn disease

Pharmacogenetic association between the TNF receptor 2 genotype and response to infliximab treatment in Crohn disease