Our objectives were to better characterize the colorectal function of patients with Spina Bifida (SB). Patients with SB and healthy volunteers (HVs) completed prospectively a standardized ...questionnaire, clinical evaluation, rectal barostat, colonoscopy with biopsies and faecal collection. The data from 36 adults with SB (age: 38.8 34.1-47.2) were compared with those of 16 HVs (age: 39.0 31.0-46.5). Compared to HVs, rectal compliance was lower in patients with SB (p = 0.01), whereas rectal tone was higher (p = 0.0015). Ex vivo paracellular permeability was increased in patients with SB (p = 0.0008) and inversely correlated with rectal compliance (r = - 0.563, p = 0.002). The expression of key tight junction proteins and inflammatory markers was comparable between SB and HVs, except for an increase in Claudin-1 immunoreactivity (p = 0.04) in SB compared to HVs. TGFβ1 and GDNF mRNAs were expressed at higher levels in patients with SB (p = 0.02 and p = 0.008). The levels of acetate, propionate and butyrate in faecal samples were reduced (p = 0.04, p = 0.01, and p = 0.02, respectively). Our findings provide evidence that anorectal and epithelial functions are altered in patients with SB. The alterations in these key functions might represent new therapeutic targets, in particular using microbiota-derived approaches.Clinical Trials: NCT02440984 and NCT03054415.
In Hirschsprung's disease (HSCR), postoperative course remains unpredictable. Our aim was to define predictive factors of the main postoperative complications: obstructive symptoms (OS) and ...Hirschsprung-associated enterocolitis (HAEC). In this prospective multicentre cohort study, samples of resected bowel were collected at time of surgery in 18 neonates with short-segment HSCR in tertiary care hospitals. OS and HAEC were noted during postoperative follow-up. We assessed the enteric nervous system and the intestinal epithelial barrier (IEB) in ganglionic segments by combining immunohistochemical, proteomic and transcriptomic approaches, with functional ex vivo analysis of motility and para/transcellular permeability. Ten HSCR patients presented postoperative complications (median follow-up 23.5 months): 6 OS, 4 HAEC (2 with OS), 2 diarrhoea (without OS/HAEC). Immunohistochemical analysis showed a significant 41% and 60% decrease in median number of nNOS-IR myenteric neurons per ganglion in HSCR with OS as compared to HSCR with HAEC/diarrhoea (without OS) and HSCR without complications (p = 0.0095; p = 0.002, respectively). Paracellular and transcellular permeability was significantly increased in HSCR with HAEC as compared to HSCR with OS/diarrhoea without HAEC (p = 0.016; p = 0.009) and HSCR without complications (p = 0.029; p = 0.017). This pilot study supports the hypothesis that modulating neuronal phenotype and enhancing IEB permeability may treat or prevent postoperative complications in HSCR.
Objectives
The aim of this study was to investigate the disease-specific urinary levels variations of neurotrophins (NGF, BDNF), mediators of inflammation (TGFβ-1, PGE-2) and markers of extracellular ...matrix alterations (TIMP-2) in patients with multiple sclerosis (MS) spinal cord injury (SCI), or spina bifida (SB), and neurogenic detrusor overactivity (NDO).
Methods
A prospective single-center study was conducted between March 2015 and March 2017. Patients aged over 18 years old, with neurological disease, with a urodynamic diagnosis of NDO were included. The urinary levels of NGF, BDNF, TIMP-2, PGE 2, and TGF-β1 were measured using dedicated ELISA kits.
Results
Forty-one patients were included: 6 with MS, 20 with SCI, and 15 with spina bifida. The average urinary level of NGF/Cr was significantly higher in MS patients compared to other neurologic populations (8 vs. 0.56 vs. 1.25 pg/mg of creatinine;
p
= 0.001) as well for the average urinary level of BDNF (88.3 vs. 5 vs. 4.8 pg/mg of creatinine;
p
< 0.0001). SCI patients had a significantly lower level of TGFβ-1 than SB patients (
p
= 0.04). The urinary level of PGE2 was significantly correlated with the Body Mass Index (
r
= 0.61;
p
= 0.0002).
Conclusion
All NDO may not be created equal from the molecular standpoint. Multiple sclerosis patients had higher urinary levels of neurotrophins than in other neurologic populations with NDO. Urinary TGFβ-1, a strong determinant of extracellular matrix, was significantly higher in spina bifida patients compared to SCI patients. These findings underscore the importance of using and interpreting those possible urinary markers in a disease-specific fashion.
The natural history of anal ulcerations in Crohn’s disease remains unknown.
To assess the long-term outcomes of anorectal ulcerations.
Data from consecutive patients with perineal Crohn’s disease ...were prospectively recorded. The data of patients with anal ulceration were extracted.
Anal ulcerations were observed in 154 of 282 patients (54.6%), and 77 cases involved cavitating ulcerations. The cumulative healing rates were 47%, 70% and 82% at 1, 2 and 3 years, respectively. Patients with a primary fistula phenotype had a shorter median time to healing of their anal ulceration (28 13–83 weeks) than those with a stricture (81 28–135 weeks) or those with isolated ulceration (74 31–181 weeks) (p=0.004). Among patients with ulcerations but no fistula at referral (n=67), only 4 (6%) developed de novo abscesses and/or fistula during follow-up. There was no benefit associated with introducing or optimising biologics, nor with combining immunosuppressants and biologics.
Anal ulceration in Crohn’s disease usually requires a long time to achieve sustained healing. Determining the impact of biologics on healing rates will require dedicated randomised trials although it does not show a significant healing benefit in the present study.
Summary
Background
There are limited data concerning infliximab drug monitoring during de‐escalation of the treatment of inflammatory bowel disease (IBD).
Aim
To define the rate and the predictors of ...relapse following infliximab de‐escalation in IBD patients in remission.
Methods
All IBD patients at a single referral centre in clinical and biological remission and in whom the dose of infliximab had been de‐escalated were included. Patients in remission with a high trough level of infliximab (>7 mg/L) were considered to be trough level‐based de‐escalation patients. The data were retrieved from a prospective IBD database. Actuarial analysis was performed for statistical purposes.
Results
A total of 146 de‐escalations were performed in 96 patients (Crohn's disease/ulcerative colitis: 68%/32%); 54 (37%) were based on clinical remission only, and 92 (63%) were based on clinical remission associated with a trough level above 7 mg/L. The cumulative probabilities of relapse following infliximab de‐escalation were 16% and 47% at 1 and 2 years, respectively. Ulcerative colitis was associated with an increased risk of relapse (HR = 3.2, P = 0.005). Conversely, combination therapy at infliximab initiation (HR = 0.39, P = 0.0110) and trough level‐based de‐escalation were associated with decreased risk of relapse (HR = 0.45, P = 0.024). Trough levels before and after de‐escalation were well correlated; a decrease by half was observed following a 2‐week interval increase or a half‐dose decrease.
Conclusion
The use of trough levels to assess the feasibility of dose de‐escalation seems to be a prerequisite for decreasing the risk of relapse.
Abstract
Patients with spinal cord injury (SCI) suffer from major bowel dysfunction, whose exact pathophysiology, particularly the involvement of the enteric nervous system or epithelial dysfunction ...is poorly understood. Herein, we aimed to characterize the mucosal biopsies of the right and left colon in SCI patients vs controls (CT): (1) remodeling of key enteric neurotransmitters, (2) remodeling of enteroendocrine cells, and (3) mucosal inflammation compared to those in controls. In SCI, mucosal ACh concentration was lower in the right colon as compared to CT, but no change was observed in the left colon, and AChE expression was lower in both the right and left colons than in CT. While the VIP concentration was similar in the right and left colons, VIP mRNA expression was increased in the right colon and decreased in the left colon, in SCI patients as compared to CT. Interestingly, 5-HT concentration was reduced in the left colon but not in the right colon in SCI patients. Moreover, in SCI patients, as compared to CT, SERT mRNA expression was selectively increased in the left colon while TPH1 mRNA expression was increased in the right and left colons. Although mucosal TNFα and IL-1β mRNA expression did not significantly differ between SCI and CT groups, we identified a significant positive correlation between TNFα and IL-1β mRNA expression and left colon transit time in the SCI group. In conclusion, region-specific changes occur in the enteric neurotransmitter, serotonergic, and inflammatory pathways in the colon of SCI patients. The significant correlations between these pathways and clinical parameters in the left colon further set a scientific basis for designing therapeutic targets to improve colonic motor dysfunction in patients.
Biobank information
: Spinal cord injury patients: PHRC ConstiCAPE—clinical trial NCT02566746. Controls: Anosain—clinical trial NCT03054415 and biobank of the “Institut des Maladies de l’Appareil Digestif (IMAD)” registered under number DC-2008-402.
This study aimed at exploring the link among individual concentrations, pharmacokinetic parameters, and the probability of relapse after de‐escalation in a real‐world prospective cohort of patients ...with inflammatory bowel disease (IBD) who underwent infliximab treatment de‐escalation. Ninety‐one patients were included. A time‐varying compartment model was used to estimate individual pharmacokinetic parameters and trough concentrations. A Cox model was implemented to explore the parameters influencing the probability of relapse after de‐escalation. Volume, clearance, and trough before and after de‐escalation were linked to the relapse risk at the univariate step. Independent predictors of relapse were tobacco use and/or ulcerative colitis (P = 0.0093), a higher C‐reactive protein (CRP; P = 0.00064), and an infliximab trough < 2.4 μg/mL after de‐escalation (P = 0.0001). Patients with trough > 5.7 μg/mL are eligible to de‐escalation, but infliximab pharmacokinetics is highly variable in time. Therefore, drug monitoring is mandatory after de‐escalation to maintain trough > 2.4 μg/mL. Clearance monitoring seems an appealing approach for patient selection and relapse prediction.
Central sensitization is frequently associated with chronic pelvic pain and requires specific management. The pain is described as hypersensitivity to an innocuous stimulus that is both widespread ...and persistent. However, no study has evaluated if central sensitization can be measured objectively with neurophysiological tests in the pelvic and perineal area to prove this concept in women with chronic pelvic pain.
To evaluate nociceptive thresholds (primary objective) and spatial and temporal diffusion of pain among women with chronic pelvic pain and high or low scores of central sensitization
This prospective, assessor-blinded, comparative study compared a cohort of women with chronic pelvic pain and a high (>5/10, n=29) versus low (<5/10, n=24) score of sensitization according to the Convergences PP criteria. Participants underwent a non-invasive bladder sensory test, a rectal barostat and a muscular (algometer) and a vulvar (vulvagesiometer) sensory test. Post-stimulation pain (minutes), quality of life (SF-36) and psychological state, comprising anxiety (State-Trait Anxiety Inventory), depression (Beck Depression Index Short Form) and catastrophizing (Pain Catastrophizing Scale), were assessed.
The participants mostly suffered from endometriosis (35.8%), irritable bowel syndrome (35.8%), bladder pain syndrome (32.1%) and vestibulodynia (28.3%). Baseline characteristics were similar. Women with a high sensitization score had more painful diseases diagnosed (2.7 ± 1.3 vs. 1.6 ± 0.8, p = 0.002) and suffered for longer (11 ± 8 vs. 6 ± 5 years, p = 0.028) than participants with a low score. The bladder maximum capacity was equivalent between participants (399 ± 168 vs. 465 ± 164 mL, p = 0.18). However, the pain felt at each cystometric threshold was significantly increased in women with a high sensitization score. No difference was identified for the rectal pain pressure step (29.3 ± 5.5 vs. 30.7 ± 6.5 mmHg, p = 0.38). The rectal compliance was decreased in women with a high sensitization score with a significant increase in pain felt. The average of pain pressure thresholds at the 5 vulvar sites tested was decreased in these participants (162.5 ± 90.5 vs. 358.7 ± 196.5 g, p = 0.0003). Similar results were found for the average of the pain pressure thresholds at 6 muscles tested (1.34 ± 0.41 vs. 2.63 ± 1.52 kg/m2, p = 0.0002). A longer period was needed for patients with high sensitization score to obtain a VAS <3/10 after the stimulation of the bladder (4.52 ± 5.26 vs. 1.27 ± 2.96 minutes, p = 0.01), the rectum (3.75 ± 3.81 vs. 1.19 ± 1.23 minutes, p = 0.009) and the muscles (1.46 ± 1.69 vs. 0.64 ± 0.40 minutes, p = 0.002). The psychological state was equivalent between groups. No association was found between the sensory thresholds and the psychological state results. The physical component of the quality of life was reduced in women with high sensitization score (p = 0.0005) with no difference in the mental component.
Using neurophysiological tests, this study shows that there are objective elements to assess for the presence of central sensitization, independently of psychological factors.
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