Clinical predictors for a complicated course of disease in an inception cohort of patients with ulcerative colitis: results from the prospective, observational EPICOL study.

PURPOSE: The clinical course of ulcerative colitis (UC) is highly heterogeneous, with 20 to 30% of patients experiencing chronic disease activity requiring immunosuppressive or biologic therapies. The aim of this study was to identify predictors for a complicated disease course in an inception cohort of patients with UC. METHODS: EPICOL was a prospective, observational, inception cohort (UC diagnosis, ≤ 6 months) study in 311 patients with UC who were naive to immunosuppressants (IS)/biologics. A complicated course of disease was defined as the need for IS and/or biologic treatment (here therapy with a TNF-α antagonist) and/or UC-related hospitalisation. Patients were followed up for 24 months. RESULTS: Of the 307 out of 311 participants (4 patients did not meet the inclusion criteria "confirmed diagnosis of active UC within the last 6 months" (n = 2) and "immunosuppressive-naïve" (n = 2), analysis population), 209 (68.1%) versus 98 (31.9%) had an uncomplicated versus a complicated disease course, respectively. In a multivariate regression analysis, prior use of corticosteroids and prior anaemia were associated with a significantly increased risk for a complicated disease course (2.3- and 1.9-fold increase, respectively; p < 0.001 and p = 0.002). Based on these parameters, a risk model for patient stratification was developed. CONCLUSION: Our study identifies anaemia and an early need for corticosteroids as predictors for a complicated course of disease in an inception cohort of patients with UC. By determining these parameters in routine clinical practice, our results may support the identification of patients who might benefit from early escalation of therapy.

Transmural Response and Transmural Healing Defined by Intestinal Ultrasound: New Potential Therapeutic Targets?

BACKGROUND AND AIMS: Intestinal ultrasound [IUS] is a useful modality to monitor patients with inflammatory bowel disease [IBD]. Little is known about the use of IUS and appropriate definitions for transmural response [TR] and healing [TH]. We aimed to establish the use of IUS in monitoring TH as a potential target in routine medical practice. METHODS: Based on the prospective, non-interventional, multicentre studies TRUST and TRUST&UC, we conducted a post-hoc analysis of 351 IBD patients with increased bowel wall thickness [BWT]. We analysed the rates of patients achieving TR and TH, comparing three definitions of TH. In 137 Crohn's disease [CD] patients, the predictive value of TR and TH was investigated for the clinical and sonographic outcome at week 52. RESULTS: Within 12 weeks of treatment intensification, 65.6% [n = 118] of CD patients and 76.6% [n = 131] of ulcerative colitis [UC] patients showed a TR. Depending on the definition, 23.9-37.2% [n = 58/67/43] of CD patients and 45.0-61.4% [n = 90/105/77] of UC patients had TH at week 12. CD patients with TH were more likely to reach clinical remission at week 12 (odds ratio [OR] 3.33 [1.09-10.2]; p = 0.044) and a favourable sonographic outcome (OR 5.59 [1.97-15.8]; p = 0.001) at week 52 compared with patients without TH. CONCLUSIONS: IUS response and TH in a relevant proportion of patients suggests that IUS is a useful method to assess transmural inflammatory activity in daily clinical practice. TR and TH are predictive for the sonographic outcome at week 52.

Functional and Molecular Characterization of Mechanoinsensitive "Silent" Nociceptors.

Mechanical and thermal hyperalgesia (pain hypersensitivity) are cardinal signs of inflammation. Although the mechanism underlying thermal hyperalgesia is well understood, the cellular and molecular basis of mechanical hyperalgesia is poorly described. Here, we have identified a subset of peptidergic C-fiber nociceptors that are insensitive to noxious mechanical stimuli under normal conditions but become sensitized to such stimuli when exposed to the inflammatory mediator nerve growth factor (NGF). Strikingly, NGF did not affect mechanosensitivity of other nociceptors. We show that these mechanoinsensitive "silent" nociceptors are characterized by the expression of the nicotinic acetylcholine receptor subunit alpha-3 (CHRNA3) and that the mechanically gated ion channel PIEZO2 mediates NGF-induced mechanosensitivity in these neurons. Retrograde tracing revealed that CHRNA3+ nociceptors account for ∼50% of all peptidergic nociceptive afferents innervating visceral organs and deep somatic tissues. Hence, our data suggest that NGF-induced "un-silencing" of CHRNA3+ nociceptors significantly contributes to the development of mechanical hyperalgesia during inflammation.