It is now clear that previously polarized T cells possess the ability to change their phenotype and repolarize towards different fates. This intrinsic flexibility is commonly referred to as ...plasticity and is influenced by the cytokine milieu, microbial products and products of metabolism which, in turn, regulate transcription factors and epigenetic machinery in the intestinal lamina propria.
The intestinal immune system faces a particularly difficult challenge. It serves to protect the largest mucosal surface against infection and injury while maintaining a state of tolerance towards dietary antigens and the largest population of commensal organisms in the body. This requires a delicate balance between regulatory and effector T cells; loss of this balance is thought to lead to the development of Crohn's disease (CD) and ulcerative colitis (UC), collectively referred to as inflammatory bowel disease (IBD). These unique immune-mediated inflammatory diseases are directed not at self-antigens but rather at the commensal microorganisms which reside within the gut lumen. However, it is thought that owing to persistence of these microbial antigens, intestinal damage and systemic inflammation ensue.
New data from mouse models of IBD suggest that T cell plasticity, particularly along the Th1-Th17 and Th17-Treg axes, plays an important role in the regulation of intestinal immune responses. Furthermore, patients with IBD demonstrate increased numbers of “transdifferentiated” T cell populations suggestive of heightened plasticity.
This review will consider the mechanisms and roles of Th17 plasticity in the pathogenesis of IBD.
•Augmented T cell transdifferentiation is found in the gut and blood of patients with IBD suggestive of T cell plasticity.•Th17 is perhaps the most plastic T cell subset due to a critical role between inflammation and homeostasis of the gut.•Th17 plasticity is greatly influenced and induced by microenvironmental factors within the gut, such as diet and microbiota.
Purpose The prevalence of inflammatory bowel diseases is much lower in Asian countries, including Japan, than in Western countries, but it is rapidly increasing. However, no recent reports describe ...the current prevalence of these diseases in Japan, so we performed a descriptive epidemiological study to remedy this situation and to elucidate various characteristics of inflammatory bowel diseases in this country. Methods Japan has a nationwide registration system of patients with intractable diseases, including ulcerative colitis and Crohn's disease. To calculate the age-standardized prevalence, we used this registration system to collect patient data, and we obtained detailed population data from the Japanese government's population estimates made in 2003 and 2004 and from the 2005 population census. In addition, information about the characteristics of ulcerative colitis and Crohn's disease patients was collected through the registration system. Results The age-standardized prevalence of ulcerative colitis in Japan in 2005 was 63.6 per 100,000 persons, and that of Crohn's disease was 21.2. Patient numbers have been steadily increasing with time. The age distribution was found to differ between the two diseases, with Crohn's disease affecting mainly younger people. In both diseases, more than 50% of the patients were male, and over 80% of the patients were classified as mild to moderate in terms of severity. Conclusions The prevalence of inflammatory bowel diseases in Japan is still much lower than in Western countries. Surveillance should be continued, and research to clarify their etiologies in association with the increasing number of patients in Japan is needed.
With ageing, normal human tissues experience an expansion of somatic clones that carry cancer mutations
. However, whether such clonal expansion exists in the non-neoplastic intestine remains ...unknown. Here, using whole-exome sequencing data from 76 clonal human colon organoids, we identify a unique pattern of somatic mutagenesis in the inflamed epithelium of patients with ulcerative colitis. The affected epithelium accumulates somatic mutations in multiple genes that are related to IL-17 signalling-including NFKBIZ, ZC3H12A and PIGR, which are genes that are rarely affected in colon cancer. Targeted sequencing validates the pervasive spread of mutations that are related to IL-17 signalling. Unbiased CRISPR-based knockout screening in colon organoids reveals that the mutations confer resistance to the pro-apoptotic response that is induced by IL-17A. Some of these genetic mutations are known to exacerbate experimental colitis in mice
, and somatic mutagenesis in human colon epithelium may be causally linked to the inflammatory process. Our findings highlight a genetic landscape that adapts to a hostile microenvironment, and demonstrate its potential contribution to the pathogenesis of ulcerative colitis.
Background
Infliximab (IFX) is one of the treatments of choice for corticosteroid-refractory and corticosteroid-dependent ulcerative colitis (UC). A high serum trough level of IFX (TL) is reported to ...be associated with sustained efficacy during maintenance treatment. As part of a phase 3 randomized controlled trial of IFX in UC, we assessed the predictive value of the first TL at week 2 for short- and long-term response.
Methods
Patients received intravenous IFX 5 mg/kg or placebo at weeks 0, 2, and 6. Patients with evidence of a response by week 8 continued treatment at weeks 14 and 22. TL was measured by enzyme-linked immunosorbent assay. Post hoc analysis was then performed for TL and clinical outcomes.
Results
Clinical response rate at week 8, the primary end point, was significantly higher in the IFX group than placebo (
p
= 0.005). The incidence of adverse events between groups was similar. Week 2 TL was significantly associated with a 14-week clinical activity index (CAI) remission. In multiple logistic regression analysis, the week 2 TL-to-CAI ratio (TL/CAI, odds ratio 8.07; 95 % confidence interval 2.84–27.07,
p
< 0.001) was an independent factor correlating with 14-week CAI remission. The week 2 TL and TL/CAI were also significantly associated with 30-week mucosal healing.
Conclusions
IFX was confirmed to be effective and safe in this population. Our results suggest that the first TL at week 2, in combination with clinical evaluation, is useful for predicting both short- and long-term outcomes, allowing an earlier decision between continuing IFX or switching to other options.
Background
The global phase 3 studies of golimumab PURSUIT-SC and PURSUIT-maintenance (M), an anti-tumor necrosis factor-α (anti-TNFα) antibody, have demonstrated clinical efficacy and safety as ...induction and maintenance therapies in patients with moderate to severely active ulcerative colitis (UC). This study aimed to evaluate the efficacy and safety of golimumab as maintenance therapy in the Japanese population.
Methods
In this phase 3, double-blind (DB), placebo-controlled, parallel group, randomized withdrawal study, 144 Japanese patients with moderately to severely active UC received golimumab doses of 200 mg (at week 0) and 100 mg (at week 2) subcutaneously during the 6-week open-label induction phase. Patients who responded to golimumab induction therapy entered the DB maintenance (M) phase and were randomized (1:1) to receive 100 mg of golimumab subcutaneous injection (SC) or placebo every 4 weeks for 52 weeks. The primary endpoint was clinical response through M-week 54; secondary endpoints included clinical remission and mucosal healing at M-week 30 and 54.
Results
Among induction responders, more patients on golimumab treatment (56.3%) maintained clinical response through M-week 54 versus the placebo group (19.4%). At both M-week 30 and 54, 50% golimumab-treated patients achieved clinical remission versus the placebo group (6.5%) and a higher proportion of patients on golimumab (59.4%) experienced mucosal healing than the placebo group (16.1%). Incidence of treatment-emergent adverse events was 96.9% in the golimumab group and 71% in the placebo group. Overall, the efficacy and safety results in this study were comparable with those observed in global studies.
Conclusions
Golimumab SC treatment maintained clinical efficacy through week 54 among induction responders, and no new safety signals were observed in the patients with moderate to severely active UC.
Clinical Trial Registration: The study is registered at ClinicalTrials.gov NCT01863771.
Summary
Background
Transabdominal ultrasound is useful to assess inflammation in patients with ulcerative colitis (UC); however, the assessment of the rectum is challenging and a barrier for its ...widespread use.
Aim
To evaluate if transperineal ultrasound is useful for predicting endoscopic and histological findings of the rectum in UC.
Methods
Fifty‐three consecutive adults with UC who required colonoscopy were included and transperineal ultrasound was performed in combination with transabdominal ultrasound within a week before or after colonoscopy with rectal biopsy. Mayo endoscopic subscore (MES) ≤1 was defined as endoscopic healing and Geboes score <2.1, Robarts histopathology index ≤6, and Nancy index ≤1 were defined as histological healing. Limberg score and bowel wall thickness were recorded with transperineal ultrasound. Faecal calprotectin was also measured.
Results
Excellent correlation was confirmed between colonoscopy and transabdominal ultrasound in all segments except for the rectum. Rectal bowel wall thickness and Limberg score in transperineal ultrasound well correlated with rectal MES and histological indices. Bowel wall thickness ≤4 mm predicted endoscopic (Area under the curve AUC = 0.90) and histological (AUC = 0.87‐0.89) healing. In multivariable logistic regression analysis, only bowel wall thickness in transperineal ultrasound was a significant independent predictor for rectal endoscopic and histologic healing (P < 0.05) and the predictability was better than faecal calprotectin.
Conclusions
Transperineal ultrasound predicts endoscopic and histological healing of the rectum. The combination of transperineal ultrasound with transabdominal ultrasound visualises the entire colorectum and is an ideal modality for the treat‐to‐target strategy.
Clinical Trials Registry number UMIN000033611 (https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000038323).
Ulcerative colitis and Crohn's disease, the most common types of inflammatory bowel disease, are idiopathic, intractable disease characterized by chronic inflammation in the intestine. In recent ...years, studies elucidating the clinical characteristics of these diseases and basic researches have suggested that the diseases are induced by the immunological abnormalities through the involvement of environmental factors with their predisposition. In Japan, significant progress of basic and epidemiological researches has been developed for these diseases and the clinical guidelines have been established. However, no fundamental treatment for these diseases has been established yet. The current number of patients in Japan continues to increase, with at least 180,000 patients suffering from ulcerative colitis and 40,000 suffering from Crohn's disease. Thus, further studies are required to understand these diseases and improve medical treatments.
Inflammatory bowel disease (IBD) is a chronic disorder involving mainly the intestinal tract, but possibly other gastrointestinal and extraintestinal organs. Although etiology is still uncertain, ...recent knowledge in pathogenesis has accumulated, and novel diagnostic and therapeutic modalities have become available for clinical use. Therefore, the previous guidelines were urged to be updated. In 2016, the Japanese Society of Gastroenterology revised the previous versions of evidence-based clinical practice guidelines for ulcerative colitis (UC) and Crohn’s disease (CD) in Japanese. A total of 59 clinical questions for 9 categories (1. clinical features of IBD; 2. diagnosis; 3. general consideration in treatment; 4. therapeutic interventions for IBD; 5. treatment of UC; 6. treatment of CD; 7. extraintestinal complications; 8. cancer surveillance; 9. IBD in special situation) were selected, and a literature search was performed for the clinical questions with use of the MEDLINE, Cochrane, and Igaku Chuo Zasshi databases. The guidelines were developed with the basic concept of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Recommendations were made using Delphi rounds. This English version was produced and edited based on the existing updated guidelines in Japanese.
Background
Fermented milk products containing
Bifidobacterium breve
strain Yakult (BFM) may improve clinical status in ulcerative colitis (UC) patients.
Aims
To assess efficacy of BFM in maintaining ...remission in Japanese patients with quiescent UC.
Methods
This double-blind study (B-FLORA) enrolled 195 patients with quiescent UC, randomized to receive one pack of BFM fermented milk per day
Bifidobacterium breve
strain Yakult (10 billion bacteria) and
Lactobacillus acidophilus
(1 billion bacteria) (
n
= 98) or matching placebo (
n
= 97) for 48 weeks. The primary efficacy endpoint was relapse-free survival (relapse: rectal bleeding score ≥ 2 on Sutherland disease activity index scale for 3 consecutive days and/or initiation of remission induction therapy for worsening of UC).
Results
An interim analysis was conducted after inclusion and follow-up of one-third of patients for the first phase of the study (
n
= 195). Relapse-free survival was not significantly different between the BFM and placebo groups (
P
= 0.643; hazard ratio 1.16; 95% CI 0.63–2.14, log-rank test), nor was the incidence of relapse. Therefore, the study was discontinued for lack of efficacy. An exploratory analysis of fecal samples from a subgroup of patients revealed no effects of either study beverage on intestinal microbiota, but there was a significant decrease in
Bifidobacterium
species before relapse, regardless of treatment group. Three mild adverse events occurred for which a causal relationship with the study beverage could not be ruled out (placebo: abdominal bloating and stress in one patient; BFM: body odor in one patient).
Conclusions
BFM had no effect on time to relapse in UC patients compared with placebo.
Study Registration
UMIN000007593.
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