1. To understand the role of IL-12 and IL-23 in the development of IBD
2. To review the pivotal UNITI and UNIFI trials
3. To review the place of ustekinumab in IBD therapy
4. To have an overview on practical modalities of ustekinumab therapy
5. To get insight in the anti-IL23 drugs that are in development
1. To understand the mechanism of action of vedolizumab and other anti interns
2. To review the key phase III clinical data
3. To highlight studies from real world cohort and discuss the safety profile of Vedolizumab
4. To understand how to position Vedolizumab in clinical practice
Educational objectives: 1. To understand the structural and functional features of the various anti-TNF agents, including originators and biosimilars 2. To review their use in Crohn's disease (CD), ulcerative colitis (UC) and in special indications 3. To have an overview of the optimal dosing of anti-TNFs, including therapeutic dose monitoring.
Anti-TNF were the first biological therapies available in IBD as well as in other immune-inflammatory disorders such as rheumatoid arthritis, spondyloarthritis and psoriasis. These agents can induce and maintain remission of CD and UC. They are also used in refractory pouchitis and microscopic colitis. Infliximab and adalimumab are approved in CD and UC, while certolizumab pegol is only approved for CD in some jurisdictions but not EU, and golimumab is approved for UC only. Biosimilars of infliximab and adalimumab are now available with all the indications of their originators. Data accumulate to support similar activity in both diseases, but some individual differences may be observed. Anti-TNF agents are increasingly used during pregnancy and for the treatment of extraintestinal manifestations of IBD. Infliximab remains the best studied biological agent in IBD. The possibility of iv administration at high doses makes it the favored agent in fulminant colitis, fistulizing CD and in pyoderma gangrenosum. As all biological agents, anti-TNFS can induce anti-drug antibodies that represent the main cause of loss of response to these therapies. Continuous dosing beyond induction, combination therapy and premedication with hydrocortisone reduce this risk. Therapeutic dose monitoring and antibody detection are now available for all anti-TNF agents, the proactive use of which improves treatment outcome and preserves long-term response.
Discontinuation of anti-tumour necrosis factor alpha agents (anti-TNF) in patients with inflammatory bowel disease (IBD) in remission may reduce side effects and costs, but this has to be weighed against the risk of relapse. We developed a risk-stratified protocol for anti-TNF withdrawal, and aimed to assess the risk of relapse after risk-stratified anti-TNF withdrawal.Methods
This was a single arm prospective observational cohort study. Patients were recruited between September 2018-2020 in 13 hospitals in the Netherlands. Inclusion criteria were a diagnosis of IBD, age >18 years, elective anti-TNF withdrawal in a patient with quiescent disease (according to the treating physician), no current or planned use of vedolizumab, ustekinumab or tofacitinib, no hospitalization, and no active or planned pregnancy. According to the protocol, patients were recommended to withdraw anti-TNF only when in endoscopic remission either without high-risk criteria (age at diagnosis <18 years, and for Crohn’s disease [CD]: smoking, stricturing/penetrating disease behaviour, small bowel resection >50cm), or when trough levels were undetectable. We constructed Kaplan-Meier curves with log-rank test to compare the risk of relapse in patients who discontinued anti-TNF in accordance with, versus against, the protocol. Cox regression analysis was performed to identify predictors of relapse.Results
We enrolled 115 patients (CD: n=61, 53%), with a median follow-up time of 1.9 (IQR 1.8 – 2.1) years. Baseline endoscopic remission was confirmed in 103 (89.6%) patients, and 35 (30.4%) patients continued an immunomodulator. During follow-up, 57 (49.6%) patients relapsed (Figure 1). The relapse rate was similar in patients in endoscopic remission who withdrew anti-TNF in according with, versus against, the protocol (50.7% versus 44.4%, p=0.65), and in patients with versus without an immunomodulator (hazard rate [HR] 0.89, 95%CI 0.50 – 1.59), but was lower in patients with subtherapeutic anti-TNF trough levels (adjusted HR: 0.55, 95%CI: 0.31 – 0.99), and in patients with UC/IBD-unclassified (IBDU) who were treated with mesalamine maintenance therapy (HR: 0.35, 95%CI 0.13 – 0.94). Anti-TNF was reintroduced in 41 (71.9%) patients, with remission rates of 64.5% and 81.8% at 3 and 12 months, respectively. In 6 (15.0%) patients anti-TNF therapy was discontinued again due to primary non-response or loss of response.
The risk of relapse after anti-TNF withdrawal remains high in a strictly selected group of patients with uncomplicated IBD in endoscopic remission. Therapeutic drug monitoring prior to anti-TNF withdrawal, and mesalamine therapy for patients with UC or IBDU, may reduce the risk of relapse.
Older adults are the fastest growing subpopulation of patients with IBD, with approximately 15% diagnosed after 60 years-of-age. Moreover, environmental exposures are thought to play a significant role in the development of older-onset IBD, given the lower genetic risk. Antibiotics have been associated with development of IBD in earlier generations, but the impact on IBD risk in older adults is uncertain. In this population-based cohort study, we assessed the impact of cumulative antibiotic use, the timing of antibiotic use, and the association between specific antibiotic classes and the development of older-onset IBD.Methods
Using Denmark nationwide registries, a cohort of residents ≥60 years-of-age was established between 2000-2018. Information on exposure to antibiotics was retrieved from the Danish National Prescription Register. The number of courses of antibiotics (overall and specific classes) was considered a time-varying variable. The outcome, IBD, was identified based on ICD-10 codes in the Danish National Patient Register. Incidence rate ratios (IRRs) for IBD according to antibiotic use 1 to 5 years prior to IBD diagnosis were calculated by log-linear Poisson regression, and adjusted for age, sex, and calendar period.Results
There were a total of 2,327,796 individuals aged 60 to 90 years included in the cohort, resulting in 22,670,484 person-years of follow-up. There were 10,773 new cases of ulcerative colitis (UC) and 3,825 new cases of Crohn’s disease (CD). Overall, any antibiotic use was associated with an IRR for the development of IBD (IRR 1.64, 95%CI 1.58-1.71), with a positive dose response observed (1 course of antibiotics IRR 1.27 95%CI 1.21-1.33; 2 courses IRR 1.54 95%CI 1.46-1.63; 3 courses IRR 1.66 95%CI 1.67-1.77; 4 courses IRR 1.96 95%CI 1.83-2.09; 5+ courses IRR 2.35, 95%CI 2.24-2.47). A higher IRR was noted between the timeframe of 1-2 years before diagnosis (IRR 1.87, 95%CI 1.79-1.94) as compared to 2-5 years before diagnosis (IRR 1.42, 95%CI 1.36-1.48). Additionally, all antibiotic classes were associated with the development of IBD, including those not used to treat gastrointestinal infections. Antibiotics with the highest IRR were fluoroquinolones (IRR 2.27, 95%CI 2.08-2.48), nitroimidazoles (IRR 2.21, 95%CI 1.95-2.50), and macrolides (IRR 1.74, 95%CI 1.64-1.84). All results remained statistically significant when stratifying by UC and CD, with effect estimates slightly higher for CD as compared to UC.Conclusion
Use of antibiotics, regardless of class studied, was associated with an increased risk of older-onset IBD. This risk was highest one to two years prior to diagnosis, but persisted even prior to that, suggesting a link between overall antibiotic use and development of older-onset IBD.
Antibody responses following SARS-CoV-2 infection or a single-dose of SARS-CoV-2 vaccine are impaired in patients with inflammatory bowel disease treated with anti-TNF compared to those treated with vedolizumab, a gut-selective anti-integrin α4β7 monoclonal antibody.
Here we sought to determine if patients treated with infliximab have attenuated serological and T cell responses and an increased risk of breakthrough COVID-19 infection following primary SARS-CoV-2 vaccination.Methods
Anti-spike (S) receptor binding domain (RBD) antibody concentration in 2306 infliximab-treated patients were compared to a cohort of 1045 vedolizumab-treated patients. Our primary outcome was anti-S RBD antibodies 2 to 10 weeks after a second dose of the BNT162b2 or ChAdOx1 nCoV-19 vaccines. Secondary outcomes were anti-spike T cell responses, durability of vaccine responses and risk of breakthrough infections following two doses of vaccine.Results
Anti-S RBD antibody concentrations were lower in patients treated with infliximab than in those treated with vedolizumab, following a second dose of BNT162b2 (567.3 U/mL [6.1] vs 4601.1 U/mL [5.3], p <0.0001) and ChAdOx1 nCoV-19 (183.9 U/mL [5.0] vs 789.4 U/mL [3.5], p <0.0001) vaccines (Fig. 1).
Vaccination with the BNT162b2 vaccine compared to the ChAdOx1 nCoV-19 was independently associated with a 3.7-fold [95% CI 3.30 – 4.13] higher anti-S RBD antibody concentration (p < 0.0001) (Fig. 2).
There were no significant differences in the magnitude of anti-spike T cell responses observed in infliximab- compared with vedolizumab-treated patients after one or two doses of either vaccine.
Antibody half-life was shorter in infliximab- than vedolizumab-treated patients following two-doses of BNT162b2 (4.0 weeks [95% CI 3.8 – 4.1] vs 7.2 weeks [95% CI 6.8 – 7.6]) and ChAdOx1 nCoV-19 (5.3 weeks [95% CI 5.1 – 5.5] vs 9.3 weeks [95% CI 8.5 – 10.2], p value < 0.0001).
Breakthrough SARS-CoV-2 infections were more frequent (5.8% (202/3467) vs 3.9% (66/1691), p = 0.0032) and the time to breakthrough shorter in patients treated with infliximab than vedolizumab (p = 0.0023) (Fig. 3).
Higher anti-S RBD antibody concentrations following a second dose of SARS-CoV-2 vaccine protected against breakthrough SARS-CoV-2 infection: overall, for every 10-fold rise in anti-S RBD antibody level we observed a 0.8-fold reduction in odds of breakthrough infection ([95% CI 0.70 – 0.99], p = 0.035).
Infliximab was associated with attenuated, less durable vaccine induced anti-S RBD antibody responses and a 50% increase in breakthrough SARS-CoV-2 infection. Further follow-up is required to assess whether third primary doses can mitigate the effects of infliximab on anti-S RBD antibody responses.
Many papers in the past underpinned the possible role of appendicectomy. Appendectomy as a therapy for Ulcerative Colitis might work in mild ulcerative colitis. In the ACCURE, patients are randomized to medical therapy only or with appendectomy after induction of remission. Incidence of exacerbations is taken as primary endpoint. The first results will be available in one year time.
In the PASSION, patients with moderate to severe ulcerative colitis refractory to anti-TNF that were referred for colectomy were offered appendectomy. At 8 years follow up 1 out of three were colectomies, 1 out of three were having minor medication being biological free, and 1 out of five was on Tofacitinib. Endoscopic response was observed in at least in 1 out of 4. The Costa study is a patient preference model were patients are randomized or can choose either appendectomy of Tofacitinib when completely refractory to anti-TNF and Vedoluzimab. At this point 75% of the required patients are included.
There is accumulating evidence that appendectomy mitigates the disease course of ulcerative colitis
There is a scarcity of data regarding the role of histopathology evaluation in Crohn’s disease (CD) and how it relates to endoscopy. Mirikizumab (miri) has shown efficacy in Ph2 studies in CD and ulcerative colitis (UC). Here we explore the agreement of histologic response and remission with endoscopic outcomes after 12 and 52 weeks of treatment with miri in a phase 2 randomized clinical trial (SERENTIY; NCT02891226) in patients with moderate-to-severe CD.Methods
Patients were randomized 2:1:1:2 across 4 treatment arms (PBO, 200, 600, 1000mg miri) administered intravenously (IV) every four weeks (Q4W) at Weeks 0, 4, and 8. Those who received miri and achieved ≥1 point improvement from baseline (BL) at W12 in Simple Endoscopic Score for Crohn’s Disease (SES-CD) were re-randomized 1:1 into double-blind maintenance to continue their IV dose assignment Q4W (IV/IV) or to 300mg miri SC Q4W (IV/SC); due to small numbers, maintenance IV arms were pooled for analysis. W12 non-improvers and all induction PBO patients received 1000mg miri Q4W from W12 through W52. Biopsies were obtained during endoscopy at W0, 12 and 52 from the edge of the ulcers and the most inflamed mucosa in terminal ileum and 4 colonic segments (ascending, transverse, descending, rectum; N=10/patient, 2 per location with the more severe score used), and scored by central readers blind to study treatment, timepoint, and response status. Histologic endpoints were defined post-hoc but prior to performing the analyses (see Table footnotes for definitions). Cohen’s Kappa Coefficient was used to evaluate the degree of agreement of two measures.Results
At Week 12, there was an overall 69.6% agreement in histologic and endoscopic response, and 84.2% agreement between histologic remission and endoscopic remission (Table 1). After 52 weeks of miri treatment, the agreement between histologic and endoscopic response was 61.9%, while the agreement between histologic and endoscopic remission was 70.6% (Table 2). Interestingly, in every comparison, the percentage of patients achieving the histologic outcome but not the endoscopic outcome was greater than that of patients achieving the endoscopic outcome but not the histologic outcome.Conclusion
Histologic and endoscopic outcomes demonstrated fair association after both 12 and 52 weeks of miri treatment. Histologic endpoints, despite the stringent criteria, appear to be more sensitive to change than endoscopic endpoints. However, variability of biopsy sampling may be an additional factor contributing to these differences.
The human gut is colonized by diverse microbes including fungi such as Candida albicans, which has been implicated in the pathogenesis of Crohn’s disease (CD). Intestinal C. albicans typically exists as commensal yeast, but can also form tissue-invasive filaments that secrete Candidalysin toxin to disrupt epithelial barriers. Commensal gut bacteria produce molecules that induce host immunity, including phosphoantigen HMB-PP which stimulates Vδ2+ T-cell homing to intestine and mucosal expression of IL-22 to promote barrier integrity. We aimed to identify mechanisms of gut barrier defence against fungal invasion in health and CD.Methods
Colonic biopsies / resected tissue were stimulated or not with HMB-PP in the presence or absence of anti-IL-22 blocking antibody and analysed by flow-cytometry / microscopy to determine extent of fungal outgrowth. Fungal isolates were identified using standard morphological and biochemical criteria before assessment of filamentation, cell wall composition, and NETosis induction.Results
Mucosal Vδ2+ T-cell activation with bacterial phosphoantigen HMB-PP, in the presence of epithelial damage-associated cytokine IL-15, potently suppressed growth of endogenous fungi in human colonic organ cultures. Vδ2-mediated fungal suppression required IL-22 and was sufficient to restrict the growth of multiple fungal species, including a range of emerging pathogenic moulds as well as archetypal pathobiont C. albicans. In Vδ2-deficient CD patients, mucosal biopsy stimulation with HMB-PP failed to control fungal growth. CD-derived C. albicans strains also displayed rapid filamentation ex vivo and higher levels of NOD2 ligand chitin than were observed in isolates from healthy controls. Comparing hypoxic with oxygenated cultures that mimic inflamed intestine, pSILAC proteomic analysis of a representative CD-derived C. albicans strain confirmed features of invasive growth (e.g. DAO1, IHD1), whereas a healthy control isolate exhibited metabolic hallmarks of symbiosis (Jen1p, SCH9). These divergent characteristics directly impacted on host anti-fungal immune responses, since the CD-derived strain rapidly induced neutrophil extracellular traps in vitro, whereas the healthy control isolate did not.Conclusion
These data suggest that commensal bacteria can activate host Vδ2 T-cells to suppress fungal invasion of the gut epithelium via an IL22-dependent mechanism that is deficient in CD patients.
Conflicting evidence exists regarding whether low baseline Triggering Receptor Expressed on Myeloid cells (TREM)1 whole-blood gene expression predicts response or non-response to anti-tumour necrosis factor agents in patients with Ulcerative Colitis (UC) or Crohn’s Disease (CD). This study investigated whether baseline TREM1 expression predicted outcomes following adalimumab treatment in patients with UC or CD in the SERENE Phase 3 studies.Methods
The SERENE studies (SERENE-UC, NCT02065622; and SERENE-CD, NCT02065570) compared a higher adalimumab induction dosing regimen versus the standard regimen in patients with UC or CD. Whole-blood TREM1 expression was analysed by RNA sequencing in patients who received standard-dose adalimumab and had clinical and endoscopic outcomes at Week 8 or 52 in SERENE-UC (n=95 for Week 8 and n=70 for Week 52 outcomes), or Week 12 or 56 in SERENE-CD (n=106 for all Week 12 outcomes; n=48 for clinical and n=50 for endoscopic outcomes at Week 56). Outcome definitions are summarised in Table 1. A 2-sample t-test was used to compare baseline TREM1 gene expression (log2 counts per million) in clinical or endoscopic remitters or responders versus non-remitters or non-responders at Weeks 8 and 52 (SERENE-UC) or Weeks 12 and 56 (SERENE-CD).
In SERENE-UC, baseline TREM1 expression did not predict clinical remission at Week 8 (Figure 1a; p=0.7942) and was only weakly predictive of clinical remission at Week 52 (Figure 1b; p=0.04997). Further, it was not predictive of clinical response at Week 8 or Week 52, nor of endoscopic remission or endoscopic response (Figure 1c) at Week 8 (p>0.05 in all cases), although a weak correlation was observed with both endoscopic remission (p=0.0484) and endoscopic response (p=0.01162; Figure 1d) at Week 52. In SERENE-CD, baseline TREM1 expression was not linked to endoscopic or clinical outcomes at either Week 12 or Week 56 (p>0.05 in all cases; Figure 2a–d). Stratification by adalimumab quartiles did not increase the ability of baseline TREM1 expression to predict clinical outcomes in either study. Of note, a highly positive correlation was observed between baseline TREM1 expression and neutrophils in endoscopic responders and non-responders in both studies. Regardless of clinical or endoscopic response or non-response, TREM1 expression decreased over time following adalimumab treatment. All results obtained with standard-dose adalimumab were replicated with the higher dose (data not shown).
The findings of this study suggest that baseline whole-blood TREM1 gene expression is not a robust predictor of clinical or endoscopic outcomes following adalimumab treatment in patients with UC or CD.
To understand the pros and cons of evidenced based diet therapy for IBD.
To understand the potential nutritional and psychological dangers of restrictive diets.
To highlight the importance of MDT working to support patients with diet therapy.
To assess the risk of postoperative peristomal pyoderma gangrenosum in Crohn’s disease patients undergoing bowel resection with formation of an ostomy.Methods
All patients with Crohn’s disease undergoing intestinal resection with formation of an ostomy were included in the present retrospective analysis. The data collection was performed prospectively. All cases of pyoderma gangrenosum were identified by clinical examination and documented on photographs. “Extended colectomies” were total colectomy and proctocolectomy.Results
Between 2009 and 2021, 99 patients underwent intestinal resections with formation of an ostomy – 95 ileostomies and 4 colostomies. Ileocolic resections were performed in 62 patients, small bowel resections in 2 and colorectal resections in 35 patients. Additional abdominoperineal rectal resections were performed in 19 out of latter 35 patients. At the time of surgery, 31 patients were on biological treatment, 19 on steroids. Postoperatively, 10 patients (10%) developed peristomal pyoderma gangrenosum – all during first 3 postoperative months and all in presence of an ileostomy. By univariate analysis, abdominoperineal resection (26% vs. 9%, p=0.03), presence of colonic disease (20% vs. 2%, p=0.005), preoperative biological treatment (24% vs. 4%, p=0.008), extended colectomy (27% vs. 5%, p=0.008), non-stricturing/non-penetrating disease (35% vs. 5%, p=0.002) were associated with an increased risk of peristomal pyoderma gangrenosum. By multivariate analysis, preoperative intake of biologic treatment (Hazard Ratio 5.5, p=0.03), and non-stricturing/non-penetrating disease (HR 8.3, p=0.006) were associated with the risk of postoperative pyoderma gangrenosum.Conclusion
Crohn’s disease patients with colonic disease undergoing bowel resections for non-stricturing/non-penetrating disease are at high risk to develop peristomal pyoderma gangrenosum during the early postoperative period. Preoperative biological treatment does not decrease the risk of pyoderma formation; moreover, it might even increase it.
Circulating serum proteins have provided insights into disease pathogenesis and are being used to identify prognostic, diagnostic and therapeutic biomarkers for chronic inflammatory diseases. With this pilot project, the Collaborative IBD Biomarker Research Initiative (COLLIBRI) consortium aimed to unravel disease heterogeneity in inflammatory bowel disease (IBD).Methods
Serum samples were cross-sectionally obtained from 3,390 individuals (Crohn's disease (CD), n=1815; ulcerative colitis (UC), n=1170; healthy, n=405) recruited at nine centres from Sweden and Belgium. Relative levels of 92 proteins were analysed using the Proseek Multiplex Inflammation I Probe kit 96x96 (Olink Proteomics, Uppsala, Sweden) and reported as arbitrary units, i.e., normalised protein expression on a log2 scale. Using a multivariate integrative approach, we identified protein signatures distinguishing CD and UC samples and attempted to identify clusters or subgroups within patients. Recruiting centre, cohort and batch information were considered for the integrative analysis. Optimisation was performed for identifying the number of components and features per component using 5-fold cross-validation and Leave-One-Group-Out-Cross-Validation, respectively. Information on transcriptional regulators was retrieved from the ReMap project using the orthogonal regulatory resource ChEA3.Results
A panel of 8 proteins was identified which could segregate CD and UC patients (Figure 1). FGF19 exhibited a consistent trend of expression (downregulated in CD) across all batches of datasets. An integrated AUC of 72.5% was achieved across the different batches of samples used in the study with the highest AUC (79.2%, P-value 8.5e-07) being recorded for a single batch of samples (CD = 42, UC = 56). On a centre-specific dataset, the cross-centre integrated signature achieved an AUC of 75.1%. We identified three transcription factors (MEF2A, BATF, NFKB2), of which the two latter ones are known to modulate intestinal inflammation and which could potentially regulate the expression of at least half of the genes encoding the proteins in the predictive 8-protein panel.
We identified an integrated proteomic biomarker panel capable of separating CD and UC patients. Through further integration of confounder variables along with using other supervised and unsupervised approaches, subsequent analyses may further refine the molecular heterogeneity among CD and UC patients. Our results demonstrate the need for large datasets to identify relevant clusters of patients with IBD, since the diagnosis exhibits a high degree of clinical heterogeneity.
Current endoscopic scoring indices such as the Simple Endoscopic Score for Crohn’s Disease (SES-CD) quantify the degree of mucosal inflammation in Crohn’s disease (CD) but lack prognostic potential. The Modified Multiplier of the Simple Endoscopic Score for Crohn’s Disease (MM-SES-CD) is an internally validated endoscopic scoring tool that quantifies the endoscopic burden of CD and can be accessed online (https://www.mcmasteribd.com/mm-ses-cd).1 This analysis aims to establish thresholds of the MM-SES-CD that classify CD endoscopic burden into inactive or very mild disease, mild, moderate, and severe disease based on the probability of achieving endoscopic remission (ER) on active therapy at one-year.Methods
This post-hoc analysis included pooled data from three CD clinical trials (n=350 patients, baseline SES-CD ≥3 with confirmed ulceration). Maximum Youden Index calculations were used to determine thresholds for severity. Chi-square tests of trend were used to compare achievement of ER between severity categories, and Kaplan-Meier survival curve analysis was used to compare time to clinical remission (CR).Results
Table 1 demonstrates the baseline characteristics of the 350 participants included in this analysis. MM-SES-CD severity categories were established as inactive or very mild (score <14), mild (score ≥14 to <31), moderate (≥31 to <45), and severe (score ≥45), which were predictive of one-year ER (50%, 30.3%, 21.7%, 8.8% respectively p<0.001) (Table 2). Lower MM-SES-CD scores had numerically higher rates of one-year CR, and time to CR over 52 weeks was superior to those with higher scores (p=0.0492) (Figure 1). MM-SES-CD thresholds for the achievement of ileal ER at one-year among 75 patients with isolated ileal disease were also established as mild (score <14), moderate (score ≥14 to <33), and severe (score ≥33), which were predictive of one-year ER (66.7%, 33.3%, 13.3%, respectively p=0.027) (Table 3).
We have established numerical cut-offs of the MM-SES-CD that categorize endoscopic disease severity and are prognostic for one-year ER and CR. These cut-offs could help ensure adequate balance between study arms (e.g. in prevalence of mild or moderate endoscopic disease) and identify patients with severe endoscopic disease and low probability of achieving ER.
1. Predicting endoscopic remission in Crohn’s disease by the modified multiplier SES-CD (MM-SES-CD). Gut, 2021: p. gutjnl-2020-323799.
Background: CCL20-CCR6 axis is growingly recognized as playing a critical role in IBD pathogenesis by influencing the recruitment of leukocytes to inflamed tissues and the balance between effector and regulatory T cells. However, CCR6 blockade has never been tested as therapeutic approach against IBD and no small-molecule CCR6 antagonists have been investigated as potential drug candidates.
Aim: Starting from the results shown by our novel CCR6 antagonist (MR120), we aimed at:
-designing and synthesizing new small-molecule CCR6 antagonists;
-identifying the most efficacious and tolerable anti-chemotactic novel compound;
-assessing the efficacy of MR120 and of the most promising derivative in adoptive transfer colitis.
Methods:By applying the previously prepared CCR6 homology model, we generated a focused collection of new derivatives around the chemotype of the active hit MR120. The compounds preserving more than 95% cells viability in PI assay were tested for their anti-chemotactic action against CCL20-induced lymphocytes recruitment, calculated as relative migration index (RMI). Adoptive transfer colitis was induced in C.B-17 Scid mice (n=8/group) by infusion of CD4+CD25- T cells or CD4+ T cells (sham mice, n=6) isolated from Balb/c mice. Colitic mice received daily either MR120 1mg/kg (MR120), MR452 1mg/kg (MR452), or vehicle (DMSO 1%) (C), while sham (S) group received only the vehicle b.i.d. s.c. Disease Activity Index (DAI) was registered for 8 weeks, until suppression; colonic macroscopic score (MS), length and thickness and colon and lung myeloperoxidase (MPO) activity were determined. All experiments were authorized and performed according to the guidelines for the Care and Use of Animals (DL26/2014).
Results:Among 31 newly synthesized molecules, 14 compounds, out of 20 derivatives tolerated up to 50mM, were selected and tested in the chemotaxis assay at 25mM. Except from 6 inactive derivatives, all displayed a remarkable improvement of the anti-chemotactic effect compared to MR120. Interestingly, MR452 strongly antagonized the CCL20-induced lymphocytes recruitment (RMI=0.43), and was therefore tested in vivo.Vehicle-treated C mice developed a moderate-to-severe colitis, with weight loss and diarrhea and increased colonic MS, thickening, and MPO activity compared with S. The treatment with MR120 or MR452 was mitigated the colonic MPO activity, in spite of not modifying the other inflammatory markers with respect to C.
Conclusions:The ability of both MR120 and MR452 to attenuate the gut neutrophil recruitment suggest that the interference with the CCL20-CCR6 axis could participate in hindering the gut homing of effector leukocytes and in mitigating their inflammatory role.
Patients with inflammatory bowel disease (IBD), particularly Crohn’s disease (CD), are at increased risk for gastrointestinal and extraintestinal malignancies. Chronic inflammation is a major risk factor for the development of gastrointestinal malignancies, while some medical therapies, that diminish the mucosal inflammatory response and represent the basis of treatment, may also promote carcinogenesis in the long These excess risks have declined substantially over time term. Patients with ulcerative colitis (UC) still are at increased risk of developing colorectal cancer (CRC). However, these excess risks have declined substantially over time. Despite they are diagnosed with significantly less advanced CRC, they still are at increased risk of dying from CRC, probably because intrinsic differences in the pathogenesis of colitis-associated cancer with respect to sporadic CRC, in which inflammation drive cancer progression. Patients with CD still are at increased risk of developing CRC, are diagnosed with no significant difference in CRC stage, but are at increased risk of dying from CRC. Incidence of CRC in CD patients is lower in recent years, but remains high in those potentially eligible for surveillance: patients diagnosed before the age of 40, with colonic location or with PSC. In conclusion, we still need to do better to prevent development of CRC in IBD patients. Small bowel cancer (SBC) and associated death are more common among patients with IBD compared with the general population, but the absolute risks are low. CD is associated with a ninefold increased risk of incident SBC and a sevenfold increased risk of death due to SBC. Among patients with CD, the relative risk of incident SBC is highest for those with recently diagnosed, childhood-onset, ileal and stricturing disease. Among patients with UC, the relative risk of incident SBC is highest for those with extensive colitis and PSC. The incidence of pouch neoplasia in patients with IBD without a history of colorectal neoplasia is relatively low. Prior dysplasia or CRC, however, is associated with increased risk of developing pouch cancer. Finally, patients with anal and/or perianal CD have a high risk of anal cancer (HPV-related anal canal squamous cell carcinoma – SCC, as well as very rare cases of anal canal adenocarcinoma), including perianal fistula-related cancer, and a high risk of rectal cancer.
Case of new diagnosis of penetrant Crohn's disease with complicated outcome
1. To understand the role of prognostic factors in treatment decisions CD
2. To review treatment strategies in CD
3. To describe future vision of markers to guide treatment decisions
Data from two nationwide populationbased Swedish studies of patients with Crohns disease will be discussed. Incidence and type of primary and secondary surgery during the period 1990-2014 and incidence of temporary and permanent stoma for patients diagnosed with CD 2003-2014.