Crohn's disease-related inflammation is characterized by reduced activity of the immunosuppressive cytokine transforming growth factor β1 (TGF-β1) due to high levels of SMAD7, an inhibitor of TGF-β1 ...signaling. Preclinical studies and a phase 1 study have shown that an oral SMAD7 antisense oligonucleotide, mongersen, targets ileal and colonic SMAD7.
In a double-blind, placebo-controlled, phase 2 trial, we evaluated the efficacy of mongersen for the treatment of persons with active Crohn's disease. Patients were randomly assigned to receive 10, 40, or 160 mg of mongersen or placebo per day for 2 weeks. The primary outcomes were clinical remission at day 15, defined as a Crohn's Disease Activity Index (CDAI) score of less than 150, with maintenance of remission for at least 2 weeks, and the safety of mongersen treatment. A secondary outcome was clinical response (defined as a reduction of 100 points or more in the CDAI score) at day 28.
The proportions of patients who reached the primary end point were 55% and 65% for the 40-mg and 160-mg mongersen groups, respectively, as compared with 10% for the placebo group (P<0.001). There was no significant difference in the percentage of participants reaching clinical remission between the 10-mg group (12%) and the placebo group. The rate of clinical response was significantly greater among patients receiving 10 mg (37%), 40 mg (58%), or 160 mg (72%) of mongersen than among those receiving placebo (17%) (P=0.04, P<0.001, and P<0.001, respectively). Most adverse events were related to complications and symptoms of Crohn's disease.
We found that study participants with Crohn's disease who received mongersen had significantly higher rates of remission and clinical response than those who received placebo. (Funded by Giuliani; EudraCT number, 2011-002640-27.).
Regulatory T cells represent a class of specialized T lymphocytes that suppress unwanted immune responses and size the activation of the immune system whereby limiting collateral damages in tissues ...involved by inflammation. In cancer, the accumulation of Tregs is generally associated with poor prognosis. Many lines of evidence indicate that Tregs accumulation in the tumor microenvironment (TME) suppresses the immune response against tumor-associated antigens (TAA), thus promoting tumor progression in non-small cell lung carcinoma (NSLC), breast carcinoma and melanoma. In colorectal cancer (CRC) the effect of Tregs accumulation is debated. Some reports describe the association of high number of Tregs in CRC stroma with a better prognosis while others failed to find any association. These discordant results stem from the heterogeneity of the immune environment generated in CRC in which anticancer immune response may coexists with tumor promoting inflammation. Moreover, different subsets of Tregs have been identified that may exert different effects on cancer progression depending on tumor stage and their location within the tumor mass. Finally, Tregs phenotypic plasticity may be induced by cytokines released in the TME by dysplastic and other tumor-infiltrating cells thus affecting their functional role in the tumor. Here, we reviewed the recent literature about the role of Tregs in CRC and in colitis-associated colorectal cancer (CAC), where inflammation is the main driver of tumor initiation and progression. We tried to explain when and how Tregs can be considered to be the "good" or the "bad" in the colon carcinogenesis process on the basis of the available data concluding that the final effect of Tregs on sporadic CRC and CAC depends on their localization within the tumor, the subtype of Tregs involved and their phenotypic plasticity.
The nutritional status in inflammatory bowel disease (IBD) is often impaired, and adherence to the Mediterranean diet (MedDiet) remains under-investigated. The aim of this study was to assess diet ...quality (DQ) and adherence to MedDiet in a cohort of Sardinian IBD patients. We conducted a case-control study in which 50 Crohn’s disease (CD) and 50 ulcerative colitis (UC) patients were matched with 100 healthy controls each. The Diet Quality Index (DQI-I) and Medi-Lite were used to assess DQ and adherence to MedDiet, respectively. Subgroup analysis by disease characteristics and use of advanced therapies were also carried out. DQI-I scored significantly lower in IBD, independently of disease localization and behavior (CD) and disease extent (UC): DQI-I: CD 34.5 (IQR 33–37) vs. CTRL 40 (IQR 38.5–43) p < 0.0001; UC 34.5 (IQR 33–37) vs. CTRL 42 (IQR 40–44) p < 0.0001. Medi-Lite scores were significantly lower in stricturing and ileo-colonic CD and in extensive UC: Medi-Lite CD 7.5 (IQR 7–9) vs. CTRL 9 (IQR 7–10) p = 0.0379; UC 8 (IQR7–10) vs. CTRL 9 (IQR 8–10.5) p = 0.0046. IBD patients had a low DQ independently of disease type and phenotype. Patients with ileo-colonic stenosing CD or extensive UC had lower MedDiet adherence, suggesting that its benefits may be mitigated by low acceptance in specific subgroups.
In normal conditions gut homeostasis is maintained by the suppressive activity of regulatory T cells (Tregs), characterized by the expression of the transcription factor FoxP3. In human inflammatory ...bowel disease, which is believed to be the consequence of the loss of tolerance toward antigens normally contained in the gut lumen, Tregs have been found to be increased and functionally active, thus pointing against their possible role in the pathogenesis of this immune-mediated disease. Though, in inflammatory conditions, Tregs have been shown to upregulate the T helper (Th) type 1-related transcription factor Tbet and to express the pro-inflammatory cytokine IFNγ, thus suggesting that at a certain point of the inflammatory process, Tregs might contribute to inflammation rather than suppress it. Starting from the observation that Tregs isolated from the lamina propria of active but not inactive IBD patients or uninflamed controls express Tbet and IFNγ, we investigated the functional role of Th1-like Tregs in the dextran sulfate model of colitis. As observed in human IBD, Th1-like Tregs were upregulated in the inflamed lamina propria of treated mice and the expression of Tbet and IFNγ in Tregs preceded the accumulation of conventional Th1 cells. By using a Treg-specific Tbet conditional knockout, we demonstrated that Tbet expression in Tregs is required for the development of colitis. Indeed, Tbet knockout mice developed milder colitis and showed an impaired Th1 immune response. In these mice not only the Tbet deficient Tregs but also the Tbet proficient conventional T cells showed reduced IFNγ expression. However, Tbet deficiency did not affect the Tregs suppressive capacity
and
in the adoptive transfer model of colitis. In conclusion here we show that Tbet expression by Tregs sustains the early phase of the Th1-mediated inflammatory response in the gut.
The drug pipeline for the treatment of inflammatory bowel disease (IBD) has dramatically expanded over the last two decades, and it is expected to further grow in the upcoming years with the ...introduction of new agents with different mechanisms of action. However, such an increase of therapeutic options needs to be paralleled with an appropriate development of research to help physicians in the decision-making process when choosing which drug to prescribe. On the population level, comparative effectiveness research (CER) is intended to explore and identify relevant differences-in terms of both efficacy and safety outcomes-amongst different therapeutic regimens and/or strategies, in order to find the correct placement for each treatment in the therapeutic algorithm. CER revolves around three cornerstones: network meta-analyses, head-to-head trials and real-world studies, each of which has specific pros and cons, and can therefore offer answers to different questions. In this review, we aim to provide an overview on the methodological features specific to each of these research approaches, as well as to illustrate the main findings coming from CER on IBD target therapies (i.e., biologics and small molecules) and to discuss their appropriate interpretation.
Background and aims
The COVID-19 pandemic has led to a deep reorganization of hospital services including inflammatory bowel disease (IBD) units. In this situation, conversion of in-person routine ...follow-up visits into phone consultations might be necessary. Here we explored the feasibility of using the validated Crohn’s Disease (CD) or Ulcerative Colitis (UC) Patient-Reported Outcomes Signs and Symptoms (CD- and UC-PRO/SS) to collect data about abdominal symptoms (abdominal/S) and bowel signs and symptoms (bowel/SS) remotely.
Methods
CD- and UC-PRO/SS were collected during phone consultations and compared among patients with active and inactive disease. The effectiveness of therapeutic intervention in patients with active disease was assessed by PRO/SS variation.
Results
Twenty-one CD and 56 UC patients were evaluated by phone. Six (28.6%) CD and 15 (26.8%) UC patients were considered to have active disease. In CD the bowel/SS but not the abdominal/S module was significantly higher in active patients (mean bowel/SS 2.50 SE ± 0.44 active vs 0.76 SE ± 0.18 remission,
p
= 0.008, AUC 0.87; mean abdominal/S 1.11 SE ± 0.38 active vs 0.24 SE ± 0.13 remission,
p
= 0.066). UC-PRO/SS measures were significantly higher in active patients as compared to patients in remission (median bowel/SS 1.63 SE ± 0.24 active vs 0.33 SE ± 0.04 remission;
p
< 0.0001, AUC 0.91; mean abdominal/S 1.03 SE ± 0.24 vs 0.37 SE ± 0.12;
p
= 0.009, AUC 0.71). Therapy was escalated in 12 patients (3 CD and 9 UC) due to disease relapse. Therapy escalation resulted in the reduction of PRO/SS as evaluated at the subsequent phone consultation.
Conclusions
PRO/SS might represent a feasible tool to evaluate disease activity and therapy outcome in IBD patients during periods of limited access to outpatient clinics.
The uncontrolled activation of the immune system toward antigens contained in the gut lumen in genetically predisposed subjects is believed to be the leading cause of inflammatory bowel disease ...(IBD). Two not mutually exclusive hypotheses can explain the pathogenic process leading to IBD. The first and mostly explored hypothesis states that the loss of tolerance toward gut microbiota antigens generates an aberrant inflammatory response that is perpetuated by continuous and unavoidable exposure to the triggering antigens. However, the discovery that the resolution of inflammation is not the mere consequence of clearing inflammatory triggers and diluting pro-inflammatory factors, but rather an active process in which molecular and cellular elements are involved, implies that a defect in the pro-resolving mechanisms might cause chronic inflammation in different immune-mediated diseases, including IBD. Here we review data on pro-resolving and counter-regulatory mechanisms involved in the resolution of inflammation, aiming to identify their possible involvement in the pathogenesis of IBD.
Abstract Background and aims The effectiveness of adalimumab in the treatment of ulcerative colitis is under debate. Although controlled trials have shown that adalimumab is significantly better than ...placebo, the absolute clinical benefit is modest. We report data on the effectiveness of adalimumab in a cohort of ulcerative colitis patients treated in 22 Italian centres. Methods All patients with active disease treated with adalimumab were retrospectively reviewed. Co-primary endpoints were clinical remission at weeks 4, 12, 24 and 54. Secondary endpoints were sustained clinical remission, steroid discontinuation, endoscopic remission and need for colectomy. Results Eighty-eight patients were included. Most patients had received previous infliximab treatment. Clinical remission rates were 17%, 28.4%, 36.4% and 43.2% at 4, 12, 24 and 54 weeks respectively. Twenty-two patients required colectomy. Clinical remission and low C-reactive protein at week 12 predicted clinical remission at week 54 (OR 4.17, 95% CI 2.36–19.44; OR 2.63, 95% CI 2.32–14.94, respectively). Previous immunosuppressant use was associated with a lower probability of clinical remission at week 54 (OR 0.67, 95% CI 0.08–0.66) and with a higher rate of colectomy (HR 9.7, 95% CI 1.46–9.07). Conclusion In this large “real-life” experience adalimumab appears effective in patients with otherwise medically refractory ulcerative colitis. Patients achieving early remission can expect a better long-term outcome.
Abstract Background The development of symptomatic strictures in Crohn's Disease after anti-Tumour Necrosis Factor-α antibodies is undefined. Aim To assess, in a prospective longitudinal study, the ...frequency of sub/obstructions in Crohn's Disease patients after treatment with Infliximab or Adalimumab . Changes of small bowel lesions after these biological therapies were searched by ultrasonography. Materials and Methods From January 2007 to October 2008, 36 Crohn's Disease patients with no previous sub/obstructions were treated with either Infliximab ( n = 13) or Adalimumab ( n = 23) for ≥12 months (mean follow-up duration after the first treatment 23.2 ± 6.8 months). Small Intestine Contrast Ultrasonography was performed before and after treatment in 19/36 patients. Sonographic parameters included: bowel wall thickness, lumen diameter, bowel dilation and lesion extent. Results Sub/obstructions developed in 3/36 patients treated with Infliximab ( n = 1) or Adalimumab ( n = 2), all with fibrostricturing Crohn's Disease. Sonographic parameters did not significantly change after treatment. Conclusions Sub/obstructive symptoms may develop in one tenth of Crohn's Disease patients treated with anti-Tumour Necrosis Factor-α antibodies, with no significant sonographic changes of the small bowel lesions.
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