Inflammatory bowel disease (IBD), including Crohn's disease (CD) and Ulcerative Colitis (UC), are immune mediated conditions associated with progressive damage of the inflamed gut tissue, and have a ...considerable impact on the patient's quality of life. The pathogenesis remains uncertain, but it is clear that complex mechanisms associated with host and luminal factors are involved, generating an unbalance between pro- and anti-inflammatory signaling. It is well established that the purpose of an adequate and complete control of the intestinal inflammation measured not only by clinical symptoms, but also with more objective data such as fecal biomarkers (calprotectin) and endoscopy. The treat to target approach possibly correlates with minor risk for complications associated with IBD, specially surgery and cancer.
The most studied inflammatory pathway in IBD, is described to be dependent of the pro-inflammatory cytokine tumor necrosis factor-alfa (TNF-α), and compose the first line studies for development of biological drugs, in this case, targeting specifically the action of TNF-α. Even though, the use of anti-TNFs drugs are associated with improvement of the inflammation in some patients, a great portion do not respond at first or lose response over time. These findings made clear about the possibility of other mechanisms involved in perpetuating the chronic inflammatory state.
Many years of intensive research have led to the identification of different inflammatory pathways that form the basis of the intensive drug development that we are experiencing today. These novel drugs include agents that target leukocyte trafficking, Interleukin (IL) 23, Janus kinases (JAK), Sphingosine 1 phosphate (S1P) and Smad7, an inhibitor of the immunosuppressive cytokine transforming growth factor β1 (TGF-β1). In this manuscript, we aim to review the most promising late-stage drug candidates for the treatment of IBD.
•Anti-TNF therapy remains an effective and safe tool in IBD, however, a substantial portion of patients show lack of response.•Anti-adhesion drugs are effective and safe gut-selective agents that have shown a salutary potential in the treatment in IBD.•Anti-IL-23 and other cytokine blockers are expected to be a valid alternative to anti-TNF in managing IBD patients.•Novel therapeutic molecules that target different inflammatory pathways and signaling may constitute a powerful alternative in the management of IBD.
Therapeutic drug and immunogenicity monitoring (TDIM) is increasingly proposed to guide therapy with biologics, characterised by high inter-individual variability of their blood levels, to permit ...objective decisions for the management of non-responders and reduce unnecessary interventions with these expensive treatments. However, TDIM has not yet entered clinical practice partly because of uncertainties regarding the accuracy and precision of enzyme-linked immunosorbent assays (ELISA). Here we report the characterisation of a novel surface plasmon resonance (SPR)-based TDIM, applied to the measurement of serum concentrations of infliximab, an antibody against tumour necrosis factor α (anti-TNFα), and anti-infliximab antibodies. SPR has the obvious advantages of directly detecting and measuring serum antibodies in minutes, avoiding the long incubation/separation/washing/detection steps of the methods proposed so far, reducing complexity and variability. Moreover, drug and anti-drug antibodies can be measured simultaneously. This new method was validated for sensitivity and reproducibility, and showed cost-effectiveness over commercial ELISA kits. This method may be applied to other biotherapeutics. These data pave the way for the development of SPR-based point-of-care devices for rapid on-site analysis.
Biosimilars of infliximab (CT-P13) are currently approved and available for the same indications as for the originator. Some concerns about safety and immunogenicity have risen in the past because of ...lack of data in IBD. Since 2015, several cohort studies have been conducted in IBD showing that CT-P13 has comparable safety and efficacy profile to the originator, both in adult and pediatric population, either in naïve patients or even in those who switched from the originator to CT-P13. This review aims to analyze the current literature data in order to define a clear patient profile, to identify those IBD patients who would benefit the most from the use of CT-P13.
Tofacitinib is an oral small molecule directed against the JAK/STAT pathway, blocking the inflammatory cascade. Oral formulation of tofacitinib has recently been approved for the treatment of ...patients with moderate–severe ulcerative colitis. Its efficacy and safety have been demonstrated in three phase III clinical trials and confirmed by promising real-life data. The purpose of this review is to summarize the available evidence on the efficacy and safety of tofacitinib and to define its role and position in the treatment algorithms for patients with ulcerative colitis.
Ulcerative colitis (UC) is a chronic relapsing disorder of the colonic tract, characterized by a dysregulated innate and adaptive immune response to gut microbiota that contributes to the ...perpetuation of intestinal inflammatory processes. The Interleukin (IL) 23/IL17 axis has been reported to play a key role in UC pathogenesis promoting Th17 cells and cytokines-related immune response. Recently, the blockade of IL23/IL17 pathways has been raised enormous interest in the treatment o several chronic inflammatory disorders. In this review, we summarize the emerging results from clinical trials that evoked both promise and discouragement in IL23/IL17 axis in the treatment of UC. Targeting IL23 p40 through Ustekinumab results safe and effective to induce and maintain clinical remission, low inflammatory indexes, mucosal healing, and a better quality of life. Studies targeting IL23 p19 through Mirikizumab, Risankizumab, Brazikumab and Guselkumab are still ongoing. To date, no clinical studies targeting IL17 pathway are ongoing in UC. IL-17 targeting is thought to have a context-dependent biological effect, based on whether cytokine is selectively targeted or if its function is dampened by the upstream block of IL23.
Colonoscopy CS is the standard for assessing disease activity in ulcerative colitis UC, although invasive and poorly tolerated. Bowel ultrasound BUS may be a valid alternative in UC patients; ...however, the comparative accuracy between BUS and CS is unknown.
Consecutive patients with UC were prospectively assessed by CS and BUS. Colonic wall thickening CWT >3 mm, colonic wall flow at power Doppler CWF, colonic wall pattern CWP, and presence of lymph nodes evaluated at BUS were compared with CS. The endoscopic activity was assessed according to the Mayo endoscopic sub-score 0-3. All BUS investigations were performed by two independent gastroenterologists and the kappa statistic for agreement was calculated. Ultrasonography-based criteria (Humanitas Ultrasound Criteria HUC) were developed.
A total of 53 UC patients 56% with left-sided colitis, 19% with pancolitis were prospectively enrolled. Of these, 22 patients had mucosal healing Mayo endoscopic sub-score 0-1 and 31 patients were in endoscopic activity. CWT, CWF, hypoechogenic CWP and the presence of lymph nodes significantly correlated with endoscopic activity p < 0.05. CWT p = 0.01 and CWF p = 0.09 were independent predictors for endoscopic activity. The HUC developed are: i the presence of a CWF and CWT > 3 mm; or ii the absence of a CWF and CWT > 4.43 mm. They showed high accuracy for the detection of disease activity sensitivity 0.71, specificity 1.00. The interobserver agreement for BUS was excellent kappa 0.86.
BUS is a non-invasive, easy-to-use tool to manage UC patients in clinical practice. HUC were very accurate in assessing disease activity in UC patients.
AIM: To determine the efficacy of calcium supplementation in reducing the recurrence of colorectal adenomas.METHODS: We conducted a systematic review and meta-analysis of published studies. We ...searched Pub Med, Scopus, the Cochrane Library, the WHO International Clinical Trials Registry Platform, and the Clinical Trials.gov website, through December 2015. Randomized, placebo-controlled trials assessing supplemental calcium intake for the prevention of recurrence of adenomas were eligible for inclusion. Two reviewers independently selected studies based on predefined criteria, extracted data and outcomes(recurrence of colorectal adenomas, and advanced or "high-risk" adenomas), and rated each trial’s riskof-bias. Between-study heterogeneity was assessed, and pooled risk ratio(RR) estimates with their 95% confidence intervals(95%CI) were calculated using fixed- and random-effects models. To express the treatment effect in clinical terms, we calculated the number needed to treat(NNT) to prevent one adenoma recurrence. We also assessed the quality of evidence using GRADE.RESULTS: Four randomized, placebo-controlled trials met the eligibility criteria and were included. Daily doses of elemental calcium ranged from 1200 to 2000 mg, while the duration of treatment and follow-up of participants ranged from 36 to 60 mo. Synthesis of intention-to-treat data, for participants who had undergone follow-up colonoscopies, indicated a modest protective effect of calcium in prevention of adenomas(fixed-effects, RR = 0.89, 95%CI: 0.82-0.96; randomeffects, RR = 0.87, 95%CI: 0.77-0.98; high quality of evidence). The NNT was 20(95%CI: 12-61) to prevent one colorectal adenoma recurrence within a period of 3 to 5 years. On the other hand, the association between calcium treatment and advanced adenomas did not reach statistical significance(fixed-effects, RR = 0.92, 95%CI: 0.75-1.13; random-effects, RR = 0.92, 95%CI: 0.71-1.18; moderate quality of evidence). CONCLUSION: Our results suggest a modest chemopreventive effect of calcium supplements against recurrent colorectal adenomas over a period of 36 to 60 mo. Further research is warranted.
Inflammatory bowel diseases (IBD) are chronic, relapsing, and destructive inflammatory disorders of the gastrointestinal tract. Both Crohn's disease (CD) and ulcerative colitis (UC) seem to arise ...from an impaired dialog between the environment and gut microbiota in genetically susceptible hosts, leading to an inappropriate immune activation and resulting in the over-production of pro-inflammatory cytokines. IL-6 is a key modulator of inflammatory response. It is a phylogenetically important cytokine with relevance in IBD, as well as in other chronic inflammatory diseases and cancer. Influencing the production of this cytokine can change the balance of effector CD4+ T cell subsets and induce B cell antibody production. Moreover, given IL-6 is mostly produced from innate immune cells such as macrophages, neutrophils and mast cells, it is a strategic bridge between the innate and the adaptive system. Interestingly, IL-6 induced signaling can be primarily seen in a relatively small number of IL-6 responsive cells whereas in a chronic phase of inflammation it is able to activate almost all cells of the body through a process known as trans-signaling. In this review, we discuss the role of IL-6 in chronic inflammation, with particular emphasis on its role in CD and UC, and we explore the potential to develop anti-IL-6 agents for IBD treatment.
The risk of coronavirus disease-19 infection for healthcare professionals and patients in hospitals remains unclear.
We investigated whether precautions adopted in our inflammatory bowel disease ...(IBD) unit have minimized the risks of infection for all patients accessing our facilities in a 1-month period by assessing the rate of coronavirus disease-19 infection in the follow-up period.
Three hundred-twenty patients with IBD were included. None were infected from severe acute respiratory syndrome-coronavirus 2 in the follow-up period. None of the IBD team members were infected.
Neither pharmacological immunosuppression nor access to the hospital seem to be risk factors for infection in patients with IBD.
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