Distal Ulcerative Colitis Research Articles

Treatment of mildandmoderateforms of ulcerativecolitis: the possibilities of mesalazine

The article indicates the specific niche and principles for choosing mesalazine formulations, and the selection of a dose for the treatment of mild to moderate extensive (left-sided and total) ulcerative colitis (UC). It doesn’t consider any approaches to the treatment of more severe UC or distal UC (proctitis). The current concepts on the use of 5-aminosalicylic acid (5-ASA) formulations to induce and maintain remission in mild to moderate active UC are discussed. The principles for drug administration and a comparative analysis of domestic and international mesalazine dosing recommendations are provided. The guidelines place special emphasis on the importance of high-dose mesalazine therapy (≥4 g/day), which allows to achieve the targets set by the Treat-to-target (T2T) strategy and to reach the clinical and endoscopic remission. The evidence from meta-analyses and comparative studies demonstrating the same efficacy of different forms of mesalazine in the treatment of UC are presented. Attention is drawn to the choice of the optimal drug with enteric coating that consists of two types of Eudragit (Eudragit L and Eudragit S) in contrast to mesalazine formulations with one and the same type of coating (only L or only S). The double Eudragit (L + S) pH-dependent coating of mesalazine tablets dissolves in the terminal ileum, cecum and partially in the right half of the colon at pH 6–7.5, while formulations coated with only L or S dissolve at a narrower pH range. The clinical efficacy of mesalazine directly depends on its intraluminal concentration that is determined by the amount of the released drug according to the pH level in the intestinal lumen. The double Eudragit coating allows to cover the entire pH range in the ileum and colon. The paper presents evidence from the domestic clinical practice that confirms the Cochrane meta-analysis statements on the comparable efficacy of different mesalazine formulations concerning the targets to reach remission and reduce the level of fecal calprotectin. In addition, a high incidence of clinical remissions (more than 80% at 48 weeks of treatment) on double coated (L + S) mesalazine is demonstrated.

MITOCHONDRIAL DYSFUNCTION CAUSES CECAL PATCH (CP) INFLAMMATION IN ULCERATIVE COLITIS

Abstract BACKGROUND Up to 17% of distal ulcerative colitis (UC) patients have discontinuous (proximal) inflammation referred to as Cecal Patch (CP), associated with greater abdominal pain, bleeding and diarrhea. Despite these known associations, the pathogenesis of CP lesions is poorly understood. Recent data suggest that reduced mitochondrial (Mito) function predicts unfavorable clinical outcomes in active UC (Haberman et al; Nat Comm 2019). We posit that inflammation and tissue injury induced in UC-associated CP involves Mito dysfunction. METHOD UC patients with/without cecal disease and normal controls were biopsied. Tissue from CP lesions or normal caecum were collected in Allprotect® (AP) and formalin. Total RNA from AP-preserved biopsies were used for cDNA synthesis and RT-qPCR for Mito complexes, cytokines, anti-oxidant and calcineurin (CaN) signaling genes and tissue processed for IHC for Mito complexes. RESULT Transcriptomic analysis showed significant downregulation in genes associated with Mito biogenesis (PGC1α, TFAM, NRF2) and Mito complexes (Ndufa1, Ndufa4, Ndufb2, Ndufb6, mtCO1, mtCO2, Cox5B, Cox6A1, ATP5A1, ATP5B, ATP5E) in CP lesions compared to normal caecum from active patients. Major regulators of Mito biogenesis (PGC1α and TFAM) revealed ~39% and ~24% reductions of mRNA respectively, while NRF2 (anti-oxidant regulator) showed ~62% reduced mRNA in CP lesions compared to normal cecum from distal UC patients. Electron transport chain complex mRNAs showed 31%, 47%, and 48% reduction in complex I (Ndufa1, Ndufa4, Ndufb2, Ndufb6), complex IV (mtCO1, mtCO2, Cox5B, Cox6A1), and complex V (ATP5A1, ATP5B, ATP5E) levels, respectively in CP lesions compared to normal controls. Concomitantly, the IHC staining also showed significant reductions in Ndufb6, MTCO1 and Cox5A protein levels in CP lesions compared to normal cecum sections. The CP-related decreased markers of Mito biogenesis and function correlates with increased proinflammatory cytokine mRNA (IL-6: 2-fold; TGFβ1: 1.6-fold; IL-2: 2.6-fold) and decreased anti-inflammatory (IL10: 3.2-fold) gene expression in CP lesions. Further investigation demonstrated that repressed Mito function in CP lesions is associated with downregulation of anti-oxidant genes (SOD1, SOD2, Prdx3, Gpx4, Trx2) compared to normal cecum. Inflammation-induced Mito dysfunction in CP lesions also stimulates CaN signaling as demonstrated by significant increases in mRNA levels of CaN and downstream regulated genes (Cathepsin-L, Rel-A Glut4, CREB-BP and Igf-1r). CONCLUSION These data represent the first indication that Mito dysfunction occurs in CP associated with distal UC. Furthermore, we speculate that Mito dysfunction-induced CaN signaling promotes regional (CP) inflammatory responses. These important findings indicate that targeting Mito metabolism may be an important therapeutic goal of treating UC patients with CP.

Niclosamide Enema for Active Distal Ulcerative Colitis: A Phase 1, Open-Label Study.

Oral and rectal formulations of 5-aminosalicylic acid are the first-line therapy for mild-to-moderate, distal ulcerative colitis (UC), but such a treatment is not effective in one-third of patients. Niclosamide is a small molecule, developed and approved as an orally administered drug to treat helminthic infections, with an excellent safety profile. Preclinical work showed that niclosamide is an anti-inflammatory agent, thereby providing the rationale to explore its safety and efficacy in patients with UC. This phase 1, open-label trial was aimed at assessing the safety of niclosamide formulated as an enema in patients with mild-to-moderate, distal UC, who relapsed on maintenance therapy with oral and/or rectal 5-aminosalicylic acid. Seventeen patients with active UC received niclosamide enema (150 mg/60 mL) twice a day for 6 weeks. The primary endpoint was the safety of niclosamide treatment. Secondary endpoints included clinical remission and improvements in endoscopic Mayo/histologic scores. Endoscopic remission percentages exclude participants meeting criteria at baseline for endoscopic remission. Niclosamide was well tolerated by all 17 patients that were enrolled and treated. No serious adverse event was registered. Fifteen mild adverse events were registered in 6 patients and considered to be unrelated to the treatment. Clinical remission was achieved in 10 (59%) of 17 patients. Improvements of endoscopic Mayo score and histologic Geboes score were seen in 7 (58%) of 12 and 7 (41.2%) of 17 patients, respectively. Niclosamide enema treatment is safe and well tolerated. Niclosamide improves clinical symptoms and endoscopic/histologic signs of UC; however, appropriately designed placebo-controlled clinical trials are required to confirm efficacy.

Propensity score analysis the clinical characteristics of active distal and extensive ulcerative colitis: a retrospective study.

Background and Objectives: Ulcerative Colitis (UC) subtypes defined by disease extent and shared pathophysiology are important. Analyzing the clinical characteristics of UC with different disease extent and optimizing clinical typing are conducive to the pathogenesis research, disease monitoring and precise treatment. Methods: 188 patients with active UC were divided into distal and extensive colitis. The clinical characteristics of the two groups were analyzed by propensity score. Spearman is used for correlation analysis, and receiver operating characteristic (ROC) curve was used to evaluate the ability of clinical indicators to predict Mayo endoscopic subscore (MES). Results: Compared with distal colitis, extensive colitis had more severe disease activity, younger age, higher utilization rate of corticosteroids and incidence of extra intestinal manifestations (EIMs), and clinical indicators were differentially expressed in the two groups. After using propensity score, the incidence of EIMs in the extensive colitis was still higher than that in distal colitis. Inflammation, coagulation and immune indicators like CRP, FC, IL-10, D-D and α1-MG are higher in extensive colitis, and metabolic indicators like LDL-C, HDL-C, TC, GSP and albumin are higher in distal colitis. The correlation between clinical indicators and MES is affected by disease extent. The area under curve (AUC) of CRP + D-D + α2-MG for predicting distal colitis MES3 was 0.85, and the AUC of IL-6+ GSP+ α1-MG predicted extensive colitis MES3 can reach 0.82. Conclusion: Differential clinical indicators can become potential markers for predicting disease progression and prognosis, and have significance for UC mechanism research and drug development. We can select biomarkers according to lesion site.

P625 Randomized controlled trial on the effect of megaboluses of intravenous corticosteroids added to oral corticosteroids in the treatment of moderately active ulcerative colitis

Abstract Background Oral corticosteroids remain as the first-line treatment for moderately active ulcerative colitis (UC). In controlled studies, they achieved clinical remission in 30-60% of patients at 30 days. In severe systemic diseases, intravenous bolus administration of methyl-prednisolone accelerates the clinical response and increases the therapeutic efficacy of corticosteroids. Aims To assess the additive effect of IV boluses of methyl-prednisolone in an outpatient Schedule on the remission rate of moderately active UC. Methods Randomized, controlled, open study. Inclusion criteria: 1) moderately active (complete May 6-10) distal or extensive UC; 2) never exposed to immunosuppressants or biologicals; 3) without corticosteroid therapy within the last 6 months. Randomization to oral prednisone 60mg/day (ORAL arm) or the same regimen preceded by intravenous boluses of 500mg methyl-prednisolone for 3 days (BOLUS arm). Primary endpoint: clinical and endoscopic remission at week 8 as defined by a complete Mayo score <3 with no subscore >1. Results are expressed in frequencies, medians and interquartile range. Results 75 patients (39 ORAL, 36 BOLUS) were included, 24% at diesease onset, 49% extensive UC, 68% were on maintenance with oral 5ASA, and 31% had ever received systemic corticosteroids. At baseline, complete Mayo score was 9 (7-9), with C-reactive protein 9.25 mg/L (3.85-20.17) and fecal calprotectin 1430 ug/g (501-2702), with no differences in the baseline clinical-epidemiological characteristics between both treatment arms. At 8 weeks, 37% of patients achieved clinical-endoscopic remission (47% BOLUS vs 28% ORAL; p=0.089), 52% mucosal healing -Mayo endoscopic subscore <2- (61% BOLUS vs 44% ORAL; p=0.129), 24% endoscopic remission -Mayo endoscopic=0- (31% BOLUS vs 18% ORAL; p=0.202) and 55% clinical remission - partial Mayo score <2- (61% BOLUS vs 49% ORAL; p=0.281). No associated factors with clinical-endoscopic remission were identified. Conclusion The addition of three intravenous megaboluses at the beginning of a conventional regimen of oral prednisone achieves a non-significant increase in clinical-endoscopic remission rates at the end of corticosteroid treatment in patients with moderately active UC.

Clinical significance and long-term prognosis of ulcerative colitis patients with appendiceal orifice inflammation

BackgroundAppendiceal orifice inflammation (AOI) or peri-appendiceal red patch is a skip lesion with segments of continuous colitis from the rectum. Frequently observed in ulcerative colitis (UC) patients, this lesion might be associated with proximal extension in some studies. However, the clinical significance of this lesion and long-term outcomes including therapy remain unclear. Thus, the aim of this study was to evaluate the clinical implication of AOI during long-term periods in patients with UC.MethodsWe retrospectively reviewed 376 patients with UC who performed complete colonoscopic examinations between April 2000 and December 2020. We compared clinical characteristics and outcomes of patients manifesting AOI with those who did not show AOI during a mean follow-up period of 66.1 months. Long-term outcomes included maximal extent of colitis, proximal extension, therapeutic medical histories, UC-related hospitalization, and relapse.ResultsNinety-eight (26.1%) patients showed AOI without evidence of inflammation in the right colon. Mild disease activity at the diagnosis of UC was more included in patients with AOI than in those without AOI. Other baseline characteristics including disease extent, smoking history, external intestinal manifestation, and terminal ileal ulceration were not significantly different between the two groups. During follow-up periods, patients with and without AOI showed no significant difference in proximal extension, Mayo endoscopic score at the last endoscopic examination, UC-related hospitalization, or relapse. Of medication history, patients with AOI were less included in the group treated with high-dose aminosalicylates than those without AOI. However, therapeutic histories of steroids, immunosuppressive agents, and biologics were not significantly different. Of 62 patients with AOI who underwent follow-up colonoscopy, 36 (58.1%) showed resolution of AOI. Clinical outcomes of the resolution group were not different than those of the non-resolution group. Biopsy results of 77 patients with AOI showed chronic active or erosive colitis.ConclusionsLong-term outcomes of UC patients with AOI were not different from those without AOI. Outcomes of resolution and non-resolution groups of AOI patients were not different either. Thus, AOI might have no prognostic implication in distal UC patients.

Periappendicular changes in patients with ulcerative collitis: overview and clinical observation

Ulcerative colitis is inflammatory bowel disease which characterized by inflammation of the colon and rectum: only 20-30% of UC patients have pancolitis, while proctitis and left-sided colon lesions are more common. There is a variant of localization of ulcerative colitis in patients with proctitis and left-sided colon lesion, which changes the rule of continuity of the lesion and is described as an additional periappendicular lesion. The article have been presented the own clinical observation of a patient with distal ulcerative colitis with periappendicular lesion. If a periappendicular lesion have been detected during endoscopy in a typical clinic for distal ulcerative colitis and doubts arise about the correctness of the previously established diagnosis, it is necessary to re-analyze the anamnesis, symptoms, instrumental and histological picture and, taking into account new knowledge about the course of ulcerative colitis in some patients with periappendicular lesion, confirm the initial diagnosis and continue therapy. Such a finding, according to the available literature data, does not require escalation of ulcerative colitis therapy and, as a rule, does not mean the spread of the disease to all parts of the colon.

Real-world evidence of quality of life improvement in patients with distal ulcerative colitis treated by mesalazine: the Quartz study.

Distal ulcerative colitis (UC) is responsible for distressing symptoms and reduces quality of life (QoL). Oral and topical formulations of 5-amino-salicylic acid are the first line therapy for mild to moderate distal UC. Our aim was to evaluate the impact of mesalazine treatment for mild to moderate ulcerative proctitis and proctosigmoiditis on patient QoL. Ninety-three patients with mild to moderate ulcerative proctitis and proctosigmoiditis, initiating a treatment with Pentasa, were prospectively included. The primary endpoint was the change from baseline to W8 in patient health-related QoL (HRQoL) as measured by the Short Inflammatory Bowel Disease Questionnaire (SIBDQ) total score. More than 80% of patients were prescribed with a rectal formulation, either alone (47.9%) or with an oral formulation (35.1%), and 17.0% of patients were prescribed oral formulation alone. Mean SIBDQ score was improved at W8 in patients affected with mild and moderate disease ( P < 0.001 versus baseline in both groups, as well as in patients who achieved clinical remission ( P < 0.001). Patients who achieved clinical remission at W8 reached a mean change of +6.7 (±7.1), whereas those who did not achieve clinical remission had a mean change of +1.1 (±8.9). Seventy-five per cent of patients had an improvement of their disability index at W8. Fecal incontinence was also improved at W8. HRQoL measuring with the SIBDQ is proportionally related to disease activity in patients with distal UC treated with mesalazine.

Time-adjusted average Mayo endoscopic score predicts the risk of disease extent progression in distal ulcerative colitis patients.

BackgroundUlcerative colitis (UC) is a chronic lifelong disease. The disease extent of UC can progress over time. This study aimed to assess whether cumulative inflammatory burden (CIB) is associated with disease extension in distal UC (proctitis [E1] and left-sided colitis [E2]) patients, and to develop a quantified indicator of CIB.MethodsIn this retrospective study based on a prospective registry, distal UC patients receiving colonoscopies in Xijing Hospital (Xi’an, China) from January 2000 to May 2019 were studied. We developed a new score, namely the time-adjusted average Mayo endoscopic score (TA-MES), calculated as dividing the sum of the cumulative average MES over a period of surveillance time by the length of the endoscopic examination interval, to quantify the CIB. Cox regression was used to identify other potential risk factors.ResultsA total of 295 UC patients were followed for 1,487.02 patient-years. Among them, 140 patients (47.5%) experienced disease extension. Multivariate analysis showed that the TA-MES was significantly associated with disease extension in E1 (hazard ratio [HR], 2.90; 95% confidence interval [CI], 1.58–5.33, P = 0.001) and E2 (HR, 1.89; 95% CI, 1.16–3.09, P = 0.011) patients. Other risk factors included hemoglobin of <90 g/L and appendiceal skip inflammation; the protective factors included age, E2 at diagnosis, former smoking, and 5-aminosalicylic acid dose. Otherwise, MES at diagnosis, maximal MES, and mean MES failed to estimate the risk of disease extension.ConclusionTA-MES is a good quantified indicator of CIB and is independently associated with increased disease extension in distal UC patients. Whether the dynamic multiple scoring system could be used as a risk factor in other chronic relapsing–remitting diseases is a direction for future research.

Intestinal Taxa Abundance and Diversity in Inflammatory Bowel Disease Patients: An Analysis including Covariates and Confounders.

Intestinal dysbiosis has been widely documented in inflammatory bowel diseases (IBDs) and is thought to influence the onset and perpetuation of gut inflammation. However, it remains unclear whether such bacterial changes rely in part on the modification of an IBD-associated lifestyle (e.g., smoking and physical activity) and diet (e.g., rich in dairy products, cereals, meat and vegetables). In this study, we investigated the impact of these habits, which we defined as confounders and covariates, on the modulation of intestinal taxa abundance and diversity in IBD patients. 16S rRNA gene sequence analysis was performed using genomic DNA extracted from the faecal samples of 52 patients with Crohn’s disease (CD) and 58 with ulcerative colitis (UC), which are the two main types of IBD, as well as 42 healthy controls (HC). A reduced microbial diversity was documented in the IBD patients compared with the HC. Moreover, we identified specific confounders and covariates that influenced the association between some bacterial taxa and disease extent (in UC patients) or behaviour (in CD patients) compared with the HC. In particular, a PERMANOVA stepwise regression identified the variables “age”, “eat yogurt at least four days per week” and “eat dairy products at least 4 days per week” as covariates when comparing the HC and patients affected by ulcerative proctitis (E1), left-sided UC (distal UC) (E2) and extensive UC (pancolitis) (E3). Instead, the variables “age”, “gender”, “eat meat at least four days per week” and “eat bread at least 4 days per week” were considered as covariates when comparing the HC with the CD patients affected by non-stricturing, non-penetrating (B1), stricturing (B2) and penetrating (B3) diseases. Considering such variables, our analysis indicated that the UC extent differentially modulated the abundance of the Bifidobacteriaceae, Rikenellaceae, Christensenellaceae, Marinifilaceae, Desulfovibrionaceae, Lactobacillaceae, Streptococcaceae and Peptostreptococcaceae families, while the CD behaviour influenced the abundance of Christensenellaceae, Marinifilaceae, Rikenellaceae, Ruminococcaceae, Barnesiellaceae and Coriobacteriaceae families. In conclusion, our study indicated that some covariates and confounders related to an IBD-associated lifestyle and dietary habits influenced the intestinal taxa diversity and relative abundance in the CD and UC patients compared with the HC. Indeed, such variables should be identified and excluded from the analysis to characterize the bacterial families whose abundance is directly modulated by IBD status, as well as disease extent or behaviour.

Effect of inflammatory bowel disease treatments on patients with diabetes mellitus.

As medical care progresses and the number of patients with chronic conditions increases there is the inevitable challenge of managing patients with multiple co-morbidities. Inflammatory bowel disease (IBD) is an umbrella term for are inflammatory conditions affecting the gastrointestinal tract, the two most common forms being Ulcerative Colitis and Crohn’s disease. These diseases, usually diagnosed in young adults, exhibit a relapsing and remitting course and usually require long-term treatment. IBD can be treated with a number of topical and systemic treatments. We conducted a review of the current published evidence for the effects these medications can have on diabetes mellitus (DM) and glycaemic control. Searches were conducted on medline and embase with a timeframe from 1947 (the date from which studies on embase are recorded) to November 2020. Suitable publications were selected and reviewed. Current evidence of the impact of aminosalicylates, corticosteroids, thiopurines, and biologic agents was reviewed. Though there was limited evidence for certain agents, IBD medications have been shown to have an effect of DM and these effects should be considered in managing patients with dual pathologies. The effects of steroids on blood sugar control is well documented, but consideration of other agents is also important. In patients requiring steroids for Ulcerative Colitis, locally acting steroid agents delivered rectally may be preferred to minimise side effects in those with distal bowel Ulcerative Colitis. A switch to other agents should be considered as soon as possible in people with diabetes to limit the impact on glycaemic control. 5-aminosalicylates appear to play a role in the reduction of hemoglobin A1c (HbA1c), although the literature suggests these may be falsely low readings. Consequently, monitoring of people with diabetes on these agents may require daily monitoring of capillary blood sugars rather than relying simply on HbA1c; for example fructosamine performed 3-6 monthly, although this risks missing the rise in readings. There is only limited evidence of the effects of thiopurines on diabetes and further investigation is needed into the possible relationship between them. However, given the current available evidence it may be preferable to commence patients with diabetes on thiopurines as soon as possible, whilst also monitoring for side effects such as pancreatitis. There appears to be more evidence supporting a link between tumor necrosis factor-α inhibitors and DM. Both infliximab and adalimumab have evidence suggesting that both can cause reduced blood sugar levels. Further studies on the effects of the various biological agents mentioned are required alongside any novel biologic therapy and the impact of dual biologic therapy in the future.

Appendiceal Orifice Inflammation in Severe Ulcerative Colitis and Its Resolution With Infliximab and Plant-based Diet as First-line Therapy.

Lay Summary Appendiceal orifice inflammation, which is often observed in mild or moderate distal ulcerative colitis, was observed in a case of severe UC. Appendiceal orifice inflammation resolved after new induction therapy for severe UC: infliximab and a plant-based diet as first-line therapy.

P523 Improvement of quality of life and continence in patients with distal ulcerative colitis treated by mesalazine: QUARTZ study

Abstract Background There is no robust data which analysed quality of life, functional disability and continence of patients with distal UC. QUARTZ is the first prospective study in this situation. Methods Observational, prospective and multicentric study involving public and private French gastroenterologist to recruit patients with mild to moderate (Mayo score ≥ 3 and ≤ 10) active proctitis or proctosigmoiditis (&amp;lt;20 cm) and under mesalazine for induction treatment. The patients followed for 12 months (±2 months). The primary objective was the quality of life evaluated by Short Inflammatory Bowel Disease (SIBDQ) at 8 weeks (±4 months). The functional disability and incontinence have been evaluated by IBD-Disability Index and Cleveland questionnaires. Results From December 2015 to November 2016, 117 patients were recruited. Data of 93 patients have been analysed and results are reported on Table 1. Among the 93 patients, 75 (81%) reached a clinical remission at week 8 with a SIBDQ score improvement of 6.7 ± 7.1 point (p &amp;lt; 0,001). Treatment adherence during the induction period was non-compliance for 76 patients (81%): 17 (18%) patients stopped treatment before W8 (all those patients received rectal formulation). After induction treatment, 72 (77%) patients received maintenance treatment. 11 (12%) patients reported adverse event not linked to the treatment. Conclusion For patients with distal ulcerative colitis treated by mesalazine, quality of life, functional disability and continence have been improved at 8 weeks of treatment despite a poor adherence.

The isolated caecal patch lesion: a clinical, endoscopic and histopathological study

ObjectiveTo describe and investigate the potential causes of the isolated caecal patch lesion, a previously undescribed endoscopic phenomenon of a lesion fulfilling endoscopic and histopathological criteria for chronic inflammatory bowel...

Hyaluronan Accelerates Intestinal Mucosal Healing through Interaction with TSG-6.

Hyaluronan (HA) has proven to be beneficial in the treatment of several diseases. Recently, it has been shown that the local application of HA (IBD98E) improves endoscopic and clinical outcomes in subjects with active distal ulcerative colitis (UC). However, the mechanisms by which this polysaccharide exerts its beneficial effects are unclear. Here, we demonstrated that HA treatment in vitro and in vivo improved mucosal healing by accelerating intestinal epithelial regeneration. Indeed, mice treated with HA showed a faster recovery from colitis and reduced endoscopic signs of mucosal inflammation compared to those receiving saline. Furthermore, histological analysis revealed less ulcerated mucosa in mice treated with HA, characterized by re-epithelialized areas. TSG-6, the secreted product of TNF-stimulated gene-6, is an HA-binding protein shown previously to have tissue-protective properties and promote wound healing. Mucosal levels of TSG-6 increased in UC patients compared to the healthy controls and also after wounding in mice. TSG-6 deletion prevented the beneficial properties of HA in mucosal wound repair, suggesting that the interaction of HA with TSG-6 is crucial for intestinal epithelial regeneration. Overall these results are consistent with HA having a therapeutic effect via the promotion of mucosal healing in patients with ulcerative colitis.

Oligonucleotides-A Novel Promising Therapeutic Option for IBD.

Inflammatory Bowel Diseases (IBD), whose denomination comprehends Crohn's Disease (CD) and Ulcerative Colitis (UC), are intestinal chronic diseases that often require lifelong medical therapy. In the last two decades monoclonal antibodies against the cytokine TNF have become integral parts in the treatment of IBD patients, however there are unwanted side-effects and one third of patients show primary non-response while another subgroup loses response over time. Finding novel drugs which could act as therapies against precise pro-inflammatory molecular targets to avoid unwanted systemic side effects and additionally the process of immunization, represents an important aim for subsequent therapeutic approaches. Oligonucleotide based therapies represent a promising novel concept for the treatment of IBD. The molecular action of oligonucleotides ranges from inhibition of the translational process of mRNA transcripts of pro-inflammatory molecules, to mimicking bacterial DNA which can activate cellular targets for immunomodulation. Alicaforsen, selectively targets ICAM-1 mRNA. ICAM-1 is an adhesion molecule which is upregulated on endothelial cells during IBD, thereby mediating the adhesion and migration of leucocytes from blood to sites of active inflammation. In CD parenteral application of alicaforsen did not show therapeutic efficacy in phase II trials, but it demonstrated an improved efficacy as a topical enema in distal UC. Topical application of alicaforsen might represent a therapeutic perspective for refractory pouchitis as well. SMAD7 is a protein that inhibits the signaling of TGFβ, which is the mainstay of a regulatory counterpart in cellular immune responses. An antisense oligonucleotide against SMAD7 mRNA (mongersen) demonstrated pre-clinical and phase II efficacy in CD, but a phase III clinical trial was stopped due to lack of efficacy. Cobitolimod is a single strand oligonucleotide, which mimics bacterial DNA as its CpG dinucleotide sequences can be recognized by the Toll-like receptor 9 on different immune cells thereby causing induction of different cytokines, for example IL10 and IFNα. Topical application of cobitolimod was studied in UC patients. We will also discuss two other novel oligonucleotides which act on the GATA3 transcription factor (SB012) and on carbohydrate sulfotransferase 15 (STNM01), which could both represent novel promising therapeutic options for the treatment of UC.

Ulcerative Colitis: Shifting Sands.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease associated with considerable disease burden. We review some current misconceptions about UC in adults with the aim of optimizing care for patients. Although UC and Crohn’s disease (CD) are considered discrete diseases, distinctions between them are not always clear-cut and phenotypes may change over time. Patient management should take into account disease manifestations, disease severity and extent, and response to prior treatments. Although disease extent often defines severity, distal UC is not always less disabling than extensive disease as patients can progress to more extensive disease. In addition, severe proctitis can give rise to severe and debilitating symptoms, with a substantial impact on health-related quality of life. UC carries an increased risk of colorectal cancer (CRC) compared with CD; however, more recent data indicate a similar risk of CRC in CD with colonic involvement as with UC. Corticosteroids are widely used to induce remission in UC, and prolonged use of steroids in patients with UC is common, but corticosteroid-free maintenance of remission is an important therapeutic goal. Although biologic therapies provide a valuable treatment option in UC, they are not clinically effective in all patients and are also associated with secondary loss of response.

Protocol for faecal microbiota transplantation in ulcerative colitis (FMTUC): a randomised feasibility study

BackgroundThe interaction of the gut microbiota with the human host is implicated in the pathogenesis of inflammatory and immunological diseases including ulcerative colitis (UC). Faecal microbiota transplantation (FMT) as a...

The safety of beclomethasone dipropionate in the treatment of ulcerative colitis

ABSTRACTIntroduction: Beclomethasone dipropionate (BDP) is a second-generation corticosteroid that uses novel drug technologies to ensure colonic targeting and potentially reducing systemic corticosteroid concentrations. It is approved for treatment of patients with mild-to-moderate ulcerative colitis (UC) who do not respond to mesalazine. The gut-selective mechanism of action has the potential to improve the safety profile of BDP compared with other conventional corticosteroids.Areas covered: We reviewed the mechanism of action, efficacy, and safety of BDP in the treatment of UC. The positioning of BDP in management algorithms is also discussed.Expert opinion: The highly selective mechanism of action of BDP restricts the steroid-related side effects. BDP is efficacious in the treatment of active UC. Topical formulation is the first choice in distal UC, while oral formulation is used in patients with an extensive involvement of the colon. The rates of adverse events (AE), serious AEs, and steroid-related side-effects are similar to placebo and mesalamine and slightly inferior to traditional corticosteroids.

Tacrolimus Suppositories in Therapy-Resistant Ulcerative Proctitis

Background: Ulcerative proctitis may often be managed with topical salicylates or steroids alone, but in some patients, symptoms are persistent and severe. We analyzed the efficacy of tacrolimus suppositories in patients who had proven refractory to combined topical and systemic treatment. Methods: In this retrospective analysis, ulcerative colitis activity index (CAI), side effects, co-medication and drug levels were assessed in 43 patients with distal ulcerative colitis who received suppositories containing 2 mg of tacrolimus b.i.d. as add-on medication. Results: A total of 23 patients with ulcerative proctitis presented to follow-up within ≤50 days (mean 27.0 days) after suppositories were started. A decrease in CAI (from 8.0 to 5.5 points) was observed and 52.3% reached clinical remission (CAI ≤4). In total, 43 patients were available for analysis, of whom 9 had inflammation of the sigmoid colon as well. For the entire cohort, the median treatment duration was 76 days; 60% were in remission on the last documented visit. Serum measurements revealed a substantial tacrolimus level with a mean of 5.5 ng/mL. We observed one case of mild reversible acute kidney injury. Conclusions: In ulcerative proctitis, adding tacrolimus suppositories can be an effective and safe option when topical mesalazine, corticoid formulations and concomitant oral or parenteral medications have failed.