Long-term outcome of patients with steroid-refractory acute severe UC treated with ciclosporin or infliximab.

OBJECTIVE: Ciclosporin and infliximab have demonstrated short-term similar efficacy as second-line therapies in patients with acute severe UC (ASUC) refractory to intravenous steroids. The aim of this study was to assess long-term outcome of patients included in a randomised trial comparing ciclosporin and infliximab. DESIGN: Between 2007 and 2010, 115 patients with steroid-refractory ASUC were randomised in 29 European centres to receive ciclosporin or infliximab in association with azathioprine. Patients were followed until death or last news up to January 2015. Colectomy-free survival rates at 1 and 5 years and changes in therapy were estimated through Kaplan-Meier method and compared between initial treatment groups through log-rank test. RESULTS: After a median follow-up of 5.4 years, colectomy-free survival rates (95% CI) at 1 and 5 years were, respectively, 70.9% (59.2% to 82.6%) and 61.5% (48.7% to 74.2%) in patients who received ciclosporin and 69.1% (56.9% to 81.3%) and 65.1% (52.4% to 77.8%) in those who received infliximab (p=0.97). Cumulative incidence of first infliximab use at 1 and 5 years in patients initially treated with ciclosporin was, respectively, 45.7% (32.6% to 57.9%) and 57.1% (43.0% to 69.0%). Only four patients from the infliximab group were subsequently switched to ciclosporin. Three patients died during the follow-up, none directly related to UC or its treatment. CONCLUSIONS: In this cohort of patients with steroid-refractory ASUC initially treated by ciclosporin or infliximab, long-term colectomy-free survival was independent from initial treatment. These long-term results further confirm a similar efficacy and good safety profiles of both drugs and do not favour one drug over the other. TRIAL REGISTRATION NUMBER: EudraCT: 2006-005299-42; ClinicalTrials.gouv number: NCT00542152; post-results.

Outcome of restorative proctocolectomy with an ileo-anal pouch for ulcerative colitis: effect of changes in clinical practice.

AIM: Surgery for ileal pouch-anal anastomosis (IPAA) has evolved over time, especially since the introduction of laparoscopy. The aim of this retrospective study was to report the impact of surgical evolution on outcome over a period of 25 years. METHOD: All patients who had IPAA surgery for ulcerative colitis from 1990 to 2015 at the University Hospitals of Leuven were included. Patients were divided into three period arms (period A 1990-1999; period B 2000-2009; period C 2010-2015). The main outcome measure was anastomotic leakage. RESULTS: A total of 335 patients (58.8% male) with a median age of 39 years (interquartile range 32-49 years) at surgery were included. Median follow-up was 5 years (interquartile range 2-10 years). Overall anastomotic leakage (grades A-C) was 14.9%. A significant decrease in leakage rate was observed over time (from 21.4% in period A to 12.1% in period B to 10.0% in period C; P = 0.04). The defunctioning ileostomy rate at the time of pouch construction decreased from 91.7% (period A) to 40.3% (period B) to 11.1% (period C) (P < 0.001). We observed an increase in the use of laparoscopy (23.9% in period A vs 72.6% in period B, vs 84.4% in period C; P = 0.001) and a shift to a modified two-stage procedure (4.1% in period A, vs 66.7% in period C; P < 0.0001). In a monocentric study with some of the data retrieved retrospectively it was not possible to account for the impact of preoperative nutritional status (weight loss, serum albumin level) or disease burden. Other outcome factors were not measured, for example sexual function and fecundity. CONCLUSION: A higher rate of laparoscopic IPAA surgery, together with a shift towards modified two-stage procedures, was associated with a lower leakage rate despite a reduction in the use of defunctioning ileostomy.

Short- and medium-term outcomes following primary ileocaecal resection for Crohn's disease in two specialist centres.

BACKGROUND: Despite improvements in medical therapy, the majority of patients with Crohn's disease still require surgery. The aim of this study was to report safety, and clinical and surgical recurrence rates, including predictors of recurrence, after ileocaecal resection for Crohn's disease. METHODS: This was a cohort analysis of consecutive patients undergoing a first ileocaecal resection for Crohn's disease between 1998 and 2013 at one of two specialist centres. Anastomotic leak rate and associated risk factors were assessed. Kaplan-Meier estimates were used to describe long-term clinical and surgical recurrence. Univariable and multivariable regression analyses were performed to identify risk factors for both endpoints. RESULTS: In total, 538 patients underwent primary ileocaecal resection (40·0 per cent male; median age at surgery 31 (i.q.r. 24-42) years). Median follow-up was 6 (2-9) years. Fifteen of 507 patients (3·0 per cent) developed an anastomotic leak. An ASA fitness grade of III (odds ratio (OR) 4·34, 95 per cent c.i. 1·12 to 16·77; P = 0·033), preoperative antitumour necrosis factor therapy (OR 3·30, 1·09 to 9·99; P = 0·035) and length of resected bowel specimen (OR 1·06, 1·03 to 1·09; P < 0·001) were significant risk factors for anastomotic leak. Rates of clinical recurrence were 17·6, 45·4 and 55·0 per cent after 1, 5 and 10 years respectively. Corresponding rates of requirement for further surgery were 0·6, 6·5 and 19·1 per cent. Smoking (hazard ratio (HR) 1·67, 95 per cent c.i. 1·14 to 2·43; P = 0·008) and a positive microscopic resection margin (HR 2·16, 1·46 to 3·21; P < 0·001) were independent risk factors for clinical recurrence. Microscopic resection margin positivity was also a risk factor for further surgery (HR 2·99, 1·36 to 6·54; P = 0·006). CONCLUSION: Ileocaecal resection achieved durable medium-term remission, but smoking and resection margin positivity were risk factors for recurrence.

Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): Determining Therapeutic Goals for Treat-to-Target.

OBJECTIVES: The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) program was initiated by the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD). It examined potential treatment targets for inflammatory bowel disease (IBD) to be used for a "treat-to-target" clinical management strategy using an evidence-based expert consensus process. METHODS: A Steering Committee of 28 IBD specialists developed recommendations based on a systematic literature review and expert opinion. Consensus was gained if ≥75% of participants scored the recommendation as 7-10 on a 10-point rating scale (where 10=agree completely). RESULTS: The group agreed upon 12 recommendations for ulcerative colitis (UC) and Crohn's disease (CD). The agreed target for UC was clinical/patient-reported outcome (PRO) remission (defined as resolution of rectal bleeding and diarrhea/altered bowel habit) and endoscopic remission (defined as a Mayo endoscopic subscore of 0-1). Histological remission was considered as an adjunctive goal. Clinical/PRO remission was also agreed upon as a target for CD and defined as resolution of abdominal pain and diarrhea/altered bowel habit; and endoscopic remission, defined as resolution of ulceration at ileocolonoscopy, or resolution of findings of inflammation on cross-sectional imaging in patients who cannot be adequately assessed with ileocolonoscopy. Biomarker remission (normal C-reactive protein (CRP) and calprotectin) was considered as an adjunctive target. CONCLUSIONS: Evidence- and consensus-based recommendations for selecting the goals for treat-to-target strategies in patients with IBD are made available. Prospective studies are needed to determine how these targets will change disease course and patients' quality of life.

Is there a therapeutic window of opportunity in early inflammatory bowel disease? Early stage inflammatory bowel disease: the actual management.

Traditionally therapy for inflammatory bowel disease (IBD) encompassed a sequential approach with subjects treated with 5-ASA products and/or corticosteroids initially, and only where failing such treatment, moving on to immunomodulator or biologic therapy. In the rheumatologic literature the importance of the early introduction of immunosuppressive therapies for inflammatory arthropathies has been increasingly recognized, however this concept remains much debated in IBD with no clear consensus on the optimal therapeutic approach. In this review we discuss how the natural history of IBD provides a rationale for the early introduction of the most effective therapy. We outline how the experience of early immunosuppressive therapy in rheumatoid arthritis informs therapeutic decision making in IBD. We review the evolving treatment strategies in IBD and the current evidence supporting the introduction of immunosuppressive treatment soon after IBD diagnosis. Finally we discuss the importance of selecting appropriate therapeutic endpoints in IBD and review the potential risks and benefits of early immunosuppressive treatment strategies in IBD.

Octreotide for the treatment of diarrhoea in patients with ileal pouch anal anastomosis: a placebo-controlled crossover study.

AIM: Diarrhoea with urgency is a debilitating long-term complication of ileal pouch anal anastomosis (IPAA) after a proctocolectomy. Somatostatin analogues are used to control diarrhoea and high-output ostomies. Hence, we designed a prospective, double-blind, crossover trial to explore the efficacy and tolerability of octreotide to reduce diarrhoea in adult patients with IPAA. METHOD: Patients were randomized to octreotide subcutaneously (SC), 500 µg three times daily (t.i.d.), or matching placebo SC for 7 days. Responders (a reduction in stool frequency of three or more stools per 24-h period and with a reduction in stool frequency of at least 30% after 7 days of treatment compared with baseline; the primary end-point) remained in the same group and nonresponders could cross over to the alternative treatment for 7 days. Open-label octeotide LAR 30 mg was offered to all responders on day 14. Flexible pouchoscopy with biopsies was performed at baseline in all patients and was repeated on days 7 and 14 in patients with pouchitis. RESULTS: Fifteen patients (11 men, median age 52 years), all with ulcerative colitis, were randomized. Three patients were withdrawn for side effects during the blinded phase. Response was achieved by two of 12 and two of 11 patients treated with octreotide or placebo, respectively (including crossover, P = 0.9). The median stool frequency remained stable in both groups [Δoctreotide: 0 (IQR, -4 to 0), Δplacebo: -1 (IQR, -1 to 1), P = 0.45]. Octreotide had no effect on the modified pouch disease activity index (mPDAI), and pouchitis persisted in five of six subjects with pouchitis at onset. One subject received open-label octreotide LAR. CONCLUSION: Octreotide has no clear beneficial effect on the stool pattern or on pouchitis severity in patients with high stool frequency after IPAA.

Long-term outcome of endoscopic dilatation in patients with Crohn's disease is not affected by disease activity or medical therapy.

BACKGROUND: Endoscopic dilatation of Crohn's disease-related strictures is an alternative to surgical resection in selected patients. The influence of disease activity and concomitant medical therapy on long-term outcomes is largely unknown. AIM AND METHODS: To study the long-term safety and efficacy of stricture dilatation in a single centre cohort. RESULTS: Between 1995 and 2006, 237 dilatations where performed in 138 patients (mean age 50.6+/-13.4, 56% female) for a clinically obstructive stricture (<5 cm, 84% anastomotic). Immediate success of a first dilatation was 97% with a 5% serious complication rate. After a median follow-up of 5.8 years (IQR 3.0-8.4), recurrent obstructive symptoms led to a new dilatation in 46% or surgery in 24%. Niether elevated levels of C-reactive protein nor endoscopic disease activity predicted the need for new intervention. None of the concomitant therapies influenced the outcome. CONCLUSION: This largest series ever reported confirms that long term efficacy of endoscopic dilatation of Crohn's disease outweighs the complication risk. Neither active disease at the time of dilatation nor medical therapy afterwards predict recurrent dilatation or surgery.

Impact of lipoteichoic acid modification on the performance of the probiotic Lactobacillus rhamnosus GG in experimental colitis.

While some probiotic strains might have adjuvant effects in the therapy for inflammatory bowel diseases (IBD), these effects remain controversial and cannot be generalized. In this study, a dltD mutant of the model probiotic Lactobacillus rhamnosus GG (LGG), having a drastic modification in its lipoteichoic acid (LTA) molecules, was analysed for its effects in an experimental colitis model. Dextran sulphate sodium (DSS) was used to induce either moderate to severe or mild chronic colitis in mice. Mice received either phosphate-buffered saline (PBS), LGG wild-type or the dltD mutant via the drinking water. Macroscopic parameters, histological abnormalities, cytokine and Toll-like receptor (TLR) expression were analysed to assess disease activity. LGG wild-type did not show efficacy in the different experimental colitis set-ups. This wild-type strain even seemed to exacerbate the severity of colitic parameters in the moderate to severe colitis model compared to untreated mice. In contrast, mice treated with the dltD mutant showed an improvement of some colitic parameters compared to LGG wild-type-treated mice in both experimental models. In addition, treatment with the dltD mutant correlated with a significant down-regulation of Toll-like receptor-2 expression and of downstream proinflammatory cytokine expression in the colitic mice. These results show that molecular cell surface characteristics of probiotics are crucial when probiotics are considered for use as supporting therapy in IBD.

Long-term safety of infliximab for the treatment of inflammatory bowel disease: a single-centre cohort study.

BACKGROUND AND AIMS: This study evaluates the long-term safety of infliximab in patients with inflammatory bowel disease (IBD) treated with the drug over a 14-year period. METHODS: The medical records of 734 patients with IBD treated with infliximab and 666 control patients not treated with infliximab were reviewed for adverse events. The time of onset and outcome, severity and concomitant medication were recorded. RESULTS: Patients and controls were followed up for serious adverse events for a median time of 58 months (IQR 33-88) and 144 months (IQR 83-163), respectively. 112 severe adverse events occurred in 93 patients (13%) treated with infliximab and 157 occurred in 126 (19%) control patients (OR 1.33 (95% CI 0.56 to 3.00, p = 0.45). There was no difference between the two groups in mortality, malignancies and infection rate. Tuberculosis was diagnosed in two patients receiving infliximab who had negative skin tests at baseline whereas none of 16 patients with positive skin tests who received prophylaxis developed tuberculosis. Concomitant treatment with steroids was the only independent risk factor for infections in patients treated with infliximab (OR 2.69 (95% CI 1.18 to 6.12), p = 0.018). The most commonly observed systemic side effects were skin eruptions including psoriasiform eruptions in 150 patients (20%). CONCLUSIONS: Long-term infliximab treatment had a good overall safety profile in the patient cohort studied.

Long-term outcome of treatment with infliximab in 614 patients with Crohn's disease: results from a single-centre cohort.

BACKGROUND AND AIMS: This observational study assessed the long-term clinical benefit of infliximab (IFX) in 614 consecutive patients with Crohn's disease (CD) from a single centre during a median follow-up of 55 months (interquartile range (IQR) 27-83). METHODS: The primary analysis looked at the proportion of patients with initial response to IFX who had sustained clinical benefit at the end of follow-up. The long-term effects of IFX on the course of CD as reflected by the rate of surgery and hospitalisations and need for corticosteroids were also analysed. RESULTS: 10.9% of patients were primary non-responders to IFX. Sustained benefit was observed in 347 of the 547 patients (63.4%) receiving long-term treatment. In 68.3% of these, treatment with IFX was ongoing and in 31.7% IFX was stopped, with the patient being in remission. Seventy patients (12.8%) had to stop IFX due to side effects and 118 (21.6%) due to loss of response. Although the yearly drop-out rates of IFX in patients with episodic (10.7%) and scheduled treatment (7.1%) were similar, the need for hospitalisations and surgery decreased less in the episodic than in the scheduled group. Steroid discontinuation also occurred in a higher proportion of patients in the scheduled group than in the episodic group. CONCLUSIONS: In this large real-life cohort of patients with CD, long-term treatment with IFX was very efficacious to maintain improvement during a median follow-up of almost 5 years and changed disease outcome by decreasing the rate of hospitalisations and surgery.

Mucosal gene signatures to predict response to infliximab in patients with ulcerative colitis.

BACKGROUND AND AIMS: Infliximab is an effective treatment for ulcerative colitis with over 60% of patients responding to treatment and up to 30% reaching remission. The mechanism of resistance to anti-tumour necrosis factor alpha (anti-TNFalpha) is unknown. This study used colonic mucosal gene expression to provide a predictive response signature for infliximab treatment in ulcerative colitis. METHODS: Two cohorts of patients who received their first treatment with infliximab for refractory ulcerative colitis were studied. Response to infliximab was defined as endoscopic and histological healing. Total RNA from pre-treatment colonic mucosal biopsies was analysed with Affymetrix Human Genome U133 Plus 2.0 Arrays. Quantitative RT-PCR was used to confirm microarray data. RESULTS: For predicting response to infliximab treatment, pre-treatment colonic mucosal expression profiles were compared for responders and non-responders. Comparative analysis identified 179 differentially expressed probe sets in cohort A and 361 in cohort B with an overlap of 74 probe sets, representing 53 known genes, between both analyses. Comparative analysis of both cohorts combined, yielded 212 differentially expressed probe sets. The top five differentially expressed genes in a combined analysis of both cohorts were osteoprotegerin, stanniocalcin-1, prostaglandin-endoperoxide synthase 2, interleukin 13 receptor alpha 2 and interleukin 11. All proteins encoded by these genes are involved in the adaptive immune response. These markers separated responders from non-responders with 95% sensitivity and 85% specificity. CONCLUSION: Gene array studies of ulcerative colitis mucosal biopsies identified predictive panels of genes for (non-)response to infliximab. Further study of the pathways involved should allow a better understanding of the mechanisms of resistance to infliximab therapy in ulcerative colitis. ClinicalTrials.gov number, NCT00639821.

Quality of care in an inflammatory bowel disease clinical trial center : a prospective study evaluating patients' satisfaction.

BACKGROUND AND STUDY AIMS: Quality of care is a very timely topic in medicine. We designed a questionnaire to measure perceived quality of care and to explore areas of improvement. PATIENTS AND METHODS: In this prospective study a questionnaire was developed and administered to all patients with inflammatory bowel disease participating in a randomized clinical trial. The questionnaire was based on validated surveys and supplemented with novel, relevant questions. Factors associated with (poor) quality of care were identified. RESULTS: Between October 2016 and January 2017, all 107 patients participating in a randomized controlled trial completed the questionnaire (63% male, 76% ulcerative colitis, median age of 47 years). The median satisfaction score was 9 out of 10. Areas of improvement were that too little attention was paid to the disease impact on family and work, dietary and exercise pattern, daily activities and quality of life. Multivariate analysis showed that clinical remission [5.77 (2.03-16.39), p=0.001] was a predictor of good quality of care. CONCLUSIONS: In this large IBD trial bureau, inflammatory bowel disease patients were very satisfied with the quality of care. Domains for quality improvement, such as attention to the impact of IBD on family and work, were identified.

Prilling of API/fatty acid suspensions: Screening of additives for drug release modification.

Current study screened additives which could modify the drug release from prills made of an active pharmaceutical ingredient/fatty acid (API/FA) suspension, without negatively influencing the processability and/or stability of the formulation. Therefore, 11 additives (i.e. emulsifiers, pore-formers and FA-based lubricants) were added in a 20% concentration to a paracetamol/behenic acid formulation. Two additives, Kolliphor® P338 and P407 provided complete drug release in less than 1 h, as their thermoreversible gel formation resulted in a disintegration of the prills. Lower Kolliphor® P338 or P407 concentrations (2.5-10%) resulted in a complete but slower drug release in 24 h as the prills no longer disintegrated and the release mechanism was dominated by pore-formation. Prills with a robust drug release profile (i.e. independent of pH and surfactant concentration of the dissolution medium) were obtained after the addition of ≥5% Kolliphor® P338 or P407 to the FA-based formulation. Based on a 6-month stability study, it was concluded that Kolliphor® P407 was a suitable additive to modify the drug release profile of API/FA suspension-based prills when formulations were stored below 25 °C at low relative humidity.

Outcome of surgery for rectovaginal fistula due to Crohn's disease.

BACKGROUND: This study examined the outcome of surgery for symptomatic Crohn's rectovaginal fistula (RVF) and assessed the effect of therapy with antibody against tumour necrosis factor (TNF) on healing. METHODS: Fifty-six patients with Crohn's disease underwent surgery for a RVF between January 1993 and December 2006. Outcome analysis was performed in February 2008 in relation to the surgical procedures used and the effect of anti-TNF treatment. RESULTS: Four patients with a healed fistula still had a stoma at final follow-up for other reasons and were excluded from the analysis. Fistula closure was achieved in 81 per cent of the remaining 52 patients. Primary and secondary surgical success rates were 56 and 57 per cent respectively. The primary healing rate was similar in patients who received anti-TNF treatment before the first operation (12 of 18 patients) and those who did not (19 of 34). In univariable analysis, duration of Crohn's disease (P = 0.037) and previous extended colonic resection (P < 0.001) were significantly related to failure of primary surgery, but only the latter remained significant in multivariable analysis (P < 0.001). Late recurrence developed in four patients. CONCLUSION: Fistula closure was achieved in most patients, but more than one operation was often required.

JC viral loads in patients with Crohn's disease treated with immunosuppression: can we screen for elevated risk of progressive multifocal leukoencephalopathy?

BACKGROUND AND AIMS: Anti-alpha4 integrin therapy with natalizumab is efficacious in refractory Crohn's disease and in multiple sclerosis, but carries an estimated 1/1000 risk of progressive multifocal leukoencephalopathy (PML) caused by reactivation of latent JC virus infection. Although anti-alpha4 integrin therapies are likely to be introduced in the clinic, screening for the risk of PML has not been developed. METHODS: We prospectively collected urine, serum, plasma and buffy coats from 125 patients with Crohn's disease, 100 control subjects with gastrointestinal (GI) disease, and 106 healthy volunteers. Four to eight weeks after this first sample collection, we additionally collected a set of urine, serum, plasma and buffy coat samples from the 125 patients with Crohn's disease, and a next set of samples was collected 12-16 weeks after the first collection. JC viral loads were determined with quantitative real-time polymerase chain reaction (PCR), and JC virus seroprevalence with a specific enzyme-linked immunosorbant assay (ELISA). RESULTS: The overall JC virus seroprevalence was 65%. JC virus DNA copies were detected in the urine from 29-44% of subjects, both those with Crohn's disease and controls. Median viral loads were significantly higher in patients with Crohn's disease who were immunosuppressed (7.36x10(6) copies/ml) compared to healthy volunteers (2.77x10(5) copies/ml) and compared to GI controls (1.8x10(6) copies/ml). Clearance at any time point occurred in 4/107 (3.7%) subjects only. JC viraemia was found in two patients with Crohn's disease. CONCLUSIONS: The natural history of JC virus in patients with Crohn's disease is still unknown. Our study results show that JC virus latency and urine viral shedding is frequent in immunosuppressed patients with Crohn's disease. More prospective studies are needed in order to agree on possible recommendations concerning the exclusion of patients with JCV viraemia from anti-alpha4 integrin treatment.

Cx601 (darvadstrocel) for the treatment of perianal fistulizing Crohn's disease.

Introduction: Given the well-documented difficulty to treat perianal fistulizing Crohn's disease (pCD), with 40% of patients experiencing recurrence even after reiterative surgery and advanced medical therapy, research in this field has focused on the role of mesenchymal stem cells (MSC). Areas covered: The aim of this article is to furnish an overview of the pathogenetic mechanisms, clinical applications and evidences for the use of MSC for pCD with particular focus on adipose-derived allogenic MSC including darvadstrocel. Expert Opinion: The effect of MSC on fistula healing is probably mediated by their anti-inflammatory properties more than by their ability to engraft and trans-differentiate in the healthy tissue. A holistic treatment of pCD, addressing different pathophysiological factors, may represent the key for an improvement in the healing rate. In this setting, MSC might play a role as 'augmentation' therapy in combination with more conventional treatments. Whether MSC have benefit in non-complex fistula in biological naïve patients, in complex fistula with many tracts and/or in rectovaginal fistulas, are unexplored fields that need further investigation. A central registry of pCD patients undergoing treatment with MSC should be created in order to elucidate the efficacy, safety and costs of stem cells treatment on long term follow up.

Prilling of API/fatty acid suspensions: Processability and characterisation.

Current study evaluated the processability and characteristics of prills made of an active pharmaceutical ingredient/fatty acid (API/FA) suspension instead of previously studied API/FA solutions to enlarge the application field of prilling. Metformin hydrochloride (MET) and paracetamol (PAR) were used as model APIs while both the effect of drug load (10-40%) and FA chain length (C14-C22) were evaluated. API/FA suspensions were processable on lab-scale prilling equipment without thermal degradation, nozzle obstruction or sedimentation in function of processing time. The collected prills were spherical (AR ≥ 0.898) with a smooth surface (sphericity ≥ 0.914) and a particle size of ±2.3 mm and 2.4 mm for MET and PAR prills, respectively, independent of drug load and/or FA chain length. In vitro drug release evaluation revealed a faster drug release at higher drug load, higher API water solubility and shorter FA chain length. Solid state characterisation via XRD and Raman spectroscopy showed that API and FA crystallinity was maintained after thermal processing via prilling and during storage. Evaluation of the similarity factor indicated a stable drug release (f2 > 50) from MET and PAR prills after 6 months storage at 25 °C or 40 °C.