Health-related quality of life in patients with primary sclerosing cholangitis: A longitudinal population-based cohort study.

BACKGROUND & AIMS: Data regarding health-related quality of life (HRQoL) in primary sclerosing cholangitis (PSC) are sparse and have only been studied cross-sectionally in a disease which runs a fluctuating and unpredictable course. We aim to describe HRQoL longitudinally by using repeated measurements in a population-based cohort. METHODS: Every 3 months from May 2017 up to August 2020, patients received digital questionnaires at home. These included the EQ-5D, 5-D Itch, patient-based SCCAI and patient-based HBI. The SF-36, measuring HRQoL over eight dimensions as well as a physical component summary (PCS) and mental component summary (MCS) score, was sent annually. Data were compared with Dutch reference data and a matched IBD disease control from the population-based POBASIC cohort. Mixed-effects modelling was performed to identify factors associated with HRQoL. RESULTS: Three hundred twenty-eight patients completed 2576 questionnaires. A significant reduction of small clinical relevance in several mean HRQoL scores was found compared with the Dutch reference population: 46.4 versus 48.0, p = .018 for PCS and 47.5 versus 50.5, p = .004 for MCS scores. HRQoL outcomes were significantly negatively associated with coexisting active IBD (PCS -12.2, p < .001 and MCS -12.0, p < .001), which was not the case in case of quiescent IBD. Decreasing HRQoL scores were also negatively associated with increasing age (PCS -0.1 per 10 years, p = .002), female sex (PCS -2.8, p < .001), diagnosis of AIH overlap (PCS -3.7, p = .059), end-stage liver disease (PCS -3.7, p = .015) and presence of itch (PCS -9.2, p < .001 and MCS -3.1, p = .078). The odds of reporting a clinically relevant reduction in EQ-5D scores showed seasonal variation, being lowest in summer (OR = 0.48 relative to spring, p = .037). In patients with liver transplant, HRQoL outcomes were comparable to the Dutch general population. CONCLUSIONS: PSC patients report impaired HRQoL of small clinical relevance compared with the general population. After liver transplantation, HRQoL scores are at comparable levels to the general population. HRQoL scores are associated with potentially modifiable factors such as itch and IBD activity.

Knotless seton for perianal fistulas: feasibility and effect on perianal disease activity.

Patients with perianal fistulas are frequently treated by a knotted seton which is well-known for causing complaints. We aimed to assess the feasibility of the knotless SuperSeton and advantages with respect to perianal disease activity. In a prospective cohort study, we included all consecutive adult patients with a knotted seton in situ or a perianal fistula requiring new seton drainage. Primary endpoint was seton feasibility (maintenance of the connection for minimally three months). Secondary endpoints included improvement of the Perianal Disease Activity Index (PDAI), complications and re-interventions within three months of follow-up. PDAI scores of patients with a knotted seton were crossover compared to PDAI scores after knotless seton replacement. Sixty patients (42% male, mean age 42 (SD 13.15), 41 with Crohn's disease) were included between August 2016 and April 2018. Of 79 knotless setons, 69 (87.3%) stayed connected for ≥ 3 months. Overall, the knotless seton significantly decreased discharge (P = 0.001), pain (P < 0.001) and induration (P < 0.001) measured by the PDAI when compared to baseline. In patients with a knotted seton, replacement by the knotless seton significantly decreased discharge (P = 0.005) and pain (P < 0.001) measured by the PDAI. Furthermore, 71% of patients reported fewer cleaning problems compared to the knotted seton. Ten patients developed a perianal abscess, and five patients required a re-intervention. This study supports the feasibility of the knotless seton with promising short-term results. The knotless seton might be preferred over the knotted seton in terms of perianal disease activity.

Laparoscopic ileocaecal resection versus infliximab for terminal ileitis in Crohn's disease: retrospective long-term follow-up of the LIR!C trial.

BACKGROUND: The LIR!C trial showed that laparoscopic ileocaecal resection is a cost-effective treatment that has similar quality-of-life outcomes to treatment with infliximab, an anti-tumour necrosis factor (TNF) drug. We aimed to compare long-term outcomes of both interventions and identify baseline factors associated with the duration of treatment effect in each group. METHODS: In this retrospective follow-up study, we collected data from patients who participated in the LIR!C trial, a multicentre randomised controlled trial that compared quality of life after surgical resection versus infliximab in adult patients with non-stricturing and immunomodulator-refractory ileocaecal Crohn's disease. From Jan 1 to May 1, 2018, we collected follow-up data from the time from enrolment in the LIR!C trial until the last visit at either the gastrointestinal surgeon or gastroenterologist. In this study, outcomes of interest were need for surgery or repeat surgery or anti-TNF therapy, duration of treatment effect, and identification of factors associated with the duration of treatment effect. Duration of treatment effect was defined as the time without need for additional Crohn's disease-related treatment (corticosteroids, immunomodulators, biologics, or surgery). FINDINGS: We collected long-term follow-up data for 134 (94%) of 143 patients included in the LIR!C trial, of whom 69 were in the resection group and 65 were in the infliximab group. Median follow-up was 63·5 months (IQR 39·0-94·5). In the resection group, 18 (26%) of 69 patients started anti-TNF therapy and none required a second resection. 29 (42%) patients in the resection group did not require additional Crohn's disease-related medication, although 14 (48%) of these patients were given prophylactic immunomodulator therapy. In the infliximab group, 31 (48%) of 65 patients had a Crohn's disease-related resection, and the remaining 34 patients maintained, switched, or escalated their anti-TNF therapy. Duration of treatment effect was similar in both groups, with a median time without additional Crohn's disease-related treatment of 33·0 months (95% CI 15·1-50·9) in the resection group and 34·0 months (0·0-69·3) in the infliximab group (log-rank p=0·52). In both groups, therapy with an immunomodulator, in addition to the allocated treatment, was associated with duration of treatment effect (hazard ratio for resection group 0·34 [95% CI 0·16-0·69] and for infliximab group 0·49 [0·26-0·93]). INTERPRETATION: These findings further support laparoscopic ileocaecal resection as a treatment option in patients with Crohn's disease with limited (affected segment ≤40 cm) and predominantly inflammatory terminal ileitis for whom conventional treatment is not successful. FUNDING: None.

Treatment of Perianal Fistulas in Crohn's Disease, Seton Versus Anti-TNF Versus Surgical Closure Following Anti-TNF [PISA]: A Randomised Controlled Trial.

BACKGROUND AND AIMS: Most patients with perianal Crohn's fistula receive medical treatment with anti-tumour necrosis factor [TNF], but the results of anti-TNF treatment have not been directly compared with chronic seton drainage or surgical closure. The aim of this study was to assess if chronic seton drainage for patients with perianal Crohn's disease fistulas would result in less re-interventions, compared with anti-TNF and compared with surgical closure. METHODS: This randomised trial was performed in 19 European centres. Patients with high perianal Crohn's fistulas with a single internal opening were randomly assigned to: i] chronic seton drainage for 1 year; ii] anti-TNF therapy for 1 year; and iii] surgical closure after 2 months under a short course anti-TNF. The primary outcome was the cumulative number of patients with fistula-related re-intervention[s] at 1.5 years. Patients declining randomisation due to a specific treatment preference were included in a parallel prospective PISA registry cohort. RESULTS: Between September 14, 2013 and November 20, 2017, 44 of the 126 planned patients were randomised. The study was stopped by the data safety monitoring board because of futility. Seton treatment was associated with the highest re-intervention rate [10/15, versus 6/15 anti-TNF and 3/14 surgical closure patients, p = 0.02]. No substantial differences in perianal disease activity and quality of life between the three treatment groups were observed. Interestingly, in the PISA prospective registry, inferiority of chronic seton treatment was not observed for any outcome measure. CONCLUSIONS: The results imply that chronic seton treatment should not be recommended as the sole treatment for perianal Crohn's fistulas.

Cost-effectiveness of laparoscopic ileocaecal resection versus infliximab treatment of terminal ileitis in Crohn's disease: the LIR!C Trial.

OBJECTIVE: Evaluate the cost-effectiveness of laparoscopic ileocaecal resection compared with infliximab in patients with ileocaecal Crohn's disease failing conventional therapy. DESIGN: A multicentre randomised controlled trial was performed in 29 centres in The Netherlands and the UK. Adult patients with Crohn's disease of the terminal ileum who failed >3 months of conventional immunomodulators or steroids without signs of critical strictures were randomised to laparoscopic ileocaecal resection or infliximab. Outcome measures included quality-adjusted life-years (QALYs) based on the EuroQol (EQ) 5D-3L Questionnaire and the Inflammatory Bowel Disease Questionnaire (IBDQ). Costs were measured from a societal perspective. Analyses were performed according to the intention-to-treat principle. Missing cost and effect data were imputed using multiple imputation. Cost-effectiveness planes and cost-effectiveness acceptability curves were estimated to show uncertainty. RESULTS: In total, 143 patients were randomised. Mean Crohn's disease total direct healthcare costs per patient at 1 year were lower in the resection group compared with the infliximab group (mean difference €-8931; 95% CI €-12 087 to €-5097). Total societal costs in the resection group were lower than in the infliximab group, however not statistically significant (mean difference €-5729, 95% CI €-10 606 to €172). The probability of resection being cost-effective compared with infliximab was 0.96 at a willingness to pay (WTP) of €0 per QALY gained and per point improvement in IBDQ Score. This probability increased to 0.98 at a WTP of €20 000/QALY gained and 0.99 at a WTP of €500/point of improvement in IBDQ Score. CONCLUSION: Laparoscopic ileocaecal resection is a cost-effective treatment option compared with infliximab. CLINICAL TRIAL REGISTRATION NUMBER: Dutch Trial Registry NTR1150; EudraCT number 2007-005042-20 (closed on 14 October 2015).

Persistent Mesorectal Inflammatory Activity is Associated With Complications After Proctectomy in Crohn's Disease.

BACKGROUND AND AIMS: Rectal resection in inflammatory bowel disease [IBD] is frequently complicated by disturbed perineal wound healing. Close rectal dissection, where the mesorectum remains in situ, is hypothesized to reduce complications by minimizing dead space, compared to total mesorectal excision. The aim of this study was to analyse post-operative outcomes of both techniques. In addition, immune activity in mesorectal tissue was assessed. METHODS: Perineal complications and healing were retrospectively assessed in a series of 74 IBD patients undergoing proctectomy using close rectal dissection or total mesorectal excision. The mesorectums of 15 patients were analysed by fluorescence-activated cell sorting, immunofluorescence and in situ hybridization. Based on the clinical and in vitro findings, a novel surgical approach for Crohn's disease patients with disturbed perineal healing after proctectomy was developed. RESULTS: In Crohn's disease, perineal complications were more frequent after close rectal dissection than after total mesorectal excision [59.5% vs 17.6%; p = 0.007] with lower healing rates [51.4% vs 88.2%; p = 0.014]. No differences were observed in ulcerative colitis. The mesorectal tissue in Crohn's disease contained enhanced numbers of tumour necrosis factor α-producing CD14+ macrophages, with less expression of the wound-healing marker CD206. Based on these findings, mesorectal excision with omentoplasty was performed in eight patients with perineal complications after close rectal dissection, resulting in complete perineal wound closure in six. Pro-inflammatory characteristics remained present in the mesorectum after close rectal dissection in these patients. CONCLUSIONS: In Crohn's disease, close rectal dissection resulted in more perineal complications, associated with a pro-inflammatory immune status of the mesorectal tissue. Excision of this pro-inflammatory mesenteric tissue resulted in improved perineal healing rates.

Laparoscopic ileocaecal resection versus infliximab for terminal ileitis in Crohn's disease: a randomised controlled, open-label, multicentre trial.

BACKGROUND: Treatment of patients with ileocaecal Crohn's disease who have not responded to conventional therapy is commonly scaled up to biological agents, but surgery can also offer excellent short-term and long-term results. We compared laparoscopic ileocaecal resection with infliximab to assess how they affect health-related quality of life. METHODS: In this randomised controlled, open-label trial, in 29 teaching hospitals and tertiary care centres in the Netherlands and the UK, adults with non-stricturing, ileocaecal Crohn's disease, in whom conventional therapy has failed were randomly allocated (1:1) by an internet randomisation module with biased-coin minimisation for participating centres and perianal fistula to receive laparoscopic ileocaecal resection or infliximab. Eligible patients were aged 18-80 years, had active Crohn's disease of the terminal ileum, and had not responded to at least 3 months of conventional therapy with glucocorticosteroids, thiopurines, or methotrexate. Patients with diseased terminal ileum longer than 40 cm or abdominal abscesses were excluded. The primary outcome was quality of life on the Inflammatory Bowel Disease Questionnaire (IBDQ) at 12 months. Secondary outcomes were general quality of life, measured by the Short Form-36 (SF-36) health survey and its physical and mental component subscales, days unable to participate in social life, days on sick leave, morbidity (additional procedures and hospital admissions), and body image and cosmesis. Analyses of the primary outcome were done in the intention-to-treat population, and safety analyses were done in the per-protocol population. This trial is registered at the Dutch Trial Registry (NTR1150). FINDINGS: Between May 2, 2008, and October 14, 2015, 73 patients were allocated to have resection and 70 to receive infliximab. Corrected for baseline differences, the mean IBDQ score at 12 months was 178·1 (95% CI 171·1-185·0) in the resection group versus 172·0 (164·3-179·6) in the infliximab group (mean difference 6·1 points, 95% CI -4·2 to 16·4; p=0·25). At 12 months, the mean SF-36 total score was 112·1 (95% CI 108·0-116·2) in the resection group versus 106·5 (102·1-110·9) in the infliximab group (mean difference 5·6, 95% CI -0·4 to 11·6), the mean physical component score was 47·7 (45·7-49·7) versus 44·6 (42·5-46·8; mean difference 3·1, 4·2 to 6·0), and the mean mental component score was 49·5 (47·0-52·1) versus 46·1 (43·3-48·9; mean difference 3·5, -0·3 to 7·3). Mean numbers of days of sick leave were 3·4 days (SD 7·1) in the resection group versus 1·4 days (4·7) in the infliximab group (p<0·0001), days not able to take part in social life were 1·8 days (6·3) versus 1·1 days (4·5; p=0·20), days of scheduled hospital admission were 6·5 days (3·8) versus 6·8 days (3·2; p=0·84), and the number of patients who had unscheduled hospital admissions were 13 (18%) of 73 versus 15 (21%) of 70 (p=0·68). Body-image scale mean scores in the patients who had resection were 16·0 (95% CI 15·2-16·8) at baseline versus 17·8 (17·1-18·4) at 12 months, and cosmetic scale mean scores were 17·6 (16·6-18·6) versus 18·6 (17·6-19·6). Surgical intervention-related complications classified as IIIa or worse on the Clavien-Dindo scale occurred in four patients in the resection group. Treatment-related serious adverse events occurred in two patients in the infliximab group. During a median follow-up of 4 years (IQR 2-6), 26 (37%) of 70 patients in the infliximab group had resection, and 19 (26%) of 73 patients in the resection group received anti-TNF. INTERPRETATION: Laparoscopic resection in patients with limited (diseased terminal ileum <40 cm), non-stricturing, ileocaecal Crohn's disease in whom conventional therapy has failed could be considered a reasonable alternative to infliximab therapy. FUNDING: Netherlands Organisation for Health Research and Development.

Burden of disease and increasing prevalence of inflammatory bowel disease in a population-based cohort in the Netherlands.

BACKGROUND: Reported epidemiology and phenotype distributions vary widely and disease burden of inflammatory bowel disease (IBD) is poorly described. Our aim was to establish these features in a population-based cohort covering 319 976 inhabitants. Furthermore, differences between tertiary referral and peripheral hospital patients were quantified. METHODS: IBD patients in the adherence area of three peripheral hospitals (2004-2012) were included. Medical and surgical treatment data were obtained. Quality of life and disease activity were evaluated. An outpatient cohort from a tertiary referral centre was accrued. RESULTS: A total of 1461 patients were included: 761 (52.1%) with ulcerative colitis (UC), 579 (39.5%) with Crohn's disease (CD) and 121 (8.3%) with IBD-unspecified. Point prevalence of IBD was 432.1 per 100 000 inhabitants in 2010, which increased significantly over time, P-value of less than 0.0001. The mean annual incidence was 17.2 for UC, 10.5 for CD and 2.2 for IBD-unspecified. Tertiary referral Crohn's patients used thiopurines and biological therapy and underwent surgery significantly more often than patients in peripheral hospitals (P<0.0001). Disease activity correlated negatively with quality of life (P<0.0001) in UC and CD. CONCLUSION: The prevalence of IBD is still increasing. Burden of disease was significantly more severe, mainly in Crohn's patients, in the referral centre, highlighting the importance of population-based studies to accurately describe phenotype distribution and disease burden.

Single-Port Surgery in Inflammatory Bowel Disease: A Review of Current Evidence.

The majority of patients with Crohn's disease and up to 35 % of patients with ulcerative colitis will ultimately require surgery during the course of their disease. Over the past few years, surgical techniques and experience in minimal invasive surgery have evolved resulting in single-incision laparoscopic surgery. The aim of this approach is to diminish the surgical trauma by reducing the number of incision sites. This review discusses the benefits and disadvantages of single-port surgery in various procedures in patients with inflammatory bowel disease (IBD). Short-term postoperative results, functional outcome, and costs available in the literature will be discussed. Single-port surgery in IBD has several benefits when compared to multi-port laparoscopic surgery. By using fewer incisions, a potential reduction of postoperative pain with less morphine use can be accomplished. In addition, accelerated postoperative recovery can result in a shorter hospital stay. Furthermore, a superior cosmesis can be reached with placement of the port at the future ostomy site or at the umbilicus. Literature on single-port surgery in IBD consists mainly of case series and a few matched case series. These studies demonstrated that single-port surgery seems to be a safe and feasible approach for the surgical treatment of IBD patients.

Multimodal treatment of perianal fistulas in Crohn's disease: seton versus anti-TNF versus advancement plasty (PISA): study protocol for a randomized controlled trial.

BACKGROUND: Currently there is no guideline for the treatment of patients with Crohn's disease and high perianal fistulas. Most patients receive anti-TNF medication, but no long-term results of this expensive medication have been described, nor has its efficiency been compared to surgical strategies. With this study, we hope to provide treatment consensus for daily clinical practice with reduction in costs. METHODS/DESIGN: This is a multicentre, randomized controlled trial. Patients with Crohn's disease who are over 18 years of age, with newly diagnosed or recurrent active high perianal fistulas, with one internal opening and no anti-TNF usage in the past three months will be considered. Patients with proctitis, recto-vaginal fistulas or anal stenosis will be excluded. Prior to randomisation, an MRI and ileocolonoscopy are required. All treatment will start with seton placement and a course of antibiotics. Patients will then be randomised to: (1) chronic seton drainage (with oral 6-mercaptopurine (6MP)) for one year, (2) anti-TNF medication (with 6MP) for one year (seton removal after six weeks) or (3) advancement plasty after eight weeks of seton drainage (under four months anti-TNF and 6MP for one year). The primary outcome parameter is the number of patients needing fistula-related re-intervention(s). Secondary outcomes are the number of patients with closed fistulas (based on an evaluated MRI score) after 18 months, disease activity, quality of life and costs. DISCUSSION: The PISA trial is a multicentre, randomised controlled trial of patients with Crohn's disease and high perianal fistulas. With the comparison of three generally accepted treatment strategies, we will be able to comment on the efficiency of the various treatment strategies, with respect to several long-term outcome parameters. TRIAL REGISTRATION: Nederlands Trial Register identifier: NTR4137 (registered on 23 August 2013).

Abdominal abscess in Crohn's disease: multidisciplinary management.

Crohn's disease (CD) is characterized by full-thickness inflammation of the bowel. For this reason, perforating complications such as intra-abdominal abscesses or fistulas are common. A concomitant intra-abdominal abscess with active CD of the small bowel is a challenging dilemma for gastroenterologists and surgeons. Since there is active and severe disease, this should be treated with immunosuppressive drugs. However, in the presence of an intra-abdominal abscess, immunosuppression can be dangerous. There are several treatment options for intra-abdominal abscesses in CD. Nowadays, the first-line treatment is antibiotic therapy with or without percutaneous drainage. Historically, patients were treated with surgical drainage. With the development of percutaneous drainage, treatment shifted to a more nonsurgical approach. Success rates for percutaneous drainage in the literature vary from 74 to 100%, and it is considered to be a relatively safe procedure. It has been reported that surgery can be avoided after successful percutaneous drainage in a variable number of patients (14-85%). If sepsis is controlled, CD medication should be started to prevent recurrence. It is important to monitor the effect upon CD lesions to avoid further perforating complications. Finally, an undrainable or small abscess can be treated with antibiotics alone, although high recurrence rates have been described with this approach. Patients with a concomitant stenosis, an enterocutaneous fistula or refractory active disease are likely to require surgery. Percutaneous drainage in combination with delayed surgery is useful to improve the patient's condition prior to surgery and is associated with less morbidity, a lower stoma rate and more limited resection. In conclusion, when feasible, percutaneous drainage and antibiotics should be the treatment of choice in patients with an intra-abdominal abscess in CD. If surgery is inevitable, this must be delayed to reduce postoperative septic complications and high stoma rates.

The effect of breast hypertrophy on patient posture.

BACKGROUND: One of the reasons women with macromastia chose to undergo a breast reduction is to relieve their complaints of back, neck, and shoulder pain. We hypothesized that changes in posture after surgery may be the reason for the pain relief and that patient posture may correlate with symptomatic macromastia and may serve as an objective measure for complaints. The purpose of our study was to evaluate the effect of reduction mammaplasty on the posture of women with macromastia. METHODS: A prospective controlled study at a university medical center. Forty-two patients that underwent breast reduction were studied before surgery and an average of 4.3 years following surgery. Thirty-seven healthy women served as controls. Standardized lateral photos were taken. The inclination angle of the back was measured. Regression analysis was performed for the inclination angle. RESULTS: Preoperatively, the mean inclination angle was 1.61 degrees ventrally; this diminished postoperatively to 0.72 degrees ventrally. This change was not significant (P-value=0.104). In the control group that angle was 0.28 degrees dorsally. Univariate regression analysis revealed that the inclination was dependent on body mass index (BMI) and having symptomatic macromastia; on multiple regression it was only dependent on BMI. CONCLUSIONS: The inclination angle of the back in breast reduction candidates is significantly different from that of controls; however, this difference is small and probably does not account for the symptoms associated with macromastia. Back inclination should not be used as a surrogate "objective" measure for symptomatic macromastia.