Ustekinumab as induction and maintenance therapy for ulcerative colitis - national extended follow-up and a review of the literature.

INTRODUCTION: Ustekinumab use in ulcerative colitis had shown low adverse event and high persistence rates to 3 years via the UNIFI long-term extension study. Outcomes beyond 3 years have not been previously described. We describe the safety signals of the entire UNIFI Australian population beyond 3 years. METHODS: This retrospective multicenter observational cohort study recruited from all Australian UNIFI centers. The primary outcome was safety via adverse events. Secondary outcomes included the clinical relapse rate on ustekinumab, and the need to switch from ustekinumab to an alternate agent. RESULTS: There were 14 patients [11 male, mean age 47 (±14) years], with a median diagnosis of 10.8 (±4.5) years prior to UNIFI enrollment. Median follow-up was 298 weeks (5.7 years) (Interquartile range (IQR): 220-311 weeks). Within the long-term extension, there were three serious adverse events and one minor event. 42.9% (6/14) patients had clinical relapses, of which clinical remission was recaptured in 83.3% (5/6). 85.7% (12/14) persisted on ustekinumab in the long-term, with 7.1% (1/14) electively ceasing ustekinumab and 7.1% (1/14) changed from ustekinumab due to clinical relapse. CONCLUSION: For moderate-to-severe UC in Australia, ustekinumab maintained efficacy beyond 3 years with a high persistence rate and no new safety signals. TRIAL REGISTRATION: The trial is registered at ANZCTR (identifier: ACTRN12622001332718).

Effect of the use of earplugs and eye masks on the quality of sleep after major abdominal surgery: a randomised controlled trial.

Significant sleep disturbance can occur following major abdominal surgery. We aimed to evaluate the effectiveness of earplugs and eye masks in improving sleep quality and patient satisfaction, reducing nursing demands and in the incidence of delirium in patients after major abdominal surgery. We conducted a randomised controlled trial in 100 patients undergoing major abdominal surgery. We randomly allocated participants to sleep with or without earplugs and eye masks on postoperative days 1-3. The primary outcome measure was sleep quality as measured by the Richards-Campbell Sleep Questionnaire. Secondary outcomes were patient satisfaction, frequency of nursing demand and incidence of delirium measured by the Neelon and Champagne Confusion Scale. Median (IQR [range]) sleep scores were 64 (38-74 [0-100] and 60 (44-82 [18-100]) for the control and intervention groups, respectively (p = 0.310). Age and Pittsburgh Sleep Quality Index scores were found to be significant factors affecting sleep quality. There were no differences in patient satisfaction, reduction in frequency of nursing demands or incidence of delirium on postoperative days 1-3 after major abdominal surgery. The compliance rate in the intervention group was 60-65%. This study has demonstrated that the use of earplugs and eye masks did not contribute to improvements in sleep quality. Of note, sleep quality was moderate, with higher age and worse baseline sleep quality contributing to worse sleep scores. More studies are needed to investigate interventions to improve sleep quality after major abdominal surgery.

Efficacy of erector spinae plane block for analgesia in breast surgery: a systematic review and meta-analysis.

The erector spinae plane block is a new regional anaesthesia technique that provides truncal anaesthesia for breast surgery. This systematic review and meta-analysis was undertaken to determine if the erector spinae plane block is effective at reducing pain scores and opioid consumption after breast surgery. This study also evaluated the outcomes of erector spinae plane blocks compared with other regional blocks. PubMed, Embase, Scopus, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov were searched. We included randomised controlled trials reporting the use of the erector spinae plane block in adult breast surgery. Risk of bias was assessed with the revised Cochrane risk-of-bias tool. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework was used to assess trial quality. Thirteen randomised controlled trials (861 patients; 418 erector spinae plane block, 215 no blocks, 228 other blocks) were included. Erector spinae plane block reduced postoperative pain compared with no block: at 0-2 hours (mean difference (95% CI) -1.63 (-2.97 to -0.29), 6 studies, 329 patients, high-quality evidence, I2  = 98%, p = 0.02); at 6 hours (mean difference (95% CI) -0.90 (-1.49 to -0.30), 5 studies, 250 patients, high-quality evidence, I2  = 91%, p = 0.003); at 12 hours (mean difference (95% CI) -0.46 (-0.67 to -0.25), 5 studies, 250 patients, high-quality evidence, I2  = 58%, p < 0.0001); and at 24 hours (mean difference (95% CI) -0.50 (-0.70 to -0.30), 6 studies, 329 patients, high-quality evidence, I2  = 76%, p < 0.00001). Compared with no block, erector spinae plane block also showed significantly lower postoperative oral morphine equivalent requirements (mean difference (95% CI) -21.55mg (-32.57 to -10.52), 7 studies, 429 patients, high-quality evidence, I2  = 99%, p = 0.0001). Separate analysis of studies comparing erector spinae plane block with pectoralis nerve block and paravertebral block showed that its analgesic efficacy was inferior to pectoralis nerve block and similar to paravertebral block. The incidence of pneumothorax was 2.6% in the paravertebral block group; there were no reports of complications of the other blocks. This review has shown that the erector spinae plane block is more effective at reducing postoperative opioid consumption and pain scores up to 24 hours compared with general anaesthesia alone. However, it was inferior to the pectoralis nerve block and its efficacy was similar to paravertebral block. Further evidence, preferably from properly blinded trials, is required to confirm these findings.

Systematic review and meta-analysis: assessment of factors affecting disability in inflammatory bowel disease and the reliability of the inflammatory bowel disease disability index.

BACKGROUND: The Inflammatory Bowel Disease Disability Index (IBD-DI) has recently been developed for patients with Crohn's disease (CD) and ulcerative colitis (UC). AIM: To assess the severity of disability and associated factors using the IBD-DI, and review the validity of the IBD-DI as a tool. METHOD: Systematic review of cross-sectional studies. Patients included had UC or CD and were classified as active, in remission, or needing surgery, biological and/or steroid treatment. We included studies assessing disability using the IBD-DI and that were captured by electronic and manual searches (January 2017). The possibility of bias was evaluated with the Newcastle-Ottawa Scale. RESULTS: Nine studies were included with 3167 patients. Comparatively, patients with active disease had higher disability rates than those in remission (SMD [CI95] = 1.49[1.11, 1.88], I2  = 94%, P<.01), while patients on biological treatment had lower disability rates than those receiving corticosteroid treatment (SMD [CI95] = -0.22[-0.36, -0.08], I2  = 0%, P<.01). Disease activity and unemployment were found to be associated factors. The IBD-DI scored "good" for internal consistency, "fair" to "excellent" for intra-rater reliability and "excellent" for inter-rater reliability. Construct validity was "moderately strong" to "very strong" and structural validity was found to be mainly unidimensional. The IBD-DI had excellent responsiveness, while its interpretability was only useful on a group level. CONCLUSIONS: This systematic review and meta-analysis found a significant association between disease activity, treatment received and disability; although significant heterogeneity was found. The IBD-DI is reliable and valid, but further studies are needed to measure its interpretability.

Review article: consensus statements on therapeutic drug monitoring of anti-tumour necrosis factor therapy in inflammatory bowel diseases.

BACKGROUND: Therapeutic drug monitoring (TDM) in inflammatory bowel disease (IBD) patients receiving anti-tumour necrosis factor (TNF) agents can help optimise outcomes. Consensus statements based on current evidence will help the development of treatment guidelines. AIM: To develop evidence-based consensus statements for TDM-guided anti-TNF therapy in IBD. METHODS: A committee of 25 Australian and international experts was assembled. The initial draft statements were produced following a systematic literature search. A modified Delphi technique was used with 3 iterations. Statements were modified according to anonymous voting and feedback at each iteration. Statements with 80% agreement without or with minor reservation were accepted. RESULTS: 22/24 statements met criteria for consensus. For anti-TNF agents, TDM should be performed upon treatment failure, following successful induction, when contemplating a drug holiday and periodically in clinical remission only when results would change management. To achieve clinical remission in luminal IBD, infliximab and adalimumab trough concentrations in the range of 3-8 and 5-12 µg/mL, respectively, were deemed appropriate. The range may differ for different disease phenotypes or treatment endpoints-such as fistulising disease or to achieve mucosal healing. In treatment failure, TDM may identify mechanisms to guide subsequent decision-making. In stable clinical response, TDM-guided dosing may avoid future relapse. Data indicate drug-tolerant anti-drug antibody assays do not offer an advantage over drug-sensitive assays. Further data are required prior to recommending TDM for non-anti-TNF biological agents. CONCLUSION: Consensus statements support the role of TDM in optimising anti-TNF agents to treat IBD, especially in situations of treatment failure.

Systematic review with meta-analysis: breastfeeding and the risk of Crohn's disease and ulcerative colitis.

BACKGROUND: Breastfeeding is a modifiable factor that may influence development of inflammatory bowel diseases. However, literature on this has been inconsistent and not accounted for heterogeneity in populations and exposure. AIM: To conduct a meta-analysis to examine the association between breastfeeding in infancy and risk of Crohn's disease (CD) and ulcerative colitis (UC). METHODS: A systematic search of Medline/PubMed and Embase was performed for full text, English-language literature through November 2016. Studies were included if they described breastfeeding in infancy in patients with CD or UC, and healthy controls. Data were pooled using a random effects model for analysis. RESULTS: A total of 35 studies were included in the final analysis, comprising 7536 individuals with CD, 7353 with UC and 330 222 controls. Ever being breastfed was associated with a lower risk of CD (OR 0.71, 95% CI 0.59-0.85) and UC (OR 0.78, 95% CI 0.67-0.91). While this inverse association was observed in all ethnicity groups, the magnitude of protection was significantly greater among Asians (OR 0.31, 95% CI 0.20-0.48) compared to Caucasians (OR 0.78, 95% CI 0.66-0.93; P = .0001) in CD. Breastfeeding duration showed a dose-dependent association, with strongest decrease in risk when breastfed for at least 12 months for CD (OR 0.20, 95% CI 0.08-0.50) and UC (OR 0.21, 95% CI 0.10-0.43) as compared to 3 or 6 months. CONCLUSION: Breastfeeding in infancy protects against the development of CD and ulcerative colitis.

Disability in Restorative Proctocolectomy Recipients Measured using the Inflammatory Bowel Disease Disability Index.

BACKGROUND AND AIMS: The inflammatory bowel disease [IBD] disability index [IBD-DI], which measures IBD-associated disability, has been validated on IBD patients but not those who have had restorative proctocolectomy with ileal pouch-anal anastomosis [RP with IPAA]. This study aimed to utilize the IBD-DI in RP with IPAA recipients and compare ulcerative colitis [UC]-indicated RP with IPAA patients to medically treated UC patients. METHODS: This study was population based. Demographic, indication, complication and direct cost data were collected via medical records while disability, quality of life [QoL] and indirect costs were measured using questionnaires and structured interviews. De-identified raw data about medically treated UC patients were provided by a previous study for comparison. RESULTS: In total there were 136 RP with IPAA patients [mean 11.5 years of follow up]. Eighty-four completed the IBD-DI and 80 completed the IBD questionnaire [IBDQ]. The IBDQ and IBD-DI were highly correlated [r = 0.84, p < 0.01]. Worse QoL and disability were found in those who had their position affected at work [both p < 0.01] and those who had more than 100 days off work in the last year [p < 0.01 for QoL and p = 0.012 for disability]. Lower QoL and disability scores were associated with higher indirect and total costs [p < 0.01]. UC patients treated with RP with IPAA had less disability than medically treated UC patients [p = 0.04]. CONCLUSIONS: Disability in RP with IPAA recipients can be measured using the IBD-DI. Perioperative complications and high costs of care are associated with higher levels of disability. Disability of RP with IPAA recipients was lower than that of medically managed UC patients.

Review article: acute severe ulcerative colitis - evidence-based consensus statements.

BACKGROUND: Acute severe ulcerative colitis (ASUC) is a potentially life-threatening complication of ulcerative colitis. AIM: To develop consensus statements based on a systematic review of the literature of the management of ASUC to improve patient outcome. METHODS: Following a literature review, the Delphi method was used to develop the consensus statements. A steering committee, based in Australia, generated the statements of interest. Three rounds of anonymous voting were carried out to achieve the final results. Acceptance of statements was pre-determined by ≥80% votes in 'complete agreement' or 'agreement with minor reservation'. RESULTS: Key recommendations include that patients with ASUC should be: hospitalised, undergo unprepared flexible sigmoidoscopy to assess severity and to exclude cytomegalovirus colitis, and be provided with venous thromboembolism prophylaxis and intravenous hydrocortisone 100 mg three or four times daily with close monitoring by a multidisciplinary team. Rescue therapy such as infliximab or ciclosporin should be started if insufficient response by day 3, and colectomy considered if no response to 7 days of rescue therapy or earlier if deterioration. With such an approach, it is expected that colectomy rate during admission will be below 30% and mortality less than 1% in specialist centres. CONCLUSION: These evidenced-based consensus statements on acute severe ulcerative colitis, developed by a multidisciplinary group, provide up-to-date best practice recommendations that improve and harmonise management as well as provide auditable quality assessments.

Efficacy of thiopurines and adalimumab in preventing Crohn's disease recurrence in high-risk patients - a POCER study analysis.

BACKGROUND: Crohn's disease recurs in the majority of patients after intestinal resection. AIM: To compare the relative efficacy of thiopurines and anti-TNF therapy in patients at high risk of disease recurrence. METHODS: As part of a larger study comparing post-operative management strategies, patients at high risk of recurrence (smoker, perforating disease, ≥2nd operation) were treated after resection of all macroscopic disease with 3 months metronidazole together with either azathioprine 2 mg/kg/day or mercaptopurine 1.5 mg/kg/day. Thiopurine-intolerant patients received adalimumab induction then 40 mg fortnightly. Patients underwent colonoscopy at 6 months with endoscopic recurrence assessed blind to treatment. RESULTS: A total of 101 patients [50% male; median (IQR) age 36 (25-46) years] were included. There were no differences in disease history between thiopurine- and adalimumab-treated patients. Fifteen patients withdrew prior to 6 months, five due to symptom recurrence (of whom four were colonoscoped). Endoscopic recurrence (Rutgeerts score i2-i4) occurred in 33 of 73 (45%) thiopurine vs. 6 of 28 (21%) adalimumab-treated patients [intention-to-treat (ITT); P = 0.028] or 24 of 62 (39%) vs. 3 of 24 (13%) respectively [per-protocol analysis (PPA); P = 0.020]. Complete mucosal endoscopic normality (Rutgeerts i0) occurred in 17/73 (23%) vs. 15/28 (54%) (ITT; P = 0.003) and in 27% vs. 63% (PPA; P = 0.002). The most advanced disease (Rutgeerts i3 and i4) occurred in 8% vs. 4% (thiopurine vs. adalimumab). CONCLUSIONS: In Crohn's disease patients at high risk of post-operative recurrence adalimumab is superior to thiopurines in preventing early disease recurrence.

Ulcerative colitis outpatient management: development and evaluation of tools to support primary care practitioners.

BACKGROUND: Current models of care for ulcerative colitis (UC) across healthcare systems are inconsistent with a paucity of existing guidelines or supportive tools for outpatient management. AIMS: This study aimed to produce and evaluate evidence-based outpatient management tools for UC to guide primary care practitioners and patients in clinical decision-making. METHODS: Three tools were developed after identifying current gaps in the provision of healthcare services for patients with UC at a Clinical Insights Meeting in 2013. Draft designs were further refined through consultation and consolidation of feedback by the steering committee. Final drafts were developed following feasibility testing in three key stakeholder groups (gastroenterologists, general practitioners and patients) by questionnaire. The tools were officially launched into mainstream use in Australia in 2014. RESULTS: Three quarters of all respondents liked the layout and content of each tool. Minimal safety concerns were aired and those, along with pieces of information that were felt to be omitted, that were reviewed by the steering committee and incorporated into the final documents. The majority (over 80%) of respondents felt that the tools would be useful and would improve outpatient management of UC. CONCLUSION: Evidence-based outpatient clinical management tools for UC can be developed. The concept and end-product have been well received by all stakeholder groups. These tools should support non-specialist clinicians to optimise UC management and empower patients by facilitating them to safely self-manage and identify when medical support is needed.

Smoking prevalence and its influence on disease course and surgery in Crohn's disease and ulcerative colitis.

BACKGROUND: Smoking demonstrates divergent effects in Crohn's disease (CD) and ulcerative colitis (UC). Smoking frequency is greater in CD and deleterious to its disease course. Conversely, UC is primarily a disease of nonsmokers and ex-smokers, with reports of disease amelioration in active smoking. AIM: To determine the prevalence of smoking and its effects on disease progression and surgery in a well-characterised cohort of inflammatory bowel diseases (IBD) patients. METHODS: Patients with smoking data of the Sydney IBD Cohort were included. Demographic, phenotypic, medical, surgical and hospitalisation data were analysed and reported on the basis of patient smoking status. RESULTS: 1203 IBD patients were identified comprising 626 CD and 557 UC with 6725 and 6672 patient-years of follow-up, respectively. CD patients were more likely to smoke than UC patients (19.2% vs. 10.2%, P < 0.001). A history of smoking in CD was associated with an increased proportional surgery rate (45.8% vs. 37.8%, P = 0.045), requirement for IBD-related hospitalisation (P = 0.009) and incidence of peripheral arthritis (29.8% vs. 22.0%, P = 0.027). Current smokers with UC demonstrated reduced corticosteroid utilisation (24.1% vs. 37.5%, P = 0.045), yet no reduction in the rates of colectomy (3.4% vs. 6.6%, P = 0.34) or hospital admission (P = 0.25) relative to nonsmokers. Ex-smokers with UC required proportionately greater immunosuppressive (36.2% vs. 26.3%, P = 0.041) and corticosteroid (43.7% vs. 34.5%, P = 0.078) therapies compared with current and never smokers. CONCLUSIONS: This study confirms the detrimental effects of smoking in CD, yet failed to demonstrate substantial benefit from smoking in UC. These data should encourage all patients with IBD to quit smoking.

Detection and density estimation of goblet cells in confocal endoscopy for the evaluation of celiac disease.

Celiac Disease (CD) is an immune-mediated enteropathy, diagnosed in the clinical practice by intestinal biopsy and the concomitant presence of a positive celiac serology. Confocal Laser Endomicroscopy (CLE) allows skilled and trained experts to potentially perform in vivo virtual histology of small-bowel mucosa. In particular, it allows the qualitative evaluation of mucosa alteration such as a decrease in goblet cells density, presence of villous atrophy or crypt hypertrophy. We present a semi-automatic computer-based method for the detection of goblet cells from confocal endoscopy images, whose density changes in case of pathological tissue. After a manual selection of a suitable region of interest, the candidate columnar and goblet cells' centers are first detected and the cellular architecture is estimated from their position using a Voronoi diagram. The region within each Voronoi cell is then analyzed and classified as goblet cell or other. The results suggest that our method is able to detect and label goblet cells immersed in a columnar epithelium in a fast, reliable and automatic way. Accepting 0.44 false positives per image, we obtain a sensitivity value of 90.3%. Furthermore, estimated and real goblet cell densities are comparable (error: 9.7 ± 16.9%, correlation: 87.2%, R(2) = 76%).

Semiautomatic detection of villi in confocal endoscopy for the evaluation of celiac disease.

Celiac Disease (CD) is an immune-mediated enteropathy, diagnosed in the clinical practice by intestinal biopsy and the concomitant presence of a positive celiac serology. Confocal Laser Endomicroscopy (CLE) allows skilled and trained experts to potentially perform in vivo virtual histology of small-bowel mucosa. In particular, it allows the qualitative evaluation of mucosa alteration such as a decrease in goblet cells density, presence of villous atrophy or crypt hypertrophy. We present a semi-automatic method for villi detection from confocal endoscopy images, whose appearance change in case of villous atrophy. Starting from a set of manual seeds, a first rough segmentation of the villi is obtained by means of mathematical morphology operations. A merge and split procedure is then performed, to ensure that each seed originates a different region in the final segmentation. A border refinement process is finally performed, evolving the shape of each region according to local gradient intensities. Mean and median Dice coefficients for 290 villi originating from 66 images when compared to manually obtained ground truth are 80.71% and 87.96% respectively.

Review article: Ulcerative colitis, smoking and nicotine therapy.

BACKGROUND: Smoking is the best-characterised environmental association of ulcerative colitis (UC). Smoking has been observed to exert protective effects on both the development and progression of UC. AIMS: To examine the association between UC and smoking, possible pathogenic mechanisms and the potential of nicotine as a therapeutic agent in the treatment of UC. METHODS: A literature search was conducted through MEDLINE, using the MeSH search terms 'ulcerative colitis' and 'smoking' or 'nicotine'. Relevant articles were identified through manual review. The reference lists of these articles were reviewed to include further appropriate articles. RESULTS: Ulcerative colitis is less prevalent in smokers. Current smokers with a prior diagnosis of UC are more likely to exhibit milder disease than ex-smokers and nonsmokers. There is conflicting evidence for smokers having reduced rates of hospitalisation, colectomy and need for oral corticosteroids and immunosuppressants to manage their disease. Multiple potential active mediators in smoke may be responsible for these clinical effects, including nicotine and carbon monoxide, but the precise mechanism remains unknown. Nicotine has demonstrated variable efficacy in the induction of remission in UC when compared to placebo and conventional medicines. Despite this, the high frequency of adverse events limits its clinical significance. CONCLUSIONS: Nicotine's application as a therapeutic treatment in ulcerative colitis is limited. Presently, it may be an option considered only in selected cases of acute ulcerative colitis refractory to conventional treatment options. This review also questions whether nicotine is the active component of smoking that modifies risk and inflammation in ulcerative colitis.

Patients' knowledge of pregnancy-related issues in inflammatory bowel disease and validation of a novel assessment tool ('CCPKnow').

BACKGROUND: Inflammatory bowel diseases (IBD) require complex therapeutic decisions and life choices concerning pregnancy, but little is known about patient's knowledge of IBD and its treatment before and during pregnancy. AIM: To develop a novel tool (Crohn's and Colitis Pregnancy Knowledge Score 'CCPKnow') to assess knowledge of pregnancy-related issues in IBD. The validated tool was then applied to determine knowledge in patients. METHOD: Discriminate ability of 'CCPKnow' was validated in four groups with different levels of IBD knowledge. Reliability and readability were tested by Cronbach-α and Flesch-Kencaid. Construct validity was subsequently assessed against general IBD knowledge (CCKnow) in 145 women with IBD. Associations between patient factors and knowledge were studied. RESULTS: Median CCPKnow scores differed significantly between the validation groups (P < 0.001). CCPKnow displayed excellent internal consistency, reliability (Cronbach-α 0.94), readability (reading age 9 years) and close correlation with CCKnow (Spearman's ρ 0.64; P < 0.001). Of 145 patients, 44.8% had poor, 27.6% adequate, 17.3% good and only 10.3% very good knowledge. Better knowledge was associated with Caucasian ethnicity, higher income, having a partner, having children, Crohn's and Colitis Association membership, longer disease duration and Crohn's disease. CONCLUSIONS: Crohn's and Colitis Pregnancy Knowledge Score, a novel knowledge assessment tool of pregnancy and IBD, demonstrated excellent test characteristics. We found that nearly half of the women with IBD had poor knowledge, identifying a pressing need for better education.