Perianal Fistulizing Crohn's Disease-Associated Anorectal and Fistula Cancers: Systematic Review and Expert Consensus.

BACKGROUND & AIMS: Perianal fistulizing Crohn's disease (PFCD)-associated anorectal and fistula cancers are rare but often devastating diagnoses. However, given the low incidence and consequent lack of data and clinical trials in the field, there is little to no guidance on screening and management of these cancers. To inform clinical practice, we developed consensus guidelines on PFCD-associated anorectal and fistula cancers by multidisciplinary experts from the international TOpClass consortium. METHODS: We conducted a systematic review by standard methodology, using the Newcastle-Ottawa Scale quality assessment tool. We subsequently developed consensus statements using a Delphi consensus approach. RESULTS: Of 561 articles identified, 110 were eligible, and 76 articles were included. The overall quality of evidence was low. The TOpClass consortium reached consensus on 6 structured statements addressing screening, risk assessment, and management of PFCD-associated anorectal and fistula cancers. Patients with long-standing (>10 years) PFCD should be considered at small but increased risk of developing perianal cancer, including squamous cell carcinoma of the anus and anorectal carcinoma. Risk factors for squamous cell carcinoma of the anus, notably human papilloma virus, should be considered. New, refractory, or progressive perianal symptoms should prompt evaluation for fistula cancer. There was no consensus on timing or frequency of screening in patients with asymptomatic perianal fistula. Multiple modalities may be required for diagnosis, including an examination under anesthesia with biopsy. Multidisciplinary team efforts were deemed central to the management of fistula cancers. CONCLUSIONS: Inflammatory bowel disease clinicians should be aware of the risk of PFCD-associated anorectal and fistula cancers in all patients with PFCD. The TOpClass consortium consensus statements outlined herein offer guidance in managing this challenging scenario.

Artificial intelligence for discrimination of Crohn's disease and gastrointestinal tuberculosis: A systematic review.

BACKGROUND AND AIM: Discrimination of gastrointestinal tuberculosis (GITB) and Crohn's disease (CD) is difficult. Use of artificial intelligence (AI)-based technologies may help in discriminating these two entities. METHODS: We conducted a systematic review on the use of AI for discrimination of GITB and CD. Electronic databases (PubMed and Embase) were searched on June 6, 2022, to identify relevant studies. We included any study reporting the use of clinical, endoscopic, and radiological information (textual or images) to discriminate GITB and CD using any AI technique. Quality of studies was assessed with MI-CLAIM checklist. RESULTS: Out of 27 identified results, a total of 9 studies were included. All studies used retrospective databases. There were five studies of only endoscopy-based AI, one of radiology-based AI, and three of multiparameter-based AI. The AI models performed fairly well with high accuracy ranging from 69.6-100%. Text-based convolutional neural network was used in three studies and Classification and regression tree analysis used in two studies. Interestingly, irrespective of the AI method used, the performance of discriminating GITB and CD did not match in discriminating from other diseases (in studies where a third disease was also considered). CONCLUSION: The use of AI in differentiating GITB and CD seem to have acceptable accuracy but there were no direct comparisons with traditional multiparameter models. The use of multiple parameter-based AI models have the potential for further exploration in search of an ideal tool and improve on the accuracy of traditional models.

Top 10 research priorities for digital technology for adolescents and young persons with inflammatory bowel disease: Results of a James Lind Alliance Priority Setting Partnership.

OBJECTIVES: Priority Setting Partnerships (PSP's) using the James Lind Alliance (JLA) methodology, bring together health professionals, patients and parents/carers to identify and prioritise unanswered questions that can be addressed by future research projects. To identify and prioritise the top 10 unanswered research priorities in digital technology for adolescents and young people (AYP) with inflammatory bowel disease (IBD). METHODS: A steering group (SG) consisting of AYP with IBD, their parents/carers, representatives from two charities (Crohn's & Colitis UK, Crohn's in Childhood Research Association), patient information forum and paediatric and adult and primary care healthcare professionals was established in 2021. The SG agreed the protocol, and scope of the PSP and oversaw all aspects. SG meetings were chaired by a JLA advisor and followed the established JLA methodology. RESULTS: The initial survey generated 414 in-scope questions from 156 respondents, thematically categorised into 10 themes and consolidated into 92 summary questions by the SG. A comprehensive literature review followed by SG deliberation narrowed the unanswered summary questions to 45, for the interim prioritising survey. One hundred and two respondents ranked their top 10 research questions. Outputs generated top 18 research priorities presented at a final virtual prioritisation workshop, facilitated by JLA advisors and attended by key stakeholders, ranked into top 10 research priorities. DISCUSSION: The top 10 research priorities will encourage researchers to undertake research that addresses these areas of unmet need for AYP living with IBD, their parents/carers and their healthcare professionals, thereby facilitating improved patient care.

Green endoscopy: British Society of Gastroenterology (BSG), Joint Accreditation Group (JAG) and Centre for Sustainable Health (CSH) joint consensus on practical measures for environmental sustainability in endoscopy.

GI endoscopy is highly resource-intensive with a significant contribution to greenhouse gas (GHG) emissions and waste generation. Sustainable endoscopy in the context of climate change is now the focus of mainstream discussions between endoscopy providers, units and professional societies. In addition to broader global challenges, there are some specific measures relevant to endoscopy units and their practices, which could significantly reduce environmental impact. Awareness of these issues and guidance on practical interventions to mitigate the carbon footprint of GI endoscopy are lacking. In this consensus, we discuss practical measures to reduce the impact of endoscopy on the environment applicable to endoscopy units and practitioners. Adoption of these measures will facilitate and promote new practices and the evolution of a more sustainable specialty.

Vaccine escape, increased breakthrough and reinfection in infliximab-treated patients with IBD during the Omicron wave of the SARS-CoV-2 pandemic.

OBJECTIVE: Antitumour necrosis factor (TNF) drugs impair serological responses following SARS-CoV-2 vaccination. We sought to assess if a third dose of a messenger RNA (mRNA)-based vaccine substantially boosted anti-SARS-CoV-2 antibody responses and protective immunity in infliximab-treated patients with IBD. DESIGN: Third dose vaccine induced anti-SARS-CoV-2 spike (anti-S) receptor-binding domain (RBD) antibody responses, breakthrough SARS-CoV-2 infection, reinfection and persistent oropharyngeal carriage in patients with IBD treated with infliximab were compared with a reference cohort treated with vedolizumab from the impaCt of bioLogic therApy on saRs-cov-2 Infection and immuniTY (CLARITY) IBD study. RESULTS: Geometric mean (SD) anti-S RBD antibody concentrations increased in both groups following a third dose of an mRNA-based vaccine. However, concentrations were lower in patients treated with infliximab than vedolizumab, irrespective of whether their first two primary vaccine doses were ChAdOx1 nCoV-19 (1856 U/mL (5.2) vs 10 728 U/mL (3.1), p<0.0001) or BNT162b2 vaccines (2164 U/mL (4.1) vs 15 116 U/mL (3.4), p<0.0001). However, no differences in anti-S RBD antibody concentrations were seen following third and fourth doses of an mRNA-based vaccine, irrespective of the combination of primary vaccinations received. Post-third dose, anti-S RBD antibody half-life estimates were shorter in infliximab-treated than vedolizumab-treated patients (37.0 days (95% CI 35.6 to 38.6) vs 52.0 days (95% CI 49.0 to 55.4), p<0.0001).Compared with vedolizumab-treated, infliximab-treated patients were more likely to experience SARS-CoV-2 breakthrough infection (HR 2.23 (95% CI 1.46 to 3.38), p=0.00018) and reinfection (HR 2.10 (95% CI 1.31 to 3.35), p=0.0019), but this effect was uncoupled from third vaccine dose anti-S RBD antibody concentrations. Reinfection occurred predominantly during the Omicron wave and was predicted by SARS-CoV-2 antinucleocapsid concentrations after the initial infection. We did not observe persistent oropharyngeal carriage of SARS-CoV-2. Hospitalisations and deaths were uncommon in both groups. CONCLUSIONS: Following a third dose of an mRNA-based vaccine, infliximab was associated with attenuated serological responses and more SARS-CoV-2 breakthrough infection and reinfection which were not predicted by the magnitude of anti-S RBD responses, indicative of vaccine escape by the Omicron variant. TRIAL REGISTRATION NUMBER: ISRCTN45176516.

Effectiveness and Durability of COVID-19 Vaccination in 9447 Patients With IBD: A Systematic Review and Meta-Analysis.

BACKGROUND AND AIMS: The serological responses after severe acute respiratory syndrome coronavirus 2 vaccination may be attenuated in immunocompromised individuals. The study aimed to systematically evaluate the seroconversion rates after complete vaccination for coronavirus disease 2019 (COVID-19) in patients with inflammatory bowel disease (IBD). METHODS: Electronic databases were searched to identify studies reporting response to COVID-19 vaccination in IBD. Pooled seroconversion rates after complete vaccination were calculated. Subgroup analysis for vaccine types was also performed. Pooled seroconversion rates for various drugs or classes were also estimated. The pooled rates of breakthrough infections in vaccinated IBD patients were estimated. The pooled neutralization rates after complete vaccination were also estimated. The studies reporting durability of titers were systematically assessed. RESULTS: A total of 46 studies were included. The pooled seroconversion rate for complete vaccination (31 studies, 9447 patients) was 0.96 (95% confidence interval [CI], 0.94-0.97; I2 = 90%). When compared with healthy control subjects, the pooled relative risk of seroconversion was lower (0.98; 95% CI, 0.98-0.99; I2 = 39%). The pooled seroconversion rates were statistically similar among various drug classes. The pooled positivity of neutralization assays (8 studies, 771 participants) was 0.80 (95% CI, 0.70-0.87; I2 = 82%). The pooled relative risk of breakthrough infections in vaccinated IBD patients was similar to vaccinated control subjects (0.60; 95% CI, 0.25-1.42; I2 = 79%). Most studies suggested that titers fall after 4 weeks of COVID-19 vaccination, and the decay was higher in patients on anti-tumor necrosis factor alone or combination with immunomodulators. An additional dose of COVID-19 vaccine elicited serological response in most nonresponders to complete vaccination. CONCLUSIONS: Complete COVID-19 vaccination is associated with seroconversion in most patients with IBD. The decay in titers over time necessitates consideration of additional doses in these patients.

Validation and Update of the Lémann Index to Measure Cumulative Structural Bowel Damage in Crohn's Disease.

BACKGROUND & AIMS: The Lémann Index is a tool measuring cumulative structural bowel damage in Crohn's disease (CD). We reported on its validation and updating. METHODS: This was an international, multicenter, prospective, cross-sectional observational study. At each center, 10 inclusions, stratified by CD duration and location, were planned. For each patient, the digestive tract was divided into 4 organs, upper tract, small bowel, colon/rectum, anus, and subsequently into segments, explored systematically by magnetic resonance imaging and by endoscopies in relation to disease location. For each segment, investigators retrieved information on previous surgical procedures, identified predefined strictures and penetrating lesions of maximal severity (grades 1-3) at each organ investigational method (gastroenterologist and radiologist for magnetic resonance imaging), provided segmental damage evaluation ranging from 0.0 to 10.0 (complete resection). Organ resection-free cumulative damage evaluation was then calculated from the sum of segmental damages. Then investigators provided a 0-10 global damage evaluation from the 4-organ standardized cumulative damage evaluations. Simple linear regressions of investigator damage evaluations on their corresponding Lémann Index were studied, as well as calibration plots. Finally, updated Lémann Index was derived through multiple linear mixed models applied to combined development and validation samples. RESULTS: In 15 centers, 134 patients were included. Correlation coefficients between investigator damage evaluations and Lémann Indexes were >0.80. When analyzing data in 272 patients from both samples and 27 centers, the unbiased correlation estimates were 0.89, 0,97, 0,94, 0.81, and 0.91 for the 4 organs and globally, and stable when applied to one sample or the other. CONCLUSIONS: The updated Lémann Index is a well-established index to assess cumulative bowel damage in CD that can be used in epidemiological studies and disease modification trials.

Patient preferences for treatment in steroid resistant ulcerative colitis - a discrete-choice experiment.

BACKGROUND AND AIM: Understanding treatment preferences in those patients who are not responding to corticosteroids for ulcerative colitis is important in informing treatment choices. This study aimed to assess the relative importance of treatment characteristics to patients by conducting a discrete-choice experiment. METHODS: Patients completed the questionnaire online. All data were collected between September and December 2020. Participants were shown 13 discrete-choice experiment tasks - a series of side-by-side comparisons of competing, hypothetical treatment characteristics and asked to select a preferred treatment. Survey responses were analysed using descriptive statistics and regression analyses. RESULTS: 115 patients completed the study. Patient preferences were strongest for treatments with a lower chance of side effects, this attribute had the most influence on the choice of treatment patients preferred. The second most important attribute was an improvement in maintaining remission. Conversely, route and frequency of administration were least important on the choice of treatment patients preferred. Respondents were willing to make trade offs and accept treatment benefits to compensate them for receiving a treatment with a less desirable attribute level. Participants were willing to accept a larger benefit of 45% improvement in maintenance of remission to accept a treatment with a higher probability of side effects. The benefit required was smaller with a 10% improvement in remission required to accept a treatment with a lower probability of side effects. CONCLUSION: Quantifying preferences helps to identify and prioritise treatment characteristics that are important to patients. The results highlight the importance of careful discussion of side effects, including the magnitude of risk, using visualisation tools during a patient consultation to support decisions.

Benefits of Structured Pediatric to Adult Transition in Inflammatory Bowel Disease: The TRANSIT Observational Study.

OBJECTIVE: To evaluate the impact of structured transition from pediatric to adult inflammatory bowel disease (IBD) services on objective patient outcomes, including disease flares, admission rates, and healthcare resource use. METHODS: A retrospective observational study in 11 United Kingdom gastroenterology centers. Transition patients attended ≥2 visits to the gastroenterology service with both pediatric and adult personnel jointly present; non-transition patients transferred to adult services without joint visits. Data were collected from medical records for the 12-month periods before and after the date of the first visit involving adult IBD services (index visit). RESULTS: A total of 129 patients were included: 95 transition patients and 34 non-transition patients. In the 12 months post-index visit, transition patients had fewer disease flares (P  = 0.05), were more likely to be steroid-free (71% vs 41%, P < 0.05), and were less likely to have an emergency department visit leading to hospital admission (5% vs 18%, P < 0.05). During this period, the mean estimated overall cost of care per patient was £1644.22 in the transition group and £1827.32 in the non-transition group (P = 0.21). CONCLUSION: Structured transition from pediatric to adult IBD care services was associated with positive and cost-neutral outcomes in patients with pediatric IBD.

Infliximab is associated with attenuated immunogenicity to BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines in patients with IBD.

OBJECTIVE: Delayed second dose SARS-CoV-2 vaccination trades maximal effectiveness for a lower level of immunity across more of the population. We investigated whether patients with inflammatory bowel disease treated with infliximab have attenuated serological responses to a single dose of a SARS-CoV-2 vaccine. DESIGN: Antibody responses and seroconversion rates in infliximab-treated patients (n=865) were compared with a cohort treated with vedolizumab (n=428), a gut-selective anti-integrin α4ß7 monoclonal antibody. Our primary outcome was anti-SARS-CoV-2 spike (S) antibody concentrations, measured using the Elecsys anti-SARS-CoV-2 spike (S) antibody assay 3-10 weeks after vaccination, in patients without evidence of prior infection. Secondary outcomes were seroconversion rates (defined by a cut-off of 15 U/mL), and antibody responses following past infection or a second dose of the BNT162b2 vaccine. RESULTS: Geometric mean (SD) anti-SARS-CoV-2 antibody concentrations were lower in patients treated with infliximab than vedolizumab, following BNT162b2 (6.0 U/mL (5.9) vs 28.8 U/mL (5.4) p<0.0001) and ChAdOx1 nCoV-19 (4.7 U/mL (4.9)) vs 13.8 U/mL (5.9) p<0.0001) vaccines. In our multivariable models, antibody concentrations were lower in infliximab-treated compared with vedolizumab-treated patients who received the BNT162b2 (fold change (FC) 0.29 (95% CI 0.21 to 0.40), p<0.0001) and ChAdOx1 nCoV-19 (FC 0.39 (95% CI 0.30 to 0.51), p<0.0001) vaccines. In both models, age ≥60 years, immunomodulator use, Crohn's disease and smoking were associated with lower, while non-white ethnicity was associated with higher, anti-SARS-CoV-2 antibody concentrations. Seroconversion rates after a single dose of either vaccine were higher in patients with prior SARS-CoV-2 infection and after two doses of BNT162b2 vaccine. CONCLUSION: Infliximab is associated with attenuated immunogenicity to a single dose of the BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines. Vaccination after SARS-CoV-2 infection, or a second dose of vaccine, led to seroconversion in most patients. Delayed second dosing should be avoided in patients treated with infliximab. TRIAL REGISTRATION NUMBER: ISRCTN45176516.

Anti-SARS-CoV-2 antibody responses are attenuated in patients with IBD treated with infliximab.

OBJECTIVE: Antitumour necrosis factor (anti-TNF) drugs impair protective immunity following pneumococcal, influenza and viral hepatitis vaccination and increase the risk of serious respiratory infections. We sought to determine whether infliximab-treated patients with IBD have attenuated serological responses to SARS-CoV-2 infections. DESIGN: Antibody responses in participants treated with infliximab were compared with a reference cohort treated with vedolizumab, a gut-selective anti-integrin α4ß7 monoclonal antibody that is not associated with impaired vaccine responses or increased susceptibility to systemic infections. 6935 patients were recruited from 92 UK hospitals between 22 September and 23 December 2020. RESULTS: Rates of symptomatic and proven SARS-CoV-2 infection were similar between groups. Seroprevalence was lower in infliximab-treated than vedolizumab-treated patients (3.4% (161/4685) vs 6.0% (134/2250), p<0.0001). Multivariable logistic regression analyses confirmed that infliximab (vs vedolizumab; OR 0.66 (95% CI 0.51 to 0.87), p=0.0027) and immunomodulator use (OR 0.70 (95% CI 0.53 to 0.92), p=0.012) were independently associated with lower seropositivity. In patients with confirmed SARS-CoV-2 infection, seroconversion was observed in fewer infliximab-treated than vedolizumab-treated patients (48% (39/81) vs 83% (30/36), p=0.00044) and the magnitude of anti-SARS-CoV-2 reactivity was lower (median 0.8 cut-off index (0.2-5.6) vs 37.0 (15.2-76.1), p<0.0001). CONCLUSIONS: Infliximab is associated with attenuated serological responses to SARS-CoV-2 that were further blunted by immunomodulators used as concomitant therapy. Impaired serological responses to SARS-CoV-2 infection might have important implications for global public health policy and individual anti-TNF-treated patients. Serological testing and virus surveillance should be considered to detect suboptimal vaccine responses, persistent infection and viral evolution to inform public health policy. TRIAL REGISTRATION NUMBER: ISRCTN45176516.

Adaptations to the British Society of Gastroenterology guidelines on the management of acute severe UC in the context of the COVID-19 pandemic: a RAND appropriateness panel.

OBJECTIVE: Management of acute severe UC (ASUC) during the novel COVID-19 pandemic presents significant dilemmas. We aimed to provide COVID-19-specific guidance using current British Society of Gastroenterology (BSG) guidelines as a reference point. DESIGN: We convened a RAND appropriateness panel comprising 14 gastroenterologists and an IBD nurse consultant supplemented by surgical and COVID-19 experts. Panellists rated the appropriateness of interventions for ASUC in the context of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Median scores and disagreement index (DI) were calculated. Results were discussed at a moderated meeting prior to a second survey. RESULTS: Panellists recommended that patients with ASUC should be isolated throughout their hospital stay and should have a SARS-CoV-2 swab performed on admission. Patients with a positive swab should be discussed with COVID-19 specialists. As per BSG guidance, intravenous hydrocortisone was considered appropriate as initial management; only in patients with COVID-19 pneumonia was its use deemed uncertain. In patients requiring rescue therapy, infliximab with continuing steroids was recommended. Delaying colectomy because of COVID-19 was deemed inappropriate. Steroid tapering as per BSG guidance was deemed appropriate for all patients apart from those with COVID-19 pneumonia in whom a 4-6 week taper was preferred. Post-ASUC maintenance therapy was dependent on SARS-CoV-2 status but, in general, biologics were more likely to be deemed appropriate than azathioprine or tofacitinib. Panellists deemed prophylactic anticoagulation postdischarge to be appropriate in patients with a positive SARS-CoV-2 swab. CONCLUSION: We have suggested COVID-19-specific adaptations to the BSG ASUC guideline using a RAND panel.

British Society of Gastroenterology guidance for management of inflammatory bowel disease during the COVID-19 pandemic.

The COVID-19 pandemic is putting unprecedented pressures on healthcare systems globally. Early insights have been made possible by rapid sharing of data from China and Italy. In the UK, we have rapidly mobilised inflammatory bowel disease (IBD) centres in order that preparations can be made to protect our patients and the clinical services they rely on. This is a novel coronavirus; much is unknown as to how it will affect people with IBD. We also lack information about the impact of different immunosuppressive medications. To address this uncertainty, the British Society of Gastroenterology (BSG) COVID-19 IBD Working Group has used the best available data and expert opinion to generate a risk grid that groups patients into highest, moderate and lowest risk categories. This grid allows patients to be instructed to follow the UK government's advice for shielding, stringent and standard advice regarding social distancing, respectively. Further considerations are given to service provision, medical and surgical therapy, endoscopy, imaging and clinical trials.

Developing a core outcome set for fistulising perianal Crohn's disease.

OBJECTIVE: Lack of standardised outcomes hampers effective analysis and comparison of data when comparing treatments in fistulising perianal Crohn's disease (pCD). Development of a standardised set of outcomes would resolve these issues. This study provides the definitive core outcome set (COS) for fistulising pCD. DESIGN: Candidate outcomes were generated through a systematic review and patient interviews. Consensus was established via a three-round Delphi process using a 9-point Likert scale based on how important they felt it was in determining treatment success culminating in a final consensus meeting. Stakeholders were recruited nationally and grouped into three panels (surgeons and radiologists, gastroenterologists and IBD specialist nurses, and patients). Participants received feedback from their panel (in the second round) and all participants (in the third round) to allow refinement of their scores. RESULTS: A total of 295 outcomes were identified from systematic reviews and interviews that were categorised into 92 domains. 187 stakeholders (response rate 78.5%) prioritised 49 outcomes through a three-round Delphi study. The final consensus meeting of 41 experts and patients generated agreement on an eight domain COS. The COS comprised three patient-reported outcome domains (quality of life, incontinence and a combined score of patient priorities) and five clinician-reported outcome domains (perianal disease activity, development of new perianal abscess/sepsis, new/recurrent fistula, unplanned surgery and faecal diversion). CONCLUSION: A fistulising pCD COS has been produced by all key stakeholders. Application of the COS will reduce heterogeneity in outcome reporting, thereby facilitating more meaningful comparisons between treatments, data synthesis and ultimately benefit patient care.

Natural disease course of Crohn's disease during the first 5 years after diagnosis in a European population-based inception cohort: an Epi-IBD study.

OBJECTIVE: The Epi-IBD cohort is a prospective population-based inception cohort of unselected patients with inflammatory bowel disease from 29 European centres covering a background population of almost 10 million people. The aim of this study was to assess the 5-year outcome and disease course of patients with Crohn's disease (CD). DESIGN: Patients were followed up prospectively from the time of diagnosis, including collection of their clinical data, demographics, disease activity, medical therapy, surgery, cancers and deaths. Associations between outcomes and multiple covariates were analysed by Cox regression analysis. RESULTS: In total, 488 patients were included in the study. During follow-up, 107 (22%) patients received surgery, while 176 (36%) patients were hospitalised because of CD. A total of 49 (14%) patients diagnosed with non-stricturing, non-penetrating disease progressed to either stricturing and/or penetrating disease. These rates did not differ between patients from Western and Eastern Europe. However, significant geographic differences were noted regarding treatment: more patients in Western Europe received biological therapy (33%) and immunomodulators (66%) than did those in Eastern Europe (14% and 54%, respectively, P<0.01), while more Eastern European patients received 5-aminosalicylates (90% vs 56%, P<0.05). Treatment with immunomodulators reduced the risk of surgery (HR: 0.4, 95% CI 0.2 to 0.6) and hospitalisation (HR: 0.3, 95% CI 0.2 to 0.5). CONCLUSION: Despite patients being treated early and frequently with immunomodulators and biological therapy in Western Europe, 5-year outcomes including surgery and phenotype progression in this cohort were comparable across Western and Eastern Europe. Differences in treatment strategies between Western and Eastern European centres did not affect the disease course. Treatment with immunomodulators reduced the risk of surgery and hospitalisation.

Disease course of inflammatory bowel disease unclassified in a European population-based inception cohort: An Epi-IBD study.

BACKGROUND AND AIM: A definitive diagnosis of Crohn's disease (CD) or ulcerative colitis (UC) is not always possible, and a proportion of patients will be diagnosed as inflammatory bowel disease unclassified (IBDU). The aim of the study was to investigate the prognosis of patients initially diagnosed with IBDU and the disease course during the following 5 years. METHODS: The Epi-IBD study is a prospective population-based cohort of 1289 IBD patients diagnosed in centers across Europe. Clinical data were captured prospectively throughout the follow-up period. RESULTS: Overall, 476 (37%) patients were initially diagnosed with CD, 701 (54%) with UC, and 112 (9%) with IBDU. During follow-up, 28 (25%) IBDU patients were changed diagnoses to either UC (n = 20, 71%) or CD (n = 8, 29%) after a median of 6 months (interquartile range: 4-12), while 84 (7% of the total cohort) remained IBDU. A total of 17 (15%) IBDU patients were hospitalized for their IBD during follow-up, while 8 (7%) patients underwent surgery. Most surgeries (n = 6, 75%) were performed on patients whose diagnosis was later changed to UC; three of these colectomies led to a definitive diagnosis of UC. Most patients (n = 107, 96%) received 5-aminosalicylic acid, while 11 (10%) patients received biologicals, of whom five remained classified as IBDU. CONCLUSIONS: In a population-based inception cohort, 7% of IBD patients were not given a definitive diagnosis of IBD after 5 years of follow-up. One in four patients with IBDU eventually was classified as CD or UC. Overall, the disease course and medication burden in IBDU patients were mild.

Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease.

Importance: Use of thiopurines may be limited by myelosuppression. TPMT pharmacogenetic testing identifies only 25% of at-risk patients of European ancestry. Among patients of East Asian ancestry, NUDT15 variants are associated with thiopurine-induced myelosuppression (TIM). Objective: To identify genetic variants associated with TIM among patients of European ancestry with inflammatory bowel disease (IBD). Design, Setting, and Participants: Case-control study of 491 patients affected by TIM and 679 thiopurine-tolerant unaffected patients who were recruited from 89 international sites between March 2012 and November 2015. Genome-wide association studies (GWAS) and exome-wide association studies (EWAS) were conducted in patients of European ancestry. The replication cohort comprised 73 patients affected by TIM and 840 thiopurine-tolerant unaffected patients. Exposures: Genetic variants associated with TIM. Main Outcomes and Measures: Thiopurine-induced myelosuppression, defined as a decline in absolute white blood cell count to 2.5 × 109/L or less or a decline in absolute neutrophil cell count to 1.0 × 109/L or less leading to a dose reduction or drug withdrawal. Results: Among 1077 patients (398 affected and 679 unaffected; median age at IBD diagnosis, 31.0 years [interquartile range, 21.2 to 44.1 years]; 540 [50%] women; 602 [56%] diagnosed as having Crohn disease), 919 (311 affected and 608 unaffected) were included in the GWAS analysis and 961 (328 affected and 633 unaffected) in the EWAS analysis. The GWAS analysis confirmed association of TPMT (chromosome 6, rs11969064) with TIM (30.5% [95/311] affected vs 16.4% [100/608] unaffected patients; odds ratio [OR], 2.3 [95% CI, 1.7 to 3.1], P = 5.2 × 10-9). The EWAS analysis demonstrated an association with an in-frame deletion in NUDT15 (chromosome 13, rs746071566) and TIM (5.8% [19/328] affected vs 0.2% [1/633] unaffected patients; OR, 38.2 [95% CI, 5.1 to 286.1], P = 1.3 × 10-8), which was replicated in a different cohort (2.7% [2/73] affected vs 0.2% [2/840] unaffected patients; OR, 11.8 [95% CI, 1.6 to 85.0], P = .03). Carriage of any of 3 coding NUDT15 variants was associated with an increased risk (OR, 27.3 [95% CI, 9.3 to 116.7], P = 1.1 × 10-7) of TIM, independent of TPMT genotype and thiopurine dose. Conclusions and Relevance: Among patients of European ancestry with IBD, variants in NUDT15 were associated with increased risk of TIM. These findings suggest that NUDT15 genotyping may be considered prior to initiation of thiopurine therapy; however, further study including additional validation in independent cohorts is required.

Quality of Care in Ulcerative Colitis: A Modified Delphi Panel Approach.

OBJECTIVES: To establish clinical consensus on important and relevant quality-of-care (QoC) attributes in ulcerative colitis (UC) treatment that may improve treatment outcomes and guide best practices. METHODS: Thirty-eight QoC attributes were identified in a literature review. Sixteen European-based experts were selected based on their contributions to UC guidelines, publications, and patient care. A 3-round, modified Delphi panel was conducted including an interview round, and 2 web-based rounds to reach consensus and finalize a QoC attribute list. RESULTS: The draft QoC attribute list derived from a literature review and Round 1, expert interviews, comprised 63 attributes. In Rounds 2 and 3, the QoC attributes frequently rated as critically important were diagnosis (n = 15, 93.8%), treatment adherence (n = 15, 93.8%), and access to care/treatment (Round 2: n = 14, 87.5%; Round 3: n = 15, 93.8%). The final QoC attribute list consisted of 61 attributes across 20 domains, with the most attributes reported in the "treatment goals" domain (n = 9). CONCLUSION: QoC is a complex and evolving concept that can improve outcomes while maximizing healthcare resources. Limited time and resources hamper clinicians' ability to openly and empathetically communicate with patients; novel technology may help to offer solutions.