Integrating the Patient Perspective to Validate a Measure of Disease Severity in Inflammatory Bowel Disease: Online Survey of Patients and Their Physicians.

BACKGROUND: The patient perspective is essential for assessing disease severity, but it is not always adequately considered. We describe how a comprehensive clinical disease severity index (DSI) for inflammatory bowel disease (IBD) correlates with patient global self-assessment (PGSA). METHODS: In an individually linked parallel online survey, physicians provided the DSI, and patients provided self-assessed severity using a global question and visual analog scale (0-100) (PGSA). Mean DSI values by PGSA were calculated with 95% confidence intervals. Pearson correlation (r) and the intraclass correlation coefficient were calculated for PGSA vs DSI. Positive predictive values for identifying severe disease with PGSA categories as a reference were based on a threshold >22 points. RESULTS: The primary analysis included 89 pairs (46 Crohn's disease [CD], 43 ulcerative colitis [UC]) with strict criteria and 147 pairs when less stringent. Common reasons for exclusion were missing values for albumin or colonoscopy. Mean DSI values showed no clear trend with increasing PGSA in CD but good discrimination between moderate, severe, and very severe PGSA in UC. For PGSA on the visual analog scale, r was 0.54 for CD and 0.59 for UC (difference in means: CD 27.7, UC 13.8; intraclass correlation coefficient: CD 0.48, UC 0.58). A high DSI predicted severe disease in 76.2% of CD and 65.2% of UC. CONCLUSIONS: The DSI showed good discrimination for patient-reported disease severity in UC but performed unsatisfactorily in CD. Correlations were moderate. Further refinement of the DSI is suggested to better reflect the patient perspective.

The performance of an inflammatory bowel disease severity score was compared with self-perceived severity based on an individually linked online survey of patients and their physicians. Agreement and prediction of severe disease were moderate and should be improved by integrating the patients' perspective.

Evaluation of a downstaging, bidirectional version of the Montreal classification of Crohn's disease: Analysis of 5-year follow-up data from the prospective BioCrohn study.

OBJECTIVE: Under the assumption of irreversibility, the Montreal classification provides a unidirectional assessment of the complications and behaviour of Crohn's disease (CD) that does not allow for downstaging. We examined the use of a bidirectional Montreal classification system that can capture disease regression. DESIGN: From the BioCrohn Registry, an inception cohort of patients with CD for ≤12 months duration was defined and followed up for 5-years. Cumulative probabilities for developing complications were estimated using the Kaplan-Meier method. Potential associations of explanatory variables with disease progression were estimated with Cox regression. RESULTS: Among 393 incident CD patients (of whom 255 completed the entire follow-up), the 5-year cumulative probability of developing complications was 41.5% (15.6% and 25.9% for stricturing and penetrating complications respectively). Perianal disease (hazard ratio [95% confidence interval]: 8.45 [4.74-15.07]) and surgical resection of the intestine (2.71 [1.50-4.92]) in the very early phase of the disease were associated with a higher risk of developing a penetrating complication within the 5-year follow-up. The use of a bidirectional Montreal classification system which can account for disease regression demonstrated that 90% of patients exhibited inflammatory disease behaviour at 5 years, in contrast to 58%, if the hierarchical, unidirectional Montreal classification system was used. CONCLUSION: An additional bidirectional disease behaviour assessment capturing reversed or fully controlled complications may provide a more realistic appraisal of the complexity and unmet needs of patients treated with advanced therapies.

I-CARE, a European Prospective Cohort Study Assessing Safety and Effectiveness of Biologics in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: There is a need to evaluate the benefit-risk ratio of current therapies in inflammatory bowel disease (IBD) patients to provide the best quality of care. The primary objective of I-CARE (IBD Cancer and serious infections in Europe) was to assess prospectively safety concerns in IBD, with specific focus on the risk of cancer/lymphoma and serious infections in patients treated with anti-tumor necrosis factor and other biologic monotherapy as well as in combination with immunomodulators. METHODS: I-CARE was designed as a European prospective longitudinal observational multicenter cohort study to include patients with a diagnosis of Crohn's disease, ulcerative colitis, or IBD unclassified established at least 3 months prior to enrollment. RESULTS: A total of 10,206 patients were enrolled between March 2016 and April 2019, including 6169 (60.4%) patients with Crohn's disease, 3853 (37.8%) with ulcerative colitis, and 184 (1.8%) with a diagnosis of IBD unclassified. Thirty-two percent of patients were receiving azathioprine/thiopurines, 4.6% 6-mercaptopurine, and 3.2% methotrexate at study entry. At inclusion, 47.3% of patients were treated with an anti-tumor necrosis factor agent, 8.8% with vedolizumab, and 3.4% with ustekinumab. Roughly one-quarter of patients (26.8%) underwent prior IBD-related surgery. Sixty-six percent of patients had been previously treated with systemic steroids. Three percent of patients had a medical history of cancer prior to inclusion and 1.1% had a history of colonic, esophageal, or uterine cervix high-grade dysplasia. CONCLUSIONS: I-CARE is an ongoing investigator-initiated observational European prospective cohort study that will provide unique information on the long-term benefits and risks of biological therapies in IBD patients. (EudraCT, Number: 2014-004728-23; ClinicalTrials.gov, Number: NCT02377258).

Early MOnitoring of REsponse (MORE) to Golimumab Therapy: Results of a Multicentre, Prospective Observational Trial.

BACKGROUND: The therapeutic goal of clinical remission in patients with moderate to severe ulcerative colitis (UC) is achieved after biological therapy only in 16-39%. Individualization of therapeutic intervention would benefit from prediction of early response. STUDY OBJECTIVE: The primary objective of our study was to assess golimumab (GLM) trough serum level of ≥2.5 µg/mL in combination with a reduction of faecal calprotectin (FC) of ≥50% at week 6 compared to baseline to predict clinical response at week 26 after regular GLM intake. METHODS: Patients with moderate to severe active UC and planned GLM treatment were recruited for a prospective, multicentre, observational study in Germany. Prediction of clinical response was assessed by FC and GLM trough level. Missing data were imputed as therapy failure according to the last observation carried forward method. RESULTS: Fifty nine patients have been enrolled. 54% of patients were anti-TNF naïve. Clinical response at week 6 was a significant predictor for achieving clinical response at week 26 (odds ratio [OR] 10.97, confidence interval [CI], 2.96-40.68; p < 0.001). Moreover, patients with a GLM trough level of ≥2.5 µg/mL and a ≥50% reduction of FC at week 6 had an OR of 5.33 (95% CI, 0.59-47.84) to achieve clinical response at week 26. CONCLUSION: Clinical response at week 6 is the best predictive marker for achieving clinical response at week 26. Consideration of significant reduction of FC and trough GLM serum levels could improve prediction of response.

[Position paper on reporting of intestinal ultrasound findings in patients with inflammatory bowel disease]. / Positionspapier zur Befunderhebung von Darmultraschallbefunden bei chronisch entzündlichen Darmerkrankungen.

BACKGROUND: Intestinal ultrasound is increasingly used for primary diagnosis, detection of complications and monitoring of patients with Crohn's disease and ulcerative colitis. Standardization of reporting is relevant to ensure quality of the methodology and to improve communication between different specialties. The current manuscript describes the features required for optimized reporting of intestinal ultrasound findings in inflammatory bowel disease (IBD). METHODS: An expert consensus panel of gastroenterologists, radiologists, pathologists, paediatric gastroenterologists and surgeons conducted a systematic literature search. In a Delphi- process members of the Kompetenznetz Darmerkrankungen in collaboration with members of the German Society for Radiology (DRG) voted on relevant criteria for reporting of findings in intestinal ultrasound. Based on the voting results statements were agreed by expert consensus. RESULTS: Clinically relevant aspects of intestinal ultrasound (IUS) findings have been defined to optimize reporting and to standardize terminology. Minimal requirements for standardized reporting are suggested. The statements focus on description of disease activity as well as on complications of IBD. Attributes of intestinal inflammation are described and illustrated by exemplary images. CONCLUSION: The current manuscript provides practical recommendations on how to standardize documentation and reporting from intestinal ultrasound findings in patients with IBD.

Transmural Response and Transmural Healing Defined by Intestinal Ultrasound: New Potential Therapeutic Targets?

BACKGROUND AND AIMS: Intestinal ultrasound [IUS] is a useful modality to monitor patients with inflammatory bowel disease [IBD]. Little is known about the use of IUS and appropriate definitions for transmural response [TR] and healing [TH]. We aimed to establish the use of IUS in monitoring TH as a potential target in routine medical practice. METHODS: Based on the prospective, non-interventional, multicentre studies TRUST and TRUST&UC, we conducted a post-hoc analysis of 351 IBD patients with increased bowel wall thickness [BWT]. We analysed the rates of patients achieving TR and TH, comparing three definitions of TH. In 137 Crohn's disease [CD] patients, the predictive value of TR and TH was investigated for the clinical and sonographic outcome at week 52. RESULTS: Within 12 weeks of treatment intensification, 65.6% [n = 118] of CD patients and 76.6% [n = 131] of ulcerative colitis [UC] patients showed a TR. Depending on the definition, 23.9-37.2% [n = 58/67/43] of CD patients and 45.0-61.4% [n = 90/105/77] of UC patients had TH at week 12. CD patients with TH were more likely to reach clinical remission at week 12 (odds ratio [OR] 3.33 [1.09-10.2]; p = 0.044) and a favourable sonographic outcome (OR 5.59 [1.97-15.8]; p = 0.001) at week 52 compared with patients without TH. CONCLUSIONS: IUS response and TH in a relevant proportion of patients suggests that IUS is a useful method to assess transmural inflammatory activity in daily clinical practice. TR and TH are predictive for the sonographic outcome at week 52.

Expression of the fructose transporter GLUT5 in patients with fructose malabsorption.

BACKGROUND: Patients with abdominal symptoms are frequently diagnosed with fructose malabsorption (FM). Fructose is absorbed by monosaccharide transporters located in the brush border of the human small intestine. The aim of this study was to investigate the histoanatomical distribution of the main fructose transporter GLUT5. MATERIALS AND METHODS: We studied 223 patients diagnosed with FM by a hydrogen breath test and grouped according to their response to a fructose-free diet. The control group were 42 healthy individuals and 29 patients with celiac disease (CD). The fructose breath test was done with 50 g fructose. The expression of Glut5 in duodenal biopsy specimens was studied by immunohistochemistry. The Kruskal-Wallis-test and Mann-Whitney U-test were used to carry out the statistical analysis. RESULTS: The histoanatomical expression pattern of GLUT5 did not differ significantly between those patients with FM who responded completely to a fructose-free diet (n = 183) and healthy individuals (n = 42); nor did it correlate to H2 production measured in fructose breath testing. In patients with FM, the GLUT5 expression pattern did not differ between those individuals responding to a fructose-free diet and those who did not. However, GLUT5 expression pattern was significantly different in patients with CD (n = 29) compared to patients with FM and to healthy individuals (p = 0.009). CONCLUSION: GLUT5 expression patterns are not be related to adult patients with FM. However, in secondary malabsorption, a decreased GLUT5 expression was found. Further investigation is needed to understand the essential factors in FM and the influence on functional gastrointestinal disorders.

A Prospective Multicenter Study on the Prevalence of Fructose Malabsorption in Patients with Chronic Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Patients with chronic inflammatory bowel disease (IBD) might have a higher prevalence of fructose malabsorption than healthy controls. This study's aim was to determine the prevalence and symptom severity of fructose malabsorption in patients with active and inactive IBD. METHODS: The present study was a multicenter noninterventional diagnostic pilot trial. Two hundred fifty-one participants were recruited from 12 outpatient clinics for internal medicine across Germany and from the University of Kiel. Fructose malabsorption was diagnosed by hydrogen breath testing. Patients diagnosed with bacterial overgrowth, non-H2 producers, and patients who were tested positive for lactose malabsorption were excluded. Gastrointestinal symptoms during breath testing were evaluated using four-point subjective items to determine severity of bloating, abdominal pain, and diarrhea. RESULTS: Two hundred five patients (45 with active IBD, 80 with IBD in remission, and 81 healthy controls) were analyzed. The number of patients diagnosed with fructose malabsorption - 35/44 (79.6%) in patients with active IBD, 59/80 (73.8%) inactive IBD, and 66/81 (81.5%) in healthy controls - did not differ between the groups (χ2 [2, N = 205] = 1.48, p = 0.48). However, abdominal pain was more frequent in patients with active IBD than patients with IBD in remission (z = -2.936, p = 0.010), and diarrhea was more frequent in patients with active IBD than in healthy controls (z = 2.489, p = 0.038). CONCLUSIONS: Fructose malabsorption is not more common among patients with IBD than healthy subjects. However, the greater prevalence of patient-reported symptoms among patients with IBD may be of pathological and therapeutic relevance.

Comparative Analysis of 3-Year Persistence With Vedolizumab Compared With Antibodies Against Tumor Necrosis Factor-Alpha in Patients With Inflammatory Bowel Disease in Germany: Retrospective Analysis of a Large Prescription Database.

AIMS: The goal of the study was to compare persistence with vedolizumab versus adalimumab, golimumab, and infliximab in biologics-naïve patients with inflammatory bowel disease treated in gastroenterological practices and outpatient clinics in Germany. METHODS: Patients aged 18 or older who had initiated a biological therapy (vedolizumab, infliximab, adalimumab, or golimumab) were included in the present study. Prescriptions between July 2014 and March 2017 of the respective biological drug emerging from gastroenterological practices or outpatient clinics in Germany were retrieved from the longitudinal prescription (LRx) database. Patients treated with vedolizumab were matched with patients treated with infliximab, adalimumab, or golimumab on the basis of age, gender, medication before biologic therapy, and index year. The primary outcome variable of the study was the rate of persistence with vedolizumab compared with antitumor necrosis factor biologics (infliximab, adalimumab, and golimumab) within 3 years of the first prescription in outpatient settings. RESULTS: Kaplan-Meier analysis was performed in 15,984 patients naïve to biologics revealing the statistically lower risk of discontinuation for vedolizumab compared with adalimumab, golimumab, or infliximab. In matched-pairs analyses, within 3 years after the first prescription, 39.5% of 2076 patients were persistent to vedolizumab compared with 33.5% of matched patients persistent to adalimumab (P<0.001). 37.6% of 716 patients were persistent to vedolizumab compared with 24.7% of matched patients persistent to golimumab (P<0.001). 35.7% of 2055 patients were persistent to vedolizumab compared with 30.2% of matched patients persistent to infliximab (P=0.119). Vedolizumab was associated with a significantly lower risk of therapy discontinuation compared with adalimumab [hazard ratio (HR)=0.86; 95% confidence interval (CI), 0.81-0.93] and golimumab (HR=0.60; 95% CI, 0.54-0.67), respectively; the vedolizumab risk of therapy discontinuation was numerically lower than infliximab but statistical significance was not achieved (HR=0.93; 95% CI, 0.85-1.02). CONCLUSION: In biologics-naïve IBD patients treated in outpatient settings in Germany, matched-pair analyses showed that vedolizumab was associated with significantly improved drug persistence compared with adalimumab or golimumab, whereas numerical improvement was shown in comparison with infliximab.

Addendum to S3-Guidelines Crohn's disease and ulcerative colitis: Management of Patients with Inflammatory Bowel Disease in the COVID-19 Pandemic - open questions and answers.

The COVID-19 pandemic is a global outbreak of new onset infections with the SARS-CoV-2 virus. To date, more than 3.4 million people have been infected throughout the world. In Germany, approximately 450,000 patients suffer from inflammatory bowel disease; these patients generally require continuous expert care and support. Against the background of a rapidly accumulating knowledge base on SARS-CoV-2, 68 expert authors of the current DGVS guidelines for Crohn's disease and ulcerative colitis took part in a virtual meeting to compile up-to-date, practice-orientated recommendations aimed at improving the care of patients with IBD. These recommendations address the risk of infection, including the risk for specific patient groups, the possible course of the disease, and consequences for pharmacological and surgical therapies of the underlying disease, as well as general measures for infection prevention and adjuvant prophylactic and therapeutic options.

Real-world clinical effectiveness and safety of vedolizumab and anti-tumor necrosis factor alpha treatment in ulcerative colitis and Crohn's disease patients: a German retrospective chart review.

BACKGROUND: Real-world comparisons of biologic treatment outcomes for ulcerative colitis (UC) or Crohn's disease (CD) patients are limited. We sought to evaluate the real-world effectiveness of vedolizumab (VDZ) and anti-tumor necrosis factor alpha (anti-TNFα) in UC and CD patients in Germany. METHODS: A retrospective chart review (15 sites) investigated UC and CD patients who were biologic-treatment naïve (biologic-naïve) or had received no more than one prior anti-TNFα before initiating treatment with VDZ or anti-TNFα between 15 July 2014 and 20 October 2015. Kaplan-Meier analyses assessed time to first chart-documented clinical remission (CR) and symptom resolution (UC: rectal bleeding [RB], stool frequency [SF]; CD: abdominal pain [AP], liquid stools [LS]) and outcome duration. RESULTS: A total of 133 UC (76 VDZ; 57 anti-TNFα) and 174 CD (69 VDZ; 105 anti-TNFα) patients were included. By Week 26, estimated cumulative rates of patients achieving CR or symptom resolution with VDZ vs anti-TNFα treatment were for UC: CR, 53.7% vs 31.7%; RB, 66.8% vs 55.8%; and SF, 59.8% vs 50.7%, respectively; and for CD: CR, 14.4% vs 32.8%; AP, 62.5% vs 56.0%; and LS, 29.9% vs 50.3%, respectively. Outcomes were sustained similarly between treatments, except RB (VDZ vs anti-TNFα: median 38.1 vs 15.1 weeks, P = 0.03). Treatment-related adverse events occurred in 5.3% vs 7.0% (UC) and 8.7% vs 19.0% (CD) of VDZ vs anti-TNFα patients, respectively. CONCLUSIONS: Although there were differences in CR, symptom resolution, and safety profiles, real-world data support both VDZ and anti-TNFα as effective treatment options in UC and CD.

Comparative Analysis of the 3-Year Persistence Rate with Second-Line Vedolizumab and Tumor Necrosis Factor-α Inhibitors in Patients with Inflammatory Bowel Disease Followed in Gastroenterology Practices in Germany.

BACKGROUND: Our goal was to investigate the 3-year persistence rates with second-line vedolizumab and tumor necrosis factor-α (TNF-α) inhibitors (i.e., adalimumab, golimumab, infliximab) in patients with inflammatory bowel disease (IBD) who were followed in gastroenterology practices in Germany. METHODS: This study included patients aged ≥18 years who had received prescriptions for second-line biological drugs in Germany between 2014 and 2017 (n = 5,150) retrieved from the longitudinal prescription database. Vedolizumab users were matched to adalimumab, golimumab, and infliximab users based on age, sex, and index year. The primary outcome of the study was the rate of persistence with vedolizumab compared with the rate of persistence with adalimumab, golimumab, and infliximab within 3 years of second-line therapy initiation in IBD patients. Persistence was estimated as therapy time without discontinuation, with discontinuation being defined as at least 90 days without any prescription for the biological drug of interest. RESULTS: After matching patients who had received vedolizumab with those who had received adalimumab, the rate of persistence after 3 therapy years was 30.3% for vedolizumab and 27.9% for adalimumab (log-rank p = 0.005). The corresponding figures were 27.8 and 20.8% in the vedolizumab-golimumab matched-pair analysis (log-rank p < 0.001) and 29.5 and 25.2% in the vedolizumab-infliximab matched-pair analysis (log-rank p value = 0.008). Vedolizumab was associated with a significant 0.85-, 0.72-, and 0.86-fold decrease in the risk of discontinuation within 3 years of therapy initiation compared to adalimumab, golimumab, and infliximab, respectively. CONCLUSIONS: Treatment persistence was higher for vedolizumab than for TNF-α inhibitors up to 3 years after initiating second-line biological therapy.

Intestinal ultrasound for monitoring therapeutic response in patients with ulcerative colitis: results from the TRUST&UC study.

OBJECTIVE: Prospective evaluation of intestinal ultrasound (IUS) for disease monitoring of patients with ulcerative colitis (UC) in routine medical practice. DESIGN: TRansabdominal Ultrasonography of the bowel in Subjects with IBD To monitor disease activity with UC (TRUST&UC) was a prospective, observational study at 42 German inflammatory bowel disease-specialised centres representing different care levels. Patients with a diagnosis of a proctosigmoiditis, left-sided colitis or pancolitis currently in clinical relapse (defined as Short Clinical Colitis Activity Index ≥5) were enrolled consecutively. Disease activity and vascularisation within the affected bowel wall areas were assessed by duplex/Colour Doppler ultrasonography. RESULTS: At baseline, 88.5% (n=224) of the patients had an increased bowel wall thickness (BWT) in the descending or sigmoid colon. Even within the first 2 weeks of the study, the percentage of patients with an increased BWT in the sigmoid or descending colon decreased significantly (sigmoid colon 89.3%-38.6%; descending colon 83.0%-42.9%; p<0.001 each) and remained low at week 6 and 12 (sigmoid colon 35.4% and 32.0%; descending colon 43.4% and 37.6%; p<0.001 each). Normalisation of BWT and clinical response after 12 weeks of treatment showed a high correlation (90.5% of patients with normalised BWT had symptomatic response vs 9.5% without symptomatic response; p<0.001). CONCLUSIONS: IUS may be preferred in general practice in a point-of-care setting for monitoring the disease course and for assessing short-term treatment response. Our findings give rise to the assumption that monitoring BWT alone has the potential to predict the therapeutic response, which has to be verified in future studies.

Monitoring of Vedolizumab Infusion Therapy (MOVE-IT) Response With Fecal Inflammation Markers, Ultrasound, and Trough Serum Level in Patients With Ulcerative Colitis: Protocol for a Multicentric, Prospective, Noninterventional Study.

BACKGROUND: Vedolizumab has been shown to induce clinical remission in patients with active ulcerative colitis. Treatment with anti-integrin vedolizumab leads to clinical remission in 16.9% and clinical response in 47.1% of cases after 6 weeks. However, in clinical practice, no decision to discontinue or continue vedolizumab therapy is made until 14 weeks at the earliest. OBJECTIVE: The aim of this study is to develop an algorithm for optimizing vedolizumab administration in patients with moderate-to-severe ulcerative colitis by calculating the probability of clinical response at week 14, on the basis of the data from week 6. METHODS: This is a prospective, single-arm, multicentric, noninterventional, observational study with no interim analyses and a sample size of 35 evaluable patients. RESULTS: The enrollment started in August 2018 and was still open at the date of submission. The study is expected to complete in September 2020. CONCLUSIONS: The early identification of patients who are responding to an integrin antibody is therapeutically beneficial. At the same time, patients who are not responding can be identified earlier. The development of a therapeutic algorithm for identifying patients as responders or nonresponders can thus help prescribing physicians avoid ineffective treatments and stop these very early.

Predictive parameters for the clinical course of Crohn's disease: development of a simple and reliable risk model.

PURPOSE: The aim of our study was to identify clinical parameters in recently diagnosed Crohn's disease (CD) patients for prediction of their disease course. METHODS: EPIC (Early Predictive parameters of Immunosuppressive therapy in Crohn's disease) is a prospective, observational study in 341 patients with a recent CD diagnosis (≤ 6 months), and naïve to immunosuppressants (IS) and anti-tumor necrosis factor α (TNF) agents. Patient characteristics were documented up to 2 years. In line with national and international guidelines, a complicated disease course was defined as need for immunosuppressants and/or anti-TNF agents, and CD-related hospitalization with or without immunosuppressants and/or anti-TNF agents. RESULTS: A total of 212 CD patients were analyzed of whom 57 (27%) had an uncomplicated disease within 24 months, while 155 (73%) had a complicated disease course: need for IS and/or anti-TNF agents (N = 115), CD-related hospitalization with or without IS/anti-TNF agents (N = 40). Identified risk predictors for a complicated disease were as follows: age at onset < 40 years (OR 2.3; 95% CI 1.2-4.5), anemia (OR 2.1; 95% CI 1.1-4.2), and treatment with systemic corticosteroids at first flare (OR 2.2; 95% CI 1.1-4.7). These three parameters were used to develop a risk model allowing prediction of the future disease course. CONCLUSION: Our three-parameter model enables an assessment of each CD patient's risk to develop a complicated disease course. Due to the easy accessibility of these parameters, this model can be utilized in daily clinical care to assist selecting the initial treatment for each individual patient.