Introduction

Clinical trials are ongoing to develop novel therapies for ulcerative colitis (UC), aiming to break the existing therapeutic ceiling. Mirikizumab, a monoclonal antibody targeting the p-19 subunit of IL-23, was evaluated in a phase-II clinical trial for the treatment of moderate-to-severe UC. Identifying predictive variables for response to therapy is still an unmet need and would serve as a valuable asset in clinical trials and clinical practice to guide therapeutic strategies.

Aims & Methods

This post-hoc data analysis aimed to identify variables predicting response to mirikizumab in UC patients from a phase II clinical trial. One-hundred and six randomly selected patients from the induction phase were considered: 26 (24.5%) were assigned to receive mirikizumab 50mg IV Q4W, 37 to 200mg IV Q4W (34.9%), 30 to 600mg IV Q4W (28.3%) and 13 to placebo (12.3%). In the maintenance phase, 44 received 200mg SC Q12W (42.3%), 47 received 200mg SC Q4W (45.2%), and 13 received placebo (12.5%). Patients who did not achieve clinical remission (14, 13.2%) were excluded from the analysis related to the maintenance phase. A stepwise analysis was conducted, initially using a principal coordinate analysis (PCoA) with permutational multivariate analysis of the variance (PERMANOVA), followed by a univariate analysis (Fisher’s or Wilcoxon signed-rank test) to select significant variables (p<.05). Further, a country-nested, three-visit repeated-measured generalized mixed ordinal logistic regression model (GLM) using significant PCoA variables was conducted. For both models the endpoint was histological remission at weeks 12 and 52, defined as Geboes score <2.

Results

At week 12, histological remission was achieved in 34 patients (32.1%) while at week 52 in 42 patients (39.6%). PCoA, PERMANOVA and univariate analysis considered histological remission to be significantly predicted by faecal calprotectin, endoscopic remission (Mayo 0, UCEIS <1) and induction therapy at weeks 12 and 52 (p<.05). Also, at week 52, the 32-IBD Questionnaire (systemic symptoms and social function), Physician Global Assessment, partial and total Mayo scores, and maintenance treatment were significant. Considering these as explanatory variables for the GLM, we confirmed the following as significant predictors of histological remission: faecal calprotectin <250 µg/g (Odds Ratio 0.26; 95% CI 0.12-0.58; p<0.001), endoscopic remission (OR 0.16; 95% CI 0.04-0.57; p=.005), induction treatment with mirikizumab 200mg IV Q4W (OR 0.09; 95% CI 0.02- 0.45; p=.004), 600 mg IV Q4W (OR 0.09; 95% CI 0.01-0.50; p=.006) and maintenance with 200 mg SC Q4W (OR 0.05; 95% CI 0.01-0.30; p=.001). A more severe Physician Global Assessment predicted histological activity (OR 2.29; 95% CI 1.03- 5.11; p=.043).

Conclusion

Our predictive model identified faecal calprotectin, endoscopic remission, and Physician Global Assessment as predictive factors for response to therapy. Notably, our model identified the most effective therapeutic strategies to achieve histological remission during induction and maintenance phases, showing promising ability to guide therapeutic choices in clinical trials and clinical practice. Additional investigation utilizing a larger clinical dataset would further enhance the ability of this model to identify variables predictive of response to therapy.

Introduction

Renal disorders are among the extra-intestinal manifestations of inflammatory bowel disease (IBD), and treatments may also lead to renal failure. However, the incidence of end-stage renal disease (ESRD), defined as the need for renal replacement therapy (dialysis and/or renal transplantation (RT)), is poorly known. The primary objective of our study was to assess the incidence of ESRD in IBD patients, and to compare it with the general health insurance scheme population.

Aims & Methods

We conducted a prognostic cohort study based on data from the French National Health Insurance Database(SNDS). Prevalent cases of IBD affiliated to the general health insurance scheme during the period 2011-2020 were identified on the basis of declarations long-term diseases ALD 24 or the presence of 2 hospital stays for IBD with ICD-10 codes or a single stay with reimbursement of specific treatments. Incident cases of ESRD were identified on the basis of a stay with a RT or a period with dialysis sessions for at least 45 days. Crude incidence rates of ESRD were calculated over the period for the IBD and the non-IBD population, with their 95% confidence intervals.

Results

A total of 280,283 IBD patients were included in the study over the period 2011-2020, 134,567 with ulcerative colitis(UC) and 145,716 with Crohn’s disease(CD). The mean age at study inclusion was 39.8 (± 17.1) years. The M/F sex ratio was 0.9. The mean age at incidence of ESRD in the non-IBD population was 65.0 (±17.0) years, the M/F sex ratio cases was 1.7.
Among IBD patients, 534 patients began replacement therapy by dialysis or RT, they were younger than non-IBD patients (60.3(±16.7)years, P<0.001).The mean incidence rate of ESRD over the period was 26.4 per 100,000 person-years (IC95% 23.1-29.6), 480 (89.9%) patients entered ESRD by dialysis, and 54 (10.1%) by preemptive RT. In the non-IBD population the mean rate of ESRD was 15.9 per 100,000 person-years (IC95% 14.8- 17.1; P<0.0001 compared with IBD): 79,606 (94.5%) patients entered ESRD by dialysis, and 4,634 (5.5%) by RT (as compared with IBD,P<0.001). In subgroup analysis, the mean incidence rate of ESRD was 22.8 per 100,000 person-years (IC95% 18.9-26.7) in UC patients and 29.5 (IC95% 25.3-33.6) in CD patients (P<0,0001). The rates of preemptive RT were 12.4% in UC patients (87.6% dialysis) and 8.6% in CD patients (91.4% dialysis).
Over a median follow-up of 6.8 years, the survival rate after ESRD was 40.8% in ESRD-IBD patients VS 34.2% in ESRD non-IBD patients (P<0.001). This difference remained significant for patients under 65 (p<0.0073).
No significant difference for the risk of re-hospitalization after RT (p=0.84), of retransplantation during the follow-up period in RT patients (p=0.67), or for the risk of hospitalization for severe infection (p=0.97) after RT in patients from the general population compared with IBD patients. The same was true for the type of severe infections after RT (p= 0.068) and for the risk of solid and haematological cancer after RT (p=0.48). However, there was a significant difference in the type of first severe infection after RT(p=0.003), but we are waiting for the results to tell us which one.

Conclusion

The incidence of ESRD is significantly higher in IBD than in the general data base population, confirming the need for regular monitoring of renal function in our patients.
Survival after ESRD onset, is higher in IBD patients.
The high incidence of RT in the IBD population confirms that access to transplantation is not restricted in this
population.

References

Kirchgesner et al, Gastroenterology 2018
Meyer et al, Aliment Pharmacol Ther. 2020
Tuppin et al, Nephrol Ther 2016

Introduction

Inflammatory bowel disease (IBD) includes Crohn's disease and ulcerative colitis, two conditions characterised by chronic inflammation of the gastrointestinal tract, which can damage the bowel and cause serious disabilities in patients' quality of life. Treatments only have a suspensive effect and the therapeutic sequences are currently based on reimbursement criteria or the prescriber's expertise, in a “trial-and-error” approach rather than on validated scientific evidence.
Routine clinical care data from 1,190 IBD patients collected by a private tertiary care centre dedicated to IBD patients, using the customised Instamed® platform, includes comprehensive information on the patient's treatment history, clinical variables and disease activity scores, in particular the Harvey-Bradshaw Index (HBI), Mayo Partial Score (MPS) and Simple Clinical Colitis Activity Index (SCCAI).
KEM® (Knowledge Extraction and Management) is an explainable Artificial Intelligence (xAI) platform using Formal Concept Analysis (FCA) that systematically extracts and evaluates all relations between variables in a database, thus enabling the identification of patient subgroups with greater likelihood of response to treatment sequences.

Aims & Methods

This study addresses the prevalent clinical challenge of uncertainty in treatment selectionfollowing the initial administration of anti-TNF or vedolizumab given as first-line therapy for IBD, aiming to identify the most effective second-line treatment options.
Data were aggregated into a consolidated database of 1,190 patients and 1,269 variables within the KEM® xAI Platform. Patients with at least 2 treatment lines were selected. To ensure a strong causality between treatment prescription and response, the maximal number of treatment lines was limited to 3. The outcome used was therapeutic response after three treatment lines, evaluated using HBI, PMS and SCCAI. Within 19,230,463 associations between sequence of the first two treatment lines and the response, 70 associations were retained by KEM® with successful treatment sequence with anti-TNFs, vedolizumab or thiopurine as first treatment line.

Results

285 patients fulfilled the analysis criteria. We identified hypotheses in favor of a second-line biological treatment (ustekinumab, JAKi, 2nd anti-TNF) after failure of a first-line treatment with anti-TNF or vedolizumab. Ustekinumab was 2 times more likely to be associated with a response to treatment. JAKi was 2 times less likely to be associated with a response to treatment. The 2nd anti-TNF was associated with a response to treatment in a specific subgroup. Moreover, successful treatment sequences with patient count above 10 and up to 30, involved thiopurine as first line of treatment, followed by anti-TNFs or thiopurine repeated as second line of treatment.

Conclusion

We show a powerful setup using routine clinical care data from an initial set of 1,190 IBD patients and the KEM® xAI platform to provide actionable hypotheses supporting therapeutic
decisions for disease management. These initial results will be further tested and validated as we accumulate real-life data on new patients and complete the follow-up of patients already included. The flexibility of our platform will enable us to include more therapeutic sequences and to add all the new treatments available in current clinical practice. This will allow us to offer continuous, up-to-date support for difficult medical decisions, enabling patient management to be guided by results observed in real life and leading de facto to precision medicine.

Disclosure

None

Introduction

Metabolic-associated fatty liver disease (MAFLD) requires complex treatment based on diet and lifestyle. The understanding of the disease by patients through medical education is an element that could bring them a therapeutic benefit. Since the process is time-consuming and medical factors all over the world are under pressure to use maximum time for diagnostic and therapeutic purposes, an important role can be played by the voluntary activity carried out by medical students, under the guidance of teaching staff, devoted to this purpose.

Aims & Methods

A group of 250 patients with MAFLD, non-cirrhotic, diagnosed in a gastroenterology outpatient clinic, were proposed to participate in an educational program consisting of 3 sessions of 2 hours of interactive course about MAFLD (including notions of anatomy, physiology, diagnosis, evolution, prognosis, complications, risks, treatment, follow-up) in order to appreciate the contribution of medical education to the effectiveness of treatment. The patients did not receive medication but only recommendations regarding lifestyle changes and the Mediterranean diet. They were re-evaluated 6 months after the initial evaluation.

Results

Of the 250 patients, only 126 (50.4%) accepted participation in the educational plan after informed consent, a disappointing proportion; the subgroup of those who did not participate in the course was reported as a control group (the main reason of non-participation was the fact that most of these patients considered to have already enough knowledge about MAFLD), being also invited to be evaluate after 6 months. Educational presentations were given by medical students under the guidance of teaching staff (power-point presentations and informative flyers designed to fix the knowledges about disease) and patients were clinically, laboratory, ultrasound and fibroscan evaluated by attending physicians. Also a questionnaire about quality of life was completed by each patient. Finally, after 6 months, only 85 patients from the control group and 118 from the study group returned for the final evaluation. The final evaluation focused on 4 elements: 1- changes in body mass (decrease of more than 7%), 2- liver ultrasonography (reduction of the degree of steatosis), 3- laboratory analyzes (liver and metabolic tests) and 4- quality of life. In the study group, significantly better results were obtained for parameters 1, 3 and 4: (78%, 87.2%, 84.7%) compared to the reference group (38.8%, 54.1%, 62.3%) which confirms the fact that patient education is an important element in understanding the disease and its treatment. Only in parameter 2 (decrease of steatosis at ultrasonography) there were no significant differences between the two groups (50.8% vs 48.2%), probably due to the too short follow-up time of the patients.

Conclusion

Therapeutic education of patients with MAFLD can bring more efficiency to the treatment of the disease in non-cirrhotic patients, mainly on body mass control, liver laboratory tests and quality of life, if they accept to participate at educational program.

References

Koutny F, Aigner E, Datz C, Gensluckner S, Maieron A, Mega A, Iglseder B, Langthaler P, Frey V, Paulweber B, Trinka E, Wernly B. Relationships between education and non-alcoholic fatty liver disease. Eur J Intern Med. 2023 Dec;118:98-107. doi: 10.1016/j.ejim.2023.07.039. Epub 2023 Aug 3. PMID: 37541922.
Lee WM, Bae JH, Chang Y, Lee SH, Moon JE, Jeong SW, Jang JY, Kim SG, Kim HS, Yoo JJ, Kim YS. Effect of Nutrition Education in NAFLD Patients Undergoing Simultaneous Hyperlipidemia Pharmacotherapy: A Randomized Controlled Trial. Nutrients. 2021 Dec 13;13(12):4453. doi: 10.3390/nu13124453. PMID: 34960005; PMCID: PMC8709046.

Introduction

Endoscopy is the gold standard for detecting mucosal inflammation in order to differentiate between Irritable Bowel Syndrome (IBS) and Inflammatory Bowel Disease (IBD) as well as for monitoring mucosal inflammation in diagnosed IBD patients. Fecal calprotectin has been established as an excellent surrogate biomarker of intestinal inflammation as it correlates well with endoscopic and histological disease activity. Most IBD diagnosis and treatment guidelines recommend using fecal calprotectin as an aid in diagnosis and to measure it routinely to follow the disease course in IBD patients. As there is no international standard to date, fecal calprotectin assay manufacturers rely on their own internal calprotectin standardization. Assays can be based on various technologies from traditional enzyme-linked immunosorbent assays (ELISA), particle enhanced turbidimetric high throughput assays (PETIA), to rapid lateral flow assays (LFA). LFAs can be read by conventional tabletop lateral flow readers or by everyday smartphone applications using the phone’s camera to acquire an image, detect the test cassette and calculate a quantitative result. It is essential that the biomarker is measured comparably across all assay methods. In this work, different assay methods were compared with clinical samples using a clinically relevant assay range.

Aims & Methods

128 raw stool samples from patients with signs and symptoms suggesting intestinal inflammation and who underwent endoscopic evaluation to determine if patients had IBD or IBS were used in this study. Samples were extracted using the BÜHLMANN CALEX Cap stool extraction device. Each extract was measured on the BÜHLMANN fCAL ELISA, fCAL turbo (PETIA), Quantum Blue fCAL extended lateral flow assay and smartphone based IBDoc fCAL home test. For the home test two phones, iPhone 11 and Samsung Galaxy S7, were used to measure the test cassettes. Each sample was measured one time on each assay and a Receiver Operating Characteristic (ROC) curve analysis was performed.

Results

ROC curves for each method were calculated in respect of differentiating between IBS and IBD with area under the curve (AUC) values ranging from 0.827 (Samsung Galaxy S7)) to 0.835 (fCAL turbo). There was no significant difference between the methods. BÜHLMANN uses a cut-off of 80 µg/g and 160 µg/g for IBS/IBD differentiation and 100 µg/g and 300 µg/g for IBD monitoring. For all methods, the sensitivity at the cut-off level of 80 µg/g was 90.8 % and specificity at 160 µg/g ranged from 67.3% to 71.2 %. Sensitivity at a cut-off of 100 µg/g ranged from 85.5% to 88.2% and specificity at 300 µg/g ranged from 82.7% to 86.5%.

Conclusion

This study shows that all BÜHLMANN fecal calprotectin assays are very comparable. They show an excellent clinical performance irrespective of the assay method performed. This allows for the use of the methods interchangeably, depending on the needs of the patients and their care team.

Disclosure

Authors are employee of BÜHLMANN Laboratories AG

Introduction

Per-Oral Endoscopic Myotomy (POEM) was introduced in clinical practice few years ago, and quickly become one of the first line treatments of esophageal motility disorders. We report on the outcomes of the first 1000 patients treated with POEM in a single tertiary referral center during 11 years.

Aims & Methods

The first 1000 patients treated with POEM between May 2011 and September 2022 were identified from a prospective database and included in this study.
Demographics, clinical and technical aspects and follow-up data were collected and analysed. After treatment, patients underwent a regular follow-up, after 6 month, 2 years, 5 years and 10 years. Additional follow-up visits were performed, if clinically indicated. Timed Barium Esophagram, EGD, and esophageal manometry were performed before endoscopic treatment and during post-operative follow-up; a 24-hour esophageal pH monitoring study was performed 6 months after POEM.
Clinical failure was defined by and Eckardt score > 3 and by the need for additional treatments.

Results

Mean age of patients was 51.5 years; 36 patients were younger than 18 years and 157 older than 70 years. Four-hundred ninety-eight patients were male. One hundred seventy-seven patients had received previous treatments for achalasia (110 pneumodilation, 46 surgical myotomy; 21 botulinum toxin injection).
A total of 141 patients had a type I achalasia, 626 a type II, 111% a type III, 30 non-achalasia spastic esophageal motility disorders; in 92 patients achalasia type were not adequately classified. A sigmoid-type esophagus was present in 45 patients.
Mean symptoms duration before POEM was 24±64.6 months.
POEM was technically successful in 979 patients.
The median length of myotomy was 8.0 cm (range 4-22 cm) in the esophagus and 3.1 cm (range 0-7 cm) in the stomach. An anterior myotomy was performed in the 83% of patients. Mean operative time was 50.4 minutes (11–180 minutes).
Length of hospital stay was a mean of 2.5 days (range 1 to 48 days) after POEM.
Mild or moderate complications occurred in 28 patients (2.8%) and were managed conservatively. Severe complications occurred in 2 patients and required prolongation of hospital stay and other interventional treatment. There were no perioperative deaths in our series.
A mean follow-up of 30.4 months (3–130 months) was available for 93.8% of patients. Overall clinical success rate (Eckardt score ≤ 3) was 95.1%. Clinical success was 97.3%, 95.2%, 90.8% and 82% after 6 months, 2 years, 5 years and 10 years, respectively.
Thirty-three patients (70.2 %) with clinical failure underwent pneumodilation (78.8% with persisting clinical benefits); 5 patients (10.6% underwent surgery), one (2.1%) underwent re-POEM.
Clinical success was 93.4% in achalasia-patients and 83.3% in those with spastic motility disorders (p=0.1742).
An altered esophageal pH-study was documented in 32.6% patients; esophagitis rate was 34% (88% grade A/B; 12% grade C/D). At the date of the last follow-up, 38% of patients was receiving daily proton-pump inhibitors for gastroesophageal reflux. Two patients underwent antireflux surgery. Non cases of post-operative Barrett esophagus were identified.

Conclusion

Our results confirm the efficacy of POEM in a large cohort of patients. Benefits of POEM seem durable; adverse events are rare and no specific mortality was reported. Prevalence of GERD is relatively high, but well controlled by medications in the vast majority of patients.