Prospective Observational Evaluation of the Time-Dependency of Adalimumab Immunogenicity and Drug Concentration in Ulcerative Colitis Patients: the POETIC II Study.

BACKGROUND AND AIMS: Home self-injection of the human anti-tumour necrosis alpha [anti-TNFα] monoclonal adalimumab complicates prospective serial-sampling studies. Although a recent study examined adalimumab levels and immunogenicity in Crohn's disease [CD] patients, prospective real-world data from ulcerative colitis [UC] patients are lacking. METHODS: A three-monthly home-visit programme from induction was established prospectively for UC patients. Clinical scores were determined at each visit, and sera were obtained for assessment of drug and anti-adalimumab antibody levels. Calprotectin was measured using a smartphone-based app. This cohort was compared to a parallel prospective cohort of adalimumab-treated CD patients [POETIC1]. RESULTS: Fifty UC patients starting adalimumab [median follow-up 28 weeks] were compared to 98 adalimumab-treated CD patients [median follow-up 44 weeks]. Only 11/50 UC patients [22%] continued treatment to the end of the follow-up compared with 50/98 [51%] CD patients (odds ratio [OR] = 0.27, p = 0.001). Loss of response was significantly more common in UC patients [OR = 3.2, p = 0.001]. Seventeen patients [34%] in the UC cohort developed anti-adalimumab antibodies, 9/17 [52.9%] as early as week 2. There was no difference between patient cohorts in the overall development of anti-adalimumab antibodies [34% vs 30.6%, respectively, OR = 1.67, p = 0.67], nor was there a difference in early immunogenicity [OR = 1.39, p = 0.35]. There was no difference in low drug levels [<3 µg/mL] between the two cohorts [OR = 0.87, p = 0.83]. CONCLUSIONS: Loss of response to adalimumab therapy was significantly more common in the UC compared to the CD cohort and was driven by a higher rate of non-immunogenic, pharmacodynamic parameters.

Evaluating the Utility of a Large Language Model in Answering Common Patients' Gastrointestinal Health-Related Questions: Are We There Yet?

BACKGROUND AND AIMS: Patients frequently have concerns about their disease and find it challenging to obtain accurate Information. OpenAI's ChatGPT chatbot (ChatGPT) is a new large language model developed to provide answers to a wide range of questions in various fields. Our aim is to evaluate the performance of ChatGPT in answering patients' questions regarding gastrointestinal health. METHODS: To evaluate the performance of ChatGPT in answering patients' questions, we used a representative sample of 110 real-life questions. The answers provided by ChatGPT were rated in consensus by three experienced gastroenterologists. The accuracy, clarity, and efficacy of the answers provided by ChatGPT were assessed. RESULTS: ChatGPT was able to provide accurate and clear answers to patients' questions in some cases, but not in others. For questions about treatments, the average accuracy, clarity, and efficacy scores (1 to 5) were 3.9 ± 0.8, 3.9 ± 0.9, and 3.3 ± 0.9, respectively. For symptoms questions, the average accuracy, clarity, and efficacy scores were 3.4 ± 0.8, 3.7 ± 0.7, and 3.2 ± 0.7, respectively. For diagnostic test questions, the average accuracy, clarity, and efficacy scores were 3.7 ± 1.7, 3.7 ± 1.8, and 3.5 ± 1.7, respectively. CONCLUSIONS: While ChatGPT has potential as a source of information, further development is needed. The quality of information is contingent upon the quality of the online information provided. These findings may be useful for healthcare providers and patients alike in understanding the capabilities and limitations of ChatGPT.

Evaluating the use of large language model in identifying top research questions in gastroenterology.

The field of gastroenterology (GI) is constantly evolving. It is essential to pinpoint the most pressing and important research questions. To evaluate the potential of chatGPT for identifying research priorities in GI and provide a starting point for further investigation. We queried chatGPT on four key topics in GI: inflammatory bowel disease, microbiome, Artificial Intelligence in GI, and advanced endoscopy in GI. A panel of experienced gastroenterologists separately reviewed and rated the generated research questions on a scale of 1-5, with 5 being the most important and relevant to current research in GI. chatGPT generated relevant and clear research questions. Yet, the questions were not considered original by the panel of gastroenterologists. On average, the questions were rated 3.6 ± 1.4, with inter-rater reliability ranging from 0.80 to 0.98 (p < 0.001). The mean grades for relevance, clarity, specificity, and originality were 4.9 ± 0.1, 4.6 ± 0.4, 3.1 ± 0.2, 1.5 ± 0.4, respectively. Our study suggests that Large Language Models (LLMs) may be a useful tool for identifying research priorities in the field of GI, but more work is needed to improve the novelty of the generated research questions.

Anti-TNFα Treatment Impairs Long-Term Immune Responses to COVID-19 mRNA Vaccine in Patients with Inflammatory Bowel Diseases.

Patients with inflammatory bowel disease (IBD) treated with anti-tumor-necrosis factor-alpha (TNFα) exhibited lower serologic responses one-month following the second dose of the COVID-19 BNT162b2 vaccine compared to those not treated with anti-TNFα (non-anti-TNFα) or to healthy controls (HCs). We comprehensively analyzed long-term humoral responses, including anti-spike (S) antibodies, serum inhibition, neutralization, cross-reactivity and circulating B cell six months post BNT162b2, in patients with IBD stratified by therapy compared to HCs. Subjects enrolled in a prospective, controlled, multi-center Israeli study received two BNT162b2 doses. Anti-S levels, functional activity, specific B cells, antigen cross-reactivity, anti-nucleocapsid levels, adverse events and IBD disease score were detected longitudinally. In total, 240 subjects, 151 with IBD (94 not treated with anti-TNFα and 57 treated with anti-TNFα) and 89 HCs participated. Six months after vaccination, patients with IBD treated with anti-TNFα had significantly impaired BNT162b2 responses, specifically, more seronegativity, decreased specific circulating B cells and cross-reactivity compared to patients untreated with anti-TNFα. Importantly, all seronegative subjects were patients with IBD; of those, >90% were treated with anti-TNFα. Finally, IBD activity was unaffected by BNT162b2. Altogether these data support the earlier booster dose administration in these patients.

Trends in inflammatory bowel disease infections and vaccinations in the past four decades: A high-level text mining analysis of PubMed publications.

AIM: We aimed at assessing the published literature on different prophylactic screening and vaccination options in inflammatory bowel disease (IBD) patients between 1980 and 2020. Special attention was attributed to latest data assessing covid-19 vaccinations. METHODS: We have queried PubMed for all available IBD-related entries published during 1980-2020. The following data were extracted for each entry: PubMed unique article ID (PMID), title, publishing journal, abstract text, keywords (if any), and authors' affiliations. Two gastrointestinal specialists decided by consensus on a list of terms to classify entries. The terms belonged to four treatment groups: opportunistic infections, prophylactic screening, prophylactic vaccinations/treatment, and routine vaccines. Annual trends of publications for the years 1980-2020 were plotted for different screening, vaccinations and infection types. Slopes of publication trends were calculated by fitting regression lines to the annual number of publications. RESULTS: Overall, 98,339 IBD entries were published between 1980 and 2020. Of those, 7773 entries belonged to the investigated groups. Entries concerning opportunistic infections showed the sharpest rise, with 19 entries and 1980 to 423 entries in 2020 (slope 11.3, p < .001). Entries concerning prophylactic screening rose from 10 entries in 1980 to 204 entries in 2020 (slope 5.4, p < .001). Both entries concerning prophylactic vaccinations/treatments and routine vaccines did not show a significant rise (slope 0.33 and slope 0.92, respectively). During the COVID 19 pandemic, a total of 44 publications were identified. Of them, 37 were relevant to vaccines and immune reaction. Nineteen publications (51%) were guidelines/recommendations, and 14 (38%) assessed immune reaction to vaccination, most of them (11, 61%) to mRNA vaccines. CONCLUSIONS: During the past two decades, along with a rapid increase in biologic therapy, publications regarding opportunistic infections and prophylactic screening increased in a steep slope compared to the two decades in the pre-biologic area. During the COVID-19 pandemic, most publications included vaccination recommendations and guidelines and only 38% included real-world data assessing reaction to vaccinations. More research is needed.

Changes in Helicobacter pylori Treatment from Discovery to Nowadays: A High-Level Analysis of PubMed Publications.

Background: Since the discovery of Helicobacter pylori (H. pylori) 40 years ago, treatment options have changed dramatically adjacent to new drugs development and the emergence of multi-drug resistance. In this study, we aimed to assess published literature on treatment regimens for H. pylori in the past four decades, with regards to specific drug resistance and geographic distribution. Methods: We have queried PubMed for all available H. pylori-related entries published during 1987-2020. For each entry, we retrieved the title, abstract, and keywords. Two gastrointestinal specialists decided in consensus on a list of terms to classify entries. The terms specify types of treatment and different types of regimens. Annual trends of publications were plotted for different treatment types and sub-analyses. Results: Overall, 47,170 H. pylori-related entries were published between 1987 and 2020. Medication treatment showed the highest number of total publications 6183/47,170 (13.1%), followed by antibiotics 5493/47,170 (11.6%), and probiotic which was substantially lower (0.7%). For treatment regimens type, triple therapy had the highest number of publications 2400/47,170 (5.1%) followed by sequential therapy 342/47,170 (0.7%), and bismuth quadruple therapy 115/47,170 (0.2%). Analysis by antibiotic resistance showed that clarithromycin treatment had the highest number of publications 3537/47,170 (7.5%). Since 2013, there is a steep upward slope (5.1±0.7 publications/year, p < 0.001) for publications originating from China. Conclusion: Our findings reflect the changes of the commonly prescribed regimens along the years, following the occurrence and the rise of H. pylori antibiotic resistance. In recent years, there is a steep rise in publications in countries with policies of screening and eradication for gastric cancer prevention, which is currently not applied in Western countries. A text-mining analysis of H. pylori publications contributes to the understanding of treatment options and development trends worldwide.

Innovation in Gastroenterology-Can We Do Better?

The health system can reap significant benefits by adopting and implementing innovative measures, as was recently demonstrated and emphasized during the COVID-19 pandemic. Herein, we present our bird's eye view of gastroenterology's innovative technologies via utilizing a text-mining technique. We analyzed five research fields that comply with innovation: artificial intelligence (AI), virtual reality (VR), telemedicine, the microbiome, and advanced endoscopy. According to gastroenterology literature, the two most innovative fields were the microbiome and advanced endoscopy. Though artificial intelligence (AI), virtual reality (VR), and telemedicine trailed behind, the number of AI publications in gastroenterology has shown an exponential trend in the last couple of years. While VR and telemedicine are neglected compared to other fields, their implementation could improve physician and patient training, patient access to care, cost reduction, and patient outcomes.

COVID-19 in Patients with Inflammatory Bowel Disease: The Israeli Experience.

BACKGROUND: Crohn's disease (CD) and ulcerative colitis (UC) are chronic, immune-mediated inflammatory bowel diseases (IBD) affecting millions of people worldwide. IBD therapies, designed for continuous immune suppression, often render patients more susceptible to infections. The effect of the immune suppression on the risk of coronavirus disease-19 (COVID-19) is not fully determined yet. OBJECTIVE: To describe COVID-19 characteristics and outcomes and to evaluate the association between IBD phenotypes, infection outcomes and immunomodulatory therapies. METHODS: In this multi-center study, we prospectively followed IBD patients with proven COVID-19. De-identified data from medical charts were collected including age, gender, IBD type, IBD clinical activity, IBD treatments, comorbidities, symptoms and outcomes of COVID-19. A multivariable regression model was used to examine the effect of immunosuppressant drugs on the risk of infection by COVID-19 and the outcomes. RESULTS: Of 144 IBD patients, 104 (72%) were CD and 40 (28%) were UC. Mean age was 32.2 ± 12.6 years. No mortalities were reported. In total, 94 patients (65.3%) received biologic therapy. Of them, 51 (54%) at escalated doses, 10 (11%) in combination with immunomodulators and 9 (10%) with concomitant corticosteroids. Disease location, behavior and activity did not correlate with the severity of COVID-19. Biologics as monotherapy or with immunomodulators or corticosteroids were not associated with more severe infection. On the contrary, patients receiving biologics had significantly milder infection course (p = 0.001) and were less likely to be hospitalized (p = 0.001). Treatment was postponed in 34.7% of patients until recovery from COVID-19, without consequent exacerbation. CONCLUSION: We did not witness aggravated COVID-19 outcomes in patients with IBD. Patients treated with biologics had a favorable outcome.

Lower Serologic Response to COVID-19 mRNA Vaccine in Patients With Inflammatory Bowel Diseases Treated With Anti-TNFα.

BACKGROUND & AIM: Patients with inflammatory bowel diseases (IBD), specifically those treated with anti-tumor necrosis factor (TNF)α biologics, are at high risk for vaccine-preventable infections. Their ability to mount adequate vaccine responses is unclear. The aim of the study was to assess serologic responses to messenger RNA-Coronavirus Disease 2019 vaccine, and safety profile, in patients with IBD stratified according to therapy, compared with healthy controls (HCs). METHODS: Prospective, controlled, multicenter Israeli study. Subjects enrolled received 2 BNT162b2 (Pfizer/BioNTech) doses. Anti-spike antibody levels and functional activity, anti-TNFα levels and adverse events (AEs) were detected longitudinally. RESULTS: Overall, 258 subjects: 185 IBD (67 treated with anti-TNFα, 118 non-anti-TNFα), and 73 HCs. After the first vaccine dose, all HCs were seropositive, whereas ∼7% of patients with IBD, regardless of treatment, remained seronegative. After the second dose, all subjects were seropositive, however anti-spike levels were significantly lower in anti-TNFα treated compared with non-anti-TNFα treated patients, and HCs (both P < .001). Neutralizing and inhibitory functions were both lower in anti-TNFα treated compared with non-anti-TNFα treated patients, and HCs (P < .03; P < .0001, respectively). Anti-TNFα drug levels and vaccine responses did not affect anti-spike levels. Infection rate (∼2%) and AEs were comparable in all groups. IBD activity was unaffected by BNT162b2. CONCLUSIONS: In this prospective study in patients with IBD stratified according to treatment, all patients mounted serologic response to 2 doses of BNT162b2; however, its magnitude was significantly lower in patients treated with anti-TNFα, regardless of administration timing and drug levels. Vaccine was safe. As vaccine serologic response longevity in this group may be limited, vaccine booster dose should be considered.

Trends in inflammatory bowel disease treatment in the past two decades-a high-level text mining analysis of PubMed publications.

AIM: Many therapeutic options for inflammatory bowel disease (IBD) emerged during the last 2 decades, along with the rise in disease prevalence and incidence. We aimed at assessing the published literature on different treatment options in that period. Special attention was attributed to specific medication mechanisms and geographic diversity. MATERIALS AND METHODS: We have queried PubMed for all available IBD-related entries published during 2000-2020. The following data were extracted for each entry: PubMed unique article ID (PMID), title, publishing journal, abstract text, keywords (if any), and authors' affiliations. Two gastrointestinal specialists decided in consensus on a list of terms to classify entries. The terms belonged to five treatment groups: medical, surgical, dietary, microbiome manipulation, and complementary medicine. The medical and complementary medicine groups were further sub-classified. Annual trends of publications for the years 2000-2020 were plotted for different treatment types. The slopes of publication trends were calculated by fitting regression lines to the annual number of publications. RESULTS: Overall, 77,505 IBD entries were published between 2000 and 2020. Medical treatment showed the highest number of total publications 21,540/77,505 (27.8%), followed by surgical 7605/77,505 (9.8%), microbiome research 5260/77,505 (6.8%), dietary 4819/77,505 (6.2%), and complementary medicine treatment 762/77,505 (1.0%). Interestingly, since 2012 there is a steep rise in microbiome publications that outnumbered surgery in the last 2 years. Trend analysis of medical treatment showed that biologics had the steepest slope (57.5, p < 0.001), followed by immunomodulators (4.9, p < 0.001), small molecules (3.9, p < 0.001), and 5-ASA (3.8, p < 0.001). CONCLUSION: According to our high-level publications trend analysis, the past 2 decades certainly deserve the reference as the "biologic era", as publications regarding biological therapy outnumbered all other treatment options. Interestingly, though very popular among patients, complementary medicine was not studied with correlation to its' acceptance among patients.

A novel PillCam Crohn's capsule score (Eliakim score) for quantification of mucosal inflammation in Crohn's disease.

INTRODUCTION: Capsule endoscopy is an important modality for monitoring of Crohn's disease. Recently, a novel panenteric capsule, PillCam Crohn's (Medtronic, USA), was approved for use. No quantitative index of inflammation for this method is currently available. This sub-study of a prospective randomized controlled Comprehensive individUalized pRoactive ThErapy of Crohn's Disease trial (CURE-CD) which aimed to compare the correlation and reliability of the novel PillCam Crohn's score with the existing small bowel capsule Lewis inflammatory score. METHODS: The study cohort included Crohn's disease patients in remission who were evaluated with PillCam Crohn's. Each result was independently reviewed by two experienced readers. Inflammation was scored in all studies using Lewis inflammatory score and PillCam Crohn's score (comprised of a sum of scores for most common and most severe lesions multiplied by percentage of segmental involvement + stricture score). RESULTS: Fifty-four PillCam Crohn's studies from 41 patients were included. The median Lewis inflammatory score was 225 for both readers. The median PillCam Crohn's score was six (0-14) and four (3-15) for readers 1 and 2, respectively. There was a high inter-rater reliability coefficient between the two readers for Lewis inflammatory and PillCam Crohn's score (0.9, p < 0.0001 for both). The correlation between PillCam Crohn's score and fecal calprotectin was stronger than for Lewis inflammatory score (r = 0.32 and 0.54 respectively, p = 0.001 for both). CONCLUSIONS: The novel panenteric capsule score correlates well with the Lewis inflammatory score, has excellent reliability, and may be potentially more accurate in estimation of the panenteric inflammatory burden.

G-EYE colonoscopy is superior to standard colonoscopy for increasing adenoma detection rate: an international randomized controlled trial (with videos).

BACKGROUND AND AIMS: Colorectal cancer (CRC) is largely preventable with routine screening and surveillance colonoscopy; however, interval cancers arising from precancerous lesions missed by standard colonoscopy still occur. An increased adenoma detection rate (ADR) has been found to be inversely associated with interval cancers. The G-EYE device includes a reusable balloon integrated at the distal tip of a standard colonoscope, which flattens haustral folds, centralizes the colonoscope's optics, and reduces bowel slippage. The insufflated balloon also aims to enhance visualization of the colon during withdrawal, thereby increasing the ADR. METHODS: In this randomized, controlled, international, multicenter study (11 centers), patients (aged ≥50 years) referred to colonoscopy for screening, surveillance, or changes in bowel habits were randomized to undergo either balloon-assisted colonoscopy by using an insufflated balloon during withdrawal or standard high-definition colonoscopy. The primary endpoint was the ADR. RESULTS: One thousand patients were enrolled between May 2014 and September 2016 to undergo colonoscopy by experienced endoscopists; 803 were finally analyzed (standard colonoscopy n = 396; balloon-assisted colonoscopy n = 407). Baseline parameters were similar in both groups. Balloon-assisted colonoscopy provided a 48.0% ADR compared with 37.5% in the standard colonoscopy group (28% increase; P = .0027). Additionally, balloon-assisted colonoscopy provided for a significant increase in detection of advanced (P = .0033) flat adenomas (P < .0001) and sessile serrated adenomas/polyps (P = .0026). CONCLUSION: Balloon-assisted colonoscopy yielded a higher ADR and increased the detection of advanced, flat, and sessile serrated adenomas/polyps when compared with standard colonoscopy. Improved detection by the G-EYE device could impact the quality of CRC screening by reducing miss rates and consequently reducing interval cancer incidence. (Clinical trial registration number: NCT01917513.).

Prospective Observational Evaluation of Time-Dependency of Adalimumab Immunogenicity and Drug Concentrations: The POETIC Study.

OBJECTIVES: Adalimumab is usually self-injected at home, making prospective serial-sampling studies challenging and scarce. This has led to a gap in knowledge about evolution of anti-adalimumab antibodies (AAAs) over time and its correlation with clinical and inflammatory outcomes. METHODS: A program for home visits by physicians at induction, every 3 months and at event of relapse, was established prospectively for Crohn's disease (CD) patients. At each visit, patients' clinical scores were determined and sera were obtained for C-reactive protein, drug, and AAA levels. This cohort was compared to a parallel prospective cohort of infliximab-treated CD patients. In a subgroup of 29 patients, trough and in-between-trough levels were compared, to elucidate the importance of timing of sampling during the injection cycle. RESULTS: Ninety-eight CD patients starting adalimumab were prospectively followed (median follow-up 44 weeks) and 621 serum samples were analyzed. Thirty-three patients (32%) developed AAA; 18/33 (55%) of them as early as week 2, and 26/33 (79%) by week 14. Induction period AAAs were strongly associated with primary non-response (odds ratio (OR) = 5.4, 95% confidence interval (CI): 1.6-17.8, p = 0.005). As compared to antibodies-to-infliximab (ATI), AAA formation rate over time was significantly lower (p = 0.01) and AAA were much more specific-85% of AAA events were associated with loss-of-response compared with 58% rate for ATI (p = 0.01). In 29 patients sampled serially during an injection cycle, levels of drug and AAA seemed comparable between four time-points during a single cycle both in patients with or without AAA (n = 8, n = 21, respectively). CONCLUSIONS: When followed prospectively and serially, AAAs are found to arise earlier than previously appreciated and their impact may be more pronounced for primary rather than secondary, non-response. Drug and AAA levels were similar both at trough and in-between injections, enabling to simplify therapeutic drug monitoring of adalimumab.

Tuberous sclerosis in a military pilot.

Tuberous sclerosis (TS) is a multisystem disorder characterized by hamartomas in various organs. It usually manifests itself during infancy or childhood with neurological features, including mental retardation and seizures. We present the case of a military pilot who was diagnosed with TS at 22 yr. of age after he had completed flight training. Suspicion of TS arose from evaluation of a chronic rash around the pilot's nose, and diagnosis was confirmed based on the presence of multiple calcified nodules on CT imaging of the brain. No neurological abnormalities were found. The primary aeromedical concerns were the risk of seizures or development of tumors at sites that might lead to sudden incapacitation. Hamartomas can be reliably detected at an early stage by means of annual history, physical examination, and imaging of tumor-prone organs. After review of the literature and consultation with medical specialists, we assessed the risk of adult-onset seizures in a TS patient without preexisting neurological findings as scarce. The pilot was therefore granted a waiver limited to flying a two-pilot helicopter with a program of tight medical follow-up.

[Drug-induced pancreatitis].

Acute pancreatitis (AP) is a rapidly onset inflammation of the pancreas. Clinical characteristics of AP are severe pain in the upper abdomen and at least a threefold elevation of pancreatic enzymes in the blood. Many conditions predispose to AP; the most common are gallstones and chronic alcohol abuse which account for 75% of acute pancreatitis in the United States. Medications are an infrequent but important and rising cause of acute pancreatitis and contribute about 2% of the cases. Over 100 drugs have been implicated as a cause for AP, mostly from case and anecdotal reports. Documentation of drug-induced pancreatitis (DIP) is more definite if other likely causes of pancreatitis are not present, if there is recovery after drug withdrawal, and if pancreatitis recurs with reintroduction of the drug. In addition, some medications reported to have caused AP have obvious patterns of presentation, including the time from initiation to the development of disease (latency). The authors describe two large reviews of the literature which have classified drugs that have been reported to cause AP based on the published weight of evidence for each agent and the pattern of clinical presentation. Among adverse drug reactions, pancreatitis is often ignored because of the difficulty in implicating a drug as its cause. The physician should have a high index of suspicion for DIP.