Use of digital health tools in inflammatory bowel disease. / Uso de herramientas digitales en salud en enfermedad inflamatoria intestinal.

OBJECTIVE: To analyse the characteristics and use of digital health tools (DHT) in inflammatory bowel disease (IBD). METHODS: We performed a qualitative study based on a narrative literature review, a questionnaire and on the opinion of 3 expert gastroenterologists. Several searches were carried out until September 2022 through Medline to identify articles on the use of DHT in IBD by healthcare professionals. A structured questionnaire was designed to be answered by health professionals involved in the care of patients with IBD. The experts generated a set of recommendations. RESULTS: There are multiple DHT for IBD with different characteristics and contents. We received 29 questionnaires. Almost 50% of the participants were 41-50 years old, the majority were women (83%) and 90% were gastroenterologists. A total of 96% reported the use of several DHT, but 20% used them occasionally or infrequently. Web pages were found the most used (62%). DHT are mostly used to get information (80%), followed by clinical practice issues (70%) and educational purposes (62%). G-Educainflamatoria website is the best known and most used HDS (96% and 64%, respectively). The main barriers to the use of DHT in IBD were the lack of time (55%), doubts about the benefit of DHT (50%) and the excess of information (40%). CONCLUSIONS: Healthcare professionals involved in the care of patients with to IBD frequently use DHT, although actions are needed to optimize their use and to guarantee their efficient and safe use.

The Natural History of Patients With Pre-Existing and De Novo Inflammatory Bowel Disease After Solid Organ Transplantation: EITOS Study of GETECCU.

BACKGROUND: Limited data are available on the outcome of inflammatory bowel disease (IBD) in patients with solid organ transplantation (SOT). We describe the natural history of pre-existing IBD and de novo IBD after SOT. METHODS: This was a retrospective, multicenter study that included patients with pre-existing IBD at the time of SOT and patients with de novo IBD after SOT. The primary outcome was IBD progression, defined by escalation of medical treatment, surgical therapy, or hospitalization due to refractory IBD. Risk factors were identified using multivariate Cox proportional hazard analysis. RESULTS: A total of 177 patients (106 pre-existing IBD and 71 de novo IBD) were included. Most patients with pre-existing IBD (92.5%) were in remission before SOT. During follow-up, 32% of patients with pre-existing IBD had disease progression, with a median time between SOT and IBD progression of 2.2 (interquartile range, 1.3-4.6) years. In the de novo cohort, 55% of patients had disease progression with a median time to flare of 1.9 (interquartile range, 0.8-3.9) years after diagnosis. In the pre-existing IBD cohort, active IBD at the time of SOT (hazard ratio, 1.80; 95% confidence interval, 1.14-2.84; P = .012) and the presence of extraintestinal manifestations (hazard ratio, 3.10; 95% confidence interval, 1.47-6.54; P = .003) were predictive factors for IBD progression. CONCLUSIONS: One-third of patients with pre-existing IBD and about half of patients with de novo IBD have disease progression after SOT. Active IBD at the time of SOT and the presence of extraintestinal manifestations were identified as risk factors for IBD progression.

Real-World Cohort Study on the Effectiveness and Safety of Filgotinib Use in Ulcerative Colitis.

BACKGROUND: Filgotinib is a small molecule with preferential inhibition of Janus kinase type 1, approved for the treatment of ulcerative colitis in Scotland in May 2022. We present the first real world experience on its use in clinical practice. METHODS: In this retrospective, observational, cohort study we assessed patients with active ulcerative colitis who received filgotinib in NHS Lothian, Scotland. Baseline demographic, phenotype and follow-up data were collected via review of electronic medical records. RESULTS: We included 91 patients with median treatment duration of 39 weeks (IQR 23-49). Among the cohort, 67% (61/91) were biologic and small molecule naïve, whilst 20.9% (19/91) had failed one and 12.1% (11/91) ≥2 classes of advanced therapy. Of the biologic and small molecule naïve patients, 18% (11/61) were also thiopurine naïve. Clinical remission (partial Mayo score <2) was achieved in 71.9% (41/57) and 76.4% (42/55) of patients at weeks 12 and 24 respectively. Biochemical remission (CRP≤5mg/L) was achieved in 87.3% (62/71) at week 12 and 88.9% (40/45) at week 24. Faecal biomarker (calprotectin <250µg/g) remission was achieved in 82.8% (48/58) at week 12 and 79.5% (35/44) at week 24.At the end of follow-up, median 42 weeks (IQR 27-50), 82.4% (75/91) of patients remained on filgotinib. Severe adverse events leading to drug discontinuation occurred in 2.2% (2/91) and there were 8.8% (8/91) moderate adverse events that required temporary discontinuation. CONCLUSION: These are the first reported data on the real-world efficacy and safety of filgotinib in ulcerative colitis. Our findings demonstrate that filgotinib is an effective and low risk treatment option for these patients.

Crossing barriers: the burden of inflammatory bowel disease across Western Europe.

An estimated 2.5-3 million individuals (0.4%) in Europe are affected by inflammatory bowel disease (IBD). Whilst incidence rates for IBD are stabilising across Europe, the prevalence is rising and subsequently resulting in a significant cost to the healthcare system of an estimated 4.6-5.6 billion euros per year. Hospitalisation and surgical resection rates are generally on a downward trend, which is contrary to the rising cost of novel medication. This signifies a large part of healthcare cost and burden. Despite publicly funded healthcare systems in most European countries, there is still wide variation in how patients receive and/or pay for biologic medication. This review will provide an overview and discuss the different healthcare systems within Western Europe and the barriers that affect overall management of a changing IBD landscape, including differences to hospitalisation and surgical rates, access to medication and clinical trial participation and recruitment. This review will also discuss the importance of standardising IBD management to attain high-quality care for all patients with IBD.

Ulcerative Colitis in Adults: A Review.

Importance: Ulcerative colitis (UC) is a chronic inflammatory condition of the colon, with a prevalence exceeding 400 per 100 000 in North America. Individuals with UC have a lower life expectancy and are at increased risk for colectomy and colorectal cancer. Observations: UC impairs quality of life secondary to inflammation of the colon causing chronic diarrhea and rectal bleeding. Extraintestinal manifestations, such as primary sclerosing cholangitis, occur in approximately 27% of patients with UC. People with UC require monitoring of symptoms and biomarkers of inflammation (eg, fecal calprotectin), and require colonoscopy at 8 years from diagnosis for surveillance of dysplasia. Risk stratification by disease location (eg, Montreal Classification) and disease activity (eg, Mayo Score) can guide management of UC. First-line therapy for induction and maintenance of remission of mild to moderate UC is 5-aminosalicylic acid. Moderate to severe UC may require oral corticosteroids for induction of remission as a bridge to medications that sustain remission (biologic monoclonal antibodies against tumor necrosis factor [eg, infliximab], α4ß7 integrins [vedolizumab], and interleukin [IL] 12 and IL-23 [ustekinumab]) and oral small molecules that inhibit janus kinase (eg, tofacitinib) or modulate sphingosine-1-phosphate (ozanimod). Despite advances in medical therapies, the highest response to these treatments ranges from 30% to 60% in clinical trials. Within 5 years of diagnosis, approximately 20% of patients with UC are hospitalized and approximately 7% undergo colectomy. The risk of colorectal cancer after 20 years of disease duration is 4.5%, and people with UC have a 1.7-fold higher risk for colorectal cancer compared with the general population. Life expectancy in people with UC is approximately 80.5 years for females and 76.7 years for males, which is approximately 5 years shorter than people without UC. Conclusions and Relevance: UC affects approximately 400 of every 100 000 people in North America. An effective treatment for mild to moderate UC is 5-aminosalicylic acid, whereas moderate to severe UC can be treated with advanced therapies that target specific inflammation pathways, including monoclonal antibodies to tumor necrosis factor, α4ß7 integrins, and IL-12 and IL-23 cytokines, as well as oral small molecule therapies targeting janus kinase or sphingosine-1-phosphate.

Safety, Effectiveness, and Treatment Persistence of Subcutaneous Vedolizumab in IBD: A Multicenter Study From the United Kingdom.

BACKGROUND AND AIMS: Despite intravenous (IV) vedolizumab being established for treatment of inflammatory bowel disease (IBD), the novel subcutaneous (SC) route of administration may provide numerous incentives to switch. However, large-scale real-world data regarding the long-term safety and effectiveness of this strategy are lacking. METHODS: IBD patients on IV vedolizumab across 11 UK sites agreed to transition to SC injections or otherwise continued IV treatment. Data regarding clinical disease activity (Simple Clinical Colitis Activity Index, partial Mayo score, and modified Harvey-Bradshaw Index), biochemical markers (C-reactive protein and calprotectin), quality of life (IBD control), adverse events, treatment persistence, and disease-related outcomes (namely corticosteroid use, IBD-related hospitalization, and IBD-related surgery) were retrospectively collected from prospectively maintained clinical records at baseline and weeks 8, 24, and 52. RESULTS: Data from 563 patients (187 [33.2%] Crohn's disease, 376 [66.8%] ulcerative colitis; 410 [72.8%] SC, 153 [27.2%] IV) demonstrated no differences in disease activity, remission rates, and quality of life between the SC and IV groups at all time points. Drug persistence at week 52 was similar (81.1% vs 81.2%; P = .98), as were rates of treatment alteration due to either active disease (12.2% vs 8.9%; P = .38) or adverse events (3.3% vs 6.3%; P = .41). At week 52, there were equivalent rates of adverse events (9.8% vs 7.8%; P = .572) and disease-related outcomes. IBD control scores were equivalent in both IV-IV and IV-SC groups. CONCLUSIONS: Switching to SC vedolizumab appears as effective, safe, and well tolerated as continued IV treatment and maintains comparable disease control and quality of life as IV treatment at 52 weeks.

Development of a Prediction Model for Short-Term Remission of Patients with Crohn's Disease Treated with Anti-TNF Drugs.

Therapy with anti-tumor necrosis factor (TNF) has dramatically changed the natural history of Crohn's disease (CD). However, these drugs are not without adverse events, and up to 40% of patients could lose efficacy in the long term. We aimed to identify reliable markers of response to anti-TNF drugs in patients with CD. A consecutive cohort of 113 anti-TNF naive patients with CD was stratified according to clinical response as short-term remission (STR) or non-STR (NSTR) at 12 weeks of treatment. We compared the protein expression profiles of plasma samples in a subset of patients from both groups prior to anti-TNF therapy by SWATH proteomics. We identified 18 differentially expressed proteins (p ≤ 0.01, fold change ≥ 2.4) involved in the organization of the cytoskeleton and cell junction, hemostasis/platelet function, carbohydrate metabolism, and immune response as candidate biomarkers of STR. Among them, vinculin was one of the most deregulated proteins (p < 0.001), whose differential expression was confirmed by ELISA (p = 0.054). In the multivariate analysis, plasma vinculin levels along with basal CD Activity Index, corticosteroids induction, and bowel resection were factors predicting NSTR.

Real-world outcomes of switching from adalimumab originator to adalimumab biosimilar in patients with inflammatory bowel disease: The ADA-SWITCH study.

BACKGROUND AND AIMS: Data on the outcomes after switching from adalimumab (ADA) originator to ADA biosimilar are limited. The aim was to compare the treatment persistence, clinical efficacy, and safety outcomes in inflammatory bowel disease patients who maintained ADA originator vs. those who switched to ADA biosimilar. METHODS: Patients receiving ADA originator who were in clinical remission at standard dose of ADA originator were included. Patients who maintained ADA originator formed the non-switch cohort (NSC), and those who switched to different ADA biosimilars constituted the switch cohort (SC). Clinical remission was defined as a Harvey-Bradshaw index ≤4 in Crohn's disease and a partial Mayo score ≤2 in ulcerative colitis. To control possible confounding effects on treatment discontinuation, an inverse probability treatment weighted proportional hazard Cox regression was performed. RESULTS: Five hundred and twenty-four patients were included: 211 in the SC and 313 in the NSC. The median follow-up was 13 months in the SC and 24 months in the NSC (p < 0.001). The incidence rate of ADA discontinuation was 8% and 7% per patient-year in the SC and in the NSC, respectively (p > 0.05). In the multivariate analysis, switching from ADA originator to ADA biosimilar was not associated with therapy discontinuation. The incidence rate of relapse was 8% per patient-year in the SC and 6% per patient-year in the NSC (p > 0.05). Six percent of the patients had adverse events in the SC vs. 5% in the NSC (p > 0.05). CONCLUSION: Switching to ADA biosimilar did not impair patients' outcomes in comparison with maintaining on the originator.

Longitudinal Fecal Calprotectin Profiles Characterize Disease Course Heterogeneity in Crohn's Disease.

BACKGROUND AND AIMS: The progressive nature of Crohn's disease is highly variable and hard to predict. In addition, symptoms correlate poorly with mucosal inflammation. There is therefore an urgent need to better characterize the heterogeneity of disease trajectories in Crohn's disease by utilizing objective markers of inflammation. We aimed to better understand this heterogeneity by clustering Crohn's disease patients with similar longitudinal fecal calprotectin profiles. METHODS: We performed a retrospective cohort study at the Edinburgh IBD Unit, a tertiary referral center, and used latent class mixed models to cluster Crohn's disease subjects using fecal calprotectin observed within 5 years of diagnosis. Information criteria, alluvial plots, and cluster trajectories were used to decide the optimal number of clusters. Chi-square test, Fisher's exact test, and analysis of variance were used to test for associations with variables commonly assessed at diagnosis. RESULTS: Our study cohort comprised 356 patients with newly diagnosed Crohn's disease and 2856 fecal calprotectin measurements taken within 5 years of diagnosis (median 7 per subject). Four distinct clusters were identified by characteristic calprotectin profiles: a cluster with consistently high fecal calprotectin and 3 clusters characterized by different downward longitudinal trends. Cluster membership was significantly associated with smoking (P = .015), upper gastrointestinal involvement (P < .001), and early biologic therapy (P < .001). CONCLUSIONS: Our analysis demonstrates a novel approach to characterizing the heterogeneity of Crohn's disease by using fecal calprotectin. The group profiles do not simply reflect different treatment regimens and do not mirror classical disease progression endpoints.

Exploring the Pipeline of Novel Therapies for Inflammatory Bowel Disease; State of the Art Review.

Crohn's disease (CD) and ulcerative colitis (UC), known as inflammatory bowel diseases (IBD), are characterized by chronic inflammation of the gastrointestinal tract. Over the last two decades, numerous medications have been developed and repurposed to induce and maintain remission in IBD patients. Despite the approval of multiple drugs, the major recurring issues continue to be primary non-response and secondary loss of response, as well as short- and long-term adverse events. Most clinical trials show percentages of response under 60%, possibly as a consequence of strict inclusion criteria and definitions of response. That is why these percentages appear to be more optimistic in real-life studies. A therapeutic ceiling has been used as a term to define this invisible bar that has not been crossed by any drug yet. This review highlights novel therapeutic target agents in phases II and III of development, such as sphingosine-1-phosphate receptor modulators, selective Janus kinase inhibitors, anti-interleukins, and other small molecules that are currently under research until 1 January 2023. Emerging treatments for CD and UC that have just received approval or are undergoing phase III clinical trials are also discussed in this review.

Multiple infliximab biosimilar switches appear to be safe and effective in a real-world inflammatory bowel disease cohort.

BACKGROUND: Switching from originator infliximab (IFX) to biosimilar IFX is effective and safe. However, data on multiple switching are scarce. The Edinburgh inflammatory bowel disease (IBD) unit has undertaken three switch programmes: (1) Remicade to CT-P13 (2016), (2) CT-P13 to SB2 (2020), and (3) SB2 to CT-P13 (2021). OBJECTIVE: The primary endpoint of this study was to assess CT-P13 persistence following switch from SB2. Secondary endpoints included persistence stratified by the number of biosimilar switches (single, double and triple), effectiveness and safety. METHODS: We performed a prospective, observational, cohort study. All adult IBD patients on IFX biosimilar SB2 underwent an elective switch to CT-P13. Patients were reviewed in a virtual biologic clinic with protocol driven collection of clinical disease activity, C-reactive protein (CRP), faecal calprotectin (FC), IFX trough/antibody levels, and drug survival. RESULTS: 297 patients (CD n = 196 [66%], ulcerative colitis/inflammatory bowel disease unclassified n = 101, [34%]) were switched (followed-up: 7.5 months [6.8-8.1]). This was the third, second and first IFX switch for 67/297 (22.5%), 138/297 (46.5%) and 92/297 (31%) of the cohort respectively. 90.6% of patients remained on IFX during follow-up. The number of switches was not independently associated with IFX persistence after adjusting for confounders. Clinical (p = 0.77), biochemical (CRP ≤5 mg/ml; p = 0.75) and faecal biomarker (FC<250 µg/g; p = 0.63) remission were comparable at baseline, week 12 and week 24. CONCLUSION: Multiple successive switches from IFX originator to biosimilars are effective and safe in patients with IBD, irrespective of the number of IFX switches.

Helicobacter Species and Hepato-Biliary Tract Malignancies: A Systematic Review and Meta-Analysis.

Helicobacter species may cause chronic inflammation of the biliary tract, but its relationship with cancer is controversial. We performed a systematic review and meta-analysis to evaluate the association between Helicobacter species and hepatobiliary tract malignancies. Twenty-six studies (4083 patients) were included in qualitative synthesis, and 18 studies (n = 1895 qualified for meta-analysis. All studies were at high-intermediate risk of bias. Most studies combined several direct microbiological methods, mostly PCR (23 studies), culture (8 studies), and/or CLOtest (5 studies). Different specimens alone or in combination were investigated, most frequently bile (16 studies), serum (7 studies), liver/biliary tissue (8 studies), and gastric tissue (3 studies). Patients with Helicobacter species infection had an increased risk of hepatobiliary tract malignancies (OR = 3.61 [95% CI 2.18-6.00]; p < 0.0001), with high heterogeneity in the analysis (I2 = 61%; p = 0.0003). This effect was consistent when Helicobacter was assessed in bile (OR = 3.57 [95% CI 1.73-7.39]; p = 0.0006), gastric tissue (OR = 42.63 [95% CI 5.25-346.24]; p = 0.0004), liver/biliary tissue (OR = 4.92 [95% CI 1.90-12.76]; p = 0.001) and serum (OR = 1.38 [95% CI 1.00-1.90]; p = 0.05). Heterogeneity was reduced in these sub-analyses (I2 = 0-27%; p = ns), except for liver/biliary tissue (I2 = 57%; p = 0.02). In conclusion, based on low-certainty data, Helicobacter species chronic infection is associated with a tripled risk of hepatobiliary tract malignancy. Prospective studies are required to delineate public health interventions.

Rates, predictive factors and effectiveness of ustekinumab intensification to 4- or 6-weekly intervals in Crohn's disease.

BACKGROUND: The UNITI trial reports efficacy of ustekinumab (UST) dose intensification in Crohn's disease (CD) from 12- to 8-weekly, but not 4-weekly. We aimed 1) to assess the cumulative incidence of UST dose intensification to 4- or 6-weekly, 2) to identify factors associated with dose intensification, and 3) to assess the effectiveness of this strategy. METHODS: We performed a retrospective, observational cohort study in NHS Lothian including all UST treated CD patients (2015-2020). RESULTS: 163 CD patients were treated with UST (median follow-up: 20.3 months [13.4-38.4]), of whom 55 (33.7%) underwent dose intensification to 4-weekly (n = 50, 30.7%) or 6-weekly (n = 5, 3.1%). After 1 year 29.9% were dose intensified. Prior exposure to both anti-TNF and vedolizumab (HR 9.5; 1.3-70.9), and concomitant steroid use at UST start (HR 1.8; 1.0-3.1) were associated with dose intensification. Following dose intensification, 62.6% patients (29/55) remained on UST beyond 1 year. Corticosteroid-free clinical remission was achieved in 27% at week 16 and 29.6% at last follow-up. CONCLUSION: One third of CD patients treated with UST underwent dose intensification to a 4- or 6-weekly interval within the first year. Patients who failed both anti-TNF and vedolizumab, or required steroids at initiation were more likely to dose intensify.

Impact of Clostridioides difficile infection in patients admitted with ulcerative colitis.

BACKGROUND: Patients with ulcerative colitis (UC) are at increased risk of Clostridioides difficile infection (CDI), which is the principal causative agent of nosocomial diarrhoea in western countries. This has been related to complications such as need of colectomy and mortality among these patients. The aim of this study was to assess the incidence and impact of CDI in patients hospitalised with UC. METHODS: Case-control retrospective study including patients admitted due to a UC flare from January 2000 to September 2018. Porpensity score matching (PSM) was performed to minimise selection bias taking into account the small number of cases compared to controls. RESULTS: 339 patients were included; CDI in 35 (10.3%) patients. After PSM, 35 (33.33%) cases and 70 (66.67%) controls were analysed. Patients with CDI presented higher rates of readmission (52.9% vs. 21.4%, p = .001), increased mortality within the first 3 months post-discharge (5.9% vs. 0%, p = .042) and increased need of therapy intensification in the first year after admission (20.7% vs. 12.5%, p = .001). No risk factors for CDI were identified. Multivariable cox regression showed that treatment with 5-aminosalycilates at baseline (HR 0.42, 95% CI 0.18-0.92) and albumin <3.5 g/dL (HR 3.11, 95% CI 1.21-8.03) were associated with worse outcomes. CONCLUSIONS: CDI is a prevalent situation in hospitalised UC patients related to higher mortality within the first 3 months after the infection, need for therapy intensification within the first year and readmission. Our results underline the importance of CDI detection in patients with a flare of UC.

Area Under Trough Concentrations of Tacrolimus as a Predictor of Progressive Renal Impairment After Liver Transplantation.

BACKGROUND: Tacrolimus minimization is usually restricted to patients with pretransplant renal impairment, and this strategy could result into worse renal outcomes after liver transplantation (LT). METHODS: A consecutive cohort of 455 LT patients receiving tacrolimus-based immunosuppression was studied (2008-2013). Cumulative exposure to tacrolimus was calculated as the area under curve of trough concentrations (AUCtc). Patients were stratified as tacrolimus minimization, conventional, or high exposure, according to the thresholds based in the COMMIT consensus. Estimated glomerular filtration rates (eGFR) were assessed by the Modification of Diet in Renal Disease formula (MDRD-4) up to 5 years after LT. RESULTS: Seventy patients (15.4%) had pretransplant eGFR < 60 mL/min, which was associated with increased mortality rates, particularly within the first 5 years post-LT (31.4% versus 17.5%; Breslow P = 0.010). After LT, there was an abrupt eGFR decline within the first 3 months (median 18.6 mL/min; P < 0.001), further decreasing up to 12 months (additional 3 mL/min), without any improvement thereafter. According to AUCtc, 33.7% of patients received tacrolimus minimization, 44.8% conventional exposure, and 21.5% high exposure. Conventional/high exposure to tacrolimus resulted in a more pronounced eGFR decline within the first 3 months when compared with minimization (23.3 mL/min versus 9.5 mL/min; P < 0.001). This gap was even higher in patients with initially preserved renal function. Tacrolimus AUCtc was an independent predictor of eGFR decline within the first 3 months after controlling for potential confounders. CONCLUSIONS: AUCtc is a surrogate of cumulative exposure to tacrolimus and may be helpful for routine dose adjustments. Tacrolimus minimization should be universally attempted after LT to preserve renal function.