Insights into treatment of complex Crohn's perianal fistulas.

Complex perianal fistula is a common complication of Crohn's disease (CD) which leads to negative impact on patient's quality of life. Successful management of the disease requires a multidisciplinary approach, including a gastroenterologist and a colorectal surgeon, applying combined surgical and medical therapy. One of frequently practiced surgical procedures is seton placement in the fistula tract, which is used to control perianal sepsis and drain the fistula, while preventing recurrent abscess formation.Darvadstrocel, a suspension of expanded, allogeneic, adipose-derived, mesenchymal stem cells, is safe and effective for treatment-refractory complex perianal fistulas in patients with Crohn's disease. Following approval of darvadstrocel, the INSPIRE registry is being conducted in order to evaluate long-term safety and effectiveness of the drug on a large, heterogenous population.An online expert meeting was held from March 20 to March 30, 2023, which provided relevant insights into the decision-making process regarding seton use and obtained feedback on the first experiences with darvadstrocel. The aim of this article is to present the perspectives from gastroenterologists and colorectal surgeons practicing in Czechia, Hungary, Israel, Lithuania, Serbia, and Slovenia in topics such as diagnosis and treatment options for patients with complex Crohn's perianal fistulas (CPF), specifically focusing on the use of setons and darvadstrocel.During this virtual session, unavailability of comprehensive data on safety and efficacy of available treatment procedures was emphasized as an important obstacle towards development of standardized recommendations and improvement of outcomes in treatment of (CPF). Furthermore, achieving consensus in seton use, duration of its placement, and frequency of change is recognized as one of CPF treatments major challenges. Despite these issues, it is important to promote better understanding and treatment of complex perianal fistulas in order to improve the quality of life of those affected by this condition.

Biological treatment approach to inflammatory bowel disease is similar in academic and nonacademic centres - prime time for decentralisation of inflammatory bowel disease care?

BACKGROUND: With the increasing number of inflammatory bowel disease (IBD) patients, it is difficult to manage them within specialised IBD teams in academic medical centres: many are therefore treated in nonacademic IBD centres. It is unclear whether the time to introducing biologics is the same in both settings. AIM: We aimed to compare treatment approach with biologics in academic vs. nonacademic centres. METHODS: We analysed Slovenian national IBD registry data (UR-CARE Registry, supported by the European Crohn's and Colitis Organisation), which included 2 academic (2319 patients) and 4 nonacademic IBD (429 patients) centres. RESULTS: The disease phenotype was similar in both settings. In total, 1687 patients received 2782 treatment episodes with biologics. We observed no differences in treatment episodes with TNF-alpha inhibitors (60% vs. 61%), vedolizumab (24% vs. 23%), or ustekinumab (17% vs. 16%) in academic compared to nonacademic centres (P = 0.949). However, TNF inhibitors were less often the first biologic in academic centres (TNF inhibitors: 67.5% vs. 74.0%, vedolizumab: 20.3% vs. 17.9%, ustekinumab: 12.1% vs. 8.1%; P = 0.0096). Consequently, more patients received ustekinumab (29.8% vs. 18.3%) and vedolizumab (17.4% vs. 13.5%) and fewer TNF inhibitors (52.7% vs. 68.2%) for Crohn's disease in academic compared to nonacademic centres, with no such differences for ulcerative colitis. The time to initiation of the first biologic from diagnosis was short and similar in both settings (11.3 vs. 10.4 months, P = 0.2). CONCLUSION: In this nationwide registry analysis, we observed that biological treatment choice was similar in academic and nonacademic settings. These findings support the decentralisation of IBD care.

Remission Is Maintained after Switch from Dose-Optimised Intravenous Treatment to Subcutaneous Treatment with Vedolizumab in Inflammatory Bowel Disease.

Background and Objectives: The subcutaneous (SC) formulation of vedolizumab has proven to be effective for the maintenance of remission after intravenous induction. Little is known about the efficacy of switching from intravenous maintenance treatment to SC. We aimed to assess the real-world efficacy of switching to SC treatment and to assess the impact of a baseline treatment regimen. Materials and Methods: In this observational cohort study, adult patients with inflammatory bowel disease who were switched to SC vedolizumab maintenance treatment were enrolled. Patients after intravenous induction and patients who switched from intravenous maintenance treatment (every 8 weeks or every 4 weeks) were included. The SC vedolizumab dosing was 108 mg every 2 weeks, regardless of the previous regimen. The clinical, biochemical, and endoscopic disease activity parameters and vedolizumab serum concentrations at the time of the switch and at the follow-up were assessed. Results: In total, 135 patients (38% Crohn's disease, 62% ulcerative colitis) were switched to SC vedolizumab treatment. The median time to the first follow-up (FU) was 14.5 weeks (IQR 12-26), and the median time to the second FU was 40 weeks (IQR 36-52). Nine patients (7%) discontinued SC vedolizumab treatment, with two-thirds of them discontinuing due to active disease. In all dosing regimens, there were no significant changes in the clinical scores and CRP at the baseline and first and second FUs. Clinical and biochemical remission appeared to be maintained irrespective of the previous dosing regimen. Conclusions: The results of this real-world study suggest that the maintenance of clinical and biomarker remission can be achieved in patients who switched from intravenous to SC vedolizumab. The baseline vedolizumab dosing regimen (every 4 weeks versus every 8 weeks) did not have an impact on outcomes.

Biopsies from ulcer edge yield higher histological activity scores than biopsies from non-ulcerated mucosa in active ulcerative colitis.

BACKGROUND: The appropriate location for biopsy collection in ulcerative colitis is unknown. OBJECTIVES: We aimed to determine the location for biopsy collection in the presence of ulcers which yields the highest histopathological score. DESIGN AND METHODS: This prospective cross-sectional study enrolled patients with ulcerative colitis and ulcers in the colon. Biopsy specimens were obtained at the edge of the ulcer; at a distance of one open forceps (7-8 mm) from the ulcer edge; at a distance of three open forceps (21-24 mm) from the ulcer edge; further referred to as locations 1, 2 and 3 respectively. Histological activity was assessed using Robarts Histopathology Index and the Nancy Histological Index. Statistical analysis was performed using mixed effects models. RESULTS: A total of 19 patients were included. Decreasing trends with distance from the ulcer edge ( P  < 0.0001) were observed. Biopsies procured from the edge of the ulcer (location 1) yielded a higher histopathological score compared to biopsies procured at locations 2 and 3 ( P  ≤ 0.001). CONCLUSION: Biopsies from the ulcer edge yield higher histopathological scores than biopsies next to the ulcer. In clinical trials with histological endpoints, biopsies should be obtained from the ulcer edge (if ulcers are present) to reliably assess histological disease activity.

IgA Nephropathy in a Patient Treated with Adalimumab.

Immunoglobulin A (IgA) nephropathy (IgAN) is the most common glomerulonephritis worldwide, characterized by IgA deposits in the glomerular mesangium. It has a progressive nature and can eventually lead to end-stage kidney failure. It can occur as a potential side effect of treatment with tumor necrosis factor alpha antagonist that has been used for numerous chronic inflammatory conditions, such as Crohn's disease. In this study, the case of a 33-year-old man with renal dysfunction, nephrotic proteinuria, and erythrocyturia is described. He had had a history of Crohn's disease for 8 years and had been treated with adalimumab for the past 7 years. The diagnosis of IgAN was confirmed by kidney biopsy. After discontinuance of adalimumab and the induction of corticosteroid therapy, he made a remarkable recovery. Four years after the first presentation of IgAN and discontinuation of adalimumab, his renal function was normal with no proteinuria and only mild erythrocyturia.

Ustekinumab Dosing Individualization in Crohn's Disease Guided by a Population Pharmacokinetic-Pharmacodynamic Model.

Ustekinumab is a monoclonal antibody used in Crohn's disease (CD). Dose optimization in case of non-response and the role of pharmacokinetic-pharmacodynamic (PK-PD) monitoring remain unresolved dilemmas in clinical practice. We aimed to develop a population PK-PD model for ustekinumab in CD and simulate efficacy of alternative dosing regimens. We included 57 patients and recorded their characteristics during 32 weeks after starting with ustekinumab therapy. Serum ustekinumab concentration was prospectively measured and fecal calprotectin (FC) concentration was used to monitor the disease activity. Ustekinumab PK-PD was described by a two-compartment target-mediated drug disposition model linked to an indirect response model. Lower fat-free mass, higher serum albumin, previous non-exposure to biologics, FCGR3A-158 V/V variant and lower C-reactive protein were associated with higher ustekinumab exposure. Model-based simulation suggested that 41.9% of patients receiving standard dosing achieve biochemical remission at week 32. In patients not achieving remission with standard dosing at week 16, transition to 4-weekly subcutaneous maintenance dosing with or without intravenous reinduction resulted in comparably higher remission rates at week 32 (51.1% vs. 49.2%, respectively). Our findings could be used to guide stratified ustekinumab treatment in CD, particularly in patients with unfavorable characteristics, who might benefit from early transition to 4-weekly maintenance dosing.

Ustekinumab concentrations shortly after escalation to monthly dosing may identify endoscopic remission in refractory Crohn's disease.

OBJECTIVES: Some patients with Crohn's disease do not achieve remission with the approved maintenance dosing of ustekinumab every 8 weeks, possibly due to insufficient drug exposure. We aimed to study the exposure-response relationship for endoscopic remission and biomarker normalization with ustekinumab dose escalation to every 4 weeks. METHODS: Out of 135 consecutive patients, 44 with active Crohn's disease despite standard maintenance dosing [at least one of C-reactive protein (CRP) >5 mg/L, fecal calprotectin >100 mg/kg, simple endoscopic score (SES) for Crohn's disease >3] underwent dose escalation to every 4 weeks. Subsequent endoscopic remission (SES-CD ≤3 without ulceration) and biomarker normalization were compared against ustekinumab concentrations. RESULTS: Dose escalation led to endoscopic remission in 28.6% (8/28), CRP normalization 29.2% (7/24) and fecal calprotectin normalization 51.7% (15/29) of patients. Ustekinumab concentrations after escalation were higher in patients with endoscopic remission (6.90 vs. 4.29 mg/L; P = 0.025) and fecal calprotectin normalization (6.65 vs. 3.74 mg/L; P = 0.001). A threshold of 6.00 mg/L identified endoscopic remission [area under the receiver operating curve (AUROC): 0.775; 95% confidence interval (CI), 0.551-0.999), a threshold of 4.40 mg/L (AUROC 0.755; 95% CI, 0.545-0.964) two months after escalation identified patients with fecal calprotectin normalization at the end of follow-up. Concentrations <3.5 mg/L after escalation precluded endoscopic remission or biomarker normalization. CONCLUSION: Endoscopic remission was associated with higher ustekinumab concentrations after dose escalation. Patients with concentrations <3.5 mg/L after dose escalation are unlikely to achieve endoscopic remission or biomarker normalization.

Peak Concentrations of Ustekinumab After Intravenous Induction Therapy Identify Patients With Crohn's Disease Likely to Achieve Endoscopic and Biochemical Remission.

BACKGROUND & AIMS: Little is known about the relationship between ustekinumab exposure during the first 2 weeks of treatment and outcomes of patients with Crohn's disease (CD). We investigated the relationship between serum concentrations of ustekinumab during the first 2 weeks of treatment and endoscopic and biochemical remission in patients with CD. METHODS: In a prospective observational study, we measured concentrations of ustekinumab in serum samples from 41 consecutive patients who started treatment with ustekinumab (approximately 6 mg/kg, intravenously, then 90 mg every 8 weeks), due to endoscopic markers of active CD, at a single center from October 2017 through January 2019. We measured ustekinumab exposure parameters during the first 2 weeks (peak concentration measured immediately after intravenous infusion, week 2 concentration, and area under the curve through week 2). We investigated the correlation between these parameters and endoscopic remission (simple endoscopic score for CD scores of 3 or less without ulceration, assessed centrally) and biochemical remission (level of fecal calprotectin below 100 mg/kg) using the Mann-Whitney U test. RESULTS: Endoscopic remission was achieved in 10 patients (24.4%) at week 24; biochemical remission was achieved in 17 patients (41.5%) at week 8, 17 patients (41.5%) at week 16, and 21 patients (51.2%) at week 24. Peak concentrations associated with endoscopic remission (area under the receiver operating characteristic curve, 0.717; 95% CI, 0.517-0.916); 6 of 13 patients (46%) with peak concentrations above 105 µg/mL (upper tercile) achieved endoscopic remission, compared with only 1 of 14 patients (7%) with peak concentrations below 88 µg/mL (lower tercile). All exposure parameters during the first 2 weeks were associated with biochemical remission. There was no significant difference between the associations of peak concentrations, week-2 concentrations, area under the curve through week 2, or later exposure measures (at weeks 4 and 8) with biochemical or endoscopic remission. CONCLUSIONS: In a prospective study, we found that serum concentrations of ustekinumab as early as 1 hour after intravenous infusion might be used to identify patients with CD most likely to achieve endoscopic remission. This early measurement might be used to optimize treatment of CD.

Endoscopic remission can be predicted by golimumab concentrations in patients with ulcerative colitis treated with the changed label.

BACKGROUND: In 2018, the European Medicines Agency (EMA) replaced a fixed 50 mg every 4-week maintenance regimen of golimumab for ulcerative colitis (UC) patients weighing <80 kg with new, flexible dosing that allows reactive dose optimization to 100 mg if clinically needed. We analyzed the endoscopic remission rates and pharmacokinetics of this new dosing regimen in real-life settings. METHODS: We prospectively recruited 30 consecutive (17 with body weight <80 kg) patients with UC who received golimumab with the new EMA label. The primary endpoint was endoscopic remission (Mayo ≤1) assessed by centrally-read endoscopy at week 14 and year 1. Golimumab concentrations, measured at nine prespecified timepoints, were correlated with endoscopic remission and identified cut-offs. RESULTS: Endoscopic remission was achieved in 15/30 (50%) and 10/30 (33%) patients at week 14 and year 1, respectively. Reactive dose optimization to 100 mg maintenance was needed in 13/17 (76%) patients. Golimumab concentrations at week 6 predicted week 14 and year 1 endoscopic remission. Week 6 concentrations >10.7 µg/ml were a strong predictor for achievement and maintenance of endoscopic remission during the first year of treatment, while concentrations <5.1 µg/ml identified the opposite. CONCLUSION: One-third of the patients reached and maintained endoscopic remission during the first year of golimumab treatment, but the need for dose optimization to 100 mg every 4 weeks of maintenance was high in patients weighing <80 kg. Golimumab concentrations <5.1 µg/ml at week 6 identified patients who are unlikely to reach and maintain endoscopic remission with the new, flexible EMA label.

Early vedolizumab trough levels predict combined endoscopic and clinical remission in inflammatory bowel disease.

Background: The relationship between vedolizumab trough levels and combined endoscopic and clinical remission is unknown. Objective: To compare vedolizumab trough levels in patients with and without combined remission within the first year of treatment. Methods: We prospectively collected vedolizumab trough levels in 51 consecutive patients (28 Crohn's disease (CD) and 23 ulcerative colitis (UC)) before all infusions up to week 22, and at weeks 38 and 54, with concentrations measured after study completion. Centrally read endoscopy was performed at a median of 46 weeks. The primary outcome was combined endoscopic (CD: Simple endoscopic score for CD (SES-CD) < 4 without ulceration; UC: Mayo endoscopic subscore ≤ 1) and clinical remission (CD: resolution of abdominal pain; UC: resolution of rectal bleeding; both: resolution of altered bowel habit). Results: Median vedolizumab trough levels at weeks 6 (25.7 vs 15.6 µg/mL; P = 0.015) and 22 (15.1 vs 4.9 µg/mL; P = 0.001) were higher in patients with combined remission. A threshold of 22 µg/mL at week 6 (area under the curve (AUC) 0.733; 95% confidence interval 0.567-0.899) and 8 µg/mL at week 22 (AUC 0.819; 95% confidence interval 0.692-0.946) predicted combined remission. Conclusion: Early vedolizumab trough levels predicted combined endoscopic and clinical remission highlighting their possible use in clinical practice.

Optimised infliximab monotherapy is as effective as optimised combination therapy, but is associated with higher drug consumption in inflammatory bowel disease.

BACKGROUND: Combination treatment with azathioprine for 6-12 months is the preferred strategy for starting infliximab due to improved pharmacokinetics. However, optimised infliximab monotherapy with proactive dose escalations in case of low trough levels is a safer but under-studied alternative. AIM: To compare the clinical success and infliximab consumption of combination vs optimised monotherapy strategies. METHODS: We studied the clinical success and infliximab consumption of both strategies in 149 patients (94 Crohn's disease; 55 ulcerative colitis) starting infliximab and undergoing intensive drug monitoring assisted treatment optimisation. RESULTS: The drug retention rates were similar for optimised monotherapy and combination treatment after induction (96% vs 97%, P = 0.73), after the first year (90% vs 83%, P = 0.23) and at the end of follow-up (74% vs 75%, P = 0.968). Similarly, no differences were observed for steroid use at year 1 (5% vs 14%, P = 0.08) or mucosal healing at the end of follow-up (64% vs 67%, P = 0.8). Higher infliximab consumption (7.6 mg/kg q8 weeks [interquartile range (IQR): 5.9-10.3] vs 6.4 mg/kg q8 weeks [IQR: 5.2-8.0], P = 0.019) combined with lower trough levels (1.7 µg/mL [IQR: 0.3-6.6] vs 5.0 µg/mL [2.5-8.7], P = 0.012) resulted in almost 3-fold higher drug-to-trough ratio (3.9 vs 1.5) in monotherapy compared to combination strategy at year 1. At the end of follow-up, when azathioprine had been discontinued for a median of 14 [IQR: 3-33] months, these differences disappeared. CONCLUSIONS: In this study, optimised infliximab monotherapy was as clinically effective as combination therapy but was associated with significantly higher infliximab consumption. The infliximab-sparing effect disappeared after azathioprine withdrawal.

Dendritic cell profiles in the inflamed colonic mucosa predict the responses to tumor necrosis factor alpha inhibitors in inflammatory bowel disease.

Background Dendritic cells play crucial roles in the control of inflammation and immune tolerance in the gut. We aimed to investigate the effects of tumor necrosis factor alpha (TNFa) inhibitors on intestinal dendritic cells in patients with inflammatory bowel disease and the potential role of intestinal dendritic cells in predicting the response to treatment. Patients and methods Intestinal biopsies were obtained from 30 patients with inflammatory bowel disease before and after treatment with TNFa inhibitors. The proportions of lamina propria dendritic cell phenotypes were analysed using flow cytometry. Disease activity was endoscopically assessed at baseline and after the induction treatment. Results At baseline, the proportion of conventional dendritic cells was higher in the inflamed mucosa (7.8%) compared to the uninflamed mucosa (4.5%) (p = 0.003), and the proportion of CD103+ dendritic cells was lower in the inflamed mucosa (47.1%) versus the uninflamed mucosa (57.3%) (p = 0.03). After 12 weeks of treatment, the proportion of conventional dendritic cells in the inflamed mucosa decreased from 7.8% to 4.5% (p = 0.014), whereas the proportion of CD103+ dendritic cells remained unchanged. Eighteen out of 30 (60%) patients responded to their treatment by week 12. Responders had a significantly higher proportion of conventional dendritic cells (9.16% vs 4.4%, p < 0.01) with higher expression of HLA-DR (median fluorescent intensity [MFI] 12152 vs 8837, p = 0.038) in the inflamed mucosa before treatment compared to nonresponders. Conclusions A proportion of conventional dendritic cells above 7% in the inflamed inflammatory bowel disease mucosa before treatment predicts an endoscopic response to TNFa inhibitors.

Success and safety of high infliximab trough levels in inflammatory bowel disease.

OBJECTIVE: A prospective trial suggests target infliximab trough levels of 3-7 µg/mL, yet data on additional therapeutic benefits and safety of higher trough levels are scarce. AIM: To explore whether high infliximab trough levels (≥7 µg/mL) are more effective and still safe. MATERIAL AND METHODS: In this cohort study of 183 patients (109 Crohn's disease and 74 ulcerative colitis) on infliximab maintenance treatment at a tertiary referral center we correlated fecal calprotectin and C-reactive protein to trough levels (426 samples) at different time points during treatment. Rates of infections were compared in quadrimesters (four-month periods) with high trough levels to quadrimesters with trough levels <7 µg/mL during 420 patient-years. RESULTS: Fecal calprotectin and C-reactive protein (median [interquartile range]) were lower in patients with high trough levels (fecal calprotectin 66 mg/kg [30-257]; C-reactive protein 3 mg/L [3-3]) compared to trough levels below 7 µg/mL (fecal calprotectin 155 mg/kg [72-474]; C-reactive protein 3 mg/L [3-14.5]) (p < .001). High trough levels were superior also after excluding samples with trough levels <3 µg/mL from analysis. No differences in rates of infections were observed in quadrimesters with high trough levels (16/129 [12.4%]) compared to quadrimesters with trough levels <7 µg/mL (32/344 [9.3%]) (p = .32). Maintaining high trough levels resulted in 32% (interquartile range: 2-54%) increase of infliximab consumption. CONCLUSION: High infliximab trough levels provide better control of inflammation in inflammatory bowel disease without increasing the risk of infection.

Comparison of radon doses based on different radon monitoring approaches.

In 43 places (23 schools, 3 kindergartens, 16 offices and one dwelling), indoor radon has been monitored as an intercomparison experiment, using α-scintillation cells (SC - Jozef Stefan Institute, Slovenia), various kinds of solid state nuclear track detectors (KfK - Karlsruhe Institute of Technology, Germany; UFO - National Institute of Radiological Sciences, Chiba, Japan; RET - University College Dublin, Ireland) and active electronic devices (EQF, Sarad, Germany). At the same place, the radon levels and, consequently, the effective doses obtained with different radon devices differed substantially (by a factor of 2 or more), and no regularity was observed as regards which detector would show a higher or lower dose.