Comparative data on the use of Janus kinase (JAK) inhibitors in ulcerative colitis (UC) patients are limited to retrospective studies. We conducted a prospective cohort study to compare the effectiveness and safety of tofacitinib (TOFA), filgotinib (FIL) and upadacitinib (UPA) in JAK-naïve UC patients. Adult UC patients who initiated TOFA, FIL or UPA treatment in routine care were enrolled in the ICC registry and prospectively followed. Patients with prior exposure to JAK inhibitors were excluded. Corticosteroid-free clinical remission (CSFR; Simple Clinical Colitis Activity Index ≤2 without corticosteroid use), biochemical remission (C-reactive protein ≤5 mg/L or faecal calprotectin ≤250 μg/g), drug persistence and frequency of adverse events (AEs) were compared after 24 weeks of treatment. Inverse probability of treatment weighting was performed to account for baseline differences and treatment selection bias. A total of 343 JAK-naïve UC patients were included (TOFA n = 185, FIL n = 108, UPA n = 50). Patients receiving UPA had more frequent exposure to three previous advanced treatment modalities (44% vs. 6.5% for TOFA and 24% for FIL). Among patients with clinical, biochemical or endoscopical signs of active disease at baseline (n = 323), CSFR rates at week 24 were 38%, 47% and 47% in the TOFA, FIL and UPA group, respectively. Biochemical remission was higher for UPA treated patients compared to TOFA (unadjusted OR 2.86, p = 0.012; adjusted OR 1.34, p = 0.0002) and FIL (unadjusted OR 2.21, p = 0.09; adjusted OR 1.21, p = 0.049). Drug persistence was 63%, 70% and 79% in the TOFA, FIL and UPA group, respectively. UPA treatment was associated with a lower discontinuation rate compared to TOFA in the unadjusted analysis (HR 0.49, p = 0.046), which was not confirmed in the adjusted analysis. FIL discontinuation rates did not differ statistically significantly. Infection rates per 100 patient-years were 48.6 (TOFA), 46.4 (FIL), and 60.8 (UPA). Rates of other AEs per 100 patient-years were 78.9 (TOFA), 54.6 (FIL), and 125 (UPA). The percentage of patients that stopped due to AEs was 6.4%, 2.8% and 6.0% for TOFA, FIL and UPA, respectively. In this prospective real-world study, we compared TOFA, FIL and UPA treatment in JAK-naïve UC patients. The three treatments showed comparable CSFR rates and drug persistence, whereas UPA was associated with higher biochemical remission rates and more AEs. Conflict of interest: Ms. Naber, Myrthe: No conflict of interest Bouwknegt, Dianne G.: Speakers fees from Alfasigma Nederland B.V. and Takeda Nederland B.V. Visschedijk, Marijn: Speakers fees from Jansen-Cilag, Abbvie, Ferring, Alfasigma, Takeda. Lourens, Leonie: No conflict of interest Van der Meulen - de Jong, Andrea Elisabeth: Speaking fees from Alfasigma, Ferring and Abbvie. Advisory board fees from Abbvie, Alfasigma, Ferring, Janssen, Takeda, Vedanta and grant/research support from Alfasigma, Cablon and Norgine. Bodelier, Alexander: Participation in advisory boards of: Johnson & Johnson, Eli Lilly, Sanofi. Received unrestricted grant from Amphia research fund. Duijvestein, Marjolijn: Grant: Speaking fees from Bristol Meyers Squibb, Takeda, Galapagos, Janssen, Dr. Falk, Advisory board fees from Abbvie, Bristol Meyers Squibb, Celltrion, Galapagos/Alfasigma, Janssen, Takeda Grant/Research support: Pfizer, Bristol Meyers Squibb, Galapagos, Alfasigma, Janssen, Lilly Van Bodegraven, Adriaan Anthonie: A A van Bodegraven is working as Consultant Gastroenterology, is member of the Dutch Society of Gastroenterologists, serving as chair of the committee on Pharmacology, and has served as a consultant or speaker for AbbVie, Alfasigma SpA, Arena Pharmaceuticals, Bristol Myers Squibb, Cablon, Celltrion, Ferring, Galapagos, Janssen, Lilly, Pfizer, Takeda, Teva, Tramedico, and Dutch Ministry of Health (ZonMW) received research grants from Ferring, Pfizer, and Teva and has performed as principal investigator in studies sponsored by Abivax, AbbVie, Alfasigma SpA, Arena Pharmaceuticals, BMS, Celltrion, Galapagos, Janssen, Pfizer, Roche, TEVA and Vedanta Biosciences. De Vries, Annemarie C.: Grant: Grants, advisory boards: Pfizer, Galapagos, Takeda, Janssen Mujagic, Zlatan: Grants from ZonMw, Niels Stensen Fellowship, Maag Lever Darm Stichting (MLDS), Academische Alliantie Fonds (AAF), Top consortium for Knowledge and Innovation (TKI) and Galapagos, advisory board fees from Johnson & Johnson, Eli Lilly, Pfizer (paid to host institution) and speaker’s fees from Friso – Friesland Campina, Galapagos / Alfasigma, Eli Lilly, Takeda (paid to host institution). Pierik, Marieke: Grant: TKI, MLDS, Galapagos, Janssen-Cilag, Takeda, Pfizer Other: Financial support to institution for consultancy or lectures: Takeda, Janssen-Cilag, BMS, MSD, Abbvie, Galapagos, Ferring Verleye, Loriane: No conflict of interest West, Rachel: Speaker fees from Ferring, Pfizer and Janssen. Römkens, Tessa: Speaker or consultant fees for Ferring, Janssen, and Takeda. Jharap, Bindia: No conflict of interest van der Marel, Sander: I have participated in advisory boards for Pfizer, AbbVie, and Janssen in the context of IBD. I have provided educational contributions for Galapagos, in the context of IBD. Additionally, I participated in a documentary project supported by Takeda, a Gastro Magazine supported by AbbVie and a podcast episode supported by Janssen, also in the context of IBD. All engagements were non-recurring. van der Voorn, Michael: No conflict of interest Mensink, Peter: No conflict of interest Mares, Wout: Speaker fees from Janssen and advisory committee AbbVie, Ferring, and Takeda. Horjus Talabur Horje, Carmen Simona: No conflict of interest Jansen, Jeroen Michiel: No conflict of interest Oldenburg, Bas: Unrestricted grants: Abbvie, Takeda, Pfizer, Galapagos Advisory boards: Abbvie, Takeda, Pfizer, Lilly, Galapagos, Janssen van Schaik, Fiona: FDM van Schaik has received consultancy fees from Takeda, Galapagos and AbbVie, speaker’s honoraria from Galapagos, Lilly, AbbVie and Janssen-Cilag B.V., hospitality fees from Ferring and dr. Falk Farma and an unrestricted research grant from Takeda. Löwenberg, Mark: Consultancy/lecture fees from Abbvie, Bristol Myers Squibb, Eli Lilly, Galapagos, Janssen-Cilag, Johnson & Johnson, Medtronic, Pfizer, Takeda, Tillotts. Grants received from Alfasigma, NFU transformation deal, ZonMW and TKI.

Intravenously applied infliximab (IFX) is commonly used for Inflammatory Bowel Disease (IBD) treatment. Recently, subcutaneous (SC) flat-dose IFX biosimilar was introduced offering potential advantages over intravenous (IV) weight-based dosing. Prospective pharmacokinetic-data and clinical outcomes in IBD practice are scarce, since drug approval was primarily based on a rheumatoid-arthritis study-population concomitantly using methotrexate. The main objective of this prospective study was to compare IFX exposure and clinical outcomes when switching IV to SC IFX therapy in IBD remission patients, also addressing the effect of concomitant immunomodulators. In this single-centre, prospective study, 38 adult IBD patients in clinical remission on a 6-8 weekly IFX IV-dosing interval were switched to biweekly dosed SC IFX and followed for 24 weeks. The primary endpoint was the comparison between Area Under the Concentration-time curves (AUCs) at steady state before and after switching. AUCs were calculated using MwPharm ++ (version 2.4.0; Hanzel 2021).[1] Secondary endpoints included trough levels, generation of anti-drug antibodies (ADAbs), time burden for application, and quality of life (IBDQ-NL). Additionally, twelve-month trough levels were compared across IFX monotherapy, combination, and thiopurine-discontinuation groups. A total of 35 patients were evaluated, of whom 20 received IFX monotherapy and 15 received IFX combination therapy. The cohort comprised 11 patients with ulcerative colitis and 24 with Crohn’s disease. Mean AUCs6-8 weeks were comparable between IV and SC administration [27,662 ± 7,116 mg·h/L vs 29,320 ± 10,505 mg·h/L (p = 0.278), independent of immunomodulator use (table 1). IFX trough levels increased on SC IFX (median [IQR] 4.6 [3.0-6.1] mg/L vs 16.1 [11.6–20.6] mg/L, p < 0.001), independent from immunomodulator use [p = 0.347]. These results were consistent at month 12, regardless of continued monotherapy, combo, or withdrawal of thiopurines at month 6. Time burden decreased substantially (median reduction 9,3 hours/6 months, p < 0.001) and IBDQ-NL score increased (189 to 197, p = 0.01). ADAbs were detected in 9% without clinical impact. During the follow-up period, no patient had an exacerbation or required escalation of treatment. The percentage still being treated with IFX SC after 6 months was 97%. Switching from IV to SC IFX in quiescent IBD patients maintained equivalent drug exposure with higher trough levels, without a higher risk of ADAb formation, reduced considerably time of application and improved quality of life, regardless of immunomodulator co-use. Reference: [1] Hanzel J, Bukkems LH, Gecse KB, D’Haens GR, Mathôt RAA. Population pharmacokinetics of subcutaneous infliximab CT-P13 in Crohn’s disease and ulcerative colitis. Aliment Pharmacol Ther. 2021 Nov;54(10):1309-1319. Doi: 10.1111/apt.16609. Conflict of interest: Ms. Van Dinter-Van De Ven, Lieke: No conflict of interest Romberg - Camps, Marielle J.L.: No conflict of interest Wong, Dennis: No conflict of interest Van Bodegraven, Adriaan Anthonie: No conflict of interest Boone, Niels: No conflict of interest

Abstract Background Multiple new treatment options have been introduced in Ulcerative Colitis (UC) in recent years, leading peers to recommend a treat-to-target treatment approach, including mucosal or even histopathological healing. Patient-reported outcomes, and explicitly those validated on subjective patient-based values, are most commonly neglected in evaluating long-term treatment outcome while being of great importance in defining treatment success. We re-examined registration and prospective trials with at least one year follow-up to estimate chance of beneficial outcome for patients using the most modern, though surely most expensive, medication. We compared endoscopic improvement and improvement on patient-reported outcomes in the long-term follow-up of new drug therapies in biological naïve patients as a marker for treatment success. Methods We assessed long-term endoscopic outcome measures and patient-reported outcomes measures in major registration trials of new biologicals and advanced small molecules in the period 2000-2023 by examination of PubMed. In these trials almost all UC patients had to be 5ASA-, corticosteroid- and/or immune suppressive refractory before inclusion in study. Results In figure 1, an overview is shown of long-term endoscopic and PROM improvement endpoints in major registration trials. When focusing on endoscopic improvement or mucosal healing achieved by biologicals or advanced small-molecules in 5ASA-, corticosteroid- and/or immune suppressive refractory UC patients, most patients did not reach the pre-defined endpoint. In addition, although some registration trials report PROM data, improvement based on PROM’s is not consistently reported. Conclusion Reaching endoscopic improvement as definition of treatment success is unsuccessful in more than 60% of patients when accounted for placebo in all modern-era therapies for ulcerative colitis. As a consequence, when endoscopic treat-to-target treatment goals are strictly applied, surgery is warranted in more than 60% of UC patients within one year. Furthermore, lack of reporting of PROMs in registration trials complicate direct comparisons of alternative important endpoints.

Abstract Background OPTIC was a prospective placebo-controlled trial investigating therapeutic drug monitoring (TDM)-based mercaptopurine (MP) therapy in ulcerative colitis (UC). Although the primary endpoint (corticosteroid-free clinical remission and endoscopic improvement at week 52) favoured patients with TDM-based MP therapy over placebo, drug-related adverse events were frequent and drop-out rates high. This post-hoc analysis was carried out to show the therapeutic implications of proactive TDM of MP. Methods UC patients with active disease, despite ≥2 g/day mesalamine, underwent remission induction treatment with corticosteroids and initiated weight-based MP therapy (1-1.5 mg/kg). TDM based optimisations were performed at week 6, 12, 18, 24, 36 and 52 using the Dervieux method, unblinded non-including thiopurine expert physicians (DA, MD and AB) provided dosing advice according to a predefined algorithm, aiming for 6-TGN levels of 600-1200 pmol/8×108 RBC and 6-MMP of <5700 pmol/8×108 RBC. Associations between 6-TGN and 6-MMP levels, MP dose and thiopurine S-methyltransferase (TPMT) polymorphisms were explored. Results In total, 29 patients initiated MP treatment (41% female, median age 46 yrs [IQR 26-58], median disease duration 6 yrs [IQR 1-14]). TPMT heterozygosity was found in 4/29 patients (3/4 TPMT*3A, 1/4 TPMT*3C). TDM dose adjustments were required in 22/29 patients: 14/29 started allopurinol and decreased MP dose, 5/29 discontinued MP before the first TDM assessment, 2/29 continued MP at the initial dose up until week 52 and the remaining underwent MP dose adjustments. Most adjustments (71%) were made at week 6, thereafter 6-MMP levels stabilised, while 6-TGN concentrations remained stable (Figure 1). TPMT variant carriers had a higher median 6-TGN concentration compared to non-carriers (1700 [IQR 1625-1850] vs 539 pmol/8×108 RBC [IQR 355-953], P<0.001) and more likely to have leukopenia (P=0.025). Two TPMT heterozygous patients achieved the primary endpoint with dose reductions, two discontinued due to myelotoxicity or hepatotoxicity. Until week 52, 16/29 patients completed the trial, 14/29 reached the endpoint with a median 6-TGN of 585 pmol/8×108 RBC (IQR 428-745) and 6-MMP of 268 pmol/8×108 RBC (IQR 110-1257). MP dose correlated with 6-MMP but not with 6-TGN levels. Independently of allopurinol co-prescription, the initial median weight-based MP dose of 100 mg (IQR 75-125) decreased significantly to 50 mg (IQR 25-100, P=0.041). Conclusion Most patients underwent TDM optimisation of MP, half of the patients initiated allopurinol with decreased MP dose. TPMT heterozygosity led to supratherapeutic 6-TGN concentrations and adverse events. Weight-based initial MP dose may need reconsideration.

Abstract Background Immunomodulators and biologicals are essential in current IBD management, but are associated with increased risk of infections. Considering the growing number of treatment options, the benefit-risk balance of drugs is becoming increasingly important in clinical decision making. To date, post-marketing surveillance studies mainly focus on severe infections. As a result, data on mild and moderate infections are scarce. These infections take longer to clear in immunosuppressed patients and can substantially impact quality of life. We aimed to assess the incidence of all infections and identify risk factors for the development of infections in IBD patients. Methods We previously developed and validated a Patient-Reported Infections Questionnaire (PRIQ), with excellent diagnostic accuracy, covering 15 infection categories with a 3-month recall period. The current prospective, multicentre, observational cohort study was performed between Jun, 1 2020 and Jul, 1 2021, enrolling consecutive IBD patients using the PRIQ implemented in myIBDcoach, an established telemedicine platform. Infection severity was defined as mild (self-limiting or topical treatment), moderate (oral antibiotics, antivirals or antifungals) or severe (hospitalization or IV treatment). Incidence rates (IR) were calculated for all infections, stratified for severity and subtype. Risk factors for infections were identified using multivariable logistic regression. Results In total, 629 IBD patients were included which completed 2391 PRIQs during 572 person-years (PY) of follow-up, resulting in 990 reported infections, corresponding to IRs of 17.3, 11.8, 5.1, and 0.4 per 10PY for all, mild, moderate, and severe infections, respectively (Tables 1-2). Upper respiratory tract (IR 26.9/100PY) and urinary tract infections (IR 14.8/100PY) were the most commonly reported mild and moderate infections (Table 3). Compared to patients without treatment, patients on immunosuppressives more frequently experienced infections of any severity (mild: IR ratio (IRR) 1.57 [95%CI 1.21-2.06] p<0.001, moderate: IRR 1.42 [95%CI 1.20-1.69] p<0.001). On multivariable logistic regression, female sex (mild aOR 1.96; moderate aOR 1.71), smoking status (mild aOR 1.66; moderate aOR 1.86), higher BMI (moderate aOR 1.05), and more comorbidities (mild aOR 2.41; moderate aOR 1.82) were all significantly associated with the development of mild and moderate infections (Table 4). Conclusion In this real-world prospective study, immune suppressive therapy was associated with mild and moderate infections of any kind in IBD patients. These infections particularly occur in females, smokers, patients with higher BMI and more comorbidities. This information should be considered in personalised treatment selection.

Abstract Background Cardiorespiratory fitness (CRF) as a potential predictor of disease outcome in Inflammatory Bowel Disease (IBD) is understudied, as are risk factors for impaired CRF. Lifestyle interventions focusing on improving CRF may aid in enhancing subjective health, decreasing disability, or even controlling inflammation. The aim of this exploratory study was to investigate risk factors for low estimated CRF (eCRF), as well as the association between eCRF and patient-reported outcomes of IBD in a real-world cohort. Methods A cross-sectional multicenter study was performed between 26 Oct 2021 and 19 Oct 2022, enrolling IBD patients using the remote monitor platform myIBDcoach. Patients reported on disease activity, lifestyle factors, and psychosocial functioning. The four-question Modified Duke Activity Status Index (M-DASI-4Q) was used to assess eCRF, which is a simple screening tool for detecting the risk of impaired CRF as objectively measured with physical exercise tests. The number of positive responses to each of the four questions determines the final score, ranging from 0 to 4. To date, no accepted cut-off for (e)CRF has been identified for patients with IBD. Therefore, an M-DASI-4Q score below the 25th percentile of the study population was exploratively used to define low eCRF. Multivariable logistic regression analysis was performed to identify factors associated with eCRF. Results In total, 410 patients were included, of which 91 (22.2%) had low eCRF. The median M-DASI-4Q score was 3 (IQR 2-4). Low eCRF was characterized by higher age, female sex, higher BMI, and more comorbidities compared to patients with adequate eCRF (Table 1). Patients with low eCRF reported statistically significant higher levels of fatigue and stress, lower subjective disease control, and, remarkably, higher physical activity levels (Table 2). Multivariable logistic regression showed that female sex (adjusted Odds Ratio [aOR] 3.09), higher BMI (aOR 1.06), more comorbidities (aOR 3.77, aOR 8.52), fatigue (aOR 2.26), lower subjective disease control (aOR 0.90), and higher physical activity levels (aOR 2.29) were associated with low eCRF (Table 3). Conclusion In this exploratory study, we described an association between eCRF and patient- and clinical characteristics (sex, BMI, and comorbidities), as well as patient-reported outcomes of IBD (fatigue, and subjective disease control). Future research should investigate the validity of the M-DASI-4Q and determine thresholds for referral for further objective assessment for patients that might benefit from personalized interventions. Furthermore, future studies should further elucidate the interaction between physical activity and (e)CRF in patients with IBD to define recommendations.

Abstract Background Since the gut microbiota is altered in patients with Inflammatory Bowel Disease (IBD), microbiome-based biomarkers may be useful for diagnosing and monitoring of IBD. Currently, endoscopy is the gold standard for diagnosis and monitoring disease activity, which can be a high burden for patients. This study aimed to compare intestinal microbiota profiles between three different sampling methods faecal samples, rectal swabs and colonic mucosal biopsies. This could provide more insight into the microbiota composition in different sample types and might contribute to the development of a less invasive biomarker for diagnosing and monitoring IBD. Methods Patients with IBD (Crohn’s Disease or Ulcerative Colitis) who were scheduled for endoscopy were asked to participate. Prior to bowel preparation, a fecal sample and rectal swab were collected. During colonoscopy, mucosal biopsies were derived 20 cm ab ano. Microbiota composition was analyzed by IS-pro, a PCR technique based on species-specific differences in the 16S-23S interspace region of the bacterial ribosomal DNA. Microbiota profiles of the three different sample types were compared within the same patient (for each patient: fecal sample vs. mucosal biopsy, fecal sample vs. rectal swab, rectal swab vs. mucosal biopsy), and between different patients (for each patient: fecal sample of one patient vs. mucosal biopsies of all patients, fecal sample of one patient vs. rectal swabs of all patients, etcetera). Results A total of 200 patients were included. For each patient, similarity of microbiota composition between two sample types was assessed by calculating the Pearson’s correlation (expressed as R2). R2 values of all patients were combined in boxplots. We found a significantly higher correlation between the microbiota profiles of different sample types within the same patient, than between microbiota profiles of different sample types of different patients (median R2 0.27–0.33 and 0.02–0.03 respectively, Figure 1). However, correlation between different sample types from the same patient was still relatively low. The highest correlation was found between microbiota profiles of faecal samples and rectal swabs (median R2 0.33, ICR 0.17–0.54). On phylum level, the highest correlation was found in the Bacteroidetes phylum (Figure 2). For a global analysis of all versus all samples, we generated a clustered heat map, which confirmed the previous finding that microbiota profiles from faecal samples and rectal swabs were most similar to each other. Conclusion Microbiota composition in different sample types from the same patient were more similar to each other than to profiles from different patients. Microbiota profiles of faecal samples and rectal swabs were most identical.

Abstract Background The thiopurines, azathioprine (AZA) and mercaptopurine (MP), are effective and remain standard treatment options in steroid sparing and maintaining remission in patients with inflammatory bowel disease (IBD). Approximately 25% of patients discontinue within three months after treatment initiation due to adverse events, of which about half due to hepatotoxicity. We hypothesise that identification of patients with an increased risk of adverse events and timely treatment optimisation (e.g. dose adjustment, adjuvant allopurinol) can prevent treatment failure due to adverse events. The primary objective of this prospective observational multicentre study was to optimise and validate a proposed hepatotoxicity predictive algorithm in IBD patients starting AZA or MP therapy. Methods We adapted an algorithm from a previous study to predict the risk of developing hepatotoxicity in thiopurine drug treatment using multivariable logistic regression and a receiver operating characteristic curve. The determinants age, BMI and 6-MMPR-concentration one week after start of treatment (T=1) were inserted as continuous variables in this algorithm. Sex was inserted as a dichotomous variable. Inclusion criteria were adult thiopurine-naive IBD patients initiating AZA or MP treatment. Subjects were treated according to guidelines and followed for 12 weeks. The primary study outcome was hepatotoxicity within 12 weeks, defined as ALAT > 2x ULN or an R value ((ALAT / ULN ALAT)/(AP / ULN ALP)) ≥ 5. The hepatotoxicity- and no-hepatotoxicity groups were compared using the Mann-Whitney U-test. Results In total, 255 patients were included from Dec 2015 to June 2019, of whom 26 were excluded because of no actual start with AZA or MP (n=18), loss to follow up (n=7) or no IBD diagnosis (n=1). Out of 229 patients 21 (9%) developed hepatotoxicity. Five out of 21 patients (24%) in the hepatotoxicity-group and 123 out of 208 patients (59%) in the no-hepatotoxicity-group had to be excluded for analysis (see Figure 1). Ninety-three % of patients received MP with a median dose of 0.7 mg/kg (95%CI 0.3–1.4 mg/kg). Median dose of AZA (7%) was 2.0 mg/kg (95%CI 1.1 - 2.6 mg/kg). There was a difference between the hepatotoxicity and no-hepatotoxicity group in BMI (28 versus 24, p=0.022) and 6-MMPR/6-TGN ratio at T=1 (16 versus 9, p=0.027). In Table 1, the number of true positives, true negatives, false positives and false negatives are presented. The diagnostic values are shown in Table 2. A specificity of 77% (95%CI 66–85%) and a sensitivity of 50% (95%CI 26–75%) was obtained. Conclusion In conclusion, the adapted algorithm does not accurately predict hepatotoxicity in this cohort of patients on relatively low-dose thiopurine treatment.

Abstract Background The thiopurine derivatives, azathioprine (AZA), mercaptopurine (MP) and tioguanine (TG), remain standard treatment of Inflammatory Bowel Diseases (IBD). To date, therapeutic drug monitoring (TDM) is used to optimize thiopurine therapy. However, since this provides mainly pharmacokinetic information, TDM is of limited use to predict clinical effectiveness or to explain therapeutic failure. A specific pharmacodynamic marker would therefore be of more beneficial use. The immune suppressive mechanism of thiopurines, by the active thiopurine metabolite 6-thioguanine triphosphate, is primarily based on blocking the Ras-related C3 botulinum toxin substrate 1 (Rac1) causing T-cell apoptosis by inhibition of the phosphorylated downstream transcription factor signal transducer and activator of transcription 3 (pSTAT3) (Figure 1). The aim of this study was to explore whether expression of Rac1 and pSTAT3 in T-cells may be used as a pharmacodynamic marker for the therapeutic effect of thiopurine therapy in IBD patients. Methods To assess feasibility, T-cell Rac1 and pSTAT3 expression was evaluated in six parallel IBD groups: patients with active disease (1) and patients in remission on AZA/MP (2), TG (3), infliximab (IFX) (4), thiopurine and IFX (5) or without medication (6). Data of healthy subjects were used as reference values. Rac1 and pSTAT3 expression of patients in remission on AZA/MP or TG were compared to all other IBD groups and healthy subjects. Results Absolute Rac1 expression in T-cells did not differ between any of the IBD patient groups (Figure 2). A decrease in absolute pSTAT3 expression was found in IBD patients in remission on AZA/MP or TG, when compared to active disease patients, although not statistically significant. Notably, Rac1-corrected pSTAT3 expression was decreased in IBD patients in remission on AZA/MP or TG compared to active disease patients (p<0.01). This effect was not observed in the IBD groups in remission on other immunosuppressive therapy. Conclusion Rac1-corrected pSTAT3 expression in T-cells was significantly decreased in IBD patients in remission on thiopurine monotherapy compared to IBD patients with active disease, resulting in comparable values to healthy subjects. Rac1/pSTAT3 expression may serve as a potential, class specific pharmacodynamic marker to assess therapeutic efficacy of thiopurine monotherapy or as a marker to explain thiopurine resistance.

Abstract Background Iron deficiency (ID) and anaemia in Inflammatory Bowel Disease (IBD) are associated with reduced quality of life, worse disease outcomes, and an increase in healthcare costs. In the European guidelines, anaemia is listed as one of the treatment goals. The data on the prevalence of anaemia and ID are inconsistent. Therefore, we evaluated the prevalence of ID, anaemia, and potential risk factors in a large Dutch outpatient population. Methods Between January and November 2021, consecutive adult outpatients with IBD, who did not have significant comorbidities associated with anaemia, were included in this study across 16 general, teaching, and academic hospitals within the Netherlands. Besides demographic and clinical data, relevant biochemical parameters such as haemoglobin (Hb), Mean Corpuscular Volume (MCV), iron indices, and inflammatory markers (e.g., C-reactive protein (CRP) and faecal calprotectin (FCP)) were extracted from medical records. Active IBD was defined by either CRP >5mg/L or FCP >150mg/g. ID was defined by ferritin <100µg/L in case of inflammation and <30µg/L in quiescent IBD, or transferrin saturation <20%. The Dutch national reference range was used to define anaemia: Hb <7.5mmol/L or <8.5mmol/L for females and males, respectively. The data were analysed by stratifying patients into Crohn’s Disease (CD) and Ulcerative Colitis (UC) groups, with the latter also including patients with IBD-unclassified (IBDU). Results In total, 2197 patients (1271 CD, 849 UC, and 77 IBDU) were included in the study. The overall prevalence of anaemia, iron-deficiency anaemia (IDA), and ID was: 18.0%, 12.2%, and 43.4%, respectively. The prevalence of all three conditions did not differ between the CD and UC groups (P>0.05). Severe anaemia (Hb<6.2 mmol/L) was observed only in 28 patients. ID was more frequently observed in biochemically active IBD compared with quiescent IBD (70.8% versus 23.9%; P<0.001). Female gender, younger age, low MCV, and a twofold increase in biochemical inflammation were associated with ID development in multivariable analysis: Log2FCP [OR 1.39; 95% CI: 1.29–1.50; P<0.001] and Log2platelets [OR 1.85; 95% CI: 1.16–2.95; P<0.01]. In multivariable analysis, low ferritin and MCV, inflammation, older age, and male gender were associated with a higher risk of anaemia; however, disease location or behaviour did not affect the risk of developing anaemia or ID. Conclusion One in five ambulatory IBD patients presents with anaemia that is primarily caused by ID. Inflammation increases the risk of ID and anaemia regardless of IBD type or disease location. High ID prevalence suggests the need for screening and treatment optimisation.

Abstract Background Conventional thiopurines such as azathioprine (AZA) and mercaptopurine (MP) remain drugs of choice in maintaining remission and corticosteroid sparing in inflammatory bowel disease (IBD). Early discontinuation of thiopurine therapy occurs frequently, due to slow onset of effect and a relatively high frequency of early adverse drug reactions (ADR). Some ADR such as hepatotoxicity and gastro-intestinal complaints are associated with the thiopurine metabolite concentrations 6-thioguanine nucleotides (6-TGN) or 6-methylmercaptopurine ribonucleotides (6-MMPR), in particular elevated 6-MMPR concentrations or unfavorable 6-MMPR/6-TGN ratios. Early measurement of thiopurine metabolites may help to optimize thiopurine therapy in IBD. The aim of this study was to assess the predictive value of thiopurine metabolite measurement one week after thiopurine therapy initiation on discontinuation during the first three months of therapy. Methods This was a multicenter prospective observational study in the Netherlands. Consecutive IBD patients who initiated thiopurine therapy were included and measurement of thiopurine metabolites was performed after 7 days (6 – 8) of treatment (T1). Patients were monitored for 12 weeks to document occurrence of ADR and early treatment discontinuation. Switching to an alternative thiopurine or adding allopurinol (as co-medication) was also considered as treatment discontinuation (to prevent ADR). 6-MMPR concentrations and 6-MMPR/6-TGN ratios were separately analyzed (Mann-Whitney U-tests) regarding therapy discontinuation within 12 weeks. P-values of ≤0.05 were considered statistically significant. Results In total, 255 patients were included, of which 83 were excluded due to either missing blood samples on T1 (n=54), dose adjustments within 12 weeks (n=25) or a delayed T1 measurement (n=4). Of the remaining 172 patients, 79 patients were male (46%), 102 patients had Crohn’s disease (59%) and 157 patients were treated with MP (91%). In total, 88 (51%) patients continued thiopurine therapy and 84 patients (49%) discontinued therapy within 12 weeks. Median 6-MMPR concentrations (1,295 versus 1,589 pmol x 108 red blood cells) and 6-TGN/6-MMPR ratios (8.8 versus 11.4) did not differ significantly between patients who continued versus discontinued therapy within 12 weeks (Figures 1 and 2). Conclusion In this study thiopurine metabolites at T1 did not relate to discontinuation of thiopurine therapy within 12 weeks. We will conduct additional pharmacodynamic studies to corroborate our hypothesis that early metabolite measurements may be of individual patients’ benefit.

Abstract Background Clinicians face difficulty in positioning biologics and JAK inhibitors in anti-TNF refractory ulcerative colitis (UC) patients. Head-to-head trials comparing the efficacy of vedolizumab and tofacitinib in UC patients are lacking. We aimed to compare the effectiveness and safety of vedolizumab and tofacitinib in anti-TNF experienced UC patients in our prospective, nationwide registry using a propensity score weighted cohort. Methods UC patients who failed anti-TNF treatment (with or without thiopurine) and initiated vedolizumab or tofacitinib treatment subsequently, were identified in the observational prospective Initiative on Crohn and Colitis (ICC) Registry. We selected patients with both clinical (Simple Clinical Colitis Activity Index (SCCAI) >2) and biochemical (C-reactive protein (CRP) >5mg/L or faecal calprotectin (FC) >250 µg/g) or endoscopic disease activity (endoscopic MAYO score ≥ 1) at initiation of therapy. Patients previously treated with vedolizumab or tofacitinib were excluded. Corticosteroid-free clinical remission (SCCAI<2), biochemical remission (CRP ≤5 mg/L and/or FC ≤250 µg/g) and safety outcomes were compared after 52 weeks of treatment. Inverse propensity scores weighted comparison was used to adjust for confounding and selection bias. Results Overall, 83 vedolizumab and 65 tofacitinib treated patients were included (table 1). Propensity score weighted analysis showed that tofacitinib treated patients were more likely to achieve corticosteroid-free clinical remission at week 12, 24 and 52 compared to vedolizumab treated patients (OR: 5.87, 95%CI:3.55–9.70, P<0.01, OR: 2.96, 95%CI: 1.85–4.73, P<0.01 and OR 2.96, 95%CI: 1.85–4.73, P<0.01, respectively) (table 2). In addition, tofacitinib treated patients were more likely to achieve biochemical remission at week 12 and week 24, remaining only statistically borderline at week 52 (OR: 2.96, 95%CI: 1.85–4.73, P<0.01, OR: 2.96, 95%CI: 1.85–4.73, P<0.01 and OR 1.68, 95%CI: 0.99–2.86, P=0.05, respectively) (table 2). There was no difference in infection rate (OR:1.057, 95%CI: 0.60–1.86, p=0.85) or severe adverse events (OR: 0.39, 95%CI: 0.03–4.33, P=0.44). No thromboembolic events were observed. Most common reason for treatment discontinuation was loss of response (table 3). Conclusion In tofacitinib treated, anti-TNF experienced, UC patients, we observed that a higher proportion of patients achieved corticosteroid-free remission after 12, 24 and 52 weeks compared to vedolizumab treated patients. In addition, more tofacitinib treated patients achieved biochemical remission at week 12 and 24. There was no statistically significant difference in severe adverse events.

Abstract Background In current guidelines, thiopurines are still recommended as first-line maintenance therapy for patients with Crohn’s disease (CD). Due to their lack of immunogenicity, oral administration route and low costs, thiopurines are an attractive first-line treatment option. However, in recent studies the position of thiopurine monotherapy in CD has been questioned as a result of relatively lower overall effectiveness rates compared to ulcerative colitis. Real-world long-term effectiveness data substantiating the use and position of thiopurines in CD management remain sparse. We assessed long-term effectiveness of thiopurine monotherapy in CD using the population-based IBD South-Limburg (IBDSL) cohort. Methods All CD patients in the IBDSL cohort starting thiopurine monotherapy as first-line maintenance therapy between 1991–2014 were included. Thiopurine monotherapy was defined effective if either: (1) no escalation to biological treatment, (2) no course of corticosteroids, (3) no resective surgery or, (4) no hospitalization for active disease was required whilst on thiopurine treatment. Patients with early treatment discontinuation (i.e. <3 months) were identified, including reason of discontinuation. Long-term effectiveness was assessed adjusting for differences in follow-up between patients using Kaplan-Meier analysis. Potential risk factors for therapy failure were identified using Cox regression. Results In total, 643/1162 (55.3%) CD patients (median follow-up: 8.5 years IQR 5.0–13.2) received first-line thiopurine monotherapy after a median of 9.7 months (IQR 3.2–31.3) after diagnosis. Therapy was discontinued within three months in 164 patients (25.5%), mainly due to adverse events [Figure 1]. Thiopurine monotherapy was effective for the duration of treatment in 229/479 (35.6%) patients, corresponding to estimated effectiveness rates of 62.9%, 43.9% and 31.2% after 1, 5 and 10 years, respectively [Figure 1–2]. No significant difference in effectiveness was observed after stratifying for era of thiopurine initiation (pre-biological (1991–1998) vs. biological (>1999) era, p=0.84). Factors associated with thiopurine failure were stricturing disease (aHR 1.41, 95%CI 1.01–1.96) and upper GI involvement (aHR 1.52, 95%CI 1.02–2.28) at diagnosis. During follow-up, 40/229 patients with a durable response discontinued treatment due to quiescent disease. Of these, 35 patients (87.5%) remained without treatment 24 months after discontinuation. Conclusion Real-world data from this population-based study demonstrate that thiopurine monotherapy remains an effective and durable first-line treatment option for CD, even in the biological era. These results should be considered in the ongoing discussion regarding the position of thiopurine therapy.

Abstract Background The broad use of immunosuppressants and biologicals in Inflammatory Bowel Disease (IBD) patients increases the susceptibility to severe infections, and possibly COVID-19. Recently, in a Swedish population-based study it was suggested that IBD patients are at an increased risk of hospitalization for COVID-19, although course of COVID-19 did not differ from controls. Data on the outcome of COVID-19 in IBD patients from heavily affected regions remain, however, limited. South-Limburg has the second highest COVID-19 mortality rate in the Netherlands. We aimed to determine the incidence rate and outcome of severe COVID-19 in IBD patients in a population-based setting in South-Limburg. Methods We identified all IBD patients who presented at the emergency department (ED) of the only two hospitals covering the whole South-Limburg region with COVID-19 associated symptoms between February 27 and November 1, 2020. Confirmed COVID-19 diagnosis was defined by a combination of COVID-19 associated symptoms and either a positive SARS-CoV-2 PCR or a CT-CORADS score ≥4. As primary outcome, the incidence rate of severe COVID-19 (i.e. confirmed COVID-19 diagnosis requiring hospitalization, and/or resulting in ICU admission or death) was determined. Baseline characteristics and data on COVID-19 course were collected. At present, the total IBD population in South-Limburg is set at 4980 patients. Results During a follow-up of 3384 person-years, a total of 61 IBD patients (1.22%) presented with COVID-19 associated symptoms at one of the two hospital’s ED. Of these, 18 IBD patients (0.36%; 11 UC, 7 CD) fulfilled the criteria for severe COVID-19, corresponding to an incidence rate of 5.3 per 1000 person-years. Furthermore, 12/18 patients were using immunosuppressive medication for their IBD. Mean age at time of admission was 64.5 years (SD: 10.8) and 55.6% were male. All hospitalized patients had at least one comorbidity (with ≥ 1 comorbidity in 13/18 patients (72.2%)), cardiovascular disease being most prevalent (12/18). Mean BMI at time of admission was 27.3 (SD: 4.2). Thirteen patients (72.2%) required oxygen support and three patients (16.7%) ICU admission (of which two needed mechanical ventilation), translating to an incidence rate of 0.9 per 1000 patient-years for ICU admission. Median length of hospitalization was 11 days (IQR: 5.3–18.3). No IBD patients died due to severe COVID-19. Conclusion The incidence rate of severe COVID-19 among IBD patients in a population-based setting in a heavily affected region was 5.3 per 1000 person-years. Despite frequent use of immunosuppressive medication and high region-specific mortality rates, clinical outcomes of severe COVID-19 were comparable to the general population and in line with recent literature.