Activated HLA-DR+CD38+ Effector Th1/17 Cells Distinguish Crohn's Disease-associated Perianal Fistulas from Cryptoglandular Fistulas.

BACKGROUND: Perianal fistulas are a debilitating complication of Crohn's disease (CD). Due to unknown reasons, CD-associated fistulas are in general more difficult to treat than cryptoglandular fistulas (non-CD-associated). Understanding the immune cell landscape is a first step towards the development of more effective therapies for CD-associated fistulas. In this work, we characterized the composition and spatial localization of disease-associated immune cells in both types of perianal fistulas by high-dimensional analyses. METHODS: We applied single-cell mass cytometry (scMC), spectral flow cytometry (SFC), and imaging mass cytometry (IMC) to profile the immune compartment in CD-associated perianal fistulas and cryptoglandular fistulas. An exploratory cohort (CD fistula, n = 10; non-CD fistula, n = 5) was analyzed by scMC to unravel disease-associated immune cell types. SFC was performed on a second fistula cohort (CD, n = 10; non-CD, n = 11) to comprehensively phenotype disease-associated T helper (Th) cells. IMC was used on a third cohort (CD, n = 5) to investigate the spatial distribution/interaction of relevant immune cell subsets. RESULTS: Our analyses revealed that activated HLA-DR+CD38+ effector CD4+ T cells with a Th1/17 phenotype were significantly enriched in CD-associated compared with cryptoglandular fistulas. These cells, displaying features of proliferation, regulation, and differentiation, were also present in blood, and colocalized with other CD4+ T cells, CCR6+ B cells, and macrophages in the fistula tracts. CONCLUSIONS: Overall, proliferating activated HLA-DR+CD38+ effector Th1/17 cells distinguish CD-associated from cryptoglandular perianal fistulas and are a promising biomarker in blood to discriminate between these 2 fistula types. Targeting HLA-DR and CD38-expressing CD4+ T cells may offer a potential new therapeutic strategy for CD-related fistulas.

We applied high-dimensional analyses to profile the immune compartment in CD-associated and cryptoglandular perianal fistulas. Data analysis revealed activated HLA-DR+CD38+ effector Th1/17 cells as distinctly increased in CD-associated fistulas, suggesting a potential novel therapeutic target.

A Prediction Model for Successful Increase of Adalimumab Dose Intervals in Patients with Crohn's Disease: Secondary Analysis of the Pragmatic Open-Label Randomised Controlled Non-inferiority LADI Trial.

BACKGROUND: In the pragmatic open-label randomised controlled non-inferiority LADI trial we showed that increasing adalimumab (ADA) dose intervals was non-inferior to conventional dosing for persistent flares in patients with Crohn's disease (CD) in clinical and biochemical remission. AIMS: To develop a prediction model to identify patients who can successfully increase their ADA dose interval based on secondary analysis of trial data. METHODS: Patients in the intervention group of the LADI trial increased ADA intervals to 3 and then to 4 weeks. The dose interval increase was defined as successful when patients had no persistent flare (> 8 weeks), no intervention-related severe adverse events, no rescue medication use during the study, and were on an increased dose interval while in clinical and biochemical remission at week 48. Prediction models were based on logistic regression with relaxed LASSO. Models were internally validated using bootstrap optimism correction. RESULTS: We included 109 patients, of which 60.6% successfully increased their dose interval. Patients that were active smokers (odds ratio [OR] 0.90), had previous CD-related intra-abdominal surgeries (OR 0.85), proximal small bowel disease (OR 0.92), an increased Harvey-Bradshaw Index (OR 0.99) or increased faecal calprotectin (OR 0.997) were less likely to successfully increase their dose interval. The model had fair discriminative ability (AUC = 0.63) and net benefit analysis showed that the model could be used to select patients who could increase their dose interval. CONCLUSION: The final prediction model seems promising to select patients who could successfully increase their ADA dose interval. The model should be validated externally before it may be applied in clinical practice. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, number NCT03172377.

Deficits in geriatric assessment are important in relation to fatigue in older patients with Inflammatory Bowel Disease.

BACKGROUND: No previous study has investigated fatigue in older patients with Inflammatory Bowel Disease (IBD). AIMS: To describe the prevalence of fatigue in older patients and compare it to the prevalence in younger patients with IBD, and to determine factors associated with fatigue. METHODS: A prospective, multicenter cohort study, including older- (≥ 65 years) and younger patients with IBD (18-64 years). A geriatric assessment was performed in older patients to measure deficits in geriatric assessment (DiG). Fatigue was defined by one item from the short Inflammatory Bowel Disease Questionnaire. Active disease was defined as the presence of clinical or biochemical disease activity. RESULTS: Fatigue prevalence in the 405 older patients varied between 45.4% (71/155) in active disease to 23.6% (60/250) in remission. Fatigue prevalence in 155 younger patients was 59.5% (47/79) and 57.4% (89/155), respectively. Female sex, clinical disease activity, use of immunomodulators and presence of DiG were associated with fatigue in older patients with IBD. CONCLUSIONS: Fatigue prevalence is lower in older patients with IBD compared to younger patients with IBD, but increases when active disease is present. Clinicians should be aware that fatigue is a relevant symptom in older patients with IBD, as it is associated with DiG.

Predicting response to iron supplementation in patients with active inflammatory bowel disease (PRIme): a randomised trial protocol.

INTRODUCTION: Iron deficiency anaemia (IDA) is the most common systemic manifestation of inflammatory bowel disease (IBD) that has detrimental effects on quality of life (QoL) and disease outcomes. Iron deficiency (ID), with or without anaemia, poses a diagnostic and therapeutic challenge in patients with IBD due to the multifactorial nature of ID(A) and its frequent recurrence. Elevated hepcidin-a systemic iron regulator that modulates systemic iron availability and intestinal iron absorption-has been associated with oral iron malabsorption in IBD. Therefore, hepcidin could assist in therapeutic decision-making. In this study, we investigate whether hepcidin can predict response to oral and intravenous iron supplementation in patients with active IBD undergoing anti-inflammatory treatment. METHODS AND ANALYSIS: PRIme is an exploratory, multicentre, open-label and randomised trial. All adult patients with active IBD and ID(A) will be assessed for eligibility. The participants (n=90) will be recruited at five academic hospitals within the Netherlands and randomised into three groups (1:1:1): oral ferrous fumarate, oral ferric maltol or intravenous iron. Clinical and biochemical data will be collected at the baseline and after 6, 14 and 24 weeks. Blood samples will be collected to measure hepcidin and other biomarkers related to iron status. In addition, patient-reported outcomes regarding QoL and disease burden will be evaluated. The primary outcome is the utility of hepcidin as a predictive biomarker for response to iron therapy, which will be assessed using receiver operating curve analysis. ETHICS AND DISSEMINATION: The study has been approved by the Institutional Review Board at the Leiden University Medical Center (IRB No. P21.109) and other study sites. All participants will provide written informed consent to enrol in the study. The findings will be published in a peer-reviewed journal and disseminated at scientific conferences; the dataset will be available on reasonable request. TRIAL REGISTRATION: Prospectively registered in the https://clinicaltrials.gov/ and the Eudra registries. First submitted on 10 May 2022 to the ClinicalTrials.gov (ID: NCT05456932) and on 3 March 2022 to the European Union Drug Regulating Authorities Clinical Trials Database (ID: 2022-000894-16).

Patient preferences in treatment options of ulcerative colitis: a discrete choice experiment.

INTRODUCTION: Since the number of medical treatment options for Ulcerative Colitis (UC) has expanded over the last decades, patients and physicians face challenges regarding decisions about the medication options. We aimed to identify patients' preferences about their UC treatment options in the Netherlands. Furthermore, we assessed after how many failed treatment options, patients are willing to consider surgical treatment. METHODS: We conducted a web-based, multicenter, discrete choice experiment (DCE) among adult UC patients. Patients were repeatedly asked to choose between two hypothetical medicinal treatment options. The choice tasks were based on administration route, administration location, chance of symptom reduction (on short and long term) and chances on infection and other adverse events. Data were analyzed by using Hierarchical Bayes estimation. RESULTS: A total of 172 UC patients participated in the DCE. More than half were anti-TNF experienced (52.9%). The chance of symptom reduction after one year (relative importance (RI) 27.7 (95% CI 26.0-29.4)) was most important in choosing between medicinal treatments, followed by the chance of infection (RI 22.3 (21.4 - 23.3)) and chance of symptom reduction after eight weeks (RI 19.5 (18.3 - 20.6)). Considering surgical treatment, nineteen patients (14.3%) would not even consider surgery after failing eight treatment options without any new available therapies left. Nine patients would consider surgery before trying any treatment options. CONCLUSION: We found that symptom reduction after one year was the most important attribute in choosing between treatments in UC patients. These outcomes can help understand the trade-offs and preferences of UC patients.

Prognostic Value of the Modified Rutgeerts Score for Long-Term Outcomes After Primary Ileocecal Resection in Crohn's Disease.

INTRODUCTION: The prognostic value of the modified Rutgeerts score (mRS) in patients with Crohn's disease (CD) needs to be further elucidated. This study assessed the prognostic value of the mRS for long-term outcomes after primary ileocecal resection in patients with CD. METHODS: Patients with CD after primary ileocecal resection with an available mRS at first postoperative ileocolonoscopy (index mRS) were retrospectively included. The primary outcome was surgical recurrence. Secondary outcomes were clinical recurrence and progression to severe endoscopic recurrence (≥i3). Cox proportional hazard models were used to assess the association between index mRS and outcomes. RESULTS: Six hundred fifty-two patients were included (mean follow-up: 6.4 years, SD: 4.6). Surgical recurrence rates were 7.7%, 5.3%, 12.9%, 19.1%, 28.8%, 47.8% for index mRS i0, i1, i2a, i2b, i3, and i4, respectively. Clinical recurrence occurred in 42.2% (i0), 53.7% (i1), 58.5% (i2a), 80.2% (i2b), 79.4% (i3), and 95.3% (i4) of patients. Progression to severe endoscopic recurrence occurred in 21.1% (i0), 33.9% (i1), 26.8% (i2a), and 33.3% (i2b) of patients. An index mRS of i2b (adjusted hazard ratio [aHR] 3.0; 1.5-5.6), i3 (aHR 4.0; 2.0-7.9) and i4 (aHR 8.0; 4.0-16.0) were associated with surgical recurrence. An index mRS of i1 (aHR 1.7; 1.2-2.4), i2a (aHR 1.7; 1.2-2.4), i2b (aHR 4.4; 3.2-6.0), i3 (aHR 3.6; 2.5-5.2), and i4 (aHR 7.3; 4.8-10.9) were associated with clinical recurrence. An index mRS of i1 (aHR 2.0; 1.1-3.7) or i2b (aHR 2.5; 1.4-4.6) was associated with progression to severe endoscopic recurrence. DISCUSSION: The increasing mRS corresponds closely with the risk of surgical and clinical recurrence. An index mRS ≥ i2b is associated with surgical recurrence, an index mRS ≥ i1 is associated with clinical recurrence, and i1 or i2b with progression to severe endoscopic recurrence. These results support tight monitoring of disease activity and treatment optimization in patients with ileal lesions and a more conservative management in patients with anastomotic lesions.

Frailty screening associates with hospitalization and decline in quality of life and functional status in older patients with inflammatory bowel disease.

BACKGROUND AND AIMS: To study frailty screening in association with hospitalization and decline in quality of life (QoL) and functional status in older patients with Inflammatory Bowel Diseases (IBD). METHODS: A prospective multicentre cohort study in IBD patients ≥65 years using frailty screening (G8 Questionnaire). Outcomes were all-cause, acute and IBD-related hospitalization, any infection, any malignancy, QoL (EQ5D-3L) and functional decline (Instrumental Activities of Daily Living, (IADL)) during 18 months follow-up. Confounders: age, IBD type, biochemical disease activity (C-reactive protein ≥10 mg/L and/or fecal calprotectin ≥250 µg/g), comorbidity (Charlson Comorbidity Index). RESULTS: Out of 405 patients, median age 70 years, 196 (48%) screened at risk for frailty. All-cause hospitalizations occurred 136 times in 96 patients (23.7%), acute hospitalizations 103 times in 74 (18.3%). Risk of frailty did not associate with all-cause (aHR 1.5, 95% CI 0.9-2.4), but did associate with acute hospitalizations (aHR 2.2, 95% CI 1.3-3.8). Infections occurred in 86 patients (21.2%) and were not associated with frailty. Decline in QoL was experienced by 108 (30.6%) patients, decline in functional status by 46 (13.3%). Frailty screening associated with decline in QoL (aOR 2.1, 95% CI 1.3-3.6) and functional status (aOR 3.7, 95% CI 1.7-8.1). CONCLUSIONS: Frailty screening associates with worse health outcomes in older patients with IBD. Further studies are needed to assess feasibility and effectiveness of implementation in routine care.

Smoking and colorectal neoplasia in patients with inflammatory bowel disease: Dose-effect relationship.

BACKGROUND AND AIMS: Prior studies on the effect of smoking on the risk of colitis-associated colorectal neoplasia (CRN) have reported conflicting results. We aimed to further elucidate the association between smoking, including possible dose-effects, and the development of colorectal neoplasia in patients with inflammatory bowel disease (IBD). METHODS: We performed a prospective multicenter cohort study including patients with colonic IBD enrolled in a surveillance program in four academic hospitals between 2011 and 2021. The effects of smoking status and pack-years at study entry on subsequent recurrent events of CRN (including indefinite, low- and high-grade dysplasia, and colorectal cancer [CRC]) were evaluated using uni- and multivariable Prentice, Williams, and Peterson total-time Cox proportional hazard models. Adjustment was performed for extensive disease, prior/index dysplasia, sex, age, first-degree relative with CRC, primary sclerosing cholangitis, and endoscopic inflammation. RESULTS: In 501 of the enrolled 576 patients, at least one follow-up surveillance was performed after the study index (median follow-up 5 years). CRN occurred at least once in 105 patients. Ever smoking was not associated with recurrent CRN risk (adjusted hazard ratio [aHR] 1.04, 95% confidence interval [CI] 0.75-1.44), but an increasing number of pack-years was associated with an increased risk of recurrent CRN (aHR per 10 pack-years 1.17, 95% CI 1.03-1.32; p < 0.05). Separate analyses per IBD type did not reveal differences. CONCLUSIONS: This study found that an increase in pack-years is associated with a higher risk of recurrent CRN in patients with IBD, independent of established CRN risk factors (NCT01464151).

Cost-Effectiveness Analysis of Increased Adalimumab Dose Intervals in Crohn's Disease Patients in Stable Remission: The Randomized Controlled LADI Trial.

BACKGROUND AND AIMS: We aimed to assess cost-effectiveness of increasing adalimumab dose intervals compared to the conventional dosing interval in patients with Crohn's disease [CD] in stable clinical and biochemical remission. DESIGN: We conducted a pragmatic, open-label, randomized controlled non-inferiority trial, comparing increased adalimumab intervals with the 2-weekly interval in adult CD patients in clinical remission. Quality of life was measured with the EQ-5D-5L. Costs were measured from a societal perspective. Results are shown as differences and incremental net monetary benefit [iNMB] at relevant willingness to accept [WTA] levels. RESULTS: We randomized 174 patients to the intervention [n = 113] and control [n = 61] groups. No difference was found in utility (difference: -0.017, 95% confidence interval [-0.044; 0.004]) and total costs (-€943, [-€2226; €1367]) over the 48-week study period between the two groups. Medication costs per patient were lower (-€2545, [-€2780; -€2192]) in the intervention group, but non-medication healthcare (+€474, [+€149; +€952]) and patient costs (+€365 [+€92; €1058]) were higher. Cost-utility analysis showed that the iNMB was €594 [-€2099; €2050], €69 [-€2908; €1965] and -€455 [-€4,096; €1984] at WTA levels of €20 000, €50 000 and €80 000, respectively. Increasing adalimumab dose intervals was more likely to be cost-effective at WTA levels below €53 960 per quality-adjusted life year. Above €53 960 continuing the conventional dose interval was more likely to be cost-effective. CONCLUSION: When the loss of a quality-adjusted life year is valued at less than €53 960, increasing the adalimumab dose interval is a cost-effective strategy in CD patients in stable clinical and biochemical remission. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, number NCT03172377.

Fecal microbiota transplantation for Parkinson's disease using levodopa - carbidopa intestinal gel percutaneous endoscopic gastro-jejeunal tube.

We report a patient with a 5-year diagnosis of akinetic-rigid Parkinson's disease under treatment with Levodopa-Carbidopa Intestinal Gel therapy through a PEG-J tube due to motor complications, in which, in the context of a clinical study, we successfully and safely administered fecal microbiota transplant through a PEG-J.

Ustekinumab Trough Concentrations Are Associated with Biochemical Outcomes in Patients with Crohn's Disease.

OBJECTIVE: It is unknown whether ustekinumab (UST) levels can predict clinical outcomes in Crohn's disease (CD) patients. We assessed the exposure-response relationship of UST trough concentrations with biochemical outcomes at week 24 in a prospective, real-world setting. METHODS: We performed a prospective study in patients with CD starting UST in four academic centres in the Netherlands. All patients received a weight-adjusted intravenous (IV) UST induction dose, followed by one subcutaneous (SC) dose of 90 mg UST at 8 weeks. Maintenance therapy consisted of 90 mg subcutaneous UST every 8 or 12 weeks. Individual UST concentration time course during treatment were estimated using a population pharmacokinetic (PK) model. Quartile analysis and logistic regression were performed to analyse if UST concentrations at week 8 were associated with biochemical remission rates at week 24 (C-reactive protein (CRP) ≤ 5 mg/L and / or faecal calprotectin (FC) ≤ 250 mg/kg). RESULTS: In total, 124 patients with CD were included. Patients achieving biochemical remission at week 12 and 24 had significantly higher UST levels at week 8 compared to patients without biochemical remission (6.6 µg/mL versus 3.9 µg/mL, P < 0.01 and 6.3 µg/mL versus 3.9 µg/mL, P < 0.01, respectively). In quartile analysis, patients with UST levels in the highest quartile (≥ 6.3 µg/mL at week 8) had higher biochemical remission rates at week 12 and week 24. There was no association between UST levels at and corticosteroid-free clinical remission rates. CONCLUSION: In this real-world cohort of patients with CD, UST levels in the highest quartile (≥ 6.3 µg/mL) at week 8 were associated with higher biochemical remission rates at week 24.

Local administration of mesenchymal stromal cells is safe and modulates the immune compartment in ulcerative proctitis.

BACKGROUNDDue to their immunoregulatory and tissue regenerative features, mesenchymal stromal cells (MSCs) are a promising novel tool for the management of ulcerative proctitis (UP). Here we report on a phase IIa clinical study that evaluated the impact of local MSC therapy on UP.METHODSThirteen refractory UP patients, with an endoscopic Mayo score (EMS) of 2 or 3, were included. Seven patients received 20-40 million allogeneic MSCs (cohort 1), while 6 patients received 40-80 million MSCs (cohort 2). Adverse events (AEs) were assessed at baseline and on weeks 2, 6, 12, and 24. Clinical, endoscopic, and biochemical parameters were assessed at baseline and on weeks 2 and 6. Furthermore, we evaluated the engraftment of MSCs, the presence of donor-specific human leukocyte antigen (HLA) antibodies (DSAs), and we determined the impact of MSC therapy on the local immune compartment.RESULTSNo serious AEs were observed. The clinical Mayo score was significantly improved on weeks 2 and 6, and the EMS was significantly improved on week 6, compared with baseline. On week 6, donor MSCs were still detectable in rectal biopsies from 4 of 9 patients and DSAs against both HLA class I and class II were found. Mass cytometry showed a reduction in activated CD8+ T cells and CD16+ monocytes and an enrichment in mononuclear phagocytes and natural killer cells in biopsies after local MSC therapy.CONCLUSIONLocal administration of allogeneic MSCs is safe, tolerable, and feasible for treatment of refractory UP and shows encouraging signs of clinical efficacy and modulation of local immune responses. This sets the stage for larger clinical trials.TRIAL REGISTRATIONEU Clinical Trials Register (EudraCT, 2017-003524-75) and the Dutch Trial Register (NTR7205).FUNDINGECCO grant 2020.

Hepcidin and Iron Status in Patients With Inflammatory Bowel Disease Undergoing Induction Therapy With Vedolizumab or Infliximab.

BACKGROUND: Hepcidin, the systemic iron regulator, could be critical in differentiating iron deficiency (ID) from functional iron restriction in inflammatory bowel disease (IBD). We assessed hepcidin as a diagnostic ID marker and explored the relationship between hepcidin and its regulators in patients with IBD undergoing induction therapy with infliximab (IFX) or vedolizumab (VEDO). METHODS: Patients with active IBD receiving induction therapy with IFX or VEDO were included. Serum samples at baseline and after 6 weeks of induction therapy were analyzed for hepcidin, inflammation- and hypoxia-associated cytokines, and oxidative stress. Data were analyzed by stratifying based on the response at week 14. Results were compared with samples from age- and sex-matched healthy control subjects. RESULTS: Patients receiving induction therapy with IFX (n = 71) or VEDO (n = 51) and healthy control subjects (n = 50) were included. At baseline, hepcidin correlated positively with ferritin and negatively with soluble transferrin receptor/log ferritin index (P < .001). ID was prevalent in 96.7% of patients who had hepcidin levels below the median. Hepcidin accurately identified ID: the area under the curve (hepcidin) was 0.89 (95% confidence interval, 0.82-0.95; P < .001). In total, 75.4% of patients responded to induction therapy; inflammation, hepcidin, and ferritin decreased significantly, while transferrin increased during induction therapy. These changes were observed only in patients who responded to the therapy. CONCLUSIONS: Hepcidin levels in IBD are primarily determined by ID, even in an inflammatory state. In addition, induction therapy can decrease hepcidin levels, which might lead to better bioavailability of iron supplements. Therefore, hepcidin is a potential diagnostic ID biomarker that could assist therapeutic decision making.

Absolute iron deficiency is the primary determinant of hepcidin levels, even in an inflammatory state. Induction therapy can decrease hepcidin levels, which might improve iron bioavailability. Hence, hepcidin is a potential diagnostic iron deficiency biomarker that could assist therapeutic decision making.

Increased versus conventional adalimumab dose interval for patients with Crohn's disease in stable remission (LADI): a pragmatic, open-label, non-inferiority, randomised controlled trial.

BACKGROUND: Despite its effectiveness in treating Crohn's disease, adalimumab is associated with an increased risk of infections and high health-care costs. We aimed to assess clinical outcomes of increased adalimumab dose intervals versus conventional dosing in patients with Crohn's disease in stable remission. METHODS: The LADI study was a pragmatic, open-label, multicentre, non-inferiority, parallel, randomised controlled trial, done in six academic hospitals and 14 general hospitals in the Netherlands. Adults (aged ≥18 years) diagnosed with luminal Crohn's disease (with or without concomitant perianal disease) were eligible when in steroid-free clinical and biochemical remission (defined as Harvey-Bradshaw Index [HBI] score <5, faecal calprotectin <150 µg/g, and C-reactive protein <10 mg/L) for at least 9 months on a stable dose of 40 mg subcutaneous adalimumab every 2 weeks. Patients were randomly assigned (2:1) to the intervention group or control group by the coordinating investigator using a secure web-based system with variable block randomisation (block sizes of 6, 9, and 12). Randomisation was stratified on concomitant use of thiopurines and methotrexate. Patients and health-care providers were not masked to group assignment. Patients allocated to the intervention group increased adalimumab dose intervals to 40 mg every 3 weeks at baseline and further to every 4 weeks if they remained in clinical and biochemical remission at week 24. Patients in the control group continued their 2-weekly dose interval. The primary outcome was the cumulative incidence of persistent flares at week 48 defined as the presence of at least two of the following criteria: HBI score of 5 or more, C-reactive protein 10 mg/L or more, and faecal calprotectin more than 250 µg/g for more than 8 weeks and a concurrent decrease in the adalimumab dose interval or start of escape medication. The non-inferiority margin was 15% on a risk difference scale. All analyses were done in the intention-to-treat and per-protocol populations. This trial was registered at ClinicalTrials.gov, NCT03172377, and is not recruiting. FINDINGS: Between May 3, 2017, and July 6, 2020, 174 patients were randomly assigned to the intervention group (n=113) or the control group (n=61). Four patients from the intervention group and one patient from the control group were excluded from the analysis for not meeting inclusion criteria. 85 (50%) of 169 participants were female and 84 (50%) were male. At week 48, the cumulative incidence of persistent flares in the intervention group (three [3%] of 109) was non-inferior compared with the control group (zero; pooled adjusted risk difference 1·86% [90% CI -0·35 to 4·07). Seven serious adverse events occurred, all in the intervention group, of which two (both patients with intestinal obstruction) were possibly related to the intervention. Per 100 person-years, 168·35 total adverse events, 59·99 infection-related adverse events, and 42·57 gastrointestinal adverse events occurred in the intervention group versus 134·67, 75·03, and 5·77 in the control group, respectively. INTERPRETATION: The individual benefit of increasing adalimumab dose intervals versus the risk of disease recurrence is a trade-off that should take patient preferences regarding medication and the risk of a flare into account. FUNDING: Netherlands Organisation for Health Research and Development.

Crohn's Disease-Associated and Cryptoglandular Fistulas: Differences and Similarities.

Perianal fistulas are defined as pathological connections between the anorectal canal and the perianal skin. Most perianal fistulas are cryptoglandular fistulas, which are thought to originate from infected anal glands. The remainder of the fistulas mainly arises as complications of Crohn's disease (CD), trauma, or as a result of malignancies. Fistulas in CD are considered as a consequence of a chronic and transmural inflammatory process in the distal bowel and can, in some cases, even precede the diagnosis of CD. Although both cryptoglandular and CD-associated fistulas might look similar macroscopically, they differ considerably in their complexity, treatment options, and healing rate. Therefore, it is of crucial importance to differentiate between these two types of fistulas. In this review, the differences between CD-associated and cryptoglandular perianal fistulas in epidemiology, pathogenesis, and clinical management are discussed. Finally, a flow chart is provided for physicians to guide them when dealing with patients displaying their first episode of perianal fistulas.

Effectiveness and safety of tofacitinib for ulcerative colitis: two-year results of the ICC Registry.

BACKGROUND: Tofacitinib is an oral Janus kinase (JAK) inhibitor and is registered for the treatment of ulcerative colitis (UC). The effectiveness of tofacitinib has been evaluated up to 12 months of treatment. AIM: The aim of this study was to assess the effectiveness and safety of 24 months of tofacitinib use in UC patients in the Netherlands. METHODS: Patients initiating tofacitinib treatment were included in the ICC Registry, a nationwide, observational registry. Patients were prospectively evaluated for up to 24 months. The primary outcome was corticosteroid-free clinical remission (CSFR, Simple Clinical Colitis Activity Index [SCCAI] ≤2) at week 104. Secondary outcomes included biochemical remission (C-reactive protein (CRP) ≤5 mg/L and faecal calprotectin (FC) ≤250 µg/g), safety, and discontinuation rate. RESULTS: We included 110 patients of whom 104 (94.5%) were anti-TNF experienced. After 104 weeks of tofacitinib, 31.8% (34/107) were in CSFR, 23.4% (25/107) in biochemical remission and 18.7% (20/107) in combined clinical and biochemical remission. Of the patients in CSFR at week 52, 76.5% (26/34) remained so after 104 weeks of treatment. Sixty-one patients (55.5%) discontinued tofacitinib after a median duration of 13 weeks (IQR 7-34). The main reasons for discontinuation were non-response (59%), loss of response (14.8%), and adverse events (18%). There were 33.9 possible tofacitinib-related adverse events per 100 patient-years during follow-up. Adverse events most probably related to tofacitinib were skin reactions and headaches. There were 6.4 herpes zoster infections per 100 patient-years. CONCLUSION: Tofacitinib was effective in 31.8% of patients after 24 months of treatment.

Superior Effectiveness of Tofacitinib Compared to Vedolizumab in Anti-TNF-experienced Ulcerative Colitis Patients: A Nationwide Dutch Registry Study.

BACKGROUND & AIMS: Clinicians face difficulty in when and in what order to position biologics and Janus kinase inhibitors in patients with anti-tumor necrosis factor-alpha (TNF) refractory ulcerative colitis (UC). We aimed to compare the effectiveness and safety of vedolizumab and tofacitinib in anti-TNF-exposed patients with UC in our prospective nationwide Initiative on Crohn and Colitis Registry. METHODS: Patients with UC who failed anti-TNF treatment and initiated vedolizumab or tofacitinib treatment were identified in the Initiative on Crohn and Colitis Registry in the Netherlands. We selected patients with both clinical as well as biochemical or endoscopic disease activity at initiation of therapy. Patients previously treated with vedolizumab or tofacitinib were excluded. Corticosteroid-free clinical remission (Simple Clinical Colitis Activity Index ≤2), biochemical remission (C-reactive protein ≤5 mg/L or fecal calprotectin ≤250 µg/g), and safety outcomes were compared after 52 weeks of treatment. Inverse propensity score-weighted comparison was used to adjust for confounding and selection bias. RESULTS: Overall, 83 vedolizumab- and 65 tofacitinib-treated patients were included. Propensity score-weighted analysis showed that tofacitinib-treated patients were more likely to achieve corticosteroid-free clinical remission and biochemical remission at weeks 12, 24, and 52 compared with vedolizumab-treated patients (odds ratio [OR], 6.33; 95% confidence interval [CI], 3.81-10.50; P < .01; OR, 3.02; 95% CI, 1.89-4.84; P < .01; and OR, 1.86; 95% CI, 1.15-2.99; P = .01; and OR, 3.27; 95% CI, 1.96-5.45; P < .01; OR, 1.87; 95% CI, 1.14-3.07; P = .01; and OR, 1.81; 95% CI, 1.06-3.09; P = .03, respectively). There was no difference in infection rate or severe adverse events. CONCLUSIONS: Tofacitinib was associated with superior effectiveness outcomes compared with vedolizumab in anti-TNF-experienced patients with UC along with comparable safety outcomes.

Anemia and Iron Deficiency in Outpatients with Inflammatory Bowel Disease: Ubiquitous Yet Suboptimally Managed.

Background: Iron deficiency (ID) and anemia in patients with Inflammatory Bowel Disease (IBD) are associated with a reduced quality of life. We assessed the prevalence of ID and anemia in Dutch outpatients with IBD and compared routine ID(A) management among medical professionals to the European Crohn's and Colitis Organisation (ECCO) treatment guidelines. Methods: Between January and November 2021, consecutive adult outpatients with IBD were included in this study across 16 Dutch hospitals. Clinical and biochemical data were extracted from medical records. Additionally, medical professionals filled out questionnaires regarding routine ID(A) management. Results: In total, 2197 patients (1271 Crohn's Disease, 849 Ulcerative Colitis, and 77 IBD-unclassified) were included. Iron parameters were available in 59.3% of cases. The overall prevalence of anemia, ID, and IDA was: 18.0%, 43.4%, and 12.2%, respectively. The prevalence of all three conditions did not differ between IBD subtypes. ID(A) was observed more frequently in patients with biochemically active IBD than in quiescent IBD (ID: 70.8% versus 23.9%; p < 0.001). Contrary to the guidelines, most respondents prescribed standard doses of intravenous or oral iron regardless of biochemical parameters or inflammation. Lastly, 25% of respondents reported not treating non-anemic ID. Conclusions: One in five patients with IBD suffers from anemia that­despite inconsistently measured iron parameters­is primarily caused by ID. Most medical professionals treat IDA with oral iron or standard doses of intravenous iron regardless of biochemical inflammation; however, non-anemic ID is often overlooked. Raising awareness about the management of ID(A) is needed to optimize and personalize routine care.

Increased stromal PFKFB3-mediated glycolysis in inflammatory bowel disease contributes to intestinal inflammation.

Inflammatory bowel disease (IBD) is a chronic relapsing inflammation of the intestinal tract with currently not well-understood pathogenesis. In addition to the involvement of immune cells, increasing studies show an important role for fibroblasts in the pathogenesis of IBD. Previous work showed that glycolysis is the preferred energy source for fibroblasts in fibrotic diseases. 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 3 (PFKFB3) is a key kinase supporting glycolysis. Increased expression of PFKFB3 in several cancers and inflammatory diseases has been previously reported, but the metabolic status of fibroblasts and the role of PFKFB3 in patients with IBD are currently unknown. Therefore, in this study, we evaluated the role of glycolysis and PFKFB3 expression in IBD. Single-sample gene set enrichment analysis (ssGSEA) revealed that glycolysis was significantly higher in IBD intestinal samples, compared to healthy controls, which was confirmed in the validation cohorts of IBD patients. Single-cell sequencing data indicated that PFKFB3 expression was higher in IBD-derived stromal cells. In vitro, PFKFB3 expression in IBD-derived fibroblasts was increased after the stimulation with pro-inflammatory cytokines. Using seahorse real-time cell metabolic analysis, inflamed fibroblasts were shown to have a higher extracellular acidification rate and a lower oxygen consumption rate, which could be reversed by inhibition of JAK/STAT pathway. Furthermore, increased expression of pro-inflammatory cytokines and chemokines in fibroblasts could be reverted by PFK15, a specific inhibitor of PFKFB3. In vivo experiments showed that PFK15 reduced the severity of dextran sulfate sodium (DSS)- and Tcell transfer induced colitis, which was accompanied by a reduction in immune cell infiltration in the intestines. These findings suggest that increased stromal PFKFB3 expression contributes to inflammation and the pathological function of fibroblasts in IBD. Inhibition of PFKFB3 suppressed their inflammatory characteristics.

Cytokine Mixtures Mimicking the Local Milieu in Patients with Inflammatory Bowel Disease Impact Phenotype and Function of Mesenchymal Stromal Cells.

Locally applied mesenchymal stromal cells (MSCs) have the capacity to promote the healing of perianal fistulas in Crohn's disease (CD) and are under clinical development for the treatment of proctitis in ulcerative colitis (UC). Despite these clinical advances, the mechanism of action of local MSC therapy in inflammatory bowel disease (IBD) is largely unknown. We hypothesized that the local cytokine environment in IBD patients affects the immunomodulatory properties of MSCs. To evaluate this, 11 cytokines were analyzed in inflamed tissues obtained from CD and UC patients. Based on the identified cytokine profiles 4 distinct cytokine mixtures that mimic various inflammatory IBD environments were established. Next, MSCs were cultured in the presence of either of these 4 cytokine mixtures after which the expression of immunomodulatory and tissue regenerative molecules and the capacity of MSCs to modulate T-cell proliferation and dendritic cell (DC) differentiation were assessed. Our data show that MSCs respond, in a cytokine-specific manner, by upregulation of immunomodulatory and tissue regenerative molecules, including cyclooxygenase-2, indoleamine 2,3-dioxygenase, and transforming growth factor-ß1. Functional studies indicate that MSCs exposed to a cytokine profile mimicking one of the 2 UC cytokine milieus were less effective in inhibition of DC differentiation. In conclusion, our data indicate that cytokine mixes mimicking the local cytokine milieus of inflamed UC colonic or CD fistulas tissues can differentially affect the immunomodulatory and tissue regenerative characteristics of MSCs. These data support the hypothesis that the local intestinal cytokine milieu serves as a critical factor in the efficacy of local MSC treatment.