Background and AimsOur goals were to study frailty screening in association with hospitalization and decline in quality of life [QoL] and functional status in older patients with inflammatory bowel... Show moreBackground and AimsOur goals were 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].MethodsThis was a prospective multicentre cohort study in IBD patients ≥65 years old 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 of follow-up. Confounders were age, IBD type, biochemical disease activity [C-reactive protein ≥10 mg/L and/or faecal calprotectin ≥250 µg/g], and comorbidity [Charlson Comorbidity Index].ResultsOf 405 patients, with a median age of 70 years, 196 [48%] were screened as being at risk for frailty. All-cause hospitalizations occurred 136 times in 96 patients [23.7%], and acute hospitalizations 103 times in 74 patients [18.3%]. Risk of frailty was not associated with all-cause (adjusted hazard ratio [aHR] 1.5, 95% confidence interval [CI] 0.9–2.4), but was associated with acute hospitalizations [aHR 2.2, 95% CI 1.3–3.8]. Infections occurred in 86 patients [21.2%] and these were not associated with frailty. A decline in QoL was experienced by 108 [30.6%] patients, and a decline in functional status by 46 patients [13.3%]. Frailty screening was associated with a decline in QoL (adjusted odds ratio [aOR] 2.1, 95% CI 1.3–3.6) and functional status [aOR 3.7, 95% CI 1.7–8.1].ConclusionsFrailty screening is associated with worse health outcomes in older patients with IBD. Further studies are needed to assess the feasibility and effectiveness of its implementation in routine care. Show less
Background and AimsPrior 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... Show moreBackground and AimsPrior 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).MethodsWe 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.ResultsIn 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.ConclusionsThis 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). Show less
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... Show moreObjective: 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 mu g/mL versus 3.9 mu g/mL, P < 0.01 and 6.3 mu g/mL versus 3.9 mu g/mL, P < 0.01, respectively). In quartile analysis, patients with UST levels in the highest quartile (>= 6.3 mu g/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 mu g/mL) at week 8 were associated with higher biochemical remission rates at week 24. Show less
Arkenbosch, J.H.C.; Beelen, E.M.J.; Dijkstra, G.; Romberg-Camps, M.; Duijvestein, M.; Hoentjen, F.; ... ; Dutch Initiative Crohns Colitis IC 2022
Background To prevent recurrence after ileocolonic resection [ICR] in Crohn's disease [CD], postoperative prophylaxis based on risk stratification is recommended in international guidelines. This... Show moreBackground To prevent recurrence after ileocolonic resection [ICR] in Crohn's disease [CD], postoperative prophylaxis based on risk stratification is recommended in international guidelines. This study aimed to evaluate postoperative CD recurrence after implementation of a clinical management algorithm and to determine the predictive value of clinical and histological risk factors [RFs]. Methods In this multicentre, prospective cohort study, CD patients [>= 16 years] scheduled for ICR were included. The algorithm advised no postoperative medication for low-risk patients, and treatment with prophylaxis [immunosuppressant/biological] for high-risk patients [>= 1 RF: active smoking, penetrating disease, prior ICR]. Clinical and histological RFs [active inflammation, granulomas, plexitis in resection margins] for endoscopic recurrence [Rutgeerts' score >= i2b at 6 months] were assessed using logistic regression and ROC curves based on predicted probabilities. Results In total, 213 CD patients after ICR were included [age 34.5 years; 65% women] (93 [44%] low-risk; 120 [56%] high-risk: 45 [38%] smoking; 51 [43%] penetrating disease; 51 [43%] prior ICR). Adherence to the algorithm was 82% in low-risk [no prophylaxis] and 51% in high-risk patients [prophylaxis]. Endoscopic recurrence was higher in patients treated without prophylaxis than with prophylaxis in both low [45% vs 16%, p = 0.012] and high-risk patients [49% vs 26%, p = 0.019]. Clinical risk stratification including the prescription of prophylaxis corresponded to an area under the curve [AUC] of 0.70 (95% confidence interval [CI] 0.61-0.79). Clinical RFs combined with histological RFs increased the AUC to 0.73 [95% CI 0.64-0.81]. Conclusion Adherence to this management algorithm is 65%. Prophylactic medication after ICR prevents endoscopic recurrence in low- and high-risk patients. Clinical risk stratification has an acceptable predictive value, but further refinement is needed. Show less
Arkenbosch, J.H.C.; Beelen, E.M.J.; Dijkstra, G.; Romberg-Camps, M.; Duijvestein, M.; Hoentjen, F.; ... ; Dutch Initiative Crohns Colitis IC 2022
BackgroundTo prevent recurrence after ileocolonic resection [ICR] in Crohn’s disease [CD], postoperative prophylaxis based on risk stratification is recommended in international guidelines. This... Show moreBackgroundTo prevent recurrence after ileocolonic resection [ICR] in Crohn’s disease [CD], postoperative prophylaxis based on risk stratification is recommended in international guidelines. This study aimed to evaluate postoperative CD recurrence after implementation of a clinical management algorithm and to determine the predictive value of clinical and histological risk factors [RFs].MethodsIn this multicentre, prospective cohort study, CD patients [≥16 years] scheduled for ICR were included. The algorithm advised no postoperative medication for low-risk patients, and treatment with prophylaxis [immunosuppressant/biological] for high-risk patients [≥1 RF: active smoking, penetrating disease, prior ICR]. Clinical and histological RFs [active inflammation, granulomas, plexitis in resection margins] for endoscopic recurrence [Rutgeerts’ score ≥i2b at 6 months] were assessed using logistic regression and ROC curves based on predicted probabilities.ResultsIn total, 213 CD patients after ICR were included [age 34.5 years; 65% women] (93 [44%] low-risk; 120 [56%] high-risk: 45 [38%] smoking; 51 [43%] penetrating disease; 51 [43%] prior ICR). Adherence to the algorithm was 82% in low-risk [no prophylaxis] and 51% in high-risk patients [prophylaxis]. Endoscopic recurrence was higher in patients treated without prophylaxis than with prophylaxis in both low [45% vs 16%, p = 0.012] and high-risk patients [49% vs 26%, p = 0.019]. Clinical risk stratification including the prescription of prophylaxis corresponded to an area under the curve [AUC] of 0.70 (95% confidence interval [CI] 0.61–0.79). Clinical RFs combined with histological RFs increased the AUC to 0.73 [95% CI 0.64–0.81].ConclusionAdherence to this management algorithm is 65%. Prophylactic medication after ICR prevents endoscopic recurrence in low- and high-risk patients. Clinical risk stratification has an acceptable predictive value, but further refinement is needed. Show less
Unen, V. van; Ouboter, L.F.; Li, N.; Schreurs, M.; Abdelaal, T.; Kooy-Winkelaar, Y.; ... ; Koning, F. 2022
Chronic intestinal inflammation underlies inflammatory bowel disease (IBD). Previous studies indicated alterations in the cellular immune system; however, it has been challenging to interrogate the... Show moreChronic intestinal inflammation underlies inflammatory bowel disease (IBD). Previous studies indicated alterations in the cellular immune system; however, it has been challenging to interrogate the role of all immune cell subsets simultaneously. Therefore, we aimed to identify immune cell types associated with inflammation in IBD using high-dimensional mass cytometry. We analyzed 188 intestinal biopsies and paired blood samples of newly-diagnosed, treatment-naive patients (n=42) and controls (n=26) in two independent cohorts. We applied mass cytometry (36-antibody panel) to resolve single cells and analyzed the data with unbiased Hierarchical-SNE. In addition, imaging-mass cytometry (IMC) was performed to reveal the spatial distribution of the immune subsets in the tissue. We identified 44 distinct immune subsets. Correlation network analysis identified a network of inflammation-associated subsets, including HLA-DR(+)CD38(+) EM CD4(+) T cells, T regulatory-like cells, PD1(+) EM CD8(+) T cells, neutrophils, CD27(+) TCR gamma delta cells and NK cells. All disease-associated subsets were validated in a second cohort. This network was abundant in a subset of patients, independent of IBD subtype, severity or intestinal location. Putative disease-associated CD4(+) T cells were detectable in blood. Finally, imaging-mass cytometry revealed the spatial colocalization of neutrophils, memory CD4(+) T cells and myeloid cells in the inflamed intestine. Our study indicates that a cellular network of both innate and adaptive immune cells colocalizes in inflamed biopsies from a subset of patients. These results contribute to dissecting disease heterogeneity and may guide the development of targeted therapeutics in IBD. Show less
Asscher, V.E.R.; Waars, S.N.; Meulen-de Jong, A.E. van der; Stuyt, R.J.L.; Baven-Pronk, A.M.C.; Marel, S. van der; ... ; Maljaars, P.W.J. 2022
BACKGROUND & AIMS: We aimed to perform geriatric assessment in older patients with inflammatory bowel disease (IBD) to evaluate which IBD characteristics associate with deficits in geriatric... Show moreBACKGROUND & AIMS: We aimed to perform geriatric assessment in older patients with inflammatory bowel disease (IBD) to evaluate which IBD characteristics associate with deficits in geriatric assessment and the impact of deficits on disease burden (health-related quality of life).METHODS: A prospective multicenter cohort study including 405 consecutive outpatient patients with IBD aged >= 65 years. Somatic domain (comorbidity, polypharmacy, malnutrition), impairments in (instrumental) activities of daily living, physical capacity (handgrip strength, gait speed), and mental (depressive symptoms, cognitive impairment) and social domain (life-partner) were assessed. Deficits in geriatric assessment were defined as >= 2 abnormal domains; 2-3 moderate deficits and 4-5 severe deficits. Clinical (Harvey Bradshaw Index >4/partial Mayo Score >2) and biochemical (C-reactive protein >= 10 mg/L and/or fecal calprotectin >= 250 mu g/g) disease activity and disease burden (short Inflammatory Bowel Disease Questionnaire) were assessed.RESULTS: Somatic domain (51.6%) and activities of daily living (43.0%) were most frequently impaired. A total of 160 (39.5%) patients had moderate deficits in their geriatric assessment; 32 (7.9%) severe. Clinical and biochemical disease activity associated with deficits (clinical: adjusted odds ratio, 2.191; 95% confidence interval, 1.284-3.743; P = .004; biochemical: adjusted odds ratio, 3.358; 95% confidence interval, 1.936-5.825; P <.001). Deficits in geriatric assessment independently associate with lower health-related quality of life.CONCLUSION: Deficits in geriatric assessment are highly prevalent in older patients with IBD. Patients with active disease are more prone to deficits, and deficits associate with lower health-related quality of life, indicating higher disease burden. Prospective data validating impact of frailty and geriatric assessment on outcomes are warranted to further improve treatment strategies. Show less
Lingen, E. van; Tushuizen, M.E.; Steenhuis, M.E.J.; Deynen, T. van; Martens, J.; Morales, D.D.I.; ... ; Maljaars, P.W.J. 2021
Purpose Liver steatosis is a frequently reported condition in patients with inflammatory bowel disease (IBD). Different factors, both metabolic and IBD-associated, are believed to contribute to the... Show morePurpose Liver steatosis is a frequently reported condition in patients with inflammatory bowel disease (IBD). Different factors, both metabolic and IBD-associated, are believed to contribute to the pathogenesis. The aim of our study was to calculate the prevalence of liver steatosis and fibrosis in IBD patients and to evaluate which factors influence changes in steatosis and fibrosis during follow-up. Methods From June 2017 to February 2018, demographic and biochemical data was collected at baseline and after 6-12 months. Measured by transient elastography (FibroScan), liver steatosis was defined as Controlled Attenuation Parameter (CAP) >= 248 and fibrosis as liver stiffness value (Emed) >= 7.3 kPa. IBD disease activity was defined as C-reactive protein (CRP) >= 10 mg/l and/or fecal calprotectin (FCP) >= 150 mu g/g. Univariate and multivariate regression analysis was performed; a p-value of <= 0.05 was considered significant. Results Eighty-two out of 112 patients were seen for follow-up; 56% were male. The mean age was 43 +/- 16.0 years, and mean BMI was 25.1 +/- 4.7 kg/m(2). The prevalence of liver steatosis was 40% and of fibrosis was 20%. At baseline, 26 patients (32%) had an active episode of IBD. Using a multivariate analysis, disease activity at baseline was associated with an increase in liver steatosis (B = 37, 95% CI 4.31-69.35, p = 0.027) and liver fibrosis (B = 1.2, 95% CI 0.27-2.14, p = 0.016) during follow-up. Conclusions This study confirms the relatively high prevalence of liver steatosis and fibrosis in IBD patients. We demonstrate that active IBD at baseline is associated with both an increase in liver steatosis and fibrosis during follow-up. Show less
Aims: Ustekinumab is a monoclonal antibody that selectively targets p40, a shared subunit of the cytokines interleukin [IL]-12 and IL-23. It is registered for the treatment of inflammatory bowel... Show moreAims: Ustekinumab is a monoclonal antibody that selectively targets p40, a shared subunit of the cytokines interleukin [IL]-12 and IL-23. It is registered for the treatment of inflammatory bowel diseases. We assessed the 2-year effectiveness and safety of ustekinumab in a real world, prospective cohort of patients with Crohn's disease [CD].Methods: Patients who started ustekinumab were prospectively enrolled in the nationwide Initiative on Crohn and Colitis [ICC] Registry. At weeks 0, 12, 24, 52 and 104, clinical remission Harvey Bradshaw Index <= 4 points], biochemical remission (faecal calprotectin <= 200 mu g/g and/or C-reactive protein <= 5 mg/L], perianal fistula remission, extra-intestinal manifestations, ustekinumab dosage and safety outcomes were determined. The primary outcome was corticosteroid-free clinical remission at week 104.Results; In total, 252 CD patients with at least 2 years of follow-up were included. Of all included patients, the proportion of patients in corticosteroid-free clinical remission was 32.3% [81/251], 41.4% [104/251], 39% [97/249] and 34.0% [84/247] at weeks 12, 24, 52 and 104, respectively. In patients with combined clinical and biochemical disease activity at baseline [n = 122], the corticosteroid-free clinical remission rates were 23.8% [29/122], 35.2% [43/122], 40.0% [48/120] and 32.8% [39/119] at weeks 12, 24, 52 and 104, respectively. The probability of remaining on ustekinumab treatment after 52 and 104 weeks in all patients was 64.3% and 54.8%, respectively. The main reason for discontinuing treatment after 52 weeks was loss of response [66.7%]. No new safety issues were observed.Conclusion: After 104 weeks of ustekinumab treatment, one-third of CD patients were in corticosteroid-free clinical remission. Show less
Background Few data are available on the effects of age and comorbidity on treatment outcomes of vedolizumab and ustekinumab in inflammatory bowel disease (IBD). Aims To evaluate the association... Show moreBackground Few data are available on the effects of age and comorbidity on treatment outcomes of vedolizumab and ustekinumab in inflammatory bowel disease (IBD). Aims To evaluate the association between age and comorbidity with safety and effectiveness outcomes of vedolizumab and ustekinumab in IBD. Methods IBD patients initiating vedolizumab or ustekinumab in regular care were enrolled prospectively. Comorbidity prevalence was assessed using the Charlson Comorbidity Index (CCI). Association between age and CCI, both continuously assessed, with safety outcomes (any infection, hospitalisation, adverse events) during treatment, and effectiveness outcomes (clinical response and remission, corticosteroid-free remission, clinical remission combined with biochemical remission) after 52 weeks of treatment were evaluated. Multivariable logistic regression was used to adjust for confounders. Results We included 203 vedolizumab- and 207 ustekinumab-treated IBD patients, mean age 42.2 (SD 16.0) and 41.6 (SD 14.4). Median treatment duration 54.0 (IQR 19.9-104.0) and 48.4 (IQR 24.4-55.1) weeks, median follow-up time 104.0 (IQR 103.1-104.0) and 52.0 weeks (IQR 49.3-100.4). On vedolizumab, CCI associated independently with any infection (OR 1.387, 95% CI 1.022-1.883,P = 0.036) and hospitalisation (OR 1.586, 95% CI 1.127-2.231,P = 0.008). On ustekinumab, CCI associated independently with hospitalisation (OR 1.621, 95% CI 1.034-2.541,P = 0.035). CCI was not associated with effectiveness, and age was not associated with any outcomes. Conclusions Comorbidity - but not age - is associated with an increased risk of hospitalisations on either treatment, and with any infection on vedolizumab. This underlines the importance of comorbidity assessment and safety monitoring of IBD patients. Show less
Asscher, V.E.R.; Vliet, Q. van der; Aalst, K. van der; Aalst, A. van der; Brand, E.C.; Meulen-de Jong, A.E. van der; ... ; Dutch ICC 2020
Purpose To assess safety and effectiveness of anti-tumor necrosis factor (anti-TNF) therapy in IBD patients >= 60 years. Methods Ninety IBD patients >= 60 years at initiation of anti-TNF... Show morePurpose To assess safety and effectiveness of anti-tumor necrosis factor (anti-TNF) therapy in IBD patients >= 60 years. Methods Ninety IBD patients >= 60 years at initiation of anti-TNF therapy, 145 IBD patients >= 60 years without anti-TNF therapy and 257 IBD patients < 60 years at initiation of anti-TNF therapy were retrospectively included in this multicentre study. Primary outcome was the occurrence of severe adverse events (SAEs), serious infections and malignancies. Secondary outcome was effectiveness of therapy. Cox regression analyses were used to assess differences in safety and effectiveness. In safety analyses, first older patients with and without anti-TNF therapy and then older and younger patients with anti-TNF therapy were assessed. Results In older IBD patients, the use of anti-TNF therapy was associated with serious infections (aHR 3.920, 95% CI 1.185-12.973,p= .025). In anti-TNF-exposed patients, cardiovascular disease associated with serious infections (aHR 3.279, 95% CI 1.098-9.790,p= .033) and the presence of multiple comorbidities (aHR 9.138 (1.248-66.935),p= .029) with malignancies, while patient age did not associate with safety outcomes. Effectiveness of therapy was not affected by age or comorbidity. Conclusion Older patients receiving anti-TNF therapy have a higher risk of serious infections compared with older IBD patients without anti-TNF therapy, but not compared with younger patients receiving anti-TNF therapy. However, in anti-TNF-exposed patients, comorbidity was found to be an indicator with regards to SAEs. Effectiveness was comparable between older and younger patients. Show less
Barnhoorn, M.C.; Wasser, M.N.J.M.; Roelofs, H.; Maljaars, P.W.J.; Molendijk, I.; Bonsing, B.A.; ... ; Meulen-de Jong, A.E. van der 2020
Background and Aims: The long-term safety and efficacy of allogeneic bone marrow-derived mesenchymal stromal cell [bmMSC] therapy in perianal Crohn's disease [CD] fistulas is unknown. We aimed to... Show moreBackground and Aims: The long-term safety and efficacy of allogeneic bone marrow-derived mesenchymal stromal cell [bmMSC] therapy in perianal Crohn's disease [CD] fistulas is unknown. We aimed to provide a 4-year clinical evaluation of allogeneic bmMSC treatment of perianal CD fistulas.Methods: A double-blind dose-finding study for local bmMSC therapy in 21 patients with refractory perianal fistulising Crohn's disease was performed at the Leiden University Medical Center in 2012-2014. All patients treated with bmMSCs [1 x 10(7) bmMSCs cohort 1, n = 5; 3 x 10(7) bmMSCs cohort 2, n = 5; 9 x 10(7) bmMSCs cohort 3, n = 5] were invited for a 4-year evaluation. Clinical events were registered, fistula closure was evaluated, and anti-human leukocyte antigen [HLA] antibodies were assessed. Patients were also asked to undergo a pelvic magnetic resonance imaging [MRI] and rectoscopy.Results: Thirteen out of 15 patients [87%] treated with bmMSCs were available for long-term follow-up. Two non-MSC related malignancies were observed. No serious adverse events thought to be related to bmMSC therapy were found. In cohort 2 [n = 4], all fistulas were closed 4 years after bmMSC therapy. In cohort 1 [n = 4] 63%, and in cohort 3 [n = 5] 43%, of the fistulas were closed, respectively. In none of the patients anti-HLA antibodies could be detected 24 weeks and 4 years after therapy. Pelvic MRI showed significantly smaller fistula tracts after 4 years.Conclusions: Allogeneic bmMSC therapy for CD-associated perianal fistulas is also in the long-term a safe therapy. In bmMSC-treated patients, fistulas with closure at Week 24 were still closed after 4 years. Show less
Fat is an important macronutrient with a high caloric density. Therefore, considerable interest exists in how fat exerts an effect on satiety and food intake, and how this effect can be increased.... Show moreFat is an important macronutrient with a high caloric density. Therefore, considerable interest exists in how fat exerts an effect on satiety and food intake, and how this effect can be increased. Here, we will discuss how digestion of fat leads to fatty acid sensing by oral and intestinal receptors, which in turn influences satiety and food intake. A number of strategies that have been developed to increase the satiating effect of fat will be discussed. A better understanding of the precise mechanisms of fatty acid sensing will assist in the development of effective ligands that maximize the satiating effect of dietary fats. Show less