Background: Perianal fstulas are a debilitating complication of Crohn’s disease (CD). Due to unknown reasons, CD-associated fstulas are in general more diffcult to treat than cryptoglandular... Show moreBackground: Perianal fstulas are a debilitating complication of Crohn’s disease (CD). Due to unknown reasons, CD-associated fstulas are in general more diffcult to treat than cryptoglandular fstulas (non-CD-associated). Understanding the immune cell landscape is a frst step towards the development of more effective therapies for CD-associated fstulas. In this work, we characterized the composition and spatial localization of disease-associated immune cells in both types of perianal fstulas by high-dimensional analyses. Methods: We applied single-cell mass cytometry (scMC), spectral fow cytometry (SFC), and imaging mass cytometry (IMC) to profle the immune compartment in CD-associated perianal fstulas and cryptoglandular fstulas. An exploratory cohort (CD fstula, n = 10; non-CD fstula, n = 5) was analyzed by scMC to unravel disease-associated immune cell types. SFC was performed on a second fstula 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 signifcantly enriched in CD-associated compared with cryptoglandular fstulas. 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 fstula tracts. Conclusions: Overall, proliferating activated HLA-DR+CD38+ effector Th1/17 cells distinguish CD-associated from cryptoglandular perianal fstulas and are a promising biomarker in blood to discriminate between these 2 fstula types. Targeting HLA-DR and CD38-expressing CD4+ T cells may offer a potential new therapeutic strategy for CD-related fstulas. Show less
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... Show moreINTRODUCTION: 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. Show less
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 AimsWe 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... Show moreBackground and AimsWe 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.DesignWe 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.ResultsWe 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.ConclusionWhen 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. Show less
Chernova, V.O.; Terveer, E.M.; Prehn, J. van; Kuijper, E.J.; Keller, J.J.; Jong, A.E.V.; ... ; Contarino, M.F. 2023
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... Show moreWe 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. Show less
Loveikyte, R.; Bourgonje, A.R.; Reijden, J.J. van der; Bulthuis, M.L.C.; Hawinkels, L.J.A.C.; Visschedijk, M.C.; ... ; Dijkstra, G. 2023
Lay Summary: 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... Show moreLay Summary: 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. 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. Show less
