Abstract
Background
Inflammatory bowel disease (IBD) patients with concomitant primary sclerosing cholangitis (PSC-IBD) have a 25-year cumulative risk of up to 50% to develop colorectal neoplasia ...(CRN). Mucosal inflammation is an important driver of CRN, but it is unknown whether this also applies to PSC-IBD patients. We aimed to assess the impact of chronic mucosal inflammation per colonic segment on CRN risk in PSC-IBD patients.
Methods
This is a multi-center case-control study including cases with PSC-IBD and CRN and controls with PSC-IBD without CRN. Subjects were included from 8 medical centers in Canada and the Netherlands. Exclusion criteria were a CRN diagnosis prior to IBD or PSC diagnosis, familial CRC syndromes, and <2 available colonoscopy reports. Data was collected on demographics, IBD and PSC disease characteristics, CRN lesions, and endoscopy reports between 1977 and 2023. Pan-colonic and segmental (right colon, transverse colon, left colon, rectum) endoscopic cumulative inflammatory burden scores were calculated as the sum of (mean) endoscopic inflammation severity between colonoscopies x length of the surveillance interval until index procedure. The index procedure was the colonoscopy during which CRN was detected (cases) or randomly selected and matched for disease duration (controls). The primary outcome was a CRN diagnosis, secondary outcomes were CRN grade and location, time to CRN (Kaplan-Meier curve), pan-colonic cumulative inflammatory burden, cumulative inflammatory burden per colonic segment harboring CRN, and colonic surgery.
Results
We included 335 PSC-IBD patients (224 UC, 101 CD) with a median follow-up of 8 years (IQR: 5.0-14.0) and 6 endoscopies (IQR: 4.0-8.0). Median disease duration was 19.5 years for IBD (IQR: 11.0-26.0) and 13 years for PSC (IQR: 7.0-19.0). Advanced neoplasia (HGD or CRC) was found in 35 out of 102 cases (34%). Fifty-six (55%) cases were diagnosed with > 1 lesion, and 43 (42%) had ≥ 1 right-sided lesion. Median time to index CRN was 17 years (IQR: 8.0-24.0). Sixty-six patients underwent (sub)total colectomy or proctocolectomy, including 49 (74%) due to CRN diagnosis. There was no difference in pan-colonic cumulative inflammatory burden scores (mean scores: 4.7 (cases) and 3.7 (controls); P=0.21, 95%-CI: -2.52-.56) and segmental scores (mean scores: 4.9 (cases) and 4.1 (controls); P=0.27, 95%-CI: -2.29-.65) between cases and controls. Mortality was 13% (n=45.)
Conclusion
In this large multi-center cohort study, the risk for CRN-associated colectomy in PSC-IBD was high, while pan-colonic and segmental cumulative inflammatory burden scores were not associated with CRN risk.
Abstract
Background
Randomised controlled trials have reported improvement of work productivity and activity impairment (WPAI) as well as quality of life in biological-treated inflammatory bowel ...disease (IBD) patients. However, data beyond clinical trials are limited.
Methods
This multicentre prospective cohort study evaluated the effect of initiating biological or small molecule therapy on work impairment in IBD patients. Subjects completed the WPAI questionnaire and Short IBD questionnaire (SIBDQ) at biological therapy initiation and at week 26. Clinical disease activity was assessed using the Harvey Bradshaw Index and Simple Clinical Colitis Activity Index. Biochemical disease activity was assessed using C-reactive protein and faecal calprotectin. Data are presented as mean ± standard deviation.
Results
In total, 156 IBD patients were included for analysis (median age 40 years, 55% male, 55% Crohn’s disease). Of these patients, 28% started infliximab, 33% adalimumab, 19% vedolizumab, 18% ustekinumab, 1% tofacitinib and 1% golimumab. Concomitant medication use at baseline included 28% prednisone, 12% budesonide, 34% mesalamine, and 46% immunomodulator. At baseline, 58% had clinical disease activity and 58% had biochemical disease activity. In our cohort, 111 (71%) were employed and 17 (11%) patients reported partial or full occupational disability. The mean total work impairment at baseline was 52% ± 36%. During follow-up, 7 patients lost their job and 8 patients started employment. For the entire cohort, improvements in all WPAI domains were observed: mean 11%-points decrease in missed working hours, 4%-points decrease in impairment while working, 15%-points decrease in total work impairment and 15%-points decrease in total activity impairment. Parallel improvements were seen in SIBDQ scores (mean improvement 7.6 ± 11.3). At week 26, 66 (42%) patients achieved the minimal clinical important difference in total work impairment (improvement ≥7%-points). Patients with clinical disease activity at baseline and clinical response to the biological (n=32) showed a larger improvement in total work impairment compared with other subjects (n=86) (mean difference 29%-points versus 10%-points; p=0.036 (T-test)). Similarly, these patients showed greater improvement in SIBDQ scores compared to other subjects (mean 13.8 versus 5.4, respectively; p<0.001 (T-test)).
Conclusion
IBD patients experienced substantial work impairment prior to initiating biological treatment. Improved work impairment scores were seen after initiation of biological therapy and patients with clinical response showed even greater improvements. These results underline the importance of IBD disease control to improve work productivity and participation.
Abstract
Background
Keratinocyte skin cancer (KSC) including basal-cell carcinomas (BCC) and cutaneous squamous cell carcinomas (SCC), is the most prevalent cancer-type in the Netherlands with an ...increasing incidence and impact on morbidity. In addition to ultraviolet radiation (UVR), thiopurines used in patients with inflammatory bowel disease (IBD), are associated with KSC development. It is unclear whether this is a dose response relationship. The aim of this study was to investigate the association between the cumulative dose of thiopurines and the development of KSCs in IBD patients.
Methods
A single-center retrospective case control study was conducted and we included patients with IBD on thiopurines and a history of KSC (n=50, cases) as well as without KSC (n= 150, controls). For each patient we calculated the cumulative dose of azathioprine (AZA), 6-mercaptopurine (6-MP) and tioguanine (6-TG) as primary outcome, and of methotrexate (MTX) as secondary outcome. Univariable and multivariable regression analyses were performed, the latter corrected for known risk factors and potential confounders: age and smoking.
Results
200 IBD patients were included (see Table 1). There were more cases (24%) using azathioprine at time of KSC onset compared to 11.3% of controls at time of inclusion (p= 0.028). Independent variables including age at inclusion (OR 1.065, CI 1.038–1.092) and IBD disease duration (OR 1.040, CI 1.016–1.065) were significantly associated with KSC. No significant association was found between KSC development and smoking, cumulative thiopurine use, nor between KSC development and cumulative MTX use. To account for possible non-linear effects, cut-offs at the registered 1- and 3-years- cumulative doses were assessed. Here, no significant results were found for any of the distinct thiopurines or MTX, the 3-years cumulative use of AZA had the highest odds ratio of 1.085 (CI 0.795–1.482). In multivariate logistic regression analyses (see Table 2), age per 10 years remained significant associated (p=0.005) (OR 1.666, CI 1.165–2.381).
Conclusion
This study showed that in IBD-patients IBD duration (only in univariable regression analysis) and age (in both uni- and multivariable regression analyses) are important risk factors for KSC development while cumulative exposure of thiopurines and MTX did not show an association. The dose response association between KSC and thiopurines requires further research.
SUMMARY
Germ‐free HLA‐B27 transgenic (TG) rats do not develop colitis, but colonization with specific pathogen‐free (SPF) bacteria induces colitis accompanied by immune activation. To study ...host‐dependent immune responses to commensal caecal bacteria we investigated cytokine profiles in mesenteric lymph node (MLN) cells from HLA‐B27 TG versus nontransgenic (non‐TG) littermates after in vitro stimulation with caecal bacterial lysates (CBL). Supernatants from CBL‐stimulated unseparated T‐ or B‐ cell‐depleted MLN cells from HLA‐B27 TG and non‐TG littermates were analysed for IFN‐γ, IL‐12, TNF, IL‐10 and TGF‐β production. Our results show that unfractionated TG MLN cells stimulated with CBL produced more IFN‐γ, IL‐12 and TNF than did non‐TG MLN cells. In contrast, CBL‐stimulated non‐TG MLN cells produced more IL‐10 and TGF‐β. T cell depletion abolished IFN‐γ and decreased IL‐12 production, but did not affect IL‐10 and TGF‐β production. Conversely, neither IL‐10 nor TGF‐β was produced in cultures of B cell‐depleted MLN. In addition, CD4+ T cells enriched from MLN of HLA‐B27 TG but not from non‐TG rats produced IFN‐γ when cocultured with CBL‐pulsed antigen presenting cells from non‐TG rats. Interestingly, IL‐10 and TGF‐β, but not IFN‐γ, IL‐12 and TNF were produced by MLN cells from germ‐free TG rats. These results indicate that the colitis that develops in SPF HLA‐B27 TG rats is accompanied by activation of IFN‐γ‐producing CD4+ T cells that respond to commensal bacteria. However, B cell cytokine production in response to components of commensal intestinal microorganisms occurs in the absence of intestinal inflammation.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Thiopurines are the mainstay of conventional maintenance therapy in inflammatory bowel disease (IBD). Unfortunately, up to 50% of patients discontinue immunosuppressive therapy within 2 years due to ...intolerance or lack of efficacy. Allopurinol with low-dose thiopurine can optimize thiopurine metabolism for IBD patients with preferential shunting toward 6-methyl mercaptopurine (6-MMP) formation. The aim of this study was to assess long-term maintenance effectiveness and tolerability of allopurinol-thiopurine therapy in a larger multicenter cohort of IBD patients.
Enrolled patients who failed monotherapy with thiopurines due to a skewed metabolism were subsequently treated with a combination therapy of allopurinol and low-dose thiopurine. Adverse events were monitored and therapeutic adherence was assessed. Seventy-seven IBD patients were enrolled with a mean follow-up of 19 months.
The median 6-thioguanine nucleotide concentration increased from 145 during monotherapy to 271 pmol/8 × 10(8) red blood cell (RBC) after at least 8 weeks of combination therapy while reducing the thiopurine dosage (P < 0.001). In contrast, median 6-MMP concentrations decreased from 10,110 to 265 pmol/8 × 10(8) RBC (P < 0.001). Leukopenia occurred in 12 patients (16%), requiring dose adaptation. Liver test abnormalities normalized in 81% of patients after the addition of allopurinol. Sixteen (21%) patients had to discontinue combination therapy. The percentage of patients still using combination therapy at 6, 12, 24, and 60 months was 87%, 85%, 76%, and 65%, respectively.
Long-term combination therapy with allopurinol and low-dose thiopurines is an effective and well-tolerated treatment in IBD patients with a skewed thiopurine metabolism.
Interleukin-10-deficient (IL-10-/-) mice develop an IL-12-mediated intestinal inflammation in the absence of endogenous IL-10. The molecular mechanisms of the dysregulated IL-12 responses in IL-10-/- ...mice are poorly understood. In this study, we investigated the role of nuclear factor-κ B (NF-κB) and signal transducers and activators of transcription 3 (STAT3) in lipopolysaccharide (LPS)-induced IL-12p40 gene expression in bone marrow derived-dendritic cells (BMDCs) isolated from wild-type (WT) and IL-10-/- mice. We report higher IL-12p40 mRNA accumulation and protein secretion in LPS-stimulated BMDCs isolated from IL-10-/- compared with WT mice. LPS-induced NF-κB signaling is similar in IL-10-/- and WT BMDCs as measured by IκBα phosphorylation and degradation, RelA phosphorylation and nuclear translocation, and NF-κB transcriptional activity, with no down-regulatory effects of exogenous IL-10. Chromatin immunoprecipitation demonstrated enhanced NF-κB (cRel, RelA) binding to the IL-12p40 promoter in IL-10-/- but not WT BMDCs. Interestingly, LPS induced STAT3 phosphorylation in WT but not IL-10-/- BMDCs, a process blocked by IL-10 receptor blocking antibody. Adenoviral gene delivery of a constitutively active STAT3 but not control green fluorescence protein (GFP) virus blocked LPS-induced IL-12p40 gene expression and cRel recruitment to the IL-12p40 promoter. In conclusion, dysregulated LPS-induced IL-12p40 gene expression in IL-10-/- mice is due to enhanced NF-κB recruitment to the IL-12p40 promoter in the absence of activated STAT3.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Background
Patients with colonic inflammatory bowel disease (IBD) undergo endoscopic surveillance to detect and remove colorectal neoplasia (CRN). Although high-definition dye-based ...chromo-endoscopy (HD-CE) is the recommended modality in guidelines, high-definition white light endoscopy (HD-WLE) with matched procedural time may yield similar neoplasia detection rates. We designed a non-blinded, randomized controlled trial in four academic hospitals aiming to compare three endoscopic surveillance techniques in IBD patients for the outcome of CRN detection rate.
Methods
Eligible patients were aged ≥18 years and scheduled for colitis-associated CRN surveillance according to Dutch IBD surveillance guidelines. Patients were excluded in case of insufficient bowel cleansing, active colitis, or if >50% of the colon was resected. Patients were randomly assigned (2:2:1) to undergo HD-WLE with segmental re-inspection (SR), HD-CE, or single pass HD-WLE. The primary outcome was CRN detection rate, defined as the proportion of procedures in which macroscopic CRN was detected. Secondary outcomes included the number of CRN and withdrawal time. To demonstrate non-inferiority of HD-WLE with SR compared to HD-CE (one-sided testing, α=0.05, 1−β=0.8, non-inferiority (NI) margin -10%), and superiority compared to single-pass HD-WLE (two-sided testing, estimated CRN detection rate of 24% and 12%, respectively1) with Mantel-Haenszel analyses, a total of 566 patients were needed.
Results
In total, 666 patients were randomized, 563 fulfilled all study criteria and were analysed per protocol (table 1). Of these, 51.8% were male, with a median age of 51 years (interquartile range 35-63). CRN detection rates were 9.8% for HD-WLE with SR, 13.1% for HD-CE, and 6.1% for single pass HD-WLE. HD-WLE with SR was non-inferior compared to HD-CE (Δ-3.1%, lower boundary of the 95% confidence interval (CI) -8.1 not exceeding the NI margin of -10%, p<.05). HD-WLE with SR was not superior compared to single-pass HD-WLE (Δ3.7%, 95% CI -2.5:9.1%, p=0.31). A significant difference was found between arms for the number of detected CRN (n=29 vs n=36 vs n=8 for HD-WLE with SR, HD-CE and single-pass HD-WLE, respectively (p=.04)) and withdrawal time (p=.03, table 1). One advanced lesion was detected (high-grade dysplasia in the HD-CE arm).
Conclusion
In this large, randomized controlled trial, HD-WLE with SR was non-inferior compared to HD-CE for CRN detection in IBD patients. HD-WLE with SR was not superior to single-pass HD-WLE, although this may have resulted from lower than expected neoplasia yields and subsequent lower power. These results suggest that HD-WLE with SR may provide a feasible alternative to HD-CE in clinical practice (NCT04291976).
1Imperatore et al. JCC 2019;13(6):714-24
Abstract
Background
Both methotrexate (MTX) and tioguanine (TG) can be considered as viable treatment options before initiating biological therapy following failure of conventional thiopurines for ...Crohn’s disease. It is unclear how safety and effectiveness compare for both therapies. This study aimed to compare tolerability and drug survival of MTX and TG therapy after failure of conventional thiopurines in patients with Crohn′s disease.
Methods
We conducted a retrospective, multi-centre study in five Dutch hospitals, including patients initiating MTX or TG for Crohn’s disease after failure (all causes) of conventional thiopurines. Patients with prior MTX or TG use, MTX or TG not primarily prescribed for Crohn’s disease, or patients receiving concomitant biological treatment at baseline were excluded. Follow-up duration from starting treatment was 104 weeks or until treatment discontinuation. Primary outcome was therapy discontinuation rate due to adverse events (AE). Secondary outcome was ongoing treatment without initiation of biological treatment.
Results
In total, 221 patients with failure of conventional thiopurines and subsequent therapy with either MTX (n=106) or TG (n=115) were included. Median follow-up was 89 weeks (IQR 28-104). Previous biological failure was present in 28 (26%) MTX and 17 (15%) TG treated patients (p=0.044). Sixty-four (29%) patients (MTX 41.5%, TG 17.4%, p<0.001) discontinued their treatment due to AE during follow-up (Figure 1). Median time until discontinuation due to AE was 16.5 weeks (IQR 8.0–39.0) for MTX and 17.5 weeks (IQR 1.3–69.8) for TG (p=0.925). MTX use was associated with a significantly higher risk of treatment failure due to AE (OR 3.37 95% CI 1.82–6.25 p<0.001). Previous biological failure was not predictive for MTX or TG failure due to AE (OR 1.086, p=0.828). The most frequent discontinuation reasons were nausea for MTX (n=11) and abdominal pain for TG (n=4). In both groups, 8 (MTX 8%, TG 7%) serious adverse events (SAE) occurred. Infections comprised the majority of all SAE, 4 (50%) for MTX and 7 (88%) for TG. Discontinuation because of elevated liver enzymes occurred in 5 (11%) MTX and 4 (20%) TG treated patients. There were no cases of histological nodular regenerative hyperplasia, liver fibrosis, or cirrhosis. Initiation of concomitant biological therapy was not significantly different (MTX: n=26, TG: n=30, p=0.877). Total monotherapy drug survival after 104 weeks was 46% for TG and 25% for MTX (p<0.001).
Conclusion
Forty-two percent of MTX, compared to 17% of TG treated patients, discontinued therapy due to AE in patients with Crohn’s disease with prior failure of conventional thiopurines. These data may aid in the selection of subsequent therapy after failure of conventional thiopurine therapy.
Abstract Background Canada is among the countries with a high burden of inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). Extraintestinal manifestations ...(EIMs) incorporate a spectrum of systemic IBD-accompanying conditions that are associated with a poorer quality of life, higher disease activity, and increased need for IBD-related surgery and treatment escalation. Aims We aimed to establish the all-time and cumulative prevalence of EIMs in a large cohort of IBD patients and assess the risk factors associated with EIMs in IBD. Methods We conducted a retrospective cohort study of 7,150 IBD patients followed at the Division of Gastroenterology, University of Alberta, diagnosed between 1954–2022, with 159,026 person-years follow-up. Data were obtained via manual chart review, from electronic medical records and administrative reporting systems. The EIMs included ophthalmological, musculoskeletal, urogenital, hepatobiliary, dermatological, and pulmonary. Univariate and multivariate logistic regression models and cumulative prevalence curves with the Kaplan-Meier analysis were used. Results Data of 3,910 CD and 3,240 UC patients (50.3% females, median age 48.0 (range 17-98 y.o.)) were analyzed. Over one-third of IBD patients (34.0%) had at least one EIM. The EIMs prevalence did not differ significantly between CD and UC (34.8% vs. 33.0%; p=0.112). In CD patients, the most common EIM was scleritis/episcleritis (10.9%), followed by nephrolithiasis (10.1%) and axial spondyloarthritis (7.3%). The UC patients most frequently had scleritis/episcleritis (10.3%), primary sclerosing cholangitis (8.4%) and nephrolithiasis (7.8%). In CD patients, age at diagnosis ≥40 y.o. (OR 1.77, 95%CI 1.33-2.37), disease duration ≥20 years (OR 2.28, 95%CI 1.62-3.21) and C-reactive protein≥8.0 mg/L (OR 1.46, 95%CI 1.01-2.12) were independent risk factors for EIMs (Fig.1a). Among UC patients, the following EIM risk factors were identified: disease duration ≥20 years (OR 1.63, 95%CI 1.19-2.22), obesity (OR 1.40, 95%CI 1.04-1.89), vitamin B12 deficiency (OR 1.64, 95%CI 1.12-2.40), and need for IBD surgery (OR 1.63, 95%CI 1.13-2.34) (Fig.1b). Cumulative probability of EIMs in CD vs. UC was 8% vs. 12%, at 10 years, 27% vs. 38% at 20 years, and 51% vs. 59% at 30 years since diagnosis (Log-rank, pampersand:003C0.001) (Fig.1c). Conclusions Over one-third of IBD patients have at least one EIM and their pattern and cumulative prevalence varies substantially between CD and UC. It is important to be aware of the EIMs’ risk factors to recognize them early and provide adequate management aiming to decrease morbidity and mortality and improve the quality of life of IBD patients. Fig. 1a. Associations between demographic, phenotypic and clinical IBD features and EIMs among CD patients - results of the multivariate logistic regression analysis. Fig. 1b. Associations between demographic, phenotypic and clinical IBD features and EIMs among UC patients - results of the multivariate logistic regression analysis. Fig 1c. Cumulative prevalence of EIMs in CD (grey line) vs. UC (pink line). Funding Agencies None
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