LINKED CONTENT
This article is linked to García et al papers. To view these articles, visit https://doi.org/10.1111/apt.17938 and https://doi.org/10.1111/apt.17993
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract
Background and Aims
There is paucity of data on safety and efficacy of anti-tumour necrosis factor TNF in elderly inflammatory bowel disease IBD patients. We aimed to compare the long-term ...treatment failure rates and safety of a first anti-TNF agent in IBD patients between different age groups <40 years/40–59 years/≥60 years.
Methods
IBD patients who started a first anti-TNF agent were identified through IBDREAM, a multicentre prospective IBD registry. Competing risk regression was used to study treatment failure, defined as time to drug discontinuation due to adverse events AEs or lack of effectiveness, with discontinuation due to remission as a competing risk.
Results
A total of 895 IBD patients were included; 546 started anti-TNF at age <40 61.0%, 268 at age 40–59 29.9%, and 81 at age ≥60 9.1%. Treatment failure rate was higher in the two older groups (subhazard rate SHR age ≥60 1.46, SHR age 40–59 1.21; p = 0.03). The SHR in the elderly >60 was 1.52 for discontinuation due to AEs and 1.11 for lack of effectiveness. Concomitant thiopurine use was associated with a lower treatment failure rate (SHR 0.78, 95% confidence interval CI 0.62–0.98, p = 0.031). Serious adverse event SAE rate, as well as serious infection rate, were significantly higher in elderly IBD patients 61.2 versus 16.0 and 12.4 per 1000 patient-years, respectively whereas the malignancy rate was low in all age groups.
Conclusions
Elderly IBD patients starting a first anti-TNF agent showed higher treatment failure rates, but concomitant thiopurine use at baseline was associated with lower failure rates. Elderly IBD patients demonstrated higher rates of SAEs and serious infections.
Summary
Background
Women with inflammatory bowel disease (IBD) are at increased risk of high‐grade cervical intraepithelial neoplasia and cervical cancer (CIN2+).
Aim
To assess the association ...between cumulative exposure to immunomodulators (IM) and biologic agents (BIO) for IBD and CIN2+
Methods
Adult women diagnosed with IBD before December 31st 2016 in the Dutch IBD biobank with available cervical records in the nationwide cytopathology database were identified. CIN2+ incidence rates in IM‐ (i.e., thiopurines, methotrexate, tacrolimus and cyclosporine) and BIO‐ (anti‐tumour necrosis factor, vedolizumab and ustekinumab) exposed patients were compared to unexposed patients and risk factors were assessed. Cumulative exposure to immunosuppressive drugs was evaluated in extended time‐dependent Cox‐regression models.
Results
The study cohort comprised 1981 women with IBD: 99 (5%) developed CIN2+ during median follow‐up of 17.2 years IQR 14.6. In total, 1305 (66%) women were exposed to immunosuppressive drugs (IM 58%, BIO 40%, IM and BIO 33%). CIN2+ risk increased per year of exposure to IM (HR 1.16, 95% CI 1.08–1.25). No association was observed between cumulative exposure to BIO or both BIO and IM and CIN2+. In multivariate analysis, smoking (HR 2.73, 95%CI 1.77–4.37) and 5‐yearly screening frequency (HR 1.74, 95% CI 1.33–2.27) were also risk factors for CIN2+ detection.
Conclusion
Cumulative exposure to IM is associated with increased risk of CIN2+ in women with IBD. In addition to active counselling of women with IBD to participate in cervical screening programs, further assessment of the benefit of intensified screening of women with IBD on long‐term IM exposure is warranted.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
IntroductionAdalimumab is effective for maintenance of remission in patients with Crohn’s disease (CD) at a dose of 40 mg subcutaneously every 2 weeks. However, adalimumab is associated with ...(long-term) adverse events and is costly. The aim of this study is to demonstrate non-inferiority and cost-effectiveness of disease activity guided adalimumab interval lengthening compared to standard dosing of every other week (EOW).Methods and analysisThe Lengthening Adalimumab Dosing Interval (LADI) study is a pragmatic, multicentre, open label, randomised controlled non-inferiority trial. Non-inferiority is reached if the difference in cumulative incidence of persistent (>8 weeks) flares does not exceed the non-inferiority margin of 15%. 174 CD patients on adalimumab maintenance therapy in long-term (>9 months) clinical and biochemical remission will be included (C-reactive protein (CRP) <10 mg/L, faecal calprotectin (FC) <150 µg/g, Harvey-Bradshaw Index (HBI) <5). Patients will be randomised 2:1 into the intervention (adalimumab interval lengthening) or control group (adalimumab EOW). The intervention group will lengthen the adalimumab administration interval to every 3 weeks, and after 24 weeks to every 4 weeks. Clinical and biochemical disease activity will be monitored every 12 weeks by physician global assessment, HBI, CRP and FC. In case of disease flare, dosing will be increased. A flare is defined as two of three of the following criteria; FC>250 µg/g, CRP≥10 mg/l, HBI≥5. Secondary outcomes include cumulative incidence of transient flares, adverse events, predictors for successful dose reduction and cost-effectiveness.Ethics and disseminationThe study is approved by the Medical Ethics Committee Arnhem-Nijmegen, the Netherlands (registration number NL58948.091.16). Results will be published in peer-reviewed journals and presented at international conferences.Trial registration numbersEudraCT registry (2016-003321-42); Clinicaltrials.gov registry (NCT03172377); Dutch trial registry (NTRID6417).
Women with inflammatory bowel disease IBD may be at higher risk for cervical intraepithelial neoplasia CIN. However, data are conflicting. The aim of this study was to assess the risk of high-grade ...dysplasia and cancer CIN2+ in IBD women and identify risk factors.
Clinical data from adult IBD women in a multicentre Dutch IBD prospective cohort PSI from 2007 onwards were linked to cervical cytology and histology records from the Dutch nationwide cytology and pathology database PALGA, from 2000 to 2016. Patients were frequency-matched 1:4 to a general population cohort. Standardised detection rates SDR were calculated for CIN2+. Longitudinal data were assessed to calculate CIN2+ risk during follow-up using incidence rate ratios IRR and risk factors were identified in multivariable analysis.
Cervical records were available from 2098 IBD women 77% and 8379 in the matched cohort; median follow-up was 13 years. CIN2+ detection rate was higher in the IBD cohort than in the matched cohort (SDR 1.27, 95% confidence interval CI 1.05-1.52). Women with IBD had an increased risk of CIN2+ IRR 1.66, 95% CI 1.21-2.25 and persistent or recurrent CIN during follow-up (odds ratio OR 1.89, 95% CI 1.06-3.38). Risk factors for CIN2+ in IBD women were smoking and disease location (ileocolonic L3 or upper gastrointestinal GI L4). CIN2+ risk was not associated with exposure to immunosuppressants.
Women with IBD are at increased risk for CIN2+ lesions. These results underline the importance of human papillomavirus HPV vaccination and adherence to cervical cancer screening guidelines in IBD women, regardless of exposure to immunosuppressants.
Abstract
Background and Aims
Both methotrexate and tioguanine can be considered as treatment options in patients with Crohn’s disease after failure of conventional thiopurines. This study aimed to ...compare tolerability and drug survival of methotrexate and tioguanine therapy after failure of conventional thiopurines in patients with Crohn’s disease.
Methods
We conducted a retrospective, multicentre study, including patients with Crohn’s disease initiating monotherapy methotrexate or tioguanine after failure all causes of conventional thiopurines. Follow-up duration was 104 weeks or until treatment discontinuation. The primary outcome was cumulative therapy discontinuation incidence due to adverse events. Secondary outcomes included total number of serious adverse events, and ongoing monotherapy.
Results
In total, 219 patients starting either methotrexate n = 105 or tioguanine n = 114 were included. In all 65 29.7% patients (methotrexate 43.8% 46/105 people, tioguanine 16.7% 19/114 people, p <0.001) discontinued their treatment due to adverse events during follow-up. Median time until discontinuation due to adverse events was 16 weeks (interquartile range IQR 7-38, p = 0.812). Serious adverse events were not significantly different. Patients treated with methotrexate experienced adverse events more often methotrexate 83%, tioguanine 46%, p <0.001. Total monotherapy drug survival after 104 weeks was 22% for methotrexate and 46% for tioguanine p <0.001.
Conclusions
We observed a higher cumulative discontinuation incidence due to adverse events for methotrexate 44% compared with tioguanine 17% in Crohn’s disease patients after failure of conventional thiopurines. The total adverse events incidence during methotrexate use was higher, whereas serious adverse events incidence was similar. These favourable results for tioguanine treatment may guide the selection of immunosuppressive therapy after failure of conventional thiopurines.
Abstract
Background and Aims
Inflammatory bowel disease IBD phenotypes are very heterogeneous between patients, and current clinical and molecular classifications do not accurately predict the course ...that IBD will take over time. Genetic determinants of disease phenotypes remain largely unknown but could aid drug development and allow for personalised management. We used genetic risk scores GRS to disentangle the genetic contributions to IBD phenotypes.
Methods
Clinical characteristics and imputed genome-wide genetic array data of patients with IBD were obtained from two independent cohorts cohort A, n = 1097; cohort B, n = 2156. Genetic risk scoring GRS was used to assess genetic aetiology shared across traits and IBD phenotypes. Significant GRS–phenotype (false-discovery rate FDR corrected p <0.05) associations identified in cohort A were put forward for replication in cohort B.
Results
Crohn’s disease CD GRS were associated with fibrostenotic CD R2 = 7.4%, FDR = 0.02 and ileocaecal resection R2 = 4.1%, FDR = 1.6E-03, and this remained significant after correcting for previously identified clinical and genetic risk factors. Ulcerative colitis UC GRS R2 = 7.1%, FDR = 0.02 and primary sclerosing cholangitis PSC GRS R2 = 3.6%, FDR = 0.03 were associated with colonic CD, and these two associations were largely driven by genetic variation in MHC. We also observed pleiotropy between PSC genetic risk and smoking behaviour R2 = 1.7%, FDR = 0.04.
Conclusions
Patients with a higher genetic burden of CD are more likely to develop fibrostenotic disease and undergo ileocaecal resection, whereas colonic CD shares genetic aetiology with PSC and UC that is largely driven by variation in MHC. These results further our understanding of specific IBD phenotypes.
Background and aims:Bacteroides vulgatus induces colitis in gnotobiotic HLA-B27 transgenic (TG) rats while broad spectrum antibiotics prevent and treat colitis in specific pathogen free (SPF) TG rats ...although disease recurs after treatment ends. Lactobacilli treat human pouchitis and experimental colitis. We investigated if Lactobacillus rhamnosus GG (L GG) can prevent colitis in TG rats monoassociated with B vulgatus and if L GG or Lactobacillus plantarum 299v (LP 299v) can treat established colitis in SPF TG rats and prevent recurrent disease after antibiotics were stopped. Methods: Germfree B27 TG rats were monoassociated with B vulgatus for four weeks following two weeks of colonisation with L GG or no bacteria. SPF B27 TG rats received oral vancomycin and imipenem for two weeks, or water alone, followed by four weeks of treatment with oral L GG, LP 299v, or water only. Disease activity was quantified by blinded gross and histological scores, caecal myeloperoxidase (MPO) activity, and levels of interleukin (IL)-1β, tumour necrosis factor (TNF), transforming growth factor β, and IL-10. Results:L GG did not prevent colitis in B vulgatus co-associated TG rats or treat established disease in SPF rats. However, L GG but not LP 299v prevented colitis relapse in antibiotic treated rats with reduced gross and histological scores, caecal MPO, IL-1β, and TNF whereas caecal IL-10 was increased. Conclusions:L GG does not prevent colitis in gnotobiotic TG rats or treat established disease in SPF rats, but is superior to LP 299v in the prevention of recurrent colitis. These studies suggest that antibiotics and probiotic agents provide synergistic therapeutic effects, perhaps mediated by altered immunomodulation with selective activity of different lactobacillus species.
The number of patients with inflammatory bowel disease IBD, of non-Caucasian descent in Western Europe, is increasing. We aimed to explore the impact of ethnicity and country of birth on IBD ...phenotype.
IBD patients treated in the eight University Medical Centers in The Netherlands Dutch IBD Biobank were divided into two groups according to their ethnicity: 1 Caucasian patients of Western and Central European descent CEU; and 2 patients of non-Caucasian descent non-CEU. The non-CEU group was subdivided according to country of birth, into: born in The Netherlands or Western Europe non-CEU European born; or born outside Western-Europe who migrated to The Netherlands non-CEU non-European born. Both comparisons were analysed for phenotype differences by chi-square test.
The Dutch IBD Biobank included 2921 CEU patients and 233 non-CEU patients. Non-CEU Crohn's disease CD patients more often had upper gastro-intestinal disease 16% vs 8%, p = 0.001 and anal stenosis 10% vs 4%, p = 0.002 than CEU CD patients. The use of anti-tumour necrosis factor TNF agents and immunomodulators was higher in non-CEU IBD patients than in CEU IBD patients 45% vs 38%, p = 0.042 and 77% vs 66%, p = 0.001, respectively. Non-CEU IBD patients born in Europe n = 116 were diagnosed at a lower age than non-CEU IBD patients born outside Europe n = 115 at 22.7 vs 28.9 years old, p < 0.001.
Non-Caucasians had more severe disease behaviour than Caucasians. Non-CEU patients born in Europe were diagnosed at a lower age with IBD than those born outside Europe who migrated to The Netherlands.
PDF
