During active inflammatory bowel disease (IBD) fatigue is a common symptom, which seems related to active gut inflammation. However, even in remission many patients suffer from fatigue that ...negatively affects quality of life and work productivity. Currently, robust knowledge on the pathogenesis and treatment of IBD-related fatigue is lacking. In order to alleviate the burden of IBD-related fatigue, a systematic approach is mandatory. We propose a fatigue attention cycle to enhance identification, evaluation and management of fatigued IBD patients. The benefits of the cycle are twofold. Firstly, it allows the systematic and uniform identification of patients with severe fatigue, in turn allowing tailored non-pharmacological and pharmacological interventions. Secondly, uniform identification of such patients creates a well-defined patient base to investigate the underlying pathogenesis of fatigue, resulting in a greater understanding of this debilitating phenomenon and possibly resulting in the discovery of predictive factors and new treatment interventions.
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.
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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
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.
Background
Outpatient visits and laboratory assessments are routinely scheduled every 3 to 4 months in thiopurine-treated patients with inflammatory bowel disease (IBD) to timely detect ...thiopurine-related adverse events (AEs). AEs that require therapy adjustment beyond 12 months of treatment are rare.
Aim and Methods
This single-center prospective cohort study evaluated the safety of a reduced 6-monthly monitoring strategy in steroid-free patients with quiescent IBD on stable dose of azathioprine, mercaptopurine, or thioguanine monotherapy. The primary outcome was thiopurine-related AEs requiring therapy adjustments during a follow-up period of 24 months. Secondary outcomes included all AEs including laboratory toxicity, disease flares until 12 months, and the net monetary benefit from this strategy concerning IBD-related health care use.
Results
We enrolled 85 patients with IBD (median age 42 years, 61% Crohn’s disease, 62% female), with a median disease duration of 12.5 years and median thiopurine treatment duration of 6.7 years. During follow-up, 3 patients (4%) ceased thiopurines due to AEs: recurrent infections, non-melanoma skin cancer, and gastrointestinal complaints (nausea, vomiting). At 12 months, 25 laboratory toxicities were observed (including 13% myelotoxicity, 17% hepatotoxicity); none required therapy adjustments and all were transient. A reduced monitoring strategy had a net benefit of €136 per patient.
Conclusion
Three patients (4%) ceased thiopurine therapy due to thiopurine-related AEs, while no laboratory toxicity required therapy adjustments. Monitoring frequency of every 6 months seems feasible in patients with stable IBD on long-term (median duration > 6 years) maintenance thiopurine therapy and may contribute to reduced patient-burden and health care costs.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Ulcerative proctitis (UP) refractory to 5-aminosalicylic acid (5-ASA) suppositories is a challenge to treat, often requiring step up to immunomodulator or biological therapy. Topical tacrolimus is ...effective and safe in patients with refractory UP. However, it is not clear how tacrolimus suppositories fit into in the treatment algorithm of UP.
We performed a randomized controlled, double-blind study at 8 hospitals in the Netherlands and Belgium from 2014 through 2017. Eighty-five patients with refractory UP (65% women) were randomly assigned to groups given once daily tacrolimus suppositories (2 mg; n = 43) or beclomethasone (3 mg; n = 42) for 4 weeks. The primary outcome was clinical response (decrease in Mayo score of 3 or more). Secondary outcomes included clinical remission, endoscopic response and remission, adverse events and quality of life. Outcomes were compared using Fisher’s exact test and Mann-Whitney U test.
Proportions of patients with clinical responses were 63% in the tacrolimus group and 59% in the beclomethasone group (P = .812); proportions of patients in clinical remission were 46% and 38%, respectively (P = .638). Proportions of patients with an endoscopic response were 68% and 60% in the tacrolimus group and in the beclomethasone group (P = .636); proportions in endoscopic remission rates were 30% and 13%, respectively (P = .092) Median increases in the inflammatory bowel disease questionnaire score were 18.0 in the tacrolimus group and 20.5 in the beclomethasone group (P = .395). Adverse event rates did not differ significantly between groups.
In a 4-week randomized controlled trial, tacrolimus and beclomethasone suppositories induce comparable clinical and endoscopic responses in patients with UP refractory to 5-ASA. There were no significant differences in adverse events rates. Tacrolimus and beclomethasone suppositories are therefore each safe and effective treatment options for 5-ASA refractory disease. EUDRACT 2013-001259-11; Netherlands Trial Register NL4205/NTR4416.
Summary
Background
Low‐dose thiopurine‐allopurinol (LDTA) combination therapy is a commonly applied optimisation strategy in IBD patients with a skewed thiopurine metabolism.
Aim
To assess continued ...LDTA maintenance treatment at annual intervals and explore risk factors for treatment cessation
Methods
Adult IBD patients treated with LDTA between 2009 and 2016 were retrospectively included. Data on the incidence of clinical and laboratory adverse events (AEs), including hepatotoxicity and myelotoxicity resulting in imposing LDTA therapy cessation and associated risk factors were collected.
Results
In total, 221 IBD patients (46% male, median age 42 years) were included. Maintenance LDTA treatment was continued in 78% of patients at 1 year (n = 145), 66% at 2 years (n = 83), 57% at 3 years (n = 52) and 52% at 4 years (n = 33). Treatment in patients receiving LDTA therapy for AEs during thiopurine monotherapy was more often continued than in patients initiating LDTA for other indications (eg, ineffectiveness of thiopurine monotherapy, routinely discovered skewed metabolism) (P = 0.016). Myelotoxicity during thiopurine monotherapy resolved in 87% and hepatotoxicity in 86% after median of 1.2 and 1.4 months after LDTA initiation. Cumulative incidence of AEs during LDTA resulting in therapy cessation within total follow‐up of 449 treatment‐years was 7% for clinical AEs, 4% for myelotoxicity and 1% for hepatotoxicity.
Conclusion
LDTA therapy is a safe and beneficial optimisation strategy in IBD patients. Continued maintenance LDTA treatment is 52% after 4 years of treatment and most commonly affected by ineffectiveness of LDTA rather than LDTA‐attributed toxicity. LDTA optimisation strategy is most advantageous in patients failing thiopurine monotherapy due to AEs.
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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
Background and Aim
Thiopurines have a favorable benefit–risk ratio in the treatment of inflammatory bowel disease. A feared adverse event of thiopurine therapy is myelotoxicity, mostly occurring due ...to toxic concentrations of the pharmacologically active metabolites 6‐thioguaninenucleotides. In oncology, myelosuppression has also been associated with elevated 6‐methylmercaptopurine (6‐MMP). In this case series, we provide a detailed overview of 6‐MMP‐induced myelotoxicity in inflammatory bowel disease patients.
Methods
We retrospectively scrutinized pharmacological laboratory databases of five participating centers over a 5‐year period. Patients with leukocytopenia at time of elevated 6‐MMP levels (>5700 pmol/8 × 108 red blood cells) were included for detailed chart review.
Results
In this case series, we describe demographic, clinical, and pharmacological aspects of 24 cases of 6‐MMP‐induced myelotoxicity on weight‐based thiopurine therapy with a median steady‐state 6‐MMP level of 14 500 pmol/8 × 108 red blood cells (range 6600–48 000). All patients developed leukocytopenia (white blood cell count 2.7 ± 0.9 × 109/L) after a median period of 11 weeks after initiation of thiopurine therapy (interquartile range 6–46 weeks). Eighteen patients (75%) developed concurrent anemia (median hemoglobin concentration 6.9 × 109/L), and four patients developed concurrent thrombocytopenia (median platelet count 104 × 109/L). Leukocytopenia resolved in 20 patients (83%) within 4 weeks upon altered thiopurine treatment regimen, and white blood cell count was increasing, but not yet normalized, in the remaining four patients.
Conclusion
We observed that thiopurine‐induced myelotoxicity also occurs because of (extremely) high 6‐MMP concentrations in patients with a skewed thiopurine metabolism. Continued treatment with adapted thiopurine therapy was successful in almost all patients.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Summary
Background
To timely detect myelotoxicity and hepatotoxicity, laboratory monitoring at 3‐month intervals is advised throughout thiopurine maintenance treatment for IBD. However, reported ...incidence rates of myelotoxicity and hepatotoxicity in maintenance treatment are low.
Aim
To assess incidence rates and clinical consequences of myelotoxicity and hepatotoxicity in thiopurine maintenance therapy after at least 1 year of thiopurine treatment.
Methods
Retrospective analysis of therapy adjustment for laboratory toxicity in adult IBD patients after 12 consecutive months of azathioprine (AZA) or mercaptopurine monotherapy (ie baseline) between 2000 and 2016. Incidence rates of laboratory toxicity (ie myelotoxicity leucocyte count <4.0 × 10e9/L, and/or platelet count <150 × 10e9/L and/or hepatotoxicity (gamma‐glutamyltransferase GGT, alkaline phosphatase AP, ALT and/or AST above ULN, excluding isolated increased AST/AP) and associated diagnostic procedures and complications were assessed.
Results
In total, 12,391 laboratory assessments were performed on 1132 patients (56% female, AZA 74%) during 3.3 years of median follow‐up. Median monitoring frequency was 3.1 assessments/treatment year. Only 83/12,391 (0.7%) assessments resulted in therapy adjustment, dose reduction in 46 patients, cessation in 28 and allopurinol initiation in nine; risk of therapy adjustment was 1.9% per treatment year. Incidence rates of myelotoxicity were 7.1% (5.1% mild/1.8% moderate/0.1% severe) and hepatotoxicity 5.1% (3.8% mild/1.1% moderate/0.2% severe) per treatment year. Treatment‐related complications with concurrent laboratory toxicity occurred in 12 patients (1.1%) and would not have been prevented by monitoring.
Conclusion
Severe laboratory toxicity is uncommon after 1 year of thiopurine monotherapy at 4‐month monitoring intervals. Therapy adjustments are rare after detection of laboratory toxicity. After 1 year of thiopurine monotherapy, laboratory monitoring may be lowered to less than a 4‐month interval.
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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
An unexpected cause of terminal ileitis Harinck, Femme, MD PhD; van Putten, Paul G., MD PhD; Kreijne, Joany E., MD ...
Gastrointestinal endoscopy,
02/2017, Volume:
85, Issue:
2
Journal Article
Peer reviewed
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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