The majority of AZA or 6-MP-intolerant IBD patients (79%) is able to tolerate maintenance treatment with 6-TG (dosages between 0.3 and 0.4 mg/kg per d). 6-TG may still be considered as an escape maintenance immunosuppressant in this difficult to treat group of patients, taking into account potential toxicity and efficacy of other alternatives. The recently reported hepatotoxicity is worrisome and 6-TG should therefore be administered only in prospective trials.

BACKGROUND AND AIMS 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 is to assess the risk of high-grade dysplasia and cancer (CIN2+) in IBD women and identify risk factors. METHODS 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. Standardized 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. RESULTS Cervical records were available from 2,098 IBD women (77%) and 8,379 in the matched cohort; median follow-up 13 years. CIN2+ detection rate was higher in the IBD cohort than in the matched cohort (SDR 1.27, 95%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 (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-GI (L4)). CIN2+ risk was not associated with exposure to immunosuppressants. CONCLUSION Women with IBD are at increased risk for CIN2+ lesions. These results underline the importance of HPV vaccination and adherence to cervical cancer screening guidelines in IBD women, regardless of exposure to immunosuppressants.

Abstract Background and aims The gut microbiota plays an important role in the metabolization and modulation of several types of drugs. With this study we aimed to review the literature about microbial drug metabolism of medication prescribed in inflammatory bowel disease practice. Methods A systematic literature search was performed in Embase and PubMed from inception to October 2019. The search was conducted with predefined MeSH/Emtree and text terms. All studies about drug metabolism by microbiota of medication prescribed in inflammatory bowel disease practice were eligible. A total of 1018 records were encountered and 89 articles were selected for full text reading Results Intestinal bacterial metabolism or modulation is of influence in four specific drugs used in inflammatory bowel disease (mesalazines, methotrexate, glucocorticoids and thioguanine). The gut microbiota cleaves the azo-bond of sulfasalazine, balsalazide and olsalazine and releases the active moiety 5-aminosalicylic acid. It has an impact on the metabolization and potentially on the response of methotrexate therapy. Especially thioguanine can be converted by intestinal bacteria into the pharmacological active 6-thioguanine nucleotides without the requirement of host metabolism. Glucocorticoid compounds can be prone to bacterial degradation. Conclusion The human intestinal microbiota can have a major impact on drug metabolism and efficacy of medication prescribed in inflammatory bowel disease practice. A better understanding of these interactions between microbiota and drugs is needed and should be an integral part of the drug development pathway of new inflammatory bowel disease medication.

Background Thioguanine (TG) is a thiopurine which has been used for patients with inflammatory bowel disease (IBD), who have failed azathioprine (AZA) or mercaptopurine (MP) due to adverse events or suboptimal response. Its widespread use has been hampered due to concerns about nodular regenerative hyperplasia (NRH) of the liver. The aim of this study was to investigate the long-term efficacy and safety of low-dose TG therapy in IBD patients failing AZA and MP. Methods A retrospective multicentre study was performed in IBD patients who failed prior treatment with conventional thiopurines with or without following immunomodulation (thiopurine-allopurinol, biologicals, methotrexate, tacrolimus) and were subsequently treated with TG as rescue monotherapy between 2003 and 2019 at three hospitals in the United Kingdom. Clinical response, adverse events, laboratory results, imaging and liver biopsies were retrospectively collected. Results A total of 193 patients (57% female and 64% Crohn’s disease) were included, with a median daily TG dose of 20 mg (range: 20–40 mg), a median treatment duration of 23 months (IQR 10–47) and a median follow-up of 36 months (IQR 22–53). The clinical response rate at 12 months was 65 and 54% remained on TG until the end of follow-up. Adverse events consisted primarily of elevated liver tests (6%), myelotoxicity (7%) and rash (5%). NRH was histologically diagnosed in two patients and two other patients (1%) developed non-cirrhotic portal hypertension. The median 6-TGN and TPMT levels were 953 pmol/8 × 105 RBC (IQR 145–1761) and 47 mu/L (IQR 34.5–96). Conclusions Long-term follow-up suggests that TG can be an effective and well-tolerated therapy in more than half of difficult-to-treat and multi-therapy failing IBD patients. Findings of this study indicate that TG can be used safely and the occurrence of hepatotoxicity was low. The incidence rate of NRH was within the background incidence.

Objective: To assess time trends in intestinal resection and re-resection in Crohn's disease (CD) patients. Summary of Background Data: CD treatment has changed considerably over the past decades. The effect of these advances on the necessity of intestinal resections and the risk of re-resection is unclear. Methods: In this nationwide cohort study, adult CD patients with ileocolonic, small bowel, colon, or rectum resections between 1991 and 2015 were included. Data were retrieved from the Dutch nationwide network and registry of histopathology and cytopathology (PALGA). Time trends were analyzed with a broken stick model and Cox proportional hazard model with smoothing splines. Results: The identified cohort comprised 8172 CD patients (3293/4879 male/female) in whom 10,315 intestinal resections were performed. The annual intestinal resection rate decreased nonlinearly from 22.7/100,000 CD patients (1991) to 2.5/100,000 (2015). A significantly steeper decrease was observed before 1999 (slope −1.56) as compared to subsequent years (slope −0.41) (P < 0.001). Analogous trends were observed for ileocolonic, small bowel, and colon resections. Overall cumulative risk of re-resection was 10.9% at 5 years, 18.6% at 10 years, and 28.3% at 20 years after intestinal resection. The hazard for intestinal re-resection showed a nonlinear decreasing trend, with hazard ratio 0.39 (95% confidence interval 0.36–0.44) in 2000 and hazard ratio 0.25 (95% confidence interval 0.18–0.34) in 2015 as compared to 1991. Conclusion: Over the past 25 years, intestinal resection rate has decreased significantly for ileocolonic, small bowel, and colonic CD. In addition, current postoperative CD patients are at 75% lower risk of intestinal re-resection.