Uphill battle: Innovation of thiopurine therapy in global inflammatory bowel disease care.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract that encompasses two major conditions: Crohn's disease (CD) and ulcerative colitis (UC). Historically, IBD has been primarily reported in western countries, but over the past decades, its prevalence is rapidly increasing, especially in lower and middle-income countries (LMICs) such as India and China and also in Sub-Saharan Africa. The prevalence of IBD in LMICs has been the subject of growing concern due to the impact of access to public healthcare and the burden it places on healthcare resources. The classical thiopurines face significant challenges due to cessation of therapy in approximately half of patients within one year due to side effects or ineffectiveness. In this article, we highlight innovating thiopurine treatment for IBD patients in downregulating side effects and improving efficacy.

The Effectiveness and Safety of First-Line Thioguanine in Thiopurine-Naïve Inflammatory Bowel Disease Patients.

BACKGROUND: Currently thioguanine is solely used as treatment for inflammatory bowel disease after azathioprine and/or mercaptopurine failure. This study aimed to determine the safety, effectiveness, and 12-month drug survival of thioguanine in thiopurine-naïve patients with inflammatory bowel disease. METHODS: A retrospective cohort study was performed in thiopurine-naïve patients with inflammatory bowel disease treated with thioguanine as first thiopurine derivate. Clinical effectiveness was defined as the continuation of thioguanine without the (re)initiation of concurrent biological therapy, systemic corticosteroids, or a surgical intervention. All adverse events were categorized by the Common Terminology Criteria for Adverse Events. RESULTS: A total of 114 patients (male 39%, Crohn's disease 53%) were included with a median treatment duration of 25 months and a median thioguanine dosage of 20 mg/d. Clinical effectiveness at 12 months was observed in 53% of patients, and 78% of these responding patients remained responsive until the end of follow-up. During the entire follow-up period, 26 patients were primary nonresponders, 8 had a secondary loss of response, and 11 patients were unable to cease therapy with systemic corticosteroids within 6 months and were therefore classified as nonresponders. After 12 months, thioguanine was still used by 86% of patients. Fifty (44%) patients developed adverse events (grade 1 or 2) and 9 (8%) patients ceased therapy due to the occurrence of adverse events. An infection was documented in 3 patients, none of them requiring hospitalization and pancytopenia occurred in 2 other patients. No signs of nodular regenerative hyperplasia or portal hypertension were observed. CONCLUSIONS: At 12 months, first-line thioguanine therapy was clinically effective in 53% of thiopurine-naïve inflammatory bowel disease patients with an acceptable safety profile.

After 12 months, first-line thioguanine therapy was still used by 86% of thiopurine-naïve patients with inflammatory bowel disease and clinically effective in 53%. The safety profile was acceptable and only 8% of patients ceased therapy due to adverse events.

Follow-Up of Celiac Disease in Adults: "When, What, Who, and Where".

For patients with celiac disease (CeD), a lifelong gluten-free diet is not a voluntary lifestyle choice-it is a necessity. The key end points in clinical follow-up are symptom resolution, the normalization of weight, prevention of overweight, seroconversion, and negation or minimization of increased long-term morbidity. For the latter, a surrogate endpoint is mucosal healing, which means the normalization of histology to Marsh 0-1. Ideally, celiac follow-up care includes a multidisciplinary approach, effective referral processes, improved access that leverages technological advances, and following guidelines with the identification of measurable quality indicators, ideally informed by evidence-based research. Face-to-face CeD care and telemedicine are considered the standards for this process, although published data are insufficient. Guidelines and statements on diagnosis are readily available. However, data are lacking on optimal clinic visit intervals and outcomes and quality indicators such as improvement of symptoms, function and quality of life, survival and disease control, and how to most effectively use healthcare resources. The results of future research should provide the basis for general recommendations for evidence-based standards of quality of care in CeD.

Drug rediscovery in gastroenterology: from off-label to on-label use of thioguanine in inflammatory bowel disease.

Drug rediscovery refers to the principle of using 'old' drugs outside the indications mentioned in the summary of product characteristics. In the past decades, several drugs were rediscovered in a wide variety of medical fields. One of the most recent examples is the unconditional registration of thioguanine (TG), a thiopurine derivative, in patients with inflammatory bowel disease in the Netherlands. In this paper, we aim to visualise potential hurdles that hamper drug rediscovery in general, emphasise the global need for optimal use and development of potentially useful drugs, and provide an overview of the registration process for TG in the Netherlands. With this summary, we aim to guide drug rediscovery trajectories in the near future.

Thioguanine is Effective as Maintenance Therapy for Inflammatory Bowel Disease: A Prospective Multicentre Registry Study.

BACKGROUND AND AIMS: Thioguanine is a well-tolerated and effective therapy for inflammatory bowel disease [IBD] patients. Prospective effectiveness data are needed to substantiate the role of thioguanine as a maintenance therapy for IBD. METHODS: IBD patients who previously failed azathioprine or mercaptopurine and initiated thioguanine were prospectively followed for 12 months starting when corticosteroid-free clinical remission was achieved (Harvey-Bradshaw Index [HBI] ≤ 4 or Simple Clinical Colitis Activity Index [SCCAI] ≤ 2). The primary endpoint was corticosteroid-free clinical remission throughout 12 months. Loss of clinical remission was defined as SCCAI > 2 or HBI > 4, need of surgery, escalation of therapy, initiation of corticosteroids or study discontinuation. Additional endpoints were adverse events, drug survival, physician global assessment [PGA] and quality of life [QoL]. RESULTS: Sustained corticosteroid-free clinical remission at 3, 6 or 12 months was observed in 75 [69%], 66 [61%] and 49 [45%] of 108 patients, respectively. Thioguanine was continued in 86 patients [80%] for at least 12 months. Loss of response [55%] included escalation to biologicals in 15%, corticosteroids in 10% and surgery in 3%. According to PGA scores, 82% of patients were still in remission after 12 months and QoL scores remained stable. Adverse events leading to discontinuation were reported in 11%, infections in 10%, myelo- and hepatotoxicity each in 6%, and portal hypertension in 1% of patients. CONCLUSION: Sustained corticosteroid-free clinical remission over 12 months was achieved in 45% of IBD patients on monotherapy with thioguanine. A drug continuation rate of 80%, together with favourable PGA and QoL scores, underlines the tolerability and effectiveness of thioguanine for IBD.

Exposure to Thioguanine During 117 Pregnancies in Women With Inflammatory Bowel Disease.

BACKGROUND: Safety of thioguanine in pregnant patients with inflammatory bowel disease [IBD] is sparsely recorded. This study was aimed to document the safety of thioguanine during pregnancy and birth. METHODS: In this multicentre case series, IBD patients treated with thioguanine during pregnancy were included. Data regarding disease and medication history, pregnancy course, obstetric complications, and neonatal outcomes were collected. RESULTS: Data on 117 thioguanine-exposed pregnancies in 99 women were collected. Most [78%] had Crohn's disease and the mean age at delivery was 31 years. In 18 pregnancies [15%], IBD flared. Obstetric and infectious complications were seen in 15% [n = 17] and 7% [n = 8] of pregnancies, respectively. Ten pregnancies [8.5%] resulted in a first trimester miscarriage, one in a stillbirth at 22 weeks of gestational age and one in an induced abortion due to trisomy 21. In total, 109 neonates were born from 101 singleton pregnancies and four twin pregnancies. One child was born with a congenital abnormality [cleft palate]. In the singleton pregnancies, 10 children were born prematurely and 10 were born small for gestational age. Screening for myelosuppresion was performed in 16 neonates [14.7%]; two had anaemia in umbilical cord blood. All outcomes were comparable to either the general Dutch population or to data from three Dutch cohort studies on the use of conventional thiopurines in pregnant IBD patients. CONCLUSION: In this large case series, the use of thioguanine during pregnancy is not associated in excess with adverse maternal or neonatal outcomes.

The Dietary and Non-Dietary Management of Osteoporosis in Adult-Onset Celiac Disease: Current Status and Practical Guidance.

Impaired bone mineral density (BMD) is a frequent complication of adult-onset celiac disease (CeD). This is usually due to malabsorption of nutrients, changes in bone metabolism in association with inflammation, and to a lesser extent, decreased overall physical health and mobility. This review aims to highlight the current status concerning surveillance, prevention, and treatment strategies for bone disease in CeD. A practical guidance on these matters is suggested. The available published research on the prevention and treatment of decreased BMD in relation to CeD is scarce. In general, publications were based on expert opinions or extrapolation from studies on postmenopausal women or inflammatory bowel disease. Optimal dietary treatment and an adequate supply of calcium and vitamin D are the cornerstones for the reduction in fracture risk in patients with CeD. In adults with low BMD or fragility fractures, CeD needs to be considered and specifically approached. When osteoporosis is documented, start treatment with an antiresorptive agent; these agents are proven to result in a long-term reduction in fracture risk in high-risk individuals. However, there are some important differences between the management of male and female patients, particularly premenopausal women, that need to be addressed. In patients with persisting diarrhea and malabsorption, parenteral medications may be preferable. Future research specifically focusing on celiac disease and the associated disorders in bone mineralization is mandatory to provide evidence-based recommendations in this field.

Safety of Thioguanine in Pediatric Inflammatory Bowel Disease: A Multi-Center Case Series.

OBJECTIVES: Thioguanine (TG) has been shown as a safe alternative in adults with inflammatory bowel disease (IBD) who did not tolerate conventional thiopurines [azathioprine (AZA)/mercaptopurine]. However, data in pediatric IBD are scarce. Therefore, we aimed to assess the safety of TG as maintenance therapy. METHODS: A retrospective, multicenter cohort study of children with IBD on TG was performed in the Netherlands. TG-related adverse events (AE) were assessed and listed according to the common terminology criteria for AE. RESULTS: Thirty-six children with IBD (median age 14.5 years) on TG (median dose 15 mg/day) were included in 6 centers. Five AE occurred during follow-up [pancreatitis (grade 3), hepatotoxicity (grade 3) (n = 2), Clostridium difficile infection (grade 2), and abdominal pain (grade 2)]. All patients (n = 8) with a previously AZA-induced pancreatitis did not redevelop pancreatitis on TG. CONCLUSIONS: In pediatric IBD, TG seems a safe alternative in case of AZA-induced pancreatitis. Further research assessing long-term TG-related safety and efficacy is needed.

Gluten Induces Subtle Histological Changes in Duodenal Mucosa of Patients with Non-Coeliac Gluten Sensitivity: A Multicentre Study.

Background: Histological changes induced by gluten in the duodenal mucosa of patients with non-coeliac gluten sensitivity (NCGS) are poorly defined. Objectives: To evaluate the structural and inflammatory features of NCGS compared to controls and coeliac disease (CeD) with milder enteropathy (Marsh I-II). Methods: Well-oriented biopsies of 262 control cases with normal gastroscopy and histologic findings, 261 CeD, and 175 NCGS biopsies from 9 contributing countries were examined. Villus height (VH, in µm), crypt depth (CrD, in µm), villus-to-crypt ratios (VCR), IELs (intraepithelial lymphocytes/100 enterocytes), and other relevant histological, serologic, and demographic parameters were quantified. Results: The median VH in NCGS was significantly shorter (600, IQR: 400−705) than controls (900, IQR: 667−1112) (p < 0.001). NCGS patients with Marsh I-II had similar VH and VCR to CeD [465 µm (IQR: 390−620) vs. 427 µm (IQR: 348−569, p = 0·176)]. The VCR in NCGS with Marsh 0 was lower than controls (p < 0.001). The median IEL in NCGS with Marsh 0 was higher than controls (23.0 vs. 13.7, p < 0.001). To distinguish Marsh 0 NCGS from controls, an IEL cut-off of 14 showed 79% sensitivity and 55% specificity. IEL densities in Marsh I-II NCGS and CeD groups were similar. Conclusion: NCGS duodenal mucosa exhibits distinctive changes consistent with an intestinal response to luminal antigens, even at the Marsh 0 stage of villus architecture.

Azathioprine with Allopurinol Is a Promising First-Line Therapy for Inflammatory Bowel Diseases.

BACKGROUND: Beneficial response to first-line immunosuppressive azathioprine in patients with inflammatory bowel disease (IBD) is low due to high rates of adverse events. Co-administrating allopurinol has been shown to improve tolerability. However, data on this co-therapy as first-line treatment are scarce. AIM: Retrospective comparison of long-term effectiveness and safety of first-line low-dose azathioprine-allopurinol co-therapy (LDAA) with first-line azathioprine monotherapy (AZAm) in patients with IBD without metabolite monitoring. METHODS: Clinical benefit was defined as ongoing therapy without initiation of steroids, biologics or surgery. Secondary outcomes included CRP, HBI/SCCAI, steroid withdrawal and adverse events. RESULTS: In total, 166 LDAA and 118 AZAm patients (median follow-up 25 and 27 months) were evaluated. Clinical benefit was more frequently observed in LDAA patients at 6 months (74% vs. 53%, p = 0.0003), 12 months (54% vs. 37%, p = 0.01) and in the long-term (median 36 months; 37% vs. 24%, p = 0.04). Throughout follow-up, AZAm patients were 60% more likely to fail therapy, due to a higher intolerance rate (45% vs. 26%, p = 0.001). Only 73% of the effective AZA dose was tolerated in AZAm patients, while LDAA could be initiated and maintained at its target dose. Incidence of myelotoxicity and elevated liver enzymes was similar in both cohorts, and both conditions led to LDAA withdrawal in only 2%. Increasing allopurinol from 100 to 200-300 mg/day significantly lowered liver enzymes in 5/6 LDAA patients with hepatotoxicity. CONCLUSIONS: Our poor AZAm outcomes emphasize that optimization of azathioprine is needed. We demonstrated a long-term safe and more effective profile of first-line LDAA. This co-therapy may therefore be considered standard first-line immunosuppressive.

Advances in Thiopurine Drug Delivery: The Current State-of-the-Art.

Thiopurines (mercaptopurine, azathioprine and thioguanine) are well-established maintenance treatments for a wide range of diseases such as leukemia, inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE) and other inflammatory and autoimmune diseases in general. Worldwide, millions of patients are treated with thiopurines. The use of thiopurines has been limited because of off-target effects such as myelotoxicity and hepatotoxicity. Therefore, seeking methods to enhance target-based thiopurine-based treatment is relevant, combined with pharmacogenetic testing. Controlled-release formulations for thiopurines have been clinically tested and have shown promising outcomes in inflammatory bowel disease. Latest developments in nano-formulations for thiopurines have shown encouraging pre-clinical results, but further research and development are needed. This review provides an overview of novel drug delivery strategies for thiopurines, reviewing modified release formulations and with a focus on nano-based formulations.

Relationship Between Thiopurine S-Methyltransferase Genotype/Phenotype and 6-Thioguanine Nucleotide Levels in 316 Patients With Inflammatory Bowel Disease on 6-Thioguanine.

BACKGROUND: In inflammatory bowel disease (IBD), conventional thiopurine users cease treatment in 60% of cases within 5 years, mostly because of adverse events or nonresponse. In this study, the authors aimed to investigate the role of 6-thioguanine nucleotide (TGN) measurements, geno/phenotyping of thiopurine S-methyltransferase (TPMT), and their mutual relationship with TG therapy in IBD. METHODS: An international retrospective, multicenter cohort study was performed at 4 centers in the Netherlands (Máxima Medical Centre) and the United Kingdom (Guy's and St. Thomas' Hospital, Queen Elizabeth Hospital, and East Surrey Hospital). RESULTS: Overall, 526 6-TGN measurements were performed in 316 patients with IBD. The median daily dosage of TG was 20 mg/d (range 10-40 mg/d), and the median duration of TG use was 21.1 months (SD, 28.0). In total, 129 patients (40.8%) had a known TPMT status. In the variant-type and wild-type TPMT genotype metabolism groups, median 6-TGN values were 1126 [interquartile range (IQR) 948-1562] and 467.5 pmol/8 × 10E8 red blood cells (RBCs) (IQR 334-593). A significant difference was observed between the 2 groups (P = 0.0001, t test). For TPMT phenotypes, in the slow, fast, and normal metabolism groups, the median 6-TGN values were 772.0 (IQR 459-1724), 296.0 (IQR 200-705), and 774.5 pmol/8 × 10E8 RBCs (IQR 500.5-981.5), with a significant difference observed between groups (P < 0.001, analysis of variance). CONCLUSIONS: Our findings indicated that TPMT measurements at TG initiation can be useful but are not necessary for daily practice. TPMT genotypes and phenotypes are both associated with significant differences in 6-TGN levels between metabolic groups. However, the advantage of TG remains that RBC 6-TGN measurements are not crucial to monitor treatments in patients with IBD because these measurements did not correlate with laboratory result abnormalities. This presents as a major advantage in countries where patients cannot access these diagnostic tests.

Adult-Onset Autoimmune Enteropathy in an European Tertiary Referral Center.

INTRODUCTION: Adult-onset autoimmune enteropathy (AIE) is a rare cause of severe chronic diarrhea because of small intestinal villous atrophy. We report on patients with adult-onset AIE in an European referral center. METHODS: Retrospective study including patients diagnosed with AIE in the Amsterdam UMC, location VUmc, between January 2003 and December 2019. Clinical, serological, and histological features and response to treatment were reported. The specificity of antienterocyte antibodies (AEA) was evaluated by examining the prevalence of AEA in (i) controls (n = 30) and in patients with (ii) AIE (n = 13), (iii) celiac disease (CD, n = 52), (iv) refractory celiac disease type 2 (n = 18), and (v) enteropathy-associated T-cell lymphoma (EATL, n = 10). RESULTS: Thirteen AIE patients were included, 8 women (62%), median age of 52 years (range 23-73), and 6 (46%) with an autoimmune disease. AEA were observed in 11 cases (85%), but were also found in CD (7.7%), refractory celiac disease type 2 (16.7%), and EATL (20%). Ten patients (77%) were human leukocyte antigen DQ2.5 heterozygous. Total parenteral nutrition was required in 8 cases (62%). Steroids induced clinical remission in 8 cases (62%). Step-up therapy with rituximab, cyclosporine, infliximab, and cladribine in steroid-refractory patients was only moderately effective. Four patients died (31%), but 4 (31%) others are in long-term drug-free remission after receiving immunosuppressive treatment, including 1 patient who underwent autologous stem cell transplantation. DISCUSSION: Adult-onset AIE is a rare but severe enteropathy that occurs in patients susceptible for autoimmune disease. Four patients (31%) died secondary to therapy-refractory malabsorption, while immunosuppressive therapy leads to a long-lasting drug-free remission in one-third of patients.

Gut fermentation syndrome: A systematic review of case reports.

BACKGROUND: The gut fermentation syndrome (GFS), also known as the endogenous alcohol fermentation syndrome or auto brewery syndrome, is a rare and underdiagnosed medical condition where consumed carbohydrates are converted to alcohol by the microbiota in the gastrointestinal or urinary tract. The symptoms of GFS can have severe impact on patients' wellbeing and can have social and legal consequences. Unfortunately, not much is reported about GFS. The aim of this systematic review was to assess the evidence for GFS, causal micro-organisms, diagnostics, and possible treatments. METHODS: A protocol was developed prior to initiation of the systematic review (PROSPERO 207182). We performed a literature search for clinical studies on 1 September 2020 using PubMed and Embase. We included all clinical studies, including case reports that described the GFS. RESULTS: In total, 17 case reports were included, consisting of 20 patients diagnosed with GFS. The species that caused the GFS included Klebsiella pneumoniae, Candida albicans, C. glabrata, Saccharomyces cerevisiae, C. intermedia, C. parapsilosis, and C. kefyr. CONCLUSIONS: GFS is a rare but underdiagnosed disease in daily practice. The disease is mostly reported by Saccharomyces and Candida genera, and some cases were previously treated with antibiotics. Studies in Nonalcoholic Fatty Liver disease suggest a bacterial origin of endogenous alcohol-production, which might also be causal micro-organisms in GFS. Current treatments for GFS include antibiotics, antifungal medication, low carbohydrate diet, and probiotics. There might be a potential role of fecal microbiota transplant in the treatment of GFS.

Water-assisted colonoscopy: an international modified Delphi review on definitions and practice recommendations.

BACKGROUND AND AIMS: Since 2008, a plethora of research studies has compared the efficacy of water-assisted (aided) colonoscopy (WAC) and underwater resection (UWR) of colorectal lesions with standard colonoscopy. We reviewed and graded the research evidence with potential clinical application. We conducted a modified Delphi consensus among experienced colonoscopists on definitions and practice of water immersion (WI), water exchange (WE), and UWR. METHODS: Major databases were searched to obtain research reports that could potentially shape clinical practice related to WAC and UWR. Pertinent references were graded (Grading of Recommendations, Assessment, Development and Evaluation). Extracted data supporting evidence-based statements were tabulated and provided to respondents. We received responses from 55 (85% surveyed) experienced colonoscopists (37 experts and 18 nonexperts in WAC) from 16 countries in 3 rounds. Voting was conducted anonymously in the second and third round, with ≥80% agreement defined as consensus. We aimed to obtain consensus in all statements. RESULTS: In the first and the second modified Delphi rounds, 20 proposed statements were decreased to 14 and then 11 statements. After the third round, the combined responses from all respondents depicted the consensus in 11 statements (S): definitions of WI (S1) and WE (S2), procedural features (S3-S5), impact on bowel cleanliness (S6), adenoma detection (S7), pain score (S8), and UWR (S9-S11). CONCLUSIONS: The most important consensus statements are that WI and WE are not the same in implementation and outcomes. Because studies that could potentially shape clinical practice of WAC and UWR were chosen for review, this modified Delphi consensus supports recommendations for the use of WAC in clinical practice.

A standardised model for stool banking for faecal microbiota transplantation: a consensus report from a multidisciplinary UEG working group.

BACKGROUND: Faecal microbiota transplantation is an emerging therapeutic option, particularly for the treatment of recurrent Clostridioides difficile infection. Stool banks that organise recruitment and screening of faeces donors are being embedded within the regulatory frameworks described in the European Union Tissue and Cells Directive and the technical guide to the quality and safety of tissue and cells for human application, published by the European Council. OBJECTIVE: Several European and international consensus statements concerning faecal microbiota transplantation have been issued. While these documents provide overall guidance, we aim to provide a detailed description of all processes that relate to the collection, handling and clinical application of human donor stool in this document. METHODS: Collaborative subgroups of experts on stool banking drafted concepts for all domains pertaining to stool banking. During a working group meeting in the United European Gastroenterology Week 2019 in Barcelona, these concepts were discussed and finalised to be included in our overall guidance document about faecal microbiota transplantation. RESULTS: A guidance document for all domains pertaining to stool banking was created. This document includes standard operating manuals for several processes involved with stool banking, such as handling of donor material, storage and donor screening. CONCLUSION: The implementation of faecal microbiota transplantation by stool banks in concordance with our guidance document will enable quality assurance and guarantee the availability of donor faeces preparations for patients.