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.

[Break the taboos on alcohol abstinence: is it time for the #StopSoberShaming initiative in the Netherlands?] / Haal alcoholonthouding uit de taboesfeer.

The consumption of alcohol is an important part of social life in the Netherlands. Excessive consumption of alcohol can lead to harmful health effects and significant costs for society. The consumption of alcohol has decreased the last couple of years in the Netherlands due to governmental policies and more awareness on the harmful effects of alcohol. Unfortunately, there is still a social stigma on the abstinence of alcohol consumption, which can lead to sober shaming. In this article, we highlight the stigma that exists around alcohol abstinence, and the importance of awareness around this subject. Is it time for the #StopSoberShaming initiative in the Netherlands?

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.

The association between radiological spreading pattern and clinical outcomes in necrotizing external otitis.

Objectives: Necrotizing external otitis (NEO) is a rare infectious disease of the skull base. The purpose of this study was to determine whether clinical outcomes of NEO can be correlated to different infectious spread patterns. Methods: Retrospective chart review from 2010 to 2019 with NEO patients, who were divided into two cohorts: single spreading patterns (group A) or complex spreading patterns (group B) as diagnosed by CT. Clinical symptoms, diagnostic and treatment delay, course of disease, complications, and duration of antibiotic exposure were retrospectively collected from patient records. Results: 41 NEO patients were included, of which 27 patients belonged to group A (66%). The disease-related mortality rate was 12.2% among the entire cohort, no differences were found between group A and B. Higher rates of N.VII (42.9% vs 14.8% P = 0.047) and N. IX palsies were found in group B compared to group A (28.6% vs 3.7%, P = 0.039). The median duration of antibiotic use was significantly different for a complex spreading pattern, clinical recovery and hospitalizations. Complications were associated with higher diagnostic delay and with a complex spread pattern. The median duration of follow-up was 12.0 (IQR 6.0-19.5) months. Conclusion: NEO is a severe disease, with significant mortality and morbidity (cranial nerve palsies). The radiological spread pattern may assist in predicting clinical outcome. Furthermore, complex spread patterns are associated with higher rates of clinical nerve palsies (N. VII and N.IX), complications, surgery rates and longer duration of antibiotic use. Diagnostic delay was associated with mortality, complications and facial palsies. Level of evidence: Level IV.

Sigmoid Volvulus in Myotonic Dystrophy Type I (Steinert Disease).

Myotonic dystrophy (MD) is a progressive multisystem genetic disorder that is characterized by progressive muscle weakness and wasting. MD1 (also known as Steinert disease) is associated with various clinical entities such as skeletal muscle weakness, myotonia, cardiac abnormalities, respiratory dysfunction, gastrointestinal involvement, and cognitive impairment. In this case report, we present a 32-year-old woman with MD1 who presented with a sigmoid volvulus, which was treated with endoscopic decompression.

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.

Management of tympanic membrane retractions: a systematic review.

IMPORTANCE: Tympanic membrane retraction (TMR) is a relatively common otological finding. However, no consensus on its management exists. We are looking especially for a treatment strategy in the military population who are unable to attend frequent follow-up visits, and who experience relatively more barotrauma at great heights and depths and easily suffer from otitis externa from less hygienic circumstances. OBJECTIVE: To assess and summarize the available evidence for the effectiveness of surgical interventions and watchful waiting policy in patients with a tympanic membrane retraction. EVIDENCE REVIEW: The protocol for this systematic review was published at Prospero (207859). PubMed, Embase, and the Cochrane Database of Systematic Reviews were systematically searched from inception up to September 2020 for published and unpublished studies. We included randomized trials and observational studies that investigated surgical interventions (tympanoplasty, ventilation tube insertion) and wait-and-see policy. The primary outcomes of this study were clinical remission of the tympanic membrane retraction, tympanic membrane perforations and cholesteatoma development. FINDINGS: In total, 27 studies were included, consisting of 1566 patients with TMRs. We included data from 2 randomized controlled trials (76 patients) and 25 observational studies (1490 patients). Seven studies (329 patients) investigated excision of the TMR with and without ventilation tube placement, 3 studies (207 patients) investigated the wait-and-see policy and 17 studies (1030 patients) investigated tympanoplasty for the treatment of TMRs. CONCLUSIONS AND RELEVANCE: This study provides all the studies that have been published on the surgical management and wait-and-policy for tympanic membrane retractions. No high level of evidence comparative studies has been performed. The evidence for the management of tympanic membrane retractions is heterogenous and depends on many factors such as the patient population, location and severity of the TMR and presence of other ear pathologies (e.g., perforation, risk of cholesteatoma and serous otitis media).

Intramuscular corticosteroid injections in seasonal allergic rhinitis: A systematic review.

OBJECTIVE: Seasonal allergic rhinitis (SAR) is an exaggerated immunological reaction to allergens (pollen) in the air. In a small subgroup of patients, SAR can be difficult to control with first-line therapy. Intramuscular corticosteroid injections (IMCIs) are an additional treatment in this subgroup of SAR patients. The aim of this systematic review is to investigate the efficacy and safety of IMCIs in SAR. METHODS: Titles and abstracts were independently screened, followed by full-text screening based on predefined criteria. Included articles were critically appraised using the Cochrane Risk of Bias 2 (RoB 2) tool. The primary outcome is reported as the final conclusion about efficacy that was stated in the included studies. The secondary outcome is the safety of IMCIs with regard to long lasting side-effects. RESULTS: The search yielded 2139 records, of which 10 were relevant and valid for our clinical question. Critical appraisal showed high risk of bias, which was due to unclear description of methods. Four out of four placebo-controlled, randomized controlled trials reported a significant and relevant difference in efficacy in favor of IMCIs compared with placebo. The occurrence of side-effects was not different between IMCIs and placebo or oral corticosteroids (OCs). CONCLUSION: The outcome of this systematic review on trials concerning intramuscular steroid injections, despite being based on individual studies claiming favorable outcome with their use, is "inconclusive." This is because of the epidemiological high risk of bias in these studies that were mostly executed more than 30 years ago. The "inconclusive" rating allows for a description as an "optional therapy" for severe cases in guideline formation.

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.

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.

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.

The Natural Course of Tympanic Membrane Retractions in the Posterosuperior Quadrant of Pars Tensa: A Watchful Waiting Policy.

INTRODUCTION: Tympanic membrane retraction (TMR) is a relatively common otologic finding. Currently, there is no consensus on the optimal treatment of TMR. Some ENT-surgeons advocate surgical correction while others opt for a watchful-waiting policy. Our aim was to investigate the natural course of retraction pockets in the posterosuperior quadrant of the pars tensa in a large cohort of patients. METHODS: An observational retrospective cohort study was conducted including patients of all ages with a posterosuperior pars tensa retraction. Primary outcome measure was difference between audiometry at first and last visits. Secondary outcomes were patients' complaints, otoscopic outcomes (Sade classification), and complications (perforation, ossicular chain damage, and/or cholesteatoma). RESULTS: A total of 71 patients with 81 ears and a median age of 23 years (IQR 14-47) were included. The median duration of follow-up was 64 months (IQR 44-102). The mean air-bone gap at first and last visits was 17.9 dB (SD 11.3) and 15.5 dB (SD 12.9), respectively, with a mean improvement of 2.4 dB (p = 0.08). In 10 ears (12%) the hearing level (air-bone gap) deteriorated with 10 dB or more. Patients who presented with a TMR Sade grade I at first visit had significantly better audiometric outcomes than patients presenting with Sade grade III (p = 0.001). Progression to cholesteatoma occurred in one patient (1%), progression to perforation occurred in five patients (6%), and progression to ossicular chain damage occurred in five patients (6%). CONCLUSIONS: Otoscopic findings and audiometric results remained stable in most TMRs without treatment. Additionally, audiometry did not worsen during last follow-up. Progression to cholesteatoma, perforation, or ossicular chain damage was rare. Shared decision making regarding TMRs should include a discussion of a wait-and-see policy.

Efficacy, safety and drug survival of thioguanine as maintenance treatment for inflammatory bowel disease: a retrospective multi-centre study in the United Kingdom.

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.

The continuous rediscovery and the benefit-risk ratio of thioguanine, a comprehensive review.

Introduction: In the 1950s, thioguanine (TG), a thiopurine-derivative together with azathioprine (AZA) and mercaptopurine (MP), were developed for the treatment of childhood leukemia. Over the years, the use of TG was also explored for other, mainly immune-mediated and inflammatory, diseases such as in the field of dermatology and rheumatology (e.g. psoriasis, systemic lupus erythematosus (SLE)) and gastroenterology and hepatology (e.g. inflammatory bowel diseases (IBD), autoimmune hepatitis).Areas covered: This review provides a comprehensive overview of all the clinical uses of TG and describes its mechanism of action, pharmacokinetic/pharmacodynamic features, and toxicity.Expert opinion: Thioguanine has shown beneficial clinical effects in hematological (particularly leukemia) and several immune-inflammatory diseases including psoriasis, SLE, polycythemia vera, Churg-Strauss syndrome, IBD, collagenous sprue, refractory celiac disease, and autoimmune hepatitis. Thioguanine is not effective in treating solid-cancers. At relatively low dosages, i.e. 0.2- 0.3mg/kg/day or 20 mg/day, TG has a favorable risk-benefit ratio and is a safe and effective drug in the long-term treatment of amongst other IBD patients. Thioguanine toxicity, especially myelotoxicity, and hepatotoxicity, including nodular regenerative hyperplasia (NRH) of the liver, is limited when dosed adequately. The occurrence of NRH appears dose-dependent and has been especially described during high dose TG above 40 mg/day.