P339 Assessment of DNA-thioguanine nucleotide identifies patients at risk of thiopurine-induced leukopoenia in inflammatory bowel disease

Abstract Background Thiopurine drugs plays an important role for immunosuppressive therapy in inflammatory bowel disease. The molecular mechanism of the thiopurine toxicity is primarily mediated by DNA-incorporated thioguanine nucleotides (DNA-TGN). The aim of this study was to assess the impact of DNA-TGN levels on thiopurine-induced toxicity. Methods Patients over 18 years who were diagnosed with IBD and prescribed on thiopurines from February 2019 to August 2019 were recruited. All of them were genotyped with NUDT15 R139C before the thiopurine therapy. A novel assay was established to measure levels of DNA-TGN in blood leucocytes. The DNA-TGN and 6TGN levels were correlated with clinical toxicity. Results 185 patients with Crohn’s disease and 5 patients with ulcerative colitis were included in this study. DNA-TGN and 6TGN levels could be quantified in 229 patients’ blood samples. Thiopurine-induced leukopoenia (TIL) arose in 19 individuals with the median 6TGN level of 308.0 pmol/8×108 RBC which was not significantly different from the patients without TIL (p = 0.050). However, there was a significant association between DNA-TGN levels and TIL. Patients who developed TIL were identified with a higher DNA-TGN levels compared with those who did not (p = 0.00030, 456.9 (63.3–879.2) vs. 268.9 (45.6–916.8) fmol/μg DNA). The area under the ROC curves of the continuous DNA-TGN concentration to predict TIL was 0.75 (95% CI: 0.63~0.87) and almost 84% (16/19) of the TIL could be explained based on the DNA-TGN cut-off value of 343.9 fmol/μg DNA Conclusion This study shows that quantification of DNA-TGN levels can be applied to gauge thioprine therapy and avoid TIL after pre-genotyping NUDT15 R139C in inflammatory bowel disease patients.

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A practical guide to thiopurine prescribing and monitoring in IBD

Frontline Gastroenterology ◽

10.1136/flgastro-2016-100738 ◽

2016 ◽

Vol 9 (1) ◽

pp. 10-15 ◽

Cited By ~ 21

Author(s):

Ben Warner ◽

Emma Johnston ◽

Monica Arenas-Hernandez ◽

Anthony Marinaki ◽

Peter Irving ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Clinical Practice ◽

Bowel Disease ◽

Practical Guide ◽

Thiopurine Therapy ◽

Thioguanine Nucleotide ◽

Inflammatory Bowel

Thiopurines are often the mainstay of treatment for many patients with inflammatory bowel disease. As such, a general understanding of the evidence behind their use and of their metabolism is extremely useful in clinical practice. This review gives a practical overview of thiopurine metabolism, the importance of thiopurine S-methyltransferase testing prior to the start of therapy and the monitoring of thioguanine nucleotide levels while on treatment, guiding a personalised approach to optimising thiopurine therapy.

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Usefulness of Measuring Thiopurine Metabolites in Children with Inflammatory Bowel Disease and Autoimmunological Hepatitis, Treated with Azathioprine

Gastroenterology Research and Practice ◽

10.1155/2021/9970019 ◽

2021 ◽

Vol 2021 ◽

pp. 1-10

Author(s):

Katarzyna Bąk-Drabik ◽

Piotr Adamczyk ◽

Justyna Duda-Wrońska ◽

Dominika Dąbrowska-Piechota ◽

Anna Jarzumbek ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Therapeutic Range ◽

Bowel Disease ◽

High Performance ◽

Thioguanine Nucleotide ◽

Patients At Risk ◽

Inflammatory Bowel ◽

The Mean ◽

Maintenance Of Remission ◽

High Doses

Introduction. Thiopurines, such as azathioprine (AZA) and 6-mercaptopurine (6-MP), are immunomodulatory agents, used for the maintenance of remission in children with inflammatory bowel disease (IBD)—Crohn’s disease (CD) and ulcerative colitis (UC), as well as with autoimmunological hepatitis (AIH). Measurements of thiopurine metabolites may allow identifying patients at risk for toxicity and nonadherence. It can also provide an explanation for the ineffectiveness of the treatment, observed in some patients. Patients and Methods. A retrospective analysis was carried out of sixty-eight patients (thirty-six patients with CD, eighteen with UC, and fourteen with AIH), treated with AZA. Thiopurine metabolites, 6-thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine (6-MMP), were assayed by high-performance liquid chromatography (HPLC), and the AZA dose was adjusted when 6-TGN concentration was known. Result. Only twenty-five (41%) children had therapeutic 6-TGN concentrations, ten (16%) subjects had suboptimal 6-TGN concentrations, and twenty-six subjects (43%) had 6-TGN concentrations above the recommended therapeutic range. 6-MMP was not above the therapeutic range in any case. Seven subjects revealed undetectable 6-TGN and 6-MMP levels, indicating nonadherence. The mean AZA dose after the 6-TGN concentration-related adjustment did not differ, in comparison to the initial dose, either in IBD or AIH groups. The mean AZA dose was lower in AIH than in IBD. The subjects with an optimal 6-TGN level presented with a higher ratio of remission (88%) than the under- or overdosed patients (60% and 69%), respectively ( Chi − square test = 3.87 , p < 0.05 ). Conclusion. Timely measurements of thiopurine metabolites can be a useful tool to identify nonadherent patients before a decision is taken to switch to another drug. We may also spot the patients who receive either too low or too high doses, compensating dose deviations in an appropriate way. The patients with optimal 6-TGN levels presented a higher percentage of remission than the under- or overdosed patients. In most patients, both initial and adjusted AZA doses, lower than suggested in guidelines, appeared to be sufficient to maintain remission.

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The impact of introducing thioguanine nucleotide monitoring into an inflammatory bowel disease clinic

International Journal of Clinical Practice ◽

10.1111/ijcp.12039 ◽

2012 ◽

Vol 67 (2) ◽

pp. 161-169 ◽

Cited By ~ 37

Author(s):

M. Smith ◽

P. Blaker ◽

C. Patel ◽

A. Marinaki ◽

M. Arenas ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Disease Clinic ◽

Thioguanine Nucleotide ◽

Inflammatory Bowel ◽

The Impact

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The impact of inflammatory bowel disease on hard teeth tissues – preliminary results from POLIBD study

10.26226/morressier.59a6b34bd462b80290b5599d ◽

2017 ◽

Author(s):

Rafa Filip

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Preliminary Results ◽

Inflammatory Bowel ◽

The Impact

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Exploitation of Marine-Derived Robust Biological Molecules to Manage Inflammatory Bowel Disease

Marine Drugs ◽

10.3390/md19040196 ◽

2021 ◽

Vol 19 (4) ◽

pp. 196

Author(s):

Muhammad Bilal ◽

Leonardo Vieira Nunes ◽

Marco Thúlio Saviatto Duarte ◽

Luiz Fernando Romanholo Ferreira ◽

Renato Nery Soriano ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bioactive Compounds ◽

Bowel Disease ◽

Clinical Translation ◽

Biologically Active ◽

Naturally Occurring ◽

Inflammatory Bowel ◽

Functional Features ◽

Biological Entities ◽

The Impact

Naturally occurring biological entities with extractable and tunable structural and functional characteristics, along with therapeutic attributes, are of supreme interest for strengthening the twenty-first-century biomedical settings. Irrespective of ongoing technological and clinical advancement, traditional medicinal practices to address and manage inflammatory bowel disease (IBD) are inefficient and the effect of the administered therapeutic cues is limited. The reasonable immune response or invasion should also be circumvented for successful clinical translation of engineered cues as highly efficient and robust bioactive entities. In this context, research is underway worldwide, and researchers have redirected or regained their interests in valorizing the naturally occurring biological entities/resources, for example, algal biome so-called “treasure of untouched or underexploited sources”. Algal biome from the marine environment is an immense source of excellence that has also been demonstrated as a source of bioactive compounds with unique chemical, structural, and functional features. Moreover, the molecular modeling and synthesis of new drugs based on marine-derived therapeutic and biological cues can show greater efficacy and specificity for the therapeutics. Herein, an effort has been made to cover the existing literature gap on the exploitation of naturally occurring biological entities/resources to address and efficiently manage IBD. Following a brief background study, a focus was given to design characteristics, performance evaluation of engineered cues, and point-of-care IBD therapeutics of diverse bioactive compounds from the algal biome. Noteworthy potentialities of marine-derived biologically active compounds have also been spotlighted to underlying the impact role of bio-active elements with the related pathways. The current review is also focused on the applied standpoint and clinical translation of marine-derived bioactive compounds. Furthermore, a detailed overview of clinical applications and future perspectives are also given in this review.

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Impact of COVID-19 on the diagnosis, assessment and management of children with inflammatory bowel disease in the UK: implications for practice

BMJ Paediatrics Open ◽

10.1136/bmjpo-2020-000786 ◽

2020 ◽

Vol 4 (1) ◽

pp. e000786

Author(s):

Abbie Maclean ◽

James J Ashton ◽

Vikki Garrick ◽

R Mark Beattie ◽

Richard Hansen

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Delayed Diagnosis ◽

High Standard ◽

Current Evidence ◽

Faecal Calprotectin ◽

Paediatric Patients ◽

Inflammatory Bowel ◽

Working Practices ◽

The Impact

The assessment and management of patients with known, or suspected, paediatric inflammatory bowel disease (PIBD) has been hugely impacted by the COVID-19 pandemic. Although current evidence of the impact of COVID-19 infection in children with PIBD has provided a degree of reassurance, there continues to be the potential for significant secondary harm caused by the changes to normal working practices and reorganisation of services.Disruption to the normal running of diagnostic and assessment procedures, such as endoscopy, has resulted in the potential for secondary harm to patients including delayed diagnosis and delay in treatment. Difficult management decisions have been made in order to minimise COVID-19 risk for this patient group while avoiding harm. Initiating and continuing immunosuppressive and biological therapies in the absence of normal surveillance and diagnostic procedures have posed many challenges.Despite this, changes to working practices, including virtual clinic appointments, home faecal calprotectin testing kits and continued intensive support from clinical nurse specialists and other members of the multidisciplinary team, have resulted in patients still receiving a high standard of care, with those who require face-to-face intervention being highlighted.These changes have the potential to revolutionise the way in which patients receive routine care in the future, with the inclusion of telemedicine increasingly attractive for stable patients. There is also the need to use lessons learnt from this pandemic to plan for a possible second wave, or future pandemics as well as implementing some permanent changes to normal working practices.In this review, we describe the diagnosis, management and direct impact of COVID-19 in paediatric patients with IBD. We summarise the guidance and describe the implemented changes, evolving evidence and the implications of this virus on paediatric patients with IBD and working practices.

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