Levels of 6-thioguanine nucleotides and clinical remission in inflammatory bowel disease – A systematic review and meta-analysis
M.M. Estevinho1,, , J. Afonso1, I. Rosa2, P. Lago3, E. Trindade4, L. Correia5, C.C. Dias6, F. Magro1,7, on behalf GEDII (Portuguese IBD Group)
1 Department of Pharmacology and Therapeutics, Faculty of Medicine of the University of Porto, Portugal
2 Gastroenterology Department, Instituto Português de Oncologia de Lisboa, Lisboa, Portugal
3 Gastroenterology Department, Centro Hospitalar do Porto, Porto, Portugal
4 Department of Pediatrics, Centro Hospitalar São João, Porto, Portugal
5 Department of Gastroenterology and Hepatology, Hospital de Santa Maria, University of Lisbon, Lisbon, Portugal
6 Department of Community Medicine, Information and Decision in Health, Faculty of Medicine of the University of Porto, Portugal; CINTESIS - Centre for Health Technology and Services Research, Porto, Portugal
7 Department of Gastroenterology, Faculty of Medicine, Centro Hospitalar São João, Porto, Portugal

Aim: This systematic review and meta-analysis aimed i) to assess the clinical value of 6-thioguanine nucleotides (6-TGN) thresholds (200, 225, 230, 235, 250 and 260pmol/8×108 RBC); and ii) to compare mean 6-TGN concentrations between patients with active disease and those achieving remission.

Introduction: Thiopurines are widely used as immunosuppressive drugs in the management of inflammatory bowel disease even though their minimum effective dose and dose–response relationship remain controversial. In addition, the monitoring of thiopurines’ pharmacological active metabolites is currently reserved for particular cases namely in refractory patients or when non-compliance or toxicity is suspected.

Methods: Literature search was carried out following PRISMA and Cochrane Collaboration Guidelines and four databases were used (PubMed, Web of Science, ScienceDirect and the Cochrane Central Register of Controlled Trials). Statistical heterogeneity was assessed using the I2 statistic followed by subgroup and sensitivity analyses. Odds ratios (ORs) were computed under the random effects model.

Results: The systematic search identified 1384 records of which 25 matched the inclusion criteria and were retained for further analysis. From these, 22 were used in the cut-off comparisons while 12 were used in the 6-TGN mean differences analysis. The global OR for remission in patients with 6-TGN concentrations above the predefined thresholds was 3.95 (95%CI, 2.63–5.94; p<0.001). When considering each of the six thresholds individually, the OR was significant for levels above 235pmol/8×108 RBC (OR=2.25) and 250pmol/8×108 (OR=4.71). Mean 6-TGN levels were significantly superior among patients achieving clinical remission, with a pooled difference of 63.37pmol/8×108 RBC (95%CI, 31.81-94.93; p<0.001).

Conclusion: These results reinforce that 6-TGN levels are related to clinical remission and give an insight into the thresholds that may be used to guide clinical decisions.

Acknowledgements: This work was supported by the Portuguese Group of Studies in Inflammatory Bowel Disease (GEDII).

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