Change in Hematologic Indices over Time in Pediatric Inflammatory Bowel Disease Treated with Azathioprine

Soman, Sherman; Ashok, D; Connolly, Sally; Cordell, Samantha J.; Taylor, Chris; Campbell, David I.

doi:10.2165/11539930-000000000-00000

Cited by 10 publications

(15 citation statements)

References 11 publications

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“…23 Several studies suggest that thiopurine-mediated inhibition of DNA synthesis in bone marrow precursor cells leads to megaloblastic erythropoiesis. 18,19,25,26 MCV elevation above 7 fl is reported to be an indicator of optimal 6-thioguanine nucleotide (6-TGN) levels. 19 However, our results clearly show that this value should be modified according to the NUDT15 genotype.…”

Section: Discussionmentioning

confidence: 99%

Long‐term effect of NUDT15 R139C on hematologic indices in inflammatory bowel disease patients treated with thiopurine

Akiyama

Matsuoka

Fukuda

et al. 2019

J of Gastro and Hepatol

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Background and Aim A missense variant of the nucleoside diphosphate‐linked moiety X‐type motif 15 (NUDT15) gene (R139C) predisposes Asian patients with inflammatory bowel disease (IBD) to thiopurine‐induced leukopenia. This study evaluates the long‐term effect of NUDT15 R139C heterozygosity on hematological parameters during thiopurine administration. Methods We enrolled 83 Japanese IBD patients who were on anti‐tumor necrosis factor‐α agents and had used thiopurine. NUDT15 R139C was genotyped by polymerase chain reaction. We retrospectively reviewed patient clinical charts to collect data on white blood cell (WBC) count, mean corpuscular volume (MCV), hemoglobin, and platelet count during the 24 months following thiopurine initiation. Results The included patients had either Crohn's disease (54; 65.1%) or ulcerative colitis (29; 34.9%). Genotyping of NUDT15 R139C identified 62 patients (74.7%) of genotype C/C and 21 (25.3%) of genotype C/T. The median dose of thiopurine was lower in the C/T group than in the C/C group after starting thiopurine. At 6 months, the mean WBC count of the C/T group became significantly lower than that of the C/C group (P = 0.008) and remained lower through the 24 months. The C/T group developed grade 2–4 leukopenia by 6 months, which persisted through 12–24 months. The mean MCV in the C/T group became higher than that of the C/C group after 3 months. Conclusions NUDT15 R139C heterozygosity affected the WBC count and MCV for 24 months after thiopurine administration. Our results indicate that careful monitoring of leukopenia and dose adjustment are necessary throughout treatment in IBD patients heterozygous for the NUDT15 R139C.

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Section: Discussionmentioning

confidence: 99%

Long‐term effect of NUDT15 R139C on hematologic indices in inflammatory bowel disease patients treated with thiopurine

Akiyama

Matsuoka

Fukuda

et al. 2019

J of Gastro and Hepatol

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“…This difference in RDW was seen even though all the patients with active disease were receiving immunosuppressive and anti-inflammatory drugs, which are known to suppress erythrocyte stem cells. 25 Therefore the main factor affecting the increase in RDW in those with active Behc¸et's disease is likely to be severe inflammation and oxidative stress resulting from disease activity.…”

Section: Discussionmentioning

confidence: 99%

Association between red blood cell distribution width and disease activity in patients with Behçet’s disease

et al. 2015

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Objectives: To examine associations between red blood cell distribution width (RDW) and organ involvement and disease activity in patients with Behçet's disease. Methods: Haematological and inflammatory parameters including RDW, high-sensitivity C-reactive protein (hsCRP) and erythrocyte sedimentation rate (ESR) were examined in patients with Behçet's disease and in healthy controls. Patients were divided into those with active or inactive disease. Results: Data from 236 patients with Behçet's disease (77 with active and 159 with inactive disease) and 72 controls were analysed. RDW, ESR and hsCRP were significantly higher in patients with Behçet's disease than in controls, and in those with active disease compared with inactive disease or controls. In addition, ESR and hsCRP were significantly higher in those with inactive disease than controls. No correlations were found between hsCRP, ESR and RDW. No differences were observed in RDW, ESR or hsCRP between patients with or without ocular or vascular involvement. Multivariate logistic regression analysis revealed that RDW was significantly higher in active disease compared with inactive disease. Conclusions: RDW was increased in active disease compared with inactive disease. No relationships were found between organ involvement and RDW. RDW may be a cost-effective, novel potential parameter to evaluate disease activity in Behçet's disease.

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“…Leucocyte counts, lymphocyte counts, the mean corpuscular volume of red blood cells (MCV) and change in MCV (ΔMCV) have been proxy markers of thiopurine activity in IBD, [197][198][199][200][201][202][203][204][205] and they have been under-evaluated in autoimmune hepatitis.…”

Section: Evaluation Of Surrogate Markers To Estimate Thiopurine Effectsmentioning

confidence: 99%

“…Early detection of thiopurine resistance during therapy 6-TGN levels below target in 9% of IBD 12 Thiopurine-dose escalation fails to correct and may increase 6-MMPR and hepatotoxicity 12 Increased ratio of 6-MMPR-to-6-TGN indicates skewed thiopurine metabolism in IBD 12,13 Split thiopurine doses can correct skew 13,196 Treatment failure in 7% 41 Incomplete response in 14% 186 Better rescue therapy needed 32,170 Therapeutic biomarkers needed 194 Unmet needs for early detection and treatment of nonresponse and drug intolerance justify investigations to assess skewed thiopurine metabolism and corrective regimens 35,170,171 Haematological changes as surrogate markers of thiopurine activity 6-TGNs produce megaloblastoid changes in erythroid precursors within marrow 206,207 MCV increases after 3-6 months 198,203 ΔMCV is proxy marker of thiopurine effect in IBD 198,200,[202][203][204][205] ΔMCV may detect sub-therapeutic 6-TGN level but may not ensure therapeutic levels 201,202 ΔMCV does not predict outcome in IBD 205 Unmet needs to detect onset and strength of drug effect without costly assays justifies investigations to assess ΔMCV as cue to nonresponse, delayed response and noncompliance 35,170,171 Allopurinol as adjunctive treatment Allopurinol inhibits 6-TUA formation 55 Promotes conversion of 6-MP to 6-TGNs 55 Increases thioxanthine inhibition of TPMT 55 Oxypurinol directly inhibits TPMT 55 Corrects skewed thiopurine metabolism 211,214 Effective in refractory IBD…”

Section: Investigational Opportunity Precedents Evidence and Unmet Ne...mentioning

confidence: 99%

Review article: opportunities to improve and expand thiopurine therapy for autoimmune hepatitis

Czaja

2020

Aliment Pharmacol Ther

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Background: Thiopurines in combination with glucocorticoids are used as first-line, second-line and maintenance therapies in autoimmune hepatitis and opportunities exist to improve and expand their use. Aims:To describe the metabolic pathways and key factors implicated in the efficacy and toxicity of the thiopurine drugs and to indicate the opportunities to improve outcomes by monitoring and manipulating metabolic pathways, individualising dosage and strengthening the response.Methods: English abstracts were identified in PubMed by multiple search terms. Fulllength articles were selected for review, and secondary and tertiary bibliographies were developed.Results: Thiopurine methyltransferase activity and 6-tioguanine (6-thioguanine) nucleotide levels influence drug efficacy and safety, and they can be manipulated to improve treatment response and prevent myelosuppression. Methylated thiopurine metabolites are associated with hepatotoxicity, drug intolerance and nonresponse and their production can be reduced or bypassed. Universal pre-treatment assessment of thiopurine methyltransferase activity and individualisation of dosage to manipulate metabolite thresholds could improve outcomes. Early detection of thiopurine resistance by metabolite testing, accurate estimations of drug onset and strength by surrogate markers and adjunctive use of allopurinol could improve the management of refractory disease. Dose-restricted tioguanine (thioguanine) could expand treatment options by reducing methylated metabolites, increasing the bioavailability of 6-tioguanine nucleotides and ameliorating thiopurine intolerance or resistance. Conclusions:The efficacy and safety of thiopurines in autoimmune hepatitis can be improved by investigational efforts that establish monitoring strategies that allow individualisation of dosage and prediction of outcome, increase bioavailability of the active metabolites and demonstrate superiority to alternative agents.

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Change in Hematologic Indices over Time in Pediatric Inflammatory Bowel Disease Treated with Azathioprine

Cited by 10 publications

References 11 publications

Long‐term effect of NUDT15 R139C on hematologic indices in inflammatory bowel disease patients treated with thiopurine

Long‐term effect of NUDT15 R139C on hematologic indices in inflammatory bowel disease patients treated with thiopurine

Association between red blood cell distribution width and disease activity in patients with Behçet’s disease

Review article: opportunities to improve and expand thiopurine therapy for autoimmune hepatitis

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