Neutropenia is not required for clinical remission during azathioprine therapy in inflammatory bowel disease

Persley, Kimberly M.; Present, Daniel H.

doi:10.1097/00042737-200109000-00009

Cited by 8 publications

(5 citation statements)

References 9 publications

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“…The balance between adequate disease control and avoiding excessive bone marrow suppression is challenging. Weight-based thiopurine dosing and dosing based on monitoring blood counts are imperfect and each leaves patients at risk of over-or undertreatment (7,8). Therapeutic drug monitoring using 6-TGN can help improve efficacy and safety (9,10).…”

Section: What Is Newmentioning

confidence: 99%

Mean Corpuscular Volume to White Blood Cell Ratio for Thiopurine Monitoring in Pediatric Inflammatory Bowel Disease

Kandavel¹,

Eder²,

Newman³

et al. 2019

J. pediatr. gastroenterol. nutr.

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Objectives:Thiopurines, commonly used to treat inflammatory bowel disease, cause lymphopenia and red blood cell macrocytosis, requiring therapeutic monitoring. Mean corpuscular volume/white blood cell (MCV/WBC) ratio has been proposed as a surrogate for therapeutic monitoring. Our aim was to investigate MCV/WBC ratio for assessing clinical response to thiopurines among pediatric patients with inflammatory bowel disease.Methods:We performed a retrospective cross-sectional study at a tertiary care center using laboratory results and standardized physician global assessments (PGA) among pediatric patients taking thiopurines. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), fecal calprotectin, and 6-thioguanine nucleotides were assessed when available. The primary outcome was association between MCV/WBC ratio and clinical remission assessed by ESR, CRP, calprotectin, or PGA. We also used a composite outcome requiring all available data to be normal. Analyses were limited to 1 occurrence per patient, >60 days after starting thiopurine, and comparators were required to be within 14 days of one another.Results:A total of 471 patients met inclusion criteria. MCV/WBC ratio poorly predicted quiescent disease as defined by PGA (area under receiver operating characteristic curve [AuROC] 0.55, 95% confidence interval [CI] 0.43–0.66). MCV/WBC ratio better predicted quiescent disease defined as normal CRP (AuROC 0.64, 95% CI 0.58–0.70) or normal ESR (AuROC 0.59, 95% CI 0.52–0.66). When the composite outcome measure was used, MCV/WBC ratio had an AuROC of 0.65 (95% CI 0.59–0.70), indicating it is reasonably accurate in discriminating between clinical remission and active disease.Conclusions:MCV/WBC ratio is a noninferior, easy, and low-cost alternative to thiopurine metabolite monitoring.

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Section: What Is Newmentioning

confidence: 99%

Mean Corpuscular Volume to White Blood Cell Ratio for Thiopurine Monitoring in Pediatric Inflammatory Bowel Disease

Kandavel¹,

Eder²,

Newman³

et al. 2019

J. pediatr. gastroenterol. nutr.

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“…However, whereas these markers correlate with TGN concentrations (1,35–39), there is considerable inter‐individual variability, limiting their value in clinical practice (34,39–42). Likewise, deliberately pushing up doses of AZA until white cell counts reduce has been shown to cause toxicity (34,43–45). Interestingly, Waljee et al.…”

Section: Introductionmentioning

confidence: 99%

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

Smith

Blaker

Patel

et al. 2012

International Journal of Clinical Practice

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Summary Background: Thioguanine nucleotides (TGNs) are the active product of thiopurine metabolism. Levels have been correlated with effective clinical response. Nonetheless, the value of TGN monitoring in clinical practice is debated. We report the influence of introducing TGN monitoring into a large adult inflammatory bowel disease (IBD) clinic. Patients and methods: Patients with IBD undergoing TGN monitoring were identified from Purine Research Laboratory records. Whole blood TGNs and methylated mercaptopurine nucleotides were hydrolysed to the base and measured using HPLC. Clinical and laboratory data were obtained retrospectively. Results: One hundred and eighty‐nine patients with 608 available TGN results were identified. In non‐responders, TGNs directed treatment change in 39/53 patients. When treatment was changed as directed by TGN, 18/20 (90%) improved vs. 7/21 (33%) where the treatment decision was not TGN‐directed, p < 0.001. Where treatment change was directed at optimisation of thiopurine therapy, 14/20 achieved steroid‐free remission at 6 months vs. 3/10 where the TGN was ignored, (p = 0.037). Six per cent of patients were non‐adherent, 25% under‐dosed and 29% over‐dosed by TGN. Twelve per cent of patients predominantly methylated thiopurines, this group had low TGN levels and high risk of hepatotoxicity. In responders, adherence and dosing issues were identified and TGN‐guided dose‐reduction was possible without precipitating relapse. Mean cell volume (MCV), white blood cell count (WBC) and lymphocyte counts were not adequate surrogate markers. MCV/WBC ratio correlated with clinical response, but was less useful than TGN for guiding clinical decisions. Conclusions: Monitoring TGNs enables thiopurine therapy to be optimised and individualised, guiding effective treatment decisions and improving clinical outcomes.

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“…AZA is among the oldest immunosuppressive drugs in use today (21). Initially, it was used to produce remission in acute leukemia (22), then it was used after kidney transplantation and also to treat rheumatologic diseases, inflammatory bowel disease (23), AIH (24, 25) and other solid organ transplantations. At postoperative year 1 AZA was used by 7.8% of pediatric liver transplant recipients at an average dose of 1.4 mg/kg/day (personal communication, Study of Pediatric Liver Transplantation, 2003).…”

Section: Discussionmentioning

confidence: 99%

Utility of azathioprine metabolite measurements in post‐transplant recurrent autoimmune and immune‐mediated hepatitis

Rumbo

Shneider

Emre

2004

Pediatric Transplantation

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Patients with post-transplant immune-mediated hepatitis (IMH) and recurrent autoimmune hepatitis (RAIH) have a poor outcome and a higher need for retransplantation. Azathioprine (AZA) is used as adjunctive immunosuppression after transplantation; optimizing its dose may be a key point in preserving graft function. Complications of high AZA dosing make dose escalation potentially problematic. Our aim was to correlate AZA metabolite levels with therapeutic effects, toxicity, and adherence to medication in children with IMH and RAIH. Charts of 14 patients were retrospectively reviewed. The post-transplant diagnosis was based on liver biopsy and autoimmune markers. AZA was prescribed after establishing the post-transplant diagnosis. AZA was started at 1.1 (1.0-1.8) mg/kg/day. Routine biochemical studies, tacrolimus levels, 6-thioguanine (6-TG) and 6-methylmercaptopurine levels were assessed every 8 wk. AZA dose was routinely adjusted to achieve 6-TG levels between 235 and 450 pmol per 8 x 10(8) RBC. A total of 92 samples from 14 patients were reviewed. Four patients were excluded because of non-adherence. AZA dose was increased by 245% resulting in eight of 10 patients in the target range; no hepatic or bone marrow toxicity was observed. ALT levels and steroid requirements were significantly reduced (p < 0.05). The AZA dose required to achieve target 6-TG levels was significantly greater in children <10 yr. AZA metabolite testing in children post-liver transplant is useful in assessing adherence to medication and it is potentially helpful in optimizing medication dosing. In younger children the AZA dose requirements were two to four times higher than previously reported standard doses.

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Neutropenia is not required for clinical remission during azathioprine therapy in inflammatory bowel disease

Cited by 8 publications

References 9 publications

Mean Corpuscular Volume to White Blood Cell Ratio for Thiopurine Monitoring in Pediatric Inflammatory Bowel Disease

Mean Corpuscular Volume to White Blood Cell Ratio for Thiopurine Monitoring in Pediatric Inflammatory Bowel Disease

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

Utility of azathioprine metabolite measurements in post‐transplant recurrent autoimmune and immune‐mediated hepatitis

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