The role of thiopurine metabolites in inflammatory bowel disease and rheumatological disorders

Friedman, Antony; Sparrow, Miles P.

doi:10.1111/1756-185x.12204

Cited by 11 publications

(5 citation statements)

References 80 publications

(151 reference statements)

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“… 34 Doses required to achieve this were approximately 3 mg/kg/day, higher than current dosing guidelines for lupus nephritis maintenance 3 and similar to maximum dosing recommendations for other autoimmune manifestations. 35 36 This suggests that inappropriate designation of patients as AZA-refractory may be common in SLE.…”

Section: Discussionmentioning

confidence: 99%

Characteristics of azathioprine use and cessation in a longitudinal lupus cohort

2015

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ObjectiveGuidelines for azathioprine (AZA) use in systemic lupus erythematosus (SLE), including indications for initiation and cessation, are lacking. Clinical decision-making could be improved if reasons for cessation of AZA treatment were standardised.MethodsWe determined the characteristics of AZA use in a cohort of patients with SLE and evaluated reasons for AZA cessation. Patients with SLE in a single centre had longitudinal recording of disease activity (Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI)-2k), laboratory investigations and treatment from 2007 to 2012.ResultsOf 183 patients studied, 67 used AZA on at least one occasion. There was no significant difference between AZA users and non-users in age or American College of Rheumatology criteria. Compared with those not treated with AZA, patients treated with AZA had higher disease activity (time-adjusted mean SLEDAI 5.2±0.3 vs 3.8±0.3, p=0.0028) and damage (Systemic Lupus International Collaborating Clinics (SLICC)-SDI 1.6±0.3 vs 1.2±0.1, p=0.0445), and were more likely to have a positive dsDNA (p=0.0130) and receive glucocorticoids (p<0.0001). AZA therapy was ceased in 30/67 (45%) patients. The predominant reasons for cessation were treatment de-escalation 14 (47%), treatment failure 12 (40%) and toxicity 3 (10%). AZA was switched to mycophenolate mofetil (MMF) in 9/12 (75%) of treatment failures, and this choice was strongly associated with active lupus nephritis.ConclusionsAZA toxicity was uncommon, and many patients ceased therapy in the context of treatment de-escalation. However, the frequent development of active lupus nephritis requiring MMF suggests the need to distinguish refractoriness, under-treatment and non-adherence to AZA in patients with SLE. These findings suggest that future studies of AZA metabolite measurement could prove valuable in the management of SLE.

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Section: Discussionmentioning

confidence: 99%

Characteristics of azathioprine use and cessation in a longitudinal lupus cohort

2015

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“…Although thiopurines are widely used, several safety concerns remain regarding the optimal treatment regimens. Thioguanine has been proposed as an alternative to overcome such problems, as it skips the metabolic conversion to 6-MMP which is responsible for hepatotoxicity ( Bar et al, 2013 ; Frei et al, 2013 ; Friedman et al, 2014 ).…”

Section: Nucleoside Analogs In Medicinal Chemistrymentioning

confidence: 99%

Nucleoside transporter proteins as biomarkers of drug responsiveness and drug targets

Pastor‐Anglada

Pérez-Torras

2015

Front. Pharmacol.

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Nucleoside and nucleobase analogs are currently used in the treatment of solid tumors, lymphoproliferative diseases, viral infections such as hepatitis and AIDS, and some inflammatory diseases such as Crohn. Two gene families are implicated in the uptake of nucleosides and nucleoside analogs into cells, SCL28 and SLC29. The former encodes hCNT1, hCNT2, and hCNT3 proteins. They translocate nucleosides in a Na+ coupled manner with high affinity and some substrate selectivity, being hCNT1 and hCNT2 pyrimidine- and purine-preferring, respectively, and hCNT3 a broad selectivity transporter. SLC29 genes encode four members, being hENT1 and hENT2 the only two which are unequivocally implicated in the translocation of nucleosides and nucleobases (the latter mostly via hENT2) at the cell plasma membrane. Some nucleoside-derived drugs can also interact with and be translocated by members of the SLC22 gene family, particularly hOCT and hOAT proteins. Inter-individual differences in transporter function and perhaps, more importantly, altered expression associated with the disease itself might modulate the transporter profile of target cells, thereby determining drug bioavailability and action. Drug transporter pharmacology has been periodically reviewed. Thus, with this contribution we aim at providing a state-of-the-art overview of the clinical evidence generated so far supporting the concept that these membrane proteins can indeed be biomarkers suitable for diagnosis and/or prognosis. Last but not least, some of these transporter proteins can also be envisaged as drug targets, as long as they can show “transceptor” functions, in some cases related to their role as modulators of extracellular adenosine levels, thereby providing a functional link between P1 receptors and transporters.

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“…A number of studies particularly in inflammatory bowel have demonstrated a correlation between TGN levels and therapeutic efficacy. For example, a therapeutic range of 235–450 pmols/8 × 10 8 red blood cells has been proposed and optimization of azathioprine dosimetry on the basis of measuring metabolite levels has led to improved outcomes . Systematic studies correlating TGN levels with therapeutic efficacy in dermatology are limited although one study has suggested a slightly lower therapeutic threshold of 179 pmol/8 × 10 8 red blood cells .…”

Section: Pharmacogenetic Dosimetrymentioning

confidence: 99%

“…For example, a therapeutic range of 235-450 pmols/8 9 10 8 red blood cells has been proposed 22 and optimization of azathioprine dosimetry on the basis of measuring metabolite levels has led to improved outcomes. 23 Systematic studies correlating TGN levels with therapeutic efficacy in dermatology are limited although one study has suggested a slightly lower therapeutic threshold of 179 pmol/8 9 10 8 red blood cells. 24 However, our unpublished experience in individual cases suggest potential utility with measuring TGN levels particularly in patients with heterozygote TPMT activity.…”

Section: Pharmacogenetic Dosimetrymentioning

confidence: 99%

Translating translation into patient benefit for atopic eczema

et al. 2016

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SummaryThis review considers, in the context of British Skin Foundation (BSF)‐funded translational research into atopic eczema conducted in Newcastle, the complex interactions between clinical and non‐clinical scientists in both academia and industry and how this may have impacted on clinical care. However, research in individual centres does not occur in isolation and clinically relevant outcomes from collaborative research are increasingly supported through regional and national networks. This is illustrated by our trial of azathioprine in adults with atopic eczema conducted across centres in the North East of England that employed pharmacogenetic dosimetry. Correspondingly the formation of a UK Translational Network for Translational Research in Dermatology (UK TREND) has facilitated the development of a UK‐wide network to support atopic eczema projects based on an e‐Delphi prioritisation exercise.

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The role of thiopurine metabolites in inflammatory bowel disease and rheumatological disorders

Cited by 11 publications

References 80 publications

Characteristics of azathioprine use and cessation in a longitudinal lupus cohort

Characteristics of azathioprine use and cessation in a longitudinal lupus cohort

Nucleoside transporter proteins as biomarkers of drug responsiveness and drug targets

Translating translation into patient benefit for atopic eczema

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