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BMC Neurology
Published in: BMC Neurology 1/2017

Open Access 01-12-2017 | Research article

Relationship between Azathioprine metabolites and therapeutic efficacy in Chinese patients with neuromyelitis optica spectrum disorders

Authors: Xindi Li, Shenghui Mei, Xiaoqing Gong, Heng Zhou, Li Yang, Anna Zhou, Yonghong Liu, Xingang Li, Zhigang Zhao, Xinghu Zhang

Published in: BMC Neurology | Issue 1/2017

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Abstract

Background

Neuromyelitis optica spectrum disorders (NMOSD) are demyelinating autoimmune diseases in the central nervous system (CNS) that are characterized by a high relapse rate and the presence of anti-aquaporin 4 antibodies (AQP4-IgG) in the serum. Azathioprine (AZA) is a first-line immunomodulatory drug that is widely used for the treatment of patients with NMOSD. However, the efficacy and safety of AZA vary in different individuals.

Method

Thirty-two patients with NMOSD who regularly took AZA were enrolled in the study at Beijing Tiantan Hospital, Capital Medical University. The efficacy of AZA was evaluated using the expanded disability status scale (EDSS) and the annual relapse rate (ARR). The erythrocyte concentrations of AZA metabolites were detected using an LC-MS/MS method.

Results

The erythrocyte concentrations of 6-thioguanine nucleotides (6-TGNs) and 6-methylmercaptopurine nucleotides (6-MMPNs) were 202.03 ± 63.35 pmol/8*108 RBC and 1618.90 ± 1607.06 pmol/8*108 RBC, respectively. After the patients had received AZA therapy for more than one year, the EDSS score decreased from 5.21 ± 0.24 to 2.57 ± 0.33 (p < 0.0001), and the ARR decreased from 1.41 ± 0.23 to 0.36 ± 0.09 (p < 0.0001). The 6-TGN and 6-MMPN levels were significantly different between the non-relapsed and relapsed groups (p < 0.0001, p = 0.006, respectively). A higher ARR was significantly correlated with higher erythrocyte concentrations of 6-TGNs (p < 0.0001) and 6-MMPNs (p = 0.004).

Conclusion

AZA can reduce the EDSS score and ARR in NMOSD patients. Additionally, the efficacy of AZA is significantly related to the erythrocyte concentrations of 6-TGNs and 6-MMPNs. Within the safe upper limits, a higher concentration of 6-TGNs is associated with better efficacy of AZA.

Trial registration number

ISRCTN16551495, retrospectively registered on May 22, 2017.
Literature
1.
Wingerchuk DM, Banwell B, Bennett JL, Cabre P, Carroll W, Chitnis T, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015;85:177–89.CrossRefPubMedPubMedCentral
2.
Sellner J, Boggild M, Clanet M, Hintzen RQ, Illes Z, Montalban X, et al. EFNS guidelines on diagnosis and management of neuromyelitis optica. Eur J Neurol. 2010;17:1019–32.CrossRefPubMed
3.
Elsone L, Kitley J, Luppe S, Lythgoe D, Mutch K, Jacob S, et al. Long-term efficacy, tolerability and retention rate of azathioprine in 103 aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder patients: a multicentre retrospective observational study from the UK. Mult Scler. 2014;20:1533–40.CrossRefPubMed
4.
Mandler RN, Ahmed W, Dencoff JE. Devic's neuromyelitis optica: a prospective study of seven patients treated with prednisone and azathioprine. Neurology. 1998;51:1219–20.CrossRefPubMed
5.
Costanzi C, Matiello M, Lucchinetti CF, Weinshenker BG, Pittock SJ, Mandrekar J, et al. Azathioprine: tolerability, efficacy, and predictors of benefit in neuromyelitis optica. Neurology. 2011;77:659–66.CrossRefPubMed
6.
Qiu W, Kermode AG, Li R, Dai Y, Wang Y, Wang J, et al. Azathioprine plus corticosteroid treatment in Chinese patients with neuromyelitis optica. J Clin Neurosci. 2015;22:1178–82.CrossRefPubMed
7.
Amin J, Huang B, Yoon J, Shih DQ. Update 2014: advances to optimize 6-mercaptopurine and azathioprine to reduce toxicity and improve efficacy in the management of IBD. Inflamm Bowel Dis. 2015;21:445–52.CrossRefPubMed
8.
Cara CJ, Pena AS, Sans M, Rodrigo L, Guerrero-Esteo M, Hinojosa J, et al. Reviewing the mechanism of action of thiopurine drugs: towards a new paradigm in clinical practice. Med Sci Monit. 2004;10:Ra247–54.PubMed
9.
Sahasranaman S, Howard D, Roy S. Clinical pharmacology and pharmacogenetics of thiopurines. Eur J Clin Pharmacol. 2008;64:753–67.CrossRefPubMed
10.
Fung C, Vaughn DJ, Mitra N, Ciosek SL, Vardhanabhuti S, Nathanson KL, et al. Chemotherapy refractory testicular germ cell tumor is associated with a variant in armadillo repeat gene deleted in Velco-cardio-facial syndrome (ARVCF). Front Endocrinol (Lausanne). 2012;3:163.
11.
Fairchild CR, Maybaum J, Kennedy KA. Concurrent unilateral chromatid damage and DNA strand breakage in response to 6-thioguanine treatment. Biochem Pharmacol. 1986;35:3533–41.CrossRefPubMed
12.
Tiede I, Fritz G, Strand S, Poppe D, Dvorsky R, Strand D, et al. CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. J Clin Invest. 2003;111:1133–45.CrossRefPubMedPubMedCentral
13.
Burnett HF, Tanoshima R, Chandranipapongse W, Madadi P, Ito S, Ungar WJ. Testing for thiopurine methyltransferase status for safe and effective thiopurine administration: a systematic review of clinical guidance documents. Pharmacogenomics J. 2014;14:493–502.CrossRefPubMed
14.
Salavaggione OE, Wang L, Wiepert M, Yee VC, Weinshilboum RM. Thiopurine S-methyltransferase pharmacogenetics: variant allele functional and comparative genomics. Pharmacogenet Genomics. 2005;15:801–15.CrossRefPubMed
15.
Collie-Duguid ES, Pritchard SC, Powrie RH, Sludden J, Collier DA, Li T, et al. The frequency and distribution of thiopurine methyltransferase alleles in Caucasian and Asian populations. Pharmacogenetics. 1999;9:37–42.CrossRefPubMed
16.
Umamaheswaran G, Kumar DK, Adithan C. Distribution of genetic polymorphisms of genes encoding drug metabolizing enzymes & drug transporters - a review with Indian perspective. Indian J Med Res. 2014;139:27–65.PubMedPubMedCentral
17.
Gray JH, Owen RP, Giacomini KM. The concentrative nucleoside transporter family, SLC28. Pflugers Arch. 2004;447:728–34.CrossRefPubMed
18.
Errasti-Murugarren E, Molina-Arcas M, Casado FJ, Pastor-Anglada M. A splice variant of the SLC28A3 gene encodes a novel human concentrative nucleoside transporter-3 (hCNT3) protein localized in the endoplasmic reticulum. FASEB J. 2009;23:172–82.CrossRefPubMed
19.
Badagnani I, Chan W, Castro RA, Brett CM, Huang CC, Stryke D, et al. Functional analysis of genetic variants in the human concentrative nucleoside transporter 3 (CNT3; SLC28A3). Pharmacogenomics J. 2005;5:157–65.CrossRefPubMed
20.
Fotoohi AK, Lindqvist M, Peterson C, Albertioni F. Involvement of the concentrative nucleoside transporter 3 and equilibrative nucleoside transporter 2 in the resistance of T-lymphoblastic cell lines to thiopurines. Biochem Biophys Res Commun. 2006;343:208–15.CrossRefPubMed
21.
Mei S, Li X, Gong X, Li X, Yang L, Zhou H, Liu Y, Zhou A, Zhu L, Zhang X et al. LC-MS/MS analysis of erythrocyte thiopurine nucleotides and their association with genetic variants in patients with neuromyelitis optica spectrum disorders taking azathioprine. Ther Drug Monit 2016; doi: 10.​1097/​FTD.​0000000000000362​.
22.
Ketelslegers IA, Modderman PW, Vennegoor A, Killestein J, Hamann D, Hintzen RQ. Antibodies against aquaporin-4 in neuromyelitis optica: distinction between recurrent and monophasic patients. Mult Scler. 2011;17:1527–30.CrossRefPubMed
23.
Rae W, Burke G, Pinto A. A study of the utility of azathioprine metabolite testing in myasthenia gravis. J Neuroimmunol. 2016;293:82–5.CrossRefPubMed
24.
Watanabe S, Misu T, Miyazawa I, Nakashima I, Shiga Y, Fujihara K, et al. Low-dose corticosteroids reduce relapses in neuromyelitis optica: a retrospective analysis. Mult Scler. 2007;13:968–74.CrossRefPubMed
25.
Swann PF, Waters TR, Moulton DC, Xu YZ, Zheng Q, Edwards M, et al. Role of postreplicative DNA mismatch repair in the cytotoxic action of thioguanine. Science (New York, NY). 1996;273:1109–11.CrossRef
26.
Elion GB. The purine path to chemotherapy. Science (New York, NY). 1989;244:41–7.CrossRef
27.
Jasiak-Zatonska M, Kalinowska-Lyszczarz A, Michalak S, Kozubski W. The immunology of Neuromyelitis Optica-current knowledge, clinical implications, controversies and future perspectives. Int J Mol Sci. 2016;17:273.CrossRefPubMedPubMedCentral
28.
Lu HF, Shih MC, Chang YS, Chang JY, Ko YC, Chang SJ, et al. Molecular analysis of thiopurine S-methyltransferase alleles in Taiwan aborigines and Taiwanese. J Clin Pharm Ther. 2006;31:93–8.CrossRefPubMed
29.
Umamaheswaran G, Krishna Kumar D, Kayathiri D, Rajan S, Shewade DG, Dkhar SA, et al. Inter and intra-ethnic differences in the distribution of the molecular variants of TPMT, UGT1A1 and MDR1 genes in the south Indian population. Mol Biol Rep. 2012;39:6343–51.CrossRefPubMed
30.
Lowry PW, Franklin CL, Weaver AL, Pike MG, Mays DC, Tremaine WJ, et al. Measurement of thiopurine methyltransferase activity and azathioprine metabolites in patients with inflammatory bowel disease. Gut. 2001;49:665–70.CrossRefPubMedPubMedCentral
31.
Fernandez-Calotti PX, Colomer D, Pastor-Anglada M. Translocation of nucleoside analogs across the plasma membrane in hematologic malignancies. Nucleosides Nucleotides Nucleic Acids. 2011;30:1324–40.CrossRefPubMed
32.
Molina-Arcas M, Marce S, Villamor N, Huber-Ruano I, Casado FJ, Bellosillo B, et al. Equilibrative nucleoside transporter-2 (hENT2) protein expression correlates with ex vivo sensitivity to fludarabine in chronic lymphocytic leukemia (CLL) cells. Leukemia. 2005;19:64–8.PubMed
33.
Minuesa G, Purcet S, Erkizia I, Molina-Arcas M, Bofill M, Izquierdo-Useros N, et al. Expression and functionality of anti-human immunodeficiency virus and anticancer drug uptake transporters in immune cells. J Pharmacol Exp Ther. 2008;324:558–67.CrossRefPubMed
Metadata
Title
Relationship between Azathioprine metabolites and therapeutic efficacy in Chinese patients with neuromyelitis optica spectrum disorders
Authors
Xindi Li
Shenghui Mei
Xiaoqing Gong
Heng Zhou
Li Yang
Anna Zhou
Yonghong Liu
Xingang Li
Zhigang Zhao
Xinghu Zhang
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Neurology / Issue 1/2017
Electronic ISSN: 1471-2377
DOI
https://doi.org/10.1186/s12883-017-0903-5

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