The use of biologics and thiopurines in patients with inflammatory bowel disease has increased rapidly over the last 2 decades with both classes of drugs being used more frequently and earlier in the disease course. This vogue has come about through a realisation that for some patients Crohn's disease and ulcerative colitis are progressive diseases and that use of these therapies can sometimes prevent that progression. However, knowledge about the optimal way in which to use these drugs continues to evolve. In this paper, the evidence regarding optimal timing and dosing of thiopurines and biologics will be reviewed as will the role of thiopurine methyltransferase testing along with therapeutic drug monitoring of both thiopurines and biologics. In addition, possible future applications of biologic drug level and anti-drug antibody testing will be considered.

Keywords:
Adalimumab, Drug levels, Inflammatory bowel disease, Infliximab, Thiopurines
1.
Chaparro M, Panes J, Garcia V, Manosa M, Esteve M, Merino O, et al: Long-term durability of infliximab treatment in Crohn's disease and efficacy of dose ‘escalation' in patients losing response. J Clin Gastroenterol 2011;45:113-118.
2.
Chaparro M, Panes J, Garcia V, Merino O, Nos P, Domenech E, et al: Long-term durability of response to adalimumab in Crohn's disease. Inflamm Bowel Dis 2012;18:685-690.
3.
Irving PM, Gearry RB, Sparrow MP, Gibson PR: Review article: appropriate use of corticosteroids in Crohn's disease. Aliment Pharmacol Ther 2007;26:313-329.
4.
Gearry RB, Irving PM: Biologics for inflammatory bowel diseases in the Asia-Pacific: can we afford to use them, can we afford not to? J Gastroenterol Hepatol 2009;24:1160-1162.
5.
Taylor KM, Irving PM: Optimization of conventional therapy in patients with IBD. Nat Rev Gastroenterol Hepatol 2011;8:646-656.
6.
van der Valk ME, Mangen MJ, Leenders M, Dijkstra G, van Bodegraven AA, Fidder HH, et al: Healthcare costs of inflammatory bowel disease have shifted from hospitalisation and surgery towards anti-TNFα therapy: results from the COIN study. Gut 2014;63:72-79.
7.
Torres J, Billioud V, Sachar DB, Peyrin-Biroulet L, Colombel JF: Ulcerative colitis as a progressive disease: the forgotten evidence. Inflamm Bowel Dis 2012;18:1356-1363.
8.
Pariente B, Cosnes J, Danese S, Sandborn WJ, Lewin M, Fletcher JG, et al: Development of the Crohn's disease digestive damage score, the Lemann score. Inflamm Bowel Dis 2011;17:1415-1422.
9.
Kugathasan S, Saubermann LJ, Smith L, Kou D, Itoh J, Binion DG, et al: Mucosal T-cell immunoregulation varies in early and late inflammatory bowel disease. Gut 2007;56:1696-1705.
10.
Schreiber S, Reinisch W, Colombel JF, Sandborn WJ, Hommes DW, Robinson AM, et al: Subgroup analysis of the placebo-controlled CHARM trial: increased remission rates through 3 years for adalimumab-treated patients with early Crohn's disease. J Crohns Colitis 2013;7:213-221.
11.
D'Haens G, Baert F, van Assche G, Caenepeel P, Vergauwe P, Tuynman H, et al: Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's disease: an open randomised trial. Lancet 2008;371:660-667.
12.
Markowitz J, Grancher K, Kohn N, Lesser M, Daum F: A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn's disease. Gastroenterology 2000;119:895-902.
13.
Punati J, Markowitz J, Lerer T, Hyams J, Kugathasan S, Griffiths A, et al: Effect of early immunomodulator use in moderate to severe pediatric Crohn disease. Inflamm Bowel Dis 2008;14:949-954.
14.
Panes J, Lopez-Sanroman A, Bermejo F, Garcia-Sanchez V, Esteve M, Torres Y, et al: Early azathioprine therapy is no more effective than placebo for newly diagnosed Crohn's disease. Gastroenterology 2013;145:766- 774.e1.
15.
Cosnes J, Bourrier A, Laharie D, Nahon S, Bouhnik Y, Carbonnel F, et al: Early administration of azathioprine vs conventional management of Crohn's disease: a randomized controlled trial. Gastroenterology 2013;145:758-765.e2.
16.
Halpin SJ, Ford AC: Prevalence of symptoms meeting criteria for irritable bowel syndrome in inflammatory bowel disease: systematic review and meta-analysis. Am J Gastroenterol 2012;107:1474-1482.
17.
Colombel JF, Sandborn WJ, Reinisch W, Mantzaris GJ, Kornbluth A, Rachmilewitz D, et al: Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med 2010;362:1383-1395.
18.
Prefontaine E, Macdonald JK, Sutherland LR: Azathioprine or 6-mercaptopurine for induction of remission in Crohn's disease. Cochrane Database Syst Rev 2010;4: CD000545.
19.
Prefontaine E, Sutherland LR, Macdonald JK, Cepoiu M: Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn's disease. Cochrane Database Syst Rev 2009;1:CD000067.
20.
Timmer A, McDonald JW, Tsoulis DJ, Macdonald JK: Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev 2012;9:CD000478.
21.
Sanderson J, Ansari A, Marinaki T, Duley J: Thiopurine methyltransferase: should it be measured before commencing thiopurine drug therapy? Ann Clin Biochem 2004;41(pt 4):294-302.
22.
Kaskas BA, Louis E, Hindorf U, Schaeffeler E, Deflandre J, Graepler F, et al: Safe treatment of thiopurine S-methyltransferase deficient Crohn's disease patients with azathioprine. Gut 2003;52:140-142.
23.
Cuffari C, Dassopoulos T, Turnbough L, Thompson RE, Bayless TM: Thiopurine methyltransferase activity influences clinical response to azathioprine in inflammatory bowel disease. Clin Gastroenterol Hepatol 2004;2:410-417.
24.
Gardiner SJ, Gearry RB, Begg EJ, Zhang M, Barclay ML: Thiopurine dose in intermediate and normal metabolizers of thiopurine methyltransferase may differ three-fold. Clin Gastroenterol Hepatol 2008;6:654-660; quiz 604.
25.
Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L, van Hogezand RA, et al: Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med 1999;340:1398-1405.
26.
Targan SR, Hanauer SB, van Deventer SJ, Mayer L, Present DH, Braakman T, et al: A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's Disease cA2 Study Group. N Engl J Med 1997;337:1029-1035.
27.
Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, et al: Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet 2002;359:1541-1549.
28.
Sands BE, Anderson FH, Bernstein CN, Chey WY, Feagan BG, Fedorak RN, et al: Infliximab maintenance therapy for fistulizing Crohn's disease. N Engl J Med 2004;350:876-885.
29.
Hanauer SB, Sandborn WJ, Rutgeerts P, Fedorak RN, Lukas M, MacIntosh D, et al: Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial. Gastroenterology 2006;130:323-333; quiz 591.
30.
Colombel JF, Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Panaccione R, et al: Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Gastroenterology 2007;132:52-65.
31.
Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, et al: Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005;353:2462-2476.
32.
Reinisch W, Sandborn WJ, Hommes DW, D'Haens G, Hanauer S, Schreiber S, et al: Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial. Gut 2011;60:780-787.
33.
Sandborn WJ, van Assche G, Reinisch W, Colombel JF, D'Haens G, Wolf DC, et al: Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology 2012;142:257-265.e1-e3.
34.
Bar-yoseph H, Chowers Y, Ben-Horin S, Waterman M: Infliximab is more immunogenic and reaches lower trough levels in ulcerative colitis patients compared to Crohn's disease patients. Gastroenterology 2013;144:S-780.
35.
Dubinsky MC, Lamothe S, Yang HY, Targan SR, Sinnett D, Theoret Y, et al: Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. Gastroenterology 2000;118:705-713.
36.
Moreau A, Laporte S, Del Tedesco E, Rinaudo-Gaujous M, Phelip JM, Paul S, Roblin X: Association between thiopurines metabolites levels and clinical remission in IBD patients: an updated meta-analysis. Gastroenterology 2013;144:S-92.
37.
Smith M, Blaker P, Patel C, Marinaki A, Arenas M, Escuredo E, et al: The impact of introducing thioguanine nucleotide monitoring into an inflammatory bowel disease clinic. Int J Clin Pract 2013;67:161-169.
38.
Gearry RB, Barclay ML: Azathioprine and 6-mercaptopurine pharmacogenetics and metabolite monitoring in inflammatory bowel disease. J Gastroenterol Hepatol 2005;20:1149-1157.
39.
Gilissen LP, Derijks LJ, Bos LP, Bus PJ, Hooymans PM, Engels LG: Therapeutic drug monitoring in patients with inflammatory bowel disease and established azathioprine therapy. Clin Drug Investig 2004;24:479-486.
40.
Gearry RB, Barclay ML, Roberts RL, Harraway J, Zhang M, Pike LS, et al: Thiopurine methyltransferase and 6-thioguanine nucleotide measurement: early experience of use in clinical practice. Intern Med J 2005;35:580-585.
41.
Smith MA, Blaker P, Marinaki AM, Anderson SH, Irving PM, Sanderson JD: Optimising outcome on thiopurines in inflammatory bowel disease by co-prescription of allopurinol. J Crohns Colitis 2012;6:905-912.
42.
Sparrow MP, Hande SA, Friedman S, Cao D, Hanauer SB: Effect of allopurinol on clinical outcomes in inflammatory bowel disease nonresponders to azathioprine or 6-mercaptopurine. Clin Gastroenterol Hepatol 2007;5:209-214.
43.
Sparrow MP, Hande SA, Friedman S, Lim WC, Reddy SI, Cao D, et al: Allopurinol safely and effectively optimizes tioguanine metabolites in inflammatory bowel disease patients not responding to azathioprine and mercaptopurine. Aliment Pharmacol Ther 2005;22:441-446.
44.
Leung Y, Sparrow MP, Schwartz M, Hanauer SB: Long term efficacy and safety of allopurinol and azathioprine or 6-mercaptopurine in patients with inflammatory bowel disease. J Crohns Colitis 2009;3:162-167.
45.
Blaker PA, Arenas-Hernandez M, Smith MA, Shobowale-Bakre EA, Fairbanks L, Irving PM, et al: Mechanism of allopurinol induced TPMT inhibition. Biochem Pharmacol 2013;86:539-547.
46.
Reinshagen M, Schütz E, Armstrong VW, Behrens C, von Tirpitz C, Stallmach A, et al: 6-thioguanine nucleotide-adapted azathioprine therapy does not lead to higher remission rates than standard therapy in chronic active Crohn disease: results from a randomized, controlled, open trial. Clin Chem 2007;53:1306-1314.
47.
Haines ML, Ajlouni Y, Irving PM, Sparrow MP, Rose R, Gearry RB, et al: Clinical usefulness of therapeutic drug monitoring of thiopurines in patients with inadequately controlled inflammatory bowel disease. Inflamm Bowel Dis 2011;17:1301-1307.
48.
Wright S, Sanders DS, Lobo AJ, Lennard L: Clinical significance of azathioprine active metabolite concentrations in inflammatory bowel disease. Gut 2004;53:1123-1128.
49.
Roblin X, Serre-Debeauvais F, Phelip JM, Faucheron JL, Hardy G, Chartier A, et al: 6-tioguanine monitoring in steroid-dependent patients with inflammatory bowel diseases receiving azathioprine. Aliment Pharmacol Ther 2005;21:829-839.
50.
Gupta P, Gokhale R, Kirschner BS: 6-mercaptopurine metabolite levels in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2001;33:450-454.
51.
Hindorf U, Lyrenas E, Nilsson A, Schmiegelow K: Monitoring of long-term thiopurine therapy among adults with inflammatory bowel disease. Scand J Gastroenterol 2004;39:1105-1112.
52.
Baert F, Noman M, Vermeire S, Van Assche G, D'Haens G, Carbonez A, et al: Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. N Engl J Med 2003;348:601-608.
53.
Maser EA, Villela R, Silverberg MS, Greenberg GR: Association of trough serum infliximab to clinical outcome after scheduled maintenance treatment for Crohn's disease. Clin Gastroenterol Hepatol 2006;4:1248-1254.
54.
Roblin X, Marotte H, Rinaudo M, Del Tedesco E, Moreau A, Phelip JM, et al: Association between pharmacokinetics of adalimumab and mucosal healing in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol 2014;12:80-84.e2.
55.
Mostafa NM, Eckert D, Pradhan RS, Mensing S, Robinson A, Sandborn W, Hanauer SB, Colombel J-F, Thakkar R, Awni WM: Exposure-efficacy relationship (ER) for adalimumab during induction phase of treatment of adult patients with moderate to severe ulcerative colitis. Gastroenterology 2013;144:S-225-S-226.
56.
Reinisch W, Feagan BG, Rutgeerts PJ, Adedokun OJ, Cornillie FJ, Diamond R, Marano CW, Sandborn WJ: Infliximab concentration and clinical outcome in patients with ulcerative colitis. Gastroenterology 2012;142:S-114.
57.
Seow CH, Newman A, Irwin SP, Steinhart AH, Silverberg MS, Greenberg GR: Trough serum infliximab: a predictive factor of clinical outcome for infliximab treatment in acute ulcerative colitis. Gut 2010;59:49-54.
58.
Afif W, Loftus EV Jr, Faubion WA, Kane SV, Bruining DH, Hanson KA, et al: Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in patients with inflammatory bowel disease. Am J Gastroenterol 2010;105:1133-1139.
59.
Steenholdt C, Brynskov J, Thomsen OO, Munck LK, Fallingborg J, Christensen LA, et al: Individualised therapy is more cost-effective than dose intensification in patients with Crohn's disease who lose response to anti-TNF treatment: a randomised, controlled trial. Gut 2013, Epub ahead of print.
60.
Lee LY, Sanderson JD, Irving PM: Anti-infliximab antibodies in inflammatory bowel disease: prevalence, infusion reactions, immunosuppression and response, a meta-analysis. Eur J Gastroenterol Hepatol 2012;24:1078-1085.
61.
Ben-Horin S, Waterman M, Kopylov U, Yavzori M, Picard O, Fudim E, et al: Addition of an immunomodulator to infliximab therapy eliminates antidrug antibodies in serum and restores clinical response of patients with inflammatory bowel disease. Clin Gastroenterol Hepatol 2013;11:444-447.
62.
Vande Casteele N, Gils A, Singh S, Ohrmund L, Hauenstein S, Rutgeerts P, et al: Antibody response to infliximab and its impact on pharmacokinetics can be transient. Am J Gastroenterol 2013;108:962-971.
63.
Melmed GY, Spiegel BM, Bressler B, Cheifetz AS, Devlin SM, Harrell LE, et al: The appropriateness of concomitant immunomodulators with anti-tumor necrosis factor agents for Crohn's disease: one size does not fit all. Clin Gastroenterol Hepatol 2010;8:655-659.
64.
Panaccione R, Gosh S, Middleton S, Marquez JR, Khalif I, Flint L, van Hoogstraten H, Zheng H, Danese S, Rutgeerts PJ: Infliximab, azathioprine, or infliximab + azathioprine for treatment of moderate to severe ulcerative colitis: the UC success trial. Gastroenterology 2011;140:S-134.
65.
Louis E, Mary JY, Vernier-Massouille G, Grimaud JC, Bouhnik Y, Laharie D, et al: Maintenance of remission among patients with Crohn's disease on antimetabolite therapy after infliximab therapy is stopped. Gastroenterology 2012;142:63-70.e5; quiz e31.
66.
Baert FJ, Drobne D, Ballet V, Gils A, Vande Casteele N, Hauenstein S, Singh S, Lockton S, Rutgeerts PJ, Vermeire S: Trough levels and antidrug antibodies predict safety and success of restarting infliximab after a long drug holiday. Gastroenterology 2013;144:S-91-S-92.
67.
Vande Casteele N, Compernolle G, Ballet V, Van Assche G, Gils A, Vermeire S, Rutgeerts PJ: Results on the optimisation phase of the prospective controlled Trough Level Adapted Infliximab Treatment (TAXIT) trial. Gastroenterology 2012;142:S-211-S-212.
© 2014 S. Karger AG, Basel
2014
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.