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How thiopurines are used for the treatment of inflammatory bowel diseases: An Italian survey

Digestive and Liver Disease, Volume 47, Issue 2, February 2015, Pages 170–173

Abstract

Background

The ideal manner of thiopurine use in inflammatory bowel disease has not been defined. We aimed at investigating the attitudes of Italian gastroenterologists on thiopurine use.

Methods

A web-based survey was performed among 295 gastroenterologists.

Results

Overall, 70 surveys were completed. At baseline, thiopurine methyltransferase genotype and phenotype were not assessed by 87.1% and 97.1% of respondents, respectively. At treatment onset, 17.1% adopted full weight-calculated dose while 80.0% preferred escalating the dose. During treatment, 87.1% and 64.3% reduced the dose for myelo- and liver toxicity, respectively; 48.6% for increased pancreatic enzymes, 17.1% for fever, and 5.7% for arthralgia. A systematic shift from one thiopurine to the other was reported by 4.3% of respondents in case of failure, and by 5.7% for adverse effects. Forty-four gastroenterologists (62.9%) stopped thiopurine treatment after 5–7 years.

Conclusions

Several discrepancies regarding the use of thiopurines in clinical practice were found, deviating from available guidelines. A more standardised attitude is needed in clinical practice.

Keywords: Crohn's disease, Inflammatory bowel disease, Thiopurines, Ulcerative colitis.

1. Introduction

The thiopurine analogues 6-mercaptopurine (6-MP) and its prodrug, the nitroimidazole derivative azathioprine (AZA), are the most widely used immunosuppressants in inflammatory bowel diseases (IBD)[1] and [2]. They can be used virtually interchangeably with the exception of dosing [3] .

The onset of thiopurines’ full activity is slow and may take more than 3 months; also, their use may be complicated by several side effects that are either dose-independent or dose-related [2] .

It has been suggested that genetic polymorphism determination, as well as phenotypical activity assessment of enzymes involved in the thiopurine metabolism (e.g. thiopurine methyl-transferase, TPMT), may be useful in preventing possible severe side effects on bone marrow function[4], [5], [6], and [7]. Interaction with concomitant medications, such as 5-aminosalycilic acid (5-ASA) [8] and allopurinol [9] , may alter the safety and efficacy profiles of thiopurines. Monitoring of the thiopurine metabolites (i.e. 6-thioguanine nucleotides, 6-TGN, and 6-methylmercaptopurine, 6-MMP) may predict toxicity and can be useful in evaluating treatment intensity and patient's adherence to treatment[10] and [11]. In addition, switching from one thiopurine to the other in case of intolerance may be useful in re-gaining a therapeutic opportunity [12] .

However, since studies provided controversial results[13] and [14]there is no unanimous agreement on the real effectiveness of these attitudes in clinical practice.

The aim of this study was to evaluate the conducts of Italian gastroenterologists (GEs) treating IBD patients with thiopurines.

2. Methods

The survey consisted of a web-based questionnaire. Questions concerned physicians’ behaviour about drug choice, starting dose, toxicity and failure management, therapy duration. Physicians flagged the answers selected, and only in some cases an open answer was required.

An invitation to complete the survey was sent by e-mail to the 295 members of the Italian Group for Inflammatory Bowel Disease (IG-IBD); a second invitation was sent after two months.

Myelotoxicity and hepatotoxicity were evaluated as previously defined [15] .

The GraphPad Instat package software (GraphPad Software Inc., San Diego, CA, USA) was used to analyse data by means of the Fisher's exact test and Chi-square test for independence, as appropriate. The statistical tests were two-tailed and the statistical significance was set atp = 0.05.

3. Results

Seventy out of 295 GEs (23.7%) filled the questionnaire comprehensively ( Table 1 ).

Table 1 Features of responding physicians.

  n (%)
Age
 <30 years 6 (8.7)
 30–39 years 19 (27.1)
 40–49 years 19 (27.1)
 50–59 years 19 (27.1)
 >60 years 7 (10.0)
 
Affiliated hospitals
 Public, non academic 35 (50.0)
 Public, academic 24 (34.3)
 Private, non-academic 7 (10.0)
 Private, academic 4 (5.7)
 
Number of IBD patients followed
 <100 5 (7.1)
 100–499 36 (51.5)
 500–999 10 (14.3)
 1.000–1.499 12 (17.1)
 >1.500 7 (10.0)

IBD, Inflammatory Bowel Disease

3.1. Treatment modalities

Before starting therapy, 61 (87.1%) and 68 (97.1%) GEs did not perform genotype or phenotype testing for TPMT, respectively; 6 (8.6%) and 2 (2.9%) GEs tested them for research purposes.

At therapy onset, 68 (97.1%) GEs chose AZA. Informed consent to treatment was obtained orally by 54 (77.1%) GEs, while signing the case history was obtained by 6 (8.6%) and signing the exhaustive document by 10 (14.3%) GEs.

As far as optimal dose is concerned, for AZA 36 (51.4%) GEs used 2 mg/kg/day, whereas 34 (48.6%) used 2.5 mg/kg/day; for 6-MP, 30 (42.9%) GEs used 1 mg/kg/day, whereas 40 (57.1%) used 1.5 mg/kg/day.

Twelve (17.1%) GEs immediately adopted the full weight-calculated dose, whereas 56 (80.0%) preferred a dose-escalation strategy. Among the latter group, 20 (35.7%) started with AZA 50 mg, increasing by 25 mg every 7–14 days, while the others did not follow any scheduled strategy. Two (2.9%) GEs established dosage according to TPMT genotype.

The concomitant use of 5-ASA was considered “irrelevant” by 55 (78.6%) GEs, “to avoid” by 6 (8.6%) GEs, and “to encourage” by 9 (12.8%).

The duration of thiopurine therapy is shown in Fig. 1 .

gr1

Fig. 1 Duration of thiopurine therapy. Bars represent the percentage of respondent physicians.

3.2. During therapy

3.2.1. Treatment monitoring and toxicity management

The parameters assessed by blood tests are shown in Fig. 2 .

gr2

Fig. 2 Blood chemistry for monitoring thiopurine toxicity. Bars represent the percentage of respondent physicians. CBC, complete blood count; ALT, alanine aminotransferase AST, aspartate aminotransferase gammaGT, gamma-glutamil transpeptidase; ALP, alkaline phosphatase; BUN, blood urea nitrogen.

Fifty-five (78.6%) GEs performed tests every 15 days for the first 3 months, monthly for 3 more months, and every 3 months during treatment. Fourteen (20.0%) GEs performed tests every 7–10 days during dose adjustment and then every 2 months; one physician performed complete blood counts (CBC) every 6 months during treatment.

In case of toxicity, 4 (5.7%) GEs systematically shifted from one thiopurine to the other, whereas 9 (12.9%) did not shift.

The side effects leading to dose reduction and thiopurines shifting are listed in Table 2 .

Table 2 Management of thiopurine toxicity.

Side effect Dose reduction

n (%)
Thiopurine shift

n (%) a
Myelotoxicity 62 (88.6) 5 (8.8)
Hepatotoxicity 47 (67.1) 16 (28.1)
Increase of pancreatic enzymes 36 (51.4) 5 (8.8)
Gastrointestinal symptoms 29 (41.4) 43 (75.4)
Fever 13 (18.6) 15 (26.3)
Arthralgias 12 (17.1) 18 (31.6)
Skin manifestations 2 (3.5)

a Denominator is 57 instead of 70 (see text).

3.2.2. Management of thiopurine failure

In the absence of clinical benefit, 2 (2.9%) GEs stopped thiopurines after 3 months, 8 (11.4%) 4 months, 46 (65.7%) 6 months, 12 (17.1%) 9 months, and 2 (2.9%) after 12 months.

In case of failure, 3 (4.3%) GEs systematically shifted from one thiopurine to the other, whereas 49 (70.0%) GEs never shifted, and 18 (25.7%) decided case-by-case.

Finally, no significant associations between the attitudes towards thiopurines use and specific physicians’ features were observed (data not shown).

4. Discussion

The percentage of GEs that responded to the questionnaire (1 out of 4) is similar to other comparable surveys[16] and [17].

As already shown [15] , in Italy AZA is largely preferred to 6-MP. All physicians aimed at the recommended doses [3] : 1–1.5 mg/kg/day for 6-MP and 2–2.5 mg/kg/day for AZA; in a previous survey [17] , respectively 5% and 6% of the GEs used a target dose above these thresholds.

Before starting therapy, very few physicians performed genotype (12.9%) or phenotype (2.9%) testing for TPMT; this differs from other surveys in which the percentage was around 30–40%[16] and [17]. None of the physicians we surveyed routinely assessed 6-TGN and 6-MMP erythrocytes concentrations during therapy, in contrast to 45–55% reported by other authors[16] and [17].

Despite the suggested usefulness of pharmacogenetics and therapeutic drug monitoring (TDM) in optimizing thiopurine therapy[18] and [19], the most recent guidelines do not mention their routine use[20] and [21]. In fact, there is no consensus on their real benefit, and they are not widely adopted in clinical practice. Other factors possibly limiting their application in Italy may be non-reimbursement, limited accessibility, and length of time to obtain the test results.

Regarding concomitant therapy with 5-ASA, the Italian GEs surveyed appear to be in agreement both with authors stating the minimal clinical significance of the putative interaction between 5-ASA and TPMT [22] , and with those continuing 5-ASA therapy in patients in whom thiopurines have been started [23] .

Thiopurine therapy was started at the full weight-calculated dose by 17% of the physicians, slightly less than reported by another survey (23% for 6-MP, and 28% for AZA) [16] . Among physicians that used a dose-escalation strategy, only one third followed a previously suggested scheme [24] . Despite larger evidence from a tertiary-centre supporting the dose-escalation method [25] , there is still no agreement on how to start thiopurine therapy. Due to the inverse relationship between TPMT enzyme activity and myelotoxicity, a previous study [19] suggested to start with the full dose in patients with normal genotype or activity level, to reduce it by half in patients with heterozygous genotype or intermediate activity level, and to strongly limit (or even avoid) the use of these drugs in patients with absent or homozygous-deficient TPMT activity. However, starting with low doses only delays, but does not prevent, dose-dependent toxicity and dose-independent reactions. On the other hand, starting with the full dose could avoid further delaying the slow onset of action of these drugs. Again, the available guidelines do not provide clear and unequivocal recommendations[20] and [21].

Four out of five physicians performed blood tests with timing modalities in agreement with the previous recommendations[24], [25], and [26]. All physicians performed CBC; a proportion essentially far from the much lower percentages (57%) previously reported [27] . Importantly, no unanimous recommendations exist on the type and frequency of the blood testing that needs to be performed[28] and [29]. CBC and liver tests empirically appear to be the parameters to assess[18] and [25], but no indication exists about pancreas and nephrotoxicity monitoring. To the best of our knowledge, these are the first exhaustive data about the real-life laboratory monitoring during thiopurine therapy.

Dose reduction was performed in case of dose-dependent side effects but, quite surprisingly, also in case of dose-independent side effects, such as increased pancreatic enzymes, fever, and arthralgia.

It has been suggested that the absence of the nitroimidazole derivative could account for a possible better tolerability of 6-MP. In recent years, a number of case series and, more recently, a larger study have shown that, in patients intolerant to AZA, a potential treatment strategy consists in switching them to 6-MP [12] . However, the rates of the reported tolerances are widely variable and no clear and reliable recommendations are available[20] and [21]. In our survey, in case of toxicity around 5% of the GEs systematically shifted from one thiopurine to the other, whereas 13% did not. The switch was more frequent in case of gastrointestinal symptoms (75.4%). In case of failure 5% of the GEs systematically shifted from one thiopurine to the other, whereas 70% did not.

In case of unsatisfactory clinical improvement thiopurine withdrawal was unevenly performed. It is known that the peak of response is reached after 17 weeks of treatment [30] , but several physicians prolonged therapy, despite inefficacy, up to 9 (17%) or 12 (3%) months.

In case of efficacy 20% of the GEs stopped thiopurine therapy after 5 years and approximately 40% after 5–7 years; of interest, around 17% of the GEs systematically stopped thiopurines after 10 years. Despite the fact that the available guidelines do not provide a definite duration of therapy[20], [21], [28], [29], [30], and [31], on basis of the available evidence one can affirm that thiopurines therapy should last at least 4–5 years. The possibility of a longer duration (e.g. more than 10 years) is also contemplated [32] ; when prolonged therapy is needed, benefits and risks, such as increased rate of lymphoproliferative disorders and non-melanoma skin cancers[33] and [34], should be discussed with the individual patients.

Our survey provides interesting, exhaustive, and reliable data. Possible limitations may be represented by its nature (i.e. asking physicians what they do, does not necessarily reflect their actual clinical practice) and by the low percentage of responders, despite the latter being similar to that of previous, comparable studies.

Overall, our findings demonstrate the scarce confidence of Italian IBD specialists with thiopurines and the persisting discrepancies in their use. The available American, British, and European guidelines are lacking the relevant practical information and, in some cases, thiopurines are even disregarded as in other IBD fields[35], [36], and [37].

Unequivocal indications regarding the persisting “grey zones” in the use of thiopurines in IBD are strongly needed in order to consolidate and improve the quality of patient care. This could be done also at a national level by considering the differences of health systems and resources availability in the different countries.

Conflict of interest

None declared.

Acknowledgement

We are indebted to Diana Song for her precious help in revising the text.

References

  • [1] B.N. Brooke, D.C. Hoffmann, E.T. Swarbrick. Azathioprine for Crohn's disease. Lancet. 1969;20:612-614 Crossref
  • [2] L.J.J. Derijks, L.P.L. Gilissen, P.M. Hooymans, et al. Review article: thiopurines in inflammatory bowel disease. Alimentary Pharmacology and Therapeutics. 2006;24:715-729 Crossref
  • [3] C.A. Siegel, B.E. Sands. Review article: practical management of inflammatory bowel disease patients taking immunomodulators. Alimentary Pharmacology and Therapeutics. 2005;22:1-16 Crossref
  • [4] S. Sahasranaman, D. Howard, S. Roy. Clinical pharmacology and pharmacogenetics of thiopurines. European Journal of Clinical Pharmacology. 2008;64:753-767 Crossref
  • [5] J.P. Gisbert, F. Gomollon. Thiopurine induced myelotoxicity in patients with inflammatory bowel disease: a review. American Journal of Gastroenterology. 2008;103:1783-1800 Crossref
  • [6] L. Lennard, J.S. Lilleyman. Individualizing therapy with 6-mercaptopurine and 6-thioguanine related to the thiopurine methyltransferase genetic polymorphism. Therapeutic Drug Monitoring. 1996;18:328-334 Crossref
  • [7] A. Ansari, C. Hassan, J. Duley, et al. Thiopurine methyltransferase activity and the use of azathioprine in inflammatory bowel disease. Alimentary Pharmacology and Therapeutics. 2002;16:1743-1750 Crossref
  • [8] S. Hande, N. Wilson-Rich, A. Bousvaros, et al. 5-Aminosalicylate therapy is associated with higher 6-thioguanine levels in adults and children with inflammatory bowel disease in remission on 6-mercaptopurine or azathioprine. Inflammatory Bowel Diseases. 2006;12:251-257 Crossref
  • [9] M.P. Sparrow, S.A. Hande, S. Friedman, et al. Effect of allopurinol on clinical outcomes in inflammatory bowel disease nonresponders to azathioprine or 6-mercaptopurine. Clinical Gastroenterology and Hepatology. 2007;5:209-214 Crossref
  • [10] J. Belaiche, J.P. Desager, Y. Horsmans, et al. Therapeutic drug monitoring of azathioprine and 6-mercaptopurine metabolites in Crohn disease. Scandinavian Journal of Gastroenterology. 2001;36:71-76 Crossref
  • [11] J.P. Gisbert, Y. Gonzalez-Lama, J. Mate. Monitoring of thiopurine methyltransferase and thiopurine metabolites to optimize azathioprine therapy in inflammatory bowel disease. Gastroenterologia y Hepatologia. 2006;29:568-583
  • [12] N.A. Kennedy, E. Rhatigan, I.D.R. Arnott, et al. A trial of mercaptopurine is a safe strategy in patients with inflammatory bowel disease intolerant to azathioprine: an observational study, systematic review and meta-analysis. Alimentary Pharmacology and Therapeutics. 2013;38:1255-1266 Crossref
  • [13] J.M. Andrews, S.P.L. Travis, P.R. Gibson, et al. Systematic review: does concurrent therapy with 5-ASA and immunomodulators in inflammatory bowel disease improve outcomes?. Alimentary Pharmacology and Therapeutics. 2009;29:459-469 Crossref
  • [14] A. Ansari, M. Arenas, S.M. Greenfield, et al. Prospective evaluation of the pharmacogenetics of azathioprine in the treatment of inflammatory bowel disease. Alimentary Pharmacology and Therapeutics. 2008;28:973-983 Crossref
  • [15] S. Saibeni, T. Virgilio, R. D’Incà, et al. The use of thiopurines for the treatment of inflammatory bowel diseases in clinical practice. Digestive and Liver Disease. 2008;40:814-820 Crossref
  • [16] X. Roblin, A. Oussalah, J.B. Chevaux, et al. Use of thiopurine testing in the management of inflammatory bowel diseases in clinical practice: a worldwide survey of experts. Inflammatory Bowel Diseases. 2011;17:2480-2487 Crossref
  • [17] J.S. Yip, M. Woodward, M.T. Abreu, et al. How are azathioprine and 6-mercaptopurine dosed by gastroenterologists. Results of a survey of clinical practice. Inflammatory Bowel Diseases. 2008;14:514-518 Crossref
  • [18] L. Chouchana, C. Narjoz, P. Beaune, et al. Review article: the benefits of pharmacogenetics for improving thiopurine therapy in inflammatory bowel disease. Alimentary Pharmacology and Therapeutics. 2012;35:15-36 Crossref
  • [19] B.G. Levesque, E.V. Loftus Jr. Initiating azathioprine for Crohn's disease. Clinical Gastroenterology and Hepatology. 2012;10:460-465 Crossref
  • [20] J.P. Terdiman, C.B. Gruss, J.J. Heidelbaugh, et al. American Gastroenterological Association Institute guideline on the use of thiopurines, methotrexate, and anti-TNF-α biologic drugs for the induction and maintenance of remission in inflammatory Crohn's disease. Gastroenterology. 2013;145:1459-1463 Crossref
  • [21] A. Dignass, J.O. Lindsay, A. Sturm, et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis. Part 2: Current management. Journal of Crohn's and Colitis. 2012;6:991-1030 Crossref
  • [22] J.B. Chevaux, L. Peyrin-Biroulet, M.P. Sparrow. Optimizing thiopurine therapy in inflammatory bowel disease. Inflammatory Bowel Diseases. 2011;17:1428-1435 Crossref
  • [23] H. Mayberry, T. Moshkovska, J.F. Mayberry. Co-prescribing azathiopurine or 6-mercaptopurine and 5-aminosalicylate compounds in ulcerative colitis. Inflammatory Bowel Diseases. 2009;15:190-192 Crossref
  • [24] G.R. Lichtenstein, M.T. Abreu, R. Cohen, et al. American Gastroenterological Association Institute technical review on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology. 2006;130:940-987 Crossref
  • [25] M. Ferrante, K. Karmiris, E. Newnham, et al. Physician perspectives on unresolved issues in the use of conventional therapy in Crohn's disease: Results from an international survey and discussion programme. Journal of Crohn's and Colitis. 2012;6:116-131 Crossref
  • [26] O.H. Nielsen, J.T. Bjerrum, H. Herfarth, et al. Recent advances using immunomodulators for inflammatory bowel disease. Journal of Clinical Pharmacology. 2013;53:575-588 Crossref
  • [27] J.K. Hou, J.R. Kramer, P. Richardson, et al. Myelosuppression monitoring after immunomodulator initiation in veterans with inflammatory bowel disease: a national practice audit. Alimentary Pharmacology and Therapeutics. 2012;36:1049-1056 Crossref
  • [28] C.N. Bernstein, M. Fried, J.H. Krabshuis, et al. World Gastroenterology Organization practice guidelines for the diagnosis and management of IBD in 2010. Inflammatory Bowel Diseases. 2010;16:112-124 Crossref
  • [29] C. Mowat, A. Cole, A. Windsor, et al. Guidelines for the management of inflammatory bowel disease in adults. Gut. 2011;60:571-607 Crossref
  • [30] E. Prefontaine, J.K. MacDonald, L.R. Sutherland. Azathioprine or 6-mercaptopurine for induction of remission in Crohn's disease (Review). Cochrane Database. 2009;Issue 4 Art. No.: CD000545
  • [31] A. Dignass, G. Van Assche, J.O. Lindsay, et al. The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Current management. Journal of Crohn's and Colitis. 2010;4:28-62 Crossref
  • [32] J.P. Gisbert, F. Gomollon. Thiopurine-induced myelotoxicity in patients with inflammatory bowel disease: a review. American Journal of Gastroenterology. 2008;103:1783-1800 Crossref
  • [33] L. Beaugerie. Lymphoma the bête noire of the long-term use of thiopurines in adult and elderly patients with inflammatory bowel disease. Gastroenterology. 2013;145:927-930 Crossref
  • [34] H. Singh, Z. Nugent, A.A. Demers, et al. Increased risk of nonmelanoma skin cancers among individuals with inflammatory bowel disease. Gastroenterology. 2011;141:1612-1620 Crossref
  • [35] F.S. Velayos, L. Liu, J.D. Lewis, et al. Prevalence of colorectal cancer surveillance for ulcerative colitis in an integrated health care delivery system. Gastroenterology. 2010;139:1511-1518 Crossref
  • [36] J.H. Wagnon, D.A. Leiman, G.D. Ayers, et al. Survey of gastroenterologists’ awareness and implementation of AGA guidelines on osteoporosis in inflammatory bowel disease patients: are the guidelines being used and what are the barriers to their use. Inflammatory Bowel Diseases. 2009;15:1082-1089 Crossref
  • [37] L. Peyrin-Biroulet, A. Oussalah, T. Boucekkine, et al. TNF antagonists in the treatment of inflammatory bowel disease: results of a survey of gastroenterologists in the French region of Lorraine. Gastroenterologie Clinique et Biologique. 2009;33:23-30 Crossref

Footnotes

a Azienda Ospedaliera Guido Salvini, Ospedale di Rho, Rho, Italy

b Azienda Ospedaliera San Camillo Forlanini, Rome, Italy

c Ospedale San Giuseppe, Milan, Italy

d Azienda Ospedaliera San Filippo Neri, Rome, Italy

lowast Corresponding author at: Gastroenterology Unit, Rho Hospital, Azienda Ospedaliera Guido Salvini, Corso Europa 250, 20017 Milano, Italy. Tel.: +39 02 99430 3264; fax: +39 02 99430 3271.