Because patients with MP were relatively higher dosed and, therefore, probably showed higher metabolite levels, we also calculated the hazard ratio adjusted for these variables. This secondary analysis in 267 patients, with adjustment for dosage in mg/kg and week 1 6-MMPR and 6-TGN metabolite levels, showed a hazard ratio of 1.79 (95% CI, 0.82–3.92; P = 0.15).
Leukopenia (defined as a white blood cell count ≤3.0 × 109/L) was observed in 58 patients (7.6%). Eight of these patients (4 patients on AZA and 4 on MP) had a variant in TPMT and were randomized to the standard-of-care group and subsequently received the standard thiopurine dose. Leukopenia was observed in 24 patients (4.9%) treated with AZA and in 34 patients (12.5%) treated with MP, hazard ratio 2.55 (95% CI, 1.51–4.30; P < 0.001). Secondary analysis with adjustment for dosage in mg/kg and week 1 6-MMPR and 6-TGN metabolite levels showed a hazard ratio of 0.92 (95% CI, 0.28–3.05; P = 0.89). The time to development of leukopenia was not significantly different between AZA and MP (P = 0.62) (Fig. 4).
Gastrointestinal Side Effects
Gastrointestinal side effects were reported by 345 patients (45.0%), of whom 216 patients (43.7%) were treated with AZA and 129 patients (47.3%) with MP, hazard ratio 1.09 (95% CI, 0.87–1.3; P = 0.46). Median time to the occurrence of gastrointestinal side effects was 14 (range, 7–34) days. No difference was observed in the Kaplan–Meier curve between AZA and MP, P = 0.52 (Fig. 5). In the secondary analysis, the hazard ratio for AZA or MP on gastrointestinal side effects was hazard ratio 1.38 (95% CI, 0.90–2.10; P = 0.17).
Thiopurine-induced Acute Pancreatitis
In total 14 patients (1.8%), of whom 11 on AZA (2.2%) and 3 on MP (1.1%) developed a TIAP for which the initial thiopurine was stopped. Characteristics of patients with a TIAP are depicted in Table 1, Supplemental Digital Content 1, http://links.lww.com/IBD/B529. Mean time to TIAP was 20 ± 5 days, and no cases of severe (necrotizing) pancreatitis were reported. One patient with a TIAP on AZA was later switched to MP; however, this was stopped after 1 day because of fever (no laboratory measurements were performed).
Information about treatment response was available for 351 patients (45.7%), AZA (n = 242) and MP (n = 109). Baseline disease activity scores (mean ± SD) were not different for patients of whom treatment response was known or unknown (Harvey–Bradshaw index, 3.43 ± 2.88 versus 3.62 ± 3.36, P = 0.63) and (partial Mayo score, 3.74 ± 1.73 versus 3.90 ± 1.70, P = 0.50), respectively. In CD, 38 patients on AZA (26%) and 21 patients on MP (26%) achieved a reduction in the Harvey–Bradshaw index of 3 points or more, P = 0.90. In UC, a reduction in the partial Mayo score of 3 points or more was seen in 22 patients on AZA (24%) and 9 patients on MP (32%), P = 0.42. For further analysis, the response rates in CD and UC were merged to have sufficient numbers. No difference in treatment response was observed between AZA (26%) and MP (27%), odds ratio 1.12 (95% CI 0.67–1.87; P = 0.66). In this group, week 1 metabolite levels and thiopurine dose were available for 126 patients. Secondary analysis in this group with adjustment for week 1 metabolite levels and thiopurine dose did not influence the odds ratio 1.11 (95% CI, 0.44–2.88; P = 0.88).
Our data showed that in thiopurine-naive patients with IBD, the treatment discontinuation rates within the first 5 months were similar between AZA and MP users. The higher rates of signs of hepatotoxicity and leukopenia in patients taking MP are most likely explained by the relatively higher average dose and subsequent higher 6-MMPR and 6-TGN metabolite levels compared with patients with AZA, rather than by interdrug differences. Furthermore, no differences were found in treatment efficacy and gastrointestinal side effects.
The baseline characteristics were similar for the patients on AZA and MP. This excluded a preference for one of both agents in particular patient groups. Our data on dosage and metabolite levels showed that patients with MP were relatively higher dosed in mg/kg bodyweight compared with AZA users. This might well explain the higher rates of dose-dependent side effects like leukopenia and signs of hepatotoxicity with MP.31 Adjustment for the baseline differences in thiopurine dose and week 1 metabolite levels annulled these higher rates of side effects. Week 1 6-MMPR and 6-TGN levels have been shown to be promising factors to predict leukopenia and hepatotoxicity.26,27 Most side effects were seen in the first weeks of treatment initiation and often led to dose reduction or treatment discontinuation. As a consequence, steady-state week 8 metabolite levels were not available or biased because of dose reductions in these patients. For this reason, we used week 1 metabolite levels for our secondary analysis. Both drug dose and thiopurine metabolite levels were significantly higher in MP users. Because most studies showed no clear correlation between drug dose and thiopurine metabolite levels, we included both variables in the multivariate analysis.32,33
Current studies exploring the safety profile of thiopurines are mostly limited by the inclusion of patients only taking AZA or MP.15,16,34 This problem is mainly due to global variation in the preference for either AZA or MP and is partly caused by the fact that not everywhere both drugs are registered for the treatment of IBD.13 Although not specifically designed for this purpose, some studies did compare AZA and MP in their analysis. In a recent study, a 5-fold higher rate of leukopenia was found in patients taking MP compared with AZA.14 Despite the large study population of almost 4000 patients, the lack of detailed information on the dosage and metabolite levels precluded detailed dose-related analysis as in our study. The incidence of hepatotoxicity in the current study was 15.8%, which is within the range of the highly variable incidence reported in previous studies.9,35 This wide range (4%–17%) is probably the result of differences in study protocols and definitions of drug-induced liver toxicity.35 The frequent routine laboratory controls in the TOPIC trial in combination with our criteria for hepatotoxicity and the fact that in the TOPIC trial patients started with the full regular dose probably contributed to the high rate found in our study. Present criteria for drug-induced liver toxicity include an increase of ALT or AST 5 times the ULN.36 Only 11 patients in our study would meet these criteria, yet most of the patients with liver test abnormalities between 2 and 5 times the ULN received a dose reduction or the treatment was (temporarily) discontinued. Given the clinical relevance, we applied the more liberal criteria formulated by Benichou.29 There are many factors involved in the development of thiopurine-induced hepatotoxicity, including thiopurine dose, bodyweight, sex, and age.27
In the TOPIC trial, patients were randomized for dose adjustment based on their TPMT genotype versus standard dosing. This resulted in a group of patients with a heterozygous variant in TPMT treated with the standard dose as well as a group who received 50% of the standard dose. Table 2, Supplemental Digital Content 2, http://links.lww.com/IBD/B530 provides detailed information about side-effect rates for these different groups. Absolute numbers are low, which precludes additional analyses to compare AZA with MP within these subgroups. However, taking the small groups into account, no large differences were seen between AZA and MP with respect to hepatotoxicity, leukopenia, and gastrointestinal side effects.
As mentioned above, our results show that when official clinical guidelines are applied, MP is prescribed in a relatively higher dose than AZA. This finding has been described previously in a large retrospective analysis, where patients with AZA received 1.94 mg/kg (0.93 mg/kg after conversion by 2.08) and MP was dosed at around 1.20 mg/kg.8 A reason might be that the only available pharmaceutical dosage form of MP is 50 mg, whereas for AZA, there are 25 and 50 mg tablets available in Europe. Introduction of 25 mg tablets of MP (and AZA, if not yet available) would allow more accurate dosing and will circumvent the need of scoring tablets to acquire the optimal tailored dose. In addition, given that the absolute dosage is lower in MP, increasing the dose with 25 or 50 mg leads to a larger effect in terms of percentages in a patient on MP compared with a patient taking AZA. Another explanation might be that in clinical practice, a more convenient conversion rate of 2.0 is used instead of 2.08 to calculate the AZA dose from the equivalent MP dose.28 Current guidelines recommend AZA in a dose between 2.0 and 2.5 mg/kg and MP between 1.0 and 1.5 mg/kg; however, when the 2.08 rate is applied to the recommended AZA dose, MP should actually be dosed between 0.96 and 1.20 mg/kg.6,37,38 The equal discontinuation rates, despite more dose-dependent side effects with MP, can be explained by the higher rate of dose reductions applied in patients treated with MP. This advocates for a slightly lower starting dose of MP.
In the TOPIC trial, a high rate (38.9%) of treatment discontinuation was observed within the first 5 months, primarily because of side effects. This rate is in line with previous studies which reported discontinuation rates of approximately 30% within the first months.8,39 The high discontinuation rate underlines the potential impact of thiopurine-induced adverse events. As expected, gastrointestinal side effects were the most frequently reported adverse event and occurred in approximately 50% of the patients. Our data corroborate with a recent study in almost 4000 patients with IBD on thiopurine therapy, which also found similar rates of gastrointestinal side effects in patients treated with AZA and MP.14 Some studies have shown the gain of switching from AZA to MP in the presence of adverse events.24 Although some patients were rechallenged after discontinuing the initial thiopurine, no detailed information was available to report on success rates of this switch.
TIAP is considered to be a non–dose-dependent adverse reaction linked with single nucleotide polymorphisms in the class II human leukocyte antigen region but also with blood group B.40,41 This makes a difference between AZA and MP in frequency unlikely. Our results showed a higher rate of TIAP in AZA compared with MP; however, given the low number of cases, we had insufficient power to perform statistic analysis.
This study provides novel insights into the comparability of AZA and MP as a result of some exclusive characteristics. First, this study focused on the comparison of AZA and MP, which was possible because of the large number of thiopurine-naive patients assigned to AZA and MP. In addition, the similarity of the baseline characteristics does not suggest selection bias.
Limitations of this study are that the current analyses were not prespecified in the original study protocol. Furthermore, week 1 metabolite levels used for the secondary analysis were only available for 267 patients.26 Importantly, there were no differences in baseline characteristics between the patients with known week 1 metabolite data compared with the patients without week 1 metabolite data, Table 3, Supplemental Digital Content 3, http://links.lww.com/IBD/B531. The use of week 1 metabolite levels is still limited to clinical trials. Secondary analyses with the use of week 8 metabolite levels instead of week 1 levels showed consistent results, however with less cases included, Table 4, Supplemental Digital Content 4, http://links.lww.com/IBD/B532. Furthermore, in the TOPIC trial, the Harvey-Bradshaw index and partial Mayo score were used to assess treatment efficacy. Ideally, colonoscopies should have been implemented for the assessment of mucosal healing; however, because the TOPIC trial primarily focused on safety outcomes rather than effectiveness, these were not included.25 Furthermore, thiopurines were started both for active disease and maintenance of remission, which limits the assessment of the treatment effect. Also, the use of co-medication, such as corticosteroids or biologic drugs, is an important confounder in the evaluation of treatment effects. Considering these limitations, the treatment response of 26% and 27% in AZA and MP users, respectively, is in line with the data from the SONIC trial.42,43 In the TOPIC trial, physicians were advised to start the full dose immediately, in which the recommended dose depended on the TPMT genotype and whether the patient was randomized to the intervention arm or not. Beginning with the full thiopurine dose might result in relative higher rates of side effects compared with a step-up approach (starting with half the dose and increase to full dose after 1 or 2 weeks if the drug is tolerated). With a step-up approach, the difference in dose-dependent side effects between AZA and MP might decrease because first signs of side effects already may result in a postponement of further increase to the intended dose.
In conclusion, in this study, we showed that when current clinical guidelines for IBD are followed, the patients treated with MP are relatively higher dosed, suffer from higher rates of dose-dependent side effects, and subsequently need more frequent dose reductions compared with those treated with AZA. This might be prevented when the initial MP dose is adjusted to 0.96 to 1.20 mg/kg bodyweight and 25 mg tablets MP are introduced for a more accurate tailored dose; however, feature studies are necessary to further evaluate this. Despite these differences, overall treatment discontinuation rates were equal for AZA and MP.
The authors thank the patients for participation in the study. They thank Rene H.M. te Morsche and Wilbert H.M. Peters from the Department of Gastroenterology, Radboud University Medical Center, Nijmegen, the Netherlands, for the measurement of TPMT activity. Furthermore, they thank Mariëlle Maas, Miet Fiddelaers, Milevis Reitsma, Leonie Peters, and Jean Cilissen from the Department of Clinical Pharmacy and Toxicology, Zuyderland Medical Center, Sittard-Geleen, the Netherlands for technical assistance with metabolite measurement and Debbie Heinen, Marjolein M.J. van Donkelaar, Freshteh Golestani, Marlies E. de Vos, J.G. Angelien M. Heister, Doménique M.W. Nijsten, Mascha M.V.A.P. Schijvenaars, and Martine E.C. Cranen from the Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands for their support in data management. They thank Dr. Sita H. Vermeulen and Prof. Dr. Barbara Franke for their contribution to the design of the TOPIC trial. At last, they thank Prof. Dr. Joost P.H. Drenth from the Department of Gastroenterology, Radboud University Medical Center, Nijmegen, the Netherlands, for intellectual contribution to the content of the manuscript.
The TOPIC recruitment team was responsible for patient recruitment and collection of clinical data. Compensation was given to the members of the recruitment team for additional biochemical measurements and examinations that had to be performed for the TOPIC study. TOPIC recruitment team members are as follows: Department of Gastroenterology, Academisch Ziekenhuis Maastricht, Maastricht, the Netherlands—AAM Masclee, MD, PhD; M Pierik, MD, PhD; W Mares, MD; and W Hameeteman, MD, PhD; Department of Gastroenterology, Rijnstate Ziekenhuis Arnhem, Arnhem, the Netherlands—PJ Wahab, MD, PhD and H Seinen, MD, PhD; Department of Gastroenterology, Amphia Ziekenhuis, Breda, the Netherlands—MCM Rijk, MD, PhD and IM Harkema, MD; Department of Gastroenterology, Atrium Medisch Centrum, Heerlen, the Netherlands—M de Bièvre, MD; L Oostenbrug, MD, PhD; CM Bakker, MD, PhD; M Aquarius, MD; C van Deursen, MD, PhD; AB van Nunen, MD, PhD; JG Goedhard, MD, PhD; and M Hamacher, MD; Department of Gastroenterology, Bernhoven Hospital, Oss, the Netherlands—IAM Gisbertz, MD, PhD and BJ Brenninkmeijer, MD, PhD; Department of Gastroenterology, Canisius Wilhelmina Ziekenhuis, Nijmegen, the Netherlands—ACITL Tan, MD, PhD; MN Aparicio-Pagés, MD, PhD; and EM Witteman, MD, PhD; Department of Gastroenterology, Diakonessenhuis, Utrecht, the Netherlands—SAC van Tuyl, MD and R Breumelhof, MD, PhD; Department of Gastroenterology, Catharina Ziekenhuis, Eindhoven, the Netherlands—A Stronkhorst, MD, PhD; LPL Gilissen, MD, PhD; and EJ Schoon, MD, PhD; Department of Gastroenterology, Elkerliek Ziekenhuis, Helmond, the Netherlands—JWM Tjhie-Wensing, MD and A Temmerman, MD; HagaZiekenhuis, 's-Gravenhage, the Netherlands—JJ Nicolaï, MD, PhD; Department of Gastroenterology, Gelderse Vallei Hospital, Ede, the Netherlands—JD van Bergeijk, MD, PhD; DJ Bac, MD, PhD; BJM Witteman, MD, PhD; N Mahmmod, MD; JJ Uil, MD, PhD; and H Akol, MD, PhD; Department of Gastroenterology, Ikazia Hospital, Rotterdam, the Netherlands—RJTh Ouwendijk, MD, PhD; Department of Gastroenterology, Jeroen Bosch Hospital, 's-Hertogenbosch, the Netherlands—IP van Munster, MD, PhD; M Pennings, MD; AMP De Schryver, MD, PhD; ThJM van Ditzhuijsen, MD, PhD; RCH Scheffer, MD, PhD; TEH Römkens, MD; and DL Schipper, MD, PhD; Department of Gastroenterology, Laurentius Hospital, Roermond, the Netherlands—PJ Bus, MD; Department of Gastroenterology, Máxima Medisch Centrum, Eindhoven-Veldhoven, the Netherlands—JWA Straathof, MD, PhD; ML Verhulst, MD, PhD; PJ Boekema, MD, PhD; JTh Kamphuis, MD; HJ van Wijk, MD, PhD; and JMJL Salemans, MD, PhD; Department of Gastroenterology, Meander MC, Amersfoort, the Netherlands—JR Vermeijden, MD; Department of Gastroenterology, MC Haaglanden, Den Haag, the Netherlands—SDJ van der Werf, MD, PhD and RJ Verburg MD, PhD; Department of Gastroenterology, Medisch Centrum Leeuwarden, Leeuwarden, the Netherlands—P Spoelstra, MD, PhD; JML de Vree, MD, PhD; K van der Linde, MD, PhD; HJA Jebbink, MD, PhD; M. Jansen; and H. Holwerda; Department of Gastroenterology, Medisch Spectrum Twente, Enschede, the Netherlands—N van Bentem, MD; JJ Kolkman, MD, PhD; MGVM Russel, MD, PhD; GH van Olffen, MD; MJ Kerbert-Dreteler, MD; M Bargeman, MD, PhD; JM Götz, MD, PhD; and R Schröder, MD; Department of Gastroenterology, Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands—JM Jansen, MD; Department of Gastroenterology, Orbis Medisch Centrum, Sittard-Geleen, the Netherlands—LP Bos, MD, PhD; LGJB Engels, MD, PhD; MJL Romberg-Camps, MD; and ETP Keulen, MD, PhD; Department of Gastroenterology, Radboud university medical center, Nijmegen, the Netherlands—AAJ van Esch, MD; JPH Drenth, MD, PhD; MCA van Kouwen, MD, PhD; GJA Wanten, MD, PhD; TJ Bisseling, MD, PhD; TEH Römkens, MD; and MWJ van Vugt; Department of Gastroenterology, Slingeland Hospital, Doetinchem, the Netherlands—PC van de Meeberg, MD, PhD and SJ van den Hazel, MD, PhD; Department of Gastroenterology, St Elisabeth Ziekenhuis, Tilburg, the Netherlands—WNHM Stuifbergen, MD, PhD; MJAL Grubben, MD, PhD; U de Wit, MD, PhD; GAH Dodemont, MD, PhD; and RF Eichhorn, MD; Department of Gastroenterology, Tergooiziekenhuizen, Blaricum-Hilversum, the Netherlands—JMH van den Brande, MD, PhD; AHJ Naber, MD, PhD; EJ van Soest, MD, PhD; and PJ Kingma, MD, PhD; Department of Gastroenterology, TweeSteden Ziekenhuis, Tilburg, the Netherlands—NC Talstra, MD; KF Bruin, MD, PhD; and FHJ Wolfhagen, MD, PhD; Department of Gastroenterology, University Medical Centre Leiden, Leiden, the Netherlands—DW Hommes, MD, PhD; PPJ van der Veek, MD, PhD; JCA Hardwick, MD, PhD; RJ Stuyt, MD, PhD; and HH Fidder, MD; Department of Gastroenterology, University Medical Centre Utrecht, Utrecht, the Netherlands—B Oldenburg, MD, PhD; and Department of Gastroenterology, Ziekenhuisgroep Twente, Hengelo, the Netherlands—TG Tan, MD.
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azathioprine; mercaptopurine; inflammatory bowel disease; side effects
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