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The use of thiopurines for the treatment of inflammatory bowel diseases in clinical practice
Available online at www.sciencedirect.com
Digestive and Liver Disease 40 (2008) 814–820
Alimentary Tract
The use of thiopurines for the treatment of inflammatory bowel diseases in clinical practice S. Saibeni a,∗ , T. Virgilio a , R. D’Inc`a b , L. Spina c , A. Bortoli d , M. Paccagnella b , M. Peli d , R. Sablich e , G. Meucci f , E. Colombo g , G. Benedetti e , C.M. Girelli h , G. Casella i , G. Grasso j , R. de Franchis a , M. Vecchi c b
a IRCCS Policlinico Hospital, Mangiagalli and Regina Elena Foundation Milan, Italy Department of Surgical and Gastroenterological Sciences, University of Padua, Padua, Italy c IRCCS Policlinico San Donato, San Donato Milanese, Italy d Rho Hospital, Rho, Italy e Hospital “S. Maria degli Angeli”, Pordenone, Italy f Valduce Hospital, Como, Italy g Hospital “G. Salvini”, Garbagnate, Italy h Busto Arsizio Hospital, Busto Arsizio, Italy i Desio Hospital, Desio, Italy j Angera Hospital, Angera, Italy
Received 30 November 2007; accepted 27 March 2008 Available online 13 May 2008
Abstract Background. Thiopurines are the most commonly used immunomodulatory drugs in inflammatory bowel diseases. Aim. To evaluate the use, the therapeutic and safety profiles of thiopurines in a large sample of IBD patients. Methods. We reviewed 3641 case histories of IBD patients. Thiopurines were prescribed in 582 patients (16.0%); the analysis was performed on the 553 (267 ulcerative colitis, 286 Crohn’s disease) with exhaustive clinical data. Results. The main indications for treatment were steroid-dependence (328/553, 59.3%) and steroid-resistance (113/553, 20.7%). Thiopurines were started when CD were younger than UC patients (p < 0.001) but earlier from diagnosis in UC than in CD patients (p = 0.003). Efficacy was defined as optimal (258/553, 46.6%), partial (108/553, 19.5%), absent (85/553, 15.4%) and not assessable (102/553, 18.4%). Efficacy was independent of disease type, location/extension or duration and age at starting. Side effects were observed in 151/553 (27.3%) patients, leading to drug discontinuation in 101 (18.3%). 15 out of the 130 (11.5%) patients who took thiopurines for more than 4 years relapsed, more frequently in CD than in UC (OR = 3.67 95% C.I. 0.98–13.69; p = 0.053). Conclusions. Thiopurines confirm their clinical usefulness and acceptable safety profile in managing complicated IBD patients. The majority of patients treated for longer than 4 years maintain response. No clinical and demographic predictive factors for efficacy and side effects were identified. © 2008 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Inflammatory bowel diseases; Therapy; Thiopurines
1. Introduction
∗ Corresponding author. Present address: Department of Internal Medicine and Hepatology, Fatebenefratelli and Oftalmico Hospital, Corso di Porta Nuova 23, 20121 Milan, Italy. Tel.: +39 0263632489; fax: +39 0263632714. E-mail address: [email protected] (S. Saibeni).
The thiopurine analogues mercaptopurine (MP) and its prodrug, the nitroimidazole derivative azathioprine (AZA), are the most widely used immunosuppressive agents in inflammatory bowel diseases (IBDs). AZA and MP are characterized by a complex metabolism in which the involved enzymes are in constant competition for
1590-8658/$30 © 2008 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2008.03.016
S. Saibeni et al. / Digestive and Liver Disease 40 (2008) 814–820
the substrate [1]; their mechanisms of action are still not fully elucidated. The main immunosuppressive effect appears to be mediated by the active metabolites 6-thioguanine nucleotides (6-TGN) by incorporation into DNA of leukocytes as fraudulent bases [2] and by induction of T-cell apoptosis [3] but additional anti-proliferative effects have been proposed [4,5]. Since the first report in the late 1960s of the past century [6], several papers investigated the role of thiopurines in IBD and the majority of data, with more or less convincing evidence, suggests that AZA is effective both in inducing and maintaining remissions of Crohn’s disease (CD) and ulcerative colitis (UC) [7], the two major forms of IBD. In clinical practice, AZA and MP are used virtually interchangeably with the exception of dosing. The onset of their full activity is slow and may take more than 3 months, and their use is complicated by several side effects which are typically considered as dose-independent or dose-related [7]. The aim of this study was to retrospectively evaluate the use, the therapeutic and the safety profiles of thiopurines in a large sample of IBD patients. Information arising from clinical practice may give a reliable measure of the effectiveness, the toxicity and acceptability of a given therapy, which may significantly differ from the data resulting from the ideal conditions created in clinical trials.
2. Materials and methods 2.1. Patients We reviewed 3641 case histories of IBD patients that were followed at the 8 participating centres; AZA or MP had been prescribed in 582 of them (16.0%). The analysis was performed on 553 patients (267 UC, 278 CD, 8 indeterminate colitis (IC)) with complete clinical and demographic data; for patients treated more than once with thiopurines we considered only the first course of therapy. The 8 IC patients were combined with patients with CD, as already suggested by other authors [8] for the purpose of clinical analysis. In most patients, blood chemistry was performed at screening, every 7–14 days for the first 3 months or during dose adjustment and then every 3 months. CD location and behaviour were defined according to the Vienna classification [9].
2.2. Thiopurines treatment The time of observation was calculated from the date of therapy initiation until the discontinuation or the last contact with the patient still taking thiopurines.
2.2.1. Indications Indications to treatment with thiopurines were defined as follows:
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• “steroid-dependence”: partial or complete clinical response to treatment with prednisone or equivalent and relapse with a dose reduction of prednisone at doses ≤15–25 mg/day for at least 6 months or relapse within 30 days of stopping prednisone treatment [10]; • “steroid-resistance”: failing to respond within 30 days to prednisone treatment at doses of 40–60 mg/day [10]; • “penetrating disease”: presence of fistulas and/or abscesses; • “post-surgery”: after surgically induced remission, as prophylactic treatment; • “extraintestinal manifestations (EIMs)”: when the main indication was represented by an extraintestinal manifestation; • “infliximab (IFX)”: when thiopurines were concomitantly prescribed in association with infliximab treatment. 2.2.2. Efficacy Efficacy of thiopurines therapy was evaluated as follows: • “optimal”, when steroids were stopped and/or no further treatment was needed over 2 years from the beginning; • “partial”, when steroids were reduced/discontinued and/or additional treatment started within 2 years from the beginning; • “absent”, when no clinical effect was observed over 6 months and/or additional treatment or surgery became necessary within 1 year from the beginning; • “not assessable”, when the available follow-up was too short (less than 6 months) [8] or side effects led to early treatment discontinuation. 2.2.3. Discontinuation Reasons for thiopurine discontinuation were classified as follows: • Side effects, long-lasting treatment (patients in remission after at least 3 years of drug), patient’s decision, inefficacy, neoplasm, infection, pregnancy. 2.2.4. Toxicity The main side effects were defined as follows: • “Myelotoxicity”: white blood cells count <3000 mm−3 and/or platelets <70,000 mm−3 and/or haemoglobin <10 g/dl. • “Liver toxicity”: transaminases and/or ␥-GT and/or ALP > 1.5 upper limit normal in at least two repeated assessments. • “Pancreatitis”: abdominal symptoms accompanied by amylase and/or lipase increase. • “Systemic toxicity”: occurrence of one of the following signs or symptoms: fever, skin rash, arthralgias, asthenia, myalgia, diarrhea, nausea, abdominal pain. • “Infection”: bacterial, viral or fungal (when requiring specific treatment and/or hospitalization and/or drug discontinuation).
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Table 1 Demographic and clinical features of IBD patients undergoing thiopurines treatment Crohn’s disease n = 286
Ulcerative colitis n = 267
Men/women 140/146 Mean age at diagnosis ± S.D.* (years) 30.7 ± 12.5
157/110 36.2 ± 14.2
Location/extension, n (%) Ileum Ileum + colon Colon Upper GI Pancolitis Left-sided colitis Procto-sigmoiditis
59 (20.6) 137 (47.9) 85 (29.7) 5 (1.7) – – –
– – – – 157 (58.8) 64 (24.0) 46 (17.2)
Behaviour, n (%) Non-stricturing, non-penetrating Penetrating Stricturing
111 (38.8) 116 (40.6) 59 (20.6)
– – –
*
Fig. 1. Indications for thiopurines therapy.
p < 0.001.
2.3. Statistical analysis GraphPad Instat package software (GraphPad Software Inc., San Diego, CA, USA) was used to analyse data by means of Student’s t-test, Mann–Whitney test, Fisher’s exact test and Chi-square test for independence, as appropriate. All the statistical tests were two-tailed and the statistical significance was set at p = 0.05.
had a twofold increased risk to undergo thiopurines therapy with respect to those with UC (OR = 2.09 95% C.I. 1.48–2.95; p < 0.0001). However, thiopurines were started significantly earlier from diagnosis in UC than in CD patients (Table 2). 130 out of 553 (23.5%) IBD patients took thiopurines for more than 4 years. 3.1. Indications Indications for treatment with thiopurines in CD and UC patients are shown in Fig. 1. 3.2. Efficacy
3. Results At participating centres, AZA was prescribed between March 1986 and September 2006 to 541 patients at a dose ranging from 1.5 to 2.5 mg(kg day)−1 , while MP was prescribed in 12 patients (8 CD, 4 UC) at a dose ranging from 1.0 to 1.5 mg(kg day)−1 . Clinical and demographic characteristics of enrolled patients are summarised in Table 1. At the beginning of the thiopurines’ therapy, CD patients were significantly younger than UC patients; in particular, in IBD patients aged less than 40 years, those with CD
Efficacy of thiopurines in CD and UC is shown in Fig. 2. We observed an overall efficacy (optimal + partial) in 366 out of 553 (66.2%) IBD patients. Efficacy was not assessable in 102 out of 553 (18.4%) patients: in 56 out of 553 (10.2%) due to too short a follow-up and in 46 out of 553 (8.3%) due to the early occurrence of side effects. No statistically significant difference was observed between CD and UC patients. We also assessed cumulative optimal and partial efficacy stratifying CD and UC patients according to clinical and demographical features (Table 3). No statistically significant
Table 2 Data about therapy starting and follow-up Crohn’s disease n = 286 Mean age at starting thiopurines ± S.D. (years) Mean time of starting from diagnosis ± S.D. (months)
38.0 ± 14.2 90.4 ± 74.6
Ulcerative colitis n = 267
p
42.3 ± 14.9 71.4 ± 76.1
<0.001 <0.003
Thiopurines starting from diagnosis, n (%) Within 12 months Between 12 and 60 months Over 60 months
63 (22.0) 90 (31.5) 133 (46.5)
72 (27.0) 99 (37.1) 96 (35.9)
0.042
Age at thiopurines starting, n (%) <40 years >40 years
192 (67.1) 94 (32.9)
132 (49.4) 135 (50.6)
<0.001
Mean duration of follow-up ± S.D. (months) Taking thiopurines for more than 4 years, n (%)
30.8 ± 32.2 72 (25.2)
28.1 ± 28.7 58 (21.7)
n.s. n.s.
S. Saibeni et al. / Digestive and Liver Disease 40 (2008) 814–820
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Fig. 4. Reasons for thiopurines discontinuation.
Fig. 2. Efficacy of thiopurines (NA, not assessable).
3.3. Discontinuation Thiopurines were withdrawn in 255 out of 553 (46.1%) patients; 298 out of 553 (53.9%) patients were still taking the drug at the time of this survey. In this latter group of patients the mean ± S.D. time of observation was 34.3 ± 32.6 months. Reasons for thiopurines discontinuation in CD and UC are shown in Fig. 4. Here we report data concerning the occurrence of side effects and spontaneous discontinuation.
Fig. 3. Disease course in patients taking thiopurines for more than 4 years (relapse CD vs. UC: p = 0.053).
difference was observed between CD and UC nor between subgroups within the single diseases. In the 130 patients who took thiopurines for more than 4 years, relapses were observed in 15 (11.5%) and more frequently in CD than in UC patients (OR = 3.67 95% C.I. 0.98–13.69; p = 0.053) (Fig. 3).
• In 101 out of 553 (18.3%) IBD patients discontinued the drug due to the occurrence of side effects, after a median of 3 months from starting (range 1–113 months). In particular, in 9 out of 553 (1.6%) patients this was due to the occurrence of infections (median 15.5 months, range 2–107): 3 CMV, 1 EBV, 1 chicken-pox, 1 measles, 1 sepsis of unknown origin, 1 osteomyelitis and 1 bacterial meningitis; all the infections but meningitis occurred in patients taking thiopurines for less than 4 years. In 5 out of 553 (0.9%) patients drug discontinuation was due to the diagnosis of neoplasm (median 52 months, range 4–94): 3 colo-rectal adenocarcinomas, 1 stomach adenocarcinoma and 1 melanoma. All colo-rectal cancers
Table 3 Optimal + partial efficacy of thiopurines according to clinical and demographical features Crohn’s disease
p
Ulcerative colitis
p
Disease duration Within 12 months Between 12 and 60 months Over 60 months
42/63 (66.7%) 58/90 (64.4%) 85/133 (63.9%)
n.s.
50/72 (69.4%) 71/99 (71.7%) 60/96 (62.5%)
n.s.
Age at thiopurines starting <40 years >40 years
122/192 (63.5%) 63/94 (67.0%)
n.s.
95/132 (72.0%) 86/135 (63.7%)
n.s.
Location/extensiona Ileum Ileum + colon Colon Pancolitis Left-sided colitis Procto-sigmoiditis
40/59 (67.8%) 87/137 (63.5%) 54/85 (63.5%) – – –
a
Upper GI excluded.
n.s. – – –
– – – 109/157 (69.4%) 40/64 (62.5%) 32/46 (69.6%)
– – – n.s.
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discontinued the drug according to the physician’s (gastroenterologist or gynaecologist) advice. One of these pregnancies was extrauterine; no adverse outcomes were observed.
4. Discussion
Fig. 5. Side effects due to thiopurines treatment.
occurred in patients with UC involving the entire colon and other known risk factors associated (disease duration >10 years or primary sclerosing cholangitis). These patients were taking thiopurines for 4, 50 and 94 months; one of them died with peritoneal carcinosis. • In 34 out of 553 (6.1%) IBD patients drug discontinuation was due to their spontaneous decision, after a median of 14 months from starting (range 1–147 months). Again, no statistically significant difference was observed between CD and UC. 3.4. Toxicity 151 out of 553 (27.3%) IBD patients experienced side effects during thiopurines’ therapy (Fig. 5). In particular, myelotoxicity was observed in 44 (7.8%) patients, after a median of 12 months from starting (range 1–154 months); liver toxicity in 30 (5.4%) patients (median 4.5 months, range 1–147); pancreatitis in 21 (3.8%) patients (median 2 months, range 1–100) and systemic toxicity in 19 (3.2%) patients (median 3 months, range 1–25). Infections were observed in 15 out of 553 (2.7%) patients, after a median of 20 months from starting (range 2–107 months). Also in this analysis, no statistically significant differences was observed between CD and UC. Reasons for discontinuation and occurrence of side effects were almost identical when we stratified CD and UC patients according to disease duration, age at treatment initiation, disease location/extension, age at diagnosis and gender (data not shown). Side effects observed in the 130 IBD patients taking thiopurines for more than 4 years were the following: myelotoxicity in 7 (5.4%), liver toxicity in 4 (3.1%), pancreatitis in 3 (2.3%), infection in 3 (2.3%) and neoplasm in 2 (1.5%). No significant difference was observed between CD and UC patients or within patients taking the drug for less than 4 years. 3.5. Pregnancy 16 (10 with CD and 6 with UC) out of 256 women (6.2%) became pregnant while receiving thiopurines and 6 of them
In this study, we assessed the use as well as the therapeutic and safety profiles of thiopurines in a large group of Italian patients affected by IBD. In our sample, which is one of the largest ever investigated by this kind of study, AZA was largely preferred to MP, in accordance with the European practice [11]. Thiopurines have been prescribed in similar percentages in UC and in CD, less frequently than in the classical observational report from Oxford [8] (16% vs. 28%) and significantly earlier from diagnosis in UC than in CD. We are aware of the methodological limitations of this kind of study. The retrospective nature makes standardized indexes to assess disease activity (and thus efficacy of the drugs) unavailable, and the lack of randomization makes the cohorts (for instance subgroups stratified for disease duration and age at diagnosis) not easily comparable. However, bearing these limitations in mind, we believe that the present study may provide a practical contribution to the issue of thiopurines utilization in IBD. Indeed, we believe that the information provided by our study represents a reliable picture of what may happen in clinical practice when a physician decides to treat an IBD patient with thiopurines. In our sample, steroid-dependence represented the most frequent indication to thiopurines treatment; overall, indications were distributed quite differently with respect to similar studies [12]. In general, no significant differences in terms of efficacy, occurrence of side effects and reasons for discontinuation were observed between CD and UC patients. However, UC patients appeared to respond even better than CD patients, as previously reported [8], especially when treated for longer than 4 years. The overall efficacy of thiopurines was observed in 2 out of 3 IBD patients; this finding is in agreement with the previous reports which were performed in clinical practice [8,13–15]. In our series, the efficacy of thiopurines appeared to be independent of clinical and demographic features of IBD patients, as previously reported by other authors [8,16,17]. The absence of a better efficacy of thiopurines when administered to younger patients and at a time closer to diagnosis provides in our opinion some argument against the systematic inversion of the traditional therapeutic pyramid proposed in adult IBD [18]. Besides the good performance in terms of clinical efficacy, we should however keep in mind that 1 out of 5 IBD patients lost the therapeutic chance represented by these drugs in a short space of time; this occurred both for the early occurrence of relevant side effects and for the concerns of the
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patients about the immunosuppressive nature of this therapy. Of interest, spontaneous discontinuation may happen very early but also after a long period of treatment; to avoid this occurrence, exhaustive and reassuring explanations on the use of these drugs and on their safety features should be provided to patients. As far as thiopurines toxicity is concerned, we observed a cumulative rate of side effects of 27.3%, and a discontinuation rate due to side effects of 18.3%. In previous studies, thiopurines discontinuation rate due to side effects varies from 5–6% [17,19] to up to 30% [8,20], but most authors reported a rate of about 20% [21–24]. The prevalence of the single side effects quite varies among the different studies, partly due to the use of non-univocal definitions. The rates of myelotoxicity (7.8%), liver toxicity (5.4%), pancreatitis (3.8%), systemic toxicity (3.2%) and infections (2.7%) observed in the present study do not significantly differ from literature data [17,19–25]. Interestly, pancreatitis, which is generally considered an idiosyncratic reaction [21], was observed up to 100 months from thiopurines initiation; this finding is not new, being already reported by Warman et al. [19]. In our sample, no drug related mortality was observed; only one patient died due to peritoneal carcinosis subsequent to colon adenocarcinoma. Moreover, no lymphoma was observed. Overall, we registered five neoplasms (1.1% of the 451 patients in whom it was possible to assess efficacy); this number is lower than that reported by other similar studies [19,21]. Three neoplasms were colonic adenocarcinoma and occurred in UC patients (1.4% of the 218 patients in whom it was possible to assess efficacy) with other known risk factors for this neoplasia; this percentage is similar to that expected in this kind of patients [26]. As a consequence, in our series thiopurines do not appear to increase the risk of developing neoplasia, in agreement with a recently published metanalysis showing no difference in the incidence of any kind of malignancy in IBD patients who received immunosuppressants compared with those who did not [27]. However, we believe that this finding ought to suggest a more radical intervention (i.e. colectomy) in those UC patients who are at increased risk of developing colo-rectal adenocarcinoma. Despite the relatively small number of pregnancies (occurring in 6.2% of the women enrolled in this study), we are quite confident about the safety of these drugs on pregnant IBD women, in agreement with the most recent evidence [28]. Over what period of time should thiopurines be given is still a matter of debate. Some authors demonstrated the lack of a therapeutic benefit beyond 4 years; they also suggested a potential increase in toxicity [29] while other authors reported a well-sustained efficacy over a period of 5 years [8]. In our series, 1 in 4 IBD patients took thiopurines for more than 4 years. In these patients, we observed a negligible loss of efficacy after 4 years of treatment, without a significant increase of side effects. We therefore agree with the studies proposing continuing the therapy in responders to thiopurines for
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at least 7 years [17] or, alternatively, allowing for a differentiated treatment algorithm according to disease activity and steroid requirement [12]. As already stated, the retrospective nature of our evaluation unavoidably implies some methodological limitations; however, we feel that the rigorous definition of events, the completeness of the assessed parameters, the adequate size of the population studied and the extended follow-up represent the strengths of the present study and provide reliability to our results. In conclusion, our study confirms the clinical usefulness and the acceptable safety profile of thiopurines in managing complicated IBD patients, even though some compliance problems may occur. No clinical or demographic factors were identified to predict the efficacy or the toxicity of thiopurines. Most of the patients treated for longer than 4 years maintained response without an increased risk of toxicity.
Practice points • Thiopurines are the most commonly used immunomodulatory drugs in the treatment of IBD. • Besides their efficacy in inducing and maintaining remissions of CD and UC, important toxicities may limit their clinical use. • No clinical or demographic factors appear to predict the efficacy or the toxicity of thiopurines. • Clinical and biochemical monitoring is mandatory in IBD patients treated with thiopurines.
Research agenda • More prospective studies are needed in order to optimize the efficacy and safety profiles of thiopurines, for example by means of geno- and phenotyping of enzymes involved in their metabolism, monitoring active and toxic metabolites and exploiting drug interactions. • Further studies are needed in order to better define the correct positioning of thiopurines in the therapeutic armamentarium of IBD (i.e. earlier utilisation vs. traditional approach). • Further efforts are needed in order to increase the patients’ compliance to treatment with thiopurines.
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Conflict of interest statement None declared.
Acknowledgement We are indebted to Ms. Kelly Lynch for her precious collaboration.
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Digestive and Liver Disease 40 (2008) 814–820
Alimentary Tract
The use of thiopurines for the treatment of inflammatory bowel diseases in clinical practice S. Saibeni a,∗ , T. Virgilio a , R. D’Inc`a b , L. Spina c , A. Bortoli d , M. Paccagnella b , M. Peli d , R. Sablich e , G. Meucci f , E. Colombo g , G. Benedetti e , C.M. Girelli h , G. Casella i , G. Grasso j , R. de Franchis a , M. Vecchi c b
a IRCCS Policlinico Hospital, Mangiagalli and Regina Elena Foundation Milan, Italy Department of Surgical and Gastroenterological Sciences, University of Padua, Padua, Italy c IRCCS Policlinico San Donato, San Donato Milanese, Italy d Rho Hospital, Rho, Italy e Hospital “S. Maria degli Angeli”, Pordenone, Italy f Valduce Hospital, Como, Italy g Hospital “G. Salvini”, Garbagnate, Italy h Busto Arsizio Hospital, Busto Arsizio, Italy i Desio Hospital, Desio, Italy j Angera Hospital, Angera, Italy
Received 30 November 2007; accepted 27 March 2008 Available online 13 May 2008
Abstract Background. Thiopurines are the most commonly used immunomodulatory drugs in inflammatory bowel diseases. Aim. To evaluate the use, the therapeutic and safety profiles of thiopurines in a large sample of IBD patients. Methods. We reviewed 3641 case histories of IBD patients. Thiopurines were prescribed in 582 patients (16.0%); the analysis was performed on the 553 (267 ulcerative colitis, 286 Crohn’s disease) with exhaustive clinical data. Results. The main indications for treatment were steroid-dependence (328/553, 59.3%) and steroid-resistance (113/553, 20.7%). Thiopurines were started when CD were younger than UC patients (p < 0.001) but earlier from diagnosis in UC than in CD patients (p = 0.003). Efficacy was defined as optimal (258/553, 46.6%), partial (108/553, 19.5%), absent (85/553, 15.4%) and not assessable (102/553, 18.4%). Efficacy was independent of disease type, location/extension or duration and age at starting. Side effects were observed in 151/553 (27.3%) patients, leading to drug discontinuation in 101 (18.3%). 15 out of the 130 (11.5%) patients who took thiopurines for more than 4 years relapsed, more frequently in CD than in UC (OR = 3.67 95% C.I. 0.98–13.69; p = 0.053). Conclusions. Thiopurines confirm their clinical usefulness and acceptable safety profile in managing complicated IBD patients. The majority of patients treated for longer than 4 years maintain response. No clinical and demographic predictive factors for efficacy and side effects were identified. © 2008 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Inflammatory bowel diseases; Therapy; Thiopurines
1. Introduction
∗ Corresponding author. Present address: Department of Internal Medicine and Hepatology, Fatebenefratelli and Oftalmico Hospital, Corso di Porta Nuova 23, 20121 Milan, Italy. Tel.: +39 0263632489; fax: +39 0263632714. E-mail address: [email protected] (S. Saibeni).
The thiopurine analogues mercaptopurine (MP) and its prodrug, the nitroimidazole derivative azathioprine (AZA), are the most widely used immunosuppressive agents in inflammatory bowel diseases (IBDs). AZA and MP are characterized by a complex metabolism in which the involved enzymes are in constant competition for
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the substrate [1]; their mechanisms of action are still not fully elucidated. The main immunosuppressive effect appears to be mediated by the active metabolites 6-thioguanine nucleotides (6-TGN) by incorporation into DNA of leukocytes as fraudulent bases [2] and by induction of T-cell apoptosis [3] but additional anti-proliferative effects have been proposed [4,5]. Since the first report in the late 1960s of the past century [6], several papers investigated the role of thiopurines in IBD and the majority of data, with more or less convincing evidence, suggests that AZA is effective both in inducing and maintaining remissions of Crohn’s disease (CD) and ulcerative colitis (UC) [7], the two major forms of IBD. In clinical practice, AZA and MP are used virtually interchangeably with the exception of dosing. The onset of their full activity is slow and may take more than 3 months, and their use is complicated by several side effects which are typically considered as dose-independent or dose-related [7]. The aim of this study was to retrospectively evaluate the use, the therapeutic and the safety profiles of thiopurines in a large sample of IBD patients. Information arising from clinical practice may give a reliable measure of the effectiveness, the toxicity and acceptability of a given therapy, which may significantly differ from the data resulting from the ideal conditions created in clinical trials.
2. Materials and methods 2.1. Patients We reviewed 3641 case histories of IBD patients that were followed at the 8 participating centres; AZA or MP had been prescribed in 582 of them (16.0%). The analysis was performed on 553 patients (267 UC, 278 CD, 8 indeterminate colitis (IC)) with complete clinical and demographic data; for patients treated more than once with thiopurines we considered only the first course of therapy. The 8 IC patients were combined with patients with CD, as already suggested by other authors [8] for the purpose of clinical analysis. In most patients, blood chemistry was performed at screening, every 7–14 days for the first 3 months or during dose adjustment and then every 3 months. CD location and behaviour were defined according to the Vienna classification [9].
2.2. Thiopurines treatment The time of observation was calculated from the date of therapy initiation until the discontinuation or the last contact with the patient still taking thiopurines.
2.2.1. Indications Indications to treatment with thiopurines were defined as follows:
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• “steroid-dependence”: partial or complete clinical response to treatment with prednisone or equivalent and relapse with a dose reduction of prednisone at doses ≤15–25 mg/day for at least 6 months or relapse within 30 days of stopping prednisone treatment [10]; • “steroid-resistance”: failing to respond within 30 days to prednisone treatment at doses of 40–60 mg/day [10]; • “penetrating disease”: presence of fistulas and/or abscesses; • “post-surgery”: after surgically induced remission, as prophylactic treatment; • “extraintestinal manifestations (EIMs)”: when the main indication was represented by an extraintestinal manifestation; • “infliximab (IFX)”: when thiopurines were concomitantly prescribed in association with infliximab treatment. 2.2.2. Efficacy Efficacy of thiopurines therapy was evaluated as follows: • “optimal”, when steroids were stopped and/or no further treatment was needed over 2 years from the beginning; • “partial”, when steroids were reduced/discontinued and/or additional treatment started within 2 years from the beginning; • “absent”, when no clinical effect was observed over 6 months and/or additional treatment or surgery became necessary within 1 year from the beginning; • “not assessable”, when the available follow-up was too short (less than 6 months) [8] or side effects led to early treatment discontinuation. 2.2.3. Discontinuation Reasons for thiopurine discontinuation were classified as follows: • Side effects, long-lasting treatment (patients in remission after at least 3 years of drug), patient’s decision, inefficacy, neoplasm, infection, pregnancy. 2.2.4. Toxicity The main side effects were defined as follows: • “Myelotoxicity”: white blood cells count <3000 mm−3 and/or platelets <70,000 mm−3 and/or haemoglobin <10 g/dl. • “Liver toxicity”: transaminases and/or ␥-GT and/or ALP > 1.5 upper limit normal in at least two repeated assessments. • “Pancreatitis”: abdominal symptoms accompanied by amylase and/or lipase increase. • “Systemic toxicity”: occurrence of one of the following signs or symptoms: fever, skin rash, arthralgias, asthenia, myalgia, diarrhea, nausea, abdominal pain. • “Infection”: bacterial, viral or fungal (when requiring specific treatment and/or hospitalization and/or drug discontinuation).
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Table 1 Demographic and clinical features of IBD patients undergoing thiopurines treatment Crohn’s disease n = 286
Ulcerative colitis n = 267
Men/women 140/146 Mean age at diagnosis ± S.D.* (years) 30.7 ± 12.5
157/110 36.2 ± 14.2
Location/extension, n (%) Ileum Ileum + colon Colon Upper GI Pancolitis Left-sided colitis Procto-sigmoiditis
59 (20.6) 137 (47.9) 85 (29.7) 5 (1.7) – – –
– – – – 157 (58.8) 64 (24.0) 46 (17.2)
Behaviour, n (%) Non-stricturing, non-penetrating Penetrating Stricturing
111 (38.8) 116 (40.6) 59 (20.6)
– – –
*
Fig. 1. Indications for thiopurines therapy.
p < 0.001.
2.3. Statistical analysis GraphPad Instat package software (GraphPad Software Inc., San Diego, CA, USA) was used to analyse data by means of Student’s t-test, Mann–Whitney test, Fisher’s exact test and Chi-square test for independence, as appropriate. All the statistical tests were two-tailed and the statistical significance was set at p = 0.05.
had a twofold increased risk to undergo thiopurines therapy with respect to those with UC (OR = 2.09 95% C.I. 1.48–2.95; p < 0.0001). However, thiopurines were started significantly earlier from diagnosis in UC than in CD patients (Table 2). 130 out of 553 (23.5%) IBD patients took thiopurines for more than 4 years. 3.1. Indications Indications for treatment with thiopurines in CD and UC patients are shown in Fig. 1. 3.2. Efficacy
3. Results At participating centres, AZA was prescribed between March 1986 and September 2006 to 541 patients at a dose ranging from 1.5 to 2.5 mg(kg day)−1 , while MP was prescribed in 12 patients (8 CD, 4 UC) at a dose ranging from 1.0 to 1.5 mg(kg day)−1 . Clinical and demographic characteristics of enrolled patients are summarised in Table 1. At the beginning of the thiopurines’ therapy, CD patients were significantly younger than UC patients; in particular, in IBD patients aged less than 40 years, those with CD
Efficacy of thiopurines in CD and UC is shown in Fig. 2. We observed an overall efficacy (optimal + partial) in 366 out of 553 (66.2%) IBD patients. Efficacy was not assessable in 102 out of 553 (18.4%) patients: in 56 out of 553 (10.2%) due to too short a follow-up and in 46 out of 553 (8.3%) due to the early occurrence of side effects. No statistically significant difference was observed between CD and UC patients. We also assessed cumulative optimal and partial efficacy stratifying CD and UC patients according to clinical and demographical features (Table 3). No statistically significant
Table 2 Data about therapy starting and follow-up Crohn’s disease n = 286 Mean age at starting thiopurines ± S.D. (years) Mean time of starting from diagnosis ± S.D. (months)
38.0 ± 14.2 90.4 ± 74.6
Ulcerative colitis n = 267
p
42.3 ± 14.9 71.4 ± 76.1
<0.001 <0.003
Thiopurines starting from diagnosis, n (%) Within 12 months Between 12 and 60 months Over 60 months
63 (22.0) 90 (31.5) 133 (46.5)
72 (27.0) 99 (37.1) 96 (35.9)
0.042
Age at thiopurines starting, n (%) <40 years >40 years
192 (67.1) 94 (32.9)
132 (49.4) 135 (50.6)
<0.001
Mean duration of follow-up ± S.D. (months) Taking thiopurines for more than 4 years, n (%)
30.8 ± 32.2 72 (25.2)
28.1 ± 28.7 58 (21.7)
n.s. n.s.
S. Saibeni et al. / Digestive and Liver Disease 40 (2008) 814–820
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Fig. 4. Reasons for thiopurines discontinuation.
Fig. 2. Efficacy of thiopurines (NA, not assessable).
3.3. Discontinuation Thiopurines were withdrawn in 255 out of 553 (46.1%) patients; 298 out of 553 (53.9%) patients were still taking the drug at the time of this survey. In this latter group of patients the mean ± S.D. time of observation was 34.3 ± 32.6 months. Reasons for thiopurines discontinuation in CD and UC are shown in Fig. 4. Here we report data concerning the occurrence of side effects and spontaneous discontinuation.
Fig. 3. Disease course in patients taking thiopurines for more than 4 years (relapse CD vs. UC: p = 0.053).
difference was observed between CD and UC nor between subgroups within the single diseases. In the 130 patients who took thiopurines for more than 4 years, relapses were observed in 15 (11.5%) and more frequently in CD than in UC patients (OR = 3.67 95% C.I. 0.98–13.69; p = 0.053) (Fig. 3).
• In 101 out of 553 (18.3%) IBD patients discontinued the drug due to the occurrence of side effects, after a median of 3 months from starting (range 1–113 months). In particular, in 9 out of 553 (1.6%) patients this was due to the occurrence of infections (median 15.5 months, range 2–107): 3 CMV, 1 EBV, 1 chicken-pox, 1 measles, 1 sepsis of unknown origin, 1 osteomyelitis and 1 bacterial meningitis; all the infections but meningitis occurred in patients taking thiopurines for less than 4 years. In 5 out of 553 (0.9%) patients drug discontinuation was due to the diagnosis of neoplasm (median 52 months, range 4–94): 3 colo-rectal adenocarcinomas, 1 stomach adenocarcinoma and 1 melanoma. All colo-rectal cancers
Table 3 Optimal + partial efficacy of thiopurines according to clinical and demographical features Crohn’s disease
p
Ulcerative colitis
p
Disease duration Within 12 months Between 12 and 60 months Over 60 months
42/63 (66.7%) 58/90 (64.4%) 85/133 (63.9%)
n.s.
50/72 (69.4%) 71/99 (71.7%) 60/96 (62.5%)
n.s.
Age at thiopurines starting <40 years >40 years
122/192 (63.5%) 63/94 (67.0%)
n.s.
95/132 (72.0%) 86/135 (63.7%)
n.s.
Location/extensiona Ileum Ileum + colon Colon Pancolitis Left-sided colitis Procto-sigmoiditis
40/59 (67.8%) 87/137 (63.5%) 54/85 (63.5%) – – –
a
Upper GI excluded.
n.s. – – –
– – – 109/157 (69.4%) 40/64 (62.5%) 32/46 (69.6%)
– – – n.s.
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discontinued the drug according to the physician’s (gastroenterologist or gynaecologist) advice. One of these pregnancies was extrauterine; no adverse outcomes were observed.
4. Discussion
Fig. 5. Side effects due to thiopurines treatment.
occurred in patients with UC involving the entire colon and other known risk factors associated (disease duration >10 years or primary sclerosing cholangitis). These patients were taking thiopurines for 4, 50 and 94 months; one of them died with peritoneal carcinosis. • In 34 out of 553 (6.1%) IBD patients drug discontinuation was due to their spontaneous decision, after a median of 14 months from starting (range 1–147 months). Again, no statistically significant difference was observed between CD and UC. 3.4. Toxicity 151 out of 553 (27.3%) IBD patients experienced side effects during thiopurines’ therapy (Fig. 5). In particular, myelotoxicity was observed in 44 (7.8%) patients, after a median of 12 months from starting (range 1–154 months); liver toxicity in 30 (5.4%) patients (median 4.5 months, range 1–147); pancreatitis in 21 (3.8%) patients (median 2 months, range 1–100) and systemic toxicity in 19 (3.2%) patients (median 3 months, range 1–25). Infections were observed in 15 out of 553 (2.7%) patients, after a median of 20 months from starting (range 2–107 months). Also in this analysis, no statistically significant differences was observed between CD and UC. Reasons for discontinuation and occurrence of side effects were almost identical when we stratified CD and UC patients according to disease duration, age at treatment initiation, disease location/extension, age at diagnosis and gender (data not shown). Side effects observed in the 130 IBD patients taking thiopurines for more than 4 years were the following: myelotoxicity in 7 (5.4%), liver toxicity in 4 (3.1%), pancreatitis in 3 (2.3%), infection in 3 (2.3%) and neoplasm in 2 (1.5%). No significant difference was observed between CD and UC patients or within patients taking the drug for less than 4 years. 3.5. Pregnancy 16 (10 with CD and 6 with UC) out of 256 women (6.2%) became pregnant while receiving thiopurines and 6 of them
In this study, we assessed the use as well as the therapeutic and safety profiles of thiopurines in a large group of Italian patients affected by IBD. In our sample, which is one of the largest ever investigated by this kind of study, AZA was largely preferred to MP, in accordance with the European practice [11]. Thiopurines have been prescribed in similar percentages in UC and in CD, less frequently than in the classical observational report from Oxford [8] (16% vs. 28%) and significantly earlier from diagnosis in UC than in CD. We are aware of the methodological limitations of this kind of study. The retrospective nature makes standardized indexes to assess disease activity (and thus efficacy of the drugs) unavailable, and the lack of randomization makes the cohorts (for instance subgroups stratified for disease duration and age at diagnosis) not easily comparable. However, bearing these limitations in mind, we believe that the present study may provide a practical contribution to the issue of thiopurines utilization in IBD. Indeed, we believe that the information provided by our study represents a reliable picture of what may happen in clinical practice when a physician decides to treat an IBD patient with thiopurines. In our sample, steroid-dependence represented the most frequent indication to thiopurines treatment; overall, indications were distributed quite differently with respect to similar studies [12]. In general, no significant differences in terms of efficacy, occurrence of side effects and reasons for discontinuation were observed between CD and UC patients. However, UC patients appeared to respond even better than CD patients, as previously reported [8], especially when treated for longer than 4 years. The overall efficacy of thiopurines was observed in 2 out of 3 IBD patients; this finding is in agreement with the previous reports which were performed in clinical practice [8,13–15]. In our series, the efficacy of thiopurines appeared to be independent of clinical and demographic features of IBD patients, as previously reported by other authors [8,16,17]. The absence of a better efficacy of thiopurines when administered to younger patients and at a time closer to diagnosis provides in our opinion some argument against the systematic inversion of the traditional therapeutic pyramid proposed in adult IBD [18]. Besides the good performance in terms of clinical efficacy, we should however keep in mind that 1 out of 5 IBD patients lost the therapeutic chance represented by these drugs in a short space of time; this occurred both for the early occurrence of relevant side effects and for the concerns of the
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patients about the immunosuppressive nature of this therapy. Of interest, spontaneous discontinuation may happen very early but also after a long period of treatment; to avoid this occurrence, exhaustive and reassuring explanations on the use of these drugs and on their safety features should be provided to patients. As far as thiopurines toxicity is concerned, we observed a cumulative rate of side effects of 27.3%, and a discontinuation rate due to side effects of 18.3%. In previous studies, thiopurines discontinuation rate due to side effects varies from 5–6% [17,19] to up to 30% [8,20], but most authors reported a rate of about 20% [21–24]. The prevalence of the single side effects quite varies among the different studies, partly due to the use of non-univocal definitions. The rates of myelotoxicity (7.8%), liver toxicity (5.4%), pancreatitis (3.8%), systemic toxicity (3.2%) and infections (2.7%) observed in the present study do not significantly differ from literature data [17,19–25]. Interestly, pancreatitis, which is generally considered an idiosyncratic reaction [21], was observed up to 100 months from thiopurines initiation; this finding is not new, being already reported by Warman et al. [19]. In our sample, no drug related mortality was observed; only one patient died due to peritoneal carcinosis subsequent to colon adenocarcinoma. Moreover, no lymphoma was observed. Overall, we registered five neoplasms (1.1% of the 451 patients in whom it was possible to assess efficacy); this number is lower than that reported by other similar studies [19,21]. Three neoplasms were colonic adenocarcinoma and occurred in UC patients (1.4% of the 218 patients in whom it was possible to assess efficacy) with other known risk factors for this neoplasia; this percentage is similar to that expected in this kind of patients [26]. As a consequence, in our series thiopurines do not appear to increase the risk of developing neoplasia, in agreement with a recently published metanalysis showing no difference in the incidence of any kind of malignancy in IBD patients who received immunosuppressants compared with those who did not [27]. However, we believe that this finding ought to suggest a more radical intervention (i.e. colectomy) in those UC patients who are at increased risk of developing colo-rectal adenocarcinoma. Despite the relatively small number of pregnancies (occurring in 6.2% of the women enrolled in this study), we are quite confident about the safety of these drugs on pregnant IBD women, in agreement with the most recent evidence [28]. Over what period of time should thiopurines be given is still a matter of debate. Some authors demonstrated the lack of a therapeutic benefit beyond 4 years; they also suggested a potential increase in toxicity [29] while other authors reported a well-sustained efficacy over a period of 5 years [8]. In our series, 1 in 4 IBD patients took thiopurines for more than 4 years. In these patients, we observed a negligible loss of efficacy after 4 years of treatment, without a significant increase of side effects. We therefore agree with the studies proposing continuing the therapy in responders to thiopurines for
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at least 7 years [17] or, alternatively, allowing for a differentiated treatment algorithm according to disease activity and steroid requirement [12]. As already stated, the retrospective nature of our evaluation unavoidably implies some methodological limitations; however, we feel that the rigorous definition of events, the completeness of the assessed parameters, the adequate size of the population studied and the extended follow-up represent the strengths of the present study and provide reliability to our results. In conclusion, our study confirms the clinical usefulness and the acceptable safety profile of thiopurines in managing complicated IBD patients, even though some compliance problems may occur. No clinical or demographic factors were identified to predict the efficacy or the toxicity of thiopurines. Most of the patients treated for longer than 4 years maintained response without an increased risk of toxicity.
Practice points • Thiopurines are the most commonly used immunomodulatory drugs in the treatment of IBD. • Besides their efficacy in inducing and maintaining remissions of CD and UC, important toxicities may limit their clinical use. • No clinical or demographic factors appear to predict the efficacy or the toxicity of thiopurines. • Clinical and biochemical monitoring is mandatory in IBD patients treated with thiopurines.
Research agenda • More prospective studies are needed in order to optimize the efficacy and safety profiles of thiopurines, for example by means of geno- and phenotyping of enzymes involved in their metabolism, monitoring active and toxic metabolites and exploiting drug interactions. • Further studies are needed in order to better define the correct positioning of thiopurines in the therapeutic armamentarium of IBD (i.e. earlier utilisation vs. traditional approach). • Further efforts are needed in order to increase the patients’ compliance to treatment with thiopurines.
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Conflict of interest statement None declared.
Acknowledgement We are indebted to Ms. Kelly Lynch for her precious collaboration.
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