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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PHARMACODYNAMICS
  5. DOSAGE
  6. INDICATIONS
  7. DURATION OF TREATMENT AND TAPERING
  8. ADVERSE EFFECTS
  9. MONITORING
  10. CANCER RISK
  11. PREGNANCY AND LACTATION
  12. CONCLUSIONS
  13. ACKNOWLEDGEMENT
  14. References

The thioguanine derivative, azathioprine, is a prodrug of 6-mercaptopurine that is further metabolized by various enzymes present in the liver and gut. Azathioprine and 6-mercaptopurine have been used in the treatment of inflammatory bowel disease, i.e. ulcerative colitis and Crohn’s disease, for more than 30 years. However, widespread use of azathioprine or 6-mercaptopurine in inflammatory bowel disease is of more recent origin, the primary reason being a long-standing debate on the efficacy of these agents in inflammatory bowel disease. Both drugs are slow acting, which is why clinical efficacy cannot be expected until several weeks or even months of treatment have elapsed. Consequently, azathioprine and 6-mercaptopurine have no place as monotherapy in the treatment of acute relapsing inflammatory bowel disease.

Today, azathioprine and 6-mercaptopurine are the most commonly used immunomodulatory drugs in the treatment of inflammatory bowel disease. Their clinical effects are probably identical, although their exact mode of action is still unknown. The mode of action of azathioprine is thought to be multifactorial, including conversion to 6-mercaptopurine (which acts as a purine antimetabolite), possible blockade of thiol groups by alkylation, inhibition of several pathways in nucleic acid biosynthesis (preventing proliferation of cells involved in the determination and amplification of the immune response) and damage to DNA through the incorporation of thiopurine analogues. However, 6-thioguanine nucleotides may accumulate in toxic doses in myeloid precursor cells, resulting in life-threatening myelosuppression. Azathioprine and 6-mercaptopurine are further known to alter lymphocyte function, reduce the number of lamina propria plasma cells and affect natural killer cell function.

The purpose of this comprehensive review is to suggest guidelines for the application of azathioprine and 6-mercaptopurine in the treatment of inflammatory bowel disease.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PHARMACODYNAMICS
  5. DOSAGE
  6. INDICATIONS
  7. DURATION OF TREATMENT AND TAPERING
  8. ADVERSE EFFECTS
  9. MONITORING
  10. CANCER RISK
  11. PREGNANCY AND LACTATION
  12. CONCLUSIONS
  13. ACKNOWLEDGEMENT
  14. References

Inflammatory bowel disease, i.e. ulcerative colitis and Crohn’s disease, is characterized by an up-regulated intestinal immune defence with an apparently uncontrolled inflammatory activity. Persons with inflammatory bowel disease live with a chronic, essentially incurable condition that frequently requires the use of potent drugs to control symptoms. Glucocorticoids are still the most effective remission-inducing medication but, for patients who fail to respond and for those who develop side-effects or require long-term glucocorticoid treatment, immunomodulatory drugs are important supplements or alternatives. Ultimately, surgery may be performed. However, Crohn’s disease is panenteric in nature and therefore surgery can never cure this condition.

Unfortunately, glucocorticoids have common and serious side-effects that limit patient acceptance and compliance. Some patients may even refuse to take glucocorticoids and instead live with symptoms of the disease. Possible benefits of various drugs always need to be balanced against the risks of side-effects and, in ulcerative colitis (where colectomy offers a ‘cure’), there has been greater reluctance to use immunosuppressive drugs than in Crohn’s disease.

It is obvious that, given the unpredictable course of inflammatory bowel disease, valid conclusions concerning the effects of azathioprine (AZA) and 6-mercaptopurine (6MP) can only be drawn from well-designed, double-blind, controlled trials. In this respect, it is important to define clearly the types of patients who have been shown to respond and not to assume uncritically that established conclusions can be extrapolated to other disease activity states. The aim of this review is to present a comprehensive analysis of the available literature that might be helpful to clinicians treating patients with inflammatory bowel disease.

PHARMACODYNAMICS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PHARMACODYNAMICS
  5. DOSAGE
  6. INDICATIONS
  7. DURATION OF TREATMENT AND TAPERING
  8. ADVERSE EFFECTS
  9. MONITORING
  10. CANCER RISK
  11. PREGNANCY AND LACTATION
  12. CONCLUSIONS
  13. ACKNOWLEDGEMENT
  14. References

The absorption of AZA is 16–50% in healthy individuals, and may be even less in patients with inflammatory bowel disease due to their faster intestinal transit time during exacerbations.1 It is a prodrug that is cleaved rapidly in the liver to 6MP by the enzyme glutathione-S-transferase, which is then metabolized in the liver and gut by one of three enzymes: (a) thiopurine-S-methyltransferase (TPMT), which catalyses the methylation of 6MP to 6-methyl-MP; (b) xanthine oxidase, which catalyses 6MP to thiourate; and (c) hypoxanthine-guanine-phosphoribosyltransferase, which converts 6MP to 6-thioguanine nucleotides.2

It is not possible to point out a single biochemical event as the cause of the beneficial effects of these drugs in inflammatory bowel disease, but AZA or 6MP therapy inhibits the proliferation of T and B lymphocytes, and thereby diminishes the production of cytotoxic T cells and plasma cells. After initiation of therapy with AZA or 6MP, 6-thioguanine nucleotides accumulate slowly in tissues, which probably accounts for the protracted onset of action. This intracellular accumulation of 6-thioguanine nucleotides is also believed to be responsible for the cytotoxic effects of these drugs through the inhibition of purine synthesis, nucleotide interconversions, DNA and RNA synthesis and chromosomal replication.3–5 Erythrocyte 6-thioguanine nucleotide concentrations, which are inversely correlated with the rate of metabolism via the TPMT pathway, correlate with the response in childhood leukaemia,6, 7 and a similar relationship may exist in inflammatory bowel disease. However, increased production of 6-thioguanine nucleotides, which is seen with TPMT deficiency due to mutations of the TPMT gene, leads to toxic levels in blood cells, causing pancytopenia or isolated leucopenia.

A diminished TPMT activity results in the metabolism of AZA and 6MP via other enzymatic pathways, leading to high concentrations of 6-thioguanine nucleotides and thiourate. Whereas no adverse effects seem to be correlated with thiourate accumulation, accumulation of 6-thioguanine nucleotides in myeloid precursor cells represents a risk factor for thiopurine drug-induced myelosuppression.8 Thus, finding the correct concentration of intracellular 6-thioguanine nucleotides is crucial. Concentrations that are too high lead to myelosuppression, and concentrations that are too low lead to a lack of an effect in patients with inflammatory bowel disease.8, 9

It should be noted that the commonly used drug in inflammatory bowel disease treatment, mesalazine, inhibits TPMT, but it has not been determined whether this drug interaction reduces the clinical effectiveness of AZA or 6MP.10, 11

DOSAGE

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PHARMACODYNAMICS
  5. DOSAGE
  6. INDICATIONS
  7. DURATION OF TREATMENT AND TAPERING
  8. ADVERSE EFFECTS
  9. MONITORING
  10. CANCER RISK
  11. PREGNANCY AND LACTATION
  12. CONCLUSIONS
  13. ACKNOWLEDGEMENT
  14. References

Given the risk of serious adverse effects and the fact that TMPT gene analysis is not available in most treatment centres, AZA should be introduced at a low dose, e.g. 50 mg daily (0.5–1.5 mg/kg daily), and increased gradually to doses of 2.5 mg/kg daily within 2 weeks, with weekly blood monitoring (i.e. haemoglobin, white blood cell count, thrombocytes, alkaline phosphatase and alanine aminotransferase) until the maintenance dose is reached. Monitoring should then be continued monthly or every second month for the duration of therapy. The molecular weight of 6MP is 55% of that of AZA, and 88% of AZA is converted to 6MP. Accordingly, a conversion factor of approximately 50% exists between AZA and 6MP. Therefore, the equivalent dose of 6MP is initially 0.25–0.5 mg/kg daily, increasing to 1.0–1.5 mg/kg daily. If the white blood cell count decreases below 3 × 109/L or the platelet count decreases below 120 × 109/L, the drug should be discontinued or the dose reduced until these parameters normalize. Furthermore, if liver biochemistry (and/or serum amylase) exceeds more than 50% of the upper limit of normal, treatment with AZA/6MP should be discontinued. It should be borne in mind that all monitoring principles have their limitations, as discussed earlier.12 If warranted, AZA may then be reintroduced cautiously. Monitoring does not always prevent bone marrow suppression, which can be sudden in onset, even after a long duration of treatment, and patients should be educated to pay close attention to unusual symptoms or signs of infection.

A recent study has suggested that the measurement of the AZA/6MP metabolite, 6-thioguanine nucleotide, in erythrocytes might be helpful in determining the adequacy of the AZA dosage.13 By gradually increasing the dosages of these agents, many of the dyspeptic side-effects can be eliminated. Furthermore, allergic side-effects detected at low doses, including pancreatitis, hepatitis, fever and rash, usually appear within the first weeks of treatment with the drug. However, it should be emphasized that these side-effects are unrelated to the bone marrow suppressive effect14 and unrelated to the enzymatic activity of TPMT.

AZA and 6MP are both slow-acting drugs, and thus their effect can only be expected after 12–17 weeks of treatment. A recent study, however, has described effects after approximately 4 weeks, and possibly AZA works faster than previously believed.15 Given their slow onset of action, these drugs have no place as monotherapy in acute relapses of inflammatory bowel disease, although AZA has been reported to be successful as a single-drug treatment in remission induction and maintenance of remission of Crohn’s disease that has been treated primarily in conjunction with a diminishing dose regimen of prednisolone over a period of 12 weeks.16 Severe adverse effects, apart from bone marrow suppression, are seen only rarely if the AZA dose does not exceed 2.5 mg/kg daily or the 6MP dose does not exceed 1.5 mg/kg daily.

Allopurinol blocks the metabolism of 6MP via the inhibition of xanthine oxidase,17 and precautions should therefore be taken in allopurinol-treated patients. In such patients, it is often adequate to use half doses of AZA or 6MP. Theoretically, mesalazine also inhibits TPMT activity, but the clinical significance of this is presumably minimal.18

INDICATIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PHARMACODYNAMICS
  5. DOSAGE
  6. INDICATIONS
  7. DURATION OF TREATMENT AND TAPERING
  8. ADVERSE EFFECTS
  9. MONITORING
  10. CANCER RISK
  11. PREGNANCY AND LACTATION
  12. CONCLUSIONS
  13. ACKNOWLEDGEMENT
  14. References

The majority of ulcerative colitis and Crohn’s disease patients who have three or more flare-ups per year that require glucocorticoids, and those who experience a relapse of symptoms on tapering off glucocorticoids, benefit from treatment with AZA or 6MP.19 In the following, indications for AZA or 6MP use in Crohn’s disease and ulcerative colitis will be described separately.

Crohn’s disease

A recent Crohn’s disease Cochrane-based meta-analysis of all AZA references in the period 1966–May 1998 showed that AZA had a positive effect on maintaining remission in Crohn’s disease,20 and a survey of all patients with inflammatory bowel disease treated in Oxford, UK, in the years 1968–99 showed that AZA was effective in the treatment of active Crohn’s disease.21 In addition to its well-documented ‘steroid-sparing effect’,22, 23 which is also found in the Cochrane review based on all literature in the period 1966–97,24 a recent study has shown that long-term AZA treatment specifically attenuates severe recurrent Crohn’s disease ileitis.25 Furthermore, AZA, unlike glucocorticoids, has been suggested to have the potential to improve or even heal fistulas in Crohn’s disease patients.12, 26, 27 However, several studies included in the meta-analysis reported to address this issue,12 but do not provide exact numbers as to the effect on fistula healing, and therefore only limited conclusions can be drawn.

Regarding antitumour necrosis factor therapy (i.e. Infliximab), concomitant use of AZA seems to inhibit the formation of human antichimeric antibodies. Also, pre- and co-treatment during antitumour necrosis factor therapy with AZA or 6MP has been suggested to be of beneficial effect, as the risk of developing serum sickness might be minimized.28 However, due to the limited data available, this hypothesis needs to be substantiated in controlled trials.29

The value of 6MP in the treatment of Crohn’s disease was established by a study performed by Present et al.30 Approximately 75% of patients receiving 6MP were able to discontinue glucocorticoid treatment, as compared with about 37% of the placebo-treated patients, and fistulas healed in 31% of patients treated with 6MP, but in only 6% of placebo-treated patients. The median period until effect with oral therapy was 3.1 months, although some patients did not respond until after 6 months.30, 31 In a recent meta-analysis, the response correlated with the cumulative dose.12 Furthermore, an open-labelled pilot study in patients with glucocorticoid-refractory active Crohn’s disease showed that intravenous AZA (1800 mg) given over 36 h reduced the response time to a few weeks.32 This effect, however, was not confirmed in a 16-week placebo-controlled trial with an initial intravenous loading dose of 40 mg/kg AZA, in which patients were started simultaneously on oral AZA. Nevertheless, with this regimen, clinical improvement occurred earlier than previously reported (4–8 weeks).15

Finally, AZA and 6MP might be efficient in preventing relapses after surgical intervention in Crohn’s disease. The evidence is, however, scarce, but an uncontrolled study showed that treatment with AZA for at least 6 months reduced the relapse in the neoterminal ileum post-operatively in Crohn’s disease.25 In another study in which Crohn’s disease patients underwent surgical intervention, it was shown that treatment with 6MP for 24 months reduced the relapse rate clinically, endoscopically and radiologically, as compared to placebo, but no difference was revealed between 6MP and mesalazine.33 Thus, whether AZA and 6MP have any place in secondary prophylaxis after Crohn’s disease surgery is still essentially unknown, and larger controlled studies are needed.

Ulcerative colitis

From the survey of all patients with inflammatory bowel disease in Oxford, UK, in the period 1968–99, AZA was shown to be effective in active ulcerative colitis, with higher remission rates observed in ulcerative colitis than in Crohn’s disease.21 In left-sided ulcerative colitis, which often fails to respond fully to glucocorticoids or mesalazine preparations, AZA and 6MP have been shown to be useful alternatives.34 Despite this, clinicians have always been reluctant to use AZA or 6MP in ulcerative colitis, presumably because of the existence of a ‘cure’ involving total colectomy, which eliminates the diseased and the potentially diseased mucosa, as well as the long-term risk of carcinoma.

AZA or 6MP treatment

Pharmacologically, no basic difference has been found between the actions of AZA or 6MP, emphasizing that they can be administered on equal indications. In two minor studies, it has been suggested that 6MP might be introduced in patients with inflammatory bowel disease intolerant of AZA (excluding those with hypersensitivity reactions), where continued immunosuppressive therapy is warranted. In more than half of the patients, 6MP may be tolerated, but the underlying mechanisms have not yet been clarified.35, 36 AZA and 6MP are licensed for the treatment of inflammatory bowel disease in only a few countries, but they enjoy widespread licensing for the suppression of rejection in organ transplant recipients. In addition, they are used widely to treat a number of autoimmune disorders, usually when glucocorticoid therapy alone has not provided adequate control, but often also as the drug of first choice.

DURATION OF TREATMENT AND TAPERING

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PHARMACODYNAMICS
  5. DOSAGE
  6. INDICATIONS
  7. DURATION OF TREATMENT AND TAPERING
  8. ADVERSE EFFECTS
  9. MONITORING
  10. CANCER RISK
  11. PREGNANCY AND LACTATION
  12. CONCLUSIONS
  13. ACKNOWLEDGEMENT
  14. References

No study has been conducted to show the necessary or optimal period of AZA or 6MP treatment in quiescent disease,37 but a retrospective survey of long-term treatment showed that two-thirds of Crohn’s disease patients remained in remission after 5 years.12 In this study, it was suggested that relapse was more likely in females and younger patients, whereas the disease site did not influence the relapse rate. Candy et al.38 reported that AZA offers therapeutic advantage over placebo in the maintenance of remission in Crohn’s disease over a period of only 15 months. Sixty-three patients were randomized to receive either 2.5 mg/kg AZA or placebo, in addition to tapering of an initial dose of prednisolone (1 mg/kg), over a period of 3 months. After this period, there was no significant difference in remission rates (76% with AZA vs. 66% with placebo) but, after 15 months of treatment, 42% of those receiving AZA and only 7% of those receiving placebo were in remission (which is highly significant).

In another study, the relapse rates of 157 patients in remission who continued AZA or 6MP for more than 6 months after withdrawal of glucocorticoids were compared with those of 42 patients who stopped therapy for reasons other than relapse.27 Relapse rates at 1 and 5 years were 11% and 32%, respectively, in the immunosuppressed group vs. 38% and 75%, respectively, in the group that had discontinued immunosuppressives. It is suggested, therefore, that withdrawal of AZA therapy may be considered in both ulcerative colitis and Crohn’s disease patients who have been in remission for 5 years or more. However, due to the small number of patients followed for the longer time period, the data must be interpreted with caution. Whether a slow dosage reduction every 6–12 months is an alternative to stopping treatment abruptly has not yet been tested in clinical trials. From the Oxford survey mentioned earlier,21 it was concluded that the treatment should not be limited to a previously specified period of time because efficacy in inflammatory bowel disease appears to be sustained for at least 5 years.21

As for Crohn’s disease, AZA has an important role in the treatment of chronic active ulcerative colitis, where it enables the reduction or cessation of glucocorticoids. Ulcerative colitis patients with frequent relapses, or those who are unable to achieve complete remission with prednisolone, particularly those with left-sided or distal disease, often have considerable collapse of their lifestyles, but do not wish to have a colectomy performed with the prospect of ileostomy or an ileal pouch. Many of these patients achieve prolonged remission on AZA with improved quality of life. A clinical trial showed no benefit of the addition of AZA in patients with troublesome, chronic, stable colitis, i.e. patients with chronic, low-grade or corticosteroid-dependent ulcerative colitis, whereas there was evidence of benefit in maintaining remission in ulcerative colitis patients with initially moderate and severe disease activity who achieved remission while taking AZA.39 Hence, with regard to the maintenance of remission of ulcerative colitis, for both patients in full remission and patients with chronic, low-grade or corticosteroid-dependent disease who have received AZA for at least 6 months, the 1-year relapse rate was 36% for patients continuing AZA and 59% for those taking placebo.39

A disadvantage of AZA or 6MP treatment of both ulcerative colitis and Crohn’s disease is the risk of relapse after stopping these drugs. The chances of relapse are 37% at 1 year and 66% at 3 years after discontinuation.21 The percentage of relapse in ulcerative colitis is higher than that reported in Crohn’s disease patients treated with AZA,27 but the ulcerative colitis patients treated with AZA included troublesome cases (see above).32

Only uncontrolled reports of the effectiveness of 6MP in maintaining remission in ulcerative colitis have been published.40, 41 The use of 6MP in inflammatory bowel disease has been documented, however, in a meta-analysis showing a clinical effect that parallels that of AZA.12

ADVERSE EFFECTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PHARMACODYNAMICS
  5. DOSAGE
  6. INDICATIONS
  7. DURATION OF TREATMENT AND TAPERING
  8. ADVERSE EFFECTS
  9. MONITORING
  10. CANCER RISK
  11. PREGNANCY AND LACTATION
  12. CONCLUSIONS
  13. ACKNOWLEDGEMENT
  14. References

Side-effects from AZA and 6MP can be divided into three areas: bone marrow suppression and short- and long-term effects. These side-effects occur in about 10–15% of patients with inflammatory bowel disease and are either dose-dependent (e.g. bone marrow depression (2%) with leucopenia and/or thrombocytopenia) or dose-independent (e.g. pancreatitis, allergic reactions or hepatitis) reactions. As described earlier, only myelosuppression is dependent on the TPMT gene.

Bone marrow suppression

Asymptomatic leucopenia was found in 37 of 739 patients (5%), resulting in effective reduction of dosage.42 However, severe leucopenia (< 2 × 109/L) was found in nine patients (1%), five of whom developed sepsis, pneumonia or upper respiratory infections. Two of these patients died. Myelotoxicity occurred at any time from 2 weeks to 11 years of therapy and either occurred suddenly or progressed over several months.42

Short-term effects

Side-effects detected at low doses, such as pancreatitis (3.3%), allergic reactions including rash (2.0%), drug-induced idiosyncratic hepatitis with hepatocyte necrosis, cholestasis or insidious onset of liver dysfunction (0.3%) and infections (7.4%), usually occur within the first weeks of treatment.43 Pancreatitis generally recurs on retreatment, which excludes the use of either AZA or 6MP. In such cases, the pancreatitis resolves upon drug withdrawal.44 Laboratory monitoring for pancreatitis does not appear to be warranted unless symptoms occur. Arthralgia may be related to AZA, and diarrhoea is a rare side-effect that is easily confused with a flare-up of the underlying inflammatory bowel disease. Hypersensitivity reactions occasionally can be severe, with rash, fever, hypotension and a decrease in liver function.

Between 5 and 10% of patients stop treatment on their own initiative because of side-effects, most often during the first month. Nausea, vomiting and malaise are the most commonly encountered problems, especially if the dose is increased too rapidly. Taking the drug with meals may minimize nausea.

Long-term effects

Infections are a theoretical risk of long-term treatment as a result of the general immunosuppression, including viral infections such as cytomegalovirus, herpes zoster and hepatitis A and B, as well as bacterial infections such as liver abscess, pneumonia and septic phlebitis.45, 46 However, such infections have also been reported in patients with inflammatory bowel disease who do not receive immunosuppressives, and the risk does not appear to be greater than that in patients receiving high-dose prednisolone.47

In this context, it is important to emphasize the risk of potentially lethal opportunistic infections with the use of glucocorticoids, which is at least as high as and perhaps higher than that for AZA or 6MP.48 One should bear in mind that, in contrast to life-threatening infections with glucocorticoids, a potentially life-threatening leucopenic episode with AZA or 6MP can be treated successfully with granulocyte colony-stimulating factor.49 Disregarding these adverse effects, the purine analogues are safe drugs in experienced hands.

MONITORING

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PHARMACODYNAMICS
  5. DOSAGE
  6. INDICATIONS
  7. DURATION OF TREATMENT AND TAPERING
  8. ADVERSE EFFECTS
  9. MONITORING
  10. CANCER RISK
  11. PREGNANCY AND LACTATION
  12. CONCLUSIONS
  13. ACKNOWLEDGEMENT
  14. References

The long-term safety of AZA and 6MP is acceptable, provided that white blood cell counts and liver enzymes are measured at regular intervals to prevent the full development of the serious adverse effects of bone marrow suppression and liver cell damage.42 As patients with high TPMT activity presumably have a poor clinical response to AZA because of the fast metabolization, it has been claimed that optimal efficacy is seen in the presence of mild neutropenia.50, 51 In contrast, recent data suggest that leucopenia is not a marker of efficacy.52

Genetic polymorphism controls the TPMT activity and thus the therapeutic effect and toxicity of AZA. In the Caucasian population, 89% have high TPMT activity (two wild-type alleles), 11% have intermediate activity (one wild-type and one mutant allele) and 0.3% have no detectable TPMT activity (two mutant alleles),53 which precisely corresponds with the frequency of severe myelotoxicity observed during AZA therapy.54

It has been argued that individuals with homozygous deficiency of TPMT activity should be identified by screening prior to treatment and excluded from AZA or 6MP therapy to avoid life-threatening neutropenia.55 However, heterozygous patients also have a potential risk of developing bone marrow suppression. Thus, a French study showed that only 27% of Crohn’s disease patients with myelosuppression during AZA treatment had mutant alleles of the TPMT gene associated with enzyme deficiency.56 Therefore, it should be emphasized that TPMT measurements cannot yet replace the need for continued haematological monitoring. As the determination of TPMT activity is not available routinely at most inflammatory bowel disease centres, this approach should await the results of a North American controlled trial. Jackson et al.57 have shown that genotyping is a cost-effective procedure. The TPMT activity in the liver and kidneys correlates with the activity of TPMT in erythrocytes, which offers an alternative monitoring modality. However, this must await studies clearly correlating erythrocyte 6-thioguanine nucleotide levels with TPMT gene activity and the risk of adverse effects.

CANCER RISK

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PHARMACODYNAMICS
  5. DOSAGE
  6. INDICATIONS
  7. DURATION OF TREATMENT AND TAPERING
  8. ADVERSE EFFECTS
  9. MONITORING
  10. CANCER RISK
  11. PREGNANCY AND LACTATION
  12. CONCLUSIONS
  13. ACKNOWLEDGEMENT
  14. References

Concerns about the potential for AZA or 6MP to increase the risk for the development of neoplastic transformations have not been confirmed in inflammatory bowel disease. There is an increased incidence of lymphoma in transplant recipients receiving AZA or 6MP,58 and cerebral lymphomas occur more frequently than expected. It has been suggested that the risk of neoplasia is a particular feature of transplant patients, but a prospective study of 1349 non-transplant patients receiving AZA, including 280 patients with inflammatory bowel disease, also showed a significant increase in non-Hodgkin’s lymphoma, squamous cell carcinoma and other tumours (overall risk increased by a factor of 1.6; < 0.03).58, 59 In contrast, reports from St. Mark’s Hospital (755 patients) and from Oxford (2205 patients) showed that the overall risk of neoplasia in patients with inflammatory bowel disease was not increased compared with the general population.60, 61 As the median duration of treatment in the St. Mark’s series61 was approximately 1 year, firm conclusions concerning the risk of lymphoma cannot be drawn. However, the incidence of colorectal cancer was increased for ulcerative colitis patients and correlated with disease duration,61 but was not greater for those taking AZA than for other ulcerative colitis patients.60, 61 Thus the increased risk appears to be due to the underlying inflammatory bowel disease process rather than the medication.

The development of non-Hodgkin’s lymphoma in patients with inflammatory bowel disease on AZA or 6MP has been assessed recently in a study evaluating both the benefits of using these drugs in inflammatory bowel disease and the risk of lymphoma complications. It was concluded that the benefits far outweigh the potential risk of neoplasia.62

PREGNANCY AND LACTATION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PHARMACODYNAMICS
  5. DOSAGE
  6. INDICATIONS
  7. DURATION OF TREATMENT AND TAPERING
  8. ADVERSE EFFECTS
  9. MONITORING
  10. CANCER RISK
  11. PREGNANCY AND LACTATION
  12. CONCLUSIONS
  13. ACKNOWLEDGEMENT
  14. References

From a database of over 2800 patients with inflammatory bowel disease, 155 patients who had been pregnant at least once while on AZA or 6MP were interviewed. The pregnancy outcomes (measured as full-term births, premature births, spontaneous abortions, congenital abnormalities and neonatal infections) did not differ from those of women with inflammatory bowel disease not receiving AZA or 6MP.63 Thus, there is no scientific rationale for physicians to advise patients planning to become pregnant to discontinue AZA or 6MP therapy,64 and AZA and 6MP can be prescribed safely to fertile women.65

Although both AZA and 6MP cross the placenta,66 no specific teratogenic effects have been reported.41, 62 The general risk of teratogenicity is found to be identical to the level in the background population (4%).63, 65, 67 Although data on the use of AZA and 6MP specifically in pregnant patients with inflammatory bowel disease are limited, studies of women taking AZA or 6MP for kidney transplantation or rheumatic disorders have not revealed increased teratogenicity.68 If either drug is essential for disease control, women should be reassured that continuing treatment is compatible with the delivery of a healthy baby. Additionally, there is no indication for the termination of pregnancy because of AZA or 6MP treatment. Cessation of AZA or 6MP treatment during gestation is likely to be more hazardous, because relapse may influence the outcome of the pregnancy negatively, i.e. increase the risk of spontaneous abortion or premature birth.69 However, breast-feeding is contraindicated in women taking AZA or 6MP because these agents are excreted in significant amounts in breast milk.70

Two recent studies have shown that conceiving a child with a man with inflammatory bowel disease undergoing AZA/6MP treatment results in a slightly increased risk of spontaneous abortion and congenital abnormalities in general.71, 72 Even though one paper has described decreased male fertility,72 it is the general opinion that AZA and 6MP do not affect male fertility.73, 74

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PHARMACODYNAMICS
  5. DOSAGE
  6. INDICATIONS
  7. DURATION OF TREATMENT AND TAPERING
  8. ADVERSE EFFECTS
  9. MONITORING
  10. CANCER RISK
  11. PREGNANCY AND LACTATION
  12. CONCLUSIONS
  13. ACKNOWLEDGEMENT
  14. References

The thioguanine derivatives 6MP and AZA are not suitable as first-line treatment in inflammatory bowel disease owing to the delay in obtaining clinical efficacy. In the clinical use of these agents, physicians must maintain a subtle balance between the therapeutic benefits and potential risks or side-effects, and patients must accept the need for regular monitoring after a thorough education in potential toxicities.

In Crohn’s disease, AZA and 6MP are indicated in chronic active disease that fails to respond to glucocorticoids, or when the prednisolone dosage cannot be reduced below 10–15 mg, particularly if adverse effects are problematic. The drugs should be used to maintain remission, but only in patients with previous extensive or troublesome chronic active disease. Furthermore, AZA and 6MP can be administered with advantage to Crohn’s disease patients with fistulous complications.

In ulcerative colitis, chronic unresponsive glucocorticoid-dependent disease and frequent relapses (more than three in 2 years) are, in our opinion, indications for AZA or 6MP treatment. In older patients with long-standing total colitis (10 years or more of pancolonic ulcerative colitis), concerns about the disease-related risk of colorectal cancer may outweigh the benefits of drug therapy and therefore result in the need for total colectomy, whereas AZA or 6MP may have a major role in younger patients with more recent onset of disease who wish to avoid surgery. Left-sided disease more commonly fails to respond fully to glucocorticoids or mesalazine preparations, and purine analogues are particularly useful in this subgroup.34 Obviously, maintenance therapy should be restricted to patients who have achieved satisfactory remission using these drugs.

For steroid-dependent patients, AZA and 6MP appear to be beneficial in both Crohn’s disease and ulcerative colitis and, for the maintenance of remission, the use of AZA or 6MP should be considered in both diseases. If effective, they can be continued for a minimum of 4–5 years, although this period may be much longer. A summary of the recommendations from this comprehensive review is given in Table 1.

Table 1.   Summary of recommendations Thumbnail image of

It may be worthwhile to introduce therapeutic drug monitoring by investigating 6-thioguanine nucleotides during standard oral AZA therapy so that more insight into the therapeutic window may be obtained. However, TMPT genotyping does not appear to satisfactorily predict the development of myelosuppression. Finally, it would be useful to design new oral AZA formulations, which deliver the active metabolites directly to the inflamed intestine, in order to reduce the toxicity or adverse effects and at the same time improve the therapeutic ratio.

References

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PHARMACODYNAMICS
  5. DOSAGE
  6. INDICATIONS
  7. DURATION OF TREATMENT AND TAPERING
  8. ADVERSE EFFECTS
  9. MONITORING
  10. CANCER RISK
  11. PREGNANCY AND LACTATION
  12. CONCLUSIONS
  13. ACKNOWLEDGEMENT
  14. References
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