Safe treatment of thiopurine S-methyltransferase deficient Crohn's disease patients with azathioprine

Thiopurine S-methyltransferase (TPMT) deficient patients develop life threatening haematotoxicity (for example, pancytopenia) when treated with a standard dose of azathioprine (AZA) and 6-mercaptopurine (6-MP) due to excessive accumulation of cytotoxic metabolites. At present, it is generally recommended that these patients should not receive AZA or 6-MP treatment for inflammatory bowel disease. We report for the first time that Crohn's disease patients with TPMT deficiency can be successfully treated with AZA. We illustrate this with three cases where treatment has been successful and toxicity has been avoided by carefully titrating the drug dose. Thus very low TPMT activity demands pharmacogenetically guided dosing.     

Normal thiopurine methyltransferase phenotype testing in a Crohn disease patient with azathioprine induced myelosuppression

Severe cytopenias in patients with autoimmune conditions treated with azathioprine are well-recognized. Thiopurine methyltransferase (TPMT) enzymatic activity is subject to individual and ethnic variability. Patients with low TPMT activity (poor metabolizers) are at high risk of developing severe and potentially fatal haematopoietic toxicity. Studies have shown that essentially all TPMT-deficient patients will develop haematopoietic toxicity on administration of conventional thiopurine dosages (6-mercaptopurine, azathioprine). Therefore, screening for TPMT polymorphisms in patients before prescribing thiopurine drugs has been proposed. However, despite normal in vitro enzymatic activity, cytopenia may still occur in vivo . This is the case report of an Asian patient with Crohn disease harbouring a rare TPMT mutation on DNA sequencing, who developed neutropenic sepsis and anaemia after a flare of Crohn disease. The report illustrates the importance of monitoring for cytopenia in the setting of active inflammatory disease despite prior normal phenotyping, the role of predictive pharmacogenetics and the limitations of TPMT phenotype assays that may result in misclassification of at-risk patients.     

Azathioprine-associated acute myeloid leukemia in a patient with Crohn's disease and thiopurine S-methyltransferase deficiency

Immunosuppressive thiopurines like azathioprine, 6-mercaptopurine, and thioguanine are commonly used in inflammatory and neoplastic disorders. A subset of these patients are genetically slow metabolizers due to point-mutations in enzyme thiopurine S-methyltransferase (TPMT), and are at a higher risk of hematologic toxicity and leukemogenesis. We present such a patient who was a slow metabolizer for azathioprine, and developed a rapidly lethal form acute myeloid leukemia after relatively low dose exposure to the drug. There was prominent hemophagocytic activity in the bone marrow, and cytogenetic analysis showed a complex karyotype with monosomy 7, but no involvement of chromosome 8.     

Adverse reactions to azathioprine cannot be predicted by thiopurine S-methyltransferase genotype in Japanese patients with inflammatory bowel disease

Background and Aims:  Azathioprine (AZA) is associated with a high frequency of adverse reactions. We examined polymorphism of the thiopurine S-methyltransferase (TPMT) gene to determine whether the TPMT genotype would be a predictive marker for the development of adverse reactions to AZA.
Methods:  The frequency of TPMT mutations was investigated in 147 Japanese inflammatory bowel disease (IBD) patients retrospectively. In these subjects, the presence of four mutant alleles (TPMT*2, *3B, *3C and *8) was determined by direct sequencing. The incidence of adverse reactions among patients carrying wild-type TPMT was investigated. The blood level of 6-thioguanine nucleotide (6-TGN) was measured and analyzed in 47 patients with wild-type TPMT. The results were analyzed in relation to the concomitant use of aminosalicylates (ASA).
Results:  Of the 147 patients, 144 (98.0%) were wild-type for TPMT (TPMT*1/*1) and three (2.0%) carried a mutant TPMT allele (TPMT*1/*3C). The incidence of adverse reactions was 33.3% (38/114) in the wild-type group. Leukopenia (WBC ≤ 3000/µL) was seen in 15.8% of the patients with wild-type TPMT. 6-TGN levels varied among 47 patients with wild-type TPMT. The blood levels of 6-TGN were significantly higher in the patients receiving concomitant ASA treatment compared with those not receiving concomitant ASA treatment ( P  = 0.0033).
Conclusion:  The frequency of TPMT gene mutations is low among Japanese IBD patients. The incidence of adverse reactions to AZA was high, even in patients carrying wild-type TPMT. It is concluded that determination of TPMT genotype may not be useful in Japanese IBD patients to predict adverse reactions to AZA.     

MDR1 polymorphisms and response to azathioprine therapy in patients with Crohn's disease

BACKGROUND: To investigate the contribution of multidrug resistance 1 (MDR1) gene pharmacogenetics (G2677T/A and C3435T) to the efficacy of azathioprine in inducing remission in patients with Crohn's disease (CD). METHODS: A cohort of 327 unrelated Spanish patients with CD recruited from a single center was studied. All patients were rigorously followed up for at least 2 years (mean time, 11.5 years). A case-control analysis of MDR1 G2677T/A and C3435T SNPs and 2 loci haplotypes in 112 steroid-dependent CD patients treated with azathioprine was performed. Patients were classified on the basis of response to azathioprine. RESULTS: A total 76 patients treated with azathioprine for longer than 3 months were included. Remission was achieved in 42 CD patients (55.3%). A higher frequency of the 2677TT genotype was found in nonresponders than in responders (17.65% versus 7.14%; OR = 2.8; 95% CI; 0.6-12.1; P = 0.11). Nonresponders to azathioprine were found to have a higher frequency of the 3435TT genotype than did CD patients who had achieved clinical remission (17.64% versus 4.76%; OR = 4.3; 95% CI, 0.8-22.8; P = 0.06). The 2677T/3435T haplotype was also more abundant in nonresponders (29.4% versus 20.2%), whereas the 2677G/3435C haplotype was more frequent in responders (58.3% versus 47.1%). Lack of response to azathioprine therapy in CD patients was 1.8-fold greater in carriers of the 2677T/3435T haplotype than in carriers of the 2677G/3435C haplotype (OR = 1.8; 95% CI, 0.82-3.9; P = 0.14). CONCLUSIONS: The results of our study indicate higher frequencies of the 2677TT and 3435TT genotypes and the 2677T/3435T haplotype in CD patients who did not respond to azathioprine. Additional replications in independent populations would confirm the real impact of these polymorphisms in response to azathioprine therapy.     

Monitoring of thiopurine methyltransferase and thiopurine metabolites to optimize azathioprine therapy in inflammatory bowel disease

Determination of the activity of thiopurine methyltransferase (TPMT) and of thiopurine metabolites (6-thioguanine and 6-methylmercaptopurine nucleotides) could be useful for individualized monitoring of azathioprine (AZA) and 6-mercaptopurine (6-MP) doses. TPMT activity in the general population follows a trimodal distribution, in which approximately 0.3% of the population is homozygotic for the low-activity allele. A notable correlation has been observed between the low TPMP activity genotype or phenotype and the risk of myelotoxicity. Patients with a high TPMT activity genotype or homozygous phenotype should receive immunosuppressive doses that have clearly been demonstrated to be effective. In contrast, in patients with a low TPMT activity genotype or homozygous phenotype, the use of AZA/6-MP should be contraindicated or only very small doses should be administered. Importantly, TPMP deficiency explains only some cases of myelotoxicity and consequently periodic laboratory testing should be performed in patients receiving AZA/6-MP, even though TPMP function may be normal. Currently, the utility of routine thiopurine metabolite determinations in patients undergoing AZA/6-MP therapy has not been established and this practice should be limited to specific situations such as lack of response to thiopurine therapy or the occurrence of thiopurine-related adverse effects. Randomized trials comparing the routine strategy of AZA/6-MP dosing (based exclusively on the patient's weight) versus individualized monitoring (based on quantification of TPMP activity and/or thiopurine metabolites) are required before definitive conclusions on the most effective alternative can be drawn.     

Alcohol binging causes peliosis hepatis during azathioprine therapy in Crohn＇s disease

Patients with inflammatory bowel disease have normal life expectancy and, due to modern immunosuppressive therapies, also a normal quality of life. Since mostly young people are affected, their social behaviour suits this environment. Alcohol binging is an increasingly disturbing factor among young people. We describe a patient with Crohn's disease, treated with azathioprine, who developed peliosis hepatis after three epsiodes of alcohol binging. Liver toxicity was not observed previously during the course of the treatment. Azathioprine-induced peliosis hepatis is thought to be idiosyncratic in humans. From animal studies, however, it is clear that hepatic depletion of glutathione leads to azathioprine toxicity to the sinusoidal endothelial cells. Damage of these cells causes peliosis hepatis. Since alcohol binging leads to hepatic glutathione depletion, we conclude that in our patient the episodes of binging have reduced liver gluathione content and therefore this has increased azathioprine toxicity causing peliosis hepatis. The problem of alcohol binging has not yet been addressed in IBD patients undertaking immunosuppressive therapy. This should be reviewed in future considerations regarding patients advice.     

Bone mineral density in patients with Crohn's disease during long-term treatment with azathioprine

Florén C-H, Ahrén B, Bengtsson M, Bartosik J, Obrant K (Lund University, Malmö, Sweden). Bone mineral density in patients with Crohn's disease during long-term treatment with azathioprine. J Intern Med 1998; 243 : 123–26.

Objectives

To ascertain whether patients with Crohn's disease treated with azathioprine maintained bone mineral mass better than patients treated with steroids alone.

Design

Retrospective study.

Setting

University Hospital of Malmö, Sweden.

Subjects

A total of 59 patients with ileocolonic, ileocaecal or colonic Crohn's disease.

Methods

Bone mass was assessed by dual photon X-ray absorptiometry at the level of L2 – L4.

Results

Patients treated with a high lifetime dose of steroids (> 5 g prednisolone) had significantly (P= 0.011) lower Z-score of L₂–L₄ (?0.87 ± 1.11; 11 SD) than steroid-treated patients, who had received a low dose of prednisolone (< 5 g) (0.08 ± 1.16 SD). Azathioprine did not negatively influence the steroid effect on bone mineral density.

Conclusions

Azathioprine does not seem to affect bone mineral density by itself. However, by being steroid-saving, it seems to conserve bone mineral mass in patients with Crohn's disease.

     

Side effects of azathioprine in patients with Crohn's disease

OBJECTIVE: In clinical trials 0-15% of patients discontinued azathioprine due to side effects. The aim of this study was to assess the rate of side effects leading to discontinuation of azathioprine and to determine predictive factors for discontinuation. DESIGN: A retrospective cohort analysis of clinical data regarding adverse events of azathioprine in Crohn's disease. PATIENTS: Azathioprine had been prescribed for 54 of 112 consecutive patients with Crohn's disease. Because incomplete data were available in four patients, the data for 50 patients were analysed. RESULTS: In 15 of the 50 patients azathioprine was preliminary discontinued due to adverse events and in 11 of these patients (22%) adverse events were probably related to azathioprine. After the onset of therapy, a small, but significant, decrease in leucocyte count was observed within 6 weeks (median from 10.6 to 9.5 x 10(9)/l) and asymptomatic leucopenia (< 3.0 x 10(9)/l) occurred in two patients. Serious adverse events occurred in three patients who, as a result, required admission to hospital. All events were reversible after discontinuation of therapy. Patients who discontinued azathioprine due to adverse events used significantly lower initial doses of prednisone compared to patients who were able to continue azathioprine. The occurrence of side effects was not related to the initial dose of azathioprine or concomitant use of 5-aminosalicylates. CONCLUSION: Twenty-two per cent of patients discontinued azathioprine prematurely probably as a result of related adverse events. Patients who discontinued azathioprine prematurely used lower doses of prednisone initially. Therefore, concomitant use of prednisone may prevent some of the adverse events.     

Methotrexate following unsuccessful thiopurine therapy in pediatric Crohn's disease

BACKGROUND: The thiopurines, azathioprine and 6-mercaptopurine, are traditional first-line immunomodulatory agents in adult and pediatric Crohn's disease, but the comparative efficacy and safety of methotrexate have seldom been examined. We report outcomes with methotrexate treatment in pediatric patients previously refractory to or intolerant of thiopurines. METHODS: In a four-center, retrospective cohort study, efficacy of methotrexate in maintaining remission was assessed by PCDAI measurements, steroid use, and height velocity. Patients served as their own historical controls. Multivariable analysis controlled for route of methotrexate administration, reason for thiopurine discontinuation, baseline disease activity, and disease duration. RESULTS: Forty-two percent of 60 children treated with methotrexate were in clinical remission without steroids at both 6 and 12 months. A strong steroid sparing effect was observed compared with the year prior to methotrexate (P<0.001). Success rates were similar in previously thiopurine-intolerant and refractory patients. Height velocity increased from -1.9 SDS to -0.14 SDS (P=0.004) in the year following therapy. In a median 3-yr follow-up, a third of the patients did not require escalation of therapy; the others required step-up therapy with infliximab or surgery. Eight children (13%) stopped methotrexate due to adverse events, including, most commonly, elevated liver enzymes, and one serious episode of sepsis. CONCLUSION: Methotrexate appears effective in maintaining remission in pediatric Crohn's disease, when thiopurines have failed. Consideration should be given to its use earlier in pediatric treatment algorithms.     

Mesenteric pulsatility index analysis predicts response to azathioprine in patients with Crohn's disease

OBJECTIVE: Mesenteric blood flow measurement has been found to predict relapse after steroid-induced remission in patients with Crohn's disease (CD) and ulcerative colitis (UC). Therefore, we assessed prospectively the possible relationship between changes in mesenteric blood flow and prognosis in chronically active patients with need of immunosuppressive therapy with azathioprine (AZA) or 6-mercaptopurine (6-MP). METHODS: Doppler ultrasound (DUS) measurements of the pulsatility index (PI) of the superior mesenteric artery (SMA) and inferior mesenteric artery (IMA) were performed in 52 patients with chronically active inflammatory bowel disease (CD 31 patients; UC 21 patients) before beginning therapy with AZA/6-MP (US1) and during clinical remission (CD activity index <150, Truelove index score I) (US2). Patients were weaned from concomitant therapy with corticosteroids as soon as possible and were followed up for 12 months. RESULTS: After 1 year, 16 patients with CD (51.6%) and 13 patients with UC (61.9%) were in remission, whereas 23 patients had recurrent disease or had undergone surgery. A decreased SMA PI at US2 predicted clinical relapse in all patients with CD [100%; P < 0.001; mean (+/-SD) 77 +/- 67 d after US1], but only 4 of 8 patients (50%; difference not significant; mean 84 +/- 75 d after US1) with UC. Conversely, an increase of SMA PI was associated with sustained remission in the majority of CD patients (12/16 patients; 75%; P < 0.002), but in only 7 of 13 patients (54%) with UC. Flow measurements in the IMA and postprandial values for both arteries were less reliable. CONCLUSION: Repeated DUS measurements of the SMA PI predict response to AZA/6-MP in patients with chronic active CD.     

Long-term results with azathioprine therapy in patients with corticosteroid-dependent Crohn's disease: open-label prospective study

BACKGROUND: A substantial number of patients with Crohn's disease (CD) become dependent on steroids after induction therapy. Treatment with azathioprine (AZA) may be beneficial in such patients. The present open-label study evaluated the long-term safety and efficacy of AZA in steroid-dependent CD patients. METHODS: Adult patients with steroid-dependent CD were enrolled for AZA therapy over a 7-year period. The average dose of AZA was 2.0-3.0 mg/kg per day, adjusted according to clinical response and occurrence of adverse effects. Steroid therapy was tapered off according to a predefined schedule. Long-term outcome and adverse reactions were evaluated. RESULTS: Sixty-nine patients were prospectively included. Steroid-free remission was achieved in 68-81% of patients, partial response in 14.5-27.3% and failure to respond to AZA in 4-15.9% over the initial 48 months. However, the rate of wean from steroid therapy decreased to 53-60% while the rate of failure increased from 6.7% to 17.6% after this period. A breakthrough of symptoms during continuous AZA therapy was common, particularly after 48 months on AZA. The mean leukocyte count at the end of 12 months of therapy was significantly lower in patients who achieved complete response on AZA than in the non-responders (5197 +/- 1250 cells/mm(3) vs 8340 +/- 1310 cells/mm(3), respectively; P < 0.01). Azathioprine was relatively well-tolerated and the incidence of serious adverse effects was small. CONCLUSIONS: Azathioprine was relatively safe and moderately effective for long-term maintenance of steroid-free clinical remission in corticosteroid-dependent CD patients. Patients were more successfully weaned from prednisone treatment, and clinical remission was more often maintained during the first 48 months of AZA therapy. A significant decrease in the white blood cell count at the end of 12 months on AZA was the single factor associated with weaning from steroid dependence.     

Measurement of thiopurine methyltransferase activity and azathioprine metabolites in patients with inflammatory bowel disease

BACKGROUND: Measurement of 6-thioguanine nucleotide concentrations may be useful for optimising treatment with azathioprine and 6-mercaptopurine. METHODS: We conducted a study of 170 patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine to determine the relationship between 6-thioguanine nucleotide concentrations and both disease activity, as measured by the inflammatory bowel disease questionnaire (active disease < 170, remission > or = 170) and leucopenia. Blood was submitted for whole blood 6-thioguanine nucleotide concentration and leucocyte count. RESULTS: Mean (SD) inflammatory bowel disease questionnaire score was 176 (32). There was no correlation between inflammatory bowel disease questionnaire scores and 6-thioguanine nucleotide concentrations (r(s) = -0.09, p = 0.24). Median 6-thioguanine nucleotide concentrations in 56 patients with active disease and 114 patients in remission were similar (139 v 131 pmol/8 x 10(8) red blood cells; p = 0.26). There was no correlation between 6-thioguanine nucleotide concentrations and leucocyte counts. CONCLUSIONS: In patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine, 6-thioguanine nucleotide concentrations did not correlate with disease activity, as measured by the inflammatory bowel disease questionnaire, or leucocyte count. These findings are discrepant with most previous studies, possibly due to selection of responding patients who tolerated the medications. A prospective, randomised, dose optimisation trial using 6-thioguanine nucleotide concentrations is warranted.     

英夫利西联合硫唑嘌呤治疗克罗恩病的临床及内镜随访

目的 观察英夫利西联合硫唑嘌呤治疗克罗恩病(CD)的疗效及黏膜愈合情况与预后的关系.方法 研究对象为广州中山大学附属第一医院接受英夫利西联合硫唑嘌呤治疗的20例活动性CD患者.根据CD活动指数分别评价治疗10周、30周、54周及2年时的临床疗效.根据内镜下黏膜应答情况分别评价治疗10周、30周、54周时的内镜下疗效.两组间比较采用方差分析或Fisher精确概率法.黏膜愈合影响因素采用Logistic回归分析.结果 治疗10周、30周、54周和2年时的无糖皮质激素临床缓解率分别为12/20、16/20、15/20和15/20,10周、30周和54周时的黏膜愈合率分别为8/20、12/20和10/20.Logistic多因素回归分析显示,年轻是影响治疗30周时黏膜愈合的惟一因素((OR=0.774,95％CI:0.630～0.950).30周时黏膜应答者与内镜下无效者在30周及2年时的无糖皮质激素临床缓解率(30周时为14/14比2/6,2年时为14/14比1/6)均差异有统计学意义(Fisher精确概率法,P均＜0.01).30周时获无糖皮质激素临床缓解的16例患者在54周时有4例停用英夫利西,其余12例继续英夫利西治疗,停用和续用英夫利西者的无糖皮质激素临床缓解率(4/4比11/12)和黏膜愈合率(2/4比7/12)均差异无统计学意义(P均＞0.05).结论 英夫利西联合硫唑嘌呤治疗可有效促进和维持CD黏膜愈合,黏膜应答者能维持较长期的无糖皮质激素临床缓解.     

Fatal infectious mononucleosis during azathioprine treatment in Crohn's disease

The benefits of immunosuppressive agents in inflammatory bowel disease have been the subject of controversy. However, extensive clinical data have conclusively proved their efficacy with respect to potential toxicity. Azathioprine is one of the most widely used immunosuppressive agents in the treatment of Crohn's disease and its effectiveness has been proved in corticosteroid dependent, corticosteroid-refractory and fistulizing Crohn's disease. We present a 24-year-old male, treated with azathioprine for corticosteroid dependent Crohn's disease who was admitted to hospital with constant fever, lymphadenopathy and liver function abnormalities secondary to infectious mononucleosis after a primary infection with Epstein-Barr virus. The patient developed constitutional symptoms and progressive jaundice and 14 days after hospital admission died because of massive upper gastrointestinal bleeding due to hemorrhagic erosive gastropathy.