The safety of 6-mercaptopurine for childbearing patients with inflammatory bowel disease: a retrospective cohort study

BACKGROUND & AIMS: 6-mercaptopurine/azathioprine is effective in IBD patients. However, data regarding toxicity associated with pregnancy are lacking, raising both patients' and physicians' concerns and sometimes resulting in elective abortion. METHODS: To evaluate potential toxicity of 6-mercaptopurine (6-MP), we reviewed the records of 485 patients who had received the drug. We contacted 462, of whom 155 had conceived at least 1 pregnancy after developing IBD. Pregnancies were analyzed as to whether the patient had taken 6-MP before, or at the time of, conception. These were compared with IBD patients who had their pregnancies before taking 6-MP. We collected data on live births, spontaneous abortions, prematurity, abortions secondary to birth defects, major and minor congenital birth defects, infections, and neoplasia. Outcomes were analyzed comparing pregnancies from men and women who had taken or were currently taking 6-MP to controls. RESULTS: There was no statistical difference in conception failures (defined as a spontaneous abortion), abortion secondary to a birth defect, major congenital malformations, neoplasia, or increased infections among male or female patients taking 6-MP compared with controls (RR = 0.85 [0.47-1.55], P = 0.59). CONCLUSIONS: 6-MP use before or at conception or during pregnancy appears to be safe. Discontinuation of the drug before and during pregnancy is not indicated.     

Azathioprine treatment and male fertility in inflammatory bowel disease.

BACKGROUND & AIMS: Long-term treatment with azathioprine (AZA) is well established in inflammatory bowel disease (IBD). AZA is metabolized to 6-mercaptopurine (6-MP), which interacts in purine metabolism and is therefore considered to have mutagenic potentials. This is the first study to examine the influence of AZA on semen quality. METHODS: Semen quality was examined and compared with World Health Organization (WHO) standards regarding sperm density, motility, morphology, ejaculate volume, and total sperm count in 23 IBD patients treated with AZA. In 10 of these patients, a semen sample was assessed before and during AZA treatment; in another 5, semen analysis was performed twice during at least 2 years of AZA therapy. RESULTS: In 18 patients treated with 1.5-2 mg/kg AZA daily for at least 3 months but without sulfasalazine, sperm density was 94 +/- 84 Mio/mL (94% within WHO standard), motility was 60% +/- 20% (67% within WHO standard), the proportion of sperm with normal morphology was 44% +/- 21% (67% within WHO standard), ejaculate volume was 3.4 +/- 1.5 mL (89% within WHO standard), and total sperm count was 297 +/- 272 Mio (94% within WHO standard). No changes in semen parameters were noted after 11 +/- 5 months of AZA administration or during long-term treatment (49 +/- 14 months). Sulfasalazine administration in 5 patients was associated with markedly reduced semen morphology. During the study period, 6 patients fathered 7 healthy children. CONCLUSIONS: Our data show that AZA does not reduce semen quality and thereby male fertility in IBD.     

6-mercaptopurine and spermatogenesis in the young rat

In recent years, 6-MP treatment has been beneficial in the treatment of inflammatory bowel disease (IBD). Since 6-MP and its metabolites interfere with various steps in nucleic acid biosynthesis, chronic use of 6-MP could theoretically alter normal cell turnover, including spermatogenesis. Therefore, we have investigated the effect of daily 6-MP administration on spermatogenesis in the young rat. 6-Mercaptopurine was administered in clinically relevant doses 24 and 40 mg/m². Testicular weights of rats treated with 24 mg/m² for 75 days or 40 mg/m² for 25 days were not significantly different among 6-MP, pair-fed, orad libitum chow-fed groups. Quantitation of the stages of seminiferous tubules or the number of homogenization-resistant, mature spermatids per testis were not affected by 6-MP treatment. In addition, 6-MP had no effect on serum testosterone or on HCG-stimulated testosterone release by the testes. These results suggest that chronic low-dose 6-MP therapy, as used in the treatment of IBD, may not carry as great a risk for suppression of spermatogenesis as theorized. Our study in animals indicates that evaluation of 6-MP and spermatogenesis in man is warranted.This project was funded by a grant from Reach Out for Youth with IBD.     

Thioguanine: a potential alternate thiopurine for IBD patients allergic to 6-mercaptopurine or azathioprine

OBJECTIVE: Approximately 10% of inflammatory bowel disease (IBD) patients receiving 6-mercaptopurine (6-MP) or azathioprine (AZA) develop drug hypersensitivity reactions necessitating early discontinuation of these traditional thiopurines. These allergic reactions typically reoccur upon rechallenge. Our recently published pilot study suggested that thioguanine (6-TG), a closely related thiopurine, was efficacious and well tolerated in IBD patients resistant to 6-MP/AZA. The aim of this study was to determine if hypersensitivity reactions to 6-MP/AZA reoccur with 6-TG therapy. METHODS: IBD patients allergic to 6-MP and/or AZA were treated with 6-TG as an alternate thiopurine. Hypersensitivity reactions to 6-MP/AZA must have been documented within 6 wk of 6-MP/AZA initiation. RESULTS: 6-TG was initiated in 21 IBD patients at a median (range) dose of 20 (10-40) mg/day. 6-TG hypersensitivity reaction occurred in only four of 21 (19%) patients after a median time interval of 9 days. Pancreatitis did not reoccur with 6-TG. Eighty-two percent of 6-TG tolerant patients were assessed as improved at last follow-up. CONCLUSIONS: These results suggest that 6-TG may be considered as a possible alternate thiopurine in patients allergic to traditional 6-MP/AZA. Despite these favorable results, candidates for 6-TG should be selected with caution, and its use should be reserved for IBD patients well informed about potential toxicities.     

6-MP metabolite profiles provide a biochemical explanation for 6-MP resistance in patients with inflammatory bowel disease

BACKGROUND & AIMS: Approximately 40% of inflammatory bowel disease (IBD) patients fail to benefit from 6-mercaptopurine (6-MP)/azathioprine (AZA). Recent reports suggest 6-thioguanine nucleotide (6-TGN) levels (>235) independently correlate with remission. An inverse correlation between 6-TGN and thiopurine methyltransferase (TPMT) has been described. The objectives of this study were to determine whether dose escalation optimizes both 6-TGN levels and efficacy in patients failing therapy because of subtherapeutic 6-TGN levels and its effect on TPMT. METHODS: Therapeutic efficacy and adverse events were recorded at baseline and upon reevaluation after dose escalation in 51 IBD patients. 6-MP metabolite levels and TPMT activity were recorded blinded to clinical information. RESULTS: Fourteen of 51 failing 6-MP/AZA at baseline achieved remission upon dose escalation, which coincided with significant rises in 6-TGN levels. Despite increased 6-MP/AZA doses, 37 continued to fail therapy at follow-up. Dose escalation resulted in minor changes in 6-TGN, yet a significant increase in 6-methylmercaptopurine ribonucleotides (6-MMPR) (P < or = 0.01) and 6-MMPR:6-TGN ratio (P < 0.001). 6-MMPR rises were associated with dose-dependent hepatotoxicity in 12 patients (24%). TPMT was not influenced by dose escalation. CONCLUSIONS: Serial metabolite monitoring identifies a novel phenotype of IBD patients resistant to 6-MP/AZA therapy biochemically characterized by suboptimal 6-TGN and preferential 6-MMPR production upon dose escalation.     

Outcome of pregnancies when fathers are treated with 6-mercaptopurine for inflammatory bowel disease

OBJECTIVE: The outcomes of pregnancies after maternal use of 6-mercaptopurine (6-MP) for inflammatory bowel disease (IBD) during pregnancy have been reported, but data are lacking for outcomes when the fathers use this drug. METHODS: Subjects were male patients with IBD seen at one center between 1970 and 1997. Patients and their wives were interviewed. Group 1 comprised pregnancies fathered by men who were taking 6-MP. This group was further subdivided into those conceived within 3 months of 6-MP use and those conceived at least 3 months after 6-MP was stopped. Group 2 comprised pregnancies fathered by men with IBD, similar in characteristics to group 1, who had not taken 6-MP before fertilization. Information was collected regarding the fathers, the mothers, and the pregnancies, as well as the health of the children, in a historical cohort study. RESULTS: There were 50 pregnancies in group 1 (13 in 1A and 37 in 1B) and 90 pregnancies in group 2. Four of the 13 pregnancies in group 1A were associated with complications. There were two spontaneous abortions, and two congenital anomalies including a missing thumb in one and acrania with multiple digital and limb abnormalities in the other. Risk of complications was significantly increased when compared with group 1B (p < 0.013) and group 2 (p < 0.002). CONCLUSION: The incidence of pregnancy-related complications was significantly increased when the fathers used 6-MP within 3 months of conception.     

Risk of postoperative infection in patients with inflammatory bowel disease]

BACKGROUND/AIMS: The clinical course of patients with inflammatory bowel disease (IBD) frequently leads to the use of immunosuppressants and immunomodulators. We investigated the risk of postoperative infection in patients with IBD undergoing elective bowel surgery and whether the use of corticosteroid (CS) and/or 6-mercaptopurine/ azathioprine (6-MP/AZA) before surgery was associated with the increased risk of postoperative infection. METHODS: Patients who were diagnosed as Crohn's disease (n=25) or ulcerative colitis (n=19) and underwent elective bowel surgery between 1986 and 2005 were identified. Medical records were retrospectively analyzed including age, sex, duration of disease, indication for surgery, duration of surgery, type of surgery, type of postoperative infection, admission period, usage of CS and 6-MP/AZA, and preoperative laboratory values. There were 27 patients receiving CS alone, 6 patients receiving 6-MP/AZA alone or with CS, and 16 patients receiving neither CS nor 6-MP/AZA. RESULTS: There were 17 postoperative infections (38.6%) among IBD patients who had undergone surgery and wound infection was the most common type of infection (76.5%). In IBD patients, patients receiving CS had higher postoperative infection rate than those patients receiving neither CS nor 6-MP/AZA (p=0.039). Patients receiving CS in conjunction with 6-MP/AZA did not have significantly higher postoperative infection rate than those with CS only (p=0.415). CONCLUSIONS: Preoperative use of CS in patients with IBD is associated with the increased risk of postoperative infections. Addition of 6-MP/AZA in patients receiving CS does not increase the risk of postoperative infections.     

The frequency and the course of the adverse effects of azathioprine/6-mercaptopurine treatment in patients with inflammatory bowel disease]

BACKGROUND/AIMS: This study was to evaluate the frequency and the course of the adverse effects of AZA/6-MP in Korean patients with inflammatory bowel disease (IBD). METHODS: Medical records of the patients with IBD treated with AZA/6-MP at Severance hospital from June 1996 to September 2006 were retrospectively analyzed. RESULTS: A total of 133 patients were studied. Male to female ratio was 1.3:1. The mean age was 31.7+/-10.9 year. Adverse effects included leukopenia occurred in 75 cases (56.4%), nausea/vomiting in 32 cases (24.1%), arthralgia in 6 cases (4.5%), hepatitis in 6 cases (4.5%), skin rash in 4 cases (3.0%), herpes zoster in 3 cases (2.3%), and headache in 1 case (0.8%). Most of leucopenia (58.7%) developed within 3 months after maximal tolerated dose of AZA/6-MP and nausea/vomiting frequently occurred within 3 months after start of AZA/6-MP treatment. Thirty-eight patients (28.6%) required the discontinuation of medication due to adverse effects. CONCLUSIONS: Leukopenia was the most common adverse effect of AZA/6-MP treatment. Leukopenia and nausea/vomiting developed frequently in the early period of treatment of AZA/6-MP in patients with IBD. AZA/6-MP should be used cautiously to scrutinize bone marrow suppression.     

6-Mercaptopurine metabolism in Crohn's disease: correlation with efficacy and toxicity.

BACKGROUND: 6-Mercaptopurine (6-MP) has confirmed short and longterm efficacy in the treatment of IBD. However, the relation between its metabolism, efficacy, and side effects is not well understood. AIMS: To assay 6-MP metabolites and to correlate levels with drug compliance, disease activity, and adverse effects of treatment. PATIENTS: Heparinised blood was obtained prior to daily administration of 6-MP in 25 adolescent Crohn's disease patients (14 ileocolitis, 11 colitis) receiving 1.2 (range 0.4-1.6) mg/kg/day for a mean of 17 (range 4-65) months. METHODS: Erythrocyte free bases 6-thioguanine (6-TG) and 6-methyl-mercaptopurine (6-MMP) were measured (pmol/8 x 10(8) red blood cells) using reverse phase high performance liquid chromatography. RESULTS: Disease activity (modified Harvey-Bradshaw index) improved significantly with 6-MP (p = 0.001). Clinical remission was achieved in 72% of patients, who stopped taking prednisone, or were successfully weaned to a low alternate day dose (< 0.4 mg/kg/OD). Remission correlated well with erythrocyte 6-TG (p < 0.05), but not 6-MMP levels. Neutropenia was associated with 6-MP use (p < 0.005), but did not correlate with erythrocyte 6-MP metabolite levels. One patient refractory to 6-MP had 6-TG, but no measureable 6-MMP production, suggesting deficient thiopurine methyl-transferase activity or poor compliance. 6-MP induced complications (hepatitis, pancreatitis, and marrow suppression) were generally associated with increased 6-MMP levels. CONCLUSIONS: These results suggest that high performance liquid chromatography measurement of erythrocyte 6-MP metabolites may provide a quantitative assessment of patient responsiveness and compliance to treatment. The data support an immunosuppressive role for 6-TG, and potential cytotoxicity of raised 6-MMP levels.     

An open-label pilot study using thioguanine as a therapeutic alternative in Crohn's disease patients resistant to 6-mercaptopurine therapy

BACKGROUND AND AIMS: A substantial number of patients with inflammatory bowel disease (IBD) fail to achieve a complete clinical response with 6-mercaptopurine (6-MP) and azathioprine (AZA). Inability to achieve therapeutic 6-thioguanine nucleotide (6-TGN) levels due to the preferential overproduction of 6-methylmercaptopurine ribonucleotides (6-MMPR) upon dose escalation characterizes a newly described subgroup of IBD patients resistant to 6-MP/AZA therapy. Treatment with 6-thioguanine (6-TG), a related thiopurine, which forms 6-TGNs more directly may be beneficial in such patients. This pilot study evaluated the safety, tolerance, and efficacy of 6-TG in the subgroup of Crohn's disease (CD) patients failing to attain adequate disease control with traditional 6-MP/AZA therapy. METHODS: Ten CD patients with preferential 6-MMPR production upon 6-MP/AZA dose escalation were enrolled in an open-label pilot study. Seven of 10 patients had experienced dose-related 6-MP toxicities. RESULTS: Seventy percent of the patients (7 of 10) responded or were in remission at week 16. Clinical response was evident by week 4 in most. 6-TGN levels were nine-fold higher with 6-TG treatment than with 6-MP, whereas 6-MMPR levels were undetectable. No patient developed a recurrence of hepatic or hematological toxicity. CONCLUSIONS: 6-TG was a safer and more efficacious thiopurine in this subgroup of IBD patients resistant to 6-MP therapy. Larger controlled trials are warranted to further evaluate both the short- and long-term safety and efficacy in this subgroup of patients as well as a broader spectrum of IBD patients.     

Incidence of neoplasms in patients who develop sustained leukopenia during or after treatment with 6-mercaptopurine for inflammatory bowel disease.

BACKGROUND & AIMS: Studies to date have not confirmed an association between neoplasms and inflammatory bowel disease (IBD) treated with 6-mercaptopurine (6-MP). We have observed the occurrence of some neoplasms in IBD patients who developed sustained leukopenia as a result of treatment with 6-MP. As a result, we sought to compare the incidence of neoplasms in patients who developed sustained leukopenia after taking 6-MP compared with patients treated with 6-MP without sustained leukopenia. METHODS: A database containing the medical records of more than 600 patients treated with 6-MP for IBD at 1 center between 1965 and 2002 was searched. The patients were divided into 2 groups. The study group consisted of patients who developed sustained leukopenia, defined as a white blood cell count of less than 4000 for 20 or more days. The control group patients matched those in the study group for age and sex. There were 3 matched controls for each patient in the study group. RESULTS: Eighteen patients developed sustained leukopenia and, of these, 4 developed neoplasms (22%)-2 leukemias, 1 non-Hodgkin's lymphoma, and 1 breast cancer. Of the 54 patients in the control group, 4 developed neoplasms (7%) (P = .10). Post hoc analysis revealed a statistically significant difference in the number of hematologic malignancies in the group with sustained leukopenia (P = .014). There was no significant difference between the 2 groups for all confounding variables examined. CONCLUSIONS: There was a trend toward a greater number of total malignancies in the sustained leukopenic patients. The data suggest that it is those patients who develop sustained leukopenia while taking 6-MP/azathioprine who are most at risk.     

Increased dosing requirements for 6-mercaptopurine and azathioprine in inflammatory bowel disease patients six years and younger

BACKGROUND: 6-Mercaptopurine (6-MP) and its prodrug azathioprine (AZA) are effective for the induction and maintenance of remission and reduction of corticosteroid exposure for pediatric inflammatory bowel disease (IBD). The standard dose of 6-MP is 1.0-1.5 mg/kg/day and for AZA is 2.0-2.5 mg/kg/day. The aim of this study was to determine whether IBD patients 6 years of age and younger require higher than standard doses of 6-MP/AZA to achieve clinical remission. METHODS: Clinical data was collected retrospectively for all IBD patients 6 years of age or younger treated with 6-MP/AZA at The Children's Hospital of Philadelphia. RESULTS: Thirty patients met the inclusion criteria. IBD was diagnosed at a median age of 3.3 years (25-75th %ile 2.3-4.6 years) and 6-MP/AZA was initiated at a median age of 3.9 years (range 0.8-6.8 years). After dose escalation, the median AZA-equivalent dose was 3.1 mg/kg/day (25-75th %ile 2.5-3.5, max. dose 5.1 mg/kg/day). At the final recorded dose, 8/13 (62%) patients receiving AZA >3.0 mg/kg/day achieved clinical remission, compared to 2/12 (17%) receiving 2-3 mg/kg/day (P = 0.02). The risk of having active disease was on average 85% lower if the AZA-equivalent dose was >3.0 mg/kg/day (95% confidence interval [CI] 72%-93%). Adverse events were experienced by 4/30 patients (hepatitis, n = 2; leukopenia, n = 2). No patients had to discontinue 6-MP/AZA, and all laboratory abnormalities improved spontaneously or with dose reduction. CONCLUSIONS: The standard dose of 6-MP/AZA may not be adequate for IBD patients 6 years of age and younger. Closely monitored dose escalation beyond the standard dosing range is effective and well-tolerated.     

Allergic reactions to 6-mercaptopurine during treatment of inflammatory bowel disease.

Hypersensitivity reactions to 6-mercaptopurine (6-MP) or azathioprine occur during the treatment of inflammatory bowel disease (IBD), raising significant diagnostic and therapeutic challenges. Charts of 591 patient with IBD treated with 6-MP in a single center were retrospectively reviewed. All allergic reactions were recorded along with results of rechallenge, desensitization, and subsequent course of IBD. Sixteen (2.7%) allergic reactions to 6-MP were noted, with fever being the most common (14 cases). Nine of these were rechallenged with 6-MP with recurrence of the same symptoms. Azathioprine was tried in six patients and in five the same symptoms recurred. Four patients underwent successful desensitization to either 6-MP or azathioprine; all four plus another patient who tolerated direct switch to azathioprine entered long-term remission. Among the remaining 11, 5 required surgery, 2 are well on methotrexate, and 4 have chronic symptoms while being treated with other medications. If an allergic reaction to 6-MP occurs during the treatment of IBD, direct switching to azathioprine is probably not justified. Instead, desensitization to either 6-MP or azathioprine should be attempted. Patients who can tolerate these medications after previous allergic reactions have improved outcomes compared with patients who resort to other forms of treatment.     

6-Thioguanine seems promising in azathioprine- or 6-mercaptopurine-intolerant inflammatory bowel disease patients: a short-term safety assessment

OBJECTIVE: 6-Mercaptopurine (6-MP) and azathioprine (AZA) have proven efficacy in the treatment of inflammatory bowel disease (IBD). However, adverse events leading to discontinuation may occur in 10-20% of patients. The efficacy of AZA and 6-MP is based on formation of their active metabolites, the 6-thioguaninenucleotides (6-TGNs). Therefore, 6-thioguanine (6-TG), an agent leading more directly to the formation of 6-TGNs and until recently used only in patients suffering from leukaemia, may be an alternative in AZA or 6-MP intolerance. The purpose of our study was to assess the short-term safety of 6-TG. METHODS: Thirty-two IBD patients with previously established AZA or 6-MP intolerance were treated with 6-TG in doses of 20 mg (n = 19) or 40 mg (n = 13) once daily. Safety parameters were obtained at 0, 1, 2, 4 and 8 weeks after start of medication. Primary outcome measures were the ability to tolerate 6-TG and the occurrence of adverse events. Secondary outcome definitions included laboratory parameters. RESULTS: Twenty-six (81%) patients were able to tolerate 6-TG during the first 8 weeks. In three of six patients, side effects leading to discontinuation were probably (n = 2) or obviously (n = 1) related to 6-TG. No clinically relevant haematological events or hepatotoxicity occurred in the observed period. Steady-state 6-TG levels were significantly higher with 40 mg once daily (1621 +/- 828 picomol/8 x 10(8) red blood cells (RBC)) than with 20 mg once daily (937 +/- 325 picomol/8 x 10(8) RBC; n = 0.001). CONCLUSIONS: 6-TG treatment seems promising in AZA- or 6-MP-intolerant IBD patients. However, long-term safety and efficacy have yet to be determined.     

Effects of Pueraria mirifica, an herb containing phytoestrogens, on reproductive organs and fertility of adult male mice

The effects of Pueraria mirifica (PM) on reproductive organs and fertility of adult male mice were investigated. Male mice were divided into four groups (10 mice/group). Groups 1–3 were orally treated with PM at doses of 0 (PM-0), 10 (PM-10), and 100 (PM-100) mg/kg BW/d in 0.2 mL distilled water, and group 4 was subcutaneously injected with 200 μg/kg BW/d of synthetic estrogen diesthylstibestol (DES). The treatment schedule was separated into two periods: treatment and posttreatment (8 wk for each period). The PM-10 and PM-100 treatments had no effect on testicular weight, sperm number, and serum LH, FSH, and testosterone levels. Only the PM-100 treatment reduced weights of epididymes and seminal vesicle and the sperm motility and viability. Histopathological examination demonstrated that testis, epididymis, and seminal vesicle were normal in all doses of PM treatment. PM-treated males showed no alterations in mating efficiency and on causing pregnancy of their female partners. DES injection impaired all those parameters. Offspring fathered by the PM-and DES-treated males exhibited neither malformations nor change of body weight gains, and the reproductive organ weights of 50-d old pups were in the normal range. The present data clearly demonstrate that a long-term treatment of PM at doses 10 and 100 mg/kg BW/d, via oral route, does not alter a male fertility and a hypothalamus pituitary-testis axis. Although PM-100 can cause some moderate impairment, no persistent effects were observed. Most of PM-treated mice increased the mating efficiency after stop treatment.     

A search for the optimal duration of treatment with 6-mercaptopurine for ulcerative colitis

BACKGROUND AND AIMS: 6-mercaptopurine has proven to be effective in the treatment and maintenance of remission of ulcerative colitis (UC). The optimal duration of treatment with 6-MP is unknown. The intention of this study was to determine the best duration of treatment with 6-MP in terms of maintenance efficacy once remission has been achieved. METHODS: We reviewed the records from the inflammatory bowel disease (IBD) center at Lenox Hill Hospital and one large IBD practice in New York City of 334 patients treated with 6-MP for UC. These patients were followed from 4 months to 28.7 yr. Sixty-one patients were treated with 6-MP for at least 6 months and had at least a 3-month disease-free interval off steroids while on the medication. These patients were divided into two groups: Group 1 continued 6-MP and group 2 discontinued the drug at various times for reasons other than relapse. Time to relapse was calculated for both groups. RESULTS: A Kaplan-Meier survival analysis was employed and differences between the two groups were analyzed using the log-rank test. The median time to relapse in group 2 was 24 wk and in group 1 was 58 wk (p < 0.05). There were no significant differences between the two groups in age, gender, extent of disease, use of concomitant 5-ASA products, dose of 6-MP during remission, duration of UC, and duration of treatment with 6-MP before remission was achieved. CONCLUSION: Discontinuation of treatment with 6-MP while UC is in remission leads to a higher relapse rate than maintenance on 6-MP. Therefore, we favor the indefinite treatment with 6-MP in most patients.     

Immunosuppressive therapy for inflammatory bowel disease: consensus by the Austrian working group on IBD

Azathioprine (AZA) or 6-mercaptopurine (6-MP) are the immunosuppressive drugs of choice in the treatment of inflammatory bowel disorders (IBD). Optimal dosage for AZA is around 2.5 mg/kg body weight and induction of remission by these drugs may take 6 - 7 months. Intramuscularly applied Methotrexate (MTX) is the second choice, while its efficacy starts earlier than that of AZA; studies assessing oral low-dose MTX treatment are lacking. Cyclosporin is the standard treatment in case of steroid-refractory severe ulcerative colitis. This drug may also be used in patients with severe extraintestinal manifestations of IBD. Regarding other immunosuppressive drugs such as mycophenolic acid or 6-thioguanine respective controlled clinical study data are not available. The risk of malignancy using immunosuppressive drugs such as AZA is low and furthermore, especially AZA and 6-MP can be used rather safely during pregnancy.     

Hepatotoxicity of 6-mercaptopurine (6-MP) and Azathioprine (AZA) in adult IBD patients

OBJECTIVE: 6-Mercaptopurine (6-MP) and azathioprine (AZA) are effective in the treatment of IBD; however, drug-induced hepatotoxicity has been reported in 10-15% of pediatric patients and has been associated with the 6-MP metabolite 6-methylmercaptopurine ribonucleotide (6-MMPR) at levels >5,700 pmol/8 x 10(8) RBC. The aim of this study was to assess the prevalence of 6-MP/AZA hepatotoxicity and its correlation with serum 6-MMPR levels in adult IBD patients. METHODS: Aminotransferases, bilirubin, and 6-MP metabolite levels were measured in 173 adult IBD patients treated with 6-MP or AZA from November 2002 to December 2003. Hepatotoxicity was defined as AST and/or ALT >2x upper limit of normal or cholestasis. RESULTS: Eight patients (4.6%) met criteria for a diagnosis of 6-MP/AZA-induced hepatotoxicity. The mean 6-MMPR level in these 8 patients was 10,537 pmol/8 x 10(8) RBC versus 3,452 pmol/8 x 10(8) RBC in the nonhepatotoxic group (P < 0.001). Risk of hepatotoxicity above the third quartile (6-MMPR > 5,300) was 5 times that below the third quartile (11.4%vs 2.3%, P < 0.05); however, nearly 90% of all patients with 6-MMPR > 5,300 pmol/8 x 10(8) RBC had no hepatotoxicity, while almost 40% of subjects with hepatotoxicity had 6-MMPR levels below this cutoff. CONCLUSIONS: 6-MP/AZA-induced hepatotoxicity is uncommon in the adult population. Although hepatotoxicity is associated with higher mean 6-MMPR levels, the sensitivity and specificity of 6-MMPR for drug-induced hepatotoxicity was poor. Monitoring liver tests in patients on 6-MP/AZA is suggested, and dose reduction or cessation of 6-MP/AZA, even with high 6-MMPR levels, should be reserved for patients with elevated aminotransferases.     

The utility of 6-thioguanine metabolite levels in managing patients with inflammatory bowel disease

OBJECTIVES: We aimed at determining the utility of measuring 6-thioguanine (6-TG) and 6-methylmercaptopurine (6-MMP) in inflammatory bowel disease (IBD) patients on azathioprine (AZA) or 6-mercaptopurine (6-MP), whether the described therapeutic range for 6-TG (235-400 pmol/8 x 10(8) red blood cells, RBC) correlated with clinical remission or leukopenia, and if 6-MMP level was a marker for hepatotoxicity (>5,700 pmol/8 x 10(8) RBC). METHODS: Study eligibility included an IBD diagnosis of >6 months and either active disease or disease remission of <6 months and the use of AZA/6-MP for >10 wk consecutively. Metabolite levels were evaluated against clinical status, CBC, and hepatic parameters. RESULTS: Seventy-four of 166 AZA/6-MP users were eligible. 6-TG levels >235 pmol/8 x 10(8) RBC were found in 22/59 (38%) with active disease and in 7/15 with remission (47%, p= 0.16). There was a trend of higher 6-TG levels among those in remission versus those with active disease (mean 325 +/- 284 vs 223 +/- 159 pmol/8 x 10(8) RBC, p= 0.2). No hepatotoxicity was observed, although 12.2% had 6-MMP levels > 5,700 pmol/8 x 10(8) RBC. The correlation between 6-MP dose and 6-TG levels was weak (r = 0.22, p= 0.08). The 6-TG level did not correlate with WBC. There were five instances, each of markedly low levels of both 6-TG and 6-MMP, suggesting noncompliance and of marked 6-MMP levels versus 6-TG. CONCLUSIONS: There was a poor correlation between 6-TG levels and remission. Nonetheless, the measurements of these levels are helpful when patients are on high doses but not achieving remission since noncompliance or metabolism favoring 6-MMP can be established.     

Complications of pregnancy and child development after cessation of treatment with 6-mercaptopurine for inflammatory bowel disease

PURPOSE: 6-Mercaptopurine (6-MP) has proven efficacy in the therapy of inflammatory bowel disease. Its teratogenicity is demonstrated in animal studies when used at very high doses, whereas human data suggest that 6-MP at maintenance doses is safe. We report the outcome of 72 pregnancies in patients with inflammatory bowel disease who were previously treated with 6-MP with three different doses of 50, 75, and 100 mg/d, for a median duration of 18 months, along with long-term follow-up of the children. METHODS: We have compared the outcome of pregnancies and development of the offspring in the following two groups: group 1, patients with inflammatory bowel disease who conceived 6 months to 22 years after stopping 6-MP (median 72 months); and group 2, patients with inflammatory bowel disease who never received 6-MP prior to conception. All pregnancies were evaluated in terms of outcome: live full-term birth, premature delivery, stillbirth, spontaneous abortion, ectopic pregnancy, and therapeutic dilatation and curettage. Data on children were obtained regarding birth weight, congenital anomalies, and development. RESULTS: Group 1 included 72 pregnancies carried by 29 women. There were 51 live births (4 premature), 16 spontaneous abortions, 1 stillbirth, 2 therapeutic abortions due to abnormal amniocentesis, and 2 ectopic pregnancies. The total incidence of fetal loss was 29.2%. In group 2, 75 women had 140 pregnancies resulting in 120 live births (8 premature), 18 spontaneous abortions, and 2 stillbirths. There were no cases of ectopic pregnancies or abnormal amniocentesis. The total incidence of fetal loss was 14.3%. There was no increase in the incidence of developmental defects when the mothers had been treated with 6-MP prior to pregnancy. CONCLUSIONS: The incidence of fetal loss is higher in women with inflammatory bowel disease who had been previously treated with 6-MP compared with those who had not. Whether this was related to the older age at conception in 6-MP group, longer duration of disease, initially more severe disease, or use of 6-MP we cannot tell.