Pediatric ulcerative colitis (UC), one form of inflammatory bowel disease (IBD), typically occurs in late childhood or early adolescence. Corticosteroid drugs play a central role in the management of this disease. However, potential complications in pediatric patients taking corticosteroids include linear growth delay, osteopenia, osteomalacia with pathologic compression fractures, cushingoid features, cataracts or glaucoma, infections, and aseptic necrosis of the femoral head (1). An alternative therapeutic method is therefore desirable. This is important in a subgroup of patients with UC who are steroid dependent or whose disease is refractory to steroid therapy. Until recently, colectomy had been recommended for this group of patients. Surgery eliminated the need for corticosteroids and the risk of colon cancer in adulthood. However pediatric patients with UC and their families are often resistant to surgery in favor of an alternative form of medical therapy, perhaps because some pediatric patients are physically or mentally unprepared for surgery.
The immunomodulators, 6-mercaptopurine (6-MP) and azathioprine (AZA), have the potential to fulfill the role of an alternative therapy to corticosteroids while keeping the option of surgery available if medical therapy fails. We sought to investigate the potential efficacy and safety of 6-MP/AZA therapy in a group of pediatric patients with UC who were observed at the IBD Center at the Children's Hospital of Philadelphia.
The medical records of patients with active UC who were observed at the Children's Hospital of Philadelphia and its satellite clinics from January 1984 through December 1997 were retrospectively reviewed to identify who had received 6-MP or AZA therapy. Patients were included if UC was diagnosed by established criteria (clinical, endoscopic, radiologic, and histologic), if they met no criteria for Crohn's colitis, and if they received treatment with 6-MP/AZA. The patients' records were analyzed for the development of side effects, the indication to use 6-MP/AZA, and the ability to discontinue corticosteroids within 6 months in patients treated with 5-acetylsalicylic acid (ASA) products who were corticosteroid dependent or whose conditions were refractory to treatment. Patients receiving methylprednisolone were converted to the equivalent prednisone dose for purposes of analysis. Excluded from the corticosteroid analyses were patients who underwent surgery for the disease and patients who received ASA only.
The Kaplan-Meier survival curve analysis was used to evaluate the efficacy of 6-MP/AZA after discontinuation of corticosteroids. The effects of time-dependent variables on this outcome were also measured by survival curve analysis. Fisher's exact test was used to compare 2 non-time-dependent groups. A paired Student's t-test and standard error of the mean were used to compare the change in the patient's initial corticosteroid dose to the dose required after 3 and 6 months of therapy. Where appropriate, the median (not the mean) values were used to represent the data most accurately, given the limited sample size and survival curve analysis.
A review of 200 medical records of patients with active US showed that 20 patients met the criteria for inclusion in the study. The patients' mean disease duration at the start of 6-MP/AZA treatment was 2.8 years (range, 5 months to 8.5 years; median, 2.2 years) and their average age was 13.8 years (range, 6.4-20 years; median, 14.6 years). The disease site was pancolonic in 16 patients and left colon (up to the splenic flexure) in 4 patients. Sixteen patients (80%) were corticosteroid dependent and 3 patients (15%) had disease refractory to corticosteroids. Two patients were treated with methylprednisolone and 17 with prednisone. One patient had severe colitis treated with ASA only. Ten patients (50%) were treated with 6-MP, and 10 patients (50%) were treated with AZA (Table 1). One patient was never treated with corticosteroids, and 3 patients underwent surgery. Of the 3 patients who had surgery, 1 patient elected to have surgery even though the the initial corticosteroid dose was reduced by 88% after 6 months of 6-MP therapy; in 1 patient, pancreatitis developed after 2 months of AZA therapy, and AZA was discontinued and surgery recommended; and in the third, 6-MP therapy failed and surgery was required.
The mean duration of 6-MP/AZA therapy was 36.45 months (range, 3-104 months; median, 28 months). The mean 6-MP dose was 1.45 mg/kg per day, and the AZA dose was 1.54 mg/kg per day. The daily average corticosteroid dose before 6-MP/AZA therapy was initiated was 30.1 ± 4.3 mg. The difference between the initial average corticosteroid dose and the dose at 3 months (11.8 ± 3.4 mg; p = 0.002) and 6 months (6.5 ± 2.9 mg; p = 0.0003) into therapy was significant (Fig. 1). Initial discontinuation of corticosteroids was accomplished in 12 (75%) of 16 patients. In this group, the mean time until discontinuation of corticosteroids was 11.2 months (range, 2-39 months), and the median time was 9 months (Fig. 2).
The median duration of clinical remission was 12 months in the 13 patients (12 patients initially receiving corticosteroids and 1 patient receiving ASA) who responded to 6-MP/AZA and did not undergo surgery. The median time without corticosteroids, either to date or until a relapse occurred, for all patients was 8.4 months-25 months in the 6-MP group and 7 months in the AZA group (not significant). Only two patients who initially received corticosteroids and who had clinical relapse, defined by the development of abdominal pain and bloody diarrhea, required continuation of corticosteroids. The remaining patients who had clinical relapse were successfully treated by adjusting their current medication regimen or by using low-dose corticosteroids (<20 mg/day) for a few weeks (Table 1).
The differences in the patients' ages, disease duration, corticosteroids dose, erythrocyte sedimentation rate, albumin level, and total white blood cell count before 6-MP/AZA use and after discontinuation of corticosteroids were not statistically significant. Finally, the extent of disease involvement, pancolitis versus left colon was not significant after discontinuation of corticosteroids. Patients with pancolitis took a longer time than those with left colon disease to reduce use of corticosteroids by approximately 75% (15 months vs. 4.5 months, respectively; -2Log[likelihood ratio]; p = 0.05). In a similar but not statistically significant trend, it took longer to discontinue corticosteroids in those with pancolitis than in those with left colon disease (15 months vs. 6.5 months, respectively; -2Log[LR]; p = 0.09).
Side effects resulting in discontinuation of AZA included pancreatitis in one patient who proceeded to collectomy and another patient in whom shingles developed. The patient's UC relapsed at 6 months and was unable to discontinue corticosteroid. Two other complications from 6-MP included mild hepatitis that resolved spontaneously in one patient and leukopenia in another that resolved when 6-MP was withheld.
6-Mercaptopurine and azathioprine are immunomodulators that have been used to treat ulcerative colitis for more than 35 years (2-4). The effectiveness of 6-MP and AZA in treating severe UC has been shown (5-17). However, similar reported experiences in pediatric patients with UC are rare (18-21). Verhave et al. (19,20) reported their experience in 21 pediatric patients with IBD (9 had UC), who were treated with AZA (2 mg/kg per day). They concluded that patients with UC treated with AZA respond similarly to their Crohn's disease counterparts because 6 of 9 patients with UC had complete response to therapy. Furthermore, they determined that this effect occurred 1 month sooner than in their Crohn's disease patients. Schafer and Blaker (21) similarly used immunomodulator therapy to treat 15 pediatric patients who had UC. In their study the initial dose of AZA was 5 mg/kg per day and was adjusted to 3 mg/kg once the disease was in clinical remission. They reported that in 13 of 15 patients the disease promptly went into clinical and proctoscopic remission, and the only reported side effects were jaundice and emesis. One patient had relapse 2 years later and cholestasis developed in the other, who was receiving AZA.
Markowitz et al. (22) compiled information regarding North American pediatric gastroenterologists' beliefs and therapeutic practices of immunomodulator therapy for treatment of IBD (22). The complication was accomplished in a survey by questionnaire that not only generated composite data about the individual cases but also determined the use, indications, perceived side effects, and efficacy of immunomodulators for treatment of pediatric patients with Crohn's disease and UC. Of the 165 case summaries, in 31% of patients the disease was reported to be in complete remission whereas in another 37% it was thought to have improved. This suggests that 68% of treated patients received some benefit from therapy. Reported side effects were not included in their study.
Our experiences and results in 6-MP/AZA approximated those of Schafer et al., (21) but eventually the majority (62%) of our patients had a clinical relapse manifested by abdominal pain and bloody diarrhea. In most of these patients, however, this increase in disease activity was controlled by an increase in current medications or by a short, low-dose course of corticosteroids (Table 1). The follow-up in the five patients who continued without corticosteroids was short (range, 3-21 months) and may inaccurately predict whether they will continue without a relapse. The advantage of 6MP/AZA therapy is also noted by the significant lowering of the corticosteroid dose after 3 and 6 months of therapy (Fig. 1). Finally, 14 (70%) of the study group of 20 patients benefited from the use of 6-MP/AZA, including those who had surgery. This result is similar to the percentage reported by markowitz et al. (22).
There may be a selection bias in our patient group caused by surgery's eliminating patients with more severe disease. Disease activity in the surgical group was comparable to that in the nonsurgical patients. One patient showed clinical improvement and the corticosteroids dose was reduced, but the patient decided to have surgery; one patient had idiosyncratic pancreatic resulting in surgery with discontinuation of AZA therapy; and in the final patient who had significant disease, 6-MP treatment failed and surgery was required.
Our data suggest a trend showing that 6-MP may be more potent than AZA in helping the patient to discontinue corticosteroids earlier and in preventing disease recurrence (p = 0.06; data not shown). We believe that a cautious interpretation of these data is warranted because of the low average dose (1.5mg/kg per day) of AZA used in our patients (19). Our data also support the safety of 6-MP/AZA in treating pediatric patients with UC; side effects were rare, anticipated, and reversible. Eighteen (90%) of the 20 patients tolerated 6-MP/AZA well.
Overall, 14 (70%) of our patients benefited from the use of 6-MP/AZA. 6-Mercaptopurine and AZA are effective, safe, and well-tolerated medications that provide the clinician with the ability to decrease the requirement for corticosteroids. Clinical relapses that occur during 6-MP/AZA therapy may respond to less aggressive medical management. The optimal dose and duration of 6-MP/AZA therapy is still to be determined. Safety is an important concern with the use of 6-MP/AZA. We support monitoring the side effects of these medications by obtaining a complete blood cell count and aminotransferase levels weekly for the first 6 weeks, then every other week for the next 6 weeks, and then every 3 months. Controlled prospective clinical trials are warranted to delineate further the role of 6-MP/AZA therapy in pediatric patients with UC.
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