A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn's disease.

BACKGROUND & AIMS: Clinical experience suggests that 6-mercaptopurine (6-MP) is effective therapy for children with active steroid-dependent Crohn's disease (CD). We report the results of a prospective, placebo-controlled, multicenter trial evaluating the combination of 6-MP and prednisone as therapy for children with newly diagnosed moderate-to-severe CD. METHODS: Fifty-five children (age, 13+/-2 years) were randomized to treatment with 6-MP (1.5 mg x kg(-1) x day(-1)) or placebo within 8 weeks of initial diagnosis. Both groups also received prednisone (40 mg/day). Prednisone dosage adjustments were based on a defined schedule determined by the change in a subject's disease activity score, and steroid administration was discontinued as remission was achieved. Study treatment with 6-MP or placebo continued for 18 months. RESULTS: Groups were comparable for age, sex, and site and activity of disease. In the 6-MP group, the duration of steroid use was shorter (P<0.001) and the cumulative steroid dose lower at 6, 12, and 18 months (P<0.01). Although remission was induced in 89% of both groups, only 9% of the remitters in the 6-MP group relapsed compared with 47% of controls (P = 0.007). Growth was comparable in both groups. No clinically significant adverse events occurred, although mild leukopenia and increases in aminotransferase activity were noted in the 6-MP group. CONCLUSIONS: Addition of 6-MP to a regimen of corticosteroids significantly lessens the need for prednisone and improves maintenance of remission. 6-MP should be part of the initial treatment regimen for children with newly diagnosed moderate-to-severe CD.

Endoscopic screening for dysplasia and mucosal aneuploidy in adolescents and young adults with childhood onset colitis.

OBJECTIVES: In adults, the premalignant nature of ulcerative colitis (UC) has long been accepted. Currently there is increasing concern that Crohn's disease (CD) may be equally premalignant. As a consequence, most adults with long-standing UC and many with chronic CD are enrolled in ongoing endoscopic cancer surveillance programs. In contrast, the risk of colonic cancer in adolescents and young adults with either form of colitis is less well recognized, and the need for dysplasia and cancer screening in this population has not been systematically evaluated. We therefore report the prospective results of colonoscopic cancer screening in such a young population. METHODS: Thirty-five adolescents and young adults with long-standing colitis (18 UC, 17 CD; 21 +/- 3 yr old, 11 +/- 3 yr colitis duration) underwent colonoscopic cancer screening. All had multiple biopsies for flow cytometry and light microscopy. RESULTS: Seven subjects had aneuploidy (3/18 UC, 4/17 CD). Of these seven, only two had dysplasia [one high grade (UC), one low grade (CD)]. One additional subject had indefinite dysplasia with normal flow cytometry. The remaining 27 subjects had both normal flow cytometry and light microscopy. Five of the seven aneuploid subjects underwent surgery within 1 yr of screening. Four, including both subjects with dysplasia, had no evidence of colon cancer at surgery. However, a 24-yr-old female with a 14-yr history of UC and no evidence of dysplasia or cancer at screening had a Dukes C adenocarcinoma. CONCLUSIONS: Adolescents and young adults with childhood onset UC or CD are at risk for aneuploidy, dysplasia, and colon cancer. Aneuploidy can be evident 10 yr after the onset of colitis and in patients as young as 16 yr of age. Therefore, the risk for colon cancer in patients with childhood onset colitis must be based on the duration of the illness, not on their chronological age. Incorporation of flow cytometry into an endoscopic screening protocol appears to enhance the ability to identify individuals at highest risk for colon cancer.

Clinical outcome of ulcerative colitis in children.

OBJECTIVES: To characterize the response to current medical therapies in children with ulcerative colitis, and to identify those factors that may predict the need for colectomy. DESIGN: Retrospective chart review at two large pediatric inflammatory bowel disease centers. RESULTS: We identified 171 subjects ranging in age from 1.5 to 17.7 years at diagnosis (mean 11.2 years). Mean follow-up was 5.1 years. Of these subjects, 43% had mild disease at presentation and 57% had disease that was classified as moderate or severe. After treatment 90% of the former group and 81% of the latter group had resolution of symptoms by 6 months. During any subsequent yearly follow-up interval, approximately 55% of the entire study population was symptom free, 38% had chronic intermittent symptoms, and 7% had continuous symptoms. A significantly lower risk of colectomy was noted for those with initially mild disease compared with those with moderate/severe disease. At 1-year the risk of colectomy was 1% among those with mild disease versus 8% with moderate/severe disease; at 5 years, the risk of colectomy was 9% in the mild disease group versus 26% in the moderate/severe disease group (p <0.03). CONCLUSIONS: In the majority of pediatric subjects with ulcerative colitis remission is achieved in the first 6 months after therapy; thereafter disease is inactive in about 50% of patients during any given year of follow-up. Severity of disease at presentation is a significant risk factor for colectomy during the first 5 years of follow-up. Future management protocols with more aggressive initial therapy may be warranted in children with moderate/severe disease.

Highly destructive perianal disease in children with Crohn's disease.

The perianal complications of Crohn's disease (CD) seen in children and adolescents include skin tags, anal fissures, fistulae, and abscesses. While these lesions are often chronic and variably responsive to medical therapy, only rarely are they severely destructive. In this report, we characterize the frequency, severity, and clinical course of a highly destructive form of perianal disease (HDPD) that we have noted in a number of children and adolescents with Crohn's disease. A database containing records from 350 children with inflammatory bowel disease was reviewed to identify all children with CD treated between 1970 and 1993. For each, the occurrence or absence of significant perianal pathology, including fistula, abscess, and HDPD, was determined. Pertinent clinical details were recorded for all patients. In addition, the clinical characteristics of those children with HDPD were compiled, and the courses of those with HDPD characterized. A search of the database identified 230 children and adolescents with CD followed for a total of 1,518 patient years. Sixty-seven of these patients (29% of the CD population) had significant perianal pathology. This included 6 with HDPD, 8 with complicated fistulae [rectourethroperineal (1), rectovaginal (1), rectolabial (2), and multiple communicating perineal (4)], and 53 with simple perianal fistulae or abscesses. All six with HDPD had deeply destructive perineal ulcerations, marked undermining of the perineal and perirectal tissues, and copious exudate, and often there was a deeply cleaved or fileted perineum on separating the buttocks. Two children with HDPD had fecal incontinence.

Characterization of hepatic abnormalities in children with inflammatory bowel disease.

: We sought to characterize the incidence, nature, and course of liver disease in children with inflammatory bowel disease (IBD). Chart review identified 555 subjects (318 Crohn's disease [CD], 237 ulcerative colitis [UC]). An alanine aminotransferase measurement of ≥80 U/L was used to identify the presence of a hepatic abnormality. Seventy-five patients (47 CD, 28 UC) had at least one ALT level ≥80 U/L. Persistent ALT elevation (>6 months) was found in 14 patients: 10 with sclerosing cholangitis (SC) (eight UC, two CD) and four with autoimmune chronic active hepatitis (CAH) (one UC, three CD). One patient with SC has had hepatic transplantation, and one other has end-stage liver disease. The remainder are clinically well. Two patients with CAH have developed cirrhosis. Nonpersisting ALT elevations (<250 U/L) were noted during disease course in 61 patients and were associated with medications, parenteral nutrition, bowel obstruction, and flare-ups of disease. Most ALT elevations in children with IBD are transient and appear to relate to medications or disease activity. Sclerosing cholangitis was noted in 3.5% of UC patients and <1% of CD patients, while CAH was found in <1% of UC or CD patients. Unless evidence of chronic liver disease is present, the initial finding of mild to moderate ALT elevation (80-250 U/L) should prompt observation before extensive evaluation.

Atypical rectosigmoid histology in children with newly diagnosed ulcerative colitis.

BACKGROUND: In the untreated patient with inflammatory colitis, rectal sparing or patchy rectal inflammation is generally considered a sign of Crohn's disease (CD), rather than ulcerative colitis (UC). METHODS: The initial endoscopic rectosigmoid mucosal biopsies obtained at disease onset from 12 untreated children with UC who ultimately required surgery were blindly reviewed (randomly mixed with another 62 specimens obtained from children with CD or treated UC). Biopsies were classified as typical UC if there was diffuse, active inflammation and severe crypt destruction or distortion. Those with patchy, active inflammation and only mild crypt changes were classified as CD. Because all 12 subjects had ultimately been proven to have UC by examination of a subtotal colectomy specimen, for the purposes of this report biopsies read as either normal or CD were both considered evidence of atypical UC with rectal sparing. RESULTS: Five of 12 subjects (seven biopsies) had atypical histology. Mild, patchy inflammation was seen in six rectal or sigmoid biopsies, whereas one rectal biopsy was normal. The remaining seven subjects (10 biopsies) had diffuse inflammation. Two of five subjects with atypical biopsies had an endoscopically normal rectosigmoid, one had patchy inflammation, and the remaining two had diffuse endoscopic changes. All seven subjects with typical UC histology had diffuse endoscopic changes. Subjects with atypical findings could not be differentiated by age, duration, or types of symptoms at presentation, years of disease at colectomy, or indications for colectomy. CONCLUSIONS: Patchy or absent inflammation of the rectum and sigmoid can be present in untreated children with UC at disease onset. Because such children may be mistakenly diagnosed as having CD, these data must be considered when treatments or clinical research protocols are designed to include children with colitis.

Growth failure in pediatric inflammatory bowel disease.

To assess whether children with inflammatory bowel disease (IBD) develop permanent impairment of linear growth, we analyzed records from 48 young adults who had IBD during childhood or early adolescence (Tanner I-III; 11.8 +/- 2.4 years old at diagnosis). All were fully grown (Tanner V; 21.1 +/- 3.0 years) at last examination. Adult heights were predicted from data obtained at or shortly after the diagnosis of IBD by three methods: height for age percentile, the Bailey-Pinneau (BP), and Roche-Wainer-Thissen (RWT) methods. Predicted adult heights were then compared with the actual ultimate height of each subject. Permanent growth failure occurred in 19-35% of subjects, depending upon the method used to assess growth. Overall, 31% (15 of 48) of the subjects had deficits of adult height identified by two or more methods, including 14 of 38 (37%) of those with Crohn's disease but only one of 10 with ulcerative colitis. Age at diagnosis of IBD, age at last examination, age at cessation of linear growth, and site of IBD did not differ between impaired and normal growth groups. Duration of corticosteroid use was longer (p < 0.05) in growth-impaired subjects. In addition, although 60% of all subjects had periods of poor growth that put them in height-for-age percentiles two or more major growth channels below previous percentiles, only 19% remained at these levels upon achieving their final adult heights. Permanent impairment of linear growth leading to clinically meaningful deficits of ultimate adult height is common in patients with IBD in childhood or early adolescence. New therapeutic approaches are needed to address this problem.

Immunosuppressive therapy in pediatric inflammatory bowel disease: results of a survey of the North American Society for Pediatric Gastroenterology and Nutrition. Subcommittee on Immunosuppressive Use of the Pediatric IBD Collaborative Research Forum.

We report the results of a survey of the membership of the North American Society for Pediatric Gastroenterology and Nutrition designed to determine pediatric gastroenterologists' attitudes toward the use of immunosuppressive therapy for inflammatory bowel disease (IBD), and to assess how these medications are actually being used in the treatment of children with IBD. One hundred five physicians (27% of surveys) responded. Eighty-eight (84%) had prescribed 6-mercaptopurine and/or azathioprine for IBD, and 66 believed that they were effective. Only 12 had used cyclosporine and four methotrexate. All physicians who had used immunosuppressives in IBD had prescribed them for patients with Crohn's disease, but only 50% had prescribed them for ulcerative colitis. The predominant indications for use included intractable symptoms despite traditional medical therapy (92%) and for corticosteroid-sparing effects (86%). Potential toxicities of greatest concern included marrow and immune suppression and malignancy. The vast majority of responders were not certain what to recommend with respect to the use of immunosuppressive agents prior to and during pregnancy. A clinical database was compiled from 165 retrospective case reports submitted by 45 physicians (33 medical facilities). At the start of immunosuppressive therapy, patients were 15.3 +/- 4.0 yr of age, and 52% were Tanner IV-V. Eighty-one percent had Crohn's disease, 8% ulcerative colitis, and 11% indeterminant colitis. One hundred twenty-two were treated with 6-mercaptopurine, and 43 with azathioprine. Five also received cyclosporine concomitantly. Overall, 68% of patients treated with an immunosuppressive improved. Complications requiring discontinuation of immunosuppressive therapy occurred in 6% of patients. It appears that immunosuppressives are commonly used to treat children with IBD despite a paucity of data regarding their safety and efficacy in this age group. Controlled, prospective trials are warranted to better define the role of immunosuppressive therapy in pediatric IBD.

Long-term 6-mercaptopurine treatment in adolescents with Crohn's disease.

Although 6-mercaptopurine is often used to treat adolescents with intractable Crohn's disease, its long-term efficacy has not yet been studied in this population. This study shows data derived from 36 adolescents (mean age +/- SD, 16.5 +/- 3.3 years; 27 males, 9 females) treated at least 6 months with 6-mercaptopurine (1.5 mg.kg-1.day-1, maximum of 75 mg/day). Sites of Crohn's disease at the start of 6-mercaptopurine therapy included 17 ileocolic, 9 pancolic, 7 small bowel, and 3 partial colon. All had received corticosteroids, sulfasalazine, antibiotics, and nutritional support for 5.0 +/- 3.0 years before administering 6-mercaptopurine, but intractable symptoms persisted. Disease activity lessened during the first year of 6-mercaptopurine, reflected by a higher Lloyd-Still disease activity score (pre, 64 +/- 9 vs. 6-mercaptopurine, 72 +/- 11; P less than 0.0001). General activity, physical examination, nutrition, and laboratory subscores all improved (P less than 0.004). Lessened disease activity occurred despite concomitant decrease in duration of prednisone use (pre, 9.5 +/- 4.2 vs. 6-mercaptopurine, 6.6 +/- 4.9 months/year; P less than 0.001) and cumulative annual prednisone exposure (pre, 3672 +/- 2106 vs. 6-mercaptopurine, 1964 +/- 1460 mg; P less than 0.0007). The frequency of perianal fistulae and abscesses also decreased (P less than 0.01) during treatment. Annual rates of hospitalization decreased in 44% of subjects during 6-mercaptopurine treatment, while increasing in only 22%. Follow-up beyond 1 year of 6-mercaptopurine treatment showed continued remission in 23 of 30 subjects. No serious complications were seen. 6-mercaptopurine is an effective long-term therapy for adolescents with intractable Crohn's disease. While inducing remission, it also has a significant steroid-sparing effect which may be of particular benefit to this population.