Long-term prognosis of early-onset Crohn ’ s disease diagnosed in childhood or adolescence

Department of Medicine, Division of Gastroenterology, University of British Columbia, Vancouver, British Columbia Correspondence: Dr Hugh Freeman, Gastroenterology, University of British Columbia Hospital, 2211 Wesbrook Mall, Vancouver, British Columbia V6T 2B5. Telephone 604-822-7216, fax 604-822-7236, e-mail hugfree@shaw.ca Received for publication April 22, 2004. Accepted August 10, 2004 HJ Freeman. Long-term prognosis of early-onset Crohn’s disease diagnosed in childhood or adolescence. Can J Gastroenterol 2004;18(11):661-665.

E arlier studies, mainly from pediatric centres in the United States and Europe (1)(2)(3)(4)(5)(6)(7)(8)(9), but also Canada (10,11), have described the clinical features and prognosis of Crohn's disease diagnosed in childhood or adolescence.Although patient numbers have been limited and durations of direct pediatric physician follow-up have been short, most features typical of adult-onset disease were seen.The disease more commonly affected adolescents than children, but diagnosis even before five years of age has been recorded (5,7,(12)(13)(14).Despite its chronic, often indolent nature, mortality has been low.Although significant morbidity, particularly growth retardation, has been recorded, recent studies (15) have suggested that the deficit in adult height after the early-onset of Crohn's disease may not be significant.
Crohn's disease is known to be phenotypically heterogeneous, involving different sites along the length of the gastrointestinal tract.Recent attention has focused on defining more homogeneous patient groups based on clinical characteristics such as disease location or behaviour, as well as seromarkers (eg, anti-Saccharomyces cerevisiae antibodies and antineutrophil cytoplasmic antibodies).Studies using a modern schema of classification (16) demonstrated that Crohn's disease was female-predominant, occasionally familial and characterized by stricturing and penetrating clinical complications (17)(18)(19).Recently, these adult phenotypical features were also recorded in early-onset or pediatric Crohn's disease (20).
Several factors noted elsewhere (7), however, have made long-term evaluation of early-onset Crohn's disease difficult, including early difficulties in differentiation from ulcerative colitis, follow-up issues associated with transition to specialist adult care, and a tendency, especially during late adolescence, for increased mobility due to educational and employment requirements.Because long-term studies in pediatric patients with Crohn's disease are limited, data based on adult-onset Crohn's disease may be extrapolated to address long-term concerns, particularly in relation to prognosis.Using a modern classification schema (16), the present study explored specific long-term issues related to mortality, malignancy and the requirement for intestinal resection in 224 patients with earlyonset disease who were diagnosed in childhood or adolescence, and seen directly over more than two decades.

Definition and inclusions
The patients were derived from an established and prospectively and consecutively accumulated clinical database (now containing over 1000 patients with Crohn's disease), evaluated and directly treated by the investigator; mean patient follow-up period was over 10 years (17)(18)(19)(20).In an earlier published report (17), this patient database was noted to be female-predominant (56.1%) with 84.4% diagnosed before 40 years of age.In addition, disease was observed to be localized to the ileum in 25.3%, the colon in 27.2%, the ileocolon in 34.6% and the upper gastrointestinal tract, despite disease involvement elsewhere, in 13.1%.Finally, disease behaviour was classified as stricturing in 33.6% and penetrating in 37.2%.Patients were selected for the present study if their diagnosis was defined before 20 years of age (20).The cohort that emerged included 224 patients, comprising 96 males (42.9%) and 128 females (57.1%).The mean duration of follow-up for the entire cohort was 12.2 years (males 12.7 years; females 11.8 years), with over 50% of patients followed for more than 10 years, and almost 10% of patients with data over 25 years (20).Statistical analyses were performed using the Student's t test or χ 2 test.

Definition of early-onset Crohn's disease
Male and female patients were classified based on a prior schema developed elsewhere (16) and applied previously to this Crohn's disease database (17)(18)(19)(20).For the purposes of the present study, modification of this schema was necessary for age at diagnosis because this classification does not specify a category for specific age groups younger than 40 years of age.Information for the present study, therefore, was restricted to age at diagnosis younger than 20 years.Other defining features were used including location of disease, defined as the maximal extent of disease or disease at the first resection (eg, L1, ileum, possibly involving cecum; L2, colon; L3, ileocolon; and L4, upper gastrointestinal tract regardless of other disease sites), and disease behaviour (eg, B1, nonstricturing and nonpenetrating; B2, stricturing; and B3, penetrating).In this classification, disease is defined as B3 if, at any time during the course of the disease, intra-abdominal or perianal fistula, perianal ulceration, inflammatory mass or abscess have developed, even if a coexisting stricture is present.In contrast to the definition of disease location, the definition of disease behaviour in this modern schema has no specific time limit.In the present study, disease behaviour was defined in a cumulative fashion as the most recent patient encounter during the past three years.Results of a comparative study for early-onset compared with adult-onset disease followed for similar periods have been recently published elsewhere (20).

Medications and parenteral nutritional support
Further defining features were tabulated for this early-onset disease cohort.Table 1 lists different treatments used over more than two decades.Individual 5-aminosalicylate products or administration route for steroid preparations were not specified.Immunosuppressive agents included azathioprine, 6-mercaptopurine, cyclosporine and methotrexate.A biological agent (eg, infliximab) was provided through a clinical trial in another hospital.Use of parenteral nutrition was recorded, but specified for home use, if required for nutritional support before or after intestinal resections.For percentages of males and females, medications were similar with a trend towards increased inhospital total parenteral nutrition use in females.Compared with earlier data (17), medications were similar in early-onset disease except for a higher percentage of patients treated with steroids (eg, overall Crohn's disease database, 53.1%).
For the present study, comparisons were done between patients not requiring an intestinal resection and those requiring one or more intestinal resections.Mean ages at diagnosis for each group (no resection, one resection and multiple resections) were 16.3, 16.0 and 15.5 years, respectively, and were not statistically significant.
Familial disease (defined as confirmed first degree relatives with Crohn's disease) (18) for each group were 10.2%, 10.8% and 9.6%, respectively, and were not statistically significant.The prevalence of use of specific medications was also similar, including the percentage in each group treated with steroids, which was 70.4%, 71.6% and 73.1%, respectively, and not statistically significant.

Recurrence and resection
Recurrence was defined in the present study as a further intestinal resection, rather than recurrent symptoms or recurrent radiological or endoscopic imaging changes.For each patient requiring another intestinal resection, durations of follow-up after the first and subsequent resections were recorded.To further clinically define the cohort being evaluated, pathological reports on resected intestinal specimens were also reviewed for reported detection of granulomas.In this cohort, granulomas were reported in 38.9% of all surgically resected specimens, including 31.1% of patients having one intestinal resection and 50.0% of those having more than one intestinal resection.

Malignancy and mortality
Only a single male with early-onset disease among these 224 patients developed an intestinal malignancy.He was initially diagnosed with Crohn's disease at 17 years of age in 1977.Endoscopic and radiological studies defined ileocolonic involvement.He was subsequently treated with different 5-aminosalicylate preparations, including sulfasalazine and eventually metronidazole, but no corticosteroids or immunosuppressive agents.He required an ileocolonic resection in 1980 for a localized ileal perforation proximal to a strictured ileal segment.Ileal and colonic ulcerations were present but granulomas were not detected in the resected intestine.Later, three colonoscopies with multiple ileal and colonic biopsies over the course of two decades showed only patchy inflammatory mucosal changes without granulomas.No dysplasia was detected.In 2003, he developed an anorectal stricture due to a low lying rectal adenocarcinoma and required an abdominoperineal resection.
To date, no patient with early-onset Crohn's disease has developed a myeloid or lymphoid malignancy, and all colonoscopic biopsies, either from macroscopically normal or abnormal intestine, have not demonstrated dysplasia.In addition, dysplasia has not been reported in resected intestine.
These findings contrast with earlier reported results on myeloid, lymphoid or intestinal malignancies in adults with Crohn's disease from the University of British Columbia hospital with a similar duration of follow-up (21).In that report, the estimated overall rate for myeloid and lymphoid malignancies was 0.5% and the estimated overall rate for intestinal malignancies was 1% (21).In addition, one patient with Hodgkin's disease, initially diagnosed at 10 years of age, was not included in the present evaluation of early-onset disease because her diagnosis of Crohn's disease was only established after 20 years of age.
Finally, to date, only one female, initially diagnosed at 15 years of age, and then followed directly by the investigator for 24 years, died following a suicidal drug overdose.

Intestinal resections
One or more intestinal resections were required in 126 of 224 patients (56.3%) with early-onset disease, including 58 of 96 males (60.4%) and 68 of 128 females (53.1%).These percentages for intestinal resection all exceeded the previously recorded rate of 44.1% for an intestinal resection for a largely adult group from this hospital (17) (P<0.05).In this earlyonset group, more than one intestinal resection was required in 52 of 224 (23.2%), including 24 of 96 males (25.0%) and 28 of 128 females (21.9%).Indeed, three or more intestinal resections were required in 21 of 224 (9.4%).
After diagnosis of early-onset Crohn's disease, mean time to the first intestinal resection was 4.2 years (range to 20 years).For males, mean time to the first resection was 4.2 years (range to 20 years), and for females, 4.1 years (range to 19 years).After the first resection, mean time to the second resection was 6.6 years (range to 25 years).For males, mean time to the second resection was 6.7 years (range to 23 years), and for females, 6.6 years (range to 25 years).
Table 2 further shows males and females with early-onset disease who required an intestinal resection for defined periods from the time of diagnosis to that of the first resection.As shown, for both sexes, the first intestinal resection was performed within the first two years after diagnosis in approximately 50%.females who required a second intestinal resection for defined periods after the first resection.The second intestinal resection was also required within two years in approximately one-third of both male and female patients.Table 4 compares disease location in males and females who did not require an intestinal resection with those who required one or multiple intestinal resections.For both males and females, most early-onset Crohn's disease with ileocolonic involvement required at least one, and usually multiple intestinal resections, while both males and females with only localized colonic disease were less likely to require an intestinal resection (P<0.05).Table 5 shows the data redistributed using the modern Vienna system (16).With this schema, the disease is categorized as upper tract in type even if it is also detected in ileum or colon.Even with this modification, for both males and females, most who eventually required an intestinal resection had ileocolonic involvement (P<0.05).
Table 6 compares clinical behaviour of males and females with early-onset Crohn's disease, defined on the basis of the modern Vienna schema (16), in patients having no intestinal resection compared with those having one or multiple intestinal resections.More resected patients could be classified as having complex disease with either strictures or penetrating disease complications (P<0.05).

DISCUSSION
The present study focused on an exploration of specific disease end points traditionally used as clinical indicators of long-term prognosis in Crohn's disease, but applied to early-onset disease diagnosed during childhood or adolescence.These included malignancy and mortality as well as the requirement for intestinal resection.As anticipated, the results show that both early malignancy and mortality are rare, each being noted only in single patients (eg, rectal cancer, suicidal drug overdose), around 40 years of age and beyond.These observations are consistent with the results in other studies on clinical features of pediatric Crohn's disease that have failed to record superimposed or complicating intestinal malignancies (5-7).Indeed, colorectal cancer complicating early-onset Crohn's disease has been rarely reported, and has been considered to be more likely related to another occult or underlying geneticallybased disorder (eg, Li-Fraumeni syndrome) than Crohn's disease per se (22).
While not systematically examined in the present study, regular colonoscopic screening programs for epithelial dysplasia (or invasive neoplasia) appear not to be indicated in children or adolescents with Crohn's disease.Not a single patient in this cohort of 224 patients followed for a prolonged period by a single clinician had epithelial dysplasia recorded in endoscopic biopsies or surgically resected specimens, including the sole patient who eventually developed colorectal cancer.Epithelial dysplasia in Crohn's disease has been recorded elsewhere in the small and large intestine, leading others to hypothesize that the so-called 'dysplasia-carcinoma sequence' may occur in Crohn's disease (23).Although very logical, data to support an endoscopic surveillance approach are limited in Crohn's disease, and are largely based on a single study conducted in an older adult population (24).Indeed, most cases of carcinoma in adults with Crohn's disease, even from large tertiary care settings, were detected only incidentally during surgical treatment (25).Evidence providing support for routine      endoscopic surveillance in pediatric Crohn's disease is lacking and should not be recommended based on the limited data from adult populations.The present study also evaluated the role of clinical characteristics, based on a modified Vienna schema for early-onset or pediatric Crohn's disease (16,20), and the likelihood for later intestinal resection(s).In this evaluation, the majority of males and females (56.3%) required at least one intestinal resection during the prolonged period of follow-up into adulthood.This exceeds the recorded frequency of 44.1% in a larger database (16), now with over 800 having adult-onset disease.These results are consistent with a prior report of a higher frequency of surgical treatment in early-versus late-onset disease over 40 years of age (26) and also provide predictive data for anticipated intestinal resection after diagnosis of Crohn's disease.The data here indicate that an intestinal resection, if required, will usually be performed within two years of the initial diagnosis.Moreover, if a second resection is required, this is also frequently done within two years following the first resection.While it was not possible to evaluate the effects of therapy on the natural history of Crohn's disease before resection in the present study, future investigations focused on new therapeutic drugs and biological agents should distinguish earlyonset from adult onset disease.
The present study in early-onset Crohn's disease also explored the effects of disease location and clinical behaviour on rates of intestinal resection.In this investigation, disease located in the ileocolonic region and characterized as complex disease with intestinal strictures or, more frequently, penetrating (or perforating) disease complications were independent risk factors that often predicted a later intestinal resection.These observations confirm the clinical experience that children or adolescents with Crohn's disease are more likely to require surgical treatment relatively soon after diagnosis if disease is clinically complicated with stricture formation or penetrating disease complications, such as the development of an abscess or a fistulous tract.Further studies are needed to define other prognostic factors that might predict the need for earlier surgical treatment of Crohn's disease.

ACKNOWLEDGEMENTS:
The investigator is particularly grateful to several pediatric-based physicians for referring some of their patients with early-onset Crohn's disease for investigation, treatment and ongoing follow-up over more than two decades of clinical practice.These include the following gastroenterologists: Drs Margaret Mullinger, George Davidson, Eric Hassall, David Israel and Richard Schreiber, all from the British Columbia Children's Hospital, Vancouver, British Columbia, along with physicians employed by the Student Health Services at the following institutions: University of British Columbia, Vancouver, British Columbia; Simon Fraser University, Burnaby, British Columbia; and Langara College, Vancouver, British Columbia.

Freeman
Can J Gastroenterol Vol 18 No 11 November 2004 664

Table 3
also shows the number of males and Crohn's disease from childhood or adolescence Can J Gastroenterol Vol 18 No 11 November 2004 663

TABLE 4
Disease location with single or multiple resections