Journal of Pediatric Gastroenterology & Nutrition:
Original Articles: Gastroenterology
Extraintestinal Manifestations of Pediatric Inflammatory Bowel Disease and Their Relation to Disease Type and Severity
Dotson, Jennifer L†; Hyams, Jeffrey S‡; Markowitz, James§; LeLeiko, Neal S||; Mack, David R¶; Evans, Jonathan S#; Pfefferkorn, Marian D**; Griffiths, Anne M††; Otley, Anthony R‡‡; Bousvaros, Athos§§; Kugathasan, Subra||||; Rosh, Joel R¶; Keljo, David##; Carvalho, Ryan S***; Tomer, Gitit†††; Mamula, Petar‡‡‡; Kay, Marsha H§§§; Kerzner, Benny||||||; Oliva-Hemker, Maria¶¶¶; Langton, Christine R‡; Crandall, Wallace†
†Nationwide Children's Hospital, Columbus, OH, USA
‡Connecticut Children's Medical Center, Hartford, CT, USA
§North Shore Long Island Jewish Health System, New Hyde Park, NY, USA
||Hasbro Children's Hospital, Providence, RI, USA
¶Children's Hospital of Eastern Ontario, Ottawa, Canada
#Nemours Clinic, Jacksonville, FL, USA
**Riley Hospital for Children, Indianapolis, IN, USA
††Hospital for Sick Children, Toronto, Ontario, Canada
‡‡IWK Health Centre, Halifax, Nova Scotia, Canada
§§Children's Hospital Boston, Boston, MA, USA
||||Children's HealthCare of Atlanta, Atlanta, GA, USA
¶¶Morristown Memorial Hospital, Morristown, NY, USA
##Children's Hospital, Pittsburgh, PA, USA
***Children's Medical Center, Dayton, OH, USA
†††Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
‡‡‡Children's Hospital of Philadelphia, Philadelphia, PA, USA
§§§Cleveland Clinic, Cleveland, OH, USA
||||||Children's National Medical Center, Washington, DC, USA
¶¶¶Johns Hopkins Medical Institute, Baltimore, MD, USA.
Received 8 April, 2009
Accepted 12 October, 2009
Address correspondence and reprint requests to Jennifer L. Dotson, MD, Nationwide Children's Hospital, 700 Children's Dr, Columbus, OH 43205 (e-mail: firstname.lastname@example.org).
The authors report no conflicts of interest.
Objectives: Although it is known that extraintestinal manifestations (EIMs) commonly occur in pediatric inflammatory bowel disease (IBD), little research has examined rates of EIMs and their relation to other disease-related factors in this population. The purpose of this study was to determine the rates of EIMs in pediatric IBD and examine correlations with age, sex, diagnosis, disease severity, and distribution.
Patients and Methods: Data were prospectively collected as part of the Pediatric IBD Collaborative Research Group Registry, an observational database enrolling newly diagnosed IBD patients <16 years old since 2002. Rates of EIM (occurring anytime during the period of enrollment) and the aforementioned variables (at baseline) were examined. Patients with indeterminate colitis were excluded from the analysis given the relatively small number of patients.
Results: One thousand nine patients were enrolled (mean age 11.6 ± 3.1 years, 57.5% boys, mean follow-up 26.2 ± 18.2 months). Two hundred eighty-five (28.2%) patients experienced 1 or more EIMs. Eighty-seven percent of EIM occurred within the first year. Increased disease severity at baseline (mild vs moderate/severe) was associated with the occurrence of any EIM (P < 0.001), arthralgia (P = 0.024), aphthous stomatitis (P = 0.001), and erythema nodosum (P = 0.009) for both Crohn disease (CD) and ulcerative colitis (UC) during the period of follow-up. Statistically significant differences in the rates of EIMs between CD and UC were seen for aphthous stomatitis, erythema nodosum, and sclerosing cholangitis.
Conclusions: EIMs as defined in this study occur in approximately one quarter of pediatric patients with IBD. Disease type and disease severity were commonly associated with the occurrence of EIMs.
The inflammatory bowel diseases (IBDs), most commonly represented by Crohn disease (CD) and ulcerative colitis (UC), are chronic, relapsing inflammatory disorders of the intestinal tract secondary to immune dysregulation that result in intestinal symptoms such as abdominal pain, diarrhea, and bleeding. Given the systemic nature of these disorders, extraintestinal manifestations (EIMs) such as arthritis, aphthous stomatitis (AS), and primary sclerosing cholangitis (PSC) are also commonly experienced by patients with IBD, and contribute to the morbidity and mortality of these patients. Despite the associated morbidity and the common onset of IBD during adolescence, EIMs in the pediatric setting have only recently begun to be systematically evaluated (1).
Limited pediatric data would suggest that one quarter to almost half of pediatric patients with IBD experience at least 1 EIM at the time of diagnosis, when EIMs are broadly defined to include problems such as growth failure and anemia in addition to more traditional EIMs such as PSC, pyoderma gangrenosum (PG), and arthritis (1–11).
The primary purpose of this study was to prospectively determine the rates of specific EIM in pediatric IBD. The secondary aim was to examine correlations between EIMs and age, sex, diagnosis, disease severity, and disease distribution at the time of diagnosis.
PATIENTS AND METHODS
Institutional review board approval was obtained at each participating center. Informed consent from a parent or legal guardian was obtained for all of the subjects, as well as assent from the participating child according to the requirements of each individual site.
Study subjects were enrolled in the Pediatric IBD Collaborative Research Group Registry Database, a prospective, multicenter, observational study, initiated in 2002, involving 19 pediatric gastroenterology centers in the United States and Canada. Investigators from the participating centers enrolled subjects younger than 16 years of age with newly diagnosed IBD. The diagnosis of IBD was made by the primary gastroenterologist for each patient based on standard clinical, endoscopic, histologic, and radiographic criteria. All of the children were managed by their primary gastroenterologists according to their usual and customary practice. Clinical and laboratory data were collected on each patient at the time of diagnosis, at 30 days after diagnosis, and quarterly thereafter. Data collection included information on EIMs, age, sex, diagnosis, disease severity, and disease distribution.
The database was locked for this analysis on August 31, 2007 and queried for all of the subjects with a diagnosis of CD or UC who had at least 1 year of available follow-up data. Patients with indeterminate colitis were excluded from the analysis due to the small number of patients.
EIMs recorded for this study included ankylosing spondylitis (AnSp), “chronic active hepatitis” (intended to reflect autoimmune hepatitis), AS, PSC, arthralgia, erythema nodosum (EN), PG, arthritis, iritis/uveitis (I/U), and pancreatitis. Other potential EIMs such as osteopenia and osteoporosis were not systematically recorded, and were therefore not included in this study.
Subjects were grouped into those with CD and those with UC. When a subject's initial IBD diagnosis changed during follow-up, the adjusted diagnosis, defined as the most current diagnosis, was used.
The prospectively recorded physician global assessment (PGA) was used as the primary indicator of disease severity for both CD and UC because it was the most consistently obtained measure. Patients were categorized as inactive, mild, or moderate/severe. Secondary measures of disease activity including the Pediatric Crohn Disease Activity Index (PCDAI) (12), Pediatric Ulcerative Colitis Activity Index (PUCAI) (13), and the erythrocyte sedimentation rate were also evaluated when available. A PCDAI score of 0 to 10 was considered remission, scores of 11 to 30 were mild, and scores >30 were classified as moderate to severe. A PUCAI score of 0 to 9 was considered remission, scores 10 to 34 were mild, scores of 35 to 64 were moderate, and scores ≥65 were classified as severe. Because EIMs may contribute to the total PCDAI score, a modified PCDAI (mPCDAI), which excluded the EIMs portion of the score, was also analyzed.
Disease distribution for CD and UC were categorized and reported according to location: small bowel, large bowel, and both small and large bowel involvement for CD, and rectosigmoid, left colon, and pancolon for UC. Six CD patients were excluded from the analysis of disease distribution; 5 patients with only upper tract disease and 1 patient without data.
Rates of EIMs at diagnosis and throughout the period of study were calculated. Associations between the most common EIMs, specifically arthralgia, AS, arthritis, EN and PSC (occurring anytime during the period of enrollment) and age, sex, diagnosis, disease severity, and disease distribution (all at baseline) were examined.
Associations between perianal disease (as measured by the PCDAI perianal subscore of 5 or 10) and EIMs were also evaluated. Guidelines for the classification of perianal subscores were 5 = “1–2 indolent fistula, scant drainage, no tenderness,” and 10 = “active fistula, drainage, tenderness or abscess.” Perianal disease not falling within these guidelines (eg, skin tags, fissuring) may have also been included in assigning a perianal subscore and were scored at the discretion of the individual investigators. Associations for both perianal disease occurring anytime during the study and limited to perianal disease preceding an EIM were performed.
The effect of medical therapy on the rate of development of EIM was also examined for the more common EIMs (ie, any EIM, arthralgia, AS). Medication use in patients who did not experience an EIM within 30 days of enrollment was compared between those who developed an EIM within the first year and those who did not.
A descriptive analysis of the patient population and rates of EIMs was performed. Data are presented as mean ± standard deviation or frequency and percent. Chi-square and exact tests were used to determine associations between EIMs and disease-related categorical variables, and 2-tailed t tests were used for disease-related continuous variables. P values of <0.05 were considered significant, with the exception of pairwise tests that were conducted for disease location and the presence of EIMs where a P < 0.017 was considered significant (Bonferroni adjustment). The cumulative probability of being free of EIMs during the course of follow-up was determined by Kaplan-Meier analysis. Statistical tests were performed using SPSS version 12.0.1 for Windows (SPSS Inc, Chicago, IL).
A total of 1009 children met inclusion criteria (mean age 11.6 ± 3.1 years, 57.5% boys, mean follow-up 26.2 ± 18.2 months, Table 1). Two hundred eighty-five (28.2%) patients experienced 1 or more EIMs, with arthralgia, AS, arthritis, and EN being most common (Table 2). Of the 285 patients with EIMs during the period of study, 169 (17% of the total study population) had EIM at baseline, with 116 (11% of the total study population) developing EIMs subsequently. The cumulative probability (based on the Kaplan-Meier analysis) of having an EIM by 51 months of follow-up was 34% (Table 3).
Increased disease severity at baseline, classified by PGA (mild vs moderate/severe), was associated with the occurrence of any EIM (P < 0.001), arthralgia (P = 0.024), AS (P = 0.001), and EN (P = 0.009) for both CD and UC during the period of follow-up. At least 1 secondary measure of disease severity at baseline was supportive of this association for each EIM, with the exception of arthralgia (Table 4). No association was noted between disease activity and either arthritis or PSC.
Statistically significant differences in the rates of EIMs between CD and UC were seen for AS (P < 0.001) and EN (P = 0.010) being more common in CD, whereas PSC (P = 0.039, Table 2) was more commonly seen in patients with UC.
Age, sex, diagnosis, and disease distribution were not generally associated with EIMs. However, female patients with UC had higher rates of arthralgia (P = 0.004), and sclerosing cholangitis was associated with older age (mean age 13.3 ± 2.7 vs 11.6 ± 3.1 years, P = 0.042) at diagnosis. No correlations were found between disease distribution and EIMs in patients with CD. However, UC patients with pancolitis were more likely to experience an EIM than patients with isolated rectosigmoid disease (P = 0.012).
No association was found between perianal disease and EIMs, either as a group or for any individual EIM reported for this study. Timing of the perianal disease (ie, whether it occurred before/concurrent with the EIM or occurred anytime during the study period) did not affect this result.
For patients with moderate to severe disease who had not experienced an EIM within 30 days of enrollment, patients treated with mesalamine/sulfasalazine (P = 0.035), infliximab (P < 0.001), or immunomodulators (P < 0.001) were less likely to experience an EIM than those who did not receive these therapies. This was also true for patients with mild disease who were treated with immunomodulators (P = 0.042). No protective effect was seen for patients treated with antibiotics or corticosteroids. Similar results were noted for patients with moderate to severe disease treated with infliximab (P = 0.030) or immunomodulators (P = 0.001) in preventing arthralgia, and for patients with moderate to severe disease treated with immunomodulators (P = 0.048) in preventing AS.
As defined in this study, EIMs were seen in more than one quarter of pediatric-onset patients with IBD. This rate is similar to that in adult patients, in which at least 25% to 40% of patients experience 1 or more EIMs (7,14–22). Likewise, our results are similar to a recently published study by Jose et al (1) indicating that 29% of pediatric patients developed an EIM within a follow-up period of up to 15 years.
However, the overall rate of EIM will vary based on which conditions are included as an EIM, as well as the period of follow-up. When EIMs are more broadly defined to include other systemic effects such as growth delay, nutritional deficiency, anemia, decreased bone mineral density, and fatigue, the rate of EIMs could approach 100%. It may therefore be more instructive to examine rates of individual EIMs.
Arthralgias (17%) were the most commonly reported EIMs noted in this study, followed by AS (8%) and arthritis (4%). These rates are comparable to those reported by Jose et al (1) for arthralgias and arthritis, but greater than that reported for AS (2.1%). Although this may reflect a true difference in the 2 study populations, this discrepancy could also be the result of differences in reporting threshold, active case finding, or other factors associated with study differences.
As noted by Jose et al and in several studies in adult patients with IBD (7,10,14–19,23–27), we also found differences in rates of EIMs between disease types. Specifically, in our study, patients with CD were 3 times more likely to develop AS than patients with UC, and 5 times more likely to develop EN. In contrast, children with UC were approximately 3 times more likely to develop PSC as compared with those with CD. The reported rate of PSC is lower in children with IBD as compared with adults (1–10,24,28–42).
The literature has previously suggested that many EIMs such as arthralgias, arthritis, and EN tend to be most prominent during periods of disease activity (18,19,26,27,43–50). Unfortunately, our database does not allow us to directly address this issue. Specifically, after initial enrollment, data for this study are collected at 30 days, then quarterly. Any EIM occurring since the last quarterly visit may be recorded/reported, but the disease activity score (PGA and PCDAI) is only recorded for the actual time of the visit. Therefore, we believed that it would not be accurate to correlate disease activity and EIMs for a given quarter because the EIM and assessment of disease activity may have occurred at different times, and some therapy may have been introduced between the events that would skew any correlation.
Although we were not able to directly investigate the temporal association between the development of EIMs and disease activity over time, we did identify an association between disease severity at the time of diagnosis and EIMs at any time during the period of follow-up. This relation was noted for EIMs generally, and for some specific EIMs, suggesting that a similar inflammatory process may be involved in both IBD and some EIMs. However, this was not true for all EIMs because we did not find an association between PSC and disease severity. This latter finding is consistent with several pediatric and adult studies that have demonstrated that the activity of PSC is independent of IBD activity (15,19,29,30,32,36,39,51–55). In fact, some cases of PSC are known to precede the onset of IBD symptoms by years (24,28–30,33,40,51–53,56).
We also noted in this study that particular classes of medications may be protective in the development of EIMs. Specifically, infliximab and immunomodulators were commonly associated with a lower risk of developing EIMs, mesalamine/sulfasalazine demonstrated some benefit, whereas other classes of medications did not.
The major strength of this study arises from the prospective collection of specifically defined EIM data from multiple North American sites. However, because the Registry protocol does not specifically define diagnostic criteria for the EIM of interest, the reporting of data from multiple sites may have resulted in some intercenter variation in what was reported. For example, the phrase “chronic active hepatitis” is used on the data forms, and was intended to represent autoimmune hepatitis. Because there is not a specific instruction on the data forms to include only autoimmune hepatitis, it is possible that other hepatic disorders may have been included here, although we believe that this is not likely. Transaminase elevations believed to be secondary to drug effect were likely not reported as “chronic active hepatitis.” Another weakness of the data drawn from the database is the inability to distinguish symptoms that may have been a result of therapy (eg, arthralgias, pancreatitis, hepatitis) rather than a true EIM. However, because pancreatitis and hepatitis are well-known potential adverse effects of thiopurines, we believe that they were less likely to be reported as an EIM if they were thought to be secondary to the medication. It is also important to note that there was a relatively short mean follow-up period in this cohort.
In conclusion, this study suggests that approximately one fourth of all pediatric patients with IBD experience at least 1 EIM within 2½ years of diagnosis. Differences exist in the prevalence of EIMs between CD and UC for AS, PSC, and EN. Increased disease severity at baseline is associated with the occurrence of developing any EIM, arthralgia, AS, and EN. Infliximab and immunomodulator therapy may be protective from developing EIMs, although more data are needed to confirm this finding.
The authors are deeply indebted to the following research coordinators, whose efforts greatly facilitated the performance of this study: Vivian Abadom, Lori Ann Ashworth, Barbara Bancroft, Kelly Boyer, Barbara Christensen, Paola Duran, Karen Frost, Allegra Gary, Kathy Grancher, Shari Huffman, Ruth Irizarry, Kelley Koslasky, Miriam Lincoln, Daniel Lotta, Sandra McRandal, Melissa Metheney, Myrna Miller, Ruth Singleton, and Gail Waltz. The authors thank Sandra Hale, Rosa Negron, and Rosa Rodrigues for their management of the data collection center.
1. Jose FA, Garnett EA, Vittinghoff E, et al
. Development of extraintestinal manifestations in pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis 2009; 15:63–68.
2. Danzi JT. Extraintestinal manifestations of idiopathic inflammatory bowel disease. Arch Intern Med 1988; 148:297–302.
3. Mamula P, Markowitz JE, Baldassano RN. Inflammatory bowel disease in early childhood and adolescence: special considerations. Gastroenterol Clin North Am 2003; 32:967–995.
4. Hyams JS. Crohn's disease in children. Pediatr Clin North Am 1996; 43:255–277.
5. Mamula P, Markowitz J, Baldassano R, eds. Pediatric Inflammatory Bowel Disease
. New York: Springer; 2008:91–9.
6. Hyams JS. Extraintestinal manifestations of inflammatory bowel disease in children. J Pediatr Gastroenterol Nutr 1994; 19:7–21.
7. Greenstein AJ, Janowitz HD, Sachar DB. The extra-intestinal complications of Crohn's disease and ulcerative colitis: a study of 700 patients. Medicine (Baltimore) 1976; 55:401–412.
8. Rankin GB, Watts HD, Melnyk CS, et al
. National Cooperative Crohn's Disease Study: extraintestinal manifestations and perianal complications. Gastroenterology 1979; 77:914–920.
9. Oliva-Hemker M. More than a gut reaction: extraintestinal complications of IBD. Contemp Pediatr 1999; 16:45–64.
10. Mendoza JL, Lana R, Taxonera C, et al
. Extraintestinal manifestations in inflammatory bowel disease: differences between Crohn's disease and ulcerative colitis. Med Clin (Barc) 2005; 125:297–300.
11. Winesett M. Inflammatory bowel disease in children and adolescents. Pediatr Ann 1997; 26:227–234.
12. Hyams JS, Ferry GD, Mandel FS, et al
. Development and validation of a pediatric Crohn's disease activity index. J Pediatr Gastroenterol Nutr 1991; 12:439–447.
13. Turner D, Otley AR, Mack D, et al
. Development, validation, and evaluation of a Pediatric Ulcerative Colitis Activity Index: a prospective multicenter study. Gastroenterology 2007; 133:423–432.
14. Aghazadeh R, Zali MR, Bahari A, et al
. Inflammatory bowel disease in Iran: a review of 457 cases. J Gastroenterol Hepatol 2005; 20:1691–1695.
15. Lakatos L, Pandur T, David G, et al
. Extra-intestinal manifestation of IBD in Veszprem county (of Hungary): results of a 25-years follow-up study. Orv Hetil 2003; 144:1965–1975.
16. Salvarani C, Vlachonikolis IG, van der Heijde DM, et al
. Musculoskeletal manifestations in a population-based cohort of inflammatory bowel disease patients. Scand J Gastroenterol 2001; 36:1307–1313.
17. Jiang L, Xia B, Li J, et al
. Retrospective survey of 452 patients with inflammatory bowel disease in Wuhan city, central China. Inflamm Bowel Dis 2006; 12:212–217.
18. Farhi D, Cosnes J, Zizi N, et al
. Significance of erythema nodosum and pyoderma gangrenosum in inflammatory bowel diseases: a cohort study of 2402 patients. Medicine (Baltimore) 2008; 87:281–293.
19. Andres PG, Friedman LS. Epidemiology and the natural course of inflammatory bowel disease. Gastroenterol Clin North Am 1999; 28:255–281.
20. Isaacs K. Extra-intestinal manifestations. In: Bayless TM, Hanauer SB, eds. Advanced Therapy of Inflammatory Bowel Disease
. Hamilton, Canada: BC Decker; 2001:267–70.
21. Kornbluth A, Sachar D, Salomon P. Crohn's disease. In: Feldman MSB, Sleisenger MH, eds. Sleisenger and Fordtran's Gastrointestinal and Liver Disease
. Philadelphia: WB Saunders; 1998:1708–34.
22. Jewell D. Ulcerative colitis. Feldman M, Scharschmidt B, Sleisenger M, eds. Sleisenger and Fordtran's Gastrointesinal and Liver Disease
. Philadelphia: WB Saunders; 1998:1735–61.
23. Grossman BJ, DeBenedetti CD. Extraintestinal manifestations of chronic inflammatory bowel disease in children. Proc Inst Med Chic 1970; 28:119.
24. Kaplan GG, Laupland KB, Butzner D, et al
. The burden of large and small duct primary sclerosing cholangitis in adults and children: a population-based analysis. Am J Gastroenterol 2007; 102:1042–1049.
25. Palm O, Moum B, Jahnsen J, et al
. The prevalence and incidence of peripheral arthritis in patients with inflammatory bowel disease, a prospective population-based study (the IBSEN study). Rheumatology (Oxford) 2001; 40:1256–1261.
26. Orchard TR, Wordsworth BP, Jewell DP. Peripheral arthropathies in inflammatory bowel disease: their articular distribution and natural history. Gut 1998; 42:387–391.
27. Lindsley CB, Schaller JG. Arthritis associated with inflammatory bowel disease in children. J Pediatr 1974; 84:16–20.
28. Broome U, Glaumann H, Hellers G, et al
. Liver disease in ulcerative colitis: an epidemiological and follow up study in the county of Stockholm. Gut 1994; 35:84–89.
29. Wilschanski M, Chait P, Wade JA, et al
. Primary sclerosing cholangitis in 32 children: clinical, laboratory, and radiographic features, with survival analysis. Hepatology 1995; 22:1415–1422.
30. Loftus EV Jr, Harewood GC, Loftus CG, et al
. PSC-IBD: a unique form of inflammatory bowel disease associated with primary sclerosing cholangitis. Gut 2005; 54:91–96.
31. Ong JC, O'Loughlin EV, Kamath KR, et al
. Sclerosing cholangitis in children with inflammatory bowel disease. Aust N Z J Med 1994; 24:149–153.
32. Faubion WA Jr, Loftus EV, Sandborn WJ, et al
. Pediatric “PSC-IBD”: a descriptive report of associated inflammatory bowel disease among pediatric patients with PSC. J Pediatr Gastroenterol Nutr 2001; 33:296–300.
33. Vajro P, Cucchiara S, Vegnente A, et al
. Primary sclerosing cholangitis preceding Crohn's disease in a child with Down's syndrome. Dig Dis Sci 1998; 43:166–169.
34. Olsson R, Danielsson A, Jarnerot G, et al
. Prevalence of primary sclerosing cholangitis in patients with ulcerative colitis. Gastroenterology 1991; 100:1319–1323.
35. Lee YM, Kaplan MM. Primary sclerosing cholangitis. N Engl J Med 1995; 332:924–933.
36. Rasmussen HH, Fallingborg J, Mortensen PB, et al
. Primary sclerosing cholangitis in patients with ulcerative colitis. Scand J Gastroenterol 1992; 27:732–736.
37. Card TR, Solaymani-Dodaran M, West J. Incidence and mortality of primary sclerosing cholangitis in the UK: a population-based cohort study. J Hepatol 2008; 48:939–944.
38. Parlak E, Kosar Y, Ulker A, et al
. Primary sclerosing cholangitis in patients with inflammatory bowel disease in Turkey. J Clin Gastroenterol 2001; 33:299–301.
39. Floreani A, Zancan L, Melis A, et al
. Primary sclerosing cholangitis (PSC): clinical, laboratory and survival analysis in children and adults. Liver 1999; 19:228–233.
40. Schrumpf E, Elgjo K, Fausa O, et al
. Sclerosing cholangitis in ulcerative colitis. Scand J Gastroenterol 1980; 15:689–697.
41. Hyams J, Markowitz J, Treem W. Characterization of hepatic abnormalities in children with inflammatory bowel disease. Inflamm Bowel Dis 1995; 1:27–33.
42. Delle Monache M, Salvio A, Fiocca F, et al
. Primary sclerosing cholangitis: an analysis of 37 retrospective cases. Ital J Gastroenterol 1992; 24:485–488.
43. Passo MH, Fitzgerald JF, Brandt KD. Arthritis associated with inflammatory bowel disease in children. Relationship of joint disease to activity and severity of bowel lesion. Dig Dis Sci 1986; 31:492–497.
44. Harty S, Fleming P, Rowland M, et al
. A prospective study of the oral manifestations of Crohn's disease. Clin Gastroenterol Hepatol 2005; 3:886–891.
45. Powell FC, Perry HO. Pyoderma gangrenosum in childhood. Arch Dermatol 1984; 120:757–761.
46. Gryboski JD, Spiro HM. Prognosis in children with Crohn's disease. Gastroenterology 1978; 74:807–817.
47. Plauth M, Jenss H, Meyle J. Oral manifestations of Crohn's disease. An analysis of 79 cases. J Clin Gastroenterol 1991; 13:29–37.
48. Kugathasan S, Miranda A, Nocton J, et al
. Dermatologic manifestations of Crohn disease in children: response to infliximab. J Pediatr Gastroenterol Nutr 2003; 37:150–154.
49. Asquith P, Thompson RA, Cooke WT. Oral manifestations of Crohn's disease. Gut 1975; 16:249–254.
50. Lu H, Qian J, Wang L. The systemic manifestations of ulcerative colitis. Zhonghua Nei Ke Za Zhi 2002; 41:675–677.
51. Feldstein AE, Perrault J, El-Youssif M, et al
. Primary sclerosing cholangitis in children: a long-term follow-up study. Hepatology 2003; 38:210–217.
52. Brackmann S, Andersen SN, Aamodt G, et al
. Relationship between clinical parameters and the colitis-colorectal cancer interval in a cohort of patients with colorectal cancer in inflammatory bowel disease. Scand J Gastroenterol 2009; 44:46–55.
53. Florin TH, Pandeya N, Radford-Smith GL. Epidemiology of appendicectomy in primary sclerosing cholangitis and ulcerative colitis: its influence on the clinical behaviour of these diseases. Gut 2004; 53:973–979.
54. Batres LA, Russo P, Mathews M, et al
. Primary sclerosing cholangitis in children: a histologic follow-up study. Pediatr Dev Pathol 2005; 8:568–576.
55. Sokol H, Cosnes J, Chazouilleres O, et al
. Disease activity and cancer risk in inflammatory bowel disease associated with primary sclerosing cholangitis. World J Gastroenterol 2008; 14:3497–3503.
56. Kane W, Miller K, Sharp HL. Inflammatory bowel disease presenting as liver disease during childhood. J Pediatr 1980; 97:775–778.
This article has been cited 3 time(s).
Inflammatory Bowel DiseasesDisease Phenotype at Diagnosis in Pediatric Crohn's Disease: 5-year Analyses of the EUROKIDS RegistryInflammatory Bowel Diseases
Expert Review of Clinical ImmunologyExclusive enteral nutrition and induction of remission of active Crohn's disease in childrenExpert Review of Clinical Immunology
HepatologyPrimary Sclerosing Cholangitis, Autoimmune Hepatitis, and Overlap in Utah Children: Epidemiology and Natural HistoryHepatology
Crohn disease; extraintestinal manifestations; inflammatory bowel disease; pediatric; ulcerative colitis
Copyright 2010 by ESPGHAN and NASPGHAN
What does "Remember me" mean?
By checking this box, you'll stay logged in until you logout. You'll get easier access to your articles, collections,
media, and all your other content, even if you close your browser or shut down your
To protect your most sensitive data and activities (like changing your password),
we'll ask you to re-enter your password when you access these services.
What if I'm on a computer that I share with others?
If you're using a public computer or you share this computer with others, we recommend
that you uncheck the "Remember me" box.
Highlight selected keywords in the article text.
Data is temporarily unavailable. Please try again soon.
Readers Of this Article Also Read