IBD across the age spectrum—is it the same disease? Joannie Ruel, Darren Ruane, Saurabh Mehandru, Corinne Gower-Rousseau and Jean-Frédéric Colombel Abstract | IBD is a chronic disorder with disease onset ranging from early childhood to beyond the sixth decade of life. The factors that determine the age of onset currently remain unexplained. Is timing of occurrence a random event or is it indicative of different pathophysiological pathways leading to different phenotypes across the age spectrum? Over the past decade, several studies have suggested that the characteristics and natural history of IBD seem to be different according to age of onset. This heterogeneity suggests that the respective contributions of genetics, host immune system and environment to the aetiology and phenotype of Crohn’s disease and ulcerative colitis are different across ages. Critical reviews that focus on differences characterizing IBD between age groups are scarce. Therefore, this Review updates the knowledge of the differences in epidemiology, clinical characteristics, and natural history of paediatric, adult and elderly-onset IBD. In addition, potential differences in host–gene–microbial interactions according to age are highlighted. Ruel, J. et al. Nat. Rev. Gastroenterol. Hepatol. 11, 88–98 (2014); published online 17 December 2013; doi:10.1038/nrgastro.2013.240
Department of Medicine, Dr Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1069, New York, NY 10029, USA (J. Ruel, D. Ruane, S. Mehandru, J.‑F. Colombel). Gastroenterology Unit, Lille University Nord de France, CHU Lille, 2 Avenue Oscar Lambret, Lille 59 000, France (C. Gower-Rousseau). Correspondence to: J.‑F. Colombel [email protected]
IBD, including Crohn’s disease and ulcerative colitis, is thought to develop as a result of dysregulation of the immune system, driven by the gut microbiota, in genetically susceptible hosts. Clinical heterogeneity within IBD has long been recognized, and evidence is growing that this heterogeneity might be explained by the existence of different mechanism-based disease subsets.1 IBD can occur at all ages, but two studies published in 2013 have demonstrated that phenotypes of late-onset IBD differ from those in the younger population.2,3 Whether these phenotypic differences between age groups reflect variations in mucosal immune response, composition of the microbiome, genetics and/or environmental risk factors is still not fully understood. The goal of this Review is to update knowledge on the differences in epidemiology, clinical characteristics and natural history of paediatric, adult and elderly-onset IBD, here defined as 60 years of age, respectively. Potential differences in host–gene–m icrobial interactions according to age are also highlighted.
Epidemiology The peak age of onset for Crohn’s disease and ulcerative colitis is 20–30 years and 30–40 years, respectively.4 Although the concept of a ‘bimodal’ distribution of IBD incidence, with a second peak at 60–70 years, has been widely circulated, the fact is that it has been documented in less than one-third of epidemiological studies.5 Overall, 5–25% of IBD cases develop during childhood or adolescence, whereas 10–15% of patients with IBD will receive their diagnosis >60 years of age.6–10 Among the Competing interests The authors declare no competing interests.
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latter group, the majority will be diagnosed in their sixties (65%), with fewer in their seventies (25%) and eighties (10%)9,10 (Table 1). The Crohn’s disease:ulcerative colitis ratio is higher in paediatric-onset than in adult-onset and elderly-onset age groups. 11 In adult-onset and elderly-onset IBD, ulcerative colitis is slightly more prevalent than Crohn’s disease.3,12 The male:female ratio also differs according to age of onset; males are more commonly affected in paediatric Crohn’s disease, whereas females are more commonly affected in adult-onset and elderly-onset Crohn’s disease.3,13–15 The change in the Crohn’s disease distribution among males and females occurs between 14–17 years of age, and this shift in sex ratio has also been observed in other immune-mediated inflammatory diseases, such as type 1 diabetes.16,17 Notably, the shift starts after puberty, suggesting that hormones might have a role. In paediatric-onset ulcerative colitis, the male:female ratio is equal, whereas in adult-onset and elderly-onset, ulcerative colitis is more frequent in males3,15 (Table 1). In the past 20 years, a striking increase in incidence of IBD has been observed in patients 60 years of age ■■ The Crohn’s disease:ulcerative colitis ratio is higher in paediatric-onset than in adult-onset and elderly-onset age groups ■■ Very-early-onset and elderly-onset Crohn’s disease are characterized by the predominance of pure colonic disease, whereas in older children and adults, ileocolonic disease is more prevalent; in ulcerative colitis, an extensive location is more prevalent in early-onset than in later-onset disease ■■ In Crohn’s disease, disease extension occurs more frequently in paediatriconset disease compared with adult and elderly age groups; complicated disease behaviour is more prevalent in early-onset than in late-onset Crohn’s disease ■■ Paediatric-onset ulcerative colitis is characterized by widespread location at diagnosis and a high rate of disease extension compared with late-onset disease ■■ Disease heterogeneity, according to age of onset, points to differences in the respective contribution of biological networks in the aetiology, phenotype and natural history of IBD across the age spectrum
the 10–19 years age group.24,28–30 According to the Swiss IBD Cohort Study (SIBDCS) Group, the observation of increasing numbers of paediatric and adolescent patients with IBD is not caused by a trend towards disease onset at a younger age, but might rather be a consequence of the overall increasing incidence of these conditions.31 Results of the SIBDCS study show that there is a slow but significant trend for both first symptoms and diagnosis occurring at an older age today compared with the past three decades.31 This finding is in contrast to other studies and might reflect a specific condition in Europe. Indeed, the numbers reported in this last study are in line with the data from the EpiCom consortium of the European Crohn’s and Colitis Organization. In this inception cohort, only 45 (3%) out of 1,560 IBD cases were paediatric-onset.32 In elderly-onset IBD, the incidence of Crohn’s disease is 2.6–11 per 100,000 personyears, whereas ulcerative colitis incidence is 3.1–16.0 per 100,000 person-years.2,3,9,10,33–35 Incidence of IBD in the elderly-onset age group is stable with similar numbers reported in patients since the 1990s.3,34–36 In developing nations, population-based epidemiological studies providing incidence rates between age groups are scarce. In countries that are becoming industrialized, a pattern of IBD incidence, similar to what has been observed in North America and Europe in the 1960s, can be depicted, that is, an initial increase in ulcerative colitis incidence followed by an increase in Crohn’s disease (Table 1).4
Phenotype at diagnosis Location and phenotype of disease at diagnosis can be differentiated among age groups (Table 2). Very-early onset (0–6 years) and elderly-onset Crohn’s disease are characterized by the predominance of pure colonic disease (L2), whereas in older children and adults, ileoc olonic disease (L3) is more prevalent.2,18,27,37–41 Childhood-onset Crohn’s disease (0–18 years) is also characterized by a more widespread extent of lesions in the proximal small bowel (L4), reported in ~40% of these patients at diagnosis, compared with adult-onset and elderly-onset Crohn’s disease, in which proximal involvement was found in only 6% of elderly patients.3,18,27 At diagnosis, all age groups are characterized by the predominance of inflammatory behaviour (B1). Indeed, stricturing (B2) and penetrating (B3) disease are relatively uncommon at presentation, although more prevalent in adults compared with children and the elderly. 27,42,43 In addition, although not reported consistently in every study, elderly-onset Crohn’s disease is generally character ized by less stricturing and penetrating disease than in paediatric disease.3,12,44,45 Perianal disease is more frequent in children than in adults.18,46 In a study from Northern France, perianal disease at diagnosis was reported in 8% of elderly-onset patients with Crohn’s disease as compared with 7%, 5%, and 6% in the ulcerative colitis
Crohn’s disease L2 >L1‡
L3 >L2 >L1
L2 >L3 >L1
B1 >B2 >B3
B1 >B2 >B3
B1 >B2 >B3
E3 >E1 >E2
E1 & E2 >E3
E2 >E1 >E3
Ulcerative colitis Location
*According to the Montreal classification. ‡L2 more prevalent in very-early onset Crohn’s disease. Classification: L1, terminal ileum; L2, colon; L3, ileocolonic disease; B1, inflammatory phenotype without stricture formation and penetrating disease; B2, stricturing disease; B3, penetrating disease; E1, proctitis; E2, left-sided disease; E3, extensive disease.
Although a study by Israeli et al. 56 reported that patients with paediatric-onset Crohn’s disease are not more likely to have more complicated disease than adults, complicated behaviour at maximal follow-up is generally more prevalent in early-onset than in adultonset and elderly-onset Crohn’s disease2,53,57 (Figure 1). Indeed, >50% of children are expected to develop complicated disease behaviour.27 By contrast, disease behaviour was reported to remain stable in 91% of patients with elderly-onset Crohn’s disease, after a median followup of 6 years.3 In an Australian study describing differences in the natural history between an elderly-onset IBD cohort and a younger-onset cohort (16–40 years of age), the cumulative probability of introducing immuno modulation (P 50% of children