INTRODUCTION
Under the name of Inflammatory Bowel Disease (IBD) are mainly collected two intestinal chronic diseases, Crohn’s Disease (CD) and Ulcerative Colitis (UC), which often evolve as systemic disorders.
Historical insight
The existence of chronic non-‐infectious diseases of the gastrointestinal tract was known since the Roman times, thanks to the work of the Greek physicians Aretaeus of Cappadocia (A.D. 300) and Soranus of Ephesus (A.D. 117), who described various forms of non-‐contagious diarrhea (1). It has been suggested that in 1745 Prince Charles, the young pretender of the throne of England, suffered probably from ulcerative colitis and cured himself by adopting a milk-‐free diet (1).
The first reference to ulcerative colitis dates back to 1859 to the report of Sir Samuel Wilks, the General Surgeon of the Union Army, who also produced photomicrographs showing the histological appearances of the disease (1). Following these pioneer descriptions, it is during the late nineteen century that the pathological and clinical features of UC were closely characterized. At the symposium of the Royal Society of Medicine, in 1909, no less than 300 cases were reported from the various London Hospitals (1,2).
As regards Crohn’s disease, it was first described by the father of the German surgeon, Wilhelm Fabry (also known as Guilhelmus Fabricius Hildanus) in 1623 and was later described by and named after the American physician Burril B. Crohn (3). Since that time the knowledge of IBD has enormously increased, but its etiology is still not completely clear.
Clinical Phenotypes
CD and UC are diagnosed on the basis of a clinical suspicion sustained by laboratory, radiological, endoscopic and histological findings (Table 1).
Crohn’s Disease
CD is a relapsing, transmural inflammatory disease of the gastrointestinal mucosa that can affect the entire gastrointestinal tract from the mouth to the anus. The diagnosis of CD is complex, because symptoms are often insidious and no definitive diagnostic test exists. The diagnosis relies on a work-‐up based on clinical history and physical examination, supported by objective findings based on laboratory, radiological, endoscopic and histological investigations. According to published criteria (4) patients could result as having a “definitive”, “probable” or “possible” CD. Typical presentations include the discontinuous involvement of various portions of the gastrointestinal tract and the development of complications, including strictures, abscesses, or fistulas. Patients with CD frequently report abdominal pain, fever and clinical signs of bowel obstruction or diarrhea with passage of blood, mucus, or both. In a patient with a clinical history and laboratory findings compatible with Crohn’s disease, such as high levels of C reactive protein (CRP) and eritrosedimentation rate (ESR), a first exclusion of a digestive infectious disease (e.g., Clostridium difficile, Yersinia enterocolitica) should be done. In case of negative results, a study of the gastrointestinal tract is mandatory through a study imaging (MRI enterography) and/or a complete endoscopic evaluation (upper esophago-‐gastro-‐duodenoscopy and complete coloscopy with ileoscopy) with biopsy samples. The macroscopic inspection could show small aphthous lesions, which may coalesce into larger irregular and deeper ulcers. Skip areas of macroscopically and even microscopically normal mucosa could be found. Cobblestoning of the surface lining may occur as a result of extensive linear and serpiginous mucosal ulceration with associated regeneration and hyperplasia, in addition to marked submucosal thickening. The histological finding of focal crypt irregularity and, in particular, epithelioid granulomas is a typical sign of Crohn’s disease.
A patient with a diagnosis of Crohn’s disease should be phenotiped as regards the disease activity, location (ileal, colonic, ileocolonic or upper gastrointestinal tract with or without a distal involvement) and behaviour (non-‐stricturing non-‐penetrating, stricturing or penetrating)
according to the Montreal Classification (5). In addition, a screening for extraintestinal manifestations and associated autoimmune diseases should be done. Taken together, endoscopic features and disease activity and phenotype help clinicians to stratify the patients and tailor the best possible therapy.
The anatomical location and behavior of the disease is fairly stable, but changes over time occur. It seems that a role in extension of the disease is played by the age at diagnosis, as suggested by the fact that in the elderly there are more than 90% of patients with a stable localization after 6 years of follow-‐up. In general, the most significant change is from non-‐stricturing to either stricturing or penetrating disease in up to 40% of patients over 10 years of disease (6).
Ulcerative Colitis
Ulcerative Colitis (UC) is a relapsing non-‐transmural inflammatory disease that is restricted to the colon. Inflammation generally starts in the rectum and extends proximally, in an uninterrupted pattern, involving parts of, or the entire, colon. Depending on the anatomical extent of the involvement, patients can be classified as having proctitis, left-‐side colitis (involving the sigmoid colon with or without involvement of descending colon) or pancolitis. A few patients could also develop ileal inflammation (backwash ileitis) or a cecal patch of inflammation in the context of a proctitis or of a left-‐side colitis. When the ileum is involved a clear distinction between UC and CD is not always easy (or even possible). Symptoms variability reflects differences in the extent of the disease. Patients typically present bloody diarrhea (often nocturnal and postprandial), passage of pus, mucus or both and abdominal cramping during bowel movement. Urgency and tenesmus are other possible symptoms, in particular in the case of proctitis.
As for CD, the diagnosis of UC is based on the clinical symptoms confirmed by objective findings from endoscopic and histological examinations. Infectious causes (e.g. bacterial, parasitic, viral and fungal) and non-‐infectious causes (e.g. diarrhea induced by drugs, malignant lesions) of diarrhea should be ruled out before the diagnosis is made. The extent of the disease should be assessed at diagnosis with a pancolic endoscopy, because knowledge of the anatomic extension of mucosal inflammation is essential for the selection of the appropriate treatment (topical or systemic) and has prognostic implications for the short-‐and long-‐term follow-‐up. In addition to the extent of the disease, a severity score, based on the number of daily stools and the presence (or absence) of systemic signs of inflammation, should be assessed.
The endoscopic appearance of the mucosa in a mild disease is characterized by diffuse erythema and loss of the normal vascular pattern. Moderate inflammation results in numerous small surface ulcerations, scattered flecks of exudate and spontaneous or contact bleeding from the mucosal surface. Large deep ulcerations covered with shaggy exudate become widespread in the more active disease. Histological findings of cryptitis, often accompanied by crypt abscesses and chronic inflammatory cells of the lamina propria, are common in colon biopsies samples of UC patients. Crypt distortion and Paneth cell metaplasia could also be found.
The clinical course of ulcerative colitis is characterized by alternating periods of remission and relapse. At diagnosis, most of the patients have a mild to moderate disease, and less than 10% have severe disease. Like in CD, the phenotype of UC tends to change over the years. At 10 years of follow-‐up almost half of the patients remain in clinical remission or have only mild symptoms and about 20% have a chronic continuous activity. Subsequent relapses are more probable if the period between the diagnosis and the first flare is less then 2 years, in the presence of systemic signs (fever, weight loss) and if the disease was active in the preceding year. Usually, extension of colonic disease can occur in the course of time. At diagnosis up to 50% of patients have a disease confined to the rectum or the sigmoid colon and 20% have pancolitis. Of those with distal colitis, 25-‐50% progress some time to more extensive forms of the disease.
In about 10% of cases (7) it is not possible to clearly distinguish between CD and UC and in these cases the term Inflammatory Bowel Disease Unclassified (IBD-‐U) is generally used. A rigorous follow-‐up of these patients could usually permit, over the time, to define the right diagnosis.
Table 1. Differential characteristics of Crohn’s disease and ulcerative colitis.
CD UC
Abdominal symptoms - Abdominal pain - Diarrhea - Hematochezia
- Passage of mucus or pus - Small bowel /colonic
obsruction
- Fistulas and perianal disease Extraintestinal manifestation - Stomatitis - Arthritis - Eritema Nodosum - Uveitis, episcleritis - Malnutrition/Growth Failure +++ ++/-‐ +/-‐ +/-‐ +++ +++ Common ++ ++ + ++ +++ ++ +++ +++ +++ -‐ -‐ Common -‐ + + + +/-‐ Laboratory - CRP - ESR - thrombocytosis - Microcytic anemia - Hypoalbuminemia - ASCA - ANCA
- Stool occult blood - Calprotectin ++ ++ ++ ++ ++ ++ -‐ ++ + ++ ++ ++ ++ ++ -‐ ++ -‐ ++ Radiology
Bowel thickening, abscess, fistulae
Endoscopy
Ulcers, small aphthous lesions, “skip areas” of grossly and even macroscopically normal mucosa, pseudopolyps (through all the GI tract)
Changes confine to the
mucosal surface and classically begin at the anal verge and extend proximally (variable extent): erythema, fine granularity, small surface ulcerations,
spontaneous/contact bleeding, deep ulcerations, pseudopolyps
Histology
- -‐ Transmural mucosal inflammation
- Distorted crypt archietecture - Cryptitis and crypt abscesses - Granulomas
- Fissures and skip lesions
++ -‐ ++ ++ ++ -‐-‐ ++ ++ -‐-‐ -‐
Adult IBD
Epidemiology
Epidemiology is the study of occurrence of illness. It studies the patterns, causes and effects of health and disease conditions in defined populations and is a cornerstone for public health.
Regarding IBD, starting from the first epidemiological studies in the 1960, many studies with different study designs, different number of patients included and different length of study periods, have been published (8). Today it is estimated that IBD afflicts as many as 1.4 million persons in the US and Canada and 2.2 million in Europe, representing a major burden for developed countries (9). Although significant advances have been made towards a better understanding of the pathophysiology of IBD, their etiology remains unclear (10,11). Some evidence show, however, that IBDs are immunologically mediated diseases and that a genetic predisposition, as well as environmental trigger factors, may play an important role in their occurrence.
Epidemiological studies of geographic and temporal variations in IBD provide important information on the natural history, health care burden and causal mechanisms of the disease. In particular, population-‐based epidemiological studies are more likely to reflect the true spectrum of illness than retrospective studies, which are based on hospital admission at referral centers and which may be affected by several selection biases.
The highest incidence rates and prevalence of CD and UC have been reported from northern Europe, the UK and North America, where the rates today are beginning to stabilize. As regards in particular CD incidence and prevalence, many studies showed an increase almost everywhere that persists even today, in particular among the early age patient groups (8,12–16). Regarding UC, on the other hand, observational studies have reported, a steady incidence increase from the 1950’s up to the early 1990s, followed by stabilization or a slight decrease (16–20). A different trend is reported in the developing countries (Southeast Asia, China, India) where the rates of both diseases, UC and CD albeit smaller, continue to rise (2,21).
Country Authors Study period
CD UC Olmsted Country, MN USA Sedlack et al (22) 1935-‐54 1,9 Olmsted Country, MN USA Loftus et al (23) 1970-‐79 7,9 10,1 Olmsted Country, MN USA Loftus et al (23) 1990-‐2000 7,9 8,8 Copenhagen County,
Denemark
Binder et al (24) 1962-‐78 2,7 8,1 Copenhagen County,
Denemark Munkholm et al (25) 1979-‐87 4,1
Stockholm County, Sweden Lapidus et al (26) 1955-‐89 4,6 Stockholm County, Sweden Lapidus et al (27) 1990-‐2001 8,3
Table. 2 Incidence (case/100.000 person-‐years) of inflammatory bowel disease in well-‐conducted studies with high-‐incidence groups in North America and northern Europe
The higher prevalence of IBD in some ethnic groups such as Ashkenazi Jews has been noticed for a long time (28). This observation, together with the high occurrence of IBD in members of the same family, reported since the 1930s, suggest a genetic role in the development of IBD (2). Indeed, a positive family history (or family aggregation) is still the strongest independent risk factor for the disease: in fact first-‐degree relatives of IBD patients, especially siblings, are at the greatest risk for this disease (29). In particular, the concordance in monozygotic twins arrives almost at 37% for Crohn’s disease and at 10% for ulcerative colitis, whereas for dizygotic twins it is at 7% and 3%, respectively (30,31). Therefore, although a level of concordance exists (higher for CD), other factors have to be involved in the occurrence of IBD.
Observations of increasing incidence rates among immigrants from low-‐incidence rates countries moving to more developed high-‐incidence rates countries and the steady increase of incidence and prevalence in the low to middle income countries, suggest additional environmental and lifestyle factors (21,32). In the past 2 decades, in fact, the IBD north-‐south and west-‐east gradient, once worldwide described, has been becoming less evident (18). Various factors inherent to the western lifestyle were taken into consideration. Socioeconomic conditions affecting hygiene such as the presence of tap and hot water, of fewer siblings and of a smaller family size, were some of the factors proposed to be at the basis of the so-‐called “hygiene hypothesis” and were found to be
associated with a higher risks of IBD (9,33,34). Other proposed factors are industrialization and higher use of antibiotics. Regarding the different nutrition, an excessive consumption of carbohydrates, typical of western country, seems to promote the risk of developing IBD, whereas no significant association was found in adopting a fatter diet. Although dietary factors may contribute to the risk of IBD, methodological difficulties and the retrospective nature of most of the research make it difficult to determine these associations with certainty. Studies on smoking habit showed that it was associated with a lower risk of UC and a higher risk of CD (35). Appendicectomy also showed a protective role in UC and a facilitating role in CD, probably due to misdiagnosis of the first CD presentation (36).
Psychological stress has also been proposed to be associated with IBD. There is scientific evidence that psychological stress may affect gut inflammation by inducing permeability changes in the intestine (37–39). In addition, an interaction between stress and immune function is well described both in animals and humans (39). However, the complexity of measuring stress in a clinical or epidemiologic setting makes association studies very difficult to be done and interpreted. It seems however that perceived stress, negative mood and major life events may represent important triggers of flares in IBD (40).
In parallel, with the (still unsatisfactory) identification of environmental risk factors, substantial advances in the understanding of IBD molecular pathogenesis have recently been made by the discovery of several susceptibility genome regions (18). These regions are located on 12 different chromosomes and account, up to today, for 163 genetic risk loci (41). Indeed, with the help of reproducible animal studies the function of many loci of those regions is clear today. It was illustrated that some of these genes are involved in the recognition of intestinal bacteria (CARD15-‐ NOD2), in lymphocyte activation (such as polymorphisms related to tumor necrosis factor α (TNF-‐ α)), in cytokine signaling, in intestinal epithelial defense (such as the scaffolding proteins (MAGUK)) and in coding intracellular adhesion molecules. Although CD and UC are both associated with genomic regions that implicate products of gene involved in leucocyte trafficking, there is evidence for association patterns that are distinct between CD and UC. CD-‐predominant associations include genes that regulate the processing of intracellular bacteria, autophagy and innate immunity, whereas in UC genetic evidence has mainly demonstrated the importance of the barrier function of the intestinal epithelium (41–43).
Despite this extensive genetic knowledge, not all loci were reproduced in all studies and none of the developed models can be considered to fully fit with the complex pathophysiological features of inflammatory bowel disease.
What seems however to be fairly established is that in the inflammatory bowel disease the well controlled balance of the intestinal immune system is disturbed at various levels with an inappropriate response to the indigenous flora and to other luminal antigens.
IBD pathophysiological and genetic aspects
In patients with inflammatory bowel disease, the epithelial barrier is leaky and has a lower epithelial resistance and an increased permeability, permitting an access to the underlying mucosal tissue by the antigens. In addition, the innate immune mechanisms of the epithelial layer are disturbed. Compared with healthy subjects, in IBD patients, in fact, the population of the toll-‐ like receptor (TLR) changes. TLR are one of the most important pattern-‐recognition receptor families in mammals localized on the intestinal epithelium and are capable of recognizing specific microbial components or microbe-‐associated molecular patterns (lipopolysaccharide, peptidoglycan, single-‐stranded and double-‐stranded RNA, and methylated DNA that are unique to microbes). TLR4 is usually up-‐regulated in both CD and UC and is responsible for the activation of the transcription nuclear factor kappa B (NFkB) and for the induction of the inflammatory cytokine cascade. Another mechanism involved in the maintenance of a chronic inflammation regards the cytosolic nucleotide-‐binding-‐oligomerisation-‐domains (NOD1 and NOD2). NOD2 gene (CARD15) is located in the IBD1 genetic linkage region on chromosome 16 and functions as an intracellular pattern recognition receptor for components of bacterial peptidoglycan. NOD2 is expressed by many leukocytes, including antigen presenting cells, macrophages, and lymphocytes as well as Paneth cells, fibroblast and epithelial cells. Activation of NOD2 by microbial ligands activates the transcription factor nuclear factor-‐kB (NFkB) and functions as a positive regulator of immune defense. Mutations on NOD2 (homozygous or compound heterozygous) interfere with the ability of NOD2 to recognize ligands and reduce their capacity to activate NFkB in response to antigen stimulation. In other words, they compromise the ability of the host to eliminate invasive and pathogenic microbes, resulting in chronic inflammation. These mutations are described in patients with Crohn’s disease and are associated with an ileal stricturing phenotype disease. Indeed, animal studies have shown that mice deficient of NOD2 have an impaired clearance of commensal
bacteria, rather than an increased colonization, that contribute to maintain a transmural inflammation as observed in ileal stricturing patients (2,11,41).
Furthermore, the recognition and processing of antigens by professional antigen-‐presenting cells is disturbed. The dendritic cells, main responsibles of antigen recognition, incorrectly recognize commensal bacteria and change their status from tolerogenic to activating and promote differentiation of naïve T cells into effector T cells (Th1, Th17, Th2) and natural killer T cells. In particular, in CD, naïve T cells preferably differentiate into Th1 cells (producing interferon γ+, interleukin 12+), whereas in UC these cells differentiate into aberrant Th2 cells (producing interleukin 5+). The proinflammatory cytokines secreted by activated effector T cells stimulates macrophages to secrete TNF-‐α, interleukin 1 and interleukin 6, which maintain inflammation. Moreover, the human leukocyte antigen (HLA) plays also a role in the susceptibility of IBD, as some aplotype has been linked to particularly aggressive course of ulcerative colitis and of colonic Crohn’s disease (e.g. DRP*0103) (2).
All the models proposed to explain the aberrant response that takes place in patients with IBD are very intricate and, despite the advanced knowledge of today, there are probably still many mechanisms that are not yet understood.
Fig 1 A Fig 1 B.
Fig. 1: Schematic representation of the intestinal immune system in healthy state (A) and in inflammatory bowel disease (B) (2). See also text.
Pediatric IBD
When compared to adults, less information is available regarding IBD in children and adolescents (see fig.2 A and B).
Fig. 2 A: time course of the number of scientific papers yearly published, according to PubMed, on “Crohn’s Disease” and on “Ulcerative Colitis” with no further search restrictions (respectively, CD tot and UC tot) and on “pediatric Crohn’s Disease” and on “pediatric Ulcerative Colitis” (respectively, CD ped and UC ped). *
As shown in Fig 2A, publications started for “UC tot” around the beginning of the last century and remained very infrequent (less than 10 publications a year) up to the late 40ies, when both “UC tot” and “CD tot” started to increase exponentially. In the year 2013, the number of papers
* The search details were:
1. for Crohn’s Disease: "crohn disease"[MeSH Terms] OR ("crohn"[All Fields] AND "disease"[All Fields]) OR "crohn disease"[All Fields] OR ("crohn's"[All Fields] AND "disease"[All Fields]) OR "crohn's disease"[All Fields]; 2. for pediatric Crohn’s Disease: "crohn disease"[MeSH Terms] OR ("crohn"[All Fields] AND "disease"[All Fields]) OR "crohn disease"[All Fields] OR ("crohn's"[All Fields] AND "disease"[All Fields]) OR "crohn's disease"[All Fields]) AND ("pediatrics"[MeSH Terms] OR "pediatrics"[All Fields] OR "pediatric"[All Fields]
3. for Ulcerative Colitis: "colitis, ulcerative"[MeSH Terms] OR ("colitis"[All Fields] AND "ulcerative"[All Fields]) OR "ulcerative colitis"[All Fields] OR ("ulcerative"[All Fields] AND "colitis"[All Fields])
4. for pediatric Ulcerative Colitis: ("colitis, ulcerative"[MeSH Terms] OR ("colitis"[All Fields] AND "ulcerative"[All Fields]) OR "ulcerative colitis"[All Fields] OR ("ulcerative"[All Fields] AND "colitis"[All Fields])) AND ("pediatrics"[MeSH Terms] OR "pediatrics"[All Fields] OR "pediatric"[All Fields])
0 500 1000 1500 2000 2500 1900 1920 1940 1960 1980 2000 CD tot CD ped UC tot UC ped
published on CD and UC were, respectively, 2271 and 1710. As regards the scientific papers on pediatric UC and CD, the first publications date back, respectively, to the early 50ies and the early 70ies, but remained very infrequent (less than 10 publications a year) up to the middle 80ies, when they started to steadily rise. In the year 2013, the number of papers published on pediatric CD and UC were, respectively, 216 and 155.
Fig 2B: Percentage of publications on pediatric diseases steadily increased in the last 10 years, approaching about 11 to 12% of overall publications in 2014 (january-‐june).
0% 2% 4% 6% 8% 10% 12% 14% 1950 1960 1970 1980 1990 2000 2010 CD ped/tot % UC ped/tot%
Pediatric IBD as a chronic condition
Since IBD is a chronic condition, children and adolescent affected by IBD have to live with it for all their future life.
The interest to pediatric chronic conditions and their management started at the beginning of the ‘80s (44). The ability to successfully manage childhood-‐onset chronic diseases is one of the greatest advances in pediatric medicine (45). Drastic improvements in life expectancy, as well as better functional outcomes, fewer disabilities and less hospitalization have been reported for many congenital conditions, including cystic fibrosis, congenital heart disease and metabolic disorders. Similar advances in survival were reached in acquired conditions such as childhood cancer, diabetes mellitus type 1, juvenile rheumatoid arthritis and renal failure. When managed appropriately, many patients with previously lethal conditions can now expect to have a normal to near-‐normal lifespan. Due to an expansion in knowledge and possibilities to observe and intervene, infant and child mortality declined, so that many congenital and acquired conditions became chronic, instead. In fact, today more than 90% of children with chronic conditions survive to adulthood. Now that survival is no longer the major challenge, the focus shifts to optimize the living with the chronic condition. In particular, young people with chronic conditions have specific needs, especially in their transition to adulthood (46). The management of a young patient with a chronic condition thus requires (among others) a careful follow-‐up of growth and puberty and a special attention to the patient life style (absenteeism, smoke habits,..). In addition, the psychological status in relation to the disease should also be carefully considered. Chronic childhood conditions opened thus the scenario of a pediatric multidisciplinary and specialized approach looking in addition to the specific diseases also to growth preservation, nutritional assessment and psychological burden.
Since IBD represent a chronic condition the survey of children and adolescent affected by this disease takes place in this setting.
Epidemiology of pediatric IBD
As already mentioned, most of the epidemiological studies on the incidence and prevalence of IBD were related to adult populations and it is only in the recent ten to twenty years that specific studies have addressed childhood IBD (Fig 1A and B) (20). Today, it is well established that among patients with IBD, between approximately 5% and 25% IBD develops during childhood or adolescence (47). Recently, attention towards this patient age group has focused on some specific characteristics that permit to recognise the paediatric IBD as a distinct phenotype (48–50).
Starting from the relative proportion of the two IBD entities, CD and UC, literature data report a higher Crohn’s disease:ulcerative colitis ratio in the pediatric-‐onset group compared to the adult (18-‐60 years) and elderly (>60 years) age onset groups (51). The male:female ratio also differs according with the age at onset. In particular, male are more commonly affected in pediatric CD, whereas females are more common in adult-‐onset and elderly-‐onset CD (52). The shift in sex ratio occurs between 14 and 17 years of age, the typical puberty period, and a similar shift of sex ratio is noticed in other immune-‐mediated diseases. It suggests that hormonal changes might play a permitting role in the developing of the disease. As regards UC, there is no difference between male and female in the pediatric age, whereas in adult and elderly age ulcerative colitis is more common in male.
As mentioned before, the incidence of IBD varies around the world, although a rising rate of pediatric IBD in both developing and developed countries has been reported (53). In particular, as described for adults, the incidence of pediatric-‐onset Crohn’s disease has risen substantially in several countries, whereas most studies have reported a stable ulcerative colitis incidence (8,16,20,50,54,55). According to recent literature data, the incidence of pediatric-‐onset IBD ranges from 0,25 to 13,30 per 100.000 person-‐years in North-‐America and Europe, that are still the countries with the highest incidence and prevalence. Whether this increase specifically affects young children or adolescents is still controversial. In fact it seems that this increase it is not caused by a trend towards disease onset at a younger age, but rather to be a consequence of an overall increasing incidence of these conditions irrespectively of age (56).
Genetic aspects of pediatric IBD
Focussing on the aetiology of pediatric IBD, it is believed that the contribution of genetic factors is greater in early-‐onset IBD patients than in late-‐onset patients (57). In fact, an increased prevalence of family history of IBD has been observed in patients diagnosed early in life (55,58,59). In particular, in patients with Crohn’s disease a family history was reported in 16% of patients aged less than 17 years, compared with 7% of patients with elderly onset Crohn’s disease (48,58). In ulcerative colitis, as mentioned before, the role of genetic factor is more limited, but, still, among pediatric patients 13% had a positive family history compared with 3% of patients aged more than 60 years. Pediatric age IBD population, thus, has recently been the subject of intensive genetic studies in order to find possible higher frequency gene mutations compared with adult IBD (57,60). Among known genes involved as risk factors in developing IBD, it was noticed that mutations of NOD2 (also known as CARD15), already mentioned as associated with a stricturing CD ileal phenotype, were associated with an earlier age of Crohn’s disease onset (2 years earlier) compared with patients without these mutations. In addition, it has also been demonstrated that NOD2 carriage tended to be higher in early onset (< 16 years of age) compared with adult onset Crohn’s disease. Moreover, several susceptibility loci, not previously reported in adults, have been discovered in a large cohort of pediatric patients with IBD, including single-‐nucleotide polymorphism (SNP) re3792876 in SLC22A4/5 (11,41,57).
Finally, recent data from studies on very early-‐onset IBD (< 6 years of age) permitted to identify other determinant genes in the development of IBD. In particular, the genetic defects that disrupt IL-‐10 signalling (IL10 or IL-‐10R) were found in children born to consanguineous parents. In these children it was described a very early severe Crohn’s disease phenotype without any apparent environmental trigger (61).
Environmental risk factors of pediatric IBD
Apart from the very early-‐onset CD, the role of genetics in IBD developing in the pediatric age is however of a limited extent, as already mentioned for adult-‐onset IBD. In particular, concordance rates of up to 37% for CD and of 10-‐15% for UC have been demonstrated for monozygotic twins. Therefore, attention should be also given to the yet unspecified environmental factors that predispose some children to an early onset disease. Children, in fact, are exposed to fewer environmental factors owing to their shorter preceding lifespan, and this may help to isolate the
environmental factors involved in the development of pediatric IBD (33). However, due to the relatively low incidence of pediatric IBD, few large studies have assessed in a rigorous manner the environmental factors potentially involved.
Starting with the analysis of perinatal and postnatal risk factors exposure, many studies were conducted leading to different and sometimes opposite conclusions. The studies of the perinatal period were conducted considering that this period corresponds to the initial development of the immune system and of the settlement of intestinal microbiota, which may interact during development. The foetal gut is generally thought to be sterile, but neonatal gut microbiome is influenced by maternal bacteria from the skin and the vaginal canal and by early life exposures (62). In some studies the caesarean section was associated with a higher risk of IBD, which was, however, not confirmed by other surveys (63–65). Prematurity, maternal age and smoking, in some studies, were also associated with a higher risk of developing IBD (66). The role of breastfeeding as a protecting factor against many infectious and immunological diseases is well recognised. Regarding IBD, two systematic meta-‐analyses were recently published that suggest a protective effect of breastfeeding on IBD development (OR 0,69; 95% CI, 0,51-‐0,94) (67,68). Although it was recognised that some of the studies included in the analyses were not optimally designed because of many recalling biases, it is well known that breast-‐fed infants have different gut flora than formula-‐fed infants, with possible causative interactions between the immune system and gut microbiome.
As already mentioned, the “hygiene hypothesis” was also a matter of investigation with the purpose of identifying environmental risk factors of IBD. Within the home environment many factors have been studied in a large number of surveys (9,33,34,69,70) such as the type and size of housing, the family size, bedroom and bathroom sharing status, water access, presence of pets and living conditions. Overall, the results of these studies were however conflicting and the role of the home environment in IBD pathogenesis is still a matter of intense study.
Also pollution was the subject of many surveys, which yielded conflicting conclusions. Regarding pediatric IBD, an age-‐dependent effect of pollution was in fact recently described (71). In particular, young individuals (< 23 years) were more likely to be diagnosed as having CD if they lived in regions of higher pollution, with a linear association between risk and increased air nitric oxide levels. Conversely, patients who developed CD between 44 and 57 years were less likely to live in areas of elevated nitric oxide (OR 0,56, 95% CI 0,33-‐0,95) (71).
The possible role of psychological stress events was already mentioned for adult disease. With regard to pediatric IBD, a recent pediatric case-‐control study showed that the frequency of stressful life events (death in the family, parental divorce, moving between countries) were higher in IBD patients than in healthy controls, even after controlling for confounders such as socioeconomic status (OR 1,7, 95% CI 1,0-‐2,9, p=0,04).
Concerning the diet there are, to our knowledge, no specific observations regarding pediatric IBD. Specific observations could be made, on the other hand, about smoking habit (or exposure). In particular, passive smoking exposure at birth was found to be significantly associated with the development of IBD (OR 3,02, 95% CI 1,28-‐7,06), with a grater effect for CD (OR 5,32) than for UC (OR 2,19) (72). In addition, a recent prospective surveillance study found that children who smoked were at increased risk for developing both CD and UC (OR 1,72, 95% CI 1,1-‐2,71) (73).
Symptoms and natural history of pediatric IBD
The symptoms and the natural course of CD and UC differentiate between the age group patients, with the most marked differences showed between pediatric-‐onset and elderly-‐onset IBD. This could be explained by the different location, behaviour and severity of the disease (49,50,58) with the pediatric-‐age IBD condition being usually more extended and more aggressive.
Among pediatric-‐onset IBD, in younger children (< 6 years) symptoms such as vomiting, asthenia and growth failure are more common and, among these patients, the diagnosis of indeterminate colitis is usually more prevalent due to this atypical presentation.
As regards CD, diarrhoea, abdominal pain and extraintestinal manifestations (fever, arthropaties, skin manifestation, uveitis) are more common in young patients than in elderly patients (49,58,74,75). However, rectal bleeding is more commonly observed in the elderly. In UC, symptoms such as rectal bleeding, abdominal pain and extraintestinal manifestations are more prevalent in children compared to adult and elderly patients.
Growth impairment is often present, in particular in children with CD and is a symptom that has to be assessed in pediatric IBD. Related to growth impairment, a delayed puberty and a decreased final adult height are other symptoms that have to be searched (49,50).
Focussing on the localisation of childhood-‐onset disease at diagnosis, CD is characterized usually by a more extensive anatomic involvement, with high rates of panenteric disease (small bowel, large bowel and upper gastrointestinal (GI) tract involvement). In particular, in two recent studies,
it was found, at diagnosis, an involvement of the three intestinal segments in 27% of patients. An ileo-‐colonic involvement was the most common localisation found in around 70% of pediatric patients, whereas in the elderly it arrived at 25% of the cases. In addition the perianal disease was also found to be more prevalent in pediatric CD than in late-‐onset Crohn’s disease (74). The colonic localisation was, on the other hand, the most common disease site in patients with more than 60 years, documented in 65% of cases (58,74). As regards localisation in UC, from other recent pediatric studies, a pancolitis was at diagnosis the most common presentation, shown in around 35% of patients (17,76).
Furthermore, disease extent is remarkably dynamic in childhood-‐onset IBD compared with adult and elderly onset. Indeed in CD, according to the results of some recent studies it was shown that a disease extension occurred in 31% of pediatric patients, while location remained stable in more then 92% of elderly patients, after a median follow-‐up of 7 and 6 years, respectively (58,74). At maximal follow-‐up, the ileo-‐colonic involvement remained the most frequent localisation in pediatric CD, but the number of upper GI involvement increased during time (74). With regard to UC, an extensive colitis is typical of the evolution of the pediatric disease. Some recent studies showed in fact that, after various periods of follow up, a pancolitis was developed in around 60% of pediatric patients (17,76). On the other hand, UC seems to remain stable in more than 80% of elderly patients.
Regarding the behaviour of the disease, complicated behaviour (stricturing [B2], and penetrating [B3]) at maximal follow-‐up is generally more prevalent in early-‐onset than in adult-‐onset and elderly-‐onset CD. In fact, more than 50% of children are expected to develop complicated disease behaviour. By contrast, the disease was reported to remain stable in 91% of patients with elderly-‐ onset CD, after a median follow-‐up of 6 years (Figure 3) (58).
Fig. 3 Comparison of evolution of Crohn’s disease behaviour between elderly-‐onset patients and pediatric-‐onset patients. Behaviour was recorded according to the Montreal classification (49).
Observing the more aggressive behavior of pediatric CD, it is not surprising that its natural history often includes bowel surgery. However, the rate of surgery is variable in the literature depending on the study population. Two recent studies reported a cumulative incidence of intestinal resection of 5-‐7% at 1 year up to 30% at 5 or 10 years (74,77), but few data are available on the long-‐term outcome of patients after the first surgery. In line with what described in pediatric CD, also in pediatric UC the natural course is considered to be more severe than that of older patients. Pediatric UC is characterized, as already mentioned, by a more widespread location at diagnosis and a high rate of disease extension. Therefore, the risk of early colectomy, related to the more extensive disease, was reported to be higher in pediatric compared to elderly UC patients (20% at 5 years of follow-‐up vs 8% at 10 years of follow-‐up)(58).
The treatment in pediatric IBD: general aspects
Since the etiology of IBD is not yet known, an etiological medical therapy does not exist and current treatment is mainly symptomatic and supportive. Theoretically, the therapeutic goals are bowel healing, long lasting remission and control of unavoidable complications. In any case, care must rely on general clinical wisdom, and treatment should mainly take into account symptoms and quality of life, and not necessarily abnormal laboratory tests, biopsies and radiographs. In other words, in the management of children with IBD, the main challenge is to alleviate symptoms and prolong period of remission via the use of specific targeted therapies, while minimizing toxicity and promoting growth and development (78).
In order to adapt the best therapy to every clinical situation and since inflammation can be present without symptoms, and symptoms may be present without inflammation, an overall assessment of disease is very important. This passage in the management of a patient with IBD could be very problematic because of the lack of a “gold standard” to use as a reference. However, there are a few score-‐systems to take into account. In children and adolescents affected by IBD, a Pediatric Crohn’s Disease Activity Index (PCDAI) and a Pediatric Ulcerative Colitis Activity Index (PUCAI) are validated multi-‐item measures of illness severity that are commonly used (79,80). In particular, as regards PCDAI, compared to the adult-‐derived Crohn’s Disease Activity Index (CDAI), it focuses on the pediatric problems of CD, including linear growth evaluation and it places less emphasis on subjectively reported symptoms and more on laboratory parameters of intestinal inflammation (80). As regards PUCAI, compared to Mayo Score usually used in adults, it is a valid non-‐invasive and easy score focused on gastrointestinal symptoms (rectal bleeding, stool frequency, abdominal pain, nocturnal stools…) that has a sufficiently strong correlation with macroscopic mucosal inflammation and allows an assessment of disease activity in children without endoscopic evaluation (79).
The management of disease activity in children and adolescent with IBD includes pharmacological, nutritional and surgical therapy.
Pharmacological therapy
Over the last thirty years, various paradigms have changed the medical treatment of IBD in children and adolescents, which was before usually based on 5-‐aminosalicilates (sulfalazine, mesalazine) and oral corticosteroids (prednisolone) (81).
