Posebne značajke upalnih bolesti crijeva u djece

Kronične neizlječive upalne bolesti crijeva (engl. inflammatory bowel disease, IBD) – Crohnova bolest (engl. Crohn’s disease, CD) i ulcerativni kolitis (engl. ulcerative colitis, UC) – kronične su upale locirane u gastrointestinalnom traktu, povezane s dugotrajnim morbiditetom i raznolikim kliničkim tijekom. Obje se bolesti mogu pojaviti u djetinjstvu, štoviše, udio zahvaćene djece i adolescenata raste iz godine u godinu. Budući da su pedijatrijski bolesnici vulnerabilna populacija, oni zahtijevaju i specifičan pristup, posebice u odnosu na održavanje normalnog rasta i razvoja. U ovom članku se stoga iznose posebne značajke epidemiologije, genetike, kliničke prezentacije i liječenja upalnih bolesti crijeva u djece. EPIDEMIOLOGY

The incidence of inflammatory bowel disease (IBD) in children has been steadily raising during the second half of the last century. However, over the last decades the trends for ulcerative colitis (UC) and Crohn's disease (CD) differ - the frequency of UC remained stable, while the incidence of CD in children is still increasing and in the present time is twice as that of UC (1, 2). It is still not clear whether this is a true increase or an increase in the pick-up (3). The peak incidence of IBD occurs between 15 and 30 years of age, being diagnosed before 20 years of age in 25-30% of patients (3). While UC has been repetitively described in infants and young children, CD has been very rarely diagnosed bellow the age of 4 (4). The British Paediatric Surveillance Unit has recently finished a study on IBD in children (up to 16 years old) in UK with the following results: I. the estimated incidence is 5.3 per 100 000 children under the age of 16; II. CD is twice as common as UC; III. the mean age at diagnosis is 11.8 years (median 12.6); IV. 13% of CD was diagnosed in children aged under 10; V. median delay period from the onset of symptoms to diagnosis was 5 months, with 25% of children having symptoms for more than one year (5). In Croatia, two epidemiological studies based on hospitalized children (both studies included children up to 18 years) with IBD have shown almost identical trends (6, 7), i.e.: I. during the observation period of 10 years diagnoses of CD doubled in the second five years period and became twice more common compared to UC; II. mean age at diagnosis was 11.8 years for UC and 9.5 years for CD, and III. the mean delay in diagnosing CD was 0.8 years compared to 0.25 years in UC (7).

P a t h o p h y s i o l og y: g e n e t i c s v s. e n v i r o n m e n t

Concerning etiology and the pathophysiology, results of recent studies are consistent with the idea that there is a genetic preponderance, probably polygenic, while the environmental factors are necessary to trigger and maintain the inflammation in both, UC and CD (4). Pediatric age and particularly infancy may be specially important for development of atopy and autoimmunity due to priming of immune system which takes place immediately after birth, and is strongly influenced by the interaction of feeding pattern and development of normal gut flora (8). However, out of 12 case-control studies, only 4/8 for UC, and 4/8 for CD have found a significant correlation of shorter duration of breast feeding with the increased prevalence of IBD – other authors did not confirm this relationship (9).
Linkage studies have implicated several genomic regions as likely containing IBD susceptibility genes, with some observed uniquely in CD (such as IBD1) or UC (such as IBD2), and others common to both disorders (10, 11). IBD genomic regions include IBD1 on chromosome 16q, IBD2 on chromosome 12q, and IBD3 on chromosome 6p containing the major histocompatibility complex region (with HLA-DRB1*0103 most often proposed as susceptibility allele) (11). The best replicated linkage region, IBD1 on chromosome 16q contains NOD2/CARD15 which has now been definitively established as the CD susceptibility gene (11, 12). The gene has over 60 variations, but there are three main mutations (Arg702Trp (Hugot SNP8), Gly908Arg (Hugot SNP12), Leu1007fsinsC (Hugot SNP13) altogether present in 15-20% of CD patients as a single risk allele (heterozygous carriage), while 10-15% of CD patients carry two major risk alleles (homozygotes and compound heterozygotes) (12). Considering genotype / phenotype concordance, recent study done by L e s a g e e t a l. (13) has shown that patients with two major risk alleles had significantly more often the following clinical features: I. at diagnosis were younger than patients with no mutations (17 vs. 20 years, P < 0.01); II. left colon was less frequently affected (43% vs. 62%, P=0.03); III. strictures were more frequent (OR=3) (13). No association was found between the genotype and the severity of the disease, extra-intestinal manifestation or response to Infliximab (14). Our own study on a limited number of children with CD compared to matched healthy controls (all were genotyped for three main mutations) have shown a markedly increased prevalence of NOD2 variants, with 28% of our patients being homozygots and compound heterozygots, while 22% had a single risk allele (15). Even higher frequency of patients with NOD2 variants in total (nearly 60%) and those with two mutations (homozygotes and compound heterozygotes; 35%) was reported by S u n e t a l. also in pediatric patients (16). As early onset of the disease, stricturing form and ileocolonic distribution of the disease are characteristic for pediatric age – all reported to be associated with two mutations (13), higher incidence of two mutations in these patients (15,16) than in adults may not be surprising.
Concerning IBD3 region, S i l v e r b e r g e t a l. demonstrated the association of the HLA-DRB1*0103 allele with both CD and UC and with large intestine-restricted disease (17). Moreover, the existence of an interaction between IBD3 and IBD1 was shown (18). Also, the very recent study done by N e w m a n e t a l. confirmed the influence of CARD15 and HLA-DRB1 alleles on both CD susceptibility and site of disease and identified genotyping of these variants as a potential tool for improved diagnosis and risk prediction in CD (19).
Influence of genetic background on the development of CD in children could also be seen from the following data: I. 30% of patients diagnosed < 20 years of age have a positive family history compared to 19% in 20 to 39-year-old and 13% in the > 40 year-old group (P < 0.005) (20); II. in an offspring with a positive family history, CD begins on an average of 10.8 years earlier compared to a diseased parent (21); III. children of fathers affected with CD tend to develop the most severe disease (21).

S p e c i f i c c l i n i c a l f e a t u r e s o f I B D i n c h i l d r e n

Compared to diseased adults, inflammatory process is more aggressive in younger children with IBD, particularly in respect to the extension of the disease. Seventy one percent to 82% of children with UC with less than 10 years of age presented with pancolitis (22, 23). Concerning CD, as many as 88% of small children presented with colonic disease alone, but at first follow-up 63% of them had extensive involvement of the terminal ileum and colon combined (22, 23). In contrast to these data, P o l i t o (20, 21) found that the younger the patient, the more likely to present with small-bowel disease. However, those results were described in the age group < 20 years, who may be substantially different from children of age bellow 10 (22, 23). In the recent British study (24), one third of CD patients had small bowel involvement, one third ileocolitis and one third colitis, with pancolitis being more common (50%) than segmental colitis. Concerning the involvement of the upper gastrointestinal tract, it is well known that its frequency in children is much higher compared to adults, being present in 30% to almost 70% of pediatric patients with CD (4, 25). The age of the patient also influences the disease type - stricturing Crohn’s disease is typically diagnosed in younger patients and inflammatory in the older age group (20).
Compared to adults, children with UC present themselves most commonly with bloody diarrhea and tenesmi. Symptoms in children with CD depend on disease location and type, and are often vague. However, periumbilical abdominal pain following the meal is the most common symptom, and the hypotrophia and stunted growth the most common findings in children with CD (26). Growth failure, present in one third of pediatric patients with IBD, deserves a special attention. The pattern of growth abnormalities is characterized by progressive delays in linear and ponderal gains, bone development, and sexual maturation. It is 2–4 times more frequent in CD due to vague and undefined symptoms responsible for a longer delay from onset of symptoms to diagnosis compared to UC (27, 28). Up to 88% of CD patients have decreased height velocity prior to diagnosis, and 46% experience a decrease in growth before gastrointestinal symptoms were noted (29). Moreover, nearly 95% of the weight deficit, present in pediatric patients with IBD, was associated with a deficit in lean body mass rather than body fat (27). The importance of growth failure is stressed by the fact that, if not corrected by medical or surgical treatment, it will persist into adulthood – stunted growth is present in 20–30% of adults with IBD (30). Osteopenia is recognized as an important complication of IBD, particularly in children with CD (31), and is presently ascribed to a combination of both, the disease itself and the treatment with steroids (32, 33).

TREATMENT

The aim of therapy in children with IBD is not only to induce and maintain remission, but also to assure normal growth and development, thereby promoting well-being and a reasonably good quality of life. Compared to adults, in pediatric patients the greatest differences are regarding the role of enteral nutrition and surgery in inducing remission in CD, and the negative effects of steroids on growth and bone metabolism. Also, during the past several years medical treatment is facing significant changes, with couple of new immunotherapeutic agents employing biotechnological products being used for the first time. Among them, to mention some, are recombinant cytokines, and monoclonal antibodies against proinflammatory cytokines, surface proteins, adhesion molecules, and antisense oligonucleotides. However, only anti-tumor necrosis factor (anti-TNF) has been studied in children, while the trials for CDP571 and etanercept are currently underway. The full description of their role in pediatric IBD could be found elsewhere (34, 35, 36).

a. The role of enteral nutrition in inducing remission in CD
Enteral nutrition is the first therapeutic option for induction of remission in children with CD (reviewed in 36, 37). In contrast to adults, in whom three meta-analyses and the recent Cochrane review have shown better efficacy of steroids (38-41), enteral nutrition in children is equally effective as steroids if used as a sole source of nutrients for 4 to 6 weeks (42). Moreover, treatment with enteral nutrition normalizes growth, is cheaper and with almost no side-effects compared to other treatment modalities. Considering the type of enteral feeding, recent studies have not shown significant differences in efficacy among elemental, semi-elemental and polymeric enteral formulas (38, 41). There is some evidence that intermittent periods of enteral feeding may maintain remission in pediatric CD (43). In UC patients, nutritional therapy is not effective in inducing remission, but is used as a support to improve the nutritional status.

b. Steroid treatment & novel therapeutic agents in children with IBD

Despite of the described therapeutic role of enteral nutrition, corticosteroids have traditionally been the treatment of choice for induction of clinical remission in children with moderate to severe CD. However, there are numerous limitations to their use in pediatric age, particularly side-effects, and also the relatively high number of children who are either steroids resistant (20%) or steroid dependent (30-40%) (44, 45). Of great concern in children is the effect of steroids on bone metabolism and thereby on growth. The risk for steroid-induced bone loss is increased even at low doses such as 7.5 mg/day. Moreover, bone mass rarely ever returns to pretreatment levels after corticosteroid therapy is discontinued (46). According to very recent results, budesonide - a novel steroid agent which is fully metabolized in the first passage through liver, has a lower rate of side-effects and the overall efficacy is not significantly lower compared to conventional steroids (47). However, more studies are warranted in pediatric patients. Finally, for those children who are resistant to other treatments, cyclosporin and anti-TNF are further options. While there has been very little work done in children regarding cyclosporine, for anti-TNF (Remicade, Infliximab) several studies evaluated safety, efficacy and pharmacokinetics. According to their results, the overall response rate at four to eight weeks on one dose of 5 mg/kg in children with CD resistant to other treatments, was 80-90% (48, 49). Moreover, children who were early in the course of CD were found to have more sustained response (12 month) compared to children with longer disease duration at the time of infusion (49, 50). No severe complications were found in any patient. However, side effects of anti-TNF include infection, infusion reaction, autoantibody formation, and also malignancies (reviewed in 34), and should therefore be thoroughly investigated before making final recommendations for pediatric patients.

c. Maintenance Therapy

Once in remission, the child has to be kept in remission, and that is presently in a significant proportion of pediatric patients almost an unachievable goal. Sulfasalazin and mesalazin derivatives are successful as a maintenance therapy for UC (51), and although they are widely used for the same purpose in CD, their efficacy has not been proven (52). Concerning corticosteroids, neither the conventional steroids (53), nor budesonide (54) are effective in preventing relapses in quiescent CD. Immunomodulating therapy with azathioprine or 6-mercaptopurine is so far the best option for the maintenance therapy of severe relapsing CD, significantly prolonging remission time in adults and in children, and having an important steroid-sparing effect (55, 56). Moreover, M a r k o w i t z e t a l. used 6-mercaptopurine as part of the initial treatment (combined with prednisone) of children with newly diagnosed moderate to severe CD and compared it to prednisone as the sole treatment in achieving remission and also in preventing relapses. No difference in remission rates was noted initially, but after 12 months 96% of patients treated with mercaptopurine and prednisone combined were still in remission compared with 60% of those treated with prednisone alone (P<0.01) (56), thereby confirming the hypothesis (50, 51) that early initiation of immunomodulatory therapy may significantly improve clinical response and alter disease course.

d. Surgery

Surgery is often necessary in children with IBD. Colectomy in UC is curative, while in CD it does not prevent recurrence, particularly for colonic disease (57). However, well-timed surgical intervention often modifies the immediate outcome and may initiate the impressive catch-up growth (58). Therefore, the surgery as a therapeutic option is indicated in children with growth problems and localized CD, when there is a failure of other treatments to induce stabile remission, and should be undertaken, if possible, before pubertal growth spurt is completed.

DISEASE COURSE, MORTALITY, QUALITY OF LIFE

The course of IBD in children is unpredictable. Based on the results of several prospective studies, it can be summarized that around 20-30% of children achieve a long remission or have a very mild symptoms, 50-60% fluctuate between remission and clinically active disease – one third to one half of them experience recurrent severe exacerbations - and some 20% continue to have severe and unremitting disease despite the treatment regimen (59, 60, 61).
The existence of an increased risk for colon cancer in UC is well known, as is its relationship to duration of the disease. However, risk for colorectal cancer is increased up to 18-fold also in patients with extensive CD, and is especially high in patients diagnosed before 25 years of age (62). Moreover, patients with long-standing CD also have an increased relative risk for developing a small bowel malignant lymphoma (63). In general, due to malignancies and to the disease process itself, patients with IBD have an increase in mortality, although not to the higher extent – a 15-year survival rate for patients with CD was 93.7% of the survival rate in general population (64).
Furthermore, problems with self-esteem, employment, cosmetic side-effects of some modes of treatment, and an increased risk towards suicide require a special concern in the pediatric patients (64, 65). Therefore, enhancing a quality of life in children with IBD should be a future treatment goal, surpassing simple improvements in clinical outcome, and disease course modification.

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