Treatment of inflammatory bowel disease in children

As no curative therapy exists, supportive measures play an important role in the management of patients with inflammatory bowel disease (IBO). Aminosalicylic acid (ASA) compounds and corticosteroids remain the mainstay of medical therapy. Aminosalicylates are recommended for therapy of mild to moderate active ulcerative colitis and for the maintenance of remission in ulcerative colitis. The role of 5-ASA preparations in Crohn's disease is less clear. In granulomatous colitis, 5-ASA therapy is recommended. With the development of new delivery systems, the role for 5-ASA in the treatment of small be 1el Crohn's disease is under investigation. Prednisone remains the drug of choice in severe ulcerative colitis and active Crohn's disease. The role of immunosuppressive drugs in pediatric patients is unclear. Nutritional therapy has been an important advance in the treatment of children with Crohn's disease, especially those with growth failure. Nutritional therapy can consist of combined total parenteral and enteral nutrition or enteral nutrition alone. An initial period of total parenteral nutrition followed by a six to eight week course of enteral therapy with a semisynthetic diet has been shown to be effective in the management of patients with severe active disease and growth failure. Can J Gastroenterol 1990;4( 7) :404-406


I NFLAMMATORY BOWEL DISEASE
(IBO) represents an important problem in the pediatric age group.Approximately 15% of patients with ul, cerative colitis and 25% of patienu with Crohn's disease present before the age of 18 years.In terms of gastroim~ tinal disorders, more patients present each year with IBO than either cysuc fibrosis or celiac disease.As seen in the adult population the incidence d Crohn's disease increased dramatically during the 1970s.At present the prevalence of Crohn's disease is tw1ct that of ulcerative colitis.While many of the symptoms and complicat101\1 seen in IBO are similar in adult and pediatric patients, there are distinctdif, ferences.Growth failure and delayed puberty are major problems in the pediatric age group, especially m patients with Crohn's disease.
TREATMENT OF lBD Supportive measures: In rhe treatment of IBD, supporti ve measures are impor, rant, as no specific curative therapy ex, ists.Patients and parents must be given insight into the nature of the illnessand an understanding of the prognosis m terms that they can accept without being terrified.T reatmcnt will allow the vast majority of pediatric paticnu with IBO to lead a normal active life, style no different from their peers.Cle, casionally patients and parents may re, la colitc ulcereuse et de la maladie de Crohn.Le role des immunosuppresseurs a usage pediatnque est peu clair.La therap1e nutnttonnellc constitue un progres important dans le traitement des enfants atteints <le mala<lie de Crohn, surtout ceux qui souffrent de retard de croissance.La thcrap1e nutritionnelle peut allier la nutrition parenterale totale (NPT) et la nutrition cntcrale ou recourir sculement a la numtton enterale.Une periode initiate de NPT suiv1e de six a huit semaincs de therapie enteralc avec regime synthctique s'est averce efficace dans le traitement de.s patients atteints de maladie active severe et ceux qui souffrent d'un retard de croissance.quire psychological support, but psychological mtervenuon 1s rarely required.Adequate nutritton without restriction 1s important.There 1s no evidence that specific foods play a role m the etiology of these diseases or in the course of illness.Patients frequently require supplemental calories, vitamins and iron.Levels of acnvity should not be restricted except in acutely ill patients.The overall a11n of treatment ts to allow the child to live a I ifestyle not substantially different than that of his or her peers.

MEDICAL THERAPY
The physician has a variety of therapeutic agents for the treatment of lBD.Ai.,mosal1cylates and cort1costero1ds remain the mainstay of medical therapy (4,5,7).However, the development of new formulatmns of aminosaltcylates raises the hope for a broader therapeutic effectiveness of these agents in both ulcerative colitis and Crohn's disease.Aminosalicylates: Unttl recently the rreatment of !BD by aminosalicylares was limited to the use of sulphasalazine.Sulphasalazine was discovered to beeffecnve in ulcerative colitis in the 1930s.The drug, initially Jevelope<l for the treatment of rheumatoid arthritis, was found to be effective in the treatment of inrestmal symptoms in a group of patients with arthritis associated with ulcerative colitis.Subsequent clinical trials confirmed the effectiveness of sulphasalazine in the treatment of patients with active ulcerative colitis and demonstrated its important role m maintenance therapy of ulcerative colitis patients.Understanding the pharmacology of sulphasalazinc and the basis for adverse reactions led to the development of a new generation of agents, the aminosalicylates.Sulphasalazine by and large traverses the mtestme mtact unul JeconJugated mto its sulfapyridme and 5-aminosalicylic acid ( 5-ASA) m01et1es hy bacterial flora usually m the distal ileum and colon.The acttve moiety of the molecule is 5-ASA.Sulphasalazme simply acts as the delivery system.If 5-ASA is mgested separately 1t ts largely absnrhed in the proximal intestine, metabolized by the liver and excreted in the urine.
In contrast, m the colon, 5-ASA 1s largely unabsorbed.This understand mg of the pharmacology of sulphasalazme stimulated the search for new delivery systems for 5-ASA.Topical and oral preparations of 5-ASA have been shown to be as effective as sulphasala:me tn the treatment of col it 1s and for maintenance therapy.Elimination of the sulpha mmety has rcsulre<l m improved tolerance.I lowever, side effects related to 5-ASA Jo occur.A small proportton of pauents will experience an exacerbation of colitis with 5-ASA, and watery J1arrhea has been a problem with at least one oral formu lation (6).Corticosteroids: Since their introduction in the l 940s, corucosteroids have been the drug of choice in moderate to severe ulcerative colitts and Crohn 's disease.Oral corticosteroi<ls have been shown to be effective m the treatment of both conditions.However, they do not have any apparent benefit in maintaining patients in remission.Topical steroi<ls arc also widely used and are effective in patients with distal coliw,.Both oral and topical agents are associated with chronic adverse side effects.Recent investigations have identified a series of compounds that possess the anti-inflammatory properties of steroids and clinical efficacy but are free from the steroid-related side Treatment of IBD in children effects (8).The absence of toxicity is related to their mode of metabolism.They undergo extensive first pass metabolism by erythrocytes and the liver, resulting m metabolites with ltttle or no biological activity.These agents have been shown to be effecttve when used topically in distal colitis.Oral formulattons are presently under study.Other agents: Metronidazole has heen shown to be effective m the treatment of active Crohn's <liscase and related penanal disease.In children, however, the drug 1s rarely used because oflim1ted rherapeuuc success and adverse side effects, including peripheral neuropathy and the poren rial for carcinogenesis (3 ).The role of immunosupprcssive agents remains concrovers1al.Azath10prine and 6-mercaptopurine have not been demonstrated to be particularly effecttve in acute Crohn's disease, hut have heen shown to have a stero1J-~paring effeu m chrome Jisease.These drugs arc employed only as a last resort m pcdiatnc patients who are refractory to steroids and aminosalicylates.A number of other medicattons including odium cromoglycate, sucralfate and clon1dme have been proposed as therapeutic agents for IBO, but their effic;1cy has not been established.

NUTRITIONAL THERAPY
Numuonal therapy has been shown to be effective in the treatment of Crohn's disease (1,2), but has little co offer patients with ulcerative colitis except in terms of nutritional support.The md1cattons for aggressive nutritional therapy in Crohn's disease m-clu<le: failure of medical therapy; chronic smoldering disease unresponsive to prednisone therapy or requiring high dose long term therapy; and growth failure and delayed puberty.In the lase group, nutritional therapy is the treatment of choice.Surgery in this type of patient should only he considered if nutrittonal therapy fails.
While growth failure can occur m chrome ulcerattve colitts, the problem of chronic growth failure and delayed puberty 1s largely confined to patients with Crohn's disease.Growth failure m chronic IBD appears to be mainly <lue to inadequate caloric mtake rather than underl ying endocrine dysfunction, ma labsorpLion or inc reased metabolic demands.Stimulation of grnwth can be achieved if adequate calorie~ are provided, even in the face of o n going disease activity.Both coral parenteral nutrition and enteral feeding with eith er a refined or low residue diet appear to be effective in controlling disease activity and promoting growth .
The a im is to achieve 120% of the recommended caloric daily intake.Unfortunately, while nutritional therapy i~ effective in inducing remission, prolonged remission after reintroduction of a normal diet is infrequent.However, long term remissions can be maintained if nutri tional therapy is combined with ongoing low Jose prednisone therapy.

RECOMMENDED THERAPY
Ulcerative colitis: Sulphasalazine remains the d rug of ch o ice in patients with mild ulcerative colitis.In moderate disease, comb ined sulphasalazine and prednisone therapy is recommended.If sulphasalazine is not colerated or if th e patient is known to be into lerant to sulpha drugs, a n ewer formulation of 5-ASA should be used.In more severe disease hospitalization and aggressive intravenous therapy with adrenocorticotropic h ormone or hydrocortisone is indicated.Myers et al (7) showed that in patients who h ave not received steroids, adrenocorticotropic ho rmone was the more effective agent, but in patients previously exposed co steroids, hydrocortisone was the drug of c hoice.In patients with limited distal co litis, 5-ASA o r h yJrocortisone e nemas are effective for inducing remission (9).A ll patients with ulcerative colitis sho uld be on long term maintenance therapy, if at all possible, with some form of 5-ASA.Crohn'sdisease: In Crohn 's disease the drug of choice is prednisone.Combination therapy with prednisone and 5-ASA h a~ not been demonstrated co be more effective than prednisone a lone.With the development of new delivery systems for 5-ASA there is the potential that these newer agents will be effective in small bowel Croh n's disease.The role for these agents is not clear at this time, but hopefully they wi II prove to be effective.In severe unremitting disease hospitalization and nutritional therapy are frequently required.Unfortunately, many patients with Crohn's disease are steroid -dependent.Approximately 60% of patients with Crohn's disease require longterm steroid therapy to control symptoms.As indicated, in these patients and in patients with growth failure and delayed puberty, nutritional therapy has proven co be a helpful adj unct.7. Myers S, Sachar DB, Goldberg JD, the development of mucosa!Jysplasia, surveillance programs are not appropriate in patients with onset of ulcerative colitis in the pediatric age group.
The use of surgery in C rohn 's disease is less well Jefined.One has little choice but surgery in patients with massive hemorrhage, imestinal obstruction due to stricture and extraintest,inal fistula formation.The other common reason for surgical intervention in Crohn's disease in child ren is fa ilure of medical therapy with growth failure and delayed puberty.However nutritional therapy sh ould be tric<l fim in these patients.One must remember that current data indicate that vi rtually 100% of patients with Crohn's disease who are operated on will eventually relapse, and many will require further surgery.

CONCLUSIONS
In summary, the majority of pediatric patients with IBO are adequately controlled with medical therapy and lead normal lives.The course, however, tends co vary considerably in the two conditions.Ulcerat ive colitis is usually remitting but can be chron ic and continuous.Occasionally it is fu lminat ing and requires emergency colcctomy.Crohn's disease can also be acute and remittent but tends to be chronic and unremitting with interspaced acute episodes.In general, patients with ulcerative colitis do fai rly well with medical therapy in th e early stages, while patients with Crohn 's disease have a more chronic continuous course.Janowicz HD.Corticotropin versus hydrocortisonc m che intravenous treatment of ulcerative colitis.A prospective, random ized, double-blind clinical trial.Gastrocncerology 1983;85:351-7.8. Peppercorn MA.Advances in <lrug therapy for inflammatory bowel disease.Ann Intern Med 1990; 112:50-60.9. Sutherland LR, Martin F, Greer S, et al. 5-Aminosalicylic acid enema in the treatment of distal ulcerative colitis, proctosigmoi<litis, an<l procmis.

SURGERY
Surgery is indicated in patients with ulcerative colitis who have fulminating life threatening disease, those who have responded poorly to treatment, and those in whom th e disease has been present for greater than 10 years or in whom there is evidence of mucosa[ dysplasia.Because of the high inc idence of colonic cancer and the variability in treatment of ulcerative colitis.Gue 1988;29: I 298-303. 5. Hodgson HJ.Assessment of drug therapy in inflammatory bowel disease.Br J C lin Pharmacol 1982; 14: 159-70.6. Meyers S, Sachar DB, Present DH, Janowiu HD.O lsalazine sodium in the treatment of ulcerative colitis among patients intolerance of sulfasalazine, a prospective randomized, placebo-controlled double-blind, dose-ranging clinical trial.Gastroenterology 1987;93:l255-62.