Treatment options

The treatment goals for children with ulcerative colitis are the control of active disease and induction of remission, the long-term maintenance of remission, and provision of education and psychosocial support for the patient and family. The initial treatment of ulcerative colitis is medical, with surgery reserved for patients with severe disease, patients with medically refractory disease, or patients who develop adverse effects of medical therapy.

Knowledge of the extent and severity of disease involvement will enable the clinician to choose the appropriate therapy for each individual patient. Distal ulcerative colitis (left-sided ulcerative colitis or proctitis) is characterized by involvement limited to the area distal to the splenic flexure, and potentially may be treated with topical agents (e.g. aminosalicylate or hydrocortisone enemas or suppositories). Extensive ulcerative colitis is defined by involvement extending proximally to the splenic flexure and requires systemic therapies with or without additional topical agents. Severity of disease is usually simple to ascertain, and can be determined by assessing stool frequency and consistency, abdominal pain, nocturnal diarrhea, hematocrit, albumin level and feeding intolerance. Separate published disease severity criteria for adults and children have been developed by Truelove and Witts,135 and Werlin and Grand,60 respectively (Tables 25.5 and 25.6). Other clinical scoring systems have been utilized in clinical trials to quantify disease severity of ulcerative colitis, but are less useful for day-to-day clinical management.136-139 Typically, severe colitis requires hospitalization and administration of either intravenous corticosteroids or other immunosuppressive agents (e.g. cyclosporin). Many patients with severe colitis will require colectomy.

Induction therapy Mild-to-moderate colitis

In the child with mild-to-moderate ulcerative colitis, with no or only minimal systemic signs

Table 25.6 Characteristics of severe colitis in children* (from reference 60)

Grossly bloody diarrhea, > 5 stools per a day Oral temperature >37.8°C during the first hospital day Tachycardia (pulse > 90) Anemia (hematocrit < 30%)

Hypoalbuminemia (serum albumin < 3.0g/100ml)

Toxic megacolon

* Patients need to fulfill four of the first five criteria or the 6th criterion alone

Table 25.5 Severity of ulcerative colitis in adults* (from reference 135)

Characteristic

Mild

Severe

Grossly bloody diarrhea

< 4 stools per day (< small amounts of blood)

> 6 stools per day

Fever

none

mean evening temperature >37.5°C, or temperature > 37.8°C, at least 2 out of 4 days

Tachycardia

none

>90beats/min

Anemia

not severe; hemoglobin essentially normal

present; hemoglobin < 75% of normal value

Erythrocyte sedimentation rate

< 30mm/h

> 30 mm/h

* Moderate severe - intermediate between severe and mild

Table 25.7 Aminosalicylate agents* (from references 325, 326)

Oral preparations

Dosage form

Mechanism of release

Site of delivery

Azo-bond

sulfasalazine

500-mg tablet

bacterial cleavage of

colon

(Azulfidine)

azo bond

olsalazine

250-mg capsule

bacterial cleavage of

colon

(Dipentum)

azo bond

balsalazide

750-mg capsule

bacterial cleavage of

colon

(Colazal/Colazide)

azo bond

Delayed-release

mesalamine

400mg/800mg

pH-dependent breakdown

distal ileum

(Asacol)

tablets

(pH >7)

to colon

mesalamine (Salofalk/

250mg/500mg

pH-dependent breakdown

ileum to colon

Mesasal/Claversal)

tablets

(pH >6)

Sustained-release

mesalamine

250mg/500mg/

ethy l cel l u lose-contro l led

small intestine

(Pentasa)

1000mg tablets

time-release

to colon

Rectal preparations

mesalamine suppository

400mg/500mg/

rectum

(Canasa - 500 mg)

1000mg

mesalamine enema

1 g/4g; 60-ml/

rectum to splenic

(Rowasa - 4g/60ml)

100-ml suspension

flexure

* Availability of different preparations and dosage forms

varies between different markets/countries

(such as elevated ESR or mild anemia), aminosalicylates (ASAs) (e.g. sulfasalazine, olsalazine, mesalamine, balsalazide) are usually the first line of therapy (Tables 25.7 and 25.8). ASAs have multiple immunological effects. Potential mechanisms of action include the inhibition of the synthesis of leukotriene B4, a potent chemotactic and chemokinetic agent, and the inhibition of the activation of nuclear transcription factor kB (NF-kB), an important mediator of the immune response in inflammatory processes.140-142 Controlled studies suggest that currently available ASAs are superior to placebo for induction of remission and prevention of relapse.143-146 However, there do not appear to be any differences in efficacy between the older agent, sulfasalazine, and newer ASA drugs.146,147 There are very few trials of ASA therapy in children with ulcerative colitis. One pediatric multicenter, randomized, double-blind study compared the efficacy and safety of olsalazine (30mg/kg per day; maximum 2g/day) to sulfasalazine (60mg/kg per day; maximum 6g/day) in the treatment of mild-to-moderate ulcerative colitis. The findings demonstrated clinical remission after 3 months in 79% of the sulfasalazine-treated children, in comparison to 39% of the olsalazine-treated children.148 The authors suggested the low dosage of olsalazine as a possible explanation for the difference in efficacy between sulfasalazine and osalazine.148

Potential advantages of the non-sulfa ASA agents include better tolerance compared to sulfa-salazine147,149 and the availability of a non-sulfa

Table 25.8 Medical therapies for ulcerative colitis

Medication

Sulfasalazine

Mesalamine oral formulation enema formulation suppository formulation

Corticosteroids intravenous or oral formulation enema formulation suppository formulation

Azathioprine*

6-Mercaptopurine*

Cyclosporin

Dosage

50-75 mg/kg per day PO divided qid, bid or tid (maximum 6g/day) adult dose: 3-4g/day divided bid or tid

50-75 mg/kg per day PO divided qid, tid, or bid (may vary according to preparation) (maximum 6g/day); adult dose: 3-4g/day divided qid, tid, or bid

1-2 mg/kg per day of prednisone or equivalent, IV or PO, divided q 12 to 24h (maximum 60 mg/day)

50-100mg of hydrocortisone PR qhs

25 mg of hydrocortisone acetate PR qhs

1.5-2.5 mg/kg per day PO qd 1.0-2.0mg/kg per day PO qd induction regimen for fulminant colitis: initial dose, 4mg/kg per day IV continuous or bid; maintenance oral dose varies according to oral preparation

Major side-effects nausea, headaches, diarrhea, photosensitivity, hypersensitivity reaction, pancreatitis, azoospermia, hemolytic anemia, neutropenia nausea, headaches, diarrhea, pancreatitis, nephritis, pericarditis, pleuritis numerous; including Cushing's syndrome, growth suppression, immunosuppression, hypertension, hyperglycemia, increased appetite, osteoporosis, aseptic necrosis (hip), cataracts nausea, emesis, immunosuppression, hepatotoxicity, pancreatitis, myelosuppression nausea, emesis, immunosuppression, hepatotoxicity, pancreatitis, myelosuppression nephrotoxicity, hypertension, headache, hirsutism, nausea, emesis, diarrhea, tremor, hypomagnesemia, hyperkalemia, hepatotoxicity, seizures, gingival hyperplasia, possibly lymphoproliferative disorder

PO, orally; bid, twice a day; tid, three times a day; qid, four times a day; PR, per rectum; q, every; qd, every day; IV, intravenously; qhs, at bedtime

* Thiopurine methyltransferase (TPMT) genotype determines metabolism and blood levels of metabolites; may help to determine risk of myelosuppression and optimal dosage of azathioprine or 6-mercaptopurine

ASA agent for sulfa-sensitive individuals. In adult-onset ulceratimve colitis, balsalazide at higher doses (6.75g/day) may provide a faster improvement in active, mild-to-moderate ulcerative colitis than lower doses of balsalazide (2.25 g/day) or mesalamine (2.4g/day).150,151 Although some studies suggest an advantage of azo-bond ASA agents (e.g. balsalazide) in comparison to delayed-release ASA agents (e.g. mesalamine), the overall data suggest equivalence between the different oral ASAs, when comparable amounts of the ASA are released at the site of disease activity.152

Common side-effects of sulfasalazine include headache, nausea and fatigue, which improve with reduction of the dose152 (Table 25.8). The sulfa moiety can cause hypersensitivity reactions resulting in rash, fever, hepatitis, hemolytic anemia, bone marrow suppression and pneumoni-tis.152,153 Other side-effects include neutropenia, oligospermia, pancreatitis and the exacerbation of colitis.60,154 Folic acid supplementation is recommended, given that sulfasalazine impairs the absorption of folic acid and may lead to anemia.152 To decrease side-effects, sulfasalazine is started at a dose of 10-20 mg/kg per day and gradually increased to the full dose (50-75 mg/kg per day) over 5-7 days. Mesalamine and the other non-sulfa ASA agents have also been associated with adverse reactions, including pancreatitis, hepatitis, nephritis, exacerbation of colitis, and pneumonitis.152,155,156

In addition to medical therapy, a low-residue diet (no popcorn, nuts, seeds, raw fruits and vegetables) and avoidance of spicy foods during acute symptoms has been anecdotally reported to reduce symptoms during a flare-up of disease.157

Moderate-to-severe colitis

Children with moderate disease are usually managed with oral corticosteroids (usually 1mg/kg per day, up to 60mg/day of prednisone) as out-patients. In an uncontrolled study of 20 children with active ulcerative colitis (three with mild, 13 with moderate, four with severe activity), 85% of the children achieved clinical remission with combination therapy of corticosteroids (oral prednisolone for pancolitis or topical prednisolone for distal colitis) and mesalamine (20-40mg/kg per day).158 Reassessment with colonoscopy at 8 weeks demonstrated complete endoscopic remission in 40% and full histological remission in only 15%, suggesting that clinical remission may not correlate with endoscopic or histological remission.158 Potential short-term complications of steroid therapy in patients with ulcerative colitis include increased appetite, weight gain, fluid retention, mood swings, hyper-glycemia, hypertension, insomnia, acne and facial swelling.

Complications of long-term steroid therapy (usually of more than 3 months) include growth restriction, osteopenia with compression fractures, aseptic necrosis of the hip, and cataracts.152,159 Given these reasons and the suppression of the hypothalamic-pituitary-adrenal axis, corticos-teroids should be tapered shortly after remission is achieved. A standard taper utilized by the authors is reduction by 5 mg/week of prednisone down to 20mg/day, and then a more gradual taper on alternate days, aiming for 10 mg every other day with further taper and cessation if remission is main-tained.159 Budesonide, a steroid with a high firstpass metabolism and fewer systemic side-effects, is available in capsule form for treatment of ileo-cecal Crohn's disease.160 In Europe and Canada, there is an enema form of budesonide for treatment of distal colitis.161 Unfortunately, there is no available oral budesonide preparation shown to treat patients with pancolitis effectively.162

Children with severe disease (e.g. more than five bowel movements/day, liquid bloody stools, or severe pain with defecation, anemia and hypo-albuminemia) require intravenous corticosteroids (methylprednisolone at 40-60 mg/day, divided into two doses/day, approximately 1-2 mg/kg per day) and hospitalization for further evaluation, observation and management.157,163 Rectal corticosteroids or 5-ASA agents may be used as an adjunctive therapy with parenteral corticosteroids for patients with severe tenesmus.152 Intravenous fluid for rehydration and correction of electrolyte imbalances should be provided. Blood transfusions and albumin infusions may be required. If bowel rest is indicated, the child may require central venous access for parenteral nutrition support. In addition to high-dose steroids, empiric antibiotics are sometimes used in severe colitis, although the efficacy of antibiotics has not been proven.164-167 Assessment for response to intensive medical therapy includes resolution of fever, tachycardia, abdominal tenderness and macroscopic blood per rectum. Stools should be decreasing in frequency, but may still be unformed. Once the child shows significant improvement, diet is advanced to a low-residue diet, intravenous methylprednisolone is switched to oral prednisone, and similar parameters for steroid wean are followed as outlined above. The optimal duration of intravenous corticosteroid therapy is unclear, but most children will respond within 7-10 days.

If the child has not responded to steroid therapy after 7-10 days, the options of surgery or more intensive immunosuppression (intravenous cyclo-sporin or oral tacrolimus) should be considered and discussed with the family. Intensive immuno-suppression should not be started if surgery is believed imminent, such as in a septic patient, a patient with toxic megacolon, or a patient with a suspected perforation. Intravenous or oral cyclosporin therapy has successfully induced remission in children with steroid-refractory ulcerative colitis.168-170 The exact dosage of cyclosporin varies in different protocols, depending upon whether intravenous or oral medication is utilized.136,169-171 In a study of 14 children treated with oral cyclosporin therapy for severe active colitis, unresponsive to high-dose intravenous steroids, 80% achieved clinical remission within 2-9 days; however, the majority of children who initially responded to cyclosporin eventually required colectomy within a year.170 In these studies, most of the children who improved with cyclosporin induction relapsed or underwent colectomy within a year.169,170 Cyclosporin may be most useful in delaying emergency colectomy at a time when the child's health status is most compromised (high-dose steroids, anemia, hypo-albuminemia, poor nutrition) and may allow time to improve the child's health and mental status in preparation for future 'elective' colectomy.170 A recent review outlines specific recommendations on the initiation and monitoring of cyclosporin therapy in children with IBD.171

Oral tacrolimus can also induce remission of disease activity in children with severe active colitis.172 If either cycloporin or tacrolimus is utilized as induction therapy, the aim should be the transition of patients off these potentially toxic agents and onto a maintenance medication (e.g. 6-mercaptopurine, azathioprine) over a 3-6-month period. Azathioprine or 6-mercaptopurine may be effective in preventing relapse after cyclosporin-induced remission in children with ulcerative colitis.173 Children on cyclosporin or tacrolimus should receive prophylaxis for Candida and Pneumocystis carinii, and have careful monitoring of electrolytes, blood glucose, renal function, blood pressure and neurological status.

The timing of colectomy in a child who is not responding to intravenous corticosteroids or other immunosuppression can be difficult. It should be emphasized that, even if a child responds to immunosuppression, such as cyclosporin, there is a high likelihood that he/she will require a colectomy within a year.170,172 If immunosuppression with cyclosporin is used and the child does not respond to these medications within 10-14 days, surgery should be strongly recommended.

Close monitoring of patients with severe colitis for the development of fulminant colitis and associated complications including hemorrhage, toxic megacolon and perforation is essential, using serial abdominal examinations, complemented by serial abdominal films or other imaging as necessary. Physical examination should look for evidence of worsening abdominal tenderness, distension and hypoactive bowel sounds; these may herald the development of toxic megacolon. The appearance of persistent abdominal pain and distension, diffuse abdominal tenderness and rebound, fever and tachycardia are worrisome signs of an acute abdomen and may signal the need for emergency surgical intervention. Opiates and loperamide should be avoided, given the increased risk of developing toxic megacolon.128 Steroid therapy may mask the typical symptoms and signs of perforation, but these may be detected by serial upright abdominal films (see Complications, p.395).

Left-sided colitis/proctitis

Topical ASA or topical corticosteroids are effective in the treatment of proctitis, proctosigmoiditis, or left-sided ulcerative colitis174-176 (see Tables 25.7 and 25.8). To be effective, topical therapy must reach the most proximal extent of the disease activity. Mesalamine enemas or suppositories are effective as first-line therapy/maintenance therapy for mild or moderately active left-sided ulcerative colitis or proctitis, respectively.152 Rectal me-salamine may be superior to oral mesalamine in the treatment of active ulcerative proctitis.177 Mesalamine enemas may be superior to rectal corticosteroids178 and are also effective in treating distal colitis that is unresponsive to oral ASAs or corticosteroids.179,180 Combination therapy with oral and topical mesalamine is more effective than one agent alone in the treatment of mild-to-moderate distal colitis.181 Mesalamine suppositories spread to the upper rectum, and enemas and foams can reach the splenic flexure or into the distal transverse colon.179,180

Corticosteroid suppositories or enemas also can be used as first-line induction therapy in patients with mild or moderately active ulcerative proctitis or left-sided ulcerative colitis.152 Rectal administration of hydrocortisone or prednisolone permits more direct delivery of steriods to distal ulcerative colitis sites; however, as with oral steroid therapy, prolonged treatment with topical steroids may induce systemic steroid side-effects, including adrenal suppression.176,180 Topical agents such as budesonide enemas, may induce remission in distal colitis with fewer systemic steroid side-effects.161,182 In a randomized, double-blind, placebo-controlled trial, budesonide enema therapy (2.0mg or 8.0mg/enema, once per evening) effectively induced remission, with significant improvement in sigmoidoscopy and histopathology scores, compared to placebo in adults with active distal ulcerative colitis/procti-tis.161 However, in another controlled trial, less frequent dosing of twice weekly budesonide enemas (2.0mg/enema) was not superior to placebo in the maintenance of remission.183 Some evidence suggests that ASA enemas may be superior to hydrocortisone enemas.175,178,180 Cyclosporin-A enemas have been used in the treatment of severe refractory distal ulcerative colitis,184 but were not found to be effective in a placebo-controlled trial for mildly to moderately active left-sided ulcerative colitis.185

Maintenance therapy 5-Aminosalicylic acid agents

Medication for the prevention of relapse after induction of remission is often started before the induction therapy is discontinued. The clinician usually aims towards a transition of the patient from corticosteroids onto sulfasalazine or another ASA agent. Multiple studies of adults with ulcerative colitis demonstrate the effectiveness of sulfasalazine and other ASA agents in preventing relapse.147 Mesalamine is well tolerated in the long-term treatment of children with IBD, with the principal adverse event being exacerbation of diar-rhea.186 Sulfasalazine and newer ASAs are all effective in maintaining remission in ulcerative colitis.149 Balsalazide, at a higher dose (6g/day), may be more effective in preventing relapses of ulcerative colitis in adults, compared to lower-dose balsalazide (3g/day) and mesalamine (1.5g/day).187 Topical mesalamine can effectively prevent relapse of active distal ulcerative colitis,188 but because of the rectal route of administration, patients may prefer oral mesalamine for maintenance therapy. The combination of oral and topical

5-ASA therapy may be more effective in preventing relapse than oral 5-ASA therapy alone, especially for distal disease.189 Some authors suggest that 5-ASA agents may reduce the risk of colorectal cancer.190-192 Children with ulcerative colitis require years of maintenance therapy. The exact duration that an ulcerative colitis patient in remission should remain on maintenance therapy is unclear, and there are no formal guidelines on when or whether maintenance therapy should be discontinued. The risk of discontinuing maintenance medication is the possibility of relapse. In addition, maintenance with 5-ASA or other agents may reduce the risk of colorectal neoplasia.193

6-Mercaptopurine and azathioprine

The immunomodulatory drugs azathioprine and its metabolite 6-mercaptopurine can reduce disease activity and allow the withdrawal of steroid therapy in children with steroid-dependent ulcerative colitis.194,195 In a small, open-label trial of children with Crohn's disease or ulcerative colitis, six of nine patients with ulcerative colitis reduced their steroid use by at least 75% with azathioprine therapy.194 In another series of 16 children with severe, steroid-dependent or steroid-refractory ulcerative colitis, 6-mercaptopurine or azathioprine therapy allowed the discontinuation of steroid use in 75%, and 67% remained without steroid therapy for 3-65 months.195 Given their steroid-sparing effects194,195 and reasonable tolerance by children with IBD,196 azathioprine and 6-mercaptopurine offer an alternative maintenance treatment of IBD in children. In a study of 95 children with either Crohn's disease or ulcerative colitis, only 18% required discontinuation of the medication; the majority of side-effects responded to dose reduction, or improved spontaneously.196 Side-effects reported include aminotransferase elevations or hepatitis, pancreatitis, bone marrow depression, hypersensitivity reactions and recurrent infections;196,197 children should be moni-

tored for the development of these complications. Some clinicians have utilized 6-mercaptopurine metabolite levels to monitor responsiveness, compliance and potential toxicity.198.199 Evaluation for thiopurine methyltransferase genetic polymorphism should be obtained prior to the institution of 6-mercaptopurine or azathioprine therapy as it can identify those children at higher risk for drug toxicity200 and guide the clinician to prescribe lower doses of azathioprine and 6-mercaptopurine, if appropriate.

Given the high relapse rate with withdrawal of 6-mercaptopurine in adults with ulcerative colitis,201 the majority of children requiring azathioprine or 6-mercaptopurine to suppress disease activity will probably require long-term maintenance therapy with these agents. There are no good data in ulcerative colitis addressing the question of when (or whether) immunomodulators should be discontinued after a patient has entered remission. Most patients are continued on the medication for several years if they respond to 6-mercaptopurine or azathioprine. At the present time, evidence does not suggest any definitive increased risk of malignancy secondary to long-term use of azathioprine in adults.202-204 However, one paper has identified a slightly increased risk of Epstein-Barr virus-associated lymphoma in a large cohort of patients treated with long-term 6-mercaptopurine or azathioprine.205

Methotrexate

Methotrexate appears to be less effective for the treatment of ulcerative colitis than for Crohn's disease.206,207 Although open-label trials in adults with ulcerative colitis suggested a benefit of methotrexate in the induction of remission,137,208 a double-blind, randomized trial failed to show any advantage of methotrexate in the induction or maintenance of remission in adults with chronic active ulcerative colitis in comparison to placebo.209 Another study of two different dosages of parenteral methotrexate in adults with IBD showed a remission rate of approximately 20%.210 While methotrexate can be useful in treating children with Crohn's disease intolerant to 6-mercap-topurine, there are currently no published studies describing its efficacy in children with ulcerative colitis.211

Other therapies

Despite the potential role of infectious agents in the pathogenesis of ulcerative colitis,17 the use of antibiotic therapy in the treatment of ulcerative colitis remains controversial. There is a lack of consistent evidence of the effectiveness of antibiotics in the induction and maintenance of remission in ulcerative colitis.165,212-215 In one study, oral tobramycin therapy improved short-term clinical and histological outcomes,212 but there was no advantage in the prevention of relapse compared to placebo.213 In two studies of active ulcerative colitis, the addition of 10-14 days of oral or intravenous ciprofloxacin to corticosteroid therapy did not improve rates of remission.167,216 In another placebo-controlled study, the administration of 6 months of treatment with ciprofloxacin, in addition to standard therapy with prednisone and mesalamine, resulted in a greater clinical response compared to placebo; however, this advantage was not sustained after the cessation of ciprofloxacin.217 Empiric broad-spectrum antibiotics are often administered in the setting of severe active ulcerative colitis,60,164 especially if there is concern for potential fulminant colitis or toxic megacolon.122

In open, uncontrolled trials, infliximab (chimeric monoclonal antibody to TNF-a) therapy resulted in clinical improvement in adults and children with ulcerative colitis.218-222 However, the clinical response of infliximab therapy may not be sustained.223 In an open-label study of nine children and adolescents with moderate-to-severe ulcerative colitis, seven children (77%) showed a decrease in disease activity measured by the Physician Global Assessment, and corticosteroid therapy was discontinued in six children (66%).222 A small, double-blind, placebo-controlled clinical trial of infliximab in 11 adults with severe, active steroid-refractory ulcerative colitis suggested a clinical benefit for patients treated with one dose of infliximab (5mg, 10mg or 20mg/kg per dose), compared to those who received placebo.224 In this study, four of eight ulcerative colitis patients receiving infliximab improved, compared to none of three receiving placebo. Because of poor recruitment, the trial was terminated prematurely and no statistical analysis was performed. In a larger, randomized, double-blind, placebo-controlled study of 43 adults with moderately active gluco-

corticoid-resistant ulcerative colitis, there was no significant difference in remission rate or sigmoi-doscopic score between the infliximab-treated group (5mg/kg per dose, at weeks 0 and 2) and the placebo group.225 Thus, the therapeutic benefit of infliximab in ulcerative colitis remains unclear at this time, and the treatment does carry a risk of infusion reactions, antinuclear antibody formation and opportunistic infections.226-230

Studies evaluating the effectiveness of mycophe-nolate mofetil therapy for ulcerative colitis show mixed results and may suggest increased side-effects compared to other immunomodulatory agents such as azathioprine.231-233

Probiotics have been studied in the maintenance of remission in adults with ulcerative colitis.234-236 In an open-label trial of the probiotic VSL no. 3, performed in adults with inactive ulcerative colitis, 75% of patients remained in remission during the 12-month study,234 but no controlled trials with VSL no. 3 for maintenance therapy for ulcerative colitis have been performed. In two randomized controlled comparison trials, non-pathogenic E. coli strains and mesalamine maintained similar rates of remission in adults with quiescent ulcerative colitis.235,236 There are no formal studies on the effectiveness of probiotics in children with ulcerative colitis.

In adults with ulcerative colitis, transdermal nicotine therapy, combined with mesalamine or corti-costeroids, may result in clinical improvement, but is associated with unwanted side-effects.237,238 Transdermal nicotine therapy does not appear to be effective in the maintenance of remission of ulcerative colitis.239 An open-label trial of nicotine enema therapy in adults with ulcerative colitis showed improvement in symptoms of urgency and stool frequency, and sigmoidoscopic and histolog-ical scores,240 but controlled studies are needed to determine true efficacy.

Several placebo-controlled studies suggested a benefit of adjunctive therapy with fish oil supplementation containing eicosapentaenoic acid, a potent inhibitor of leukotriene B4 synthesis, in the treatment of active ulcerative colitis.241-243 However, fish oil supplementation did not appear to show any benefit in maintenance therapy.243,244 Unfortunately, given the large number of capsules required for daily therapy and the intolerance to unwanted fishy odor, patients' compliance has been suboptimal.

Randomized, controlled trials in adults with active distal ulcerative colitis suggest that therapy with topical short-chain fatty acid (SCFA) preparations result in clinical symptomatic improvement, but there is no statistically significant advantage in comparison to placebo.245-247 In one double-blind, placebo-controlled, 6-week trial of rectal SCFA, 103 patients with distal ulcerative colitis were entered and those on SCFA had larger, but statistically non-significant, reductions in every component of their clinical and histological activity scores.246

In several open-label trials, adults with steroid-resistant ulcerative colitis showed a clinical response to heparin therapy;248-250 however, a controlled trial did not show any advantage of heparin treatment for moderate-to-severe ulcerative colitis, compared to corticosteroid therapy.251 In an open-label pilot study, daclizumab (humanized anti-IL-2R antibody; CD25) resulted in clinical and endoscopic improvement in adults with refractory ulcerative colitis;252 further study is needed to determine the effectiveness of this novel therapy.

Nutritional therapy

The importance of nutrition in the management of ulcerative colitis is extensively reviewed else-where.253,254 Children with ulcerative colitis can develop nutritional deficits with poor oral intake secondary to symptoms; and thus, promotion of continued good nutritional intake is essential for appropriate healing and nutritional repletion.255 Enteral nutrition is preferred to total parenteral nutrition when possible. In contrast to Crohn's disease, enteral nutrition is not an effective primary therapy for active ulcerative colitis.152,171 Studies suggest no advantage of total nutritional support and bowel rest in addition to conventional medical therapy alone in the treatment of ulcerative colitis.256,257 In a randomized, controlled trial of corticosteroid therapy combined with either polymeric enteral nutrition or total parenteral nutrition, adults with moderate or severe ulcerative colitis showed no differences in remission rate, need for colectomy, or changes in anthropo-

metric parameters.258 Total parenteral nutrition is often utilized for nutritional repletion in severe ulcerative colitis, especially if the patient develops severe cramps and diarrhea when challenged with enteral nutrition.

Surgical therapy

In the majority of cases, medical therapy remains the first-line treatment for ulcerative colitis. However, colectomy may be required for patients with severe or medically refractory disease, or to prevent colon cancer. Since the inflammation in ulcerative colitis is limited to the colon, colonic resection will most often result in resolution of symptoms. However, colectomy is not without potential complications, such as the development of pouchitis in patients who undergo ileoanal anastomosis.259,260 It is important to consider timely surgical intervention in the appropriate setting to avoid complications of ulcerative colitis. Indications for colectomy in a patient with ulcerative colitis include fulminant colitis or a complication of colitis, such as massive hemorrhage, perforation, or toxic megacolon; medical therapy failure; steroid dependency, which may lead to undesired side-effects; and the presence of colonic dysplasia.261 Prepubertal children may experience catch-up growth after colectomy for ulcerative colitis. In one series, 11 of 18 children increased their median height velocity from 3.85cm/year preoperatively to 7.35 cm/year postoperatively.262 As medical treatment for ulcerative colitis was developed, the frequency of colectomy decreased. At one center, a retrospective review of children and adolescents with ulcerative colitis revealed a decrease in the frequency of colectomy from 48.9% (between 1955 and 1964) to 26.2% (between 1965 and 1974).263

There are no early predictors to help determine who will proceed to colectomy. Hyams et al, in a retrospective review, reported that the 5-year colectomy rate in patients with mild disease at presentation was 8%, compared to 26% in patients with moderate-to-severe disease at presentation.264 In another retrospective review of 73 children with ulcerative colitis between the ages of 1 and 18 years, the combination of steroid dependency and pancolitis was associated with an increased need for colectomy.265 Seventy-three per cent of the children with steroid-dependent pancolitis required colectomy within 3 years of diagnosis.265

Except in the setting of emergency colectomy, a complete evaluation should be performed to ensure that there is no evidence of Crohn's disease prior to colectomy. If there is evidence suggesting the possibility of Crohn's disease, the patient and family need to be informed of the potential for postoperative recurrence, and the relative contraindications of ileoanal pull-through procedures in patients with known Crohn's disease. The authors recommend an upper gastrointestinal series with small-bowel follow-through and upper gastrointestinal endoscopy, in addition to a full colonoscopy with ileoscopy, if there is no clinical contraindication. Prior endoscopies and pathology reports should be carefully reviewed to establish that there is no evidence of Crohn's disease.

The surgical options available for ulcerative colitis are reviewed in detail elsewhere.261 The ileal pouch-anal canal anastomosis (IPAA) is the operation most commonly performed in the majority of patients with ulcerative colitis. The IPAA removes the entire colon and the rectal mucosa, avoids permanent ileostomy, and preserves anorectal function. Several types of ileal pouches can be constructed, including the J-shaped, S-shaped, W-shaped and the lateral-lateral pouch.261 The J-pouch design is now most commonly used for the IPAA operation.266,267 If the rectal mucosa is in good condition, many centers use the two-stage operative approach. During the first stage, a subtotal colectomy of the cecum to proximal rectum, the removal of the distal rectal and proximal anal mucosa, and the formation of the ileal pouch are performed. In this initial stage, a diverting loop ileostomy is performed in order to allow the pouch to heal. The second stage involves closure of the loop ileostomy with restoration of fecal flow to the pouch. Surgeons at some surgical centers also complete the IPAA in one stage, without the loop ileostomy;268 however, this would not be the procedure of choice in patients receiving highdose corticosteroids.267 Some authors261 believe that the omission of the diverting ileostomy may increase the risk of anastomotic leaks and prolong recovery;269 thus, candidate patients for the one-stage IAPP should be selected carefully.270

If the patient presents for emergency surgical intervention, such as with fulminant colitis, a three-stage operative approach is often utilized. At the time of acute presentation, a subtotal colectomy is performed with formation of a rectal stump (the so-called Hartman pouch) and Brooke ileostomy. After the first operation, the rectal mucosa is treated with topical therapies (e.g. hydrocortisone, aminosalicylates) to induce mucosal healing. At the second operation, the distal rectal and proximal anal mucosa is removed and the ileal pouch is created. The ileostomy is reversed at the third operation.

The potential complications of IPAA include small-bowel obstruction, pelvic sepsis, anasto-motic leak, fecal incontinence, pouchitis, strictures or fistulae.261,270,271 The development of fistulae raises the suspicion of Crohn's disease.261 In one series of children aged 9-16 who underwent proctocolectomy with IPAA, 12/29 (41%) of patients with ulcerative colitis developed early complications (wound infection, early bowel obstruction, prolonged fever).272 Late complications (bowel obstruction, pouch fistula) occurred in 11/29 (38%) and pouchitis developed in 9/29 (31%) of the children with ulcerative colitis. Median follow-up was 4 years (range 6 months to 9 years). In this same study, daytime continence was noted in 100% and night-time continence in 93%. The median frequency of bowel movements was four in 24h, and 7% of patients had night-time bowel movements.

Pouchitis, or inflammation of the newly created reservoir, is the most significant chronic complication in ulcerative colitis patients undergoing IPAA; as many as 44-53% of children and young adults with ulcerative colitis and ileoanal anastomosis will develop pouchitis on long-term follow-up.259,260 The etiology of pouchitis is unknown, but theories involve the role of genetic susceptibility, fecal stasis, bacterial overgrowth, disruption of the balance of luminal bacteria, nutritional deficiencies, ischemia and IBD recurrence.273 Symptoms of pouchitis include diarrhea, rectal bleeding, abdominal cramping, urgency and incontinence of stool, malaise and fever.261,273,274 Patients with ulcerative colitis who undergo IPAA develop pouchitis more commonly than patients with familial polyposis who undergo the same procedure.275 Pouchitis may occur more frequently

How Treat Pouchitis
Figure 25.5 Chronic active inflammation of an ileal J-pouch (pouchitis) in a patient with a history of ulcerative colitis. Note that both limbs of the ileal reservoir are erythematous with exudate.

in children and adults with primary sclerosing cholangitis (PSC)-associated ulcerative colitis276,277 and in individuals with extraintestinal manifestations of ulcerative colitis.273 Laboratory studies may demonstrate anemia and an elevated ESR. The definitive diagnosis is established by flexible endoscopy of the pouch with biopsies (Figure 25.5). In some patients, a contrast enema may be useful in identifying fistulae.

Broad-spectrum antibiotics are usually the firstline treatment for pouchitis.273,278 Metronidazole is the most commonly used antibiotic, but alternative therapies include ciprofloxacin, amoxicillin-clavulanic acid, erythromycin and tetracy-cline.274,279 If there is no improvement with antibiotics, other options include mesalamine enemas and steroid enemas or oral therapy with mesalamine, sulfasalazine or steroids.274,280,281 Other therapies examined include cyclosporin enemas, SCFA enemas, butyrate suppositories and glutamine suppositories.184,274,282,283

Probiotic therapy may prevent the onset of acute pouchitis after ileostomy closure284 and effectively maintain remission after chronic pouchitis.285 A double-blind, placebo-controlled study evaluated the efficacy of a probiotic preparation VSL no. 3, (containing 5 x 1011per gram of viable lyophilized bacteria of four strains of lactobacilli, three strains of bifidobacteria, and one strain of Streptococcus salivarius subsp. thermophilus), compared with placebo in maintenance of remission of chronic pouchitis in 40 patients in clinical and endoscopic remission. Three patients (15%) in the VSL no. 3 group had relapses within the 9-month follow-up period, compared with 20 (100%) in the placebo group.285 In another double-blind, placebo-controlled study performed by the same authors in 40 patients, VSL no. 3, administered immediately after ileostomy closure for 1 year, effectively reduced the onset of acute pouchitis in the VSL no. 3 group (10%) in comparison to the placebo group

Several studies have suggested that the risk of dysplasia in the ileal pouch appears to be low286,287 and may be associated with chronic pouchitis.288 The development of adenocarcinoma has been reported in the ileal pouch.289 In a follow-up study (mean of 5 years) of 76 children and adolescents with ulcerative colitis who had an IPAA, no dysplasia was identified in screening pouch biopsy specimens.286 The authors cautioned that the long-term risk of development of dysplasia is not yet known and recommended screening of the pouch for dysplasia. In the rare patient who has undergone an ileorectal anastomosis without rectal mucosectomy, surveillance of the rectum should be performed to screen for rectal cancer.

Psychosocial support

The social impact of ulcerative colitis on the lives of children with the disease needs to be considered. Ulcerative colitis often has its onset in adolescence, a time when body image issues are paramount. Children and teenagers with IBD may often experience anxiety over the diagnosis of a chronic disease, the need for invasive procedures and the uncertainty of the future. In addition, there may be struggles with parents about proper diet, and 'medication fatigue' from having to take more than ten pills per day. Social, school-related and extracurricular activities may be affected and may need appropriate modification. For example, a self-limited reduction of physical education activities and permission for special bathroom privileges may be needed.

Previous studies report an increased risk of psychiatric and behavioral issues in children with IBD including depression, anxiety and low self-esteem.290-294 Burke and colleagues reported that children are at increased risk for depression as early as the time of diagnosis.290 The physician caring for these patients needs to discuss the above issues openly with the patient and family, and be alert to the possibility that a patient may develop anxiety or depressive symptoms. More recently, two patient-generated, disease-specific, health-related quality of life (HRQoL) questionnaires for children with IBD have been validated: the IMPACT and Impact-II questionnaires.295,296 Impact-II is a modified version of the IMPACT questionnaire. The use of these instruments may provide important information to improve the care of children with IBD. Referral to an educational support group, such as those sponsored by the Crohn's and Colitis Foundation of America (www.ccfa.org), may be helpful for patients and their famililies.

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