Treatment

Management of children with Crohn's disease includes medical therapy, potential surgical intervention as well as nutritional and psychiatric support. Education of the patient and the family is a critical aspect of care that should not be overlooked. The IBD Notebook that is available through the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition is a valuable resource empowering patients to understand and control their disease. The general guiding principles for treatment are to control inflammation and achieve normal growth while maintaining a high quality of life. For patients with mild-to-moderate disease, initial therapy with 5-aminosalicylic acid (5-ASA) and antibiotics may induce remission. For patients with more active disease, corticosteroids may provide a more rapid response. Initial treatment with 6-mercaptopurine seems to decrease steroid dependency, but most clinicians reserve immunomodulator therapy for patients who fail to maintain a remission.

Nutrition support

Nutritional therapy is a necessary and essential aspect of therapy for all children with Crohn's disease; achieving normal growth potential is one of the major therapeutic challenges. Nutrition has been used as a primary therapy for children with

Crohn's disease, but when compared to cortico-steroids, children treated with nutritional therapy relapsed sooner. Although the impact on linear growth was less in the nutrition group, compliance with nutritional regimens is more difficult. Suboptimal intake related to anorexia or fear of symptoms with eating, stool losses of nutrients caused by inflammation, ulceration or resection, increased nutritional requirements secondary to fever or increased metabolic requirements, treatment with corticosteroids that inhibit insulin-like growth factor-1, or circulating cytokines that delay linear growth are all relevant factors that impair growth. Medical or surgical therapy may correct or in some situations exacerbate some of the causes of undernutrition, but finding a tolerable nutritional supplement is the key to successful nutritional therapy.

Careful plotting of weight, height and rate of growth, and calculation of the body mass index (BMI) (weight in kg/(height in m)2) is a critical part of the evaluation that enables one to assess when growth delay began. Anthropometric measurements such as triceps skin-fold thickness and mid-arm circumference provide an estimation of body fat and muscle mass. CT scans and magnetic resonance imaging (MRI) may also be beneficial in assessing body composition. Bioelectric impedance analysis (BIA) and total body electrical conductance (TOBEC) assess total body water and fat mass, but have not been validated in the pediatric IBD population. Dual energy X-ray absorptiometry (DEXA) scanning of the spine is a valuable tool to assess bone mineralization.

Daily energy requirements are increased in children with Crohn's disease, and during a flare of disease energy requirements increase while energy generation decreases. Catch-up growth is possible, but may require daily dietary energy intakes over 130% of the recommended values for ideal body weight. In practical terms, this corresponds to intakes ranging between 60 and 75kcal/kg per day. Daily protein intake should approximate 3g/kg, but the requirements of specific proteins such as glutamine is not substantiated. Amino acid-based, hydrolyzed or intact protein diets appear to be equally beneficial although there is a theoretical immunological benefit to giving protein that is less antigenic. In practice this does not seem to be beneficial for most patients. Total amount of protein rather than composition appears most relevant.

Growing children with Crohn's disease who are treated with corticosteroids stimulate osteoclastic bone resorption, inhibit osteoblast proliferation, decrease calcitriol synthesis and do not absorb calcium efficiently. These processes result in decreased bone mineralization. Patients who are at greatest risk for decreased bone mineralization seem to be those who take more than 7.5mg/day, have a greater than 5g lifetime cumulative dose or more than 1 year lifetime exposure. For a growing adolescent 1300mg/day of calcium is recommended along with 400IU/day of vitamin D.

Other minerals and vitamins should be replaced if deficient. Zinc is decreased with inflammation and serum zinc may not reflect intracellular stores. Many patients with Crohn's disease take zinc along with selenium and vitamin E as an antioxidant cocktail without strong supportive evidence for efficacy. Folate requirements may increase in active Crohn's disease, but the folic acid requirement for children with Crohn's disease is not known. Many clinicians recommend a dose of 1 mg daily, but the dose is not based on sound evidence. Vitamin B12 deficiency may need to be treated with subcutaneous injections as ileal absorption is often impaired. Release in 2003 of a nasal form of vitamin B12 may permit children who require vitamin B12 to avoid painful injections.

5-Aminosalicylic acid drugs

The anti-inflammatory effects of this class of medication results from the inhibitory effect of 5-ASA on leukotriene biosynthesis. Effective delivery of these drugs is achieved by various structural modifications that permit the medication to reach the area of inflamed mucosa. Sulfasalazine, a prototype of this class of drug, consists of 5-ASA linked to sulfapyridine via an azo bond. The sulfa moiety serves as a carrier to facilitate delivery of therapeutically active 5-ASA to the colon, which is achieved by bacterial cleavage of the diazo bond and release of the 5-ASA in the intestinal lumen. A number of different 5-ASA preparations have been developed based on a similar strategy. A summary of the different chemical modifications of 5-ASA preparations, and their release mechanisms are listed in Table 23.7. The dosage and site of effect as well as side-effects are listed in Tables 23.8 and 23.9, respectively. A profile of release within the gastrointestinal tract of the different 5-ASA preparations is shown in Figure 23.11. The medication should be selected that targets the areas of inflammation. The dose ranges between 30-60 mg/kg per day, but some clinicians use higher doses. Pediatric dosing should not exceed the adult recommended dose. Topical 5-ASA preparations (enema or suppository) are used more commonly in ulcerative colitis or in those patients with Crohn's disease who do not have rectal sparing.

Corticosteroids

Systemic corticosteroid treatment remains an important and effective therapy for children with Crohn's disease, but side-effects often limit their use. The anti-inflammatory effect of cortico-steroids is related to inhibition of cell-mediated immunity, decreased cytokine production, decreased capillary permeability, impaired neutrophil and monocyte chemotaxis and stabilization of lysosomal membranes.147'148 Prednisone or prednisolone is commonly used in children with Crohn's disease who have active mucosal inflammation that does not respond to initial therapy with 5-ASA and antibiotics. Prednisone is a synthetic glucocorticoid of intermediate potency, and is converted to its active form, prednisolone, in the liver.103 Prednisone or prednisolone is administrated orally or intravenously at 1-2 mg/kg

Table 23.7 Chemical modification and release mechanisms of 5-aminosalicylic acid (5-ASA)

preparations

Preparation

Trade name

Chemical modification

Release mechanism

Sulfasalazine

Azulfidine

azo bond to sulfapyridine

bacterial cleavage

Olsalazine

Dipentum

5-ASA attaches to 5-ASA

bacterial cleavage

Ipsalazide

azo bond to inert carrier

bacterial cleavage

Balsalazide

Colazal

azo bond to inert carrier

bacterial cleavage

Mesalamine/mesalazine

Asacol

attach to acrylic-based resins

pH-dependent release (pH >7)

Mesalamine/mesalazine

Salofalk, Claversal

attach to acrylic-based resins

pH-dependent release (pH >5.6)

Mesalamine/mesalazine

Pentasa

coated with ethyl cellulose

time and moisture-dependent

release

Mesalamine/mesalazine

Rowasa, Canasa

uncoated

direct local effect (rectum to left

enema/suppository

colon)

Table 23.8 Dosage and site of effect of 5-aminosalicylic acid preparations

Preparation

Trade name

Dosage

Site of effect

Sulfasalazine

Azulfidine

For maintenance 30mg/kg per day ■

For maintenance 2 g/day ■ QID

colon

Olsalazine

Dipentum

C: not available A: 1.5-3g/day ■ BID - QID

colon

Balsalazide

For maintenance 3-4 g/day ■ BID

colon

Mesalamine

Asacol

C: 25-50 mg/kg per day ■ BID - TID A: 2.4-4.8g/day ■ TID - QID

distal ileum or right colon

Mesalamine

Salofalk, Claversal

C: not available

A: 2.4-4 g/day ■ TID - QID

mid- to small bowel

Mesalamine

Pentasa

C: 25-50mg/kg per day ■ BID - TID A: 4g/day ■ TID - QID

small bowel and colon

Mesalamine enema/suppository

Rowasa enema, Canasa suppository

C: not available

A: 4g enema nightly; 500mg suppository BID

rectum and left colon

C, children; A, adults; BID, twice a day; QID, four times a day; TID, three times a day

Table 23.9 Side-effects of 5-aminosalicylic

acid preparations

Preparation

Side-effect

Sulfasalazine (mainly related to sulfa moiety)

dose-dependent (nausea, vomiting, headaches, hemolysis)

hypersensitivity (fever, rashes, Stevens-Johnson syndrome,

agranulocytosis, pulmonary fibrosis, hepatotoxicity)

male fertility impairment

folate deficiency

Mesalamine/mesalazine

acute pancreatitis

Olsalazine

diarrhea

Preparation Stomach Jejunum Ileum Colon

Pentasa Asaciil

Sulfasalazine Olsalazine Balsaiazide Rowasa/Canasa nzM

Figure 23.11 Gastrointestinal release profile of 5-aminosalicylic acid preparations. The diagram of gradient indicates increased release.

per day to a maximum of 40-60 mg/day, and gradually tapered after establishment of remission. A typical adolescent patient who required corticosteroids might start on 40 mg of prednisone once daily (or 2 mg/kg per day, whichever was less). If the clinical response is suboptimal, the dose may be divided twice a day. Splitting the dose further has little proven efficacy and increases adrenal suppression. Although some clinicians may increase the dose to a maximum of 60 mg/day for those patients who do not respond, there is no evidence that higher doses are beneficial and they are associated with increased untoward events. Systemic corticosteroid therapy is generally not used as a maintenance regimen. The adverse effects of systemic corticosteroid therapy are summarized in Table 23.10. Topical intrarectal corticosteroids (hydrocortisone enemas or foam) are also available for those patients with rectal disease.

Oral budesonide is designed for release in the ileum, cecum and right colon and is usually prescribed at 9 mg/day initially for an adult for 8 weeks and then tapered by 3-mg increments. Budesonide is not approved by the Food and Drug Administration (FDA) for use in children. Because of its high first-pass hepatic metabolism, budesonide has significant local effect with much less systemic effect.149 The incidence of overall adverse effects is less than with prednisolone as noted in clinical trials with adult patients with Crohn's disease.150 However, long-term use of oral budesonide may still cause significant systemic glucocorticoid effects, since budesonide has an affinity for the glucocorticoid receptor 50-100 times more than that of prednisone.2 Experience with pediatric patients with Crohn's disease has demonstrated that growth failure remains an active issue in long-term treatment with budesonide, because

Table 23.10 Adverse effect of systemic corticosteroid therapy

Common

Rare

Long term

Acne

seizure

growth failure

Moon facies

pseudotumor cerebri

nephrolithiasis (hypercalciuria)

Hirsutism

psychosis

osteopenia

Cutaneous striae

myopathy

osteoporosis

aseptic necrosis of femoral head

diabetes

cataracts

secondary hyperparathyroidism

increased intraocular pressure

of either direct suppression of linear growth or an inability to control disease activity fully.151

Immunoregulatory agents

Azathioprine and 6-mercaptopurine

Growing evidence supports the use of the immunoregulatory agents azathioprine and 6-mercaptopurine in treating Crohn's disease as effective therapy to maintain control of intestinal inflammation. These agents are particularly useful in patients who are steroid-dependent. 6-Mercaptopurine is a purine analog capable of interfering with DNA and RNA synthesis by competing with endogenous purines. Azathio-purine is a prodrug that exerts its immunosuppressive effect through its metabolite 6-mercaptopurine. 6-Mercaptopurine undergoes extensive transformations to form cytotoxic intracellular metabolites responsible for the immunosuppressive effect. Studies suggest that the intracellular levels of the metabolite 6-thioguanine (6-TG) correlate with efficacy, and the intracellular levels of the metabolite 6-methyl mercaptopurine (6-MMP) with hepatotox-icity.152 Genetic polymorphisms of thiopurine methyltransferase (TPMT), an enzyme that catabo-lizes 6-mercaptopurine to 6-MMP, controls the baseline enzymatic activity of TPMT. One in 300 subjects has very low enzyme activity or none at all, and 11% of the population has intermediate enzyme activity. Inherited low TPMT activity appears to be a risk factor for acute bone marrow failure by leaving more 6-mercaptopurine available for conversion to cytotoxic 6-TG.

In a prospective, double-blind, placebo-controlled pediatric trial, 55 children (mean age of 13 years)

with newly diagnosed Crohn's disease were randomly assigned to receive prednisone plus either 6-mercaptopurine (1.5mg/kg per day) or placebo.153 Markowitz et al found that the duration of steroid use and the cumulative steroid dose was significantly decreased in the group that received steroids plus 6-mercaptopurine. Although the rate of remission achieved in both groups was similar (89%), relapse was less frequent in the group that received 6-mercaptopurine.153 Base on these findings, 6-mercaptopurine should be considered as part of the initial treatment prescribed for children with newly diagnosed moderate-to-severe Crohn's disease activity who are started on cortico-steroids.153 The dosages, adverse effects, and monitoring parameters for azathioprine and 6-mercap-topurine are listed in Table 23.11. The monitoring of 6-TG and 6-MMP remains controversial, as discussed by Dubinsky and Griffiths.154

Methotrexate

Methotrexate exerts its cytotoxic effect by interfering with thymidine synthesis, by inhibiting the conversion of the folic acid to its active form tetrahydrofolate. Intramuscular administration of methotrexate weekly has proved effective in inducing and maintaining remission in adult patients with Crohn's disease who are either steroid-refractory or -dependent,155 or in pediatric patients with Crohn's disease intolerant or refractory to azathio-prine/6-mercaptopurine treatment.156 Common adverse effects of methotrexate include nausea and abnormal liver serum transaminase levels. Concerns about possible hepatic fibrosis may limit the long-term use of methotrexate.

Table 23.11 6-Mercaptopurine and azathioprine therapy

Dosage

Azathioprine 6-Mercaptopurine

Potential adverse effects

Monitoring program

1.5-2.5 mg/kg per day 1-2 mg/kg per day

fever

TPMT level before therapy

pancreatitis

rash

arthralgia

weekly for 4 weeks, then

nausea

every 3 months: CBC with

vomiting

differential, liver function

diarrhea, leukopenia

tests, amylase, lipase

thrombocytopenia

opportunistic infection

hepatitis

consider: monitoring 6-TG

malignancy

and 6-MMP

TPMT, thiopurine methyltransferase; CBC, complete blood count; 6-TG, 6-thioguanine, mercaptopurine

6-MMP, 6-methyl

Anti-tumor necrosis factor-a agents

TNF-a is a pro-inflammatory cytokine produced by activated macrophages, and is thought to play an important role in the pathogenesis and clinical manifestations of IBD. Several reagents have been developed as antagonists of TNF-a in the treatment of Crohn's disease. Infliximab (Remicade®) is a chimeric monoclonal antibody composed of a complement-fixing 'human' IgGl constant region and a mouse-derived antigen-binding variable region, and binds directly to soluble TNF-a.2 Infliximab is efficacious as therapy in about two-thirds of adult patients with moderately to severely active Crohn's disease resistant to corticosteroid and azathioprine/6-mercaptopurine therapy. However, about half of those who respond initially will have a sustained response over the first year. Infliximab is also effective in patients with fistulae that are refractory to antibiotic and/or azathioprine/6-mercaptopurine treatment.157-159 Infliximab is administered intravenously with a recommended regimen for treatment of fistulae of three initial doses at 0, 2 and 6 weeks, followed by repeat infusions at 2-month intervals, for patients who demonstrate response to the initial doses.160 Although this regimen is not FDA approved, most patients with Crohn's disease including those without fistulae are treated thus. Common side-effects associated with infliximab therapy include fever, rash, vomiting and chest pain.160 Rarely, a serious hypersensitivity reaction may also occur with repeat infusion. Reactivation of tuberculosis associated with infliximab therapy has been reported as a potential lethal complication.160 Therefore, all patients must receive tuberculosis screening prior to initiation of therapy. Lymphoma has developed in a small number of patients receiving infliximab, although a causal relationship has not been established.2,160

In a retrospective open-labeled pediatric study, 19 children with Crohn's disease (mean age 14.4 years) received 1-3 infusions of infliximab (5mg/kg per dose) over a 12-week period for corti-costeroid-resistant (n = 7) or corticosteroid-depen-dent disease (n = 12).161 Significant initial improvement (first 4 weeks after infusion) was noted in all subjects, with pediatric Crohn's disease activity index (PCDAI) values decreasing significantly (42.1 ± 13.7 to 10.0±5.6, p <0.0001), but over the subsequent 8 weeks, eight of 19 treated children had worsening of symptoms, although none deteriorated to a level of severe disease activity.161 The requirement of prednisone was also significantly reduced with infliximab treatment. Adverse effects were noted in three children during infusion (dyspnea, rash) and were self-limited.161 In a recent prospective multicenter, open-label, dose-blinded clinical trial, 21 children with Crohn's disease (aged 8-17 years) were randomized to receive a single infusion of inflix-imab 1mg/kg (n = 6), 5mg/kg (n = 7), or 10mg/kg (n = 8).162 Improvement in the PCDAI, ESR and C-reactive protein (CRP) was observed with all inflix-imab doses, beginning at week 1. All treated patients experienced approximately 50% improvement in the PCDAI by week 2, and by week 12, the PCDAI remained approximately 30% improved from baseline.162 During the study, all 21 patients (100%) achieved a clinical response, and ten patients (48%) achieved clinical remission; there were no infusion reactions in any of the treated patients.162 Appropriately powered pediatric studies of infliximab are needed to establish safety and efficacy.163

Antibiotics

Antibiotics are often used to treat newly diagnosed or relapsed patients with Crohn's disease or patients with perianal fistulae/abscesses. There are no randomized clinical trials to support efficacy in the pediatric population. Commonly used antibiotics and their dosage and side-effects are listed in Table 23.12.

Surgery

The most common reasons for surgery are intractable symptoms despite medical therapy, obstruction, intra-abdominal abscess, fistula refractory to medical therapy, or intractable hemorrhage. In patients with a well-defined region of disease that has not been progressive over time, surgical resection can be a highly effective therapy. The potential benefits of surgery include rapid resolution of symptoms, enhanced growth and pubertal development, and improved quality of life. Postoperative recurrence of disease is a significant risk. Data from adults have indicated that the incidence of clinical recurrence following resection is about 10% per year.

Supportive measures

Psychological support and psychiatric counseling are important adjunctive therapies to cope with chronic disease. Children with Crohn's disease may have to face delayed sexual maturation and short stature. Missing school impacts on social maturation and relationships. Psychiatric and psychological support is a critical aspect of a pedi-atric IBD program; anti-anxiety or antidepressant medications may be beneficial. Long-term therapy should be considered for any child having difficulty in school or with interpersonal relationships.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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