Controlling Childhood Crohn's Disease Requires a Multipronged Approach

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Controlling Childhood Crohn's Disease Requires a Multipronged Approach

[Drug & Ther Perspect 17(7):5-8, 2001. © 2001 Adis International Limited]

Introduction

s Crohn's disease in childhood is a chronic relapsing condition which can

significantly impair the growth and quality of life of the child affected.

The aim of therapy is to induce and then maintain disease remission to

promote well-being and normal development (see Patient care guidelines). A

number of therapeutic options are available for Crohn's disease. Nutritional

support accompanied by maintenance therapy with a mesalazine derivative such

as sulfasalazine is the preferred first-line therapy in children. Failing

this, corticosteroids are typically used, especially in patients with more

severe disease. Due to the relapsing nature of this disease, alternative

therapies, such as azathioprine, cyclosporin and methotrexate, or surgery

are often required.

Special Considerations in Children

Crohn's disease is an inflammatory disorder that can affect any part of the

gut from the mouth to the anus.[1] The classical presentation is abdominal

pain, diarrhoea and bodyweight loss, with the disease most commonly being

seen in the ileum and colon. Crohn's disease is most commonly seen in

adults; approximately 10 to 15% of cases present in childhood. However,

there is evidence that the prevalence is rising in children.[2] The problems

associated with Crohn's disease in children are different from those faced

in adults and the management of paediatric patients can be particularly

challenging. In addition to symptom control, growth, puberty and quality of

life need to be carefully considered.[1]

Growth fFilure a Major Problem

Up to 50% of children and adolescents have growth failure at presentation

and up to 90% are underweight.[3,4] Therefore, assessment of growth and

nutritional status is a fundamental part of management of children with this

disorder.

Providing the appropriate therapy is offered, particularly during the

mid-pubertal growth spurt, disease remission with treatment results in

improved growth and nutritional status with a reasonable adult height in

most cases.[1]

Nutritional Support Primary Therapy

Enteral nutrition should be used as the initial therapy for Crohn's disease

in most children. Numerous studies in children confirm the efficacy of

elemental diets for improving well-being and increasing height velocity and

bodyweight. In 3 comparative studies,[5-7] elemental formula was shown to be

as effective as corticosteroids in the induction of remission in children

and adolescents with Crohn's disease, with elemental formula producing a

better effect on long term linear growth. More recently, cheaper and more

palatable polymeric formulae have been used, which appear to be just as

effective as elemental diets.[8]

Individualise Therapy

At present, it is recommended that enteral nutrition (polymeric or

elemental) should be given for 6 to 8 weeks.[1] The amount required depends

on the degree of nutritional impairment and recommended daily allowances.

Most feeds are about 0.7 to 1 kcal/ml which means a 12-year-old will need

between 2 and 2.5 L/day.[1] Such large volumes are difficult to tolerate in

the first few days so the feed quantity and strength should be increased

gradually. After the initial few days most patients will tolerate some of

the diet by mouth and continuing therapy can be drunk, given by nasogastric

tube or a combination of the two.[1]

At the end of the period on enteral nutrition, food should be gradually

reintroduced. There are various regimens for this,[6] but no consensus

regarding how rapidly it should be done. It is sensible to start with simple

foods such as potato, chicken and rice and to introduce milk, fibre and

wheat-based products later.[1]

Relapse is Common

Unfortunately, relapse is common in patients with Crohn's disease and

medically or surgically induced remissions are typically short-lived. In

adult studies, the rate of relapse following enteral nutrition is between 50

and 90% at 12 months.[1] Although it is difficult to determine from the

paediatric literature, the relapse rate in children is likely to be similar.

This means a second course of enteral nutrition or alternative therapies,

such as corticosteroids, are frequently needed. Even then, patients continue

to relapse and the majority ultimately require surgery for their disease.[1]

Mesalazine Derivatives Reduce Relapse

Preventing relapse once remission has been achieved is a major challenge in

the management of Crohn's disease. Mesalazine derivatives are an effective

therapeutic option for patients with mild Crohn's disease but are

principally used as maintenance therapy in children.[1] These agents should

be started in all children at diagnosis as part of the overall treatment

plan (see Patient care guidelines), although it is often necessary to delay

introduction in children treated with enteral nutrition because of poor

tolerance.[1]

In small children, sulfasalazine (a prodrug converted to mesalazine and

sulfapyridine) is most appropriate to use as it is available in syrup form.

Older patients typically receive mesalazine given as either a controlled-or

delayed-release tablet preparation. There is some debate about which

preparation to use: the newer controlled-release preparations such as

Pentasa ® work better proximally and delayed-release preparations such as

Asacol ® work better distally.[1,9] Although sulfasalazine can be

administered to children via the rectal route, the use of rectal

preparations of mesalazine and its other derivatives is not recommended in

children.[10]

Mesalazine derivatives can be used either alone or in combination with

corticosteroid (preferably at a low dose) or nutritional supplementation.

In patients who have relapsed, mesalazine should be continued for at least 2

years after the last relapse, but probably longer.[11]

Corticosteroids: Keep the Dose Low

Corticosteroids are powerful immunosuppressives with proven efficacy in the

induction of clinical remission in patients with Crohn's disease.[1]

Although widely used in adults, their use in children is usually reserved

for patients with severe or refractory disease because of the potential

adverse effects associated with these agents, particularly on growth (see

Differential features table). However, due to the high rate of relapse of

Crohn's disease, corticosteroids are frequently used to treat this disease

in childhood.

Corticosteroids are generally administered as a single daily dose of

prednisolone (or prednisone) 1 to 2 mg/kg/ day.[1] Once clinical improvement

is evident, the dose should be lowered by 5 mg/day each week until the child

is receiving a dose of 5 to 10mg on alternate days. Prednisolone 5mg on

alternate days does not inhibit growth and can be used long term to maintain

remission.[1]

Another corticosteroid, budesonide, has recently been investigated for use

in Crohn's disease but is not yet widely used in children. Although efficacy

is similar to prednisolone in the treatment of acute episodes, there is no

evidence in children to suggest a better tolerability profile for budesonide

than that seen with prednisolone.[1]

Despite the efficacy of corticosteroids, many patients develop

corticosteroid-dependent or corticosteroid-resistant disease and require

therapy with alternative agents.[1]

Topical corticosteroids administered via the rectal route may demonstrate

significant systemic absorption and bioavailability[12] and therefore offer

no advantage over the oral route. Topical corticosteroids are generally not

recommended for use in children.[10]

Azathioprine for Steroid Dependence

Azathioprine and its metabolite mercaptopurine are widely used as

corticosteroid sparing therapy, particularly in corticosteroid-dependent

patients, to reduce corticosteroid-induced toxicity.[1] Azathioprine or

mercaptopurine have been shown to induce remission and allow corticosteroids

to be tapered off in 60 to 80% of patients with difficult-to-treat Crohn's

disease.[13,14] One drawback about these agents is that they take up to 10

to 12 weeks to exert an effect. The usual daily dose of azathioprine is

between 1 and 2 mg/kg. In children, azathioprine therapy should be

maintained for 2 years after the last relapse before weaning off.

Alternatives for Steroid Resistance

A number of agents have shown efficacy in inducing remission in patients

with Crohn's disease refractory to conventional therapies. However,

experience with these agents in children is limited.[1]

Immunomodulators (cyclosporin, methotrexate) and antibacterials

(metronidazole, ciprofloxacin) are often used in adults with

corticosteroid-refractory Crohn's disease.[1] These agents are effective at

inducing remission but relapse rate and/or toxicity are often high (see

Differential features table). Drugs which act as immunosuppressants

(cyclosporin) should be used with caution in patients with Crohn's disease

as carcinoma may complicate long-standing colitis.[15] Cyclosporin is

contraindicated in patients with evidence of malignancy.[10]

Infliximab, an anti-tumour necrosis factor monoclonal antibody, is a

relatively new agent for Crohn's disease which presents a novel therapeutic

approach. Recent clinical data show that this agent rapidly reduces signs

and symptoms of Crohn's disease and is well tolerated in adults[16] and

children.[17] Furthermore, this agent has shown activity as a maintenance

therapy in adults.[16] Additional investigation into optimal dosing

strategies and the long term safety profile of infliximab is required.

Investigations into other therapeutic approaches, such as intercellular

adhesion molecule inhibitors and anti-tuberculous therapy, may yield

additional therapeutic options for Crohn's disease in the future.[1]

Surgery Can Help Growth

Surgery is required in up to 50% of children within 5 years of diagnosis of

Crohn's disease.[18] The indications for surgery are either local

complications (such as stricture formation or peri-anal abscess) or disease

resistant to maximal medical therapy. In children with disease resistant to

medical therapy, growth failure is common and an impressive catch up to

normal growth rates may be seen postoperatively.[19,20] However, this

depends on pubertal status as catch up growth is not seen once puberty is

complete. Again, the relapse rate is high following surgery, particularly in

colonic disease,[20] and relapse can often occur at a new site.