Therapeutic strategies for pediatric Crohn disease

Richard J. Grand, MD
Jyoti Ramakrishna, MD
Kathleen A. Calenda, MD

Clin Invest Med 1996; 19 (5): 373-80

[résumé]

Drs. Grand, Ramakrishna and Calenda are from the Division of Pediatric Gastroenterology and Nutrition, The Floating Hospital for Children, the Center for Gastroenterology Research on Absorptive and Secretory Processes (GRASP), New England Medical Center Hospitals, and Tufts University School of Medicine, Boston, Mass.

Paper reprints may be obtained from: Dr. Richard J. Grand, New England Medical Center, 750 Washington St., PO Box 213, Boston MA 02111-1533; fax 617 636-8718.

Contents

Abstract

The main aims of therapy for inflammatory bowel disease (Crohn disease) in children and adolescents are (1) the induction and maintenance of remission, (2) the correction of nutrient deficits and (3) the restoration of growth and maturation. These goals are reached with the use of a combination of therapeutic methods, including pharmacologic agents, nutritional and psychological support, and surgical intervention. The commonly used drugs sulfasalazine, corticosteroids and metronidazole have all been shown to be safe and efficacious when given to children. Newer steroid preparations that are rapidly degraded either in the target tissue or elsewhere are being studied. Of these, budesonide currently shows promise as an efficacious drug with few side effects, but its use in children needs further study. Newer 5-aminosalicylate preparations such as Asacol have been shown to be effective in children, but the number of patients studied is small. Immunomodulatory drugs such as azathioprine and 6-mercaptopurine appear to be safe and efficacious for children; cyclosporine has been used infrequently to treat refractory Crohn disease in children. The use of other agents such as methotrexate, tacrolimus, monoclonal antibodies to cytokines, antibiotics and specific dietary products such as fish oils have not been intensively studied in children with Crohn disease. Nutritional therapy remains a mainstay of treatment because it corrects nutritional deficits, replaces losses and stimulates growth.

Résumé

Les buts du traitement de la maladie inflammatoire du tube digestif (maladie de Crohn) chez l'enfant et l'adolescent sont l'induction et le maintien d'une rémission, la correction des déficits nutritionnels, et la restauration de la croissance et de la maturation. Ces objectifs sont atteints par l'utilisation combinée de méthodes thérapeutiques qui incluent les médicaments, le soutien nutritionnel et psychologique et la chirurgie. L'emploi courant de la sulfasalazine, des corticostéroïdes et du métronidazole est à la fois sûr et efficace chez l'enfant. De nouveaux stéroïdes rapidement dégradés sont à l'étude. Parmi ceux-ci, le budesonide semble prometteur en tant que médicament à la fois efficace et avec peu d'effets secondaires, mais son emploi chez l'enfant doit faire l'objet d'études plus approfondies. Les préparations nouvelle de 5-aminosalicylate telles que l'Asacol sont efficaces chez l'enfant, mais le nombre de sujets étudiés est petit. Les médicaments immuno-modulateur tels que l'azathioprine et la 5-mercaptopurine semblent sûrs et efficaces chez l'enfant; quant à la cyclosporine, elle a été utilisée peu fréquemment pour traiter la maladie de Crohn rebelle chez l'enfant. D'autres traitements, tels que méthotrexate, tacrolimus, anticorps monoclonaux anti-cytokines, antibiotiques et produits diététiques spécifiques telles que les huiles de poissons, n'ont pas fait l'objet d'études intensives chez les enfants avec la maladie de Crohn. La thérapie nutritionnelle demeure une pierre angulaire du traitement parce qu'elle corrige les déficits nutritionnels, remplace les pertes et stimule la croissance.

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Introduction

There is an emerging consensus that a major pathogenic mechanism in inflammatory bowel disease (IBD, which includes Crohn disease and ulcerative colitis) is aberrant activation of the mucosal immune system. Although there are differences between the immunological abnormalities found in Crohn disease and those found in ulcerative colitis, it appears that many of these abnormalities are common to both diseases.[1, 2] Indeed, this principle guides available therapy for both disorders and serves as the basis for current drug trials. This article focuses on current therapeutic strategies for Crohn disease, since the widespread involvement of the gastrointestinal tract and the extraintestinal manifestations seen in Crohn disease but not in ulcerative colitis are a particular challenge. Furthermore, children and adolescents in general are in a dynamic state of growth and of physical and psychological development. The onset of IBD comes at an especially vulnerable time. Although less than 2% of all patients with IBD present before the age of 10 years, 30% present between the ages of 10 and 19 years.[3] Thus, in a significant proportion of young patients with IBD, the disease develops just before or during puberty.

Any inflammatory disease at this age is likely to have a major effect on nutritional status and growth, which is characterized by the rapid accumulation of lean body mass. Accordingly, the aims of therapy are the induction and maintenance of remission, the correction of nutrient deficits and the re-establishment of growth and maturation. This is generally accomplished through the use of a combination of pharmacologic agents, nutritional support, psychological support and, when indicated, surgery.

A further challenge in the successful management of Crohn disease in children is the varied phenotypic expression of the disease. Depending on factors that are not yet entirely identified, children with Crohn disease may demonstrate remarkably different clinical expressions of disease: extraintestinal signs, growth failure, upper gastrointestinal involvement, ileocolitis or colonic disease alone, and perianal disease.[4] Although in a few studies of therapy patients are stratified on the basis of the location and the character of involvement, in most they are not. This may add significant bias to the outcomes, leaving numerous questions unanswered. These considerations must be taken into account when the success of individual or combined therapeutic approaches is evaluated.

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Corticosteroids

Despite the availability of new and novel drugs (to be discussed later), corticosteroids remain the mainstay of treatment for active Crohn disease.[5] They are not usually recommended for long-term low-dose treatment, however, not only because of their adverse effects but also because they are ineffective in maintaining a remission. Nevertheless, the most common error made in the use of steroids for the treatment of active IBD is to prescribe too small a dose for too short a time to establish a solid remission. Patients with severe acute disease or with moderately severe disease that is unresponsive to oral therapy are given intravenous methylprednisolone (1 to 2 mg/kg per day in divided doses), often in conjunction with bowel rest and parenteral nutrition. Once clinical improvement is achieved, therapy may be changed to prednisone, taken orally at the same dosage. This dosage is given for 4 to 6 weeks and then tapered off by 5 mg each week, initially to an alternate-day dosage and then completely while the patient is taking a maintenance drug (5-aminosalicylate [ASA] or immunomodulatory agents). Alternate-day dosage is associated with fewer side effects and also allows linear growth to continue.[6] In moderately active disease, corticosteroids taken orally, such as prednisone (1 to 2 mg/kg per day), are given in a single morning dose for 4 to 6 weeks and then tapered off as above. Some patients have a relapse during the tapering-off period and may need to receive a higher dose. They may then tolerate slower tapering-off of the dosage. On occasion this strategy also fails. In this case, immunomodulatory therapy (discussed later) may be useful. For rectal disease, hydrocortisone and prednisolone are available in the form of retention enemas, suppositories or foams. The side effects of steroids are well known and are discussed elsewhere.[5]

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New steroid preparations

Several new steroid preparations with lower systemic bioavailability, such as beclomethasone, prednisolone metasulfobenzoate, tixocortol pivalate and budesonide, have recently become available.[7] Most of these drugs are either (1) poorly absorbed or rapidly inactivated locally, or (2) absorbed well and rapidly cleared by first-pass metabolism by the liver. Budesonide is currently the most widely studied of these agents.[8] It is water soluble, has high tissue uptake, a higher affinity for the glucocorticoid receptor and remains in the mucosa longer than more commonly used glucocorticosteroids; it then undergoes rapid metabolism by the cytochrome P450 system. In several clinical trials, it has been found to be effective in the treatment of active Crohn disease in adult and to have fewer side effects than prednisone.[8] Two such trials deserve mention.[9,10] In one study, adults patients with Crohn ileitis or ileocolitis were randomly assigned to receive either a placebo or budesonide at dosages of 3, 9 or 15 mg per day in two divided doses for 8 weeks. At entry, the mean Crohn Disease Activity Index (CDAI) was approximately 290 points in all groups. At the end of the study period, the 9-mg dose was found to be effective in reducing the mean CDAI to approximately 175 points, whereas the placebo reduced the mean CDAI only by 21 points. The quality-of-life score also increased significantly for those receiving the 9-mg dose. Side effects related to steroids affected only 16% of patients, and the rate of side effects did not differ in the budesonide group compared with the control group, except for that of "moon face," which was more common in the treatment group. However, the group receiving budesonide did show significantly lower fasting plasma cortisol levels.[9] In the second study, budesonide (9 mg per day for 10 weeks) was compared with prednisolone in a randomized, double-blind trial. The CDAI fell from a mean 275 to 175 points in the group taking budesonide, and from a mean 279 to 136 points in the group taking prednisolone. Steroid side effects were approximately twice as common in the prednisolone as in the budesonide group, and the fasting plasma cortisol levels were more markedly depressed in the prednisolone group.[10]

Budesonide has also been studied as a maintenance drug for Crohn disease.[11] Patients were randomly assigned to receive a placebo or 3 or 6 mg per day of budesonide for 1 year. At both dosages, budesonide prolonged the relapse-free interval, although the annual relapse rates were the same for budesonide- as for placebo-treated patients. Surprisingly, side effects were reported to be "minimal," but details were not provided.[11] Further studies of the long-term use of budesonide and careful studies of this agent in children and adolescents with IBD are needed.

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Sulfasalazine

Sulfasalazine is often used in the initial treatment of mild Crohn disease in a dosage of 50 to 75 mg/kg per day, given in divided doses, to a maximum of 4 or 5 g per day.[5] There is a lower incidence of dose-related side effects if the drug treatment is started at a low dosage and progressively increased to the desired dosage over 6 to 8 days. As in adults, the response is seen at a mean interval of 3 to 4 weeks after initiation of treatment. Sulfasalazine is also useful in the maintenance of remission in Crohn colitis and ileocolitis, and it decreases the relapse rate from approximately 60% to 30%.[12] Its beneficial effect in patients with Crohn ileitis remains unclear. Side effects are seen in 10% to 40% of patients who take sulfasalazine, and these are discussed elsewhere.[5] The dose-dependent side effects, foremost of which is male infertility, are due to the sulfapyridine molecule, and these have led to the development of newer drugs that deliver 5-ASA without the sulfapyridine carrier.

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New 5-ASA preparations

5-ASA taken orally in a nonprotected form is rapidly absorbed in the proximal small intestine. Therefore, delivery systems have been developed to facilitate its release in the distal small bowel or colon. There are three groups of products available. The first, olsalazine (Dipentum, 250-mg capsules), contains two 5-ASA molecules linked by an azo bond that requires cleavage by colonic bacteria for activation. The second, mesalazine (mesalamine), consists of delayed-release preparations coated with different resins designed to be released at a set pH. Of these, Asacol (400-mg tablets) is released at a pH higher than 7 in the distal ileum and colon; Salofalk and Claversal (250-mg tablets) are released at a pH higher than 5.6 from the mid-small bowel distally. The third, Pentasa (250-mg tablets), is a timed-release preparation in the form of microgranules coated with a semipermeable membrane of ethyl cellulose. Release occurs continuously throughout the small bowel and colon, but the rate is affected by pH. The commercial availability of these products differs around the world.[5]

5-ASA preparations are an alternative to sulfasalazine in the treatment of mild to moderate Crohn colitis and in the maintenance of remission. Their beneficial effect on the small bowel in Crohn disease is probably related to local bioavailability of the active drug. Only small clinical trials have been performed in children. In one study, 12 children with Crohn disease received 50 mg/kg per day of mesalamine or a placebo.[13] After 8 weeks, the van Hees index improved to +14 in the treated group, compared with -18 in the placebo group. In another study, a dosage of mesalamine of 30 mg/kg per day was found to be effective, but the definition of remission was not provided.[14] The main advantage of these agents is reduced risk of allergic reactions, although, in a controlled trial of olsalazine and sulfasalazine in children with ulcerative colitis, there were more side effects in the olsalazine group.[15] Large-scale studies of efficacy and optimal dosage of these new 5-ASA preparations in children are needed.

5-ASA is also available in topical form. Rowasa enemas contain 4 g of 5-ASA in a 60-mL suspension. Suppositories of 250 mg are also available and are well tolerated even when given to children. Topical treatment with these can be used alone as first-line therapy for rectal disease or for tenesmus accompanying more extensive colonic disease.

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Antibiotics

Metronidazole is useful in the treatment of Crohn disease; it has been found to be at least as effective as sulfasalazine.[12] It is particularly useful for treating perineal or perianal lesions, in which it heals more than 80% of cases.[16,17] It is also used as an adjunct to therapy when suppurative lesions are suspected or detected. It is given at a dosage of 15 to 20 mg/kg per day intravenously or orally in divided doses.[5] A recently published study evaluated the potential role for metronidazole in the prevention of recurrence of Crohn disease after surgery.[18] In the treated group, at 12 weeks 52% of patients had relapses, as compared with 75% of those in the control group taking a placebo. At 1 year after surgery, the clinical recurrence rates were 4% in treated patients and 25% in controls; however, at 2 and 3 years, recurrence rates were not significantly different between the two groups. Unfortunately, metronidazole has certain unpleasant side effects that limit its use in many patients. Adolescents should be warned of its disulfiram-like action when alcohol is consumed. Long-term use is not recommended, since metronidazole causes peripheral neuropathy in as many as 50% of patients.[19] This side effect is usually dose-related and reversible but may persist long after the drug is discontinued.

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New antibiotic agents

Ciprofloxacin is an antibiotic that has been used recently and seems effective for the same indications as metronidazole.[5] Combinations of ciprofloxacin and metronidazole have been used recently with success in maintaining remissions in Crohn disease in adults.[20] The possibility that some cases of Crohn disease may be due to infection with Mycobacterium paratuberculosis has led some investigators to use clarithromycin to treat Crohn disease.[21] This approach requires further study.

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Immunomodulatory drugs

Azathioprine and 6-mercaptopurine (6-MP) are the two immunomodulatory drugs most extensively used to treat Crohn disease in children, and the drugs most extensively studied.[22] These have been in use for more than 20 years and have been shown to be safe and effective. Azathioprine is metabolized to 6-MP and both are precursors of other metabolites in vivo. The parent compounds and their breakdown products are active immunosuppressives. Immunomodulatory drugs are generally used in treating Crohn disease in children when repeated (two or three) attempts to taper off steroids have failed or when physicians wish to avoid prolonged steroid use.[23,24] In 75% of patients who previously depended on steroids, immunosuppressives offer a steroid-sparing effect, allowing steroid reduction and eventual discontinuation. They are also useful when frequent relapses prompt the physician to look for alternative treatments. 6-MP is given at a dosage of 1.5 mg/kg per day and azathioprine at 2 mg/kg per day, each in two divided doses. The drugs are usually started at a low dose and increased over 7 to 10 days to the full dose. The beneficial effect is delayed for 6 weeks to 6 months, and an average of 4 months in children, after starting therapy. Although these are relatively low doses, potential toxicity must always be kept in mind, although there is currently no evidence that these drugs lead to an increased risk of cancer.[25] Azathioprine and 6-MP agents are cytotoxic, destroy stimulated lymphoid cells and, hence, suppress inflammation. However, at the doses used in the treatment of IBD, recurrent systemic infections are uncommon. Immediate side effects include allergic reactions and acute pancreatitis. The latter reverses completely when the drug is withdrawn but precludes its further use. Rarer side effects include leukopenia and hepatitis, which can occur at any time.

Cyclosporine has been used recently in children with acute, severe, refractory Crohn disease unresponsive to steroids, but only a few studies have been conducted to date.[26­28] More data are available concerning its use in treating ulcerative colitis. Cyclosporine has been administered for this disease when a high dosage of steroids, administered intravenously, has failed to achieve a clinical remission or when the patient's condition has worsened in spite of the use of steroids.[26] Cyclosporine is customarily started as a continuous intravenous infusion at 1 to 2 mg/kg per day, and then switched to the oral form at a dosage of 4 to 8 mg/kg per day. Subsequently, either azathioprine or 6-MP are begun, and cyclosporine is tapered off and discontinued after 8 to 12 weeks.[28] Cyclosporine absorption may be erratic, and its levels must be followed. Of four controlled clinical trials of cyclosporine in adults with Crohn disease, only one demonstrated a beneficial effect Table 1.[26] In three uncontrolled studies in children with Crohn disease, 11 patients received the drug and 8 achieved remission. However, four of the eight subsequently required surgery, which is a similar rate to that in the patients who did not respond.[28] Thus, cyclosporine may be of value for selected children with Crohn disease, but its routine use cannot be supported on the basis of the available data. Side effects include hypertension, renal and hepatic dysfunction, opportunistic infection (which may be life-threatening), hirsutism, peripheral neuropathy and seizures. Cancer such as non-Hodgkin's lymphoma can occur with long-term use.

Methotrexate and tacrolimus (FK506) are also being tried for similar indications; however, data concerning their use in children are only anecdotal. Methotrexate has been used recently as an alternative therapy in adults with refractory Crohn disease.[29] In a double-blind, placebo-controlled trial, 97 patients received methotrexate (25 mg intramuscularly) as a single dose each week for 16 weeks and 47 patients were given a placebo. Prednisone (20 mg per day) was administered and was tapered off by 10 weeks unless the disease worsened. The primary outcome variable was a CDAI of 150 points or lower and discontinuation of prednisone. Of those receiving methotrexate, 39% had a remission (CDAI 162 ± 12) by 16 weeks compared with 19% of controls (CDAI 204 ± 17). Despite these positive results, 17% of the patients treated with methotrexate and 2% of the controls withdrew from the study. Although the data clearly show the efficacy of methotrexate in some patients, whether it can be applied to children will require further investigation. Furthermore, the role of methotrexate as maintenance therapy needs evaluation.

As mentioned, proinflammatory cytokines play an important role in initiating and propagating the abnormal immune responses observed in Crohn disease.[1] Of these, tumour necrosis factor alpha (TNF alpha) has been cited as a major contributor to disease activity. This hypothesis is supported by a recent clinical trial of anti-TNF antibody.[30] Ten adult patients with active Crohn disease who were unresponsive to steroid therapy (mean CDAI 258) received a single dose of anti-TNF chimeric monoclonal antibody. Eight of these patients had normalization of the CDAI (mean 79) by 4 weeks, accompanied by colonoscopic evidence of healing. Remission was maintained for a mean of 4 months. Additional trials are currently being conducted to expand the experience with this agent and to define the indications for its use.

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Nutritional therapy

Malnutrition is a well-recognized complication of Crohn disease. Nutritional support has been shown to be safe and effective as primary therapy for Crohn disease in children and is also a critical adjunct to drug therapy[5] in children with nutritional or growth failure. Faltering growth occurs in 20% to 65% of children with Crohn disease, depending on the measure used. Nutritional therapy restores intake, replenishes deficits and stimulates growth. Indeed, one of the main concerns in children with Crohn disease is achievement of optimal or catch-up growth.

In children with nutritional or growth failure, energy supplementation in the form of commercially available high-energy formulas or drinks is given either orally or as night-time nasogastric infusions. Most teenagers can learn to pass their own nasogastric tube; silicon-rubber tubes are the best tolerated. At least 150% of the recommended daily energy and protein intakes for height and age may be needed for catch-up growth.[5] The role of growth-hormone treatment as an adjunct to nutritional therapy is currently under investigation in our unit. Patients who have had several operations and have only a residual short gut may need central parenteral nutrition. However, the complications of a central line must be weighed against the need for such therapy.

In an acute, severe presentation of Crohn disease, oral nutrition may be impossible and parenteral nutrition may become necessary. However, the oral route is still the preferred one, and patients initially treated with parenteral nutrition should be fed normally as soon as possible. Although elemental and polymeric liquid diets have been useful in inducing a remission in patients with Crohn disease, they are seldom tolerated well for a long period.[5] A recently published meta-analysis comparing the efficacy of a liquid diet with steroid therapy in achieving remission in patients of all ages with Crohn disease clearly demonstrated that steroids are superior in adults.[31] Another study indicated that nutritional support and steroid therapy were equally effective in establishing a remission in children.[32] Long-term studies of the impact of nutritional support on relapse rates are needed.

Although most studies of nutritional therapy for Crohn disease have been devoted to liquid formulas, a few have focused on individual nutrients. Of these, an intriguing response to fish oil has recently been reported.[33] Adult patients with Crohn disease in remission (CDAI 150) for more than 3 months were randomly assigned to receive either a fish-oil preparation or a placebo for 1 year. The fish oil was 40% eicosapentenoic acid (EPA) and 20% docosahexanoic acid (DHA) (whereas the commercially available product in the United States contains 18% EPA and 12% DHA). In 34 patients taking fish oil, there were 11 relapses at the end of the study (32%), whereas, in 37 patients taking the placebo, there were 27 relapses (73%). There were no complications observed. The potential for such therapy to maintain remission in Crohn disease needs to be assessed in comparison with other available maintenance drugs.

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Novel therapeutic approaches

Several specific abnormalities in the immune response of patients with Crohn disease or current animal models of IBD have pointed the way to therapeutic strategies. Interleukin-10 (IL-10) is undergoing clinical trials in the Netherlands, Canada and the United States.[34] Its potential benefit stems from its role in down-regulating the immune response, a feature derived from studies of mice with IL-10 knockout.[35] Targeted drugs or receptor antagonists for a variety of cytokines have been studied experimentally and may be promising for future clinical trials.[22,36]

Oral tolerance is an emerging concept in therapy that may apply to several autoimmune disorders.[37] The feeding of specific purified proteins to patients with certain diseases is associated with reduction in markers of inflammatory activity.[38] Whether this can be applied to IBD depends on the demonstration of a specific protein that links abnormal immune responses to bowel involvement.

Recently, D'Amato and colleagues[39] have commented on the interaction between TNF alpha and thalidomide. Thalidomide suppresses TNF alpha production by macrophages and is antiangiogenic. Its role in inflammatory diseases in humans remains to be defined.

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Measuring outcomes in Crohn disease

No matter which therapeutic strategy is studied in patients with IBD, measures are needed to define endpoints and assess alterations in disease activity objectively.[40] Physiological measures such as the serum orosomucoid level or erythrocyte sedimentation rate provide markers of disease activity that can be readily measured. However, they do not provide reliable indices of patients' overall responses to interventions.

Accordingly, many studies in adults have relied on the CDAI, the Harvey­Bradshaw Index, the van Hees Index and other scales.[40] In pediatrics, the Harvey­Bradshaw Index has been shown to reflect the physician's global assessment effectively and to correlate well with the Pediatric CDAI.[41,42] The Lloyd­Still scale is not widely used.[43]

In addition to biochemical and clinical measures, the patient's quality of life should be used as a marker of therapeutic efficacy. Such outcome measures have been introduced into clinical studies of IBD in adults.[44] Measuring health outcomes in children and adolescents is a challenge and is the subject of continuing research in our unit.

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Acknowledgements

This research was supported in part by a National Institutes of Health (NIH) Digestive Disease Core Center Grant no. P30 DK 34928 and a NIH Research Training Grant no. T32 DK 07471. We thank Carol Joubert for secretarial assistance. The publication of this article was supported in part by a grant from the Fonds de la recherche en santé du Québec. We would like to thank Marion Merrell Dow, Canada, for its sponsorship of the invited speakers' program.

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| CIM: October 1996 / MCE: octobre 1996
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