Pediatric ulcerative colitis: a review of the disease and current therapy.
Although the current treatment for UC provides risk for all patients, children have the additional risk of having their growth and development affected by agents such as corticosteroids. This article will provide a short background of UC and will discuss the current options for treatment in children. The agents currently being investigated in the adult population will also be introduced.
Epidemiology and Clinical Presentation of UC
Ulcerative colitis occurs in 2-4 per 100,000 children, and the median age of diagnosis for the disease is 10 years of age (Leichtner, Jackson, & Grand, 1996). The disease presents as a chronic inflammation of the mucosal lining of the colon and rectum. It is unclear to date if this disease is due to a genetic, autoimmune phenomenon in which the body is attacking its own mucosa, or if it is the result of factors such as diet or infection. Patients usually present with stools mixed with blood and mucus, rectal bleeding, fecal urgency and incontinence, and lower abdominal cramping. The cramping usually worsens with food and improves upon defacation. Weight loss and loss of appetite usually accompany these symptoms. Because of the pronounced inflammation that occurs, other systems of the body can also be affected. Children can present with arthralgias of the large joints (i.e., elbows), skin and/or mouth lesions, and ocular involvement. Liver disease and systemic vasculitis are rare complications that have been seen in severe disease. In general, due to malnutrition from poor oral intake and chronic diarrhea, children become susceptible to delays in growth, development, and sexual maturity. These delays, along with the symptoms that occur with UC, place children at a very high risk for periods of depression (Kirschner, 1996; Leichtner et al., 1996).
Complications of UC
In general there are two potential life-threatening manifestations of UC -- toxic megacolon and colorectal cancer. Toxic megacolon is an uncontrolled dilation of the colonic area, which has an increased incidence with the use of agents that slow gastric motility (i.e., loperamide [Immodium[R]], atropine with diphenoxylate [Lomotil[R]], opioid analgesics [morphine, demerol, codeine, etc.]). Colorectal cancer occurs in 30% of patients over 30 years of age that present with UC in childhood. This makes cancer screening of prime importance, especially once patients pass out of their teenage years (Kirschner, 1996; Leichtner et al., 1996).
Goals of Therapy
The goals of therapy for the treatment of a child are similar to those for an adult, with a high emphasis placed on maintaining the quality of life, relieving the symptoms of this disease, and providing adequate nutrition for growth and development. Maintenance of quality of life for a child, in general, means a life with few limitations, maintaining normal activities that school-age children are involved in, and a normal diet. An additional goal of therapy may also be to provide medical treatment that can extend the time to which surgery would have to be performed.
Sulfasalazine. Sulfasalazine (Azulfidine[R]) was one of the first medications to show benefit in patients with UC and today remains a first-line therapeutic option for patients with mild to moderate disease. Sulfasalazine is a compound that consists of an aminosalicylate group (5-ASA) hooked to a sulfur component. It is the 5-ASA portion that is thought to be responsible for the agents efficacy, whereas the sulfur component allows the drug to be delivered to the colon, its site of action. It is the sulfa component that is thought to produce the high side-effect profile that accompanies this agent's use (Kirschner, 1996).
The most common and predictable side effects are gastrointestinal upset (nausea, vomiting, diarrhea) and hypersensitivity reactions (itching, skin rash, photosensitivity). These side effects, which make the drug intolerable in some patients, can require the drug to be discontinued. Rare complications of bone marrow suppression, hepatotoxicity, and Steven Johnson's syndrome have also been observed. Both tablet and a compounded oral suspension formulation are available, and because of the predictable side-effect profile, it is usually titrated slowly during the first week to allow the patient to develop tolerance to the GI effects. The recommended starting dose is 5 mg/kg/day. The drug is titrated as tolerated during the first week to a maximum of 75 mg/kg/day (usual range is 40-60 mg/kg/day). For maintenance therapy the usual dose is 30 mg/kg/day. Sulfasalazine is given in multiple daily doses and should be administered after meals to minimize stomach upset. Patients and parents should be educated on the importance of adequate fluid intake and to be aware that a yellow-orange discoloration of the urine and/or skin can occur (Azulfidine EN-tabs[R] Official Package Circular, 1994; Kirschner, 1996).
Mesalamine and osalazine. Because of the high degree of intolerability seen with sulfasalazine, the quest for new agents that could deliver the effective drug component (5-ASA) without the sulfa component was begun. Mesalamine (Asacol[R], Pentasa[R], Rowasa[R]) is a product that consists of the 5-ASA portion of sulfasalazine, which is encapsulated and formulated to release in the colonic area of the GI tract (Brynskov & Norby Rasmussen, 1996). Osalazine is a product similar to sulfasalazine in that it lacks the sulfa component, but differs in its formulation in that it consists of two (5-ASA) molecules linked together by a bond that is cut by bacteria in the colon, thus releasing the product to its site of action (Dipentum[R] Official Package Circular, 1996).
Although these medications have a lower side effect profile than sulfasalazine, some of the same side effects are seen, but usually to a lesser degree (Leichtner et al., 1996). This indicates that it is not solely the sulfa component of sulfasalazine that is responsible for producing its side effects. Osalazine, in particular, has up to a 20% incidence of watery diarrhea that can require the drug to be discontinued (Dipentum[R] Official Package Circular, 1996).
These agents are also associated with a much higher cost of therapy as well, and there are some health professionals who believe that these expensive agents provide little benefit to the overall patient population (Sutherland, May, & Shaffer, 1993). Mesalamine and osalazine would be considered drugs of choice, however, in children who have mild to moderate UC as well as a history of a sulfa allergy and/or intolerance to sulfasalazine. Mesalamine is available in both capsule and tablet formulations. Suppositories and retention enemas (Rowasa[R]) are also available for patients with very limited disease. The recommended oral dose of mesalamine is 30-50 mg/kg/day, given in 2 or 3 divided doses after meals. Although the package information for osalazine does not recommend a pediatric dose, the dose used would be half of the recommended mesalamine dose (Kirschner, 1996).
Azathioprine and 6-Mercaptopurine. Azathioprine (AZA) and 6-Mercaptopurine (6-MP), immunosuppressant agents that are used most commonly in organ transplant patients and patients with rheumatoid arthritis, have also shown to be efficacious in inflammatory bowel disease. AZA and 6-MP are related entities in that AZA is simply a 6-MP product that has a molecule substitution that produces a slower, sustained release. 6-MP is thus the active metabolite of AZA.
Some health professionals feel that these two agents are similar enough to be interchangeable, whereas others feel they are two separate entities and practitioners should use one or the other. Regardless, there are no clinical trials available comparing the two agents, therefore the choice depends on physician preference. The use of either agent in UC is usually as an adjunct to steroids in patients with moderate to severe disease that is refractory to steroids alone. Azathioprine (Imuran[R]) and 6-MP are not considered therapeutic options in patients with mild disease. One of the negative aspects of the use of these agents is their time to response, which is reported to be a median of 3 months. Also, the use of these medications which suppress the immune system carry the risk of bone marrow suppression and increased risk of infection, although these effects are uncommon with the current recommended dose for this patient population.
Gastrointestinal complaints, liver toxicity, pancreatitis, and hypersensitivity reactions are also possible, usually presenting during the first few months of therapy. Because of possible bone marrow suppression, weekly CBC counts are recommended for the first few weeks of therapy and then less often thereafter when a consistent dose is used. Periodic liver function tests (LFT) should also be ordered to detect any signs of liver damage. The recommended doses that are used in children with UC are lower than those used in the transplant population (AZA = 1.5-2 mg/kg/day, 6-MP = 1-1.5 mg/kg/day). Both oral and intravenous formulations are available for administration (Imuran[R]) Official Package Circular, 1996; Kirschner, 1996; Leichtner et al., 1996).
Corticosteroids. Until the past decade corticosteroids had remained the final therapeutic option for severe disease, before surgery would be considered. The most extensively studied corticosteroids have been intravenous hydrocortisone or methylprednisolone for acute flares of the disease, and oral prednisone or prednisolone for maintenance of remission. Although their effect on the immune response make these agents effective treatment options, their side effect profile is of a particular concern, especially in the pediatric population. Along with the toxicities of Cushing syndrome, adrenal suppression, metabolic abnormalities, osteoporosis, and cataract formation, children are also at an increased risk for growth and developmental delays and more severe varicella infections when they occur (Spahn & Kamada, 1995).
Corticosteroids are beneficial in their rapid time to response, which usually occurs within 2 weeks from the start of treatment. Children can be treated with 1-2 mg/kg/day in two divided doses until remission is obtained. A single daily dose is then administered for 2-4 weeks, with a taper to an every other day dose, an eventual drug withdrawal over 2-3 months. It is crucial to have the drug decreased to an every other day dose as soon as clinically possible because of a decreased effect on growth and development with this schedule. Any oral product should be administered with food to minimize stomach upset from the medication. Also, nighttime doses should be avoided because insomnia can occur (Kirschner, 1996; Leichtner et al., 1996; Spahn & Kamada, 1995).
Patients and parents need to be educated about possible increased appetite and weight gain, along with the possible risks of steroid use. Parents need to also be aware of the importance of reporting any chickenpox exposure immediately, if the child has yet to be immunized through active infection or immunization.
Cyclosporine. Until the current decade, patients were considered surgical candidates once steroids had failed, sometimes despite nutritional status and emotional instability. Within the past decade, cyclosporine, a potent immunosuppressant widely used in the transplant population, has shown efficacy in children and adults with UC. Although there are a limited number of clinical trials currently published, data have shown that as high as 80% of children unresponsive to steroids can have a clinical remission of their disease induced by cyclosporine (Lichtiger et al., 1994; Neoral[R] Official Package Circular, 1996; Treem et al., 1995).
Although cyclosporine usually produces a rapid time to remission within 1 week, relapse, requiring colectomy or a retrial with the agent, appears to be high within the first year (Brynskov, & Norby Rasmussen, 1996; Treem et al., 1995). Patients can be treated with either intravenous or oral cyclosporine, although some limited data exist indicating that there is a lower absorption of oral formulations in patients with UC compared to a normal population (Atkinson et al., 1983).
Patients started on intravenous cyclosporine can be switched to the oral formulations at any time, but usually are switched once the symptoms of the disease begin to subside. There are two different oral formulations of cyclosporine available -- Sandimmune[R] and Neoral[R]. Neoral[R] is a microencapsulated cyclosporine formulation that has a more predictable absorption than Sandimmune[R]. Although both formulations contain cyclosporine they should not be interchanged, and health professionals should confirm with the patient which product they have been prescribed. In general, Neoral[R] is the preferred product and has been quickly replacing Sandimmune[R].
Blood will be drawn to determine the concentration of cyclosporine, which appears to require a range similar to that of the transplant population. The most common side effects requiring patient monitoring include renal dysfunction, tremor, hirsuitism, hypertension, and gum hyperplasia. Both Sandimmune[R] and Neoral[R] are given in two divided oral doses on a consistent schedule in relation to time of day and meals. In reference to the preparation and administration of Neoral[R] oral solution, it is recommended to dilute with apple or orange juice to make it more palatable. Milk should not be mixed with Neoral[R] as it produces an unpalatable mixture (Kirschner, 1996; Leichtner et al., 1996; Neoral[R] Official Package Circular). Grapefruit juice inhibits the metabolism of cyclosporine, increases blood levels, and may increase the risk for toxicity. There are instances in which grapefruit juice may be used in conjunction with cyclosporine in some institutions in an attempt to manage cost by allowing lower cyclosporine doses to be given. Patients should be asked how they have been instructed to take their cyclosporine. Those patients who have not been instructed to take it with grapefruit juice should be strictly advised to avoid this beverage during their therapy.
Investigational Agents Currently Studied in Adults
Current clinical research in the adult patients with UC includes such agents as anti-TNF antibodies, fish oil supplements, transdermal nicotine patches, fractionated heparin, 5-lipoxygenase inhibitors (i.e., zileuton, MK-501), and new classes of steroids with potentially decreased side effect profiles (Evans et al., 1996; Hawkey et al., 1997; Lofberg et al., 1996; Roberts et al., 1997; Sandborn et al., 1997; Stenson et al., 1992). There are hopes that the use of these agents could be valuable supplements to therapy with minimal added toxicities. It would be beneficial if lower doses of cyclosporine or steroids could be used or if the new agents could possibly replace them in the future. Pediatric patients would greatly benefit from the development and use of agents that would limit their need for steroid exposure. Optimism exists that the 21st century will be an era of new, effective alternatives for UC that can be applied to the pediatric and adult medicine.
Although there are a number of medications available for the treatment of UC, the medications used depend mainly on the severity of disease. The risk versus benefit issue is of key importance in this population because of the risk of serious toxicities with the available medications. Although surgery may be the final alternative for many patients, the available medications, if prescribed, administered, and monitored appropriately, can maintain quality of life and extend the time to needed surgery. Current studies are focusing on new classes of agents with potentially lower side effect profiles. With all of the current research underway, it becomes crucial to refer to the available literature for updated guidelines for treating children with UC.
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(Imuran[R]) (azathioprine) Official Package Circular (1996). Research Triangle Park, NC: Glaxo Wellcome.
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Lofberg, R., Danielsson, A., Suhr, O., Nilsson, A., Schioler, R., Nyberg, A., Hutlcrantz, R., Kollberg, B., Gillberg, R., Willen, R., Persson, T., & Salde, L. (1996). Oral budesonide versus prednisolone in patients with active extensive and left-sided ulcerative colitis. Gastroenterology, 110(6), 2000-2002.
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Roberts, W.G., Simon, T.J., Berlin, R.G., Haggitt, R.C., Snyder, E.S., Stenson, W.F., Hanauer, S.B., Reagan, J.E., Caglioa, A., Tanaka, W.K., Simon, S., & Berger, M.C. (1997). Leukotrienes in ulcerative colitis: Results of a multicenter trial of a leukotriene biosynthesis inhibitor, MK-591. Gastroenterology, 112(3), 725-732.
Sandborn, W.J., Tremaine, W.J., Offord, K.P., Lawson, G., Peterse, G.T., Batts, K.P., Croghan, I.T., Dale, L.C., Schroeder, D.R., & Hurt, R.D. (1997). Transdermal nicotine for mildly to moderately active ulcerative colitis. A randomized, double-blind, placebo controlled trial. Annals of Internal Medicine, 126(5), 364-371.
Spahn, J.D., & Kamada, A.K. (1995). Special considerations in the use of glucocortocoids in children. Pediatrics in Review, 16(7), 266-272.
Stenson, W.F., Cort, D., & Rodgers, J.(1992). Dietary supplementation with fish oil in ulcerative colitis. Annals of Internal Medicine, 116, 609-614.
Sutherland, L.R., May, G.R., & Shaffer, R.A. (1993). Sulfasalazine revisited: A meta-analysis of 5-aminosalicylic acid in the treatment of ulcerative colitis. Annals of Internal Medicine, 118, 504-509.
Treem, W.R., Cohen, J., Davis, P.M., Justinich, C.J., & Hyams, J.S. (1995). Cyclosporine for the treatment of fulminant ulcerative colitis in children. Diseases of the Colon and Rectum, 38(5), 474-479.
Laurie A. Orloski is a PharmD student, University of Pittsburgh, Pittsburgh, PA.
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|Author:||Orloski, Laurie A.|
|Date:||Mar 1, 1998|
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