Crohn’s Disease - DRUG THERAPY

Posted by Alex

Aminosalicylates

Sulfasalazine

Introduced into clinical medicine in the early 1940s, sulfasalazine (Azulfidine)* has since become a mainstay in the therapy for inflammatory bowel disease. Controlled trials have shown its efficacy for active Crohn’s disease involving the colon, and although the studies have not uniformly demonstrated the drug’s benefit in isolated ileitis, there appears to be a subset of patients with Crohn’s ileitis who benefit from its use. It has not been shown to be useful in maintaining remission in Crohn’s disease and in preventing recurrence after operation. In any patient with mild to moderately active Crohn’s disease, the drug should be considered and given initially at a dose of 500 mg orally twice daily with advancement if tolerated to 3 to 4 grams per day. Folic acid, 1 mg per day, should be added because sulfasalazine may interfere with dietary folate absorption. Responses are usually seen within 4 weeks, and the drug should be continued at the level that achieved the clinical response for 4 to 6 months. If relapse occurs quickly on stopping of the agent, then reinstitution and long-term maintenance at a dose of 3 to 4 grams per day should be considered.

Adverse effects with sulfasalazine may be seen in as many as 20% of patients receiving the drug. Anorexia, nausea, and dyspepsia may be overcome by lowering the dosage and/or using an enteric-coated preparation. The complete blood count should be monitored carefully during the initial few weeks of therapy, because neutropenia and hemolysis may occur and be reversed by lowering the dose. Although a process of gradual desensitization may overcome minor allergic reactions such as fever and rash, almost all patients experiencing such a reaction will be switched to one of the new oral aminosalicylate agents. Serious adverse reactions such as agranulocytosis, severe hemolysis, pancreatitis, hepatitis, pneumonitis, pericarditis, neuropathy, alteration of sperm counts and morphologic features with reversible male infertility, and exacerbation of colitis mandate stopping the drug.

Sulfasalazine links sulfapyridine to 5-aminosalicylic acid (5-ASA) by an azo bond. The azo bond is first reduced by intestinal bacteria with release of the two moieties. The sulfapyridine is largely absorbed and excreted in the urine and accounts for most of the drug’s toxicity. The 5-ASA component stays largely within the lumen of the intestinal tract and is excreted with the feces. Observations on the distribution of the metabolites of sulfasalazine led to investigations of the 5-ASA moiety itself, in both topical and oral formulations.

Topical 5-Aminosalicylic Acid Agents

Controlled trials confirmed the hypothesis that 5-ASA might be the active moiety in sulfasalazine. Moreover, 80 to 90% of patients intolerant of or allergic to sulfasalazine tolerate the 5-ASA derivative. Although not well studied in controlled trials in Crohn’s disease, the enema and suppository forms of 5-ASA, known generically as mesalamine (Rowasa),* should be used for patients with Crohn’s disease involving the distal colon or rectum alone. A response is usually seen within 6 weeks, at which point maintenance therapy can be attempted on an every-other-night or every-third-night basis.

Oral 5-Aminosalicylic Acid Agents

For the patient with small bowel Crohn’s disease or with colonic disease above the rectosigmoid, oral 5-ASA agents can be considered an alternative to sulfasalazine. Available oral forms include mesalamine (Pentasa)* encapsulated in ethylcellulose microspheres, mesalamine (Asacol)* coated with an acrylic resin that dissolves at pH greater than 6, and olsalazine (Dipentum) that links 5-ASA to itself by an azo bond requiring bacterial metabolism as in sulfasalazine. Although controlled trials in active disease have given conflicting results, it is reasonable to consider oral mesalamine as a first-line agent for any patient with mild to moderately active Crohn’s ileitis, ileocolitis, or colitis, using the drugs in doses up to 4.8 grams per day. If remission is achieved, long-term maintenance therapy at a dosage of 3 grams per day should be considered because there is evidence to suggest the benefit of these drugs in preventing relapse. Their use should also be considered in the patient undergoing resection and anastomosis because doses of 3 grams per day have been shown to delay endoscopic and clinical recurrence up to 3 years.

Although 5-ASA agents are well tolerated, adverse effects have been reported and include serum sickness-like reactions, pericarditis, pneumonitis, exacerbation of colitis, and nephritis. Because of nephritis, periodic monitoring of the urine sediments and the blood urea nitrogen and creatinine concentrations should be done.

Antibiotics

Metronidazole (Flagyl)* is the best studied of the antimicrobial agents and has been shown in controlled trials to be effective in active Crohn’s colitis and ileocolitis but not in isolated ileitis. A largely uncontrolled experience suggests utility in perianal disease as well. Although there are no trials investigating its use in relapse prevention in Crohn’s disease, a 3-month course of the drug after ileal resection and anastomosis was more effective than placebo at preventing endoscopic and clinical recurrence up to 1 year.

For patients with colonic disease who are unresponsive to or intolerant of one of the aminosalicylates, metronidazole should be considered at a dose of 10 mg per kg per day. A therapeutic response is usually seen in 2 to 4 weeks, and the drug can be continued for 3 to 6 months, at which point it is usually stopped. Patients with severe perianal disease, however, often require the agent for indefinite periods and at least initially may require doses of 20 mg per kg per day. Side effects are common and include nausea, anorexia, tongue discomfort, and paresthesias. Paresthesias are usually dose dependent and reversible but may be prolonged.

Great enthusiasm has recently emerged for other antimicrobial agents as primary therapy for Crohn’s disease, although they are less well tested. The history of the use of broad-spectrum antibiotics, including cephalosporins and tetracycline, in the management of active Crohn’s disease goes back 25 years, but new agents such as ciprofloxacin (Cipro)* and clarithromycin (Biaxin)* have rekindled interest in their use. Open trials have suggested impressive efficacy for ciprofloxacin alone and in combination with metronidazole* in active Crohn’s ileitis and colitis. A small controlled trial and one large open trial gave similar results for clarithromycin. Clarithromycin may work through its effects on an atypical mycobacterium reported to be causally important in Crohn’s disease. Other trials of multiple antituberculous agents have given conflicting results in both active and remitted Crohn’s disease. However, further controlled data are awaited with regard to these agents. It is currently reasonable to consider the use of ciprofloxin, clarithromycin, and metronidazole as primary therapy; response is usually seen within 2 to 3 weeks. For responders, continuation of therapy for up to 6 months may provide prolonged remissions.

Corticosteroids

For patients not responding to or intolerant of the preceding measures, and for those presenting with severe manifestations of disease activity, corticosteroids need to be considered. Hydrocortisone enemas (Cortenema) can be used in patients with active proctosigmoiditis; foam preparations (Cortifoam) are available for those with proctitis. One preparation should be given every night for 2 to 3 weeks and then tapered to every other night during the subsequent 2 weeks.

For patients with mild to moderate symptoms and with colonic disease proximal to the rectosigmoid, and for those with small bowel involvement, prednisone 40 to 60 mg per day is initiated and continued at the initial dose for 10 days to 2 weeks. If a desired response is obtained, the dosage should be tapered by 5 mg every 7 to 10 days. Once remission is achieved, there is no benefit of continued steroid therapy as prophylaxis against relapse of disease activity. However, some patients with mild smoldering activity as the dose is tapered may benefit from continued low-dose therapy in the range of 5 to 10 mg per day. Alternate-day steroid therapy should be considered for such patients, in whom the risks of such long-term steroid therapy have to be weighed against the benefit and treatment alternatives.

More rapidly metabolized forms of steroids have emerged as efficacious in short-term trials with considerably fewer side effects than standard preparations. Budesonide enemas have proved to be as effective as hydrocortisone and 5-ASA enemas in ulcerative proctosigmoiditis but have not been formally studied in distal Crohn’s colitis. A slow-release oral preparation of budesonide has been shown to be more effective than placebo and as effective as oral prednisolone in active Crohn’s ileitis with or without right colon involvement. Preparations are now being studied in more distal disease. Although budesonide taken chronically by patients in remission delayed the onset of relapse of activity, the relapse rate after 1 year was no different in patients taking or not taking the drug. The ultimate role of this agent, not yet approved for use in the United States, is not clear, but its high benefit/side effect ratio suggests that it may replace standard steroids in the management of some patients with active disease.

Parenteral corticosteroids are indicated for patients with severe symptoms of Crohn’s disease requiring hospitalization. Such patients in addition usually receive parenteral nutrition and broad-spectrum antibiotics. Intravenous hydrocortisone (Solu-Cortef) 300 mg per day, or the less salt-retaining and less potassium-wasting preparations methylprednisolone (Solu-Medrol) or prednisolone 48 to 60 mg per day, should be administered. Some prefer intravenous adrenocorticotropic hormone, 120 units* per 24 hours as a continuous infusion, although no benefit of this agent over standard preparations for Crohn’s disease patients has been shown. For patients responsive to such therapy, oral prednisone should be substituted for the parenteral agent initially at a dose of 40 to 60 mg per day with subsequent gradual tapering.

Immunomodulators

6-Mercaptopurine (Purinethol) and azathioprine (Imuran)* have emerged as important agents in the management of Crohn’s disease patients dependent on steroids and refractory to other agents and with nonhealing fistulas. In more seriously ill patients, their use adjunctively with steroids as initial therapy should be considered. The drugs can be used interchangeably and should be started at 50 mg per day with advance to 1.5 mg per kg per day for 6-mercaptopurine and 2.5 mg per kg per day for azathioprine, depending on the clinical response and effects on bone marrow. Careful monitoring of a complete blood count will usually avoid problems with bone marrow depression, although some believe that achievement of mild leukopenia may be necessary to obtain a maximal benefit of the drugs. The mean onset of action is 3 months; some patients do not show benefit for 6 to 9 months. The use of azathioprine intravenously to induce a more rapid response is under study.

Ten percent of patients will experience irreversible adverse hypersensitivity reaction including fever, rash, pancreatitis, and hepatitis. An increased risk for malignant neoplasm, especially lymphoma, has been of concern with use of these drugs, but studies of large numbers of patients with inflammatory bowel disease receiving 6-mercaptopurine and azathioprine suggest that the risk is minimal and may not be increased above that of patients with Crohn’s disease not receiving the drugs. The patient should attempt to stop the agents before conception, although the emerging experience is that the risk for fetal abnormalities in those becoming pregnant and carrying to term is extremely low.

These drugs are effective at maintaining remission in Crohn’s disease. Their long-term use for a period of at least 4 years should be considered in those patients who have flare-ups frequently while receiving 5-ASA agents, who are steroid dependent, and who have had recurrence early after resection.

For patients refractory to or intolerant of 6-mercaptopurine or azathioprine, methotrexate* has emerged as a useful alternative. The drug may be especially useful at inducing remission in patients who are steroid dependent. Its long-term efficacy as a remission agent is under study. Administration intramuscularly at a dose of 25 mg per week should be initiated and continued for 3 months in those responding, and an attempt to convert to oral administration can be made with gradual reduction of dosage. However, in patients with prior small bowel surgery, the variability in absorption after oral administration may mandate its continued use intramuscularly. Folic acid at 1 mg per day should be administered concomitantly to avoid side effects. Adverse reactions include leukopenia, abnormalities of liver function, and a hypersensitivity pneumonitis. Liver biopsy should be performed to exclude the development of fibrosis in those who have taken a cumulative dose of 1500 mg.

For patients refractory to these therapies and for those with nonhealing fistulas, cyclosporine (Sandimmune)* therapy should be considered. In hospitalized patients with severe active disease or those with refractory fistulas, the drug should be used intravenously as a continuous infusion at a dose of 2 to 4 mg per kg per 24 hours with careful monitoring of blood levels. A response can be expected within 7 to 10 days. Once a response is achieved, oral administration of the drug at a dose of 6 to 8 mg per kg per day should be tried. For less severely ill patients with refractory disease, initial therapy with cyclosporine orally can be attempted. Adverse effects may include hirsutism, paresthesias, seizures, hypertension, irreversible renal dysfunction, and predisposition to infection. Long-term studies of low-dose oral cyclosporine have not shown efficacy over placebo for Crohn’s disease patients, so the use of this drug as a remission agent cannot be recommended.

Modifications of the immune system with interferon* and T lymphocyte apheresis have been of use in patients with refractory disease, although their use has not been supported by placebo-controlled trials. A promising alternative may emerge from studies of monoclonal antibodies directed at T cells and proinflammatory cytokines. An initial short-term placebo-controlled trial of anti-tumor necrosis factor-alpha showed great promise, but more studies will be needed before this class of agents becomes available for routine use.

Nonspecific Antidiarrheal Drugs and Cholestyramine

For patients with mild chronic symptoms, agents such as loperamide (Imodium), diphenoxylate with atropine (Lomotil), codeine, and deodorized tincture of opium may be of use. Given their addictive potential, except for loperamide, their use should be limited, and they should be avoided as drugs to control pain in patients with acute severe symptoms because of the risk for precipitating ileus. Fiber in various forms including bran and psyllium (Citrucel, Metamucil, Perdiem) may be of use in decreasing watery diarrhea and in treating those with constipation alternating with diarrhea.

Cholestyramine (Questran) can be of major benefit in the patient with nonstenosing ileitis or in one who has had an ileal resection. In such patients, watery diarrhea due to bile acid malabsorption can usually be controlled with 1 scoop or packet (4 grams) in a glass of juice taken once or twice daily.