GI Consult: Crohn's Disease

Recent advances in the medical approach to this chronic inflammatory bowel disorder include new diagnostic tests and a new drug that may be capable of holding the disease in remission.

By Charles Maltz, MD

1.There have been considerable changes in both the diagnosis and treatment of Crohn's disease. What should I be aware of in the diagnosis of the disorder?

The diagnosis of Crohn's disease remains a clinical one in which confirmatory evidence is usually obtained radiologically or endoscopically. However, new serologic tests have become available recently to aid in the diagnosis of Crohn's disease and in differentiating Crohn's colitis from ulcerative colitis. Perinuclear antineutrophil cytoplasmic antibodies (pANCA) have been identified in some patients who have ulcerative colitis, and anti-Saccharomyces cerevisiae antibodies (ASCA) have been found in patients who have Crohn's disease. A combined test for these two types of antibodies, along with a related antibody marker, is 94% sensitive in differentiating inflammatory bowel disease from irritable bowel syndrome. When Crohn's colitis cannot be differentiated from ulcerative colitis, antibody testing may allow a definitive classification to be made.

2. What are the goals of therapy for Crohn's disease and how can they be achieved?

The objective is to induce and maintain remission, which may be achieved either medically or surgically; in some cases, the disorder resolves spontaneously. Before a treatment plan can be devised, the extent of the disease and the symptomatic areas must first be determined. For example, a patient with a localized small intestinal stricture with recurrent small bowel obstruction will more likely achieve remission with surgical resection than with any medical treatment. On the other hand, a patient who has multiple inflamed areas of the small or large bowel should receive medical treatment, and any abscesses should be drained.

The treatment of Crohn's disease is in many ways similar to that of AIDS. The disease process has many stages, and a number of new medications have appeared that produce or may produce toxic effects. Just as practitioners often must rely on input from specialists in the treatment of complex AIDS, clinicians would almost always benefit from the assistance of a gastroenterologist when treating Crohn's disease. Ideally, primary physicians would establish the diagnosis and then either refer their patients to a gastroenterologist or, if they desire, administer therapy with the assistance of the specialist.

3. Are steroids still the mainstay of treatment for Crohn's disease?

Steroids represent a Faustian bargain for both the clinician and patient. Although the drugs have been shown time and again to be effective in inducing clinical remission in patients who have active Crohn's disease, they are not effective in maintaining the remission. All steroid agents also produce adverse effects, specifically osteonecrosis of the hip, which are a considerable medicolegal concern for the prescribing practitioner. In addition, steroid therapy does not modify the disease-that is, the drugs do not significantly reduce or eliminate lesions in the bowel. Budesonide, a steroid metabolized on its first pass through the liver, has been tried and may have a role, but it is no panacea.

4. How useful are sulfasalazine and the 5-aminosalicylic acid (5-ASA) compounds?

Sulfasalazine is one of the oldest treatments for inflammatory bowel disease. The sulfa part of the compound attached to the active 5-ASA fragment prevents the medication from being absorbed in the proximal intestine, thereby allowing the 5-ASA fragment to be delivered to the colon. When colonic bacteria split the molecule, the 5-ASA compound is liberated.

Sulfasalazine has proved to be somewhat effective in treating Crohn's disease in the large bowel but not in the small bowel. The drug has been supplanted for the most part by forms of 5-ASA that do not contain sulfa but are protected by a wax matrix that delays the release of the drug until it reaches the distal small bowel or the colon. Because these new varieties do not contain the sulfa moiety, they produce fewer adverse effects, but they are more expensive. Balsalazide, a new 5-ASA medication, consists of 5-ASA linked to a nonsulfa fragment that liberates the 5-ASA portion in the colon. The 5-ASA compounds have not been effective in maintaining either surgically or medically induced remission.

5. Do topical treatments such as enemas and suppositories have a role in the management of Crohn's disease?

Enemas or suppositories containing 5-ASA or hydrocortisone can be helpful when the disease is limited to the rectum (proctitis) or sigmoid colon. However, in such cases the disorder is usually ulcerative colitis, not Crohn's disease.

6. Is there a place for antibiotics in the treatment of Crohn's disease?

Study results from 20 years ago have demonstrated metronidazole's usefulness in the temporary healing of perianal Crohn's disease. A more recent study found that in the treatment of mild to moderate Crohn's disease, ciprofloxacin at 1 gm/day was as effective as mesalamine at 4 gm/day. Further studies are ongoing, but antibiotics seem to be a reasonable alternative to steroids and are better tolerated.

7. Which medications have been effective in either allowing steroid dosage to be reduced or maintaining a remission?

Azathioprine, or its metabolite 6-mercaptopurine, has been demonstrated in several studies to be effective in maintaining remission of Crohn's disease. Although initial concerns about carcinogenic effects associated with azathioprine in clinical practice have not been substantiated, its delayed onset of action (approximately three months, on average) makes it unsuitable as a single-drug therapy for active Crohn's disease.

Methotrexate is not used as often, but as a remission-inducing agent, it provides a similar effect, at least in patients whose remission was induced with steroids and methotrexate. Finally, early results from trials of infliximab, an antitumor necrosis factor antibody, have indicated that it can maintain remission in patients who used the drug to induce the remission.

8. I know that a decreased granulocyte count is one of the adverse effects of azathioprine/6-mercaptopurine therapy, but a decreased white blood cell count is also associated with a favorable response. How do I determine the proper dosage?

Recent research has delineated the several competing pathways involved in the metabolism of azathioprine/ 6-mercaptopurine. One pathway leads to the active metabolite 6-thioguanine, and another leads to the toxic metabolite 6-methylmercaptopurine. In some cases, a genetic predisposition to the formation of the toxic metabolite has been noted. Investigation of the several pathways is still continuing, but the goal is to enable clinicians to provide safer, more effective dosages of azathioprine/6-mercaptopurine. In the meantime, for patients who do not appear to be responding to the drug, clinicians should monitor metabolite levels to determine whether an increased dosage is necessary.

9. Are there any new drug therapies for Crohn's disease?

Infliximab, a chimeric, part human (75%), part murine (25%), genetically engineered antibody designed to fight tumor necrosis factor, is the latest advance in the treatment of Crohn's disease and has generated a lot of excitement. The murine component was included because the mouse antibody, in addition to being more active than the human counterpart, is more immunogenic. Infliximab binds to tumor necrosis factor, causing it to become biologically inactive, and decreases the number of T-cells in the intestinal lamina propria as well.

The results of extensive clinical research in the use of infliximab as a treatment for Crohn's disease have shown that two thirds of patients demonstrated a response within four weeks of receiving a single 5 mg/kg infusion of the drug. In addition, among patients who were in remission at four weeks, the number who received infliximab was significantly greater than the number who received placebo.

One of the more striking features of infliximab is that it often promotes mucosal healing. Not even prednisone has demonstrated that benefit, even among patients who respond clinically to the drug. Researchers who have investigated the effect of infliximab on perianal and enterocutaneous fistulae have shown the drug to be particularly useful in the healing of those lesions. Unfortunately, the remission appears to be short-lived, and repeated doses of infliximab are required to maintain the remission.

Adverse effects from the drug do not appear to be severe, at least in the short term, and consist mainly of chest pain or rash that occurs during the infusion. Such effects can usually be controlled by slowing the rate of infusion and administering antihistamines or steroids. The infliximab-induced formation of antibodies, known as human antichimeric antibodies, appears to be more frequent among patients who undergo infusions at widely spaced intervals and among those who are not undergoing concomitant azathioprine/6-mercaptopurine therapy.

The rates of lymphoma and other grave complications associated with infliximab therapy have not been as high as expected. A higher rate of respiratory infection has been noted, as have reports of dormant tuberculosis being reactivated. The specific role of infliximab, as well as of human anti-tumor necrosis factor antibodies undergoing testing, is still evolving. Currently under evaluation are the immunosuppressant mycophenolate mofetil (used during transplant operations), growth hormone, thalidomide, and tacrolimus.