Medical Therapies for IBD

Gary R. Lichtenstein, M.D

Of the many exciting recent developments in inflammatory bowel diseases (IBD), medical therapies have received the most attention and funding. Before 1990, only a few medications were available: corticosteroids, sulfasalazine, metronidazole, azathioprine, and 6-mercaptopurine. Since then, there has been a dramatic increase both in research and medications to treat IBD.

The primary goals of medical therapy for IBD are: providing symptomatic relief (inducing remission); improving quality of life; maintaining adequate nutritional status; suppressing inflammation in the intestine; and reducing the number of disease flare-ups (maintaining remission). The ideal medication would be effective, safe (have few side effects), simple to administer, and affordable. As this overview shows, however, IBD treatments must be tailored to each person's needs. It is important that you and your physician discuss the best course of therapy.

AMINOSALICYLATES

Aminosalicylates were the first class of drug shown to be beneficial in IBD. The first aminosalicylate to be widely used was sulfasalazine (Azulfidine^®). To make this drug, sulfapyridine is bonded to an aspirin-like compound known as 5-aminosalicylate (5-ASA). 5-ASA, which has anti-inflammatory properties, is the active portion of the drug. The sulfapyridine portion, which carries 5-ASA to the intestine, is responsible for most of the drug's side effects (headache, nausea, etc.).

To reduce these side effects, researchers developed newer oral drugs that deliver the 5-ASA molecule without using the sulfapyridine carrier. Examples are olsalazine (Dipentum^®) and mesalamine (Asacol^®, Pentasa^®). Up to 90 percent of people who cannot tolerate sulfasalazine are able to take other mesalamine products. There are several ways to deliver 5-ASA to the bowel:

· Enema formulations (Rowasa^®), which allow mesalamine to be applied directly to the left colon (up to the splenic flexure), or Rowasa suppositories, which allow direct application from the rectum up to the sigmoid colon;

· A foam formulation, which delivers mesalamine to the colon (not yet FDA-approved and is not available in the U.S.);

· Drugs that link 5-ASA to a molecule that is less toxic than sulfapyridine (e.g., balsalazide, which has not yet been FDA-approved and is not available in the U.S.);

· Oral, delayed-release preparations that deliver 5-ASA directly to the small intestine and colon (e.g., Pentasa) or to the ileum and/or the colon (e.g., Asacol). This ensures that 5-ASA will be active where inflammation is located.

In patients with mild to moderately active ulcerative colitis, sulfasalazine is as effective as the mesalamine products, when used in equal doses. But most trials have shown that the newer 5-ASAs have significantly fewer side effects. The dose of oral aminosalicylates needed to achieve remission is typically the same dose needed to maintain remission. The use of any of the aminosalicylates, including sulfasalazine, for severely active ulcerative colitis has not been adequately tested.

Topical mesalamine (Rowasa enemas) is effective in mild to moderate left-sided colitis, with clinical responses occurring in up to 80 percent of patients who are treated once a day. A similar proportion of ulcerative proctitis patients will respond to mesalamine suppositories (dosed twice daily). A combination of mesalamine enemas and pills is more effective than pills alone. Remission has been maintained with mesalamine suppositories in people with proctitis (colitis limited to the rectum and beginning of the colon), or enemas in people with left-sided colitis.

The data are less clear for the use of aminosalicylates in Crohn's disease. Early trials did not demonstrate that these drugs achieved remission in people with active Crohn's. But two recent trials showed that a higher dose (four grams of Pentasa, and 3.2 grams of Asacol) was beneficial, suggesting that high doses are required for effectiveness. Similarly, mesalamine pills have been shown to maintain remission. This beneficial effect is most marked in patients who have recently undergone surgery. Mesalamine delayed or prevented the disease from recurring after bowel resection. Sulfasalazine is effective when Crohn's disease is limited to the colon.

CORTICOSTEROIDS

Corticosteroids (prednisone, medrol, methylprednisolone, hydrocortisone, etc.) have been the mainstay of treatment for acute flare-ups since these drugs were first used for IBD in the 1950s. In mild to moderately active disease, steroid pills are usually effective. In severe IBD, intravenously administered steroids are often necessary. Rectally administered steroids (enemas, suppositories, or foams) are helpful to people with left-sided colitis. They also may be used, with other therapies, in patients with more widespread disease that begins at the rectum.

Twenty to 30 percent of patients with acute ulcerative colitis or Crohn's will not respond to corticosteroids (regardless of dose or route of administration). In addition 30-40 percent of patients have steroid-dependent disease; they are unable to taper off steroids without experiencing flare-ups of IBD. Based on data from controlled studies, steroids have not been beneficial for maintaining remission in either disease. Further, the anti-inflammatory effects of steroids often are counterbalanced by their side effects. For example, osteoporosis (bone loss) frequently occurs after long-term use. Thus, physicians often choose safer medications (e.g., mesalamine products, antibiotics) as initial therapy. Physicians employ several strategies to reduce the risk of developing side effects: tapering off steroids rapidly, yet carefully; every-other-day dosing; rectally applied cortico-steroids (enemas, foam, or suppositories); and rapidly metabolized corticosteroids (such as budesonide, described below, which has not yet been approved by the FDA and is not available in the U.S.). To help prevent osteoporosis, many physicians routinely prescribe multivitamins (containing vitamin D) and calcium supplements. Hormone replacement therapy also has been shown to be effective in preventing osteoporosis in women with IBD. Bisphospho-nates, compounds that have been shown to inhibit bone loss, have not yet been fully tested in IBD patients on steroids, but are effective in people with other diseases that require long-term steroid therapy.

Budesonide is the most notable and best-evaluated of the rapidly metabolized corticosteroids. These drugs are quickly cleared from the bloodstream, thus reducing most side effects. Specially formulated budesonide pills release the drug in the ileum and colon. This therapy has been shown to be effective in treating active Crohn's that involves these areas. In fact, recent data showed budesonide pills to be as effective as traditional steroids, with fewer side effects. One study suggested that a dose of 6 mg of budesonide may maintain remission in Crohn's disease; however, further studies are needed. Budesonide and the other rapidly metabolized corticosteroids are not yet approved by the FDA, and the long-term effects (such as osteoporosis and other corticosteroid-related side effects) are not known.

ANTIBIOTICS

In IBD, antibiotics are used as a primary therapy and to treat infection. It should be noted, however, that infections that affect the small intestine (e.g., Salmonella, Shigella, Clostridium difficile) can lead to subsequent flare-ups of underlying IBD.

Metronidazole (Flagyl^®) is the most extensively studied antibiotic. As a primary therapy for active Crohn's, this drug has been shown to be superior to placebo and equal to sulfasalazine, particularly when Crohn's affects the colon. It also may delay the recurrence of Crohn's for the first two to three years after a person undergoes ileal resection (surgical removal of a diseased portion of intestine, and reconnection of the remaining intestine). In more than 50 percent of individuals treated, metronidazole can be very effective in managing perineal Crohn's (disease involving the pelvic area). The drug's effectiveness for maintaining remission in Crohn's has yet to be rigorously tested in large, placebo-controlled trials. Metronidazole has not been shown to be beneficial in active ulcerative colitis, and the consensus is that it has no role in maintaining remission in ulcerative colitis.

Large trials have failed to demonstrate that antibiotics have value in treating severe ulcerative colitis. Severely ill patients, however, may benefit from taking broad-spectrum antibiotics (i.e., those that fight a broad range of bacteria), before these persons are considered unresponsive to all medical therapy. Metronidazole also has proven effective in patients who develop pouchitis after ileoanal anastomosis surgery. This surgery is an ostomy alternative, in which an internal pouch is formed from the patient's ileum, eliminating the need to wear an external appliance. The pouch sometimes becomes severely inflamed.

Ciprofloxacin (Cipro^®) is a second antibiotic that is commonly used to treat active Crohn's, heal fistulas (abnormal channels connecting the intestine to another organ or to the skin), and improve anal symptoms. A recent controlled study suggests that a six-month course of ciprofloxacin pills will help achieve and maintain remission in people with ulcerative colitis who are using mesalamine and corticosteroids.

Early data suggest that clarithromycin (Biaxin^®) also may be a promising drug for treating Crohn's. This antibiotic is used against tuberculosis-like organisms, but also is active against normal intestinal bacteria. The role of such an organism (e.g., Mycobacterium paratuberculosis) in causing IBD, particularly Crohn's, has long been proposed. Evidence has failed to universally demonstrate that these minute organisms appear in patients' tissues, however, and people with IBD do not consistently respond to antimycobacterial agents.

IMMUNOMODULATORS

The use of immunosuppressant agents, such as azathioprine (Imuran^®) and 6-mercaptopurine (6-MP, Purinethol^®), has emerged as a tool in treating both active and inactive IBD. These drugs block activation of the immune system, which plays a prominent role in causing the inflammatory symptoms of IBD.

Azathioprine and 6-MP have been used to treat patients with active Crohn's since the late 1960s. They are considered appropriate for individuals who:

· have disease that does not respond to treatment with aminosalicylates, antibiotics, or corticosteroids;

· have steroid-dependent disease;

· have experienced side effects with corticosteroids;

· have perineal disease that does not respond to antibiotics;

· have fistulas;

· require maintenance of remission.

The majority of studies suggest that these agents are significantly more effective than placebo for active Crohn's disease. The use of these drugs, however, is limited by their slow onset of action (three to six months for full effect). Azathioprine and 6-MP also have reduced relapses in Crohn's patients who are in remission. These medications are taken orally; intravenous administration does not speed up their effectiveness.

The role of azathioprine and 6-MP in ulcerative colitis is emerging. Although their slow onset of action usually dictates that they be combined with a second drug (such as corticosteroids), these medications have proven to be superior to placebo for active colitis in controlled trials. There has been one controlled trial regarding the use of azathioprine for maintaining remission in colitis, and this also demonstrated significant benefit. Because azathioprine and 6-MP have fewer side effects than corticosteroids, they are particularly useful in sparing IBD patients from steroid use. A recent CCFA-sponsored study showed that, when compared to placebo pills, the use of Pentasa or 6MP reduced the rate of recurrence of Crohn's disease after surgical resection of the small bowel.

Azathioprine and 6-MP have lower long-term toxicity than corticosteroids. Approximately 10 percent of patients cannot tolerate these drugs. Side effects can include allergic-type reactions, bone marrow toxicity, infections, inflammation of the pancreas, inflammation of the liver (rare), and lymphoma (very rare, and it is unclear if this is related to medication use). Suppression of the bone marrow can lead to abnormally low levels of the various types of blood cells that the marrow produces. Therefore, regular monitoring of blood counts is recommended during treatment. Some physicians advocate using 6-MP or azathioprine at doses that purposely lower the white blood cell count to below-normal levels, but further testing is needed to determine if this is a more effective approach.

Cyclosporine A (Sandimmune^®, Neoral^®) is an immunosuppressant that has been extensively used in organ transplantation, and has recently been used for treatment of IBD. It has the advantage of a more rapid onset of action (one to two weeks) than azathioprine and 6-MP (three to six months). The drug is effective in patients with active Crohn's disease (who are also receiving steroids) only when given at high doses. Cyclosporine also has been given to people with fistulas that failed to close when they were taking other medications. Although the fistulas closed in a number of these patients, most reopened when the cyclosporine was stopped. Fewer than one-third of the fistulas remained closed, even if 6-MP or azathioprine were administered.

Cyclosporine has been more successful in treating severe ulcerative colitis. Eighty percent of patients who were hospitalized for severe ulcerative colitis, and who faced surgery despite high doses of intravenous steroids, responded to intravenous cyclosporine. Early reports indicated that as many as 70 percent of these people will require surgery within one to two years anyway after a six-month course of cyclosporine alone. But more recent data suggest that the majority will avoid surgery and stay in remission with the use of 6-MP or azathioprine. This suggests that cyclosporine A can be used in two ways in ulcerative colitis: as a "bridge" to curative elective surgery, which can be performed when the patient is well enough to undergo the procedure; or to control the disease until other inummomodulators, such as 6-MP, have enough time to begin working.

Cyclosporine enemas have been tested in patients with left-sided ulcerative colitis, with mixed results. In general, it is believed that cyclosporine enemas will not be an effective alternative for most patients.

Finally, cyclosporine's benefits must be balanced against its numerous potential serious side effects, which include kidney damage, inflammation of the liver, high blood pressure, seizures, increased susceptibility to infections, and increased risk of lymphomas. Its use is reserved for seriously ill patients or for fistulas that have not improved with the other therapies. Also, cyclosporine is used for a maximum of six months.

Methotrexate is a medication that has been used to effectively treat rheumatoid arthritis and psoriasis. Due to this success, an open trial was conducted in 14 Crohn's patients and seven ulcerative colitis patients who had not responded to other medical therapies. More than 70 percent of the patients improved. Although none of the colitis patients achieved remission, more than one-third of the Crohn's patients did. Methotrexate may work more rapidly than azathioprine and 6-MP, which may require three to six months before symptoms lessen. In this study, most patients who responded to the drug improved markedly by eight to 10 weeks. In a larger, placebo-controlled trial, people with chronically active Crohn's received weekly methotrexate injections. Corticosteroids could be reduced or eliminated while inducing remission in these patients. But long-term trials are still needed to evaluate effectiveness.

Methotrexate pills have not been as effective as injections. Indeed, they are not effective in ulcerative colitis. A recent controlled study in people with chronic, active Crohn's suggested that methotrexate is moderately better than 6-MP and placebo. In these patients, the corticosteroid dose was reduced, general well-being improved, and abdominal pain decreased. Currently, studies are evaluating the various ways to administer methotrexate--either by injections into the muscle, under the skin, or in pill form.

Toxicity is an important issue that limits methotrexate use in many patients. Side effects are most commonly "flu-like symptoms," nausea, vomiting, fatigue and diarrhea, although serious side effects involving the bone marrow, liver, and, rarely, the lungs also have been reported. Methotrexate causes fetal death and congenital abnormalities. Thus, if either partner is receiving methotrexate, pregnancy must be avoided for least three months after the drug is stopped (for men), or after one full ovulation cycle (for women). If a woman gets pregnant while on the medication, termination of the pregnancy is advised, if this is consistent with her beliefs. Women should not nurse while taking methotrexate.

BIOLOGIC THERAPY

Biologic therapy has come to the forefront for treating a multitude of disorders. In August 1998, the FDA approved a biologic therapy for Crohn's disease. Infliximab (Remicade) is a chimeric (75 percent human, 25 percent mouse protein) monoclonal antibody. This antibody blocks the production of tumor necrosis factor-alpha (TNF-alpha), a cytokine (chemical) that is released by cells in the immune system. Studies show that TNF-alpha plays a role in inflammation. In people with active Crohn's disease, there is increased production of TNF-alpha in the intestinal lining, and increased excretion of this cytokine in stools.

Infliximab was given as a single two-hour intravenous infusion to more than 100 Crohn's patients with moderate to severe disease that resisted other therapies. Two-thirds of these patients improved and one-third achieved remission. A second study involved nearly 100 patients with fistulas; some had multiple fistulas. In two-thirds of the patients, most of the fistulas closed; in more than half, all of the fistulas closed. The patients in this second study had received three infusions of either infliximab or placebo over a six-week period. Both studies suggested that a single infusion of the drug was effective in the short-term treatment of moderate to severe, previously resistant Crohn's disease, and that three infusions given in a six-week period were effective in closing most fistulas.

Based on these studies, the FDA has approved infliximab for moderately to severely active Crohn's in individuals who have had an inadequate response to conventional therapy, and for reducing the number of draining enterocutaneous fistulas (channels to the skin). Additionally, preliminary data suggest that the beneficial effect of infliximab persists when the medication is reinfused every two months. A large prospective analysis of reinfusion is being done.

At the present time, the effectiveness and possible side effects of infliximab following long-term use are unclear. The possibility of allergic reactions to repeated infusions, and even the appearance of malignancies, are being evaluated. Treatment should be reserved for patients who do not respond to conventional therapies

MEDICATIONS UNDER INVESTIGATION

There has been significant progress in the arena of organ transplantation, with the development of new medications that prevent rejection of transplanted organs. Two of these agents, tacrolimus (FK506) and mycophenolate mofetil, are now being tested in people with IBD. Tacrolimus has been used successfully to treat patients suffering from acute attacks of IBD who had not responded to steroids. In a preliminary report, seven of 11 patients achieved remission rapidly. Similarly, mycophenolate mofetil, in combination with corticosteroids, has been shown to be effective for chronic, active Crohn's that has not responded to other therapies.

Antisense oglionucleotides also have shown some benefit in a small study of 20 Crohn's patients who were steroid-dependent. This agent targets intercellular adhesion molecule-1 (ICAM-1), a molecule that boosts and prolongs the inflammatory reaction in the immune system of people with IBD. By blocking the genetic messages that instruct ICAM-1, antisense therapy prevents production of this molecule. This therapy is currently under further analysis and investigation.

Other treatments involving cytokines are being assessed. Some involve injections of cytokines that suppress inflammation; others are antibodies that block cytokines that promote inflammation (e.g., anti-TNF-alpha). Preparations under study include interleukin-10 and interleukin-11 in people with active Crohn's disease. Similarly, trials will begin with antibodies targeted against interleukin-12 in Crohn's patients who need steroids and are not responding to other forms of treatment.

Currently, the Bowman-Birk Protease Inhibitor is undergoing clinical trials in ulcerative colitis. This agent has been shown to prevent cancer in animals. In small uncontrolled and controlled trials, heparin, a blood thinner, has demonstrated effectiveness in ulcerative colitis patients who are unresponsive to corticosteroids. Researchers are not certain why heparin may be effective in IBD; it is possible that the compound interferes with cytokines that cause inflammation.

Short-chain fatty acids (SCFAs), such as butyrate, are nutrients in the lining of the colon. SCFAs are produced as the colon digests complex carbohydrates. Research has shown that patients with ulcerative colitis may not be able to produce these necessary nutrients in their intestinal lining. Several small clinical trials have evaluated the effectiveness of SCFA enemas. A recent review of these trials noted that 35 of 41 patients who did not respond to other therapies benefited from these enemas. Preliminary data suggest that SCFAs may also benefit patients who do not respond to first-line treatments for pouchitis.

Omega-3 fatty acids, such those found in fish oils, may have an anti-inflammatory effect. These acids may alter the levels of leukotrienes, compounds that play a role in inflammation. Early studies have shown that omega-3 fatty acids benefit people with active ulcerative colitis, though they appear not to be helpful in maintaining remission. One controlled trial has demonstrated that they effectively maintain remission in Crohn's.

Smoking appears to be protective in ulcerative colitis and harmful in Crohn's disease. In light of these findings, the use of nicotine gum and patches has been attempted in colitis. Nicotine has been shown to be effective for the acute treatment of active colitis; however, its effectiveness for maintaining remission is not well established and remains controversial. The primary difficulty is patients' inability to tolerate the side effects of nicotine.

Probiotic agents, or beneficial types of bacteria (e.g., Lactobacilli), are being investigated after promising results in animal models. These bacteria can replace more toxic bacteria, and also release protective chemicals. In a study of patients with recurrent pouchitis, a combination of eight probiotic organisms was quite effective in preventing relapse after treatment with antibiotics.

SUMMARY

In general, aminosalicylate pills, enemas, and suppositories remain the first line of therapy for controlling symptoms in people with active ulcerative colitis or Crohn's disease, as well as for maintaining remission. Additionally, it has been demonstrated that oral aminosalicylates can prevent Crohn's from recurring after surgery. Oral corticosteroids are usually reserved for those individuals who fail to respond to aminosalicylates or who require rapid control of symptoms. For patients who are not responding to standard approaches or who require continuous corticosteroids, 6-MP or azathioprine should be considered. These agents are effective for achieving and maintaining remission in both Crohn's and ulcerative colitis. If these cannot be used successfully, methotrexate should be considered, especially in Crohn's. In cases of active, severe ulcerative colitis that does not respond to intravenous corticosteroids, intravenous cyclosporine A may be considered, with addition of 6-MP or azathioprine to possibly reduce the risk for colectomy. Antibiotics may be beneficial in certain clinical situations. Infliximab is appropriate for those with Crohn's who fail to respond to conventional medical therapy or who have fistulous disease. There is no standard regimen for managing all persons with IBD. The symptoms, course of disease, and prognosis vary considerably among people with Crohn's disease and ulcerative colitis. Management depends upon an accurate diagnosis. This typically requires endoscopic, radiologic, and pathologic (analysis of tissues) observations. A successful treatment strategy employs not only the medical therapies discussed in this review, but careful attention to detail, and judicious use of common sense.

Finally, surgical consultants experienced in the management of IBD are vital to proper management. Though beyond the scope of this review, surgical intervention is integral to the care of people with IBD, and knowing when surgery is indicated and how to operate on these diseases is of paramount importance to both the immediate and long-term outcomes. At the present time, surgical resection of the colon is the only cure for ulcerative colitis. Although the majority of patients with Crohn's disease recur after resection, recent trials demonstrate that postoperative recurrences can be diminished by continuous preventive treatment with aminosalicylates, 6-MP, or metronidazole.

As active partners in the management of your illness, you and your doctor should discuss, in detail, all of the medical and surgical options available to you.

GARY R. LICHTENSTEIN, M.D. Associate Professor of Medicine Director, Inflammatory Bowel Disease Center Division of Gastroenterology, Department of Medicine Hospital of the University of Pennsylvania, University of Pennsylvania School of Medicine University of Pennsylvania Health System
Philadelphia, PA

This article first appeared in the Spring, 1999 issue of CCFA's Foundation Focus, which is sent to our members. If you would like a copy, or information on joining CCFA, as a member, please call our national office at 800-932-2423.

Date Posted: June 04, 1999  

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