What Is Crohn's Disease?
Crohn's disease is a chronic inflammatory disease of the intestines. It primarily causes ulcerations of the small and large intestines, but can affect the digestive system anywhere from the mouth to the anus. It is named after the physician who described the disease in 1932. It also is called granulomatous enteritis or colitis, regional enteritis, ileitis, or terminal ileitis. Crohn's disease is related closely to another chronic inflammatory condition that involves only the colon called ulcerative colitis. Together, Crohn's disease and ulcerative colitis are frequently referred to as inflammatory bowel disease (IBD). Ulcerative colitis and Crohn's disease have no medical cure. Once the diseases begin, they tend to fluctuate between periods of inactivity (remission) and activity (relapse). Men and women are equally affected. IBD most commonly begins during adolescence and early adulthood, but it also can begin during childhood and later in life. Crohn's disease tends to be more common in relatives of patients with Crohn's disease. It also is more common among relatives of patients with ulcerative colitis.
Causes Of Crohn's Disease
The cause of Crohn's disease is unknown. Some scientists suspect that infection by certain bacteria, such as strains of mycobacterium, may be the cause of Crohn's disease. To date, however, there has been no convincing evidence that the disease is caused by infection. Crohn's disease is not contagious. Although diet may affect the symptoms in patients with Crohn's disease, it is unlikely that diet is responsible for the disease. Activation of the immune system in the intestines appears to be important in IBD. The immune system is composed of immune cells and the proteins that these immune cells produce. Normally, these cells and proteins defend the body against harmful bacteria, viruses, fungi, and other foreign invaders. Activation of the immune system causes inflammation within the tissues where the activation occurs. (Inflammation is an important mechanism of defense used by the immune system.) Normally, the immune system is activated only when the body is exposed to harmful invaders. In patients with IBD, however, the immune system is abnormally and chronically activated in the absence of any known invader. The continued abnormal activation of the immune system results in chronic inflammation and ulceration. The susceptibility to abnormal activation of the immune system is genetically inherited. Thus, first degree relatives (brothers, sisters, children, and parents) of patients with IBD are more likely to develop these diseases. Recently a gene called NOD2 has been identified as being associated with Crohn's disease. This gene is important in determining how the body responds to some bacterial products. Individuals with mutations in this gene are more susceptible to developing Crohn's disease.
How does Crohn's disease affect the intestines?
In the early stages, Crohn's disease causes small, scattered, shallow, crater-like areas (erosions) on the inner surface of the bowel. These erosions are called aphthous ulcers. With time, the erosions become deeper and larger, ultimately becoming true ulcers (which are deeper than erosions) and causing scarring and stiffness of the bowel. As the disease progresses, the bowel becomes increasingly narrowed, and ultimately can become obstructed. Deep ulcers can puncture holes in the wall of the bowel, and bacteria from within the bowel can spread to infect adjacent organs and the surrounding abdominal cavity. When Crohn's disease narrows the small intestine to the point of obstruction, the flow of the contents through the intestine ceases. Sometimes, the obstruction can be caused suddenly by poorly-digestible fruit or vegetables that plug the already-narrowed segment of the intestine. When the intestine is obstructed, digesting food, fluid and gas from the stomach and the small intestine cannot pass into the colon. The symptoms of small intestinal obstruction then appear, including severe abdominal cramps, nausea, vomiting, and abdominal distention. Obstruction of the small intestine is much more likely since the small intestine is much narrower than the colon to begin with. Deep ulcers can puncture holes in the walls of the small intestine and the colon, and create a tunnel between the intestine and adjacent organs. If the ulcer tunnel reaches an adjacent empty space inside the abdominal cavity, a collection of infected pus (an abdominal abscess) is formed. Patients with abdominal abscesses can develop tender abdominal masses, high fevers, and abdominal pain. When the ulcer tunnels into an adjacent organ, a channel (fistula) is formed. The formation of a fistula between the intestine and the bladder (enteric-vesicular fistula) can cause frequent urinary tract infections and the passage of gas and feces during urination. When a fistula develops between the intestine and the skin (enteric-cutaneous fistula), pus and mucous emerge from a small painful opening on the skin of the abdomen. The development of a fistula between the colon and the vagina (colonic-vaginal fistula) causes gas and feces to emerge through the vagina. The presence of a fistula from the intestines to the anus (anal fistula) leads to a discharge of mucous and pus from the fistula's opening around the anus.
How is Crohn's disease different from ulcerative colitis?
While ulcerative colitis causes inflammation only in the colon (colitis) and/or the rectum (proctitis), Crohn's disease may cause inflammation in the colon, rectum, small intestine (jejunum and ileum), and, occasionally, even the stomach, mouth, and esophagus. The patterns of inflammation in Crohn's disease are different from ulcerative colitis. Except in the most severe cases, the inflammation of ulcerative colitis tends to involve the superficial layers of the inner lining of the bowel. The inflammation also tends to be diffuse and uniform. (All of the lining in the affected segment of the intestine is inflamed.) Unlike ulcerative colitis, the inflammation of Crohn's disease is concentrated in some areas more than others and involves layers of the bowel that are deeper than the superficial inner layers. Therefore, the affected segment(s) of bowel in Crohn's disease often is studded with deeper ulcers with normal lining between these ulcers.
The symptoms of Crohn's disease:
Common symptoms of Crohn's disease include abdominal pain, diarrhea, and weight loss. Less common symptoms include poor appetite, fever, night sweats, rectal pain, and rectal bleeding. The symptoms of Crohn's disease are dependent on the location, the extent, and the severity of the inflammation. The different subtypes of Crohn's disease and their symptoms are:
Complications of Crohn's disease may be related or unrelated to the inflammation within the intestine (i.e., intestinal or extra-intestinal). Intestinal complications of Crohn's disease include obstruction and perforation of the small intestine, abscesses (collections of pus), fistulae, and intestinal bleeding. Massive distention or dilatation of the colon (megacolon), and rupture (perforation) of the intestine are potentially life-threatening complications. Both generally require surgery, but, fortunately, these two complications are rare. Recent data suggest that there is an increased risk of cancer of the small intestine and colon in patients with long-standing Crohn's disease. Extra-intestinal complications involve the skin, joints, spine, eyes, liver, and bile ducts. Skin involvement includes painful red raised spots on the legs (erythema nodosum) and an ulcerating skin condition generally found around the ankles called pyoderma gangrenosum. Painful eye conditions (uveitis, episcleritis) can cause visual difficulties. Arthritis can cause pain, swelling, and stiffness of the joints of the extremities. Inflammation of the low back (sacroiliac joint arthritis) and of the spine (ankylosing spondylitis) can cause pain and stiffness of the spine. Inflammation of the liver (hepatitis) or bile ducts (primary sclerosing cholangitis) also can occur. Sclerosing cholangitis causes narrowing and obstruction of the ducts draining the liver and can lead to yellow skin (jaundice), recurrent bacterial infections, and liver cirrhosis with liver failure. Sclerosing cholangitis with liver failure is one of the reasons for performing liver transplantation. Sclerosing cholangitis frequently is complicated by the development of cancer of the bile ducts.
Diagnosis Of Crohn's Disease:
The diagnosis of Crohn's disease is suspected in patients with fever, abdominal pain and tenderness, diarrhea with or without bleeding, and anal diseases. Laboratory blood tests may show elevated white cell counts and sedimentation rates, both of which suggest infection or inflammation. Other blood tests may show low red blood cell counts (anemia), low blood proteins, and low body minerals, reflecting loss of these elements due to chronic diarrhea. Barium x-ray studies can be used to define the distribution, nature, and severity of the disease. Barium is a chalky material that is visible by x-ray and appears white on x-ray films. When barium is ingested orally (Upper GI Series)it fills the intestine and pictures (x-rays) can be taken of the stomach and the small intestines. When barium is administered through the rectum (Barium Enema), pictures of the colon and the terminal ileum can be obtained. Barium x-rays can show ulcerations, narrowing, and, sometimes, fistulae of the bowel. Direct visualization of the rectum and the large intestine can be accomplished with flexible viewing tubes (colonoscopes). Colonoscopy is more accurate than barium x-rays in detecting small ulcers or small areas of inflammation of the colon and terminal ileum. Colonoscopy also allows for small tissue samples (biopsies) to be taken and sent for examination under the microscope to confirm the diagnosis of Crohn's disease. Colonoscopy also is more accurate than barium x-rays in assessing the degree (activity) of inflammation. Computerized Axial Tomography (CAT or CT) scanning is a computerized x-ray technique that allows imaging of the entire abdomen and pelvis. It can be especially helpful in detecting abscesses. Most recently, video capsule endoscopy has been added to the list of diagnostic tests for diagnosing Crohn's disease. For video capsule endoscopy, a capsule containing a minature video camera is swallowed. As the capsule travels through the small intestine, it sends video images of the lining of the small intestine to a receiver carried on a belt at the waist. The images are downloaded and then reviewed on a computer. The value of video capsule endoscopy is that it can identify the early, mild abnormalities of Crohn's disease. Video capsule endoscopy may be particularly useful when there is a strong suspicion of Crohn's disease but the barium x-rays are normal. (Barium x-rays are not as good at identifying early, mild Crohn's disease.) Video capsule endoscopy should not be performed in patients who have obstruction of the small intestine. The capsule may get stuck behind the obstruction and make the obstruction worse. Doctors usually also are reluctant to perform video-capsule endoscopy for the same reason in patients who they suspect of having small intestinal strictures (narrowed segments of small intestine that can result from prior surgery, prior radiation, or chronic ulceration, for example, from Crohn's disease).There is also a theoretical concern for electrical interference between the capsule and implanted cardiac pacemakers and defibrillators; however, so far in a small number of patients with pacemakers or defibrillators who have undergone video capsule endoscopy there have been no problems.
Treatments Of Crohn's Disease:
The symptoms and severity of Crohn's disease vary among patients. Patients with mild or no symptoms may not need treatment. Patients whose disease is in remission (where symptoms are absent) also may not need treatment. There is no medication that can cure Crohn's disease. Patients with Crohn's disease typically will experience periods of relapse (worsening of inflammation) followed by periods of remission (reduced inflammation) lasting months to years. During relapses, symptoms of abdominal pain, diarrhea, and rectal bleeding worsen. During remissions, these symptoms improve. Remissions usually occur because of treatment with medications or surgery, but occasionally they occur spontaneously, that is, without any treatment. Since there is no cure for Crohn's disease, the goals of treatment are to 1) induce remissions, 2) maintain remissions, 3) minimize side effects of treatment, and 4) improve the quality of life. Treatment of Crohn's disease and ulcerative colitis with medications is similar though not always identical. Medications for treating Crohn's disease include 1) anti-inflammatory agents such as 5-ASA compounds, corticosteroids, topical antibiotics, 2) immuno-modulators, 3)other medications.
Anti-inflammatory medications that decrease intestinal inflammation are analogous to arthritis medications that decrease joint inflammation. Different types of anti-inflammatory medications used in the treatment of Crohn's disease are:
5-aminosalicylic acid (5-ASA)), also called mesalamine, is similar chemically to aspirin. Aspirin has been used for many years for treating arthritis, bursitis, and tendonitis (conditions of tissue inflammation). Aspirin, however, is not effective in treating Crohn's disease and ulcerative colitis, and even may worsen the inflammation. On the other hand, 5-ASA can be effective in treating Crohn's disease and ulcerative colitis if the drug can be delivered topically onto the inflamed intestinal lining. For example, Rowasa is an enema containing 5-ASA that is effective in treating inflammation in the rectum. However, the enema solution cannot reach high enough to treat inflammation in the upper colon and the small intestine. Therefore, for most patients with Crohn's disease involving both the ileum (distal small intestine) and colon, 5-ASA must be taken orally. If pure 5-ASA is taken orally, however, most of the 5-ASA would be absorbed in the stomach and the upper small intestine, and very little 5-ASA would reach the ileum and colon. To be effective as an oral agent in treating Crohn's disease, 5-ASA has to be modified chemically to escape absorption by the stomach and the upper intestines.
Azulfidine (sulfasalazine) was the first modified 5-ASA compound used in the treatment of Crohn's colitis and ulcerative colitis. It has been used successfully for many years to induce remissions among patients with mild to moderate ulcerative colitis. Azulfidine also has been used for prolonged periods for maintaining remissions. Sulfasalazine consists of a 5-ASA molecule linked chemically to a sulfapyridine molecule. (Sulfapyridine is a sulfa antibiotic). Connecting the two molecules together prevents absorption by the stomach and the upper intestines. When Azulfidine reaches the ileum and the colon, the bacteria that normally are present break the link between the two molecules. After breaking away from 5-ASA, sulfapyridine is absorbed into the body and later eliminated in the urine. Most of the active 5-ASA, however, is available within the terminal ileum and colon to treat the colitis. Most of the side effects of Azulfidine are due to the sulfapyridine molecule. These side effects include nausea, heartburn, headache, anemia, skin rashes, and, in rare instances, hepatitis and kidney inflammation. In men, Azulfidine can reduce the sperm count. The reduction in sperm count is reversible, and the count usually becomes normal after the Azulfidine is discontinued or changed to a different 5- ASA compound. Because the newer 5-ASA compounds (e.g., Asacol and Pentasa) do not have the sulfapyridine component and have fewer side effects than Azulfidine, they are being used more frequently in treating Crohn's disease and ulcerative colitis.
Asacol is a tablet consisting of the 5-ASA compound surrounded by an acrylic resin coating. (Asacol is sulfa-free). The resin coating prevents the 5-ASA from being absorbed as it passes through the stomach and the small intestine. When the tablet reaches the terminal ileum and the colon, the resin coating dissolves, and the active 5-ASA drug is released. Asacol is effective in inducing remissions in patients with mild to moderate ulcerative colitis. It also is effective when used in the longer term to maintain remissions. Some studies have shown that Asacol also is effective in treating Crohn's ileitis and ileo-colitis, as well as in maintaining remission in patients with Crohn's disease. The recommended dose of Asacol for inducing remissions is two 400 mg tablets three times daily (a total of 2.4 grams a day). At least two tablets of Asacol twice daily (1.6 grams a day) is recommended for maintaining remission. Occasionally, the maintenance dose is higher. As with Azulfidine, the benefits of Asacol are dose-related. If patients do not respond to 2.4 grams a day of Asacol, the dose frequently is increased to 3.6 - 4.8 grams a day to induce remission. If patients fail to respond to the higher doses of Asacol, then other alternatives such as corticosteroids are considered.
Pentasa is a capsule consisting of small spheres containing 5-ASA. It is sulfa-free. As the capsule travels down the intestines, the 5-ASA inside the spheres is released slowly into the intestine. Unlike Asacol, the active drug 5-ASA in Pentasa is released into the small intestine as well as the colon. Therefore, Pentasa can be effective in treating inflammation in the small intestine and is currently the most commonly used 5-ASA compound for treating mild to moderate Crohn's disease in the small intestine. Patients with Crohn's disease occasionally undergo surgery to relieve small intestinal obstruction, drain abscesses, or remove fistulae. Usually, the diseased portions of the intestines are removed during surgery. After successful surgery, patients can be free of disease and symptoms (in remission) for a while. In many patients, however, Crohn's disease eventually returns. Pentasa helps maintain remissions and reduces the chances of the recurrence of Crohn's disease after surgery. In the treatment of Crohn's ileitis or ileocolitis, the dose of Pentasa usually is four 250 mg capsules four times daily (a total of 4 grams a day). For maintenance of remission in patients after surgery, the dose of Pentasa is between 3-4 grams daily.
Dipentum (olsalazine) is a capsule in which two molecules of 5-ASA are joined together by a chemical bond. In this form, the 5-ASA cannot be absorbed from the stomach and intestine. Intestinal bacteria are able to break apart the two molecules, releasing the active, individual 5-ASA molecules into the intestine. Since intestinal bacteria are more abundant in the ileum and colon, most of the active 5-ASA is released in these areas. Therefore, Dipentum is most effective for disease that is limited to the ileum or colon. Although clinical studies have shown that Dipentum is effective for maintenance of remission in ulcerative colitis, up to 11% of patients experience diarrhea when taking Dipentum. Because of this, Dipentum is not often used. The recommended dose of Dipentum is 500 mg twice a day.
Colazal (balsalazide) is a capsule in which the 5-ASA is linked by a chemical bond to another molecule that is inert (without effect on the intestine) and prevents the 5-ASA from being absorbed. This drug is able to travel through the intestine unchanged until it reaches the end of the small bowel (terminal ileum) and colon. There, intestinal bacteria break apart the 5-ASA and the inert molecule, releasing the 5-ASA. Because intestinal bacteria are most abundant in the terminal ileum and colon, Colazal is used to treat inflammatory bowel disease predominantly localized to the colon. Colazal recently has been approved by the FDA for use in the United States.
Side effects of oral 5-ASA compounds
The 5-ASA compounds have fewer side effects than Azulfidine and also do not reduce sperm counts. They are safe medications for long-term use and are well-tolerated. Patients allergic to aspirin should avoid 5-ASA compounds because they are similar chemically to aspirin. Rare kidney and lung inflammation has been reported with the use of 5-ASA compounds. Therefore, 5-ASA should be used with caution in patients with kidney disease. It also is recommended that blood tests of kidney function be done before starting and periodically during treatment. Rare instances of worsening of diarrhea, cramps, and abdominal pain, at times accompanied by fever, rash, and malaise, may occur. This reaction is believed to represent an allergy to the 5-ASA compound.
5-ASA rectal medications (Rowasa Canasa)
Rowasa is 5-ASA in enema form. 5-ASA by enema is most useful for treating ulcerative colitis involving only the distal colon since the enema easily can reach the inflamed tissues of the distal colon. Rowasa also is used in treating Crohn's disease in which there is inflammation in and near the rectum. Each Rowasa enema contains 4 grams of 5-ASA. The enema usually is administered at bedtime, and patients are encouraged to retain the enema through the night. The enema contains sulfite and should not be used by patients with sulfite allergy. Otherwise, Rowasa enemas are safe and well-tolerated. Canasa is 5-ASA in suppository form. It is used for treating ulcerative proctitis. Each suppository contains 500 mg of 5-ASA and usually is administered twice daily. Both enemas and suppositories have been shown to be effective in maintaining remission in patients with ulcerative colitis limited to the distal colon and rectum. Corticosteroids Corticosteroids (e.g., prednisone, prednisolone, hydrocortisone, etc.) have been used for many years to treat patients with moderate to severe Crohn's disease and ulcerative colitis and to treat patients who fail to respond to 5-ASA. Unlike 5-ASA, corticosteroids do not require direct contact with the inflamed intestinal tissues to be effective. Oral corticosteroids are potent anti-inflammatory medications. After absorption, corticosteroids exert prompt anti-inflammatory actions throughout the body, including the intestines. Consequently, they are used in treating Crohn's disease anywhere in the small intestine, as well as ulcerative and Crohn's colitis. In critically ill patients, intravenous corticosteroids (such as hydrocortisone) can be given in the hospital. For patients with proctitis, hydrocortisone enemas (Cortenema) can be used to deliver the corticosteroid directly to the inflamed tissue. By using the corticosteroid topically, less of it is absorbed into the body and the frequency and severity of side effects are lessened (but not eliminated) as compared with systemic corticosteroids. Corticosteroids are faster-acting than 5-ASA, and patients frequently experience improvement in their symptoms within days of beginning them. Corticosteroids, however, do not appear to be useful in maintaining remission in Crohn's disease and ulcerative colitis or in preventing the return of Crohn's disease after surgery.
Side effects of corticosteroids
The frequency and severity of side effects of corticosteroids depend on the dose and duration of their use. Short courses of corticosteroids, for example, usually are well-tolerated with few and mild side effects. Long-term use of high doses of corticosteroids usually produces predictable and potentially serious side effects. Common side effects include rounding of the face (moon face), acne, increased body hair, diabetes, weight gain, high blood pressure, cataracts, glaucoma, increased susceptibility to infections, muscle weakness, depression, insomnia, mood swings, personality changes, irritability, and thinning of the bones (osteoporosis) with fractures of the spine. Children receiving corticosteroids experience stunted growth. The most serious complication from long term corticosteroid use is aseptic necrosis of the hip joints. Aseptic necrosis is a condition in which there is death and degeneration of the hip bone. It is a painful condition that can ultimately lead to the need for surgical replacement of the hip. Aseptic necrosis also has been reported in the knee joints. It is not known how corticosteroids cause aseptic necrosis. The estimated incidence of aseptic necrosis among corticosteroid users is 3-4%. Patients on corticosteroids who develop pain in the hips or knees should report the pain to their doctors promptly. Early diagnosis of aseptic necrosis with cessation of corticosteroids might decrease the severity of the aseptic necrosis and the need for hip replacement surgery. Prolonged use of corticosteroids can depress the ability of the body's adrenal glands to produce cortisol (a natural corticosteroid necessary for proper functioning of the body). Therefore, abruptly discontinuing corticosteroids can cause symptoms due to a lack of natural cortisol (a condition called adrenal insufficiency). Symptoms of adrenal insufficiency include nausea, vomiting, and even shock. Withdrawing corticosteroids too quickly also can produce symptoms of joint pain, fever, and malaise. Therefore, when corticosteroids are discontinued, the dose usually is tapered gradually rather than stopped abruptly. Even after corticosteroids are discontinued, the adrenal glands' ability to produce cortisol can remain depressed from months up to two years. The depressed adrenal glands may not be able to produce increased amounts of cortisol to help the body handle the stress of accidents, surgery, and infections. Therefore, patients need additional corticosteroids during stressful situations to avoid developing adrenal insufficiency. Because corticosteroids are not useful in maintaining remission in ulcerative colitis and Crohn's disease, and because they have predictable and potentially serious side effects, they should be used for the shortest possible length of time.
Proper use of corticosteroids
Once the decision is made to use systemic corticosteroids, treatment usually is initiated with prednisone, 40-60 mg daily. The majority of patients with Crohn's disease respond with an improvement in symptoms within a few weeks. Once symptoms have improved, prednisone is reduced by 5-10 mg per week until a dose of 20 mg per day is reached. The dose then is reduced at a slower rate until the corticosteroid is discontinued. Gradually reducing corticosteroids not only minimizes the symptoms of adrenal insufficiency, it also reduces the chances of an abrupt recurrence of inflammation. Many doctors use 5-ASA compounds and corticosteroids together. In patients who achieve remission with corticosteroids, 5-ASA compounds often are continued alone to maintain remission. In patients whose symptoms return corticosteroids are slowly being reduced, the dose of corticosteroids is increased slightly to control the symptoms. Once the symptoms are under control, the reduction of corticosteroids can resume at a slower pace. Unfortunately, many patients who require corticosteroids to induce remissions become corticosteroid dependent. These patients consistently develop symptoms whenever the corticosteroid dose falls below a certain level. In such patients who are corticosteroid dependent as well as in patients who are unresponsive to corticosteroids and other anti-inflammatory medications, immuno-modulator medications or surgery must be considered. The management of patients who are corticosteroid dependent or patients with severe disease that responds poorly to medications is complex. Doctors who are experienced in treating ulcerative colitis and Crohn's disease and in using immuno-modulators should evaluate these patients.
Prevention of osteoporosis
Long-term use of corticosteroids can cause osteoporosis. Calcium is very important in the formation and maintenance of healthy bones. Corticosteroids decrease the absorption of calcium from the intestine and increase the loss of calcium from the kidneys. Increasing dietary calcium intake is important but alone cannot halt corticosteroid-induced osteoporosis. To prevent or minimize osteoporosis, management of patients on long-term corticosteroids should include:
Budesonide (Entocort EC) is a new type of corticosteroid for treating Crohn's disease. Like other corticosteroids, budesonide is a potent anti-inflammatory medication. Unlike other corticosteroids, however, budesonide acts only via direct contact with the inflamed tissues (topically) and not systemically. As soon as budesonide is absorbed into the body, the liver converts it into inactive chemicals. Therefore, for effective treatment of Crohn's disease, budesonide, like topical 5-ASA, must be brought into direct contact with the inflamed intestinal tissue. Budesonide capsules contain granules that allow a slow release of the drug into the ileum and the colon. In a double-blind multicenter study (published in 1998), 182 patients with Crohn's ileitis and/or Crohn's disease of the right colon were treated with either budesonide (9 mg daily) or Pentasa (2 grams twice daily). Budesonide was more effective than Pentasa in inducing remissions while the side effects were similar to Pentasa. In another study comparing the effectiveness of budesonide with corticosteroids, budesonide was not better than corticosteroids in treating Crohn's disease but had fewer side effects. Because budesonide is broken down by the liver into inactive chemicals, it has fewer side effects than systemic corticosteroids. It also suppresses the adrenal glands less than systemic corticosteroids. Budesonide will be available as an enema for the treatment of proctitis. Budesonide has not been shown to be effective in maintaining remission in patients with Crohn's disease. If used long-term, budesonide also may cause some of the same side effects as corticosteroids. Because of this, the use of budesonide should be limited to short-term treatment for inducing remission. Most budesonide is released in the terminal ileum, it will have its best results in Crohn's disease limited to the terminal ileum. It is not known whether budesonide is effective in treating patients with ulcerative colitis, and it is currently not recommended for the treatment of ulcerative colitis.
Antibiotics for Crohn's disease
Antibiotics such as metronidazole (Flagyl) and ciprofloxacin (Cipro) have been used for treating Crohn's colitis. Flagyl also has been useful in treating anal fistulae in patients with Crohn's disease. The mechanism of action of these antibiotics in Crohn's disease is not well understood.
Metronidazole (Flagyl) is an antibiotic that is used for treating several infections caused by parasites (e.g., giardia) and bacteria (e.g., infections caused by anaerobic bacteria, and vaginal infections). It is effective in treating Crohn's colitis and is particularly useful in treating patients with anal fistulae. Chronic use of metronidazole in doses higher than 1 gram daily can be associated with permanent nerve damage (peripheral neuropathy). The early symptoms of peripheral neuropathy are numbness and tingling in the fingertips, toes, and other parts of the extremities. Metronidazole should be stopped promptly if these symptoms appear. Metronidazole and alcohol together can cause severe nausea, vomiting, cramps, flushing, and headache. Patients taking metronidazole should avoid alcohol. Other side effects of metronidazole include nausea, headaches, loss of appetite, a metallic taste, and, rarely, a rash.
Ciprofloxacin (Cipro) is another antibiotic used in the treatment of Crohn's disease. It can be used in combination with metronidazole.
Summary of anti-inflammatory medications
Immuno-modulators are medications that affect the body's immune system. The immune system is composed of immune cells and the proteins that they produce. These cells and proteins serve to protect the body against harmful bacteria, viruses, fungi, and other foreign invaders. Activation of the immune system causes inflammation within the tissues where the activation occurs. (Inflammation is, in fact, an important mechanism used by the immune system to defend the body.) Normally, the immune system is activated only when the body is exposed to foreign invaders. In patients with Crohn's disease and ulcerative colitis, however, the immune system is abnormally and chronically activated in the absence of any known invader. Immuno-modulators decrease tissue inflammation by reducing the population of immune cells and/or by interfering with their production of proteins. Decreasing the activity of the immune system with immuno-modulators increases the risk of infections; however, the benefits of controlling moderate to severe Crohn's disease usually outweigh the risks of infection due to weakened immunity. Examples of immuno-modulators are 6-mercaptopurine (6-MP), azathioprine, methotrexate, and infliximab.
Azathioprine (Imuran) and 6-mercaptopurine (6-MP, Purinethol)
Azathioprine (Imuran) and 6-mercaptopurine (6-MP, Purinethol) are medications that weaken the body's immune system by reducing the population of a class of immune cells called lymphocytes. Azathioprine and 6-MP are related chemically. (Actually, azathioprine is converted into 6-MP within the body.) In high doses, these two drugs have been useful in preventing rejection of transplanted organs and in treating leukemia. In low doses, they have been used for many years to treat patients with moderate to severe Crohn's disease and ulcerative colitis. Azathioprine and 6-MP are increasingly recognized by doctors as valuable drugs in treating Crohn's disease and ulcerative colitis. Some 70% of patients with moderate to severe disease will benefit from these drugs. Azathioprine and 6-MP are used primarily in the following situations:
Side effects of azathioprine and 6-MP
Side effects of azathioprine and 6-MP include increased vulnerability to infections, inflammation of the liver (hepatitis) and the pancreas (pancreatitis), and bone marrow toxicity (interference with the formation of cells that circulate in the blood). The goal of treatment with azathioprine and 6-MP is to lower the body's production of certain types of white blood cells (lymphocytes) in order to decrease the inflammation in the intestines; however, lowering the number of lymphocytes may increase vulnerability to infections. For example, in a group of patients with severe Crohn's disease unresponsive to standard doses of azathioprine, raising the dose of azathioprine helped to control the disease, but two patients developed cytomegalovirus (CMV) infection. (CMV typically infects individuals with weakened immune systems such as patients with AIDS and cancer patients receiving chemotherapy). Azathioprine and 6-MP can induce inflammation of the liver (hepatitis) and pancreas (pancreatitis). Pancreatitis typically causes severe abdominal pain and sometimes vomiting. Pancreatitis due to azathioprine or 6-MP occurs in 3%-5% of patients, usually during the first several weeks of treatment. Patients who develop pancreatitis should not receive either of these two medications again. Azathioprine and 6-MP also suppress the bone marrow. The bone marrow is where the red blood cells, white blood cells, and platelets are made. Actually, a slight reduction in the white cell count during treatment is desirable since it suggests that the dose of azathioprine or 6-MP is high enough to have an effect; however, excessively low red or white blood cell counts indicates bone marrow toxicity. Therefore, patients on azathioprine or 6-MP should have periodic blood counts (usually every two weeks initially and then every 3 months during maintenance) to monitor the effect of the drugs on the bone marrow. Patients on long-term, high dose azathioprine to prevent rejection of the kidney after kidney transplantation have an increased risk of developing lymphoma, a malignant disease of lymph cells. There is no evidence at present that long term use of azathioprine or 6-MP, in the lower doses used in Crohn's disease, increases the risk of lymphoma, leukemia or other malignancies. The use of azathioprine and 6-MP in pregnant women must be carefully considered. There are reports suggesting that the use of azathioprine or 6-MP in pregnancy is safer than once thought. The risk of continuing azathioprine or 6-MP during conception and pregnancy must be weighed against the risk of worsening disease if they are stopped. On the other hand, worsening disease has been shown clearly to be a significant risk to the fetus.
Other issues with azathioprine and 6-MP
One problem with 6-MP and azathioprine is their slow onset of action. Typically, full benefit of these drugs is not realized for 3 months or longer. During this time, corticosteroids frequently have to be maintained at high levels to control inflammation. The reason for this slow onset of action is partly due to the way doctors prescribe these drugs. For example, 6-MP is typically started at a dose of 50 mg daily. The blood count is then checked two weeks later. If the lymphocytes are not reduced, the dose of 6-MP is increased. This cautious, stepwise approach helps reduce bone marrow and liver toxicity but also delays benefit from the drug. Studies have shown that giving higher doses of 6-MP early can hasten the benefit of 6-MP without increasing the toxicity in most patients, but some patients do develop severe bone marrow toxicity. Scientists now believe that an individual's vulnerability to 6-MP toxicity is genetically inherited. Blood tests can be performed to identify those individuals with increased vulnerability to 6-MP toxicity. Blood tests also can be performed to measure the levels of certain by-products of 6-MP. The levels of these by-products in the blood help doctors more quickly determine whether the dose of 6-MP is right for the patient. TPMT genetics and safety of azathioprine and 6-MP Azathioprine is converted into 6-MP in the body and 6-MP then is partially converted in the body into inactive and non-toxic chemicals by an enzyme called TPMT. These chemicals then are eliminated from the body. The activity of TPMT enzyme (i.e. the ability of the enzyme to convert 6-MP into inactive and non-toxic chemicals) is genetically determined, and approximately 10% of the population in the Untied States has a reduced or absent TPMT activity. In this 10% of patients, 6-MP accumulates and is converted into chemicals that are toxic to the bone marrow where blood cells are produced. Thus, when given normal doses of azathioprine or 6-MP, these patients with reduced or absent TPMT activities can develop seriously low white blood cell counts for prolonged periods of time, exposing them to serious life-threatening infections. Doctors now can perform genetic testing for TPMT before starting azathioprine or 6-MP. Patients found to have genes associated with reduced or absent TPMT activity are treated with alternative medications or are prescribed substantially lower than normal doses of 6-MP or Azathioprine. A word of caution is in order, however. Having normal TPMT genes is no guarantee against azathioprine or 6-MP toxicity. Rarely, a patient with normal TPMT genes can develop severe toxicity in the bone marrow and a low white blood cell count even with normal doses of 6-MP or azathioprine. Therefore, all patients taking 6-MP or azathioprine (regardless of TPMT genetics) have to be closely monitored by a doctor who will order periodic blood counts for as long as the medication is taken. Another cautionary note; allopurinol (Zyloprim), used in treating high blood uric acids levels, can induce bone marrow toxicity when used together with azathioprine or 6 MP. Zyloprim used together with azathiprine or 6-MP has similar effect as having reduced TPMT activity, causing increased accumulation of the 6-MP metabolite that is toxic to the bone marrow. 6-MP metabolite levels In addition to monitoring blood cell counts and liver tests, doctors also may measure blood levels of the chemicals that are formed from 6-MP (6-MP metabolites), which can be helpful in several situations such as:
Patients have been maintained on 6-MP or azathioprine for years without important long-term side effects. Patients on long-term azathioprine or 6-MP, however, should be closely monitored by their doctors. There are data suggesting that patients on long-term maintenance fare better than those who stop these medications. Thus, those who stop azathioprine or 6-MP are more likely to experience recurrence of their disease and are more likely to need corticosteroids or undergo surgery.
Infliximab (Remicade) is an antibody that attaches to a protein called tumor necrosis factor-alpha (TNF-alpha). TNF-alpha is one of the proteins produced by immune cells during activation of the immune system. TNF-alpha, in turn, stimulates other cells of the immune system to produce and release other proteins that promote inflammation. In Crohn's disease, there is continued production of TNF-alpha as part of the immune activation. Infliximab, by attaching to TNF-alpha, blocks its activity and in so doing decreases the inflammation. Infliximab, an antibody to TNF-alpha, is produced by the immune system of mice after the mice are injected with human TNF-alpha. The mouse antibody then is modified to make it look more like a human antibody, and this modified antibody is infliximab. Such modifications are necessary to decrease the likelihood of allergic reactions when the antibody is administered to humans. Infliximab is given by intravenous infusion over two hours. Patients are monitored throughout the infusion for adverse reactions. In August, 1998 the United States Food and Drug Administration approved the use of infliximab for the short-term treatment of moderate to severe Crohn's disease patients who respond inadequately to corticosteroids, azathioprine, or 6-MP.
Effectiveness of infliximab
Infliximab is an effective and fast-acting drug for the treatment of active Crohn's disease. In a study involving patients with moderate to severe Crohn's disease who were not responding to corticosteroids or immuno-modulators, 65% experienced improvement in their disease after one infusion of infliximab. Some patients noticed improvement in symptoms within days of the infusion. Most patients experienced improvement within 2 weeks. In patients who respond to infliximab, the improvements in symptoms can be dramatic. Moreover, there can be impressively rapid healing of the ulcers and the inflammation in the intestines after just one infusion. The anal fistulae of Crohn's disease are troublesome and often difficult to treat. Infliximab has been found to be effective for treating fistulae.
Duration of benefits with infliximab
The majority of the patients who responded to a first infusion of infliximab developed recurrence of their disease within 3 months. However, studies have shown that repeated infusions of Infliximab every 8 weeks are safe and effective in maintaining remission in many patients over a 1-2 year period. Response to infliximab after repeated infusions sometimes is lost if the patient starts to develop antibodies to the infliximab (which attach to the infliximab and prevent it from working). Studies are now being done to determine the long-term safety and effectiveness of repeated infusions of infliximab. One potential use of infliximab is to quickly control active and severe disease. The use of infliximab then may be followed by maintenance treatment with azathioprine, 6-MP or 5-ASA compounds. Azathioprine or 6-MP also may be helpful in preventing the development of antibodies against infliximab.
Side effects of infliximab
Infliximab generally is well-tolerated. There have been rare reports of side effects during infusions, including chest pain, shortness of breath, and nausea. These effects usually resolve spontaneously within minutes if the infusion is stopped. Other commonly-reported side effects include headache and upper respiratory tract infection. TNF-alpha is an important protein for defending the body against infections. Infliximab, like immuno-modulators, increases the risk for infection. One case of salmonella colitis and several cases of pneumonia have been reported with the use of infliximab. Because infliximab is partly a mouse protein, it may induce an immune reaction when given to humans, especially with repeated infusions. In addition to the side effects that occur while the infusion is being given, patients also may develop a "delayed allergic reaction" that occurs 7-10 days after receiving the infliximab. This type of reaction may cause flu-like symptoms with fever, joint pain and swelling, and a worsening of Crohn's disease symptoms. It can be serious, and if it occurs, a physician should be contacted. Paradoxically, those patients who have more frequent infusions of Remicade are less likely to develop this type of delayed reaction compared to those patients who receive infusions separated by long intervals (6-12 months). Although Remicade is only FDA approved at this time for a single infusion, patients should be aware that they are likely to require repeated infusions once Remicade therapy has been initiated.
Precautions with infliximab
Infliximab can aggravate and cause the spread of an existing infection. Therefore, it should not be given to patients with pneumonia, urinary tract infection or abscess (localized collection of pus). There also have been cases of tuberculosis (TB) reported after the use of infliximab. The majority of these cases occurred in Europe and in individuals who had tuberculosis in the past. It now is recommended that patients be tested for TB prior to receiving infliximab. Patients who previously had TB should inform their physician of this before they receive infliximab Infliximab can cause the spread of cancer cells. Therefore, it should not be given to patients with cancer or a history of cancer. Infliximab can promote intestinal scarring (part of the process of healing) and, therefore, can worsen strictures (narrowed areas of the intestine caused by inflammation and subsequent scaring) and lead to intestinal obstruction. It also can cause partial healing (partial closure) of anal fistulae. Partial closure of fistulae impedes drainage of fluid through the fistulae and may result in collections of fluid in which bacteria multiply. This can result in abscesses. Infliximab also should be avoided in pregnancy since its effects on the fetus are not known. Because infliximab is partly a mouse protein, some patients can develop antibodies against infliximab with repeated infusions. Such antibodies occur in approximately 13% of patients. There are some reports of worsening heart disease in patients who have received Remicade. The precise mechanism and role of infliximab in the development of this side effect is unclear. As a precaution, individuals with heart disease should inform their physician of this condition before receiving infliximab. While infliximab represents an exciting new class of medications in the fight against Crohn's disease, caution is warranted in its use. The long-term safety and effectiveness is not yet known.
Identifying patients who will respond to infliximab
There is insufficient data regarding infliximab in ulcerative colitis. Infliximab most likely is not effective in treating ulcerative colitis. PANCA and ASCA are serologic tests performed on blood that frequently are abnormal in patients with ulcerative colitis and Crohn's disease. These serologic tests can be helpful in establishing a diagnosis of ulcerative colitis and Crohn's disease and in distinguishing Crohn's disease from ulcerative colitis. Studies are now being done to see whether these antibodies are useful in predicting which patients will respond to infliximab.
Methotrexate is both an immuno-modulator and anti-inflammatory medication. Methotrexate has been used for many years in the treatment of severe rheumatoid arthritis and psoriasis. It has been helpful in treating patients with moderate to severe Crohn's disease who are either not responding to azathioprine and 6- MP or are intolerant of them. Methotrexate also may be effective in patients with moderate to severe ulcerative colitis who are not responding to corticosteroids, azathioprine, or 6-MP. It can be given orally or by weekly injections under the skin or into the muscles, but it is more reliably absorbed with the injections. One major complication of methotrexate is the development of liver cirrhosis when the medication is given over a prolonged period of time (years). The risk of liver damage is higher in patients who also abuse alcohol or are severely obese. Although it has been recommended that a liver biopsy should be obtained in patients who have received a cumulative (total) methotrexate dose of 1.5 grams or higher, the need for such biopsies is controversial. Other side effects of methotrexate include low white blood cell counts and inflammation of the lungs. Methotrexate should not be used in pregnant women because of toxic effects on the fetus.
Surgery in Crohn's disease
There is no surgical cure for Crohn's disease. Even when all of the diseased parts of the intestines are removed, inflammation frequently recurs in previously healthy intestines months to years after the surgery. Therefore, surgery in Crohn's disease is used primarily for:
General measures which may help control Crohn's disease include dietary changes and supplementation. Since fiber is poorly digestible, it can worsen the symptoms of intestinal obstruction. Hence, a low fiber diet may be recommended, especially in those patients with small intestinal disease. A liquid diet may be of benefit when symptoms are more severe. Intravenous nutrition or TPN (total peripheral nutrition) may be utilized when it is felt that the intestine needs to "rest." Supplementation of calcium, folate and vitamin B12 is helpful when malabsorption of these nutrients is apparent. The use of anti-diarrheal agents (Lomotil, Imodium) and anti-spasmotics also can help relieve symptoms of cramps and diarrhea.
Crohn's disease is a chronic inflammatory disease involving predominantly the small intestine and colon. The symptoms and the activity of the disease can come and go. Even though many effective medications are available to control the activity of the disease, there is as yet no cure for Crohn's disease. Surgery can significantly improve the quality of life in selected individuals, but recurrence of the disease after surgery is common. The disease can have complications, both within and outside of the intestine. Newer treatments are actively being evaluated. A better understanding of the role of genetics and environmental factors in the cause of Crohn's disease may lead to improved treatments and prevention of the disease.
Crohn's Disease At A Glance