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In This Report

•	Highlights
•	Introduction
•	Causes
•	Symptoms
•	Complications
•	Risk Factors
•	Diagnosis
•	Dietary Factors
•	Symptom Management
•	Medications
•	Surgery
•	Resources
•	References

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•	Peptic ulcers
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•	Ulcerative colitis

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Crohn's disease

Highlights

Drug Approval

Adalimumab (Humira) was approved in 2007 to treat adults with moderate-to-severe Crohn's disease.

Infliximab (Remicade) was approved in 2006 for treating active Crohn’s disease in children. The drug was previously approved for adults with Crohn’s disease.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

NSAIDS such as acetaminophen (Tylenol), naproxen (Aleve), and celecoxib (Celebrex) are as safe for patients with inflammatory bowel diseases (IBD) as for people without IBD, according to several 2006 studies. The studies found that NSAIDs may provide pain relief and prevent symptom relapse. Still, patients with IBD should always discuss NSAID use with their doctors.

MMR Vaccine and Crohn’s Disease

The measles, mumps, and rubella (MMR) vaccine does not cause Crohn’s disease or ulcerative colitis, according to a review in the Cochrane Database. The report is the most in-depth review of the vaccine to date.

Complications

According to recent studies in Gastroenterology:

• Asthma is the most common accompanying condition among patients with Crohn’s disease. Patients with Crohn’s and ulcerative colitis also have a higher risk for developing arthritis, bronchitis, psoriasis, and pericarditis.
• The risk for small bowel cancer (a rare type of cancer) is greatly increased among patients with Crohn’s disease, and colorectal cancer risk is slightly increased.
• Patients with IBD have a greater risk for developing multiple sclerosis and other disease that attack myelin (the fatty sheath that covers nerves).

Diet

Crohn’s disease, and some medications used to treat it, can cause low bone density and bone loss. According to a 2005 study, however, patients with Crohn’s disease may not need to take osteoporosis drugs. Calcium and vitamin D supplements may be adequate.

Investigational Drugs

Several biologic drugs are showing promising results in clinical trials for Crohn’s disease. Some of these drugs have already been approved to treat other inflammatory or autoimmune conditions:

• Natalizumab (Tysabri)
• Certolizumab (Cimzia)
• Sargramostim (Leukine)
• Fontolizumab (HuZAF)

Introduction

Inflammatory bowel disease (IBD) is a general term that covers two disorders:

• Ulcerative colitis (UC)
• Crohn's disease (CD)

Some evidence suggests that these two diseases are part of a biologic continuum, but at this time they are considered distinct disorders with somewhat different treatment options. The basic distinctions between UC and CD are location and severity. However, as many as 10% of patients with IBD have findings and symptoms that match the criteria for both disorders, at least in the early stages (a situation called indeterminate colitis).

Crohn's disease, also called regional enteritis, is a chronic inflammation of the intestines which is usually confined to the terminal portion of the small intestine, the ileum. Ulcerative colitis is a similar inflammation of the colon, or large intestine. These and other IBDs (inflammatory bowel disease) have been linked with an increased risk of colorectal cancer.

Crohn's Disease. Crohn's disease is an inflammation that extends into the deeper layers of the intestinal wall. It is found most often in the area bridging the small and large intestines, specifically in the ileum and the cecum, sometimes referred to as the ileocecal region. Crohn's disease occurs less frequently in other parts of the gastrointestinal tract, including the anus, stomach, esophagus, and even the mouth. It may affect the entire colon or form a string of contiguous ulcers in one part of the colon or develop as multiple scattered clusters of ulcers skipping healthy tissue in between.

Click the icon to see an image of Crohn's disease.

Ulcerative Colitis. Ulcerative colitis is an inflammatory disease of the large intestine. Ulcers form in the inner lining, or mucosa, of the colon or rectum, often resulting in diarrhea, blood, and pus. The inflammation is usually most severe in the sigmoid and rectum and typically diminishes higher in the colon. The disease develops uniformly and consistently until, in some cases, the colon becomes rigid and foreshortened. [For more information, see In-Depth Report #69: Ulcerative colitis.]

Click the icon to see an image of the structure of the colon.

Click the icon to see an image of the digestive system.

Click the icon to see an image of the stomach.

Click the icon to see an image of the structure of the small intestine.

Click the icon to see an image of the structure of the colon.

Causes

Inflammatory bowel disease has many different causes. It is due in many cases to a genetic susceptibility that enables an organism such as a virus or bacteria to trigger an abnormal immune reaction, which in turn, causes an inflammatory response in the intestines. Although Crohn's disease has features that resemble an autoimmune disease (in which the body's immune system attacks its own cells), some researchers think that it may be due to initial immune deficiencies.

The Inflammatory Response

The Immune System's Infection Fighters. The primary infection-fighting units are two types of white blood cells: lymphocytes and leukocytes.

Lymphocytes include two subtypes known as T cells and B cells. Both types of cells are designed to recognize foreign invaders (antigens) and to launch an offensive or defensive action against them:

• B cells produce antibodies, which are separate substances that can either ride along with a B cell or travel on their own to attack the antigen.
• T cells have special receptors attached to their surface that recognize the specific antigen.

T cells are further categorized as killer T cells or helper T cells.

• Killer T cells directly attack antigens that occur in any cells that contain a nucleus.
• Helper T cells also recognize antigens, but their role is two fold. They stimulate B cells and other white cells to attack the antigen. They also produce cytokines, powerful immune factors that have an important role in the inflammatory process.

Helper T cells and Inflammatory Bowel Disease. The actions of the helper T cells (TH cells) are of special interest in inflammatory bowel disease:

• TH cells stimulate other white blood cells called B cells to produce antibodies. In this case, however, they appear to direct the B cells to produce autoantibodies, which are directed against the body's own cells.
• TH cells also secrete or stimulate the production of powerful immune factors called cytokines. In small amounts, cytokines are indispensable for healing. If overproduced, however, they can cause serious damage, including inflammation and cellular injury. Cytokines, particularly specific ones known as tumor necrosis factor, interferon-gamma, and interleukins, cause intestinal inflammation and damage, which, in a vicious cycle, attract even more helper T cells.

Helper T cells are further categorized as TH1 and TH2. An imbalance in these two types appear to occur in IBD, although each disorder has a different balance:

• Ulcerative colitis patients favor a TH2 response, which activates the interleukins IL-5, IL-6, and IL-10. These mostly affect mucosal areas in the intestine.
• Research indicates that patients with Crohn's disease have increased activity in TH1 helper cells, activating interleukin-2 (IL-2) and interferon-gamma, which affect intestinal cells. Tumor necrosis factor (TNF) may be a particularly potent immune factor in Crohn's disease. It is important in properties that regulate inflammation and cell proliferation. If genetic or other factors increase production of this immune compound, it can lead to great harm.

Interleukin 6 appears to play a part in both IBDs, by inhibiting a natural mechanism called apoptosis, a process whereby cells self-destruct. In such cases, cells proliferate faster than they die, causing an excessively strong immune response.

Adhesion Molecules. Increased levels of certain molecules called E-selectin and intercellular adhesion molecule-1 (ICAM-1) also appear to play a major role in the inflammatory process by causing damaging immune factors to accumulate on intestinal cells. E-selectin may be involved in the early stages of the disease (especially ulcerative colitis) and ICAM-1 in the persistence of either inflammatory bowel disease.

Matrix Metalloproteinase. Greater activity of enzymes called matrix metalloproteinase has been detected in the colons of patients with IBD. Such increased levels tend to break down the extracellular matrix, a barrier composed of structural proteins and elastic fibers that surrounds and supports cells, in this case in the colon. Researchers suggest that this activity may cause persistent damage once the inflammatory process has triggered IBD.

Genetic Factors

Although the causes of inflammatory bowel disease are not yet known, genetic factors certainly play some role. Between 10 - 20% of people with ulcerative colitis have family members with the disease. Several candidate genes and chromosome locations have been identified that might prove to play a role in the development of ulcerative colitis, Crohn's disease, or both. Genetic factors appear to be more important in Crohn's disease, although there is evidence that they may have genetic defects in common. In either case, multiple genetic factors are likely to be responsible for susceptibility to these disorders.

Specific Genes Involved. One of the most important genetic discoveries to date was the identification of a genetic variant called NOD2, which appears to alter the immune system so that it launches an over-reaction in response to bacteria, causing inflammation. This genetic factor might be involved in 15% of Crohn's disease cases. Those with one copy of the mutated gene have twice the average risk of developing Crohn's, and those with two defective genes face 20 - 40 times the risk.

Infections

One theory suggests that viruses or bacteria within the intestine may alter properties in the lining and intestinal tract. Over time, these changes may trigger the injurious processes that lead to inflammatory bowel disease.

Measles. Some studies report that children with IBD may have had more and earlier childhood infections. The measles virus has been of particular interest. According to the U.S. Centers for Disease Control, and many studies, the measles virus does not cause Crohn’s or IBD.

Much publicity has centered on whether the vaccine for measles, mumps, and rubella (the MMR vaccine) causes conditions such as autism and Crohn’s disease. This theory has been rigorously reviewed and refuted in many well-conducted studies, including several published in 2006. The evidence clearly indicates that the MMR vaccine does not increase the risk of Crohn’s disease, other inflammatory bowel disease, or autism.

Mycobacteria. A type of bacterium associated with tuberculosis is another possible candidate for an infectious cause of Crohn’s disease.

Escherichia coli. The intestine normally harbors E. coli bacteria. In most cases, the bacteria are harmless and even protective. Some E. coli strains, however, can bind to the intestinal walls and penetrate the lining. These damaging strains may be associated with Crohn’s disease.

Cytomegalovirus. Cytomegalovirus (CMV) is a common virus that is also under suspicion as a contributor to severe cases of IBD.

Dietary Factors

Inflammatory bowel disease is much more prevalent in industrialized nations and in higher-income groups. Experts believe, then, that diet must play some role, although studies have been conflicting over its importance.

Symptoms

The two major inflammatory bowel diseases (IBDs), ulcerative colitis and Crohn's disease, share certain characteristics:

• Symptoms usually appear in young adults.
• Symptoms can develop gradually or have a sudden onset.
• Both are chronic. In either disease, symptoms may flare up (relapse) after symptom-free periods (remission) or symptoms may be continuous without treatment.
• Symptoms can be mild or very severe and disabling.
• The severity of symptoms and relapse rates of both IBDs vary with seasons, with the highest risk in the winter and autumn and lowest in summer.

The two disorders, however, have different symptom profiles and is it important to differentiate between them, since they require different treatments.

There are three body views (front, back and side) that may be helpful if you are uncertain of a body area. Many areas are referred to by both descriptive and technical names. For example, the back of the knee is called the popliteal fossa. However, areas like the "flank" may not have both names, so the location may be unclear.

Click the icon to see a depiction of an anorectal fistula.

Complications

The outlook for Crohn's disease varies widely. Crohn's disease can range from being benign (such as when limited Crohn's disease occurs only around the anus in older people) or it can be very severe. At the extreme end, some patients may experience only one episode and others suffer continuously. Although recurrences tend to be the norm, disease-free periods can last for years or decades in some patients. Although Crohn's disease cannot be cured even with surgery, treatments are now available that can offer significant help to most patients. Crohn's disease is rarely a direct cause of death, and most people can live a normal lifespan with this condition.

Mild Crohn's Disease. The fewer bowel movements, the milder the disease. In mild disease, abdominal pain is absent or minimal. The patient has a sense of well-being that is normal or close to normal. There are few, if any, complications outside the intestinal tract. The doctor does not detect any mass when pressing the abdomen. The red blood cell count is normal or close to normal, and the patient is not underweight.

Severe Crohn's Disease. In severe Crohn's disease, the patient has bowel movements frequent enough to require opiates or other potent anti-diarrhea medication. Abdominal pain is severe and usually located in the lower right quadrant of the abdomen. (The location of the pain might not indicate the site of the actual problem, a phenomenon known as referred pain.) The red blood cell count is low. The patient has a poor sense of well-being and experiences complications that may include weight loss, joint pain, inflammation in the eyes, reddened or ulcerated skin, fistulas, abscesses, and fever. The surgical and medical treatments of Crohn's disease, as with ulcerative colitis, have complications of their own that can be severe.

Complications in the Intestine

Malabsorption and malnutrition. Malabsorption is the inability of the intestines to absorb nutrients. In IBD, this occurs as a result of bleeding and diarrhea, as a side effect from some of the medications, and as a result of surgery. Malnutrition usually develops slowly and tends to become severe, with multiple nutritional deficiencies. It is very common, ranging from 25 - 80% of patients with Crohn's disease.

Ulcer, Fistulas, and Abscesses. Between 30 - 40% of patients with Crohn's disease experience complications around the anal area from inflammation. Fistulas (channels beneath the skin) frequently develop from the deep ulcers that can form with Crohn's. If fistulas develop between the loops of the small and large intestines, they can interfere with absorption of nutrients. They often form pockets of infection or abscesses, which may become life threatening without treatment.

Bleeding. Massive bleeding can occur in 1 - 2% of cases and may be recurrent. Bleeding is usually from a localized area in the intestine. Surgery may be performed to remove the bleeding sites.

Colorectal Cancers. Patients with inflammatory bowel disease have a slightly higher risk for colorectal cancer. The risk is greater for patients with severe ulcerative colitis than for those with Crohn’s disease. Patients with Crohn’s disease do have a 40-fold increased risk for small bowel cancer. (However, small bowel cancer is a very rare type of cancer.) The risk increases with the severity of the condition and the length of time the patient has had Crohn’s. [For more information, see In-Depth Report #55: Colon and rectal cancers.]

Intestinal Blockage. Inflammation from Crohn's disease produces segments of scar tissue known as strictures that can constrict the passages of the intestines, causing bowel obstruction with severe cramps and vomiting. Strictures usually occur in the small intestine but can also occur in the large intestine.

Complications Outside the Intestine

People with inflammatory bowel disease have a higher risk of developing other inflammatory diseases that affect the lungs and central nervous system.

Asthma. According to a 2005 study, people with IBD are 1.5 times more likely to have asthma than people without IBD. Of all the conditions that can accompany IBD, asthma is the most common. People with IBD are also at increased risk for bronchitis and other lung inflammations

Eyes. Inflammation in the eyes may be an early sign of Crohn’s in some cases. Retinal disease, including detachment, can occur but is rare. People with accompanying arthritic complications may be at higher risk for eye problems.

Joints. Inflammation causes arthritis and stiffness in the joints. The back is commonly affected. Patients with Crohn’s disease are also at risk for clubbing (abnormal thickening and widening at the ends of fingers and toes).

Click the icon to see an image of nail clubbing.

Bones. Crohn’s disease, and the corticosteroid drugs used to treat it, can cause osteopenia (low bone density) and osteoporosis (bone loss).

Anemia. Internal blood loss from ulcers in the intestine is a particular problem in Crohn's disease because of the impaired ability to absorb vitamins and minerals necessary for blood production.

Liver and Gallbladder Disorders. Patients have a higher than average risk for mild but not severe liver abnormalities. They have double the normal risk for gallstones.

Click the icon to see an image of gallstones.

Mouth Sores. Canker sores are common, and when they occur they persist. Those at higher risk are males and younger people. Mouth yeast infections also common in Crohn's disease.

Skin Disorders. Patients with Crohn’s disease are likely to develop red knot-like swellings. Such swellings or other skin lesions, such as ulcers, may spread to sites far removed from the colon, (including the arms and legs.) People with Crohn's disease have an increased risk for psoriasis.

Thromboembolism (Blood Clots). Clots may occur, most likely in lower extremities and pelvic area.

Click the icon to see an image of a thrombus.

Urinary Tract and Kidney Disorders. Urinary tract infections are common. Patients have an increased risk for kidney stones. Amyloidosis (deposits of a protein called amyloid in the kidney or other organs) is a rare but very serious kidney condition.

Click the icon to see an image of kidney stones.

Delayed Growth and Development in Children. Up to half of children with Crohn’s disease have impaired physical growth, and nearly all are underweight. About 30% reach puberty later, but once it occurs, hormonal cycles tend to be normal.

Infertility. Infertility rates are only slightly lower than average. Active disease at conception increases risk for miscarriage or prematurity. Men may have lower sperm count during active disease or because of impaired nutrition, but in general fertility is normal.

Menstrual Problems. Menstrual problems in women are common, including premenstrual disorder, abnormal bleeding, and pain. Pain with intercourse occurs in about half of patients. Sexual function may be impaired, not only because of the emotional impact, but also by treatment side effects and complications of the disease, such as fistulas.

Neurologic Factors. Inflammatory bowel disease has been associated with neurologic complications, including a higher risk for dementia, movement disorder, and stroke. People with IBD have a higher risk for developing multiple sclerosis and inflammation of the optic nerve (optic neuritis).

Emotional Factors. The emotional consequences of UC cannot be overestimated, particularly in children. Eating becomes associated with fear of abdominal pain before the end of the meal. Frequent attacks of diarrhea can cause such a strong sense of humiliation that social isolation and low self-esteem may result. Adolescents with IBD may have added problems that increase emotional distress, including weight gain from steroid treatments and delayed puberty.

Risk Factors

An estimated 1 - 2 million Americans suffer from inflammatory bowel disease (IBD) and about 400,000 of these patients have Crohn's disease. (This wide statistical variation is due to the difficulty in diagnosing these disorders and because people in remission may not be identified.) The number of people with Crohn's disease may be increasing, and Crohn's disease is now considered to be the second most common chronic inflammatory disorder (after rheumatoid arthritis).

IBD often runs in families. The incidence may vary depending on gender, age, and geography:

• Women may be slightly more at risk for Crohn's disease than men. Both genders are equally at risk for ulcerative colitis.
• IBDs in general are diagnosed most often in young people between the ages of 10 and 19, but they can occur at any age. Another lesser peak onset occurs between ages 50 and 80. About 2% of IBD cases appear in children below age 10. Between 10 - 15% of patients with Crohn's are children, and the childhood prevalence appears to be increasing.
• IBD occurs four times more often in Americans of Northern European descent than in African Americans. Scandinavia has the highest rate of Crohn's disease in the world. Studies in Britain suggest, however, that Asians may have a higher rate of IBD than people of European descent. Jewish people of European descent have an even higher risk: Five times that of the general population.
• IBD seems to be more common among city than country dwellers and occurs more frequently in developed than in less developed nations, indicating that both genetic factors and environmental conditions, such as diet, may be involved in its development.
• People who are left-handed have a significantly higher risk for both IBDs as well as certain other diseases associated with problems in the immune system.

Diagnosis

The doctor will take a history and perform a thorough physical examination. The disease is particularly difficult to diagnose in children. In children, IBD may be mistaken for an infection or even depression if other characteristic symptoms, such as bloody diarrhea and weight loss, are not present. Slow growth may be a key feature in making a diagnosis, particularly of Crohn's disease, in children.

Several laboratory tests may be performed:

• Blood tests are used for various purposes. An increased number of white blood cells may indicate the presence of inflammation. Blood tests are used to determine the presence of anemia and to measure liver enzymes. (They are abnormal in about 3% of ulcerative colitis patients.) New blood tests that measure certain antibodies may make it easier to differentiate Crohn's disease from ulcerative colitis in children.
• A stool sample is taken and examined for blood, infectious organisms, or both.

Procedures Used for Diagnosis

Standard Endoscopic Procedures. Flexible sigmoidoscopy and colonoscopy are procedures that involve snaking a fiberoptic tube called an endoscope through the rectum to view the lining of the colon. The doctor can also insert instruments through it to remove tissue samples.

• Sigmoidoscopy, which is used to examine only the rectum and left (sigmoid) colon, lasts about 10 minutes and is done without sedation. It may be mildly uncomfortable, but it is not painful.
• Colonoscopy allows a view of the entire colon and requires a sedative, but it is still performed on an outpatient basis. It is important in differentiating between Crohn's disease and ulcerative colitis and in screening for colon cancer.

There are three basic tests for colon cancer: a stool test (to check for blood); sigmoidoscopy (inspection of the lower colon); and colonoscopy (inspection of the entire colon). All three are effective in catching cancers in the early stages, when treatment is most beneficial.

The procedures may help the doctor to distinguish between ulcerative colitis and Crohn's disease, as well as other diseases. A variation called chromoendoscopy uses a blue stain during the process to reveal fine details on the intestinal lining. It might prove to be useful for identifying areas that may be precancerous and need to be biopsied.

Wireless Capsule Endoscopy. Wireless capsule endoscopy (WCE) is a new imaging approach that is very useful for diagnosing Crohn's disease. With WCE, the patient swallows a capsule containing a tiny camera that records and transmits images as it passes through the gastrointestinal tract. Some studies have found it to be much more accurate for evaluating small bowel disease than barium x-rays or CT scans. Patients also find it easier to tolerate than standard endoscopy.

Ultrasound. Intestinal wall ultrasound is proving to be useful for identifying the extent and severity of Crohn's disease. Although it is unclear if ultrasound is useful for an initial diagnosis, one study indicated that it is effective for identifying Crohn's disease or ulcerative colitis when used by experienced professionals.

Upper and Lower Gastrointestinal Barium X-Rays. An upper gastrointestinal barium x-ray may be used if Crohn's disease is suspected in the small intestine. Swallowed barium passes into the small intestine and shows up on an x-ray image, which may reveal inflammation, ulcers, and other abnormalities.

Click the icon to see an image of the barium enema procedure.

Computed Tomography (CT) Scans. Computed tomography (CT) scans are proving to be useful in evaluating active IBD. With Crohn's disease, CT scans may show thickened walls and complications, such as fistulas, which occur outside the intestine.

Magnetic Resonance Imaging (MRI). Magnetic resonance imaging is another advanced imaging technique that may be useful for detecting abscesses and other injuries related to Crohn's disease in the pelvis. A variant called magnetic resonance spectroscopy (MRS) may prove to be useful for differentiating between Crohn's disease and ulcerative colitis.

Ruling Out Diseases Resembling Inflammatory Bowel Disease

Irritable Bowel Syndrome. Irritable bowel syndrome (IBS), also known as spastic colon, functional bowel disease, and spastic colitis, causes many of the same symptoms as inflammatory bowel disease. (However, it is NOT the same as inflammatory bowel disease.) Bloating, diarrhea, constipation, and abdominal cramps are all symptoms of IBS. Irritable bowel syndrome is not caused by inflammation, however, and no fever or bleeding occurs. Behavioral therapy may be helpful in treating IBS. (No psychologic therapy improves inflammatory bowel disease.)

Microscopic Colitis. Microscopic colitis causes chronic watery diarrhea, but the colon lining shows little or no signs of inflammation. It may be genetically linked to celiac sprue. Most patients can expect to improve.

Celiac Sprue. Celiac sprue, or celiac disease, is an intolerance to gluten (found in wheat) that triggers inflammation in the small intestine and causes diarrhea, vitamin deficiencies, and stool abnormalities. It occurs in a significant number of people with IBD and is usually first noticed in children.

Click the icon to see foods to avoid if you have celiac sprue.

Interstitial Cystitis. Interstitial cystitis (IC) is an inflammation of the bladder wall that occurs almost exclusively in women. Some evidence suggests that the risk for IBD in these patients is 100 times above that in the general population and that there may be some common factor to both conditions. The average age of patients with IC is 40, but 25% of cases occur in women under 30. Symptoms are very similar to urinary tract infections, but no bacteria are present. Pain during sex is a very common complaint in these patients, and stress may intensify symptoms.

Infections. If endoscopy reveals inflammation, a doctor must always rule out possible infections before a diagnosis of inflammatory bowel disease can be confirmed.

Acute Appendicitis. Crohn's disease may cause tenderness in the right lower part of the abdomen where the appendix is located and resemble appendicitis.

Click the icon to see an image of the appendix.

Cancer. Colon or rectal cancers must always be ruled out when symptoms of IBD occur.

Intestinal Ischemia. Symptoms similar to IBD can be caused by blockage of blood flow in the intestine. This is more likely to occur in elderly people.

Dietary Factors

The role of diet and nutrition is very important in Crohn's disease and should be considered for four separate situations:

• As important add-on treatment to medical therapies for maintaining nutrition and correcting any nutritional deficiencies.
• As primary treatment for reducing disease activity.
• As maintenance therapy on a long-term basis in the case of severe intestinal failure or short-bowel syndrome.
• For reversing growth-failure in children.

Maintaining or Achieving Normal Weight

Malnutrition is very common in Crohn's disease. In fact, patients with Crohn's appear to burn fat calories at a higher rate than the general population and most patients are underweight. Some experts recommend that children with IBD increase their calorie and protein intake by 150% of the daily recommended allowance for their specific ages and heights. Studies indicate that nutritional support in children is as important as medications for achieving remission. People whose weights are normal or no less than 90% of normal do not need to add extra calories.

Foods Important for Protection

Fluids (non-caffeinated). Drinking plenty of water is extremely important. Vegetable juice and sports drinks may be helpful for restoring important minerals. Caffeinated beverages should be avoided in general, although green tea may have some benefits for Crohn's disease.

Protein. Proteins are very important for growth in children and for repair of cells. Diarrhea can cause protein deficiency and patients with IBD may need more protein than the general population. Patients should choose fish and soy as primary protein sources. One study reported that a soy protein diet was particularly useful for patients who were intolerant to milk products. Oily fish, such as salmon and tuna, may be particularly beneficial in Crohn's disease. Other options are poultry and lean meats. Dried beans and legumes also provide protein.

Complex Carbohydrates. Complex carbohydrates found in whole grains, fruits, and vegetables should make up half of a patient's calories. Fresh fruit (such as apples, grapefruit, oranges, plums, blueberries, raspberries, and strawberries) may actually be specifically protective for IBD and may possibly reduce the risk for colon cancer. (Simple sugars can increase inflammation, however, so patients should avoid dried fruits and high-sugar fruits, such as grapes, pineapple, and watermelon.)

Foods made up of complex carbohydrates are also often a good source of fiber, which may help reduce damage in the intestinal tract caused by inflammation. However, high-fiber foods can cause gas, bloating, and pain, particularly in IBD patients. Commercial products (such as Beano) are available that can reduce gas. Eating small, frequent meals can also help.

Fish Oil. Omega-3 fatty acids, which are found in oily fish, have been associated with protection against inflammation, including in the intestinal tract. Some studies have reported lowered use of anti-inflammatory medications in people who consume fish oil. Such fatty acids are also available in supplements as docosahexaenoic (DHA) and eicosapentaneoic (EPA) acids. Standards for optimal amounts and forms of omega-3 fatty acids have not yet been established, however.

Liquid Supplements. Over-the-counter liquid diets, such as Ensure, Sustacal, and others that meet full nutritional needs and are absorbed in the upper intestine may be helpful for some patients with Crohn's, but no studies have determined this.

Potassium-rich Foods. Examples are potatoes, avocados, and bananas.

Foods Associated with Higher Risk for Symptoms

Exclusion Diets. Exclusion diets are those that eliminate certain foods that may cause allergies or irritate the intestine. To determine these foods, patients use an "elimination/challenge" approach. First, they remove all suspect foods from their diet for 2 weeks and then reintroduce one food every 3 days. Patients then watch for any symptoms that might indicate an allergic or irritant response, including gastrointestinal problems, headaches, and flushing. Some experts believe, however, that this approach is very difficult, and studies are weak in confirming its value for maintaining remission.

Typical foods to avoid include:

• Fats. Fats appear to worsen intestinal inflammation in Crohn's disease. Patients should limit fats, particularly saturated fats, found in meat and dairy products. However, certain fatty acids, such as those found in fish oil, may be helpful. Experts are investigating the optimal balance between a low-fat diet with addition of these fatty acids.
• Milk products. Some people with IBD are lactose intolerant (unable to digest the sugar lactose, found in milk products). However, milk, along with the calcium it contains, have been associated with a lower risk for colon cancer. Taking lactase tablets or specially prepared dairy products may help. (Many lactose-intolerant patients are still able to eat yogurt with active cultures, which could be helpful for IBD.)
• Foods associated with inflammation (alcohol, simple sugars, and caffeine).
• Fruits may be protective, but patients should avoid dried fruits or high-sugar fruits, such as grapes, watermelon, or pineapple.
• Products containing corn or gluten (those made from wheat, oats, barley, or triticale).
• Common allergenic foods, such as soy, eggs, peanuts, tomatoes.
• Foods that may irritate the intestine, particularly so-called Brassica vegetables (cabbage, Brussels sprouts, broccoli, cauliflower, kale).

Dietary Considerations for Reducing Kidney Stones

Kidney stones are painful and common complications in IBD, particularly in patients who have had intestinal surgery. IBD patients are at risk for the most common types of stones -- those composed of either calcium oxalate or uric acid crystals. The following are some considerations in reducing the risk for stones:

• The most important dietary recommendation is to increase fluid and restrict sodium intake.
• Limiting protein is recommended for reducing kidney stones. However, people with IBD with frequent diarrhea are protein deficient. Sufficient protein, particularly in children with IBD, is very important and should be weighed against any risk for stones.
• Patients should increase intake of potassium-rich foods (bananas, watermelon, cantaloupe, oranges, tomatoes, beans).
• Patients should try to correct any dietary habits that cause acidic or alkaline imbalances in the urine that promote stone formation.
• Many kidney stones are formed from calcium-oxalate stones. Patients should avoid or limit intake of oxalate-rich foods, such as beets, beet tops, black tea, chenopodium, chocolate, cocoa, dried figs, ground pepper, lamb quarters, lime peel, nuts, parsley, poppy seeds, purslane, rhubarb, sorrel, spinach, and Swiss chard. A high calcium diet does not appear to increase the risk for kidney stones as long as it also contains plenty of fluids and dietary potassium and phosphate. Importantly calcium is associated with protection against colon cancer and osteoporosis -- two conditions that are associated with IBD.
• Patients who have stones associated with short-bowel syndrome should restrict their intake of fat as well oxalates. In such cases, calcium may bind to unabsorbed fat instead of to oxalates, which increase oxalate levels.

The general recommendations for avoiding kidney stones need to be tailored to the dietary requirements of IBD. Patients should work with their doctors to develop an individualized plan.

Probiotics and Prebiotics

Researchers are currently investigating bacteria (called probiotics) and specific foods (called prebiotics) that are metabolized by these bacteria, and the compounds they produce (called synbiotics). Some evidence suggests that alone or in combination, they may have significant benefits in the intestine.

• Probiotics are bacterial strains that by themselves may provide a barrier against harmful bacteria, possibly through various mechanisms such as excreting certain acids (lactate, acetate) that inhibit harmful bacteria or compete with them for nutrients. It has been suggested that probiotics may help maintain remission in patients with IBD. The specific bacterial strains that might be beneficial, however, are not fully known. The most well-known probiotics are the lactobacilli strains, such as acidophilus, which are found in yogurt and other fermented milk products. Others, however, may prove to be more important, such as bifidobacteria and GG lactobacilli. Other probiotics that may be beneficial for patients with IBD include lactobacilli rhamnosus, casel, plantarium, bulgaricus, and salivarius, and also Enterococcus faecium and Streptococcus thermophilus.
• Prebiotics are specific non-digestible molecules called fructo-oligosaccharides (FOS), which stimulate the growth of probiotics. FOS are found in many foods, including Jerusalem artichokes, onions, salsify, bananas, honey, garlic, and leeks. (However, some of these foods can irritate the intestine in patients with IBD.)

Researchers are investigating probiotics, prebiotics, or both for intestinal protection, including benefits for patients with IBD. Foods and supplements containing these substances are available in the U.S. and are heavily marketed in Europe, Japan, and Australia. To date, however, no studies have determined any clear benefits of any specific organism or formulation.

Vitamins and Other Supplements

Crohn's disease and surgical procedures that remove parts of the small intestine can inhibit absorption of vitamins, fats, and other important supplements. Taking certain supplements, such as fish oil, antioxidants, and mineral supplements may be beneficial for patients with Crohn's disease.

Vitamins. Deficiencies of vitamins A, C, D, E, B12, and folate (a B vitamin) may result from malabsorption. In general, vitamin supplements may be recommended for everyone with IBD, particularly for children to avoid growth retardation. Vitamins A, C, and E are antioxidants, which are scavengers of damaging particles in the body. Folic acid supplements are particularly important for patients who must restrict fresh fruits and vegetables and for those taking sulfasalazine. Folate deficiencies may contribute to the increased risk for colon cancer. Monthly injections of vitamin B-12 may be necessary. Vitamin D is necessary for bone protection. Because some vitamins, such as A and D, can be toxic at high doses, patients should discuss specific dosages with their doctors.

Omega-3 Fatty Acids. The role of fats in inflammatory bowel disease is complex and not fully known. Some evidence suggests that patients with Crohn's burn fat calories at a higher rate than the general population. Patients with IBD may be deficient in essential fatty acids, particularly omega-3 fatty acids (polyunsaturated fats found in oily fish and certain vegetable products such as flaxseed and canola oils). Such fatty acids are also available in supplements as docosahexaenoic (DHA) and eicosapentaneoic (EPA) acids, which are specific compounds found in fish oil.

Omega-3 fatty acids, found plentifully in oily fish and flaxseed and canola oils, are beneficial to people afflicted with IBD (inflammatory bowel disease).

Mineral Supplements. Supplements of calcium, magnesium, zinc, selenium, and iron may be needed to offset deficiencies in patients with severe IBD.

• Calcium and magnesium are critical for health and strong bones. Many patients with IBD suffer from calcium and vitamin D deficiencies, which cause low bone density. Studies indicate that calcium and vitamin D supplements may be adequate to increase bone density without drugs.
• Selenium is a potent antioxidant.
• Zinc is important for wound healing, and deficiencies may promote fistulas in Crohn's disease.
• Iron supplements may be required for anemia. However, iron overdose is very dangerous. As few as three adult iron tablets can poison children, even fatally. No one, even adults, should take a double dose of iron if one is missed. A doctor should advise patients on correct dosage.

Diets as Primary Treatment for Severe Malnutrition

Enteral Nutrition. Enteral nutrition uses a feeding tube that is inserted either through the nose and down through the throat or directly through the abdominal wall into the gastrointestinal tract. It is the preferred method for feeding patients with malnutrition who cannot tolerate eating by mouth. The nutritional formulas used in enteral administration include:

• Polymeric diets (containing a balance of standard nutrients).
• Elemental diets (predigested nutrients that are absorbed in the first meter of the small intestine). These diets are used less commonly than polymeric diets.

In children, enteral nutrition is given for 6 - 8 weeks. Simple foods are then introduced (chicken, potato, rice), and more complex foods (milk, fiber, wheat-based foods) are then added gradually. However, relapse is still common.

A major 2002 analysis did not confirm any advantages of enteral feedings over corticosteroids, nor did it find any additional benefits from elemental diets compared to polymeric diets. Still, they may be helpful for specific patients. For example, in a 2001 study of children with steroid-dependent Crohn's disease that was already in remission, elemental supplements allowed many of them to withdraw from the medication. Further research is needed to determine if there is an optimal balance of nutrients in the enteral diet formula for IBD that might improve their effects.

Total Parenteral Nutrition. Total parenteral nutrition (TPN), or hyperalimentation, is the intravenous administration of nutrients through an indwelling catheter (tube). It is used for very severe IBD when patients cannot tolerate any nutrition by mouth or with a feeding tube, and may even be useful as a primary therapy for patients with Crohn's (although not for those with fistulas). It is usually administered in the hospital, although increasingly people are self-administering it at home. The procedure carries a risk for complications, some serious, including infection, blood clots, and liver failure.

Symptom Management

Diarrhea and Constipation

The following are some ways of managing diarrhea, constipation, or both:

• Mild to moderate diarrhea may be reduced by taking one teaspoon of psyllium hydrophilic colloid (Metamucil) twice a day in a glass of water.
• Antidiarrheal drugs include loperamide (Imodium) and a combination of atropine and diphenoxylate (Lomotil). In very ill patients, large doses of some antidiarrheal drugs, such as Lomotil, can trigger the onset of toxic megacolon. Toxic megacolon is a life-threatening complication of other intestinal conditions. It is characterized by a very inflated colon, abdominal distention, and sometimes fever, abdominal pain, or shock.
• Opiates or drugs used to relax muscle spasms may help relieve mild to moderate diarrhea and abdominal cramps, but they should be used for very short periods and not for severe cases.
• Cholestyramine (Questran) has been found to be useful for reducing diarrhea in patients who have had ileal resections.
• Bulk-type laxatives can help constipation.

Treating Anemia

Iron supplements may be required for anemia. Intravenous iron with or without erythropoietin (a hormone that acts in the bone marrow to increase the production of red blood cells) is effective for severe anemia in IBD that does not respond to iron alone. Patients with Crohn's disease benefit most from the combination.

Antidepressants

Antidepressants may help relieve emotional problems. However, inflammatory bowel disease is not a psychologic disorder, and such drugs will not affect the basic illness.

Pain-Relievers

Acetaminophen (Tylenol) is the drug of choice for mild pain. Acetaminophen is not a nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs include, among dozens of others, aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve), and Celebrex, the only Cox-2 inhibitor left on the market. NSAIDs have been thought to cause symptom flare-ups in patients with IBD. However, a comprehensive 2006 study concluded that these drugs are as safe for patients with IBD as for other people, and that they can help prevent relapse as well as provide short-term pain relief. Patients should discuss with their doctors whether NSAIDs are appropriate for them.

Stress Reduction

Although stress is not a cause of inflammatory bowel disease, there are reports of an association between stress and symptom flare-ups. Although no evidence exists to confirm that stress reduction techniques such as relaxation methods, meditation, or cognitive therapy, manage the disease, they might be helpful.

Exercise

The effects of exercise in Crohn's disease are uncertain. Some research indicates that moderate exercise may trigger excess production of chemicals that could cause flare-up. One small study, however, reported significant improvement in patients who had been sedentary and who then embarked on a 12-week exercise program. They walked a little over 2 miles three times a week. During that period there were no flare-ups, and they felt physically and emotionally better than before.

Medications

The primary goal of drug therapy is to reduce inflammation in the intestine. Drugs are effective in reducing the inflammation and accompanying symptoms in up to 80% of patients. Unfortunately, relapses are still frequent, and researchers continue to look for the optimal treatments that will both control symptoms and prevent relapse.

Drugs Used for Crohn's Disease. The drugs used depend on the severity of the condition:

• Mild-to-moderate Crohn's disease is generally treated with antibiotics and an oral mesalamine or sulfasalazine. (Some researchers suggest, however, that corticosteroids are more effective than these drugs in patients with disease in the small intestine and ascending colon. Furthermore, new forms of oral corticosteroids, such as budesonide capsules, pose a lower risk for adverse effects.)
• Moderate to severe Crohn's disease is treated with corticosteroids, infliximab, and drugs that modify or suppress the immune system. Such drugs may be used alone or in combinations. Some patients with severe Crohn's may be candidates for surgery.

Determining Success. The success of therapy is determined by its ability to induce and maintain remissions without incurring significant side effects. The patient's condition is generally considered in remission when the intestinal lining has healed and symptoms, such as diarrhea, abdominal cramps, and tenesmus (painful defecation), are normal or close to normal. It is more difficult to define remission in Crohn's disease because diagnostic test results do not always correlate with a patient's symptoms or complications outside the intestine.

Corticosteroids

General Guidelines. Corticosteroids (commonly called steroids) are powerful anti-inflammatory drugs that are the drugs most often used for Crohn's disease in adults. Because of their adverse effects, in treating children, steroids should be reserved for those with severe disease or who relapse after other therapies. Steroids appear to be safe for pregnant women and can be used if necessary during pregnancy.

Steroids are frequently combined with other drugs to produce more rapid symptom relief and to allow quicker withdrawal, although such combinations do not improve remission time.

In general, they are recommended only for active Crohn's, because long-term treatments cause significant side effects and alternative drugs exist. Unfortunately, most doctors also use them for maintenance treatment, in spite of the fact that two major analyses of oral steroids reported no reduction in relapse rates with their use.

Patients who are malnourished are less likely to respond to steroids, and those who had an initial inadequate response to steroids are also less likely to do well with repeat therapy. Some patients who have had Crohn's disease for a long time may have partial or complete resistance to corticosteroids.

Corticosteroid Types. Prednisone, prednisolone, hydrocortisone, and methylprednisolone are the most common corticosteroids. Newer steroids, such as budesonide, fluticasone, beclomethasone, dipropionate, prednisolone-21-methasulphobenzoate, and tixocortol, affect only local areas in the intestine and do not circulate throughout the body. Such drugs may avoid the widespread side effects that are a serious problem with long-term treatment using the older conventional steroids. Recent studies suggest that budesonide can help prolong and maintain remission periods in patients with Crohn’s disease.

Administering Corticosteroids. Steroids can be taken orally, intravenously, by injection, or rectally as a suppository, enema, or foam. The severity or location of the condition often determines the form.

In general, oral preparations are used for moderate to severe Crohn's disease. Delayed-release forms of corticosteroids, such as beclomethasone or budesonide, affect only local areas of the intestine and may be useful for mild to moderate Crohn's disease without causing systemic side effects.

If the patient requires hospitalization, intravenous steroid therapy is administered initially. (If these drugs are not effective after a week of intravenous therapy, they are not likely to work.)

Side Effects of Corticosteroids. Standard steroids can have distressing and sometimes serious long-term side effects, including:

• Susceptibility to infection
• Weight gain (particularly increased fatty tissue on the face and upper trunk and back)
• Acne
• Excess hair growth
• High blood pressure (hypertension)
• Accelerated osteoporosis
• Cataracts and glaucoma
• Diabetes
• Wasting of the muscles
• Menstrual irregularities
• Upper gastrointestinal ulcers
• Personality change, including irritability, insomnia, psychosis, and depression; such emotional changes are sometimes severe enough to produce suicidal thoughts
• Growth may be retarded in children

Treatments are available for steroid-induced diabetes, swelling, and hypertension. Vaccines are available to help prevent influenza and pneumonia. Any infection should be treated promptly. Supplemental calcium and vitamin D are important to help preserve bone mass against osteoporosis. The newer oral steroids, such as budesonide, have far fewer and less severe side effects.

Withdrawing from Corticosteroids. Once the intestinal inflammation has subsided, steroids must be withdrawn very gradually in order to give the body time to recover its own ability to produce natural steroids. Withdrawal symptoms, including fever, malaise, and joint pain may occur if the dosage is lowered too rapidly. If this happens, the dosage is increased slightly and maintained until symptoms are gone. More gradual withdrawal is then resumed.

Mesalamine (5-Aminosalicylic Acid): Sulfasalazine and Other Preparations

Mesalamine is the common name of the compound 5-aminosalicylic acid or 5-ASA. This drug inhibits factors in the immune system, especially cytokines that cause inflammation. Mesalamine and its different preparations are very effective for IBD. Some evidence suggests that mesalamine reduces the risk for colon cancer. Mesalamine is not very effective in preventing recurrence in Crohn's disease, however.

Mesalamine has few side effects, but it is absorbed so quickly in the upper gastrointestinal tract that it usually fails to reach the colon if used orally and as a single drug. Other substances, therefore, are added to mesalamine or it is formulated so that it can reach the lower intestine before it is absorbed. Sulfasalazine (Azulfidine), which contains mesalamine and sulfapyridine (a sulfa antibiotic), is the standard preparation.

Mesalamine seems to benefit women more than men. All mesalamine preparations, including sulfasalazine, appear to be safe for children and for women who are pregnant or nursing.

Sulfasalazine. Sulfasalazine (Azulfidine) is the standard mesalamine preparation. Sulfasalazine is known as a prodrug because it becomes an active drug when it breaks down by intestinal bacteria. It is broken down into two components: mesalamine and sulfapyridine:

• Mesalamine, the active component, blocks the inflammatory process.
• Sulfapyridine (a sulfa antibiotic) plays no role in treating the disease, but it does prevent mesalamine from being absorbed until it reaches the colon.

For patients with mild-to-moderate Crohn's disease, sulfasalazine and other mesalamine preparations and formulations are generally most useful in combination with steroids and when the disease is limited to the colon. A syrup form of sulfasalazine is available for children.

Side effects of sulfasalazine differ depending on the specific component.

• Mesalamine Component. Mesalamine has a chemical structure similar to aspirin. Therefore, people allergic to aspirin should not take any of the 5-ASA drugs or preparations. Mesalamine itself has few side effects and is considered safe to take during pregnancy. One of the most common side effects is diarrhea, which varies depending on the preparation. For example, olsalazine poses a risk for diarrhea, which may be minimized by starting out with lower doses and taking the medication with meals. Other side effects of all oral forms of mesalamine are skin disorders, nausea, cramps, itchiness, anxiety attacks, and inflammation of other organs. Oral mesalamine, particularly Asacol, may slightly increase the risk for kidney damage. (Olsalazine has a lesser effect on the kidneys.)
• Sulfapyridine, the Sulfa Component. The sulfa component is responsible for most of sulfasalazine's adverse side effects, which are experienced by up to 30% of patients taking this drug. Common side effects include allergic reactions, heartburn, headache, loss of appetite, abdominal discomfort, dizziness, anemia, fever, and rashes. The sulfa component may temporarily lower sperm count in men and can turn urine a bright orange-yellow color. Rare but serious side effects include a lupus-like disorder, pancreatitis, liver damage, and blood disorders, such as hemolytic anemia. Blood counts should be performed regularly, particularly during the first few weeks of treatment. Sulfasalazine completely inhibits the absorption of folic acid and patients should take supplements of this important B vitamin. This is critical during pregnancy. As with most major drugs for IBD, withdrawal of sulfasalazine when the disease is still active can trigger a severe relapse.

Other Mesalamine Prodrugs. Olsalazine (Dipentum) and balsalazide (Colazide) are similar to sulfasalazine, in that they are broken down by intestinal bacteria into two components, one of which is mesalamine. Unlike sulfasalazine, however, the other component in each drug is a harmless molecule that does not produce side effects that are as severe as those of sulfasalazine.

Delayed Release Mesalamine. Formulations have been developed that allow mesalamine alone to reach the lower intestine without the need for the sulfa component. A number of oral forms of mesalamine use coatings or time-released formulations to prevent absorption in the upper intestine. Different brands affect different regions in the intestine:

• Pentasa is an oral sustained-release mesalamine that is coated in a substance called ethyl cellulose. It is slowly released from the stomach through the intestine and is the only aminosalicylate that works in both the small intestine and colon. Twelve-month remission rates of up to 64% have been reported in ulcerative colitis patients with mild to moderate disease. It also appears to be useful in some patients with Crohn's, particularly in those with disease confined to the small intestine.
• Asacol and Salofalk are coated with an acrylic, and the active drug is released in an alkaline environment. It is effective from the colon through the last section of the ileum. Limited data has also suggested that it produces remission in up to 45% of patients with active Crohn's disease and prevents relapse in as many as two-thirds of patients for up to a year. Asacol may become a good choice for mild-to-moderate Crohn's disease.

Immunosuppressive Drugs

For very active inflammatory bowel disease that does not respond to standard treatments, immunosuppressant drugs are now used for long-term therapy. Such drugs suppress actions of the immune system and therefore its inflammatory response, which causes Crohn's disease. Immunosuppressants may help maintain remission in Crohn's disease and to heal fistulas and intestinal ulcers caused by this disease.

The standard drugs are purine analogues, especially azathioprine and mercaptopurine. Other immunosuppressants being investigated include methotrexate, cyclosporine, and mycophenolate. Methotrexate is the least expensive of these drugs, but it also has the greatest adverse effects on the liver and in pregnant women. Experts recommend that they be used very cautiously in children, generally only if they relapse after being treated with mesalamine drugs and corticosteroids.

Most of these drugs can take up to 10 - 12 weeks to achieve peak effectiveness. (They may work more rapidly for subsequent attacks). Administering an immunosuppressant intravenously (called a loading dose) may speed up the initial response.

An immunosuppressant is often combined with a corticosteroid to speed up response during active attacks. Lower doses of the steroid are then needed, resulting in fewer side effects. Corticosteroids may also be withdrawn more quickly. For this reason, immunosuppressants are sometimes referred to as steroid-sparing drugs.

Purine Analogues. Purine analogues include mercaptopurine (Purinethol) and its prodrug azathioprine (Imuran). (A prodrug is a compound that breaks down into the active drug.) These drugs prevent cell proliferation in ways that are not yet clear. Both are useful for maintenance treatment in Crohn's disease to reduce dependency on steroids. However, purine analogues can take several weeks to 6 months to achieve peak effectiveness, so they are not useful for treating an acute attack.

Studies of the effects of purine analogues on fistulas report that about a third that occur around the anus close completely, and a quarter improve during treatment. In one study, intestinal and abdominal fistulas healed even better than anal fistulas with azathioprine. They may be helpful for children with moderate-to-severe Crohn's disease. Some evidence suggests that these drugs are safe during pregnancy. Mercaptopurine may have fewer adverse effects than its parent drug, azathioprine.

Complications include a higher risk for infections, such as pneumonia and herpes zoster, a risk for diabetes, and liver toxicity. Other serious side effects include pancreatitis, which occurs in about 1.2% of patients taking these drugs. Symptoms of pancreatitis usually occur within the first few weeks and include nausea, vomiting, and upper abdominal pain that may radiate to the back. Both of these effects are reversible when the drugs are stopped. A small percentage of patients carry a genetic factor that poses a risk for a life-threatening side effect of the drug, which is bone-marrow suppression, causing a dangerous drop in white blood cell production. (However, a mild drop in white blood cells is an indicator that the drug is working.) Monitoring specific enzymes that are metabolized by these drugs may help predict patients genetically at risk for these effects and for determining adequate doses.

Methotrexate. Methotrexate (Rheumatrex) may be an effective alternative for patients with Crohn's disease who have failed other treatments and cannot tolerate the standard purine analogues. According to a 2000 study, 40 weeks of low dose weekly injections reduced the rates of Crohn's disease relapse by 26% and the use of prednisone by about half. These results suggest a role for methotrexate in long-term maintenance of remission. Methotrexate may also be useful in treating fistulas in patients with Crohn's. Methotrexate does not appear to help ulcerative colitis. Methotrexate can cause liver scarring and lung inflammation and should not be used by people with liver damage or who are at risk for it. Use of methotrexate in children is limited due to its toxicity.

Cyclosporine. Cyclosporine, particularly administered intravenously, may be useful for Crohn's disease accompanied by severe fistulas. (It is not generally used in treating Crohn's disease itself, however.) In one study, the rate of overall response to cyclosporine was 83% and improvement occurred within 2 weeks. Other studies show even stronger results. Relapses and adverse effects occur commonly with cyclosporine, however, when patients are switched to oral forms, so it does not seem to be beneficial for long-term maintenance. Several studies indicated that patients with fistula who received cyclosporine overlapping with a combination of azathioprine and mercaptopurine for more than 4 months were more likely to maintain their response when cyclosporine therapy was stopped.

Other Immunosuppressants. Tacrolimus is similar to cyclosporine, but its oral form is better absorbed than oral cyclosporine. It is showing promise in small studies of severe Crohn's disease. Less than half of patients, however, achieve long-term remission.

Mycophenolate mofetil (CellCept), also called MMF, is being studied as an alternative for patients with fistulas who cannot tolerate azathioprine or mercaptopurine. It appears to be roughly equivalent in effectiveness and safety to the other drugs, although not as effective in maintaining remission. Very small studies have shown a 75% closure rate with an average of 8 months treatment with MMF.

General Side Effects of Immunosuppressants. Although experts have been concerned about dangerous side effects based on experience with immunosuppressants used in transplant operations, the lower doses of the drugs required for IBD and other inflammatory disorders may make them safer for long-term treatments than steroids. Specific side effects occur with individual drugs.

The most common side effects of immunosuppressants include:

• Stomach and intestinal distress
• Rash
• Numbness or tingling in the hands and feet, mouth sores
• Hair loss (or excessive hair growth with cyclosporine)

The actions of immunosuppressants, however, also have more serious effects:

• They inhibit certain rapidly growing immune system cells, including those that produce antibodies, causing an increased risk for infections.
• Oversuppression of the immune system can result in low blood cell counts and anemia.
• Between 3 - 15% of patients taking immunosuppressants develop pancreatitis, which is usually mild and resolves on withdrawal. In some cases patients may be able to resume the immunosuppressants. Symptoms of pancreatitis usually occur within the first few weeks and include nausea, vomiting, and upper abdominal pain that may radiate to the back.
• In pregnancy, the use of immunosuppressants by the mother is associated with birth defects, such as cleft palate, limb deformities, and eye problems. Their use is generally not recommended for women during pregnancy or breastfeeding. Pregnant women should absolutely avoid methotrexate.
• Other serious adverse effects include hepatitis, bladder problems, and menstrual irregularity with possible sterility. (Administering pulsed doses at the time of menstruation may prevent infertility in women.)

Antibiotics

Antibiotics are often used to induce remission in mild-to-moderate Crohn's disease. They are also important for treating fistulas, bacterial overgrowth, abdominal abscesses, and any infections around the anus and genital areas. Stopping antibiotics brings on relapse, so long-term therapy is required, carrying a risk for side effects.

The standard antibiotics used for inducing remission in Crohn's disease are ciprofloxacin (Cipro) and metronidazole (Flagyl). Ciprofloxacin is the antibiotic of choice. Evidence for the benefit of metronidazole (Flagyl) is weaker than for Cipro. Furthermore, over time Flagyl can cause peripheral neuropathy, which are nerve abnormalities that can cause numbness and tingling in the hands and feet. Other antibiotics used for Crohn's disease include trimethoprim/sulfamethoxazole (Bactrim, Cotrim, Septra) and tetracycline.

Small studies have reported that either ciprofloxacin or metronidazole has produced disease remission rates of about 70% that last a year. Comparison studies with corticosteroids, however, have not clearly identified any additional benefits from antibiotics for mild-to-moderate Crohn's disease. More research is needed to clarify this issue.

Infliximab and Other Tumor Necrosis Factors (TNF) Modifiers

Biologic response modifiers are drugs that interfere with the inflammatory response. Of special interest for patients with Crohn's disease are drugs that target the inflammatory immune factor known as tumor necrosis factor (TNF).

Infliximab. Infliximab (Remicade) acts against TNF and was the first genetically engineered drug approved for treating adults with Crohn's disease. It is made from a genetically designed antibody called a monoclonal antibody (MAb) that blocks the activity of tumor necrosis factor-alpha (TNF-a). In 2006, the FDA approved infliximab for children with active Crohn’s disease.

Infliximab cannot cure Crohn’s disease, but it can help control symptoms and, possibly, keep the disease in remission. Studies suggest that up to 80% of patients respond initially, and about a third of all patients remain in remission after a single infusion. Remissions last a few weeks to several months. A 6-week course of infliximab helps close and heal fistulas in half of patients and reduces drainage in 70%. The drug is also being studied for maintenance therapy, although given some significant side effects, it will most likely be reserved for active disease that does not respond to other treatments.

Infliximab’s severe side effects may include tuberculosis, pneumonia, and other infections; lymphoma (a type of cancer); liver failure; and aplastic anemia.

Adalimumab. The Food and Drug administration approved adalimumab (Humira) early in 2007 for treating adult patients with moderate-to-severe Crohn's disease. Like infliximab, adalimumab blocks TNF, an immune system chemical that promotes inflammation. Also approved for treating symptoms of rheumatoid arthritis, adalimumab requires injections to initiate treatment, followed by a maintenance shot every other week.

Adalimumab's label includes a boxed warning. The medicine has been associated with serious, sometimes fatal, infections, including tuberculosis and sepsis. Other severe side effects may include lymphoma, upper respiratory infections, sinusitis, and nausea.

Other Anti-TNF Drugs. Several other TNF modifiers are being investigated. To date, however, infliximab (Remicade) and adalimumab (Humira) are the only TNF modifiers that have been useful for Crohn's disease. An investigative anti-TNF monoclonal antibodies that is showing promise in clinical trials is called certolizumab (Cimzia).

Investigational Therapies

Selective Adhesion Molecule Inhibitors. Selective adhesion molecule inhibitors block the genetic expression of cell adhesion molecules (CAMs). CAMs play an important role in the accumulation of immune factors that cause the inflammatory response. Natalizumab (Tysabri) is a monoclonal antibody that blocks alpha4 integrin, a protein that binds to CAMs. This drug is approved to treat multiple sclerosis and is also being studied for Crohn’s disease. Some studies suggest that natalizumab can help patients achieve and maintain remission. However, natalizumab is associated with severe side effects, including a rare neurological condition called progressive multifocal leukoencephalopathy (PML). A 2006 study found that patients who take natalizumab have a very low risk for PML. Still, the potential benefits of natalizumab need to be weighed against its risks for serious side effects.

Other Biologic Therapies. Biologic therapies are designed to block immune factors that play a role in the inflammatory response. Among them are interferons, anti-interferon antibodies, anti-interleukin antibodies, p65 anti-sense oligonucleotides, growth factors, and others. Several 2006 studies indicated that fontolizumab (HuZaf), an anti-interferon gamma monoclonal antibody, shows promise as a treatment for Crohn’s disease. Sargramostim (Leukine), a granulocyte-macrophage colony stimulating factor, is another biologic drug that may help improve symptoms and quality of life for patients with active Crohn’s disease.

Parasites. Inflammatory bowel disease is rare in countries where intestinal infection with parasites called helminthes is common. Small studies are reporting significant remission rates in patients with Crohn's disease or ulcerative colitis who have swallowed the eggs of a specific parasitic worm. The parasite does not invade tissue or spread other diseases. The parasite induces production of specific T cells, called TH-2, which are immune factors that may be protective against overactivity of cytokines that trigger Crohn's.

Growth Factors. Growth factor hormones increase immune factors, so one would think they might be harmful for patients with Crohn's disease. However, some research suggests that using growth factors might be helpful for certain patients. For example, small studies on granulocyte macrophage colony stimulating factors are reporting some promise.

Heparin. Heparin is an anti-blood clotting drug that also has anti-inflammatory properties. Some evidence suggests that specific forms of heparin, notably low-molecular weight heparin, may prove to be beneficial for patients with IBD.

Surgery

Between two-thirds to three-quarters of patients with Crohn's eventually need surgery when symptoms cannot be controlled by medication. Among children with Crohn's, half require surgery within 5 years of diagnosis.

In general, surgery is used to remove damaged areas of the colon:

• The entire colon (proctocolectomy) or a section of it (subtotal colectomy) may need to be removed in cases of extensive disease in the large intestine.
• Resection or strictureplasty, which removes limited sections of the colon, may be appropriate for many patients.

Surgery is useful only for reducing symptoms. Crohn's disease cannot be cured with surgery because new disease can appear in other areas of the intestine. Surgery may be helpful for relieving symptoms and to correct blockage, perforation, fistulas, or bleeding.

Surgery has reportedly improved the quality of life in most patients, except for those who continued to have active disease. Many children with Crohn's who have suffered growth problems catch up to near-normal growth levels after surgery. Some experts urge, in fact, that many patients should consider surgery in the early stages of the disease.

Strictureplasty

Some patients may be candidates for a procedure called strictureplasty, which involves cutting and stitching only the areas obstructing the intestine, so that it widens the intestine without removing sections of it. It involves the following:

• A balloon attached to a catheter (a thin tube) is passed along the intestine.
• If it becomes blocked, then a stricture (an obstruction) is indicated.
• The surgeon widens the intestine at the point, but does not remove sections of it.
• The procedure is by no means foolproof. Nearly half of patients require re-operation, but strictureplasty in the jejunum and ileum of the small intestine is safe and generally effective over the long term. It may not be useful for Crohn's disease in duodenum (the first section of the small intestine).

Procedures Used to Remove Damaged Portions of the Colon

The invasiveness of the surgical procedure to remove damaged portions of the colon depends on the severity of the disease.

Resection of the Colon. In most cases of Crohn's disease, only a part of the colon needs to be removed, a procedure called resection.

Click the icon to see an illustrated series depicting large bowel resection surgery.

Subtotal Colectomy. Subtotal colectomy is more extensive than resection and removes more of the colon. Disease in the upper parts of the small intestine tends to require more extensive surgery than in the lower small intestine.

In general, either procedure requires a general anesthetic and involves the following:

• An incision is made in the abdomen.
• The diseased portion of the colon is identified and removed. (Strictureplasty is sometimes used alone with resection.)
• Once a diseased segment of the colon is removed, the two ends are reconnected, and this connection is called an anastomosis.

Open Surgery or Laparoscopy. Resection or subtotal colectomy may be performed using one of two surgical approaches:

• Open surgery, which requires a wide abdominal incision.
• Laparoscopy, which uses a few small incisions through which a tube is inserted containing a tiny camera for viewing the area. To date, however, this procedure is best suited for patients with short-segment disease in the ileum who also have no other complications, such as fistulas and abscesses.

Click the icon to see an image of a laparoscopy procedure.

Complications After Resection or Subtotal Colectomy

• Short-bowel syndrome. If large segments of the small intestine are removed, the patient is at higher risk for short-bowel syndrome, a complication in which there is a problem absorbing nutrients. The risk is far lower with strictureplasty. The condition used to be fatal, but patients now can live normal and productive lives using total parenteral nutrition (the intravenous administration of nutrients), which can be self-administered at home in many cases.
• Leakage or obstruction in the areas where the colon has been reconnected (the anastomosis).
• Infections. In a 2003 study, the use of drugs that modify the immune system (azathioprine, 6-MP, methotrexate, and infliximab) was effective in reducing the risk for serious infection in the abdomen.

Proctocolectomy and Ileostomy

Proctocolectomy with ileostomy is removal of the entire colon and creation of an ileostomy. It involves the following:

• To perform proctocolectomy, the surgeon removes the entire colon, including the lower part of the rectum and the sphincter muscles that control bowel movements.
• To perform ileostomy, the surgeon makes a small opening in the lower right corner of the abdomen called a stoma. The surgeon then connects cut ends of the small intestine to this opening. A bag is placed over the opening and accumulates waste matter. It requires emptying several times a day.

Disease Recurrence After Surgery

Recurrence of Crohn's disease is very common after any procedure. One expert described the risk as being between 7 - 25% for each year after resection, with an average risk of 50% at 5 years after resection. (Even if the entire colon is removed there is still a high chance of recurrence in the rectum and a somewhat lower risk for recurrence in the small intestine.)

Patients at highest risk for recurrence include:

• Smokers
• Those whose disease occurred in the ileum (the lowest part of the small intestine) and colon
• Those with abscesses or fistulas
• Those have had previous surgeries

Various drugs are used to prevent recurrence. They include the antibiotic metronidazole (Flagyl), mesalamine, infliximab, and mercaptopurine. These drugs can have severe side effects. And, it is not clear if these or any other drugs are effective in preventing recurrence. Even if medications can help prevent recurrence in some patients, it is not yet known who these individuals might be. (In any case, steroids do not appear to help prevent recurrence.)

Emergency Surgeries

In some cases, surgery is needed for emergency conditions that can occur with Crohn's disease. Emergency surgery is used to:

• Stop severe intestinal bleeding
• Clear small bowel obstruction
• Drain and heal abscesses or fistulas
• Repair perforation

Small Intestine Transplantation

Procedures for transplanting the small intestine in patients with intestinal failure are under investigation. These are still experimental and are being tested in patients who have lost so much of their small intestine that they must rely on total parenteral nutrition (intravenous administration of nutrition). Small-bowel transplantation is a more difficult procedure than some other transplants, because of the high rate of potential complications, including infection and organ rejection. Patients who have transplants must be on immunosuppressant drugs for the rest of their lives. Furthermore, there is some evidence that Crohn's disease recurs in the transplanted bowel.

Resources

• www.ccfa.org -- Crohn's & Colitis Foundation of America
• www.gastro.org -- American Gastroenterological Association
• www.acg.gi.org -- American College of Gastroenterology
• www2.niddk.nih.gov -- National Digestive Diseases Information Clearinghouse

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