Inflammatory Bowel Disease: Frequently Asked Questions, Part 2 of 3

1.8 Q: How is ulcerative colitis diagnosed?

Diagnosis is made based on symptoms and the exclusion of other diseases by observation of typical findings at endoscopy and failure to find evidence of infection. The presence of often bloody diarrhea will prompt your doctor to perform an endoscopic examination; either a sigmoidoscopy and/or colonoscopy (described below). If inflammation is seen by these techniques, the physician will then attempt to rule out an infectious cause with stool cultures and blood tests.

Usually it is possible to tell the difference between CD and UC but not always. Particularly, there may be some uncertainty between a diagnosis of UC and CD affecting the colon; this is termed indeterminate colitis. Occasionally a diagnosis of UC will eventually turn out to be CD.

1.8.1 Q: What are flexible sigmoidoscopy and colonoscopy?

Flexible sigmoidoscopy and colonoscopy are endoscopic procedures that allow doctors to examine the lining of the large intestine. In both procedures, the physician inserts a flexible tube known generically as an endoscope through the anus. The doctor is able to move this tube through the gut to view the mucosal lining of the intestines. This also enables him to take tiny samples of the lining using a forceps passed through the endoscope. These samples (called biopsies) can then be viewed under a microscope by a pathologist. Examination of these biopsies by a pathologist is particularly helpful in making the distinction between CD and UC and also for detecting the early evidence of cancerous change indicated by dysplasia.

Flexible sigmoidoscopy is an endoscopic procedure done without sedation which examines the rectum, sigmoid colon and often a little bit more of the colon reaching as far as the splenic flexure (the bend at which point the descending colon and transverse colon meet).

Colonoscopy is a more elaborate procedure that is used to examine the entire length of the colon which is usually done with sedation.

From the patient's perspective, the main difference between the two procedures is that flexible sigmoidoscopy may be performed in the doctors office and does not normally reach farther than the splenic flexure. Biopsies, or tissue samples may be taken during either procedure.

1.9 Q: How is Crohn's disease diagnosed?

Diagnosis of Crohn's disease of the colon is similar to diagnosis of ulcerative colitis. The differences between the two are found by studying the nature and location of the specific inflammation.

Colonic CD has larger, deeper, thicker ulcers than UC (which instead has an even "micro-carpet" of tiny ulcers on the surface lining of the inner mucosa). In CD, areas of ulceration are often separated by skip areas, a phenomenon not seen in UC. There is a marked contrast between the "cobblestone" appearance often seen with CD and the even "micro-carpet" seen with UC. Sometimes, "granulomas", a microscopic indicator of CD may be seen on biopsy samples.

A diagnosis of probable small bowel CD is frequently made by clinical observations of small bowel Crohn's symptoms accompanied by the detection on physical examination of a palpable mass (which may be tender) in the right lower part of the abdomen. To confirm the diagnosis an upper GI barium x-ray with small bowel follow through is generally performed. In small bowel follow through the small bowel is radiographed as barium passes through it producing silhouette images of the lining. The barium can be introduced either by swallowing, or via a "small-bowel enema" (in which the barium is pumped to the small bowel through a tube). The former method, while more comfortable for the patient and much more commonly used, produces inferior results because the barium is diluted by gastric juices. The latter method is generally used in more perplexing cases. A small bowel enema is also know as an "enteroclysis."

2.1 Q: What Drug therapies are used in IBD?

Lots. The two most widely used drug families are steroids and 5-aminosalicylic acid (5-ASA) drugs , both of which reduce inflammation of the affected parts of the intestines.

Immunosuppressive drugs such as 6-mercaptopurine (Purinethol) are being increasingly used for long-term treatment of IBD. They are particularly useful in the setting of a patient who is dependent on chronic high-dose steroid therapy with its severe and predictable side effects.

2.1.1 Q: What are 5-ASA Drugs?

5-aminosalicylic acid (5-ASA), also called mesalamine, is an anti-inflammatory drug used in treating IBD. 5-ASA has a similar chemical structure to aspirin, but has a 5-amino group in place of aspirin's acetyl group (aspirin is acetylsalicylic acid).

Pure unmodified 5-ASA is easily absorbed in the upper GI tract. To enable its delivery to the lower GI tract where it is needed it must be chemically modified or packaged. Different 5-ASA drugs are formulated to allow delivery to different locations.

Because of the chemical similarities to aspirin, patients allergic to aspirin should not take 5-ASA drugs.

2.1.1.1 Q: What is Azulfidine?

Sulfasalazine (Azulfidine, Azulfidine EN-Tabs in the US; Salazopyrin EN-Tabs, SAS in Canada; salazosulfapyridine, salicylazosulfapyridine):

This is the "staple" drug generally first prescribed for IBD patients. It is taken by mouth and is intended to first reduce inflammation of the intestinal lining and then to maintain remission in mild to moderate cases.

Sulfasalazine is a combination of sulfapyridine and an aspirin-like compound, 5-aminosalicylic acid (5-ASA). The bond between the two is broken by intestinal bacteria, making the 5-ASA available in the terminal ileum and colon. A significant amount of the sulfapyridine component is absorbed, metabolized by the liver, and excreted in urine. Side effects are experienced by some patients and can include nausea, heartburn, headache, dizziness, anemia, and skin rashes. It is also known to cause a reduced sperm count in men, but only for the duration of treatment. It may also turn urine a bright orange-yellow color. The side effects generally result from the sulfapyridine component. Hence the efforts to develop formulations of 5-ASA which do not contain sulfapyridine or other sulfa drugs.

Azulfidine was developed in the 1930's for the treatment of rheumatoid arthritis. During clinical trials in the 1940's, arthritis patients who also suffered from IBD reported improvements in their IBD symptoms while taking it. This led to its current use as the mainstay IBD treatment.

For active disease initially, 1 gram every 6-8 hours is taken by mouth. Adverse effects may be lessened by reducing the dosage to 500 mg every 6-12 hours. Maintenance dose is usually 500 mg every 6 hours, adjusted to patient response and tolerance. Total doses of more than 4 g/day may increase the risk of adverse effects and toxicity but some patients may benefit from taking up to 6 g/day. Azulfadine is generally taken with a full glass of water after meals or with food to minimize indigestion.

When indigestion is a problem enteric-coated tablets may be used which are frequently better tolerated.

2.1.1.2 Q: What is Dipentum?

Olsalazine Sodium (Dipentum)

Olsalazine is a drug that uses a different mechanism to deliver 5-ASA to the terminal ileum and colon. Whereas sulfasalazine links a 5-ASA molecule with a sulfapyridine molecule, olsalazine links two 5-ASA molecules. This compound passes through the stomach and upper ileum. It is then broken down by intestinal bacteria in the terminal ileum, making 5-ASA available there and also in the colon.

The major side effect is watery diarrhea, seen in many patients. Patients with UC or CD affecting the entire colon seem especially susceptible. Increased cramping and audible bowel sounds are also commonly reported.

The usual dose of olsalazine is 500 mg by mouth twice a day.

2.1.1.3 Q: What is Asacol?

Mesalamine, USA; Mesalazine, Europe :

Asacol is essentially "Azulfidine without the sulfa". The Asacol formulation of 5-ASA places 5-ASA in an acrylic resin coating which dissolves at pH greater than 7. The tablets are then able to pass through the stomach and upper ileum before the coating is dissolved, releasing the drug in the terminal ileum and colon where the pH is typically greater than 7.

Asacol is generally well tolerated. The recommended dose is 2.4 g a day though patients frequently seem to tolerate and benefit from taking up to 4.8 g daily.

2.1.1.4 Q: What is Salofalk?

Mesalazine, Europe (Salofalk)

Similar to Asacol, but dissolves at pH greater than 6.

2.1.1.5 Q: What is Pentasa?

Mesalamine, USA; Mesalazine, Europe (Pentasa) :

Yet another "Azulfidine without the sulfa" formulation, this drug packages 5-ASA in a time-release capsule. This method of delivery is thought to make the drug available throughout most of the intestines and provide better release in the small intestine than the other 5-ASA drugs. For this reason Pentasa is the 5-ASA preparation of choice for Crohn's disease involving the small intestine.

Pentasa is generally well tolerated. The recommended dose is 2g a day though patients frequently seem to tolerate and benefit from taking up to 4g daily. There is data that the higher dose may be more effective.

2.1.1.6 Q: What is Balsalazide?

Balsalazide:

Another 5-ASA drug that uses a variant on sulfasalazine's delivery mechanism, Balsalazide contains 5-ASA joined to an inert vehicle. This combination passes through the stomach and upper ileum. It is then broken down by intestinal bacteria in the terminal ileum, making 5-ASA available in the terminal ileum and colon.

2.1.1.7 Q: What is Rowasa?

Mesalamine (Rowasa) :

Rowasa is 5-ASA in enema form and is effective in treating distal UC, which is simply UC affecting the lower part of the colon, near the rectum, and the rectum itself. One enema contains 4 g of 5-ASA.

Rowasa also comes in suppository form for treating proctitis (rectal inflammation). Each suppository contains 500 mg of 5-ASA.

2.1.2 Q: What is Metronidazole?

Metronidazole (Flagyl) :

Metronidazole is an antibiotic that is most frequently used for treating vaginal infections. However, there is some evidence (much of it anecdotal rather than derived from formal studies) that it is useful in treating CD. Some studies have shown that it has an anti-inflammatory action on CD that is at least as effective as sulfasalazine. The mechanism of this action is unknown, and it has not been found in other antibiotics having the same antibiotic spectrum. Metronidazole appears to be particularly effective in the treatment of CD in the colon. The dose is generally 250 mg three times a day. Some patients are unable to tolerate alcohol while taking metronidazole; accordingly it is generally recommended that patients avoid alcohol while taking it.

Though it has been shown to cause cancer in laboratory rodents exposed to very high doses (much, much higher than used in humans) there is NO evidence that it has any similar effect in humans.

The major side effect of metronidazole is irritation of nerves which can result in permanent nerve damage if the medication is not promptly stopped. The first hint of this problem is usually a sensation of "pins and needles" in the finger tips and toes. If this is noted the medication should be stopped immediately.

Current issues of the PDR contain the disclaimer "Crohn's disease is not an approved indication for metronidazole".

2.1.3 Q: What is Ciprofloxacin?

Ciprofloxacin ("Cipro") is another antibiotic frequently used in the treatment of CD. Many physicians and patients report positive results from a trial of cipro, although the formal evidence to justify its use is limited. An infrequent side effect of prolonged use is the development of inflammation of tendons (tendonitis) which may result in rupture especially of the achilles tendon.

2.1.4 Q: What is Clarithromycin (Biaxin)?

Another antibiotic used in the treatment of CD. As with the others there is currently little formal evidence to justify its use.

2.1.5 Q: What are adrenal corticosteroids (steroids), and when and why are they used?

Prednisone, Prednisolone, Hydrocortisone:

When 5-ASA drugs fail or when symptoms are more severe, the next therapeutic step usually involves steroids which are very powerful anti-inflammatory drugs. These are available in oral, enema, or suppository forms. The topical forms are useful in treating distal colitis, the oral forms are useful for achieving remission in mild to moderate active UC and CD. They are NOT useful for continued use in order to maintain a remission. The oral forms can, however, be effective in suppressing active CD to the point where it appears to be in remission.

2.1.5.1 Q: What are the side effects from taking steroids?

Side effects from steroids vary widely between patients, but are generally pretty severe particularly when used at moderate to high doses (> 15mg prednisone daily). Common side effects include rounding of the face (moon face) and increase in the size of fat pads on the upper back and back of the neck (buffalo hump), acne, increased appetite with consequent weight gain, increased body hair, osteoporosis (especially in women), compression fractures in vertebrae, diabetes, hypertension, cataracts, increased susceptibility to infections, glaucoma, weakness of arm, leg, shoulder, and pelvic muscles, personality changes including depression (suicidal tendencies are not uncommon), irritability, nervousness, and insomnia. Children's growth may also be affected, even by small doses.

An important and serious complication of steroid therapy is avascular necrosis of the hip. This results in death of the bone in the hip joint resulting in arthritis and severe pain. Fortunately, it is a rare complication.

Side effects are not as severe with the topical forms in the short term, but increase to about the level of the oral drugs with long term use.

Some people report inconsistent response to treatment with Prednisone, saying they respond better at some times to a particular treatment course than they do at others.

Corticosteroids suppress the activity of the adrenal glands, which must be restored gradually when the drug is discontinued. This requires gradual tapering of the steroid. Most physicians will not taper long term steroid users faster than roughly 1mg per week or 5 mg per month. For short term users, dosage may be lowered at a faster rate, such as 5 to 10 mg per week.

Withdrawal symptoms can occur when the dosage is lowered too quickly. These may include fever, malaise, and joint pains. Since these can also be symptoms of IBD, it is often difficult to tell whether they are the result of insufficient steroid levels, or a true relapse of IBD.

If IBD symptoms begin to return during tapering, standard procedure is to return to a slightly higher dose, which is maintained until symptoms subside. Tapering may then be resumed at a slower rate.

Long term use of steroids (more than a few days) suppresses the adrenal gland's normal production of steroids and can affect its function for a long time (up to a year, or in some cases even two) even after steroid use has stopped. During this period, the body may not be able to produce an adequate supply of steroids during extreme stress, such as surgery or severe infection.

If you've been taking steroids for a while you should probably wear a MEDIC-ALERT necklace or bracelet indicating the quantity and duration of steroid use. (Some suggest carrying a note in the wallet, but such a note will likely never be seen because standard operating procedure for emergency medical personnel is to avoid any contact with a patient's valuables for liability reasons). If you require emergency surgery, this information can be of vital importance since you'll need to be administered additional steroids. Your body isn't capable of producing enough steroids on its own to help survive the stress.

Because of the potential problems it is very important that steroid therapy is closely supervised by a physician.

2.1.5.2 Q: What is meant by "Alternate Day Therapy"?

Increasing the period of time between steroid doses can allow the adrenal glands to recover somewhat. Alternate day therapy is simply taking double the daily dose on every other day. Due to the duration of the effects of steroids such as Prednisone, this can have the same therapeutic results with fewer side effects.

2.1.5.3 Q: What is Budesonide?

Budesonide is currently in "beta testing". It is a steroid that is processed by the liver so that there are less severe side effects. Oral and enema forms are available, depending upon the location of the disease to be treated. Its role compared to the more established steroid agents has yet to be defined. The impression of many is that though it may be safer it may also be less effective.

2.1.5.4 Q: What is ACTH?

Adreno-cortico-tropic hormone is a drug that stimulates the adrenal gland to release cortisone. It is seldom used any more.

2.1.5.5 Q: What do steroids do to bones?

Steroid drugs unfortunately can cause osteoporosis. Osteoporosis is a disease which results in the destruction of bones causing them to become weak and much more likely to fracture. Without protection within the first six months of steroid therapy a person can lose 10 percent to 20 percent of bone mass. As many as one in four of these people may eventually suffer a fracture as a result. Unlike osteoporosis associated with aging, steroid-induced osteoporosis can occur at any age, even in children. For many years it was thought that only high (>20mgs a day) doses of steroids were a problem, more recent studies have shown that chronic use of low oral doses -- as little as 7.5 milligrams a day -- can cause significant though gradual bone loss.

Steroids reduce the amount of calcium the body absorbs from food and increase calcium loss through the kidneys. These actions result in a tendency for the level of calcium in the blood to fall. To prevent this happening the body responds by producing increased amounts of parathyroid hormone. Parathyroid hormone is released to remove calcium from storage in the bone and restore a normal level. In addition steroids also cause bone breakdown directly.

2.1.5.6 Q:  What should be done to minimize the damage done by steroids to bones when I am being treated for IBD?

The best strategy is to avoid the problem entirely by using the lowest effective dose of steroid. Also to use topical steroids if possible instead of systemic steroids by mouth. Recently the American College of Rheumatology recommended that either before or at the very start of steroid therapy, patients should ideally be given a bone density test, especially of the lower spine and the neck of the thigh bone near where it meets the pelvis. This test should be repeated every six to 12 months to monitor the effectiveness of preventive measures and, if necessary, to modify the course of treatment. Everyone who must take corticosteroids should consume at least 1,500 milligrams of calcium and 800 international units of vitamin D a day, either through diet or supplements. Vitamin D is needed to enhance the body's ability to absorb calcium and use it to build bone.

Patients on steroids should get regular weight-bearing exercise, preferably for 30 to 60 minutes a day as this can help prevent bone loss. They should should not smoke or drink more than moderate amounts of alcohol as these are associated with increased rates of bone loss. Consideration should be given to hormone replacement therapy in woman who are post menopause. Women who have not yet reached menopause whose periods become irregular or stop while on steroids should take oral contraceptives unless there is a medical reason for not taking them. For men on steroids consideration should be given to measuring their testosterone level and, if found to be low, given testosterone replacement.

2.1.6 Q: What are immunosuppressive drugs and when are they used?

Immunosuppressives such as 6-mercaptopurine (6-MP or purinethol) or azathioprine (imuran) are increasingly used in treating more severe IBD that does not respond to 5-ASA therapy and short term steroid therapy. The most frequent use of these drugs is in the context of inability to reduce the steroid dosages in steroid dependent patients without causing a disease flare. Physicians without significant experience in their use can be reluctant to try them because they rarely can have extreme side effects. Generally these side effects occur at higher doses than are used in the treatment of IBD. However, the emphatic opinion of most physician experts in the management of IBD is that they are significantly safer and more effective than long term use of high dose steroids. The side effects that occur in a small minority of the patients who take them can include various blood problems, bone marrow suppression, extensive immune suppression, kidney damage, liver damage and others. There is no convincing evidence that they predispose to the development of cancer at the doses used in treating IBD patients. Usage of these drugs requires frequent monitoring by blood tests; ideally a complete blood count should be obtained every 3 months.

2.1.6.1 Q: What are Azathioprine and 6-MP?

Azathioprine (Imuran)
6-Mercaptopurine (6-MP, Purinethol ) :

Azathioprine is a drug that was originally used to prevent rejection in organ transplant patients. 6-MP is one of the metabolites of Azathioprine; that means that Azathioprine is converted into 6-MP in the body.

Both drugs have shown some degree of efficacy when used in combination with prednisone. Because they facilitate the use of lower steroid doses they are frequently called "steroid sparing" drugs. Most people can tolerate these drugs without difficulty thus helping avoid long term high dose steroids and the predictable associated side effects. At this time it is the consensus of experts in the management of IBD that it is clearly preferable to treat a patient with long term Azathioprine or 6-MP rather than with continued or even intermittent high dose steroids.

Despite impressive data from clinical trials supporting the use of 6-MP and azathioprine in both CD and UC many patients are still treated with prednisone for longer periods than are appropriate because of the erroneous perception that Azathioprine and 6-MP are more hazardous.

This perception is derived in part from the side effect profile seen when these drugs were originally used in preventing transplant rejection and also in the treatment of leukemia. The important difference is that significantly higher doses were used in these situations than are now used in the treatment of both CD and UC. These drugs were developed in the 1950s and were first used for the treatment of IBD 30 years ago! Obviously a lot has been learned about how to use them to maximum advantage over the intervening years.

The minimum time to respond to the drug is about three months and can be as long as 12 months. These drugs are effective in maintaining remission in 60 - 80% of patients.

An important side effect that occurs in 3-5% of patients is pancreatitis. This usually occurs within a few weeks of starting treatment and is manifested by upper abdominal pain which may radiate to the back and be associated with nausea and vomiting. If pancreatitis occurs then the patient cannot take either Azathioprine or 6-MP in the future.

Because of occasional problems with a reduced white blood cell count it is recommended that patients have complete blood counts on a regular basis; every three months is recommended though they should be more frequent during the first few months of therapy.

The issue of how long these drugs can safely be used for has not been definitively resolved. An increasing number of patients have been maintained on these drugs for several years (> 3) without any significant long term side effects noted.

2.1.6.2 Q: What is Methotrexate?

Methotrexate (Folex, Mexate in the US) :

Like the other immunosuppressants, methotrexate may have some benefit in treating active Crohn's disease. Methotrexate has not been used as extensively as Azathioprine or 6-MP but there is increasing data that it may be useful. Methotrexate may be a useful option in patients who are intolerant of  Azathioprine or 6-MP. Because of the occurence of liver disease in patients taking methotrexate over a sustained period careful monitoring of liver function is necessary. Patients should not drink alcohol while taking methotrexate.

Methotrexate should not be used in pregnancy. Patients taking methotrexate should not get pregnant.

2.1.6.3 Q: What is Cyclosporine?

Cyclosporine is another immunosuppressant drug that was originally and is still used extensively for preventing rejection of organ transplants such as kidney and liver transplants.

Though initial hopes were high that it would be a very good drug for severe and complicated CD the results have been somewhat disappointing.

In severe CD particularly complicated by fistulas there is data that high dose intravenous cyclosporine may be useful in the short term. Low dose therapy for maintenance of remission does not seem to be effective and has unacceptable side effects.

In severe UC, particularly when a patient is on the threshold of requiring urgent surgery there has been some success with cyclosporine in inducing a remission. These patients are generally treated simulataneously with high dose steroids also and are started on 6-MP or azathioprine also. After 3-6 months of therapy, when 6-MP or azathioprine has hopefully become effective, cyclosporine is stopped and simultaneously steroids are reduced and stopped if possible. This approach seems to be effective in the short term with a significant proportion of patients with severe UC. However, a significant proportion of these patients subsequently have surgery because of inability to maintain them in remission.

Continue with Part 3 of 3


Source: Copyright 1997 by Kevin Horgan, M.D., Christopher Holmes and Michael Bloom. All Rights reserved.   This document, or any derivative works thereof, may not be sold or redistributed for profit in any way without express (not email) written permission of the authors. This includes, but is not limited to, translations into foreign languages, mass archival as on a CD_ROM and inclusion in commercially published compilations (books). You are free to copy this list for personal use, or to make it available for redistribution in its electronic format, provided that: (1) it remains wholly unedited and unmodified, (2) no fee or compensation is charged for copies of or access to this list, and (3) this copyright notice and the following disclaimer remain attached.