Ulcerative colitis is a chronic inflammation of the large intestine (colon). The colon is the part of the digestive system where waste material is stored. The rectum is the end of the colon adjacent to the anus. In patients with ulcerative colitis, ulcers and inflammation of the inner lining of the colon lead to symptoms of abdominal pain, diarrhea, and rectal bleeding.
Ulcerative colitis is closely related to another condition of inflammation of the intestines called Crohn's disease. Together, they are frequently referred to as inflammatory bowel disease (IBD). Ulcerative colitis and Crohn's diseases are chronic conditions that can last years to decades. They affect approximately 500,000 to 2 million people In the United States. Men and women are affected equally. They most commonly begin during adolescence and early adulthood, but they also can begin during childhood and later in life.
It is found worldwide, but is most common in the United States, England, and northern Europe. It is especially common in people of Jewish descent. Ulcerative colitis is rarely seen in Eastern Europe, Asia, and South America, and is rare in the black population. For unknown reasons, an increased frequency of this condition has been recently observed in developing nations.
What Causes Ulcerative Colitis?
The causes of ulcerative colitis and Crohn's disease are unknown. To date, there has been no convincing evidence that these two diseases are caused by infection. Neither disease is contagious.
Ulcerative colitis and Crohn's disease are caused by abnormal activation of the immune system in the intestines. The immune system is composed of immune cells and the proteins that these cells produce. These cells and proteins serve to defend the body against harmful bacteria, viruses, fungi, and other foreign invaders. Activation of the immune system causes inflammation within the tissues where the activation occurs. (Inflammation is, in fact, an important mechanism of defense used by the immune system.) Normally, the immune system is activated only when the body is exposed to harmful invaders. In patients with Crohn's disease and ulcerative colitis, however, the immune system is abnormally and chronically activated in the absence of any known invader. The continued abnormal activation of the immune systems causes chronic inflammation and ulceration. The susceptibility to abnormal activation of the immune system is genetically inherited. First degree relatives (brothers, sisters, children, and parents) of patients with IBD are thus more likely to develop these diseases.
What are the Symptoms of Ulcerative Colitis?
Common symptoms of ulcerative colitis include rectal bleeding and diarrhea, but there is a wide range of symptoms among patients with this disease. Variability of symptoms reflects differences in the extent of disease (the amount of the colon and rectum that are inflamed) and the intensity of inflammation. Generally, patients with inflammation confined to the rectum and a short segment of the colon adjacent to the rectum have milder symptoms and a better prognosis than patients with more widespread inflammation of the colon. The different types of ulcerative colitis are classified according to the location and the extent of inflammation:
- Ulcerative proctitis refers to inflammation that is limited to the rectum. In many patients with ulcerative proctitis, mild intermittent rectal bleeding may be the only symptom. Other patients with more severe rectal inflammation may, in addition, experience rectal pain, urgency (sudden feeling of having to defecate and a need to rush to the bathroom for fear of soiling), and tenesmus (ineffective, painful urge to move one's bowels).
- Proctosigmoiditis involves inflammation of the rectum and the sigmoid colon (a short segment of the colon contiguous to the rectum). Symptoms of proctosigmoiditis, like that of proctitis, include rectal bleeding, urgency, and tenesmus. Some patients with proctosigmoiditis also develop bloody diarrhea and cramps.
- Left–sided colitis involves inflammation that starts at the rectum and extends up the left colon (sigmoid colon and the descending colon). Symptoms of left–sided colitis include bloody diarrhea, abdominal cramps, weight loss, and left–sided abdominal pain.
- Pancolitis or universal colitis refers to inflammation affecting the entire colon (right colon, left colon, transverse colon and the rectum). Symptoms of pancolitis include bloody diarrhea, abdominal pain and cramps, weight loss, fatigue, fever, and night sweats. Some patients with pancolitis have low–grade inflammation and mild symptoms that respond readily to medications. Generally, however, patients with pancolitis suffer more severe disease and are more difficult to treat than those with more limited forms of ulcerative colitis.
- Fulminant colitis is a rare but severe form of pancolitis. Patients with fulminant colitis are extremely ill with dehydration, severe abdominal pain, protracted diarrhea with bleeding, and even shock. They are at risk of developing toxic megacolon (marked dilatation of the colon due to severe inflammation) and colon rupture (perforation). Patients with fulminant colitis and toxic megacolon are treated in the hospital with potent intravenous medications. Unless they respond to treatment promptly, surgical removal of the diseased colon is necessary to prevent colon rupture.
While the intensity of colon inflammation in ulcerative colitis waxes and wanes over time, the location and the extent of disease in a patient generally stays constant. Therefore, when a patient with ulcerative proctitis develops a relapse of his disease, the inflammation usually is confined to the rectum. Nevertheless, a small number of patients (less than 10%) with ulcerative proctitis or proctosigmoiditis can later develop more extensive colitis. Thus, patients who initially only have ulcerative proctitis can later develop left–sided colitis or even pancolitis.
How is the Diagnosis of Ulcerative Colitis Made?
The diagnosis of ulcerative colitis is suggested by the symptoms of abdominal pain, rectal bleeding, and diarrhea. Stool specimens are collected for analysis to exclude infection and parasites, since these conditions can cause colitis that mimics ulcerative colitis. Blood tests may show anemia and an elevated white blood cell count or sedimentation rate (commonly referred to as sed rate). An elevated white blood cell count and sed rate both reflect ongoing inflammation in the colon. Confirmation of ulcerative colitis requires a test to visualize the large intestine. Flexible tubes inserted through the rectum (sigmoidoscopes and colonoscopes) permit direct visualization of the inside of the colon to establish the diagnosis and to measure the extent of the colitis. Small tissue samples (biopsies) can be obtained during the procedure to determine the severity of the colitis.
Knowledge of the extent and severity of the colitis is important in choosing among treatment options. A barium enema x–ray may also indicate the diagnosis of ulcerative colitis. During a barium enema, a chalky substance is administered into the rectum and injected into the colon. Barium is radiopaque and can outline the colon on x–ray pictures. A barium enema is less accurate and useful than direct visualization techniques in the diagnosis of ulcerative colitis.
What are the Complications of Ulcerative Colitis?
Patients with ulcerative colitis limited to the rectum (proctitis) or colitis limited to the end of the left colon (proctosigmoiditis) usually do quite well. Brief periodic treatments using oral medications or enemas may be sufficient. Serious complications are rare in these patients. In those with more extensive disease, blood loss from the inflamed intestines can lead to anemia and may require treatment with iron supplements or even blood transfusions. Rarely, the colon can acutely dilate to a large size when the inflammation becomes very severe. This condition is called toxic megacolon. Patients with toxic megacolon are extremely ill with fever, abdominal pain and distention, dehydration, and malnutrition. Unless the patient improves rapidly with medication, surgery usually is necessary to prevent colon rupture.
Colon cancer is a recognized complication of chronic ulcerative colitis. The risk for cancer begins to rise after eight to ten years of colitis. Patients with only ulcerative proctitis probably do not have increased risk of colon cancer compared to the general population. Among patients with active pancolitis (involving the entire colon) for 10 years or longer, the risk of colon cancer is increased compared to the general population. In patients with colitis limited to the left side of the colon, the risk of colon cancer is increased but not as high as in patients with chronic pancolitis.
The current estimates for the cumulative incidence of colon cancer associated with ulcerative colitis are 2.5% at 10 years, 7.6% at 30 years, and 10.8% at 50 years. Patients at higher risk of cancer are patients with positive family histories of colon cancer, long durations of colitis, extensive colon involvement, and primary sclerosing cholangitis (PSC), another complication of ulcerative colitis.
Since these cancers have a more favorable outcome when diagnosed and treated at an earlier stage, yearly colon examinations may be recommended after eight years of known extensive disease. During these examinations, samples of tissue (biopsies) can be taken to search for precancerous changes in the lining cells of the colon. When precancerous changes are found, removal of the colon may be necessary to prevent colon cancer.
Complications of ulcerative colitis can involve other parts of the body. Ten percent of the patients can develop inflammation of the joints (arthritis). Some patients have low back pain due to arthritis of the sacroiliac joints. Rarely, patients may develop painful, red, skin nodules (erythema nodosum). Yet others can have painful, red eyes (uveitis, episcleritis). Because these particular complications can risk permanent vision impairment, eye pain or redness are symptoms that require a physician's evaluation. Diseases of the liver and bile ducts may also be associated with ulcerative colitis. For example, in rare patients with a condition called sclerosing cholangitis, repeated infections and inflammation in the bile ducts can lead to recurrent fever, yellowing of skin (jaundice), cirrhosis, and the need for a liver transplant.
What are the Treatments for Ulcerative Colitis?
Both medications and surgery have been used to treat ulcerative colitis. However, surgery is reserved for those with severe inflammation and life–threatening complications. There is no medication that can cure ulcerative colitis. Patients with ulcerative colitis will typically experience periods of relapse (worsening of inflammation) followed by periods of remission (resolution of inflammation) lasting months to years. During relapses, symptoms of abdominal pain, diarrhea, and rectal bleeding worsen. During remissions, these symptoms subside. Remissions usually occur because of treatment with medications or surgery, but occasionally they occur spontaneously, that is, without any treatment.
Medications
Since ulcerative colitis cannot be cured by medication, the goals of treatment with medication are to 1) induce remissions, 2) maintain remissions, 3) minimize side effects of treatment, and 4) improve the quality of life. Treatment of ulcerative colitis with medications is similar, though not always identical, to treatment of Crohn's disease.
Medications treating ulcerative colitis include 1) anti–inflammatory agents such as 5–ASA compounds, systemic corticosteroids, topical corticosteroids, and 2) immunomodulators.
Anti–inflammatory medications that decrease intestinal inflammation are analogous to arthritis medications that decrease joint inflammation (arthritis). The anti–inflammatory medications that are used in the treatment of ulcerative colitis are:
- Topical 5–ASA compounds such as sulfasalazine (Azulfidine), olsalazine (Dipentum), and mesalamine (Pentasa, Asacol, Rowasa enema) that need direct contact with the inflamed tissue in order to be effective.
- Systemic anti–inflammatory medications such as corticosteroids that decrease inflammation throughout the body without direct contact with the inflamed tissue. Systemic corticosteroids have predictable side effects with long term use.
Immunomodulators are medications that suppress the body's immune system either by reducing the cells that are responsible for immunity, or by interfering with proteins that are important in promoting inflammation. Immunomodulators increasingly are becoming important treatments for patients with severe ulcerative colitis who do not respond adequately to anti–inflammatory agents. Examples of immunomodulators include 6–mercaptopurine (6–MP), azathioprine (Imuran), methotrexate (Rheumatrex, Trexall), cyclosporine (Gengraf, Neoral).
It has long been observed that the risk of ulcerative colitis appears to be higher in nonsmokers and in ex–smokers. In certain circumstances, patients improve when treated with nicotine.
5–ASA Compounds (Azulfidine, Asacol, Pentasa, Dipentum)
5–ASA (5–aminosalicylic acid), also called mesalamine, is chemically similar to aspirin. Aspirin (acetylsalicylic acid) has been used for many years in treating arthritis, bursitis, and tendinitis (conditions of tissue inflammation). Aspirin, however, is not effective in treating ulcerative colitis. On the other hand, 5–ASA can be effective in treating ulcerative colitis if the drug can be delivered directly (topically) onto the inflamed colon lining. For example, Rowasa enema is a 5–ASA solution that is effective in treating inflammation in and near the rectum (ulcerative proctitis and ulcerative proctosigmoiditis). However, the enema solution cannot reach high enough to treat inflammation in the upper colon. Therefore, for most patients with ulcerative colitis, 5–ASA must be taken orally. When pure 5–ASA is taken orally, however, the stomach and upper small intestine absorb most of the drug before it reaches the colon. Therefore, to be effective as an oral agent for ulcerative colitis, 5–ASA has to be modified chemically to escape absorption by the stomach and the upper intestines. These modified 5–ASA compounds are sulfasalazine (Azulfidine), mesalamine (Pentasa, Rowasa, Asacol), and olsalazine (Dipentum).
Azulfidine
Sulfasalazine (Azulfidine) has been used successfully for many years in inducing remission among patients with mild to moderate ulcerative colitis. Inducing remission means decreasing intestinal inflammation and relieving symptoms of abdominal pain, diarrhea, and rectal bleeding. Sulfasalazine has also been used for prolonged periods of time to maintain remissions.
Sulfasalazine consists of a 5–ASA molecule linked chemically to a sulfapyridine molecule. (Sulfapyridine is a sulfa antibiotic). Connecting the two molecules together prevents absorption by the stomach and the upper intestines prior to reaching the colon. When sulfasalazine reaches the colon, the bacteria in the colon will break the linkage between the two molecules. After breaking away from 5–ASA, sulfapyridine is absorbed into the body and then excreted in the urine. Most of the active 5–ASA drug, however, remains in the colon to treat colitis.
Most of the side effects of sulfasalazine are due to the sulfapyridine molecule. These side effects include nausea, heartburn, headache, anemia, skin rashes, and, in rare instances, hepatitis and kidney inflammation. In men, sulfasalazine can reduce the sperm count. The reduction in sperm count is reversible, and the count usually returns to normal after discontinuing sulfasalazine or by changing to a different 5– ASA compound.
The benefits of sulfasalazine generally are dose related. Therefore, high doses of sulfasalazine may be necessary to induce remission. Some patients cannot tolerate high doses because of nausea and stomach upset. To minimize stomach upset, sulfasalazine generally is taken after or with meals. Some patients find it easier to take Azulfidine–EN (enteric–coated form of sulfasalazine). Enteric–coating helps decrease stomach upset. The newer 5–ASA compounds do not have the sulfapyridine component and have fewer side effects than sulfasalazine.
Asacol
Asacol is a tablet consisting of the 5–ASA compound, mesalamine, surrounded by an acrylic resin coating. (Asacol is sulfa free). The resin coating prevents the 5–ASA from being absorbed as it passes through the stomach and the small intestine. When the tablet reaches the terminal ileum and the colon, the resin coating dissolves, thus releasing 5–ASA into the colon.
Asacol is effective in inducing remissions in patients with mild to moderate ulcerative colitis. It also is effective when used for prolonged periods of time to maintain remissions. The recommended dose of Asacol to induce remission is two 400–mg tablets three times daily (total of 2.4 grams a day). Two tablets of Asacol twice daily (1.6 grams a day) is recommended for maintaining remission. Occasionally, the maintenance dose is higher.
As with Azulfidine, the benefits of Asacol are dose–related. If patients do not respond to 2.4 grams a day of Asacol, the dose frequently is increased to 3.6 grams a day (and sometimes even higher) to induce remission. If patients fail to respond to the higher doses of Asacol, then alternatives, such as corticosteroids, are considered.
Pentasa
Pentasa is a capsule consisting of the 5–ASA compound mesalamine inside controlled–release spheres. Like Asacol, it is sulfa free. As the capsule travels down the intestines, the 5–ASA inside the spheres is slowly released into the intestines. Unlike Asacol, the mesalamine in Pentasa is released into the small intestine as well as the colon. Therefore, Pentasa can be effective in treating inflammation in the small intestine and the colon. Pentasa is currently the most logical 5–ASA compound for treating mild to moderate Crohn's disease involving the small intestine. Pentasa also is used to induce remission and maintain remission among patients with mild to moderate ulcerative colitis.
Olsalazine (Dipentum)
Olsalazine (Dipentum) consists of two 5–ASA molecules linked together. It is sulfa free. The linked 5–ASA molecules travel through the stomach and the small intestine unabsorbed. When the drug reaches the terminal ileum and the colon, the normal bacteria in the intestine break the linkage and releases the active drug into the colon and the terminal ileum. Olsalazine has been used in treating ulcerative colitis and in maintaining remissions. A side effect unique to olsalazine is secretory diarrhea (diarrhea resulting from excessive production of fluid in the intestines). This condition occurs in 5–10% of patients, and the diarrhea sometimes can be severe.
Colazal
Colazal (balsalazide) is a capsule in which the 5–ASA is linked by a chemical bond to another molecule that is inert (without effect on the intestine) and prevents the 5–ASA from being absorbed. This drug is able to travel through the intestine unchanged until it reaches the end of the small bowel (terminal ileum) and colon. There, intestinal bacteria break apart the 5–ASA and the inert molecule, releasing the 5–ASA. Because intestinal bacteria are most abundant in the terminal ileum and colon, Colazal is used to treat inflammation predominantly localized to the colon. Colazal recently has been approved by the FDA for use in the United States.
More clinical trials are needed to compare the effectiveness of Colazal to the other mesalamine compounds such as Asacol in treating ulcerative colitis. Therefore in the United States, choosing which 5–ASA compound has to be individualized. Some doctors prescribe Colazal for patients who cannot tolerate or fail to respond to Asacol. Others prescribe Colazal for patients with predominantly left sided colitis, since some studies seem to indicate that Colazal is effective in treating left sided colitis.
Side Effects of 5–ASA Compounds
The sulfa–free 5–ASA compounds have fewer side effects than sulfasalazine and also do not impair male fertility. In general, they are safe medications for long–term use and are well–tolerated.
Patients allergic to aspirin should avoid 5–ASA compounds because they are chemically similar to aspirin.
Rare kidney inflammation has been reported with the use of 5–ASA compounds. These compounds should be used with caution in patients with known kidney disease. It also is recommended that blood tests of kidney function be obtained before starting and periodically during treatment.
Rare instances of acute worsening of diarrhea, cramps, and abdominal pain may occur which is at times may be accompanied by fever, rash, and malaise. This reaction is believed to represent an allergy to the 5–ASA compound.
Rowasa Enema
Rowasa is the 5–ASA compound mesalamine in enema form and is effective in ulcerative proctitis and ulcerative proctosigmoiditis (two conditions where active 5–ASA drugs taken as enemas can easily reach the inflamed tissues directly). Each Rowasa enema contains 4 grams of mesalamine in 60 cc of fluid. The enema usually is administered at bedtime, and patients are encouraged to retain the enema through the night.
The enema contains sulfite and should not be used by patients with sulfite allergy. Otherwise, Rowasa enemas are safe and well–tolerated.
Rowasa also comes in suppository form for treating limited proctitis. Each suppository contains 500 mg of mesalamine and usually is administered twice daily.
While some patients improve within several days of starting Rowasa, the usual course of treatment is three to six weeks. Some patients may need even longer courses of treatment for optimal benefit. In patients who do not respond to Rowasa, oral 5–ASA compounds (such as Asacol) can be added. Some studies have reported increased effectiveness in treating ulcerative proctitis and proctosigmoiditis by combining oral 5–ASA compounds with Rowasa enemas. Oral 5–ASA compounds also are used to maintain remission in ulcerative proctitis and proctosigmoiditis.
Another alternative for patients who fail to respond to Rowasa or who cannot use Rowasa is cortisone enemas (Cortenema). Cortisone is a corticosteroid that is a potent anti–inflammatory agent. Oral corticosteroids are systemic drugs with serious and predictable long–term side effects. Cortenema is a topical corticosteroid that is less absorbed into the body than oral corticosteroids, and, therefore, it has fewer and less severe side effects.
Systemic Corticosteroids (including side effects)
Corticosteroids (Prednisone, prednisolone, hydrocortisone, etc.) have been used for many years in the treatment of patients with moderate to severe Crohn's disease and ulcerative colitis or who fail to respond to optimal doses of 5–ASA compounds. Unlike the 5–ASA compounds, corticosteroids do not require direct contact with the inflamed intestinal tissues to be effective. Oral corticosteroids are potent anti–inflammatory agents. After absorption, corticosteroids exert prompt anti–inflammatory action throughout the body. Consequently, they are used in treating Crohn's enteritis, ileitis, and ileocolitis, as well as ulcerative and Crohn's colitis. In critically ill patients, intravenous corticosteroids (such as hydrocortisone) can be given in the hospital.
Corticosteroids are faster acting than the 5–ASA compounds. Patients frequently experience improvement in their symptoms within days of starting corticosteroids. Corticosteroids, however, do not appear to be useful in maintaining remissions in ulcerative colitis.
Corticosteroid side effects
Side effects of corticosteroids depend on the dose and duration of use. Short courses of prednisone, for example, usually are well tolerated with few and mild side effects. Long term, high doses of corticosteroids usually produce predictable and potentially serious side effects. Common side effects include rounding of the face (moon face), acne, increased body hair, diabetes, weight gain, high blood pressure, cataracts, glaucoma, increased susceptibility to infections, muscle weakness, depression, insomnia, mood swings, personality changes, irritability, and thinning of the bones (osteoporosis) with an accompanying increased risk of compression fractures of the spine. Children on corticosteroids can experience stunted growth.
The most serious complication from long term corticosteroid use is aseptic necrosis of the hip joints. Aseptic necrosis means death of bone tissue. It is a painful condition that can ultimately lead to the need for surgical replacement of the hips. Aseptic necrosis also has been reported in knee joints. It is unknown how corticosteroids cause aseptic necrosis. The estimated incidence of aseptic necrosis among corticosteroid users is 3–4%. Patients on corticosteroids who develop pain in the hips or knees should report the pain to their doctors promptly. Early diagnosis of aseptic necrosis with cessation of corticosteroids has been reported in some patients to decrease the severity of the condition and possibly help avoid hip replacement.
Prolonged use of corticosteroids can depress the ability of the body's adrenal glands to produce cortisol (a natural corticosteroid necessary for proper functioning of the body). Abruptly discontinuing corticosteroids can cause symptoms due to a lack of natural cortisol (a condition called adrenal insufficiency). Symptoms of adrenal insufficiency include nausea, vomiting, and even shock. Withdrawing corticosteroids too quickly also can produce symptoms of joint aches, fever, and malaise. Therefore, corticosteroids need to be gradually reduced rather than abruptly stopped.
Even after the corticosteroids are discontinued, the adrenal glands' ability to produce cortisol can remain depressed for months to two years. The depressed adrenal glands may not be able to produce enough cortisol to help the body handle stress such as accidents, surgery, and infections. These patients will need treatment with corticosteroids (prednisone, hydrocortisone, etc.) during stressful situations to avoid developing adrenal insufficiency.
Because corticosteroids are not useful in maintaining remission in ulcerative colitis and Crohn's disease and because they have predictable and potentially serious side effects, these drugs should be used for the shortest possible length of time.
Proper Use of Corticosteroids
Once the decision is made to use oral corticosteroids, treatment usually is initiated with prednisone, 40–60 mg daily. The majority of patients with ulcerative colitis respond with an improvement in symptoms. Once symptoms improve, prednisone is reduced by 5–10 mg per week until the dose of 20 mg per day is reached. The dose then is tapered at a slower rate until the prednisone ultimately is discontinued. Gradually reducing corticosteroids not only minimizes the symptoms of adrenal insufficiency, it also reduces the chances of abrupt relapse of the colitis.
Many doctors use 5–ASA compounds at the same time as corticosteroids. In patients who achieve remission with systemic corticosteroids, 5–ASA compounds such as Asacol are often continued to maintain remissions.
In patients whose symptoms return during reduction of the dose of corticosteroid, the dose of corticosteroids is increased slightly to control the symptoms. Once the symptoms are under control, the reduction can resume at a slower pace. Some patients become corticosteroid dependent. These patients consistently develop symptoms of colitis whenever the corticosteroid dose reaches below a certain level. In patients who are corticosteroid dependent or who are unresponsive to corticosteroids, other anti–inflammatory medications, immunomodulator medications or surgery are considered.
The management of patients who are corticosteroid dependent or patients with severe disease which responds poorly to medications is complex. Doctors who are experienced in treating inflammatory bowel disease and in using the immunomodulators should evaluate these patients.
Preventing Corticosteroid–induced Osteoporosis
Long–term use of corticosteroids such as prednisolone or prednisone can cause osteoporosis . Corticosteroids cause decreased calcium absorption from the intestines and increased loss of calcium from the kidneys and bones. Increasing dietary calcium intake is important but alone cannot halt corticosteroid–induced bone loss. Management of patients on long term corticosteroids should include:
- Adequate calcium (1000 mg daily if premenopausal, 1500 mg daily if postmenopausal) and vitamin D (800 units daily) intake.
- Periodic review with the doctor on the need for continued corticosteroid treatment and the lowest effective dose if continued treatment is necessary.
- A bone density study to measure the extent of bone loss in patients taking corticosteroids for more than three months.
- Regular weight–bearing exercise, and stop smoking cigarettes.
- Discussion with the doctor regarding the use of alendronate (Fosamax) or risedronate (Actonel) in the prevention and the treatment of corticosteroid induced osteoporosis.
What are Immunomodulator medications?
Immunomodulators are medications that weaken the body's immune system. The immune system is composed of immune cells and the proteins that these cells produce. These cells and proteins serve to defend the body against harmful bacteria, viruses, fungi, and other foreign invaders. Activation of the immune system causes inflammation within the tissues where the activation occurs. (Inflammation is, in fact, an important mechanism to defend the body used by the immune system.) Normally, the immune system is activated only when the body is exposed to harmful invaders. In patients with Crohn's disease and ulcerative colitis, however, the immune system is abnormally and chronically activated in the absence of any known invader. Immunomodulators decrease tissue inflammation by reducing the population of immune cells and/or by interfering with their production of proteins that promote immune activation and inflammation. Generally, the benefits of controlling moderate to severe ulcerative colitis outweigh the risks of infection due to weakened immunity. Examples of immunomodulators include azathioprine (Imuran), 6–mercaptopurine (6–MP, Purinethol), cyclosporine (Sandimmune), and methotrexate (Rheumatrex, Trexall).
Azathioprine (Imuran) and 6–MP (Purinethol)
Azathioprine and 6–mercaptopurine (6–MP) are medications that weaken the body's immunity by reducing the population of a class of immune cells called lymphocytes. Azathioprine and 6–MP are related chemically. Specifically, azathioprine is converted into 6–MP inside the body. In high doses, these two drugs have been useful in preventing rejection of transplanted organs and in treating leukemia. In low doses, they have been used for many years to treat patients with moderate to severe Crohn's disease and ulcerative colitis.
Azathioprine and 6–MP are increasingly recognized by doctors as valuable drugs in treating Crohn's disease and ulcerative colitis. Some 70% of patients with moderate to severe disease will benefit from these drugs. Because of the slow onset of action and the potential for side effects, however, 6–MP and azathioprine are used mainly in the following situations:
- Ulcerative colitis and Crohn's disease patients with severe disease not responding to corticosteroids.
- Patients who are experiencing undesirable corticosteroid–related side effects.
- Patients who are dependent on corticosteroids and are unable to discontinue them without developing relapses.
When azathioprine and 6–MP are added to corticosteroids in the treatment of ulcerative colitis patients who do not respond to corticosteroids alone, there may be an improved response or smaller doses and shorter courses of corticosteroids may be able to be used. Some patients can discontinue corticosteroids altogether without experiencing relapses. The ability to reduce corticosteroid requirements has earned 6–MP and azathioprine their reputation as "steroid–sparing" medications.
In ulcerative colitis patients with severe disease who suffer frequent relapses, 5–ASA may not be sufficient, and more potent azathioprine and 6–MP will be necessary to maintain remissions. In the doses used for treating ulcerative colitis and Crohn's disease, the long–term side effects of azathioprine and 6–MP are less serious than long–term oral corticosteroids or repeated courses of oral corticosteroids.
What Are the Side Effects of 6–MP and Azathioprine?
Side effects of 6–MP and azathioprine include increased vulnerability to infections, inflammation of the liver (hepatitis) and pancreas, (pancreatitis), and bone marrow toxicity (interfering with the formation of cells that circulate in the blood).
The goal of treatment with 6–MP and azathioprine is to weaken the body's immune system in order to decrease the intensity of inflammation in the intestines; however, weakening the immune system increases the vulnerability to infections. For example, in a group of patients with severe Crohn's disease unresponsive to standard doses of azathioprine, raising the dose of azathioprine helped to control the disease, but two patients developed cytomegalovirus (CMV) infection. (CMV usually infects individuals with weakened immune systems such as patients with AIDS or cancer, especially if they are receiving chemotherapy, which further weakens the immune system.
Azathioprine and 6–MP–induced inflammation of the liver (hepatitis) and pancreas (pancreatitis) are rare. Pancreatitis typically causes severe abdominal pain and sometimes vomiting. Pancreatitis due to 6–MP or azathioprine occurs in 3%–5% of patients, usually during the first several weeks of treatment. Patients who develop pancreatitis should not receive either of these two medications again.
Azathioprine and 6–MP also suppress the bone marrow. The bone marrow is where red blood cells, white blood cells, and platelets are made. Actually, a slight reduction in the white blood cell count during treatment is desirable since it indicates that the dose of 6–MP or azathioprine is high enough to have an effect; however, excessively low red or white blood cell counts indicates bone marrow toxicity. Therefore, patients on 6–MP and azathioprine should have periodic blood counts (usually every two weeks initially and then every 3 months during maintenance) to monitor the effect of the drugs on their bone marrow.
6–MP can reduce the sperm count in men. When the partners of male patients on 6–MP conceive, there is a higher incidence of miscarriages and vaginal bleeding. There also are respiratory difficulties in the newborn. Therefore, it is recommended that whenever feasible, male patients should stop 6–MP and azathioprine for three months before conception.
Patients on long–term, high dose azathioprine to prevent rejection of the kidney after kidney transplantation have an increased risk of developing lymphoma, a malignant disease of lymphatic cells. There is no evidence at present that long term use of azathioprine and 6–MP in the low doses used in IBD increases the risk for lymphoma, leukemia or other malignancies.
Other Issues in the Use of 6–MP
One problem with 6–MP and azathioprine is their slow onset of action. Typically, full benefit of these drugs is not realized for three months or longer. During this time, corticosteroids frequently have to be maintained at high levels to control inflammation.
The reason for this slow onset of action is partly due to the way doctors prescribe 6–MP. Typically, 6–MP is started at a dose of 50 mg daily. The blood count is then checked two weeks later. If the white blood cell count (specifically the lymphocyte count) is not reduced, the dose is increased. This cautious, stepwise approach helps prevent severe bone marrow and liver toxicity, but also delays benefit from the drug.
Studies have shown that giving higher doses of 6–MP early can speed up the benefit of 6–MP without increased toxicity in most patients, but some patients do develop severe bone marrow toxicity. Therefore, the dose of 6–MP has to be individualized. Scientists now believe that an individual's vulnerability to 6–MP toxicity is genetically inherited. Blood tests can be performed to identify those individuals with increased vulnerability to 6–MP toxicity. In these individuals, lower initial doses can be used. Blood tests can also be performed to measure the levels of certain by–products of 6–MP. The levels of these by–products in the blood help doctors more quickly determine whether the dose of 6–MP is right for the patient.
How Long Can Patients Continue on 6–MP?
Patients have been maintained on 6–MP or azathioprine for years without any important long–term side effects. Their doctors, however, should closely monitor their patients on long–term 6–MP. There is data suggesting that patients on long–term maintenance with 6–MP or azathioprine fare better than those who stop these medications. Those who stop 6–MP or azathioprine are more likely to experience relapses, more likely to need corticosteroids or undergo surgery.
Methotrexate
Methotrexate (Rheumatrex, Trexall) is an immunomodulator and anti–inflammatory medication. Methotrexate has been used for many years in the treatment of severe rheumatoid arthritis and psoriasis. It has been helpful in treating patients with moderate to severe Crohn's disease who are either not responding to 6–MP and azathioprine or are intolerant of these two medications. Methotrexate also may be effective in patients with moderate to severe ulcerative colitis who are not responding to corticosteroids or 6–MP and azathioprine. It can be given orally or by weekly injections under the skin or into the muscles. It is more reliably absorbed with the injections.
One major complication of methotrexate is the development of liver cirrhosis when the medication is given over a prolonged period of time (years). The risk of liver damage is higher in patients who also abuse alcohol or have morbid (severe) obesity. Generally, periodic liver biopsies are recommended for a patient who has received a cumulative (total) methotrexate dose of 1.5 grams and higher.
Other side effects of methotrexate include low white blood cell counts and inflammation of the lungs.
Methotrexate should not be used in pregnancy.
Cyclosporine
Cyclosporine (Sandimmune) is a potent immunosuppressant used in preventing organ rejection after transplantation, for example, of the liver. It also has been used to treat patients with severe ulcerative colitis and Crohn's disease. Because of the approval of infliximab (Remicade) for treating severe Crohn's disease, cyclosporine probably will be used primarily in severe ulcerative colitis. Cyclosporine is useful in fulminant ulcerative colitis and in severely ill patients who are not responding to systemic corticosteroids. Administered intravenously, cyclosporine can be very effective in rapidly controlling severe colitis and avoiding or delaying surgery.
Cyclosporine also is available as an oral medication, but the relapse rate with oral cyclosporine is high. Therefore, cyclosporine seems most useful when administered intravenously in acute situations.
Side effects of cyclosporine include high blood pressure, impairment of kidney function, and tingling sensations in the extremities. More serous side effects include anaphylactic shock and seizures.
Infliximab (Remicade)
Infliximab (Remicade) is an antibody that attaches to a protein called tumor necrosis factor–alpha (TNF–alpha). TNF–alpha is one of the proteins produced by immune cells during activation of the immune system. TNF–alpha, in turn, stimulates other cells of the immune system to produce and release other proteins that promote inflammation. In Crohn's disease and in ulcerative colitis, there is continued production of TNF–alpha as part of the immune activation. Infliximab, by attaching to TNF–alpha, blocks its activity and in so doing decreases the inflammation.
Infliximab, an antibody to TNF–alpha, is produced by the immune system of mice after the mice are injected with human TNF–alpha. The mouse antibody then is modified to make it look more like a human antibody, and this modified antibody is infliximab. Such modifications are necessary to decrease the likelihood of allergic reactions when the antibody is administered to humans. Infliximab is given by intravenous infusion over two hours. Patients are monitored throughout the infusion for adverse reactions.
Infliximab has been used effectively for many years for the treatment of moderate to severe Crohn's disease that was not responding to corticosteroids or immuno–modulators. In Crohn's disease patients, 65% experienced improvement in their disease after one infusion of infliximab. Some patients noticed improvement in symptoms within days of the infusion. Most patients experienced improvement within two weeks. In patients who respond to infliximab, the improvements in symptoms can be dramatic. Moreover, there can be impressively rapid healing of the ulcers and the inflammation in the intestines after just one infusion.
For many years doctors were uncertain whether infliximab could be used to treat ulcerative colitis. Only recently, have doctors begun to use infliximab as treatment for ulcerative colitis. In one randomized placebo controlled study involving more than 700 patients with moderate to severe ulcerative colitis, infliximab (5mg or 10 mg per kilogram body weight) given intravenously was more effective than placebo in inducing and maintaining remission.
Side effects of infliximab
Infliximab, generally, is well tolerated. There have been rare reports of side effects during infusions, including chest pain, shortness of breath, and nausea. These effects usually resolve spontaneously within minutes if the infusion is stopped. Other commonly reported side effects include headache and upper respiratory tract infection.
Infliximab, like immuno–modulators, increases the risk for infection. One case of salmonella colitis and several cases of pneumonia have been reported with the use of infliximab. There also have been cases of tuberculosis (TB) reported after the use of infliximab.
Because infliximab is partly a mouse protein, it may induce an immune reaction when given to humans, especially with repeated infusions. In addition to the side effects that occur while the infusion is being given, patients also may develop a "delayed allergic reaction" that occurs 7–10 days after receiving the infliximab. This type of reaction may cause flu–like symptoms with fever, joint pain and swelling, and a worsening of Crohn's disease symptoms. It can be serious, and if it occurs, a physician should be contacted. Paradoxically, those patients who have more frequent infusions of Remicade are less likely to develop this type of delayed reaction compared to those patients who receive infusions separated by long intervals (6–12 months). Although Remicade is only FDA approved for a single infusion at this time, patients should be aware that they are likely to require repeated infusions once Remicade therapy has been initiated.
There are some reports of worsening heart disease in patients who have received Remicade. The precise mechanism and role of infliximab in the development of this side effect is unclear. As a precaution, individuals with heart disease should inform their physician of this condition before receiving infliximab.
There have been rare reports of nerve damage such as optic neuritis (inflammation of the nerve of the eye) and motor neuropathy.
Precautions with infliximab
Infliximab can aggravate and cause the spread of an existing infection. Therefore, it should not be given to patients with pneumonia, urinary tract infection or abscess (localized collection of pus).
It now is recommended that patients be tested for TB prior to receiving infliximab. Patients who previously had TB should inform their physician of this before they receive infliximab.
Infliximab can cause the spread of cancer cells, therefore, it should not be given to patients with cancer.
Infliximab's effects on the fetus are not known.
Because infliximab is partly a mouse protein, some patients can develop antibodies against infliximab with repeated infusions. The development of these antibodies can decrease the effectiveness of the drug. The chances of developing these antibodies can be decreased by concomitant use of 6–MP and corticosteroids.
While infliximab represents an exciting new class of medications in the fight against Crohn's disease and ulcerative colitis, caution is warranted because of potentially serious side effects. Doctors are using infliximab in moderate to severe ulcerative colitis not responding to other medications.
Summary of Medication Treatment
- Azulfidine, Asacol, Pentasa, Dipentum, Colazal, and Rowasa all contain 5–ASA compounds which are topical anti–inflammatory ingredients. These medications are effective in inducing remission among patients with mild to moderate ulcerative colitis. They also are safe and effective in maintaining remission.
- Pentasa is more commonly used in treating Crohn's ileitis because the Pentasa capsules release more 5–ASA compounds into the small intestine than the Asacol tablets. Pentasa also can be used for treating mild to moderate ulcerative colitis.
- Rowasa enemas are safe and effective in treating ulcerative proctitis and proctosigmoiditis.
- The sulfa–free 5–ASA compounds (Asacol, Pentasa, Dipentum, Colazal, Rowasa) have fewer side effects than Azulfidine, which contains sulfa.
- In ulcerative colitis patients with moderate to severe disease and in patients who fail to respond to 5–ASA compounds, systemic (oral) corticosteroids can be used. Systemic corticosteroids (prednisone, prednisolone, cortisone, etc.) are potent and fast–acting anti–inflammatory agents for treating Crohn's ileitis, ileocolitis, and ulcerative colitis.
- Systemic corticosteroids are not effective in maintaining remission in patients with ulcerative colitis. Serious side effects can result from prolonged corticosteroid treatment.
- To minimize side effects, corticosteroids should be gradually reduced as soon as disease remission is achieved. In patients who become corticosteroid dependent or are unresponsive to corticosteroid treatment, surgery or immunomodulator treatments are considered.
- Immunomodulators used for treating severe ulcerative colitis include azathioprine/6–MP, methotrexate, and cyclosporine.
- Infliximab (Remicade) may be beneficial in controlling moderate to severe ulcerative colitis and in decreasing the need for urgent removal of the colon.
Surgery
Surgery for ulcerative colitis usually involves removing the entire colon and the rectum. Removal of the colon and rectum is the only permanent cure for ulcerative colitis. This procedure also eliminates the risk of developing colon cancer. Surgery in ulcerative colitis is reserved for the following patients:
- Patients with fulminant colitis and toxic megacolon who are not responding readily to medications.
- Patients with long standing pancolitis or left–sided colitis who are at risk of developing colon cancers. Removal of the colon is important when precancerous changes are detected in the colon lining.
- Patients who have had years of severe colitis which has responded poorly to medications.
Standard surgery involves the removal of the entire colon, including the rectum. A small opening is made in the abdominal wall. and the end of the small intestine is attached to the skin of the abdomen to form an ileostomy. Stool collects in a bag that is attached over the ileostomy. Recent improvements in the construction of ileostomies have allowed for continent ileostomies. A continent ileostomy is a pouch created from the intestine. The pouch serves as a reservoir similar to a rectum, and is emptied on a regular basis with a small tube. Patients with continent ileostomies do not need to wear collecting bags.
More recently, a surgery has been developed which allows stool to be passed normally through the anus. In an ileo–anal anastomosis, the large intestine is removed and the small intestine is attached just above the anus. Only the diseased lining of the anus is removed and the muscles of the anus remain intact. In this "pull–through" procedure, the normal route of stool elimination is maintained.
What research is being done regarding ulcerative colitis?
Infliximab (Remicade) is an antibody that attaches to a protein called tumor necrosis factor–alpha (TNF–alpha). TNF–alpha is one fo the proteins produced by immune cells that promote inflammation. By attaching to TNF–alpha, infliximab blocks its activity and in so doing decreases inflammation.
Infliximab has been used successfully in treating severe Crohn's disease patients who are not responding adequately to steroids and immunomodulators such as 6–MP/azathioprine. But for many years doctors thought infliximab would not be beneficial in treating ulcerative colitis.
Recent studies involving small numbers of patients with severe ulcerative colitis who are not responding to high dose steroids indicated infliximab may be beneficial in controlling disease and in decreasing the need for urgent removal of the colon. Placebo controlled studies involving larger number of patients will be conducted to determine the efficacy and safety of infliximab in ulcerative colitis.
Active research is also ongoing to find other anti–TNF agents that are potentially more effective with less side effects in treating ulcerative colitis.
Research in ulcerative colitis is very active, and many questions remain to be answered. The cause, mechanism of inflammation, and optimal treatments have yet to be defined. Researchers have recently identified genetic differences among patients which may allow them to select certain subgroups of patients with ulcerative colitis who may respond differently to medications. Newer and safer medications are being developed. Improvements in surgical procedures to make them safer and more effective continue to emerge.
Ulcerative Colitis At A Glance
- Ulcerative colitis is an inflammation of the large intestine (colon).
- The cause of ulcerative colitis is unknown.
- Intermittent rectal bleeding, crampy abdominal pain and diarrhea often are symptoms of ulcerative colitis.
- The diagnosis of ulcerative colitis can be made with a barium enema, but direct visualization (sigmoidoscopy or colonoscopy) is the most accurate means of diagnosis.
- Long–standing ulcerative colitis is a risk factor for colon cancer.
- Treatment of ulcerative colitis may involve both medications and surgery.
- Ulcerative colitis also can cause inflammation in joints, spine, skin, eyes, and the liver and its bile ducts.
reference Link:
http://www.medicinenet.com/ulcerative_colitis/index.htm
