Treatment of ulcerative colitis

This article concerns the treatment of ulcerative colitis, a form of inflammatory bowel disease (IBD). Ulcerative colitis is a form of colitis, a disease of the intestine, specifically the large intestine or colon, that includes characteristic ulcers, or open sores, in the colon. The main symptom of active disease is usually diarrhea mixed with blood, of gradual onset. Ulcerative colitis is, however, a systemic disease that affects many parts of the body outside the intestine.

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Clinical presentation

GI symptoms

The clinical presentation^[1] of ulcerative colitis depends on the extent of the disease process. Patients usually present with diarrhea mixed with blood and mucus, of gradual onset. They also may have signs of weight loss, abdominal pain and blood on rectal examination.

Ulcerative colitis is a systemic disease that affects many parts of the body. Sometimes the extra-intestinal manifestations of the disease are the initial signs, such as painful, arthritic knees in a teenager. It is, however, unlikely that the disease will be correctly diagnosed until the onset of the intestinal manifestations.

Extent of involvement

Ulcerative colitis is normally continuous from the rectum up the colon. The disease is classified by the extent of involvement, depending on how far up the colon the disease extends:

• Proctitis: Involvement limited to the rectum.
• Proctosigmoiditis or distal colitis: Involvement of the rectosigmoid colon, the portion of the colon adjacent to the rectum.
• Left-sided colitis: Involvement of the descending colon, which runs along the patient's left side, up to the splenic flexure and the beginning of the transverse colon.
• Pancolitis: Involvement of the entire colon, extending from the rectum to the cecum, beyond which the small intestine begins.

Severity of disease

UC patients may be characterized by the severity of their disease:

• Mild disease correlates with intermittent loose bloody stools (up to 4 times a day) with passage of thick, white mucus. Involvement is usually limited to the rectum (proctitis) or the rectosigmoid colon (proctosigmoiditis or distal colitis). There may be mild abdominal pain or cramping. Patients may believe they are constipated when in fact they are experiencing tenesmus, which is a constant feeling of the need to empty the bowel accompanied by involuntary straining efforts, pain, and cramping with little or no fecal output. Rectal pain is uncommon.

• Moderate disease correlates with frequent loose bloody stools (about 10 times a day), anemia (not requiring transfusions), moderate abdominal pain, and low grade fever, 38 to 39 °C (99.5 to 102.2 °F). Involvement can extend up to the splenic flexure (left-sided colitis).

• Severe disease, or fulminant disease, correlates with more than 10 loose bloody stools a day, severe abdominal cramps, fever up to 39.5 C, anemia requiring transfusions, hypotension, and rapid weight loss with inadequate nutrition. Involvement may or may not extend to the cecum (pancolitis). Patients in this category may have inflammation extending beyond just the mucosal layer, causing impaired colonic motility and leading to toxic megacolon. If the serous membrane is involved, colonic perforation may ensue.

Treatment with drugs

Standard treatment for ulcerative colitis depends on extent of involvement and disease severity. The goal is to induce remission initially with medications, followed by the administration of maintenance medications to prevent a relapse of the disease. The concept of induction of remission and maintenance of remission is very important. The medications used to induce and maintain a remission somewhat overlap, but the treatments are different. Physicians first direct treatment to inducing a remission which involves relief of symptoms and mucosal healing of the lining of the colon and then longer term treatment to maintain the remission.

Drugs used

Aminosalicylates

Aminosalicylates are the main anti-inflammatory drugs used to treat ulcerative colitis. Sometimes remission can be achieved, or at least maintained, with these drugs alone. If not, they are usually used in combination with the drugs listed in the ensuing sections.

The anti-inflammatory action in all these drugs is produced by 5-aminosalicylic acid (5-ASA), the active ingredient in Mesalazine. 5-ASA is produced from the other drugs in the intestine. The aminosalicylates used to treat ulcerative colitis include the following:

• Mesalazine, also known as 5-aminosalicylic acid, 5-ASA, Asacol, Pentasa and Mesalamine.
• Sulfasalazine, also known as Azulfidine. This drug belongs a traditional class of antibiotics, but decomposes in the intestine, releasing 5-ASA.
• Balsalazide, also known as Colazal, intended to release 5-ASA only in the large intestine.
• Olsalazine, also known as Dipentum, intended to release 5-ASA only in the large intestine.

5-ASA is poorly-absorbed by the intestines, and hence provides topical relief within the intestine. It is therefore a non-systemic drug. 5-ASA is related to the systemic non-steroidal anti-inflammatory drugs (NSAIDs), such as Aspirin and Ibuprofin, which tend to promote intestinal bleeding, and which should therefore be avoided by persons with ulcerative colitis.

The free radical induction theory, discussed above, proposes that 5-ASA is serving not just as an anti-inflammatory, but also as a free radical trap, destroying the hydroxyl and other radicals that may damage colonic epithelial barrier.^[2]

Sulfasalazine side-effects

Possible side effects of 5ASA include, nausea and vomiting, reduced sperm count and damage to red or white blood cells, or to the liver, kidneys, pancreas, nerves or hearing. Allergic reactions to sulfasalazine characterized by dizziness, fever and skin rash have been reported in a small percentage of patients. In some cases, sulfasalazine can exacerbate ulcerative colitis resulting in diarahea, abdominal cramps and discomfort.

In the intestine sulfasalazine is converted to 5-ASA and sulfapyridine, which is responsible for some of its side-effects, and which should be monitored in patients taking sulfasalazine. Sulfapyridine levels above 50 mcg/L are associated with the side-effects.

Patients on high dose sulfasalazine require folic supplementation (1 mg/day) (1000 mcg/day) to maintain normal cell division. This may, however, be counter-productive for patients who are also taking methotrexate, which is a folic acid inhibitor. Folic acid might also be counter-productive for patients taking 6-MP and related drugs that inhibit all cell division.

Corticosteroids

It is often necessary to use Corticosteroids in conjunction with NSAIDs to bring about remission of ulcerative colitis. Thereafter it may be possible to maintain remission with NSAIDs alone, or it may be necessary to continue administering corticosteroids to maintain.

Corticosteroids reduce inflammation by blocking portions of the leukocyte adhesion cascade which results in inflammation.

Side effects of corticosteroids include Cushing's syndrome, which most often exhibits itself as temporary facial puffyness, called "moon face". Cushing's syndrome can, however, involve psychosis, including manic behavior. These drugs have been known to trigger bipolar disorder. In prescribing these drugs it might be well to inquire as to any family history of bipolar disorder.

Corticosteroids should not be confused with anabolic steroids, the controversial performance-building "steroids" that are banned in certain sports.

The following corticosteroids are used as immune system suppressants in treatment of ulcerative colitis:

• Cortisone
• Prednisone
• Hydrocortisone
• Methylprednisolone
• Budesonide, also known as Entocort, available for oral use or as an enema. Budesonide is metabolized faster than traditional steroids and appears to produce fewer side effects.

Immunosuppressive drugs

Immunosuppressive drugs inhibit the immune system generally. These include the cytostatic drugs that inhibit cell division, including the cloning of white blood cells that is a part of the immune response. Immunosuppressive drugs used with ulcerative colitis include:

• Mercaptopurine, also known as 6-Mercaptopurine, 6-MP and Purinethiol.
• Azathioprine, also known as Imuran (US) or Azasan, which metabolises to 6-MP.
• Methotrexate, which inhibits folic acid

Mercaptopurine is a cytostatic drug that is an antimetabolite. The mercaptopurine molecule mimics purine, which is necessary for the synthesis of DNA. With mercaptopurine present, cells are not able to make DNA, and cell division is inhibited.

In administering mercaptopurine it is necessary to monitor the levels of mercaptopurine metabolites in the blood to establish the correct dosage for a patient. An initial concern is hepatotoxicity.

Mercaptopurine inhibits the production of white blood cells generally. Because this makes the body more susceptible to infection, patients need to watched for infections. Vaccinations should also be done with caution.

Frequent blood cell counts are also recommended during administration of mercaptopurine. The drug may be toxic to bone marrow, where many blood components are made. If there is an abnormally large drop in white blood cell count, or any blood cell count, administration of the drug should be halted at least temporarily.

Methotrexate is another immunosuppressive drug. It works by inhibiting folic acid, which is necessary for DNA replication and, therefore, cell division.

TNF inhibitors

Main article: Biological therapy for inflammatory bowel disease

TNF is a protein that is released by activated white blood cells, triggering more inflammation, an immune system response and more damage to the mucosa of the colon because of the immune activation. Certain drugs inhibit TNF, hence reducing inflammation and immune system involvement. Infliximab was approved by the FDA for treating ulcerative colitis in March 2005. It is usually given as an intravenous infusions at weeks 0,2 and 6 and then every eight weeks thereafter. It is very useful for inducing and maintaining a remission of ulcerative colitis. Some physicians think that infliximab works better when used in combination with immunmodulators such as 6-mercaptopurine or azathioprine, but there is no definitive evidence based medicine to conclude that infliximab must be used with 6-mp or azathioprine.

• Infliximab

Treatment for proctitis

Proctitis usually involves the distal, or lower, 10-15 cm (4 to 6 inches) of the colon, including the rectum. Approximately 30% of ulcerative colitis patients initially present with proctitis.

Standard treatment for active disease includes Mesalazine suppositories and cortisone foam (Cortifoam®). Mesalazine 1 g SUPP QHS or Cortifoam QHS/BID is continued until remission, with response seen usually within three weeks.

Maintenance therapy is with Mesalazine 1g QHS or Q3HS. Those with anal irritation or discomfort from the suppositories may switch to oral medications, such as sulfasalazine, Mesalazine, or Colazol, although they are not as effective as suppositories for proctitis. Maintenance therapy is not recommended for those with a first episode that responded to the Mesalazine. Steroid foam is not shown to prevent relapse.

Systemic steroids such as prednisone are not used unless proctitis fails to respond to the above treatments.^[3]

Treatment for proctosigmoiditis and left-sided colitis

Proctosigmoiditis and left-sided colitis involves the lower colon, from the rectum up the left side of the patient.

Patients often respond to topical agents alone, such as Mesalazine, or hydrocortisone enemas. Again, the Mesalazine is preferred for maintenance therapy.

• Initially a 4 g Mesalazine enema (Rowasa) is given nightly.
• If response is seen, the enemas can be tapered to every third night.
• If no response, a morning Mesalazine, or hydrocortisone enema (Cortenema) can be given.
• If still no response, oral anti-inflammatory drugs, with or without enemas, can be given, such as sulfasalazine, Mesalazine (Asacol, Pentasa), olsalazine (Dipentum), or balsalazide (Colazal).
• If still no response, dose should be increased to maximum: sulfasalazine maxes at 4-6 g/day, Mesalazine maxes at 4.8 g/day, and olsalazine at 3 g/day. They are usually divided tid or bid.

Oral anti-inflammatory drugs require four to six weeks to work.

Once remission is induced, maintenance levels can be used: sulfasalazine 2 g/day, mesalamine 1.2-2.4 g/day, or olsalazine 1 g/day. Patients on high dose sulfasalazine require folic supplementation (1 mg/day) because it inhibits folate absorption.

If oral Mesalazine is still not working, prednisone should be given, starting at 40-60 mg/day. Prednisone should take effect within 10-14 days. The dose should then be tapered by about 5 mg/week until it can be stopped altogether.

Treatment for extensive or pancolitis

Extensive or pancolitis. Patients usually require a combination of oral Mesalazine or sulfasalazine along with topical Mesalazine or steroid enemas. Oral prednisone (40-60 mg/day) should be given only in severe cases or if oral Mesalazine fails. Once remission is induced, maintenance therapy is with standard oral Mesalazine doses. Supplemental iron (ferrous sulfate or ferrous gluconate) may be given due to chronic blood loss. Loperamide may be given for symptomatic relief of chronic diarrhea, but should not be given in suspected toxic megacolon.

Treatment for severe or fulminant colitis

Severe or fulminant colitis. Patients need to be hospitalized immediately with subsequent bowel rest, nutrition, and IV steroids. Typical starting choices are hydrocortisone 100 mg IV q8h, prednisolone 30 mg IV q12h, or methylprednisolone 16-20 mg IV q8h. The last two are preferred due to less sodium retention and potassium wasting. 24-hour continuous infusion is preferred than the stated dosing. If the patient has not had any corticosteroids within the last 30 days, IV ACTH 120 units/day as continuous infusion is superior than the IV steroids mentioned above. In either case, if symptoms persist after 2-3 days, Mesalazine or hydrocortisone enemas daily or bid can be given. The use of antibiotics in those with severe colitis is not clear. However, there are those patients who have sub-optimal response to corticosteroids and continue to run a low grade fever with bandemia. Typically they can be treated with IV ciprofloxacin and metronidazole. However, in those with fulminant colitis or megacolon, with high fever, leukocytosis with high bandemia, and peritoneal signs, broad spectrum antibiotics should be given (i.e., ceftazidime, cefepime, imipeneum, meropenem, etc). Abdominal x-ray should also be ordered. If intestinal dilation is seen, patients should be decompressed with NG tube and or rectal tube.

Treatment for refractory ulcerative colitis

Refractory ulcerative colitis. Patients with toxic megacolon (colonic dilation > 6 cm and toxic appearing) who do not respond to steroid therapy within 72 hours should be consulted for colectomy. Those with less severe disease but do not respond to IV steroids within 7-10 days should be considered for colectomy or IV cyclosporine. IV cyclosporine at a rate of 2 mg/kg/day and if no response in 7-10 days, colectomy should be considered. If response is seen, oral cyclosporine at 8 mg/kg/day should be continued for 3-4 months while 6-MP or azathioprine is introduced. Those already on 6-MP or azathioprine should continue with these medications. A cholesterol level should be checked in patients taking cyclosporine as low cholesterol may predispose to seizures. Also, prophylaxis against PCP (Pneumocystis carinii) pneumonia is advised.

Drugs being tested

• Methotrexate. Results inconclusive.
• Heparin. Heparin has antiinflammatory effects but role is inconclusive.
• Anti-integrin antibodies. Integrins are proteins that modulate migration of leukocytes to the gut.

Surgery

Unlike Crohn's disease, ulcerative colitis can generally be cured by surgical removal of the large intestine. This procedure is necessary in the event of: exsanguinating hemorrhage, frank perforation or documented or strongly suspected carcinoma. Surgery is also indicated for patients with severe colitis or toxic megacolon. Patients with symptoms that are disabling and do not respond to drugs may wish to consider whether surgery would improve the quality of life.

Ulcerative colitis is a disease that affects many parts of the body outside the intestinal tract. In rare cases the extra-intestinal manifestations of the disease may require removal of the colon. ^[4]

Alternative treatments

Although hotly debated, some people achieved a complete remission with the Specific Carbohydrate Diet (Elaine Gottschall) and/or the Anti-Fungal Diet (Doug Kaufmann & David Holland).

Dietary modification

• Lactose intolerance is noted in many ulcerative colitis patients. Those with suspicious symptoms should get a lactose breath hydrogen test. If lactose is restricted, calcium may need to be supplemented to avoid bone loss.
• Patients with abdominal cramping or diarrhea should avoid fresh fruits and vegetables, caffeine, carbonated drinks and sorbitol-containing foods.
• Fermentable dietary fiber may be beneficial to maintain remission.

Fats and oils

• Fish oil. Eicosapentaenoic acid (EPA), derived from fish oil. This is an Eicosanoid that inhibits leukotriene activity. It is effective as an adjunct therapy. Usual dose is 15-18 capsules a day. [1]
• Short chain fatty acid (butyrate) enema. Results not conclusive.

Antioxidants

The free radical induction theory suggests that the initial cause of ulcerative colitis may be a metabolic defect that allows a build up of chemicals related to hydrogen peroxide beneath the membrane that protects the cells of the intestinal wall from the bacteria inside the intestine, resulting in destruction of the membrane. During remission the membrane is reestablished, but may be subject to new damage, resulting in a flare up of the disease.^[2] To the extent this may be true, it would be appropriate to take antioxidants, dietary supplements that may support the body's defenses against oxidants like hydrogen peroxide. Antioxidants include:

• Vitamins A, C and E
• Coenzyme Q10
• Selenium and manganese.

Vitamin B6 and iron may be associated with increased hydrogen peroxide levels, and should not be taken in excess under this theory. ^[2]

Herbals

• [Vitamin U] (methylmethioninesulfonium chloride, MMSC) has been shown to reverse ulcers in a number of different studies:

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http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=8565766&query_hl=12&itool=pubmed_docsum

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16845938&query_hl=9&itool=pubmed_docsum

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=8881814&query_hl=8&itool=pubmed_docsum

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=1619573&query_hl=12&itool=pubmed_docsum

• Kampo medicine is used in Japan; Oren-gedoku-to is one such traditional herbal medicine being used both in Japan and China since the Han Dynasty. The traditional Chinese medicine name for this is Huang-Liang-Jie-Du-Tang; its and English name is Coptis Detoxifying Formula.

Bacterial recolonization

• Probiotics may have benefit. One study looked at a probiotic known as VSL-3 has shown promise for people with ulcerative colitis.

• Fecal bacteriotherapy involves the infusion of human probiotics through fecal enemas ^[5]. It suggests that the cause of ulcerative colitis may be a previous infection by a still unknown pathogen. This initial infection resolves itself naturally, but somehow causes an imbalance in the colonic bacterial flora, leading to a cycle of inflammation which can be broken by "recolonizing" the colon with bacteria from a healthy bowel. There have been several reported cases of patients who have remained in remission for up to 13 years.^[6].

Intestinal parasites

Inflammatory bowel disease is less common in the developing world. Some have suggested that this may be because intestinal parasites are more common in underdeveloped countries. Some parasites are able to reduce the immune response of the intestine, an adaptation that helps the parasite colonize the intestine. The decrease in immune response could reduce or eliminate the inflammatory bowel disease

Helminthic therapy using the whipworm Trichuris suis has been shown in a randomized control trial from Iowa to show benefit in patients with ulcerative colitis. The therapy tests the hygiene hypothesis which argues that the absence of helminths in the colons of patients in the western world may lead to inflammation. Both helminthic therapy and fecal bacteriotherapy induce a characteristic Th2 white cell response in the diseased areas, which is somewhat paradoxical given that ulcerative colitis immunology was thought to classically involve Th2 overproduction ^[7]

References