Management of ulcerative colitis

Management of ulcerative colitis involves first treating the acute symptoms of the disease, then maintaining remission. 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.

Medications

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.

The following sections are sorted first by drug type and, second, by the type of ulcerative colitis.

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, mesalamine, or 5-ASA. Brand names include: Asacol, Octasa, Pentasa, Salofalk, Lialda, Ipocol and Mezavant.
• 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 Ibuprofen.

The free radical induction theory, discussed below, 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.^[1]

Sulfasalazine side-effects

Possible side effects of 5-ASA 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 5-ASA drugs to bring about remission of ulcerative colitis. Thereafter it may be possible to maintain remission with 5-ASAs 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 (3.9–5.9 in) 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.^[2]

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.

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.^[3]

Alternative treatments

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^{[citation needed]}.
• Patients with abdominal cramping or diarrhea should avoid fresh fruit, caffeine, carbonated drinks, high fructose corn syrup and sorbitol-containing foods^{[citation needed]}.
• The Specific Carbohydrate Diet has been promoted as helping with the symptoms of various auto-immune and gastrointestinal problems, including ulcerative colitis^{[citation needed]}.

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.^[4]
• Slow release phosphatidylcholine has some evidence of benefit in ulcerative colitis.^[5]

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.^[1] 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.^[1]

Herbals

• Vitamin U (methylmethioninesulfonium chloride, MMSC) has been shown to reverse ulcers in a number of different studies:^[6][7][8][9]

• 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 English name is Coptis Detoxifying Formula^{[citation needed]}.

• Boswellia is an ayurvedic (Indian traditional medicine) herb, used as a natural alternative to manufactured drugs. One study has found its effectiveness similar to sulfasalazine.^[10]

Bacterial recolonization

• Probiotics may have benefit^{[citation needed]}.

• Fecal bacteriotherapy involves the infusion of human probiotics through fecal enemas.^[11] 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.^[12]

Helminthic therapy

Inflammatory bowel disease is less common in the developing world^{[citation needed]}. Some^[who?] 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^{[citation needed]}. 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^[13]

References

1. ^ ^{a b c} Pravda J (April 2005). "Radical induction theory of ulcerative colitis". World J. Gastroenterol. 11 (16): 2371–84. PMID 15832404. http://www.wjgnet.com/1007-9327/11/2371.asp. 
2. ^ Kornbluth A, Sachar DB (July 2004). "Ulcerative colitis practice guidelines in adults (update): American College of Gastroenterology, Practice Parameters Committee". Am. J. Gastroenterol. 99 (7): 1371–85. doi:10.1111/j.1572-0241.2004.40036.x. PMID 15233681. 
3. ^ Ulcerative Colitis Practice Guidelines in Adults, Am. Coll. Gastroenterology, 2004. PDF
4. ^ "MedlinePlus Herbs and Supplements: Omega-3 fatty acids, fish oil, alpha-linolenic acid". http://www.nlm.nih.gov/medlineplus/druginfo/natural/patient-fishoil.html. Retrieved 2008-06-30. 
5. ^ Stremmel W, Merle U, Zahn A, Autschbach F, Hinz U, Ehehalt R (2005). "Retarded release phosphatidylcholine benefits patients with chronic active ulcerative colitis". Gut 54 (7): 966–971. doi:10.1136/gut.2004.052316. PMC 1774598. PMID 15951544. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1774598. 
6. ^ Watanabe T, Ohara S, Ichikawa T, Saigenji K, Hotta K (January 1996). "Mechanisms for cytoprotection by vitamin U from ethanol-induced gastric mucosal damage in rats". Dig. Dis. Sci. 41 (1): 49–54. doi:10.1007/BF02208583. PMID 8565766. 
7. ^ Sergienko AV (2006). "[Studying the anti-ulcer activity of gastrobiol]" (in Russian). Eksp Klin Farmakol 69 (2): 37–9. PMID 16845938. 
8. ^ Roediger WE, Babidge W, Millard S (July 1996). "Methionine derivatives diminish sulphide damage to colonocytes—implications for ulcerative colitis". Gut 39 (1): 77–81. doi:10.1136/gut.39.1.77. PMC 1383236. PMID 8881814. http://gut.bmj.com/cgi/pmidlookup?view=long&pmid=8881814. 
9. ^ Salim AS (January 1992). "Role of sulfhydryl-containing agents in the healing of erosive gastritis and chronic gastric ulceration in the rat". J Pharm Sci 81 (1): 70–3. doi:10.1002/jps.2600810114. PMID 1619573. 
10. ^ Gupta, I.; Parihar, A.; Malhotra, P.; Singh, G.; Lüdtke, R.; Safayhi, H.; Ammon, H. (1997). "Effects of Boswellia serrata gum resin in patients with ulcerative colitis". European journal of medical research 2 (1): 37–43. PMID 9049593.  edit
11. ^ Borody TJ, Warren EF, Leis SM, Surace R, Ashman O, Siarakas S (July 2004). "Bacteriotherapy using fecal flora: toying with human motions". J. Clin. Gastroenterol. 38 (6): 475–83. doi:10.1097/01.mcg.0000128988.13808.dc. PMID 15220681. http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0192-0790&volume=38&issue=6&spage=475. 
12. ^ Borody TJ, Warren EF, Leis S, Surace R, Ashman O (July 2003). "Treatment of ulcerative colitis using fecal bacteriotherapy". J. Clin. Gastroenterol. 37 (1): 42–7. doi:10.1097/00004836-200307000-00012. PMID 12811208. http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0192-0790&volume=37&issue=1&spage=42. 
13. ^ Summers RW, Elliott DE, Urban JF, Thompson RA, Weinstock JV (April 2005). "Trichuris suis therapy for active ulcerative colitis: a randomized controlled trial". Gastroenterology 128 (4): 825–32. doi:10.1053/j.gastro.2005.01.005. PMID 15825065. http://linkinghub.elsevier.com/retrieve/pii/S0016508505000259.