- 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 diseaseof 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 diarrheamixed with blood, of gradual onset. Ulcerative colitis is, however, a systemicdisease that affects many parts of the body outside the intestine.
The clinical presentationHanauer SB. Inflammatory bowel disease. "N Engl J Med" 1996;334:841-848. PMID 8596552.] of ulcerative colitis depends on the extent of the disease process. Patients usually present with
diarrheamixed 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 membraneis 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
remissioninitially 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.
Aminosalicylates are the main
anti-inflammatorydrugs 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, 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 Aspirinand Ibuprofin.
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.
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.
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 cascadewhich 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:
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 inhibit the immune system generally. These include the cytostatic drugs that inhibit cell division, including the cloningof 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
Mercaptopurine inhibits the production of
white blood cellsgenerally. 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 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.
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. [Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults (update): American College of Gastroenterology, Practice Parameters Committee. "Am J Gastroenterol" 2004; 99:1371-85. PMID 15233681.]
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 sulfateor ferrous gluconate) may be given due to chronic blood loss. Loperamidemay 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.
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. Ulcerative Colitis Practice Guidelines in Adults, Am. Coll. Gastroenterology, 2004. [http://www.acg.gi.org/physicians/guidelines/UlcerativeColitisUpdate.pdf PDF] ]
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 fiber is beneficial.cite journal
author=Akhtar MS, Munir M
title=Evaluation of the gastric anti-ulcerogenic effects of Solanum nigrum, Brassica oleracea and Ocimum basilicum in rats.
quote=Brassica oleracea (leaf) powder did not affect the ulcer index significantly but its aqueous extract lowered the index and increased hexosamine levels, suggesting gastric mucosal protection.]
Lactose intoleranceis 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 fruit, caffeine, carbonated drinks, high fructose corn syrup and
Fats and oils
* Fish oil.
Eicosapentaenoic acid(EPA), derived from fish oil. This is an Eicosanoidthat inhibits leukotrieneactivity. It is effective as an adjunct therapy. Usual dose is 15-18 capsules a day. [cite web|url = http://www.nlm.nih.gov/medlineplus/druginfo/natural/patient-fishoil.html |title = MedlinePlus Herbs and Supplements: Omega-3 fatty acids, fish oil, alpha-linolenic acid |accessdate = 2008-06-30]
* Short chain fatty acid (butyrate) enema. Results not conclusive.
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. 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: Vitamin B6and ironmay be associated with increased hydrogen peroxide levels, and should not be taken in excess under this theory.
Vitamin U(methylmethioninesulfonium chloride, MMSC) has been shown to reverse ulcers in a number of different studies: [cite web|url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=8565766&query_hl=12&itool=pubmed_docsum |title = Mechanisms for cytoprotection by vitamin U from et... [Dig Dis Sci. 1996 - PubMed Result |accessdate = 2008-06-30] [cite web|url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16845938&query_hl=9&itool=pubmed_docsum |title = [Studying the anti-ulcer activity of gastrobiol [Eksp Klin Farmakol. 2006 Mar-Apr - PubMed Result |accessdate = 2008-06-30] [cite web|url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=8881814&query_hl=8&itool=pubmed_docsum |title = Methionine derivatives diminish sulphide damage to... [Gut. 1996 - PubMed Result |accessdate = 2008-06-30] [cite web|url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=1619573&query_hl=12&itool=pubmed_docsum |title = Role of sulfhydryl-containing agents in the healin... [J Pharm Sci. 1992 - PubMed Result |accessdate = 2008-06-30]
Kampomedicine 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 medicinename for this is Huang-Liang-Jie-Du-Tang; its and English name is Coptis Detoxifying Formula.
Probioticsmay have benefit. One study looked at a probiotic known as VSL-3has shown promise for people with ulcerative colitis.
Fecal bacteriotherapyinvolves the infusion of human probiotics through fecal enemas Borody TJ, Warren EF, Leis SM, Surace R, Ashman O, Siarakas S. Bacteriotherapy using fecal flora: toying with human motions. "J Clin Gastroenterol" 2004;38:475-83. PMID 15220681.] . 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. [Borody TJ, Warren EF, Leis S, Surace R, Ashman O. Treatment of ulcerative colitis using fecal bacteriotherapy. "J Clin Gastroenterol" 2003;37:42-7. PMID 12811208.] .
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 therapyusing the whipworm"Trichuris suis" has been shown in a randomized control trialfrom Iowa to show benefit in patients with ulcerative colitis. The therapy tests the hygiene hypothesiswhich argues that the absence of helminthsin the colons of patients in the western world may lead to inflammation. Both helminthic therapyand fecal bacteriotherapyinduce a characteristic Th2white cell response in the diseased areas, which is somewhat paradoxical given that ulcerative colitis immunology was thought to classically involve Th2 overproduction [Summers RW, Elliott DE, Urban JF Jr, Thompson RA, Weinstock JV. Trichuris suis therapy for active ulcerative colitis: a randomized controlled trial. "Gastroenterology" 2005;128:825-32. PMID 15825065.]
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