Treatment of Crohn's disease

Treatment of Crohn's disease involves first treating the acute symptoms of the disease, then maintaining remission. Treatment initially involves the use of medications to eliminate infections, generally antibiotics, and reduce inflammation, generally aminosalicylate anti-inflammatory drugs and corticosteroids. Surgery may be required for complications such as obstructions or abscesses, or if the disease does not respond to drugs within a reasonable time.

Once remission is induced, the goal of treatment becomes maintenance of remission, avoiding the return of active disease, or "flares". Because of side-effects, the prolonged use of corticosteroids is avoided. Although some people are able to maintain remission with aminosalicylates alone, many require immunosuppressive drugs.cite journal |author=Hanauer SB, Sandborn W |title=Management of Crohn's disease in adults |journal=Am. J. Gastroenterol. |volume=96 |issue=3 |pages=635–43 |year=2001 |pmid=11280528 |url = http://www.ibdforum.com/proto/acghanauer.pdf | accessdate = 2008-02-15 | format = pdf |doi=10.1111/j.1572-0241.2001.03671.x]

Aminosalicylate anti-inflammatory drugs

5-aminosalicylates (5-ASA) include the following:
*Mesalazine or mesalamine, which is marketed in the forms Asacol, Pentasa, Salofalk, Dipentum and Rowasa.
*Sulfasalazine, which is converted to 5-ASA and sulfapyridine by intestinal bacteria. The sulfapyridine may have some therapeutic effect in rheumatoid arthritis. However, the sulfapyridine component is often the limiting factor in treatment of Crohn's disease because of high side-effect profile.5-ASA compounds have been shown to be useful in the treatment of mild-to-moderate Crohn's disease. [cite journal |author=Hanauer SB, Strömberg U |title=Oral Pentasa in the treatment of active Crohn's disease: A meta-analysis of double-blind, placebo-controlled trials |journal=Clin. Gastroenterol. Hepatol. |volume=2 |issue=5 |pages=379–88 |year=2004 |pmid=15118975 |doi=] They are usually considered to be first line therapy for disease in the ileum and right side of the colon particularly due to their lower side effect profile compared to corticosteroids. [cite journal |author=Prantera C, Cottone M, Pallone F, "et al" |title=Mesalamine in the treatment of mild to moderate active Crohn's ileitis: results of a randomized, multicenter trial |journal=Gastroenterology |volume=116 |issue=3 |pages=521–6 |year=1999 |pmid=10029609 |doi=.]

Corticosteroid anti-inflammatory drugs

Corticosteroids are a class of anti-inflammatory drug that are used primarily for treatment of moderate to severe flares of Crohn's disease. They are used more sparingly due to the availability of effective treatments with less side-effects. The side effects of corticosteroids include Cushing's syndrome, mania, insomnia, hypertension, high blood glucose, osteoporosis, and avascular necrosis of long bones. These should not be confused with the anabolic steroids used to enhance athletic performance.

The most commonly prescribed oral steroid is prednisone, which is typically dosed at 0.5 mg/kg for induction of remission. [cite journal |author=Hanauer SB |title=Sulfasalazine vs. steroids in Crohn's disease: David vs. Goliath? |journal=Gastroenterology |volume=101 |issue=4 |pages=1130–1 |year=1991 |pmid=1679735 |doi=] Intravenous steroids are used for cases refractory to oral steroids, or where oral steroids cannot be taken.cite web|first= Latha|last= Gopal|coauthors=Senthil Nachimuthu|publisher=eMedicine|title=Crohn Disease|url=http://www.emedicine.com/MED/topic477.htm|accessdate=2006-07-02|date=2006-05-23] These are administered in the hospital setting. Because corticosteroids reduce the ability to fight infection, care must be used to ensure that there isn't an active infection, particularly an intra-abdominal abscess before the initiation of steroids.

Budesonide is an oral corticosteroid with limited absorption and high level of first-pass metabolism, meaning that less quantities of steroid enter into the bloodstream. It has been shown to be useful in the treatment of mild-to-moderate Crohn's diseasecite journal |author=Greenberg GR, Feagan BG, Martin F, "et al" |title=Oral budesonide for active Crohn's disease. Canadian Inflammatory Bowel Disease Study Group |journal=N. Engl. J. Med. |volume=331 |issue=13 |pages=836–41 |year=1994 |pmid=8078529 |doi=] and for maintenance of remission in Crohn's disease. [cite journal |author=Sandborn WJ, Löfberg R, Feagan BG, Hanauer SB, Campieri M, Greenberg GR |title=Budesonide for maintenance of remission in patients with Crohn's disease in medically induced remission: a predetermined pooled analysis of four randomized, double-blind, placebo-controlled trials |journal=Am. J. Gastroenterol. |volume=100 |issue=8 |pages=1780–7 |year=2005 |pmid=16086715 |doi=10.1111/j.1572-0241.2005.41992.x] Formulated as Entocort, budesonide is released in the ileum and right colon, and is therefore has a topical effect against disease in that area.

Steroid enemas can also be used for disease of the lower colon and rectum, in order to treat symptoms. Hydrocortisone and budesonide liquid and foam enemas are being marketed for these reasons.

Corticosteroids however have a host of side effects, some very serious, and it is desirable to curtail their use whenever possible.

Mercaptopurine immunosuppressing drugs

Azathioprine and 6-mercaptopurine (6-MP) are the most used immunosuppressants for maintenance therapy of Crohn's disease. They are purine anti-metabolites, meaning that they interfere with the synthesis of purines required for inflammatory cells. They have a duration of action of months, making it unwieldy to use them for induction of remission. Both drugs are dosed at 1.5 to 2.5 mg/kg, with literature supporting the use of higher doses.Cite journal|last=Podolsky|first= Daniel K.|title=Inflammatory bowel disease|journal=New England Journal of Medicine|month=August|year=2002|volume=346|issue=6|pages=417–29
url=http://content.nejm.org/cgi/content/extract/347/6/417|accessdate=2006-07-02|pmid=12167685|doi=10.1056/NEJMra020831]

Azathioprine is however a particularily dangerous drug, with great potential for inviting a host of potentially fatal infections, and is also listed by the FDA as a human carcinogen.

Infliximab

Infliximab, marketed as Remicade, is a mouse-human chimeric antibody that targets tumour necrosis factor, a cytokine in the inflammatory response. It is administered intravenously and dosed per weight.

Infliximab has found utility as follows:
*Maintenance of remission for people with Crohn's disease.cite journal |author=Hanauer SB, Feagan BG, Lichtenstein GR, "et al" |title=Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial |journal=Lancet |volume=359 |issue=9317 |pages=1541–9 |year=2002 |pmid=12047962 |doi=]
*Induction of remission for people with Crohn's disease.
*Maintenance for fistulizing Crohn's disease. [Sands BE, Anderson FH, Bernstein CN, Chey WY, Feagan BG, Fedorak RN, Kamm MA, Korzenik JR, Lashner BA, Onken JE, Rachmilewitz D, Rutgeerts P, Wild G, Wolf DC, Marsters PA, Travers SB, Blank MA, van Deventer SJ. Infliximab maintenance therapy for fistulizing Crohn's disease. N Engl J Med. 2004 Feb 26;350(9):876-85. PMID 14985485]

Side effects of infliximab, like other immunosuppressants of the TNF class, can be serious and potentially fatal, and infliximab carries an FDA black-box warning on the label. Listed side effects include hypersensitivity and allergic reactions, risk of re-activation of tuberculosis, serum sickness, and risk of multiple sclerosis. [cite journal |author=Rutgeerts P, Van Assche G, Vermeire S |title=Review article: Infliximab therapy for inflammatory bowel disease--seven years on |journal=Aliment. Pharmacol. Ther. |volume=23 |issue=4 |pages=451–63 |year=2006 |pmid=16441465 |doi=10.1111/j.1365-2036.2006.02786.x] Serious side effect also include lymphoma and severe infections, inclduing progressive multifocal leukoencephalopathy (PML) an opportunistic viral infection of the brain that can cause death.

Adalimumab

Adalimumab, marketed as Humira, like infliximab is an antibody that targets tumour necrosis factor. [cite journal |author=Hanauer SB, Sandborn WJ, Rutgeerts P, "et al" |title=Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial |journal=Gastroenterology |volume=130 |issue=2 |pages=323–33; quiz 591 |year=2006 |pmid=16472588 |doi=10.1053/j.gastro.2005.11.030] Adalimumab has been shown to reduce the signs and symptoms of, and is approved for treatment of, moderate to severe Crohn’s disease (CD) in adults who have not responded well to conventional treatments and who have lost response to, or are unable to tolerate infliximab. [cite web | url = http://www.rxabbott.com/pdf/humira_medguide.pdf | title = Medication guide: Humira | accessdate = 2008-03-25 | date = 2008-02-01 | format = pdf | publisher = Abbott Laboratories ]

Adalimumab also has a number of serious, potentially fatal, safety concerns characteristic of the anti-TNFα drugs. It too has a black-box warning on its FDA label. Listed potential side effects include serious and sometimes fatal blood disorders; serious infections including include TB (tuberculosis) and infections caused by viruses, fungi, or bacteria; rare reports of lymphoma and solid tissue cancers; rare reports of serious liver injury; and rare reports of demyelinating central nervous system disorders); and rare reports of cardiac failure.

Natalizumab

In January 2008, the FDA approved natalizumab for both induction of remission and maintenance of remission for moderate to severe Crohn's disease. [cite web | url = http://www.fda.gov/bbs/topics/NEWS/2008/NEW01775.html | publisher = Food and Drug Administration | title = FDA Approves Tysabri to Treat Moderate-to-Severe Crohn's Disease | date = 2008-01-14 | accessdate = 2008-03-09 ]

Surgery

Surgery is normally reserved for complications of Crohn's disease or when disease that resists treatment with drugs is confined to one location that can be removed.cite journal | last = Hanauer | first = Stephen B. | year = 1996 | month = March | title = Inflammatory bowel disease | journal = New England Journal of Medicine | volume = 334 | issue = 13 | pages = 841–848 | pmid = 8596552 | url = http://content.nejm.org/cgi/content/extract/334/13/841 | accessdate = 2006-11-10 | doi = 10.1056/NEJM199603283341307] Surgery is often used to manage complications of Crohn's disease, including fistulae, small bowel obstruction, colon cancer, small intestine cancer and fibrostenotic strictures, when strictureplasty (expansion of the stricture) is sometimes performed. Otherwise, and for other complications, resection and anastomosis - the removal of the affected section of intestine and the rejoining of the healthy sections - is the surgery usually performed for Crohn's disease (e.g., ileocolonic resection). Neither type of surgery cures Crohn's disease, as recurrence often reappears in previously unaffected areas of the intestine.cite web| url=http://www.ccfa.org/info/surgery/surgerycd| title=Surgery for Crohn's Disease| year=2006| month=March| accessdate=2006-06-08 |publisher=Crohn's and Colitis Foundation of America]

Small intestine transplants are experimental as of yet, and are usually only done when there is a risk of short bowel syndrome due to repeated resection surgeries.Fact|date=March 2008

Diet and lifestyle

There is no evidence that diet causes or cures Crohn's disease. If a person with Crohn's finds that certain foods increase or decrease the symptoms, then they may adjust their diet accordingly. A food diary is recommended to see what positive or negative effects particular foods have [http://www.ccfa.org] .

Fish oil has been found to be effective in reducing the chance of relapse in less severe cases. [cite journal | author = A Belluzzi, C Brignola, M Campieri, A Pera, S Boschi, and M Miglioli | year = 1996 | month = June | title = Effect of an Enteric-Coated Fish-Oil Preparation on Relapses in Crohn's Disease | journal = New England Journal of Medicine | volume = 334 | issue = 24 | pages = 1557–60 | url = http://content.nejm.org/cgi/content/abstract/334/24/1557?ijkey=6460c4103d06d06d427a2779ed0d755c3a7671cc&keytype2=tf_ipsecsha | doi = 10.1056/NEJM199606133342401 | format = abstract page] People with lactose intolerance due to small bowel disease may benefit from avoiding lactose-containing foods. Many diets, for instance, Specific Carbohydrate Diet, have been proposed for treatment of Crohn's disease, and many do improve symptoms, but none have been proven to actually cure Crohn's disease. [cite book | last = Gottschall | first = Elaine | year = 1994 | title = Breaking the Vicious Cycle: Intestinal Health Through Diet | publisher = Kirkton Press | location = Baltimore | id = ISBN 0-9692768-1-8] This diet though usually needs adjustments for patients so that they can handle the diet. A low residue diet may be used to reduce the volume of stools excreted daily. Patients who cannot eat are recommended to take total parenteral nutrition (TPN) - a source of vitamins and nutrients. [http://hopkins-gi.nts.jhu.edu/pages/latin/templates/index.cfm?pg=disease2&organ=6&disease=21&lang_id=1] Stress is not proven to aggravate or induce the symptoms of Crohn’s disease. [http://www.ccfa.org/printview?pageUrl=/info/about/crohns] If sufferers observe that Stress Management is a successful method of suppressing the illness in their bodies, then they may manage stress as they see fit. Conversely, stress is likely to be caused by the flaring up of the disease and this would make day to day life more difficult.Smoking has also been noted to have an association with Crohn's, and smokers with Crohn's are encouraged to quit.

Because the terminal ileum is the most common site of involvement and is the site for vitamin Bssub|12 absorption, people with Crohn's disease are at risk for Bssub|12 deficiency and may need supplementation. In cases with extensive small intestine involvement, the fat soluble vitamins A, D, E and K can be deficient. Folate deficiency is a risk when being treated with methotrexate.

Helminthic therapy

In an experimental idea called Helminthic therapy, moderate hookworm infections have been demonstrated to have beneficial effects on hosts suffering from diseases linked to overactive immune systems. This is possibly explained by the hygiene hypothesis. Helminthic therapy may help sufferers of Crohn's Diseasecite journal | author = Croese, J. | coauthors = O'Neil, J.; Masson, J.; Cooke, S.; Melrose, W.; Pritchard, D.; Speare, R. | year = 2006 | title = A proof of concept study establishing Necator americanus in Crohn's patients and reservoir donors | journal = British Medical Journal | volume = 55 | issue = 1 | pages = 136 | doi = 10.1136/gut.2005.079129 ; [http://www.dailymail.co.uk/pages/live/articles/technology/technology.html?in_article_id=481875&in_page_id=1965 lay summary] ] Hookworm therapy is currently in the trial stage at the University of Nottingham. Due to the unconventional nature of this therapy, it is not widely used.

Complementary and alternative medicine

More than half of Crohn's disease sufferers have tried complementary or alternative therapy. [cite journal | author = Caprilli R, Gassull M, Escher J "et al" | title = European evidence based consensus on the diagnosis and management of Crohn's disease: special situations | journal = Gut | volume = 55 Suppl 1 | issue = | pages = i36–58 | year = | pmid = 16481630] These include diets, probiotics, fish oil and other herbal and nutritional supplements. The benefit of these medications is uncertain.

Acupuncture

Acupuncture is used to treat inflammatory bowel disease in China, and is being used more frequently in Western society.cite journal |author=Joos S, Brinkhaus B, Maluche C, "et al" |title=Acupuncture and moxibustion in the treatment of active Crohn's disease: a randomized controlled study |journal=Digestion |volume=69 |issue=3 |pages=131–9 |year=2004 |pmid=15114043 |doi=10.1159/000078151] There is evidence that acupuncture has benefits beyond the placebo effect, improving quality of life, general well-being and a small decrease in blood-bound inflammatory markers.

Other medications

*Methotrexate is a folate anti-metabolite drug which is also used for chemotherapy. It is useful in maintenance of remission for those no longer taking corticosteroids. [cite journal |author=Feagan BG, Fedorak RN, Irvine EJ, "et al" |title=A comparison of methotrexate with placebo for the maintenance of remission in Crohn's disease. North American Crohn's Study Group Investigators |journal=N. Engl. J. Med. |volume=342 |issue=22 |pages=1627–32 |year=2000 |pmid=10833208 |doi=]
*Metronidazole and ciprofloxacin are antibiotics which are used to treat Crohn's that have colonic or perianal involvement, although this use has not been approved by the Food and Drug Administration. [cite journal |author=Ursing B, Alm T, Bárány F, "et al" |title=A comparative study of metronidazole and sulfasalazine for active Crohn's disease: the cooperative Crohn's disease study in Sweden. II. Result |journal=Gastroenterology |volume=83 |issue=3 |pages=550–62 |year=1982 |pmid=6124474 |doi=] They are also used for treatment of complications, including abscesses and other infections accompanying Crohn's disease.
*Thalidomide has shown response in reversing endoscopic evidence of disease. [cite journal |author=Cohen LB |title=Re: Disappearance of Crohn's ulcers in the terminal ileum after thalidomide therapy. Can J Gastroenterol 2004; 18(2): 101-104 |journal=Can. J. Gastroenterol. |volume=18 |issue=6 |pages=419; author reply 419 |year=2004 |pmid=15230268 |doi=]
*Cannabis may also be used to treat Crohn's Disease with its anti-inflammatory properties. Cannabis and cannabis-derived drugs may also help to heal the gut lining. [ [http://www.medicalnewstoday.com/articles/28584.php Cannabis-based drugs could offer new hope for inflammatory bowel disease patients] ]

Research on medications in progress

Many clinical trials have been recently completed or are ongoing for new therapies for Crohn's disease. They include the following:
*Certolizumab is a PEGylated Fab fragment of a humanized anti-TNF alpha monoclonal antibody that was found to have efficacy over placebo in one large trial. [cite journal | author = Schreiber S, Rutgeerts P, Fedorak R, Khaliq-Kareemi M, Kamm M, Boivin M, Bernstein C, Staun M, Thomsen O, Innes A | title = A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn's disease. | journal = Gastroenterology | volume = 129 | issue = 3 | pages = 807–18 | year = 2005 | pmid = 16143120 | doi = 10.1053/j.gastro.2005.06.064]
*"ABT-874" is a human anti-IL-12 monoclonal antibody being developed by Abbott Laboratories in conjunction with Cambridge Antibody Technology for the treatment of multiple autoimmune diseases including Crohn's disease. Phase II trials have been completed and showed promising results, [cite journal |author=Mannon PJ, Fuss IJ, Mayer L, "et al" |title=Anti-interleukin-12 antibody for active Crohn's disease |journal=N. Engl. J. Med. |volume=351 |issue=20 |pages=2069–79 |year=2004 |pmid=15537905 |doi=10.1056/NEJMoa033402]
*Sargramostim, or granulocyte-monocyte colony stimulating factor (GM-CSF) has been shown to substabtially improve health-related quality of life in pilot studies, measured by an increase in score of a 32-item IBD questionnaire. [cite journal |author=Korzenik JR, Dieckgraefe BK, Valentine JF, Hausman DF, Gilbert MJ |title=Sargramostim for active Crohn's disease |journal=N. Engl. J. Med. |volume=352 |issue=21 |pages=2193–201 |year=2005 |pmid=15917384 |doi=10.1056/NEJMoa041109] A recent Phase II trial showed that Sargramostim significantly decreased CD severity (48% compared to 26% placebo group) and improved quality of life (40% versus 19% for placebo). [ cite web | author=B. Dieckgraefe |year=2006 | title=Improving Mucosal Barrier Function - A Novel Therapeutic Strategy for Crohn's Disease|url=http://www.touchalimentarydisease.com/articles.cfm?article_id=6363&level=2]
*"Trichuris suis" is a pig whipworm that been shown in one study to improve Crohn's disease symptoms. [cite journal |author=Summers RW, Elliott DE, Urban JF, Thompson R, Weinstock JV |title=Trichuris suis therapy in Crohn's disease |journal=Gut |volume=54 |issue=1 |pages=87–90 |year=2005 |pmid=15591509 |doi=10.1136/gut.2004.041749]
*Autologous stem cell transplants have also been evaluated. [cite journal |author=Oyama Y, Craig RM, Traynor AE, "et al" |title=Autologous hematopoietic stem cell transplantation in patients with refractory Crohn's disease |journal=Gastroenterology |volume=128 |issue=3 |pages=552–63 |year=2005 |pmid=15765390 |doi=]
*Rifabutin, clarithromycin and clofazimine are antibiotics designed to attack mycobacterium avium subsp. paratuberculosis, which may be a cause of Chron's disease. This treatment, called Myoconda, is being tested by Giaconda.

References

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