Treatment of Crohn's disease
From Wikipedia, the free encyclopedia
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.[1]
[edit] 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.[2] 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.[3]
[edit] 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.[4] 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.[5] Intravenous steroids are used for cases refractory to oral steroids, or where oral steroids cannot be taken.[4] 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 disease[6] and for maintenance of remission in Crohn's disease.[7] Formulated as Entocort, budesonide is released in the ileum and right colon, and is therefore has a topical effect against disease in that area.[6]
Budesonide is also useful when used in combination with antibiotics for active Crohn's disease.[8]
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.
[edit] 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.[9]
Azathioprine and 6-MP have been found to be useful for the following indications:
- For maintenance therapy for people who are dependent on steroids.[10]
- Fistulizing disease.[11]
- Induction of remission in steroid refractory disease.[12]
- Maintenance of remission after surgery for Crohn's disease.[13]
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.
[edit] 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.[14]
- Induction of remission for people with Crohn's disease.[14]
- Maintenance for fistulizing Crohn's disease.[15]
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.[16] 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.
[edit] Adalimumab
Adalimumab, marketed as Humira, like infliximab is an antibody that targets tumour necrosis factor.[17] 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.[18]
Adalimumab also has a number of serious safety concerns, potentially fatal, typical of the TNF class, and it too 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.
[edit] Natalizumab
Natalizumab, marketed as Tysabri, is an anti-integrin monoclonal antibody that has shown utility as induction and maintenance treatment for moderate to severe Crohn's disease.[19] Natalizumab may be appropriate in patients who do not respond to medications that block tumor necrosis factor-alpha such as infliximab.[20]
In January 2008, the FDA approved natalizumab for both induction of remission and maintenance of remission for moderate to severe Crohn's disease.[21]
A total of 3 large randomized controlled trials have demonstrated that natalizumab is effective in increasing rates of remission[22] and maintaining symptom-free status[23] in patients with Crohn's disease.
Like infliximab, natalizumab has also been linked to PML (though only when used in combination with interferon beta-1a).[24][25] The label also recommends monitoring of liver enzymes due to conerns over possible damage or failure.[26]
[edit] 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.[27] 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.[28]
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.[citation needed]
[edit] 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 [1].
Fish oil has been found to be effective in reducing the chance of relapse in less severe cases.[29] 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.[30] 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.[2] Stress is not proven to aggravate or induce the symptoms of Crohn’s disease.[3] 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 B12 absorption, people with Crohn's disease are at risk for B12 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.
[edit] 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 Disease[31] 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.
[edit] Complementary and alternative medicine
More than half of Crohn's disease sufferers have tried complementary or alternative therapy.[32] These include diets, probiotics, fish oil and other herbal and nutritional supplements. The benefit of these medications is uncertain.
[edit] Acupuncture
Acupuncture is used to treat inflammatory bowel disease in China, and is being used more frequently in Western society.[33] 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.[33]
[edit] 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.[34]
- 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.[35] They are also used for treatment of complications, including abscesses and other infections accompanying Crohn's disease.[4]
- Thalidomide has shown response in reversing endoscopic evidence of disease.[36]
[edit] 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.[37]
- 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,[38]
- 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. [39] 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).[40]
- Trichuris suis is a pig whipworm that been shown in one study to improve Crohn's disease symptoms.[41]
- Autologous stem cell transplants have also been evaluated.[42]
- 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.
[edit] References
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