What are the treatments for Crohn's disease?
The treatment for Crohn's disease depends on the location (i.e. upper GI, small bowel, colon, or perianal), severity, type (i.e. inflammatory, perforating, stricturing), complications of the Crohn's disease, and the patient's response to previous medical treatments. Once remission is induced and the patients' symptoms are relieved, the majority of patients will need to remain on maintenance therapy in order to prevent flares of the disease. Unfortunately, despite medical therapy, approximately 75% of patients with Crohn's disease will eventually require surgery to control their disease or help manage one of the associated complications.
The current model for the treatment of Crohn's disease is referred to as "step-up" therapy. Under this model, patients are treated first with medications that have fewer side effects but may not be as effective as stronger medications that are associated with more potential toxicity. This scheme is often shown visually as a pyramid, with the more mild therapies at the base of the pyramid and the more powerful (but potentially more toxic) medications at the top.
Drugs from the bottom of the pyramid are often tried, in those patients with more mild symptoms. If treatment fails, the physician will try "stepping up" therapy with stronger medications. Sicker patients will require stronger medications from the start.
Currently, there is debate amongst physicians as to whether the pyramid should be flipped to result in a "top down" approach rather than a "step up" model for treatment. This is based on the theory that using more effective medications from the outset may change the natural history of Crohn's disease and prevent flares, hospitalizations, and surgeries. In practice, each patient must receive individualized care in which the risks of the medications are weighed against the benefits for that particular patient. Affected individuals and their physicians must discuss the options in great detail and come to a decision that is right for that patient.
In the future, the goal will be to predict which patients are going to have a more aggressive form of Crohn's disease and treat them more aggressively from the beginning. For those patients who are predicted to have a more mild form of the disease, less aggressive therapy would be indicated and potential side effects of medications avoided. The predictions will likely be based on a combination of genetic tests, serologic markers, and specific disease characteristics; unfortunately, the ability to effectively obtain this information is still a number of years away.
Medications Used in the Treatment of Crohn's Disease
1. 5-amniosalicylates (5-ASAs)
5-ASA's are medications used to treat mild Crohn's disease. Although it is uncertain exactly how they work, the 5-ASAs appear to act topically on the GI tract (not by being absorbed into the blood stream)and exert an anti-inflammatory effect. There are a number of these agents available which can be delivered both orally or rectally. Depending on how each specific drug is designed, the active 5-ASA is released at various locations throughout the GI tract.
The original 5-aminosalicylate, known as
(Azufidine), has been used to treat IBD for decades. It is most effective for mild to moderate Crohn's disease, particularly when the disease affects the colon. The 5-ASA is bound to a compound called sulfapyridine, from which it detaches when it reaches the colon. Unfortunately, sulfasalazine has a number of side effects due to the part of the sulfapyridine molecule (moiety) to which it is attached, including symptoms such as nausea and headache, and up to 1/3 of patients cannot tolerate it over the long-term. Patients who have allergies to sulfa medications will also be intolerant of sulfasalzine. Patients who take Sulfasalazine must also take folic acid 1 mg daily, as the Sulfasalazine depletes folic acid stores.
Because many patients cannot tolerate sulfasalazine, other methods of delivering 5-ASA to the small intestine and colon have been developed that do not contain a sulfapyridine moiety. Almost all of the patients intolerant of sulfasalazine are able to take these other 5-ASA agents, which are designed to release 5-ASA at specific locations throughout the GI tract.
These medications include a free 5-ASA, known as
, which is enclosed within special capsules that release the active drug only when they reach the small intestine or colon. Asacol, Asacol HD, Apriso, and Lialda release the mesalamine in the terminal ileum and colon. Pentasa releases mesalamine throughout the small intestine and colon.
Other agents include 5-ASA bound to another 5-ASA molecule (
, Dipentum) or a carrier molecule (
, Colazal). These drugs release 5-ASA specifically to the colon.
The data on the efficacy of 5-ASA use in Crohn's disease is not nearly as strong as for its use in ulcerative colitis. A number of GI physicians have argued that 5-ASAs other than sulfasalazine should not be used to treat Crohn's disease, that it is no better than placebo (sugar pill), but we believe that 5-ASA may be effective in some patients with mild Crohn's disease and has a role in treatment for particular individuals. Patients with new onset, mild, colonic disease are probably the best candidates for therapy with 5-ASA. However, if patients are not having a response, medical therapy should be stepped up to another medication sooner rather than later. Also, it is likely that patients with Crohn's disease require larger doses (4.8g) of mesalamine rather than the smaller doses (2.4g) which may be effective in ulcerative colitis.
One of the main issues with 5-ASA therapy is compliance. The pill burden can be substantial (4-12 pills per day). While the older drugs were designed to be taken three to four times a day, most physicians prescribe these medications twice a day to make it easier for patients to take, and this strategy appears to be just as effective. The newer 5-ASA's, Lialda, and Apriso, are approved for ulcerative colitis for once daily dosing, with as few as four pills delivering 4.8g of mesalamine. Currently, other pharmaceutical companies are working on similar designs to make administration of this class of drugs as easy for patients as possible.
Mesalamine also comes in enema (Rowasa) and suppository (Canasa) forms, which is ideal for patients with disease limited to the lower third of the colon or rectum, respectively. These formulations are used more commonly in patients with ulcerative colitis.
Side-effects from 5-ASA compounds are uncommon , but may include abdominal pain, gas, nausea, hair loss, headache, and dizziness. An important side effect for patients and physicians to recognize is a paradoxical worsening of diarrhea, which is due either to an allergic-type reaction or an increase in the secretion of water by the small bowel. If diarrhea worsens with initiation of these agents, this should be considered as a possible cause, and the drug should be stopped. There also are a number of rare but more serious side-effects from 5-ASA compounds, including allergic-type reactions in the pancreas, lungs, kidneys, skin, and bone marrow. Kidney function should be monitored annually in patients on 5-ASA. Reduced sperm counts have been noted in the majority of men on sulfasalazine (Azulfidine), so this should be kept in mind for male patients who are trying to conceive. Headache, nausea, loss of appetite, and vomiting are seen much more commonly with sulfasalazine therapy. Allergy to sulfa (rash, fever), a decreased red or white blood cell count, and abnormal liver tests can also be associated with sulfasalazine. Regular monitoring of blood counts and liver tests should be carried out in patients who are receiving this medication. The majority of these adverse effects are reversible once the drug is stopped.
2. Corticosteroids (Steroids)
Like sulfasalazine, corticosteroids (or "steroids") have been used to treat IBD for decades and have become a mainstay of treatment for active flares. They are used to treat moderate-to-severe Crohn's disease and when 5-aminosalicilates, and in some cases antibiotics, fail to control the disease. These drugs exert an anti-inflammatory and immunosuppressive effect and can be given by mouth, by rectum, or intravenously, depending on the location and severity of the disease.
, the most commonly used oral steroid, produces consistent responses, and induces remission in about 70-80% of patients. Steroids also act quickly, with most patients noticing a response within one week.
Although steroids induce remission, they are not effective in the long-term to maintain remission. In addition, steroids are associated with a number of serious side-effects including low bone density (osteoporosis), diabetes, high blood pressure (hypertension), cataracts, psychosis, depression, increased risk of infections, acne, weight gain, difficulty sleeping (insomnia), and facial swelling. Steroids also cause the body's adrenal glands to stop producing their own endogenous steroid (cortisol). If the administered steroids are tapered off too quickly, the body can go into a "steroid withdrawal" or adrenal crisis. Once started, steroids are usually slowly reduced in dose over a number of weeks to prevent a sudden flare of the disease or adrenal crisis.
Patients who are on steroids also need to be on adequate amounts of calcium (1200mg) and vitamin D (800 IU). Some patients, with underlying osteopenia or osteoporosis, or patients who remain on steroids for prolonged periods of time, may require additional drugs (bisphosphonates) to prevent further bone loss. Bisphosphonates (alendronate or risidronate) have been shown to be useful in this situation, particularly in postmenopausal females and in those patients on long-term steroids.
Although steroids are effective in quickly inducing remission, a number of patients are unable to reduce their steroids without a worsening of their symptoms, and essentially become steroid-dependent. These patients require further medical or surgical therapy in order to help get them off of the steroids. In fact, studies have shown that one year after starting steroids approximately 30% of patients are steroid dependent and 38% of patients have required surgery. Less than 1/3 of patients are in remission and off steroids at one year. Therefore, once steroids are utilized to induce remission, other drugs are needed to help wean patients off of steroids, avoid surgery, and maintain remission. The agents typically used in this situation are known as immunomodulators,which will be discussed in greater detail below.
Budesonide (Entocort EC) is a new type of steroid developed in order to avoid some of the side effects caused by systemic coriticosteroids. Budesonide is released in the distal small intestine and right colon (cecum and ascending colon) and exerts its effects locally. As a result, this medication is only useful in those patients with Crohn's disease restricted to these areas. Once absorbed, the vast majority of the drug is broken down quickly by the liver before it reaches the rest of the body, thereby avoiding many of the side effects associated with traditional steroids such as prednisone. However, budesonide is not completely without steroid side effects. Budesonide has been shown to increase the time to relapse as far out as nine months, but like traditional steroids, it does not prevent flares of the disease in the long run. Even at one year, budesonide is no better than placebo at maintaining remission.
In addition to oral formulations, corticosteroids are also available as intravenous (IV) and rectal formulations. Intravenous corticosteroids (methylprednisolone,
hydrocortisone, dexamethasone) are used in patients with severe disease that require hospitalization. For patients with colonic disease,
hydrocortisone enemas (Cortenema),
hydrocortisone acetate foam (Cortifoam, ProctoFoam-HC), and
steroid suppositories are also available.
Immunomodulators, or immunosuppressants, alter the body's immune response by inihibiting the inflammatory action of white blood cells. Since patients with Crohn's disease are believed to have an overactive immune system as the cause of their uncontrolled GI infIammation, the use of a medication that tones down the immune response makes great sense. The immunomodulators used in the treatment of Crohn's disease are azathioprine (Imuran), 6-mercaptopurine (Purinethol), and methotrexate.
These immunomodulators have a role in several circumstances. Most often they are used to maintain remission in those patients who initially required steroids, in those who have become steroid dependent, and in patients with perianal fistulae. In patients with milder symptoms, immunomodulators can also be used to induce remssion. The reason that they are not used to induce remission in sicker patients is that they have a slow onset of action of up to three months before taking effect.
(AZA) is the pro-drug (precursor) of
(6-MP) and breaks down to 6MP when it is absorbed into the bloodstream. These drugs may take six to 12 weeks to become effective. Over this time period, if patients are taking corticosteroids, the steroid dose is slowly reduced or tapered. These drugs appear to work to maintain remission in up to 2/3 of the patients. The dose of 6-MP/AZA is calculated based upon the pateints' weight. Typically, prior to starting these drugs, a special blood test is checked to make sure the patient isn't at high risk for a low white blood count.
The most common side-effect of 6MP/AZA therapy is nausea. Interestingly, some patients who cannot tolerate 6MP due to nausea are able to tolerate AZA well, and vice-versa.
A small percentage of patients may be allergic to 6MP/AZA or develop inflammation of the pancreas known as pancreatitis. This occurs in approximtely 2% (2 out of 100 patients). The symptoms are an upper abdominal pain, and can be associated with nausea, and vomiting. If a patient develops this type of reaction to either drug, the other should not be used because the same reaction will develop. Once the medication is stopped, the pancreatitis usually quickly resolves.
Patients can also develop a low blood counts (typically white blood cells) or elevated liver tests (10% or 1 out of 10 patients) and therefore need frequent blood tests to monitor their blood cell counts and liver function. No matter how long one remains on the drug, these tests need to be continually monitored no less frequently than every three months, and more frequently at the initiation of therapy or after a dose change. There is now a test available that may identify those patients at greatest risk for developing a low white blood cell count. Also, it is now possible to measure the levels of the drug in the blood, known as metabolites. Assessing metabolite levels appears to be helpful in certain situations, such as assessing patients with suspected medication noncompliance, patients with abnormal liver tests, or patients who are not responding well to the 6MP/AZA.
Taking 6MP or AZA does put you at a slightly higher risk of both infection and lymphoma (a cancer of the lymph nodes. However, these potential risks are often outweighed by their benefits. Each individual considering these agents should discuss the pros and cons with their physician.
(MTX) works similarly to AZA/6MP in that it modulates the body's immune system and also can take six weeks to demonstrate an effect. As opposed to AZA/6MP which are taken orally, MTX is taken as a weekly injection. It also appears to be effective in maintaining remission in up to 2/3 of patients. Nausea and flu-like symptoms are the most common side effects. Less common side effects are low blood counts, abnormal liver tests, and liver damage. Similar to 6MP/AZA, blood tests are required for continuous monitoring. There is also a rare chance of lung inflammation, and like other immunomodulators patients are at slightly higher risk of infection.
This medication can cause serious birth defects and therefore is absolutely contraindicated in pregnancy or if someone is trying to conceive. In addition, because methotrexate essentially depletes the body's levels of folic acid, this vitamin should be taken at a dose of 1mg daily when receiving methotrexate therapy.
4. Anti-tumor Necrosis Factor-alpha (TNF-α) Therapy
These drugs are specifically designed to bind to, and block the effects of TNFα, inflammatory protein or cytokine that is seen in high levels in patients with Crohn's disease. There are currently three anti-TNF agents approved for the treatment of Crohn's disease, infliximab (Remicade), adalimumab (Humira), and Certolizumab pegol (Cimzia). Infliximab is approved for the treatment of moderate-to-severe Crohn's disease that does not respond to standard therapies (discussed above) and is also used for the treatment of fistulas. Adalimumab is approved for the treatment of moderate-to-severe Crohn's disease that does not respond to standard therapies and for those patients who have lost response to or are intolerant of infliximab. Certolizumab was approved in 2008 for the treatment of patients with moderate to severe Crohn's disease in adults who have not been helped by usual treatments.
Approximately 66% (2 out of 3) patients with Crohn's disease will respond within the first two doses, and approximately 30-50% of those patients, will maintain response for up to one year. If you are well at 1 year, you are likely to remain well, with approximately 10% (1 out of 10) of patients coming off of drug each year due to loss of effect or side effects. Approximately 30-50% (1/3-1/2) of patients will require a change in dose or interval of drug administration at some time during the course of therapy.
(Remicade) is a chimeric antibody, meaning that it is made up of material that is 25% mouse and 75% human. It is an antibody that binds to and blocks the effects of TNF-an inflammatory protein (cytokine) that is seen in high levels in patients with Crohn's disease. Infliximab has been in use to treat Crohn's disease since 1998 and is FDA approved for use in both adult and pediatric patients. Infliximab has demonstrated great efficacy in those patients who have failed conventional therapy with moderate to severe Crohn's disease and those patients with fistulizing disease, particularly perianal. Even some of the extra-intestinal manifestations of IBD (discussed above) may respond to infliximab therapy.
Infliximab is given intravenously. Administration typically takes place over two to three hours, and is usually well tolerated. After the initial infusion of infliximab, patients typically are given another IV dose two weeks and six weeks later, after which the drug is administered at consistent eight week intervals. This regimen of giving the drug more frequently at the beginning and then regularly thereafter has been shown to be more effective than receiving the drug just "on demand" when the patient has symptoms of a flare.
Although infliximab may prove highly effective in the initial stages of treatment, unfortunately some patients may lose response to infliximab over time. In such cases, the drug may need to be administered more frequently than every eight weeks or the dose may need to be increased. Patients can also develop reactions to the medication, which usually occur during the infusion. Most infusion reactions are mild and take the form of flushing, fevers, aches, and pains, but they can be more severe with associated chest pain, shortness of breath, hives, or a drop in blood pressure. Most of these reactions can be managed by slowing or stopping the infusion and giving intravenous fluids along with antihistamines, acetaminophen, or corticosteroids. Rarely the reactions can be delayed and occur a few days after the infusion. These types of reactions usually consist of joint pains, muscle aches, rash, and occasionally a fever. The vast majority of the infusion reactions are not true allergies. Hence, infusions can usually be completed and often do not preclude further use of the drug.
(Humira) is a fully human antibody that binds to and blocks the effects of TNF-α an inflammatory protien (cytokine) that is seen in high levels in patients with Crohn's disease. Adalimumab has been shown to be extremely effective in those patients who have failed conventional therapy and have moderate-to-severe Crohn's disease. It also is effective in those patients that have lost response to infliximab or have become intolerant of infliximab,usually due to infusion reactions. Humira was approved by the FDA for use in Crohn's disease in 2007 but was previously approved for the use of rheumatoid arthritis in 2002.
Adalimumab is given as a single subcutaneous injection (40mg) every other week after an initial induction regimen of four injections the first week, and two injections the third week. The drug is available as an injection pen to make it easier for patients to use. Pain or swelling can occur at the site of injection, but is usually minor.
Although adaliumumab may prove highly effective in the initial stages of treatment, unfortunately some patients may lose response to adalimumab over time. In such cases, the drug may need to be administered weekly.
(Cimzia) is a biologic called a PEGylated anti-TNF . Pegylation is a method of prolonging the effect of a drug. It was approved in 2008 and works by targeting a protein called TNF-alpha and blocking it from causing inflammation. It is used to lessen the signs and symptoms of moderately to severely active Crohn's disease, in adult patients who have not been helped by usual treamtents. Certolizumab works by targeting TNF-alpha and blocking it from causing inflammation.
Cimzia is given as monthly subcutaneous injections. It comes in two vials that can either be reconstituted to form a solution, which are given by a nurse, or in a prefilled syringe that you can self inject. The company that makes the medication has nurses who will come to your home for the monthly injections.
Although there are side effects associated with these medications, it is important to remember that anti-TNF therapy is both safe and extremely effective for the treatment of Crohn's disease. There is a small increased risk of infections, including tuberculosis, as well as rare risks of heart failure, multiple sclerosis, lymphoma, autoimmunity (lupus-like reactions), and liver dysfunction, including reactivation of hepatitis B. These risks are relatively low, but should be considered.
Ongoing infection is an absolute contraindication to the treatment with any anti-TNF inhibitor. Prior to initiating treatment with infliximab or adalimumab, patients must be screened to make sure that they do not have an asymptomatic infection with tuberculosis. This is usually accomplished with a skin test (PPD test) and a chest x-ray. Patients who were born in countries where TB is more common may require treatment for TB before starting therapy with an anti-TNF agent. We recommend annual screening for TB while on anti-TNF therapy. We also recommend testing for previous exposure to hepatitis B virus prior to initiation of anti-TNF therapy.
A recent trial (SONIC) compared 6MP vs. infliximab vs. the
combination of 6MP and infliximab in patients with moderate to severely active Crohn's disease who had not previously been on immunomodulator or anti-TNF therapy. This study found that the combination of 6MP and infliximab was more effective than infliximab alone, which was more effective that 6MP alone. The number of patients in remission in each group at 6 months was 57% vs. 45% vs. 30%. The benefits of combination therapy need to be weighed against the potential increased risks of infection and lymphoma.
5. Anti-adhesion Molecules
These drugs are designed to block certain inflammatory cells from travelling from the bloodstream to the intestine, thereby decreasing intestinal inflammation.
(Tysabri) is a drug used for the treatment of multiple sclerosis (MS) that was approved in 2008 for the treatment of moderate-to-severe Crohn's disease, specifically fo.r patients who have failed treatment with anti-TNF therapy. In addition, the Crohn's disease must be active based on evidence from labs (elevated c-reative protein), imaging studies, or endoscopy. The drug has been shown to be effective for both induction and maintenance of remission of Crohn's disease in this situation. It is given as a monthly intravenous infusion.
As with other therapies, natalizumab has been associated with rare, but serious side effects. In fact, this drug was temporarily taken off of the marketin 2005 after three patients developed progressive multifocal leukoenephalopathy (PML), a very rare but often fatal brain infection. Since then, the drug has been brought back to the market for MS and was just recently approved for Crohn's disease. However, its distribution is restricted and is only available through a closely monitored program known as TOUCH. The drug cannot be prescibed in combination with any other immunomodulators (6MP, methotrexate, anti-TNF) due to the risk of PML.
The risk of PML at this time appears to be about 1 in 1000.
Antibiotics are used to treat infectious complications of Crohn's disease such as abscesses. They are also effective in the treatment of perianal fistulas, although the symptoms will often recur when the antibiotics are discontinued. There is some data that antibiotics also may be effective in treating mild-to-moderately active Crohn's disease, particularly colonic Crohn's disease, although this has not been established in large, well designed clinical trials.
(Flagyl) are the two most commonly prescribed antibiotics for Crohn's disease. There is some emerging evidence that
(Xifaxan), a nonabsorbed antibiotic, is effective for the treatment of bacterial overgrowth and may be useful in treating mild-to-moderate Crohn's disease.
Side effects with metronidazole are not uncommon, especially at higher doses. Side effects include nausea, loss of appetite, metallic taste, diarrhea, dizziness, headaches, and dark urine. Numbness or tingling of the hands (peripheral neuropathy) is rare, but may be irreversible. If this occurs, the drug must be discontinued. Metronidazole can also react with alcohol and cause a rare, severe reaction (antabuse-like) of nausea, vomiting, and shortness of breath. As a result, most patients on short courses of metronidazole are cautioned to avoid alcohol. Ciprofloxacin is better tolerated than metronidazole, but still has rare side effects including headaches, nausea, and sun-sensitivity. There is also a very rare risk of tendon rupture. Patients on Ciprofloxacin are also at increased risk for clostridium difficile colitis, a type of antibiotic-induced colitis that can be severe and requires specific therapy with metronidazole or vancomycin, another antibiotic.
7. Complementary Therapies
The agents listed above are considered standard medical treatments for Crohn's disease. A number of complementary therapies are used by patients although very few have actually been studied in clinical trials and none have been proven scientifically to have a substantial benefit. Patients taking any complementary therapies should let their physicans know.
are organisms, either bacteria or fungus, that promote beneficial effects in the colon. Lactobacillus, Bifidobacteria, Saccharomyces and Streptobacillus are considered to have such protective properties. Probiotics are not uncommonly used by patients with IBD. However, most studies examining probiotics to treat Crohn's disease have not shown a substantial benefit. Almost none of the probiotics sold in stores or over the internet have been tested in well designed trials, and the concentrations of the active ingredient in these over-the-counter probiotics are not well standardized.
restricted carbohydrate diet, known as the "Specific Carbohydrate Diet," is advocated by some patients with IBD. Although some individuals report benefits, this diet has never been studied scientifically.
8. Investigational Treatments
There are a number of novel treatments for Crohn's disease that are currently under development or in
that deserve mention. Most of these treatments are aimed at decreasing the body's dysfunctional inflammatory activity. These investigational treatments include:
- Antibodies directed against specific types of immune cells or inflammatory proteins (anti-IL12/23 antibodies, anti-IL6)
- Anti-adhesion molecules (MLN-02)
- Pig whip worm ova (Trichiuris suis) to influence the immune response
- Removal of certain immune cells (like dialysis) from the circulation (leukapheresis)
- Stem cell therapy
Access to these therapies is currently only available through clinical trials as they are not F.D.A. approved for this condition.