Crohn's disease (treatments)

Authors : Adam S. Cheifetz MD Center for Inflammatory Bowel Disease, Alan C. Moss MD Beth Israel Deaconess Medical Center, Mark A. Peppercorn MD Harvard Medical School Boston, MA.

2008-10-20

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What are the goals in treating Crohn’s disease?

The main goals in treating Crohn’s disease are to:

1. Induce remission
2. Maintain remission
3. Improve the patient’s quality of life
4. Minimize toxicity

There is no cure for Crohn’s disease; it is a chronic illness that patients will be dealing with throughout their life.  Therefore, the goals of therapy are to control the inflammation and the patient’s symptoms and get the patient feeling back to normal (induce remission), keep the patient feeling normal, and reduce the number of recurrent flares (maintain remission), and do so with the least toxic medications (fewest side effects).  By accomplishing this, the patient’s quality of life is enhanced.  The hope is that patients are able to live normal lives without any limitations related to their disease.

 Since Crohn’s disease tends to relapse, most patients will require long-term medication to sustain remission.  Although, this knol will focus on medical therapy for Crohn’s disease, the treatment of Crohn’s disease requires a team of healthcare professionals including the primary care physician, gastroenterologist, and often a surgeon.  A nutritionist, social worker, or psychologist may also be a part of the healthcare team if the situation dictates.  The patients themselves need to take an active role in their treatment.  They should understand what their options are, how the medications work, what the side effects and toxicities of the medications are, and what the surgical options are.  Most importantly, they should not be afraid to ask questions. 

 With the discovery of new, more powerful medications, the goals of treating Crohn’s disease may be slowly evolving.  In the near future, the goals in treating Crohn’s disease may expand to include:

1. Healing the intestinal mucosa
2. Preventing the complications of Crohn’s disease (fistulae, abscesses, cancer)
3. Preventing hospitalization
4. Preventing surgery

 Recent data suggests that the newer biologic therapies can heal the mucosa successfully  in a significant number of patients.  At least in the short term, these biologics have been associated with fewer hospitalizations and surgeries.  However, these more powerful medications are also associated with potentially more significant toxicity.  Balancing the risks and benefits of the medications becomes an extremely important issue for patients and physicians dealing with the treatment of Crohn’s disease.

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 of the disease, the type of disease (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 stay 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 paradigm 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.In those patients with more mild symptoms, drugs from the bottom of the pyramid are tried.   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.  To date, there is little evidence that this approach is more effective than the “step-up” approach and is likely associated with more severe medication toxicity.  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 to moderate Crohn’s disease.  Although it is uncertain exactly how they work, the 5-ASAs appear to act topically on the GI tract 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 sulfasalazine (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.   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.

 These other  agents are designed to release 5-ASA at specific locations in the GI tract.  They include free 5-ASA, known as mesalamine, which is enclosed within special capsules that release  the active drug only when they reach the small intestine or colon.   Asacol 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 (olsalazine, Dipentum) or a carrier molecule (Balsalazide, 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.  We believe that 5-ASA is effective in some patients with mild-to-moderate 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, larger doses (4.8g) of mesalamine are probably needed rather than the smaller doses (2.4g) which may be effective in ulcerative colitis.

 One of the main issues with 5-ASA is compliance.  The pill burden can be substantial (8-12 pills per day), while the older drugs were designed to be taken three to four times a day.  However, 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 newest 5-ASA, Lialda, is approved for ulcerative colitis for once daily dosing, with 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

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.  Prednisone is the most commonly used oral steroid.  It 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.

 In order to avoid some of the side effects caused by systemic coriticosteroids, a new type of steroid was developed known as budesonide (Entocort EC).  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 systemic 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 requires hospitalization.  For patients with colonic disease, hydrocortisone enemas (Cortenema), hydrocortisone acetate foam (ProctoFoam-HC), and steroid suppositories are also available.

3. Immunomodulators

Immunomodulators, or immunosuppressants, mitigate 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 those individuals with milder symptoms, immunomodulators also can 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.

 Azathioprine (AZA) is the pro-drug (precursor) of 6-mercaptopurine (6-MP) and breaks down to 6MP when it is absorbed into the bloodstream.  These drugs take six to 12 weeks to inhibit the immune system and become effective.  Over this time period, if patients are taking corticosteroids, the steroid dose is slowly reduced or tapered.  These drugs appear to work in up to 2/3 of the patients.  The dose is based upon the pateints’ weight.

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.  If a patient develops this type of reaction to either drug, the other should not be used because the same reaction will develop.  Patients can also develop low white blood cell counts or elevated liver tests 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 these agents does confer a slightly higher risk of both infection and a certain cancer of the lymph nodes (lymphoma).  However, these potential risks  are often outweighed by their benefits.  Each individual considering these agents should discuss the pros and cons with their physician.

 Methotrexate (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 and abnormal liver tests.  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, an inflammatory protein or cytokine that is seen in high levels in patients with Crohn’s disease.  There are currently two anti-TNF agents approved for the treatment of Crohn’s disease, infliximab (Remicade) and adalimumab (Humira).  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.

 Infliximab (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 protien (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. Unlike the previously discussed medications, 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. 

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.  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.

  Adalimumab (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.  It 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.

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 since 2002.

 Although anti-TNF therapy is extremely effective for the treatment of Crohn’s disease, several side effects are possible.  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.

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. 

Natalizumab (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 for  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 less than 1 in 1000.

6. Antibiotics

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.  Small bowel bacterial overgrowth, which can present with diarrhea, bloating, and abdominal cramping, is also managed with antibiotics.  Ciprofloxacin and metronidazole (Flagyl) are the two most commonly prescribed antibiotics for Crohn’s disease.  There is some emerging evidence that Rifaxamin (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 tolerated better 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.

Probiotics 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. 

A 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 clinical trials that deserve mention. Most of these treatments are aimed at decreasing the body’s dysfunctional inflammatory activity.  All registered studies can be accessed at http://clinicaltrials.gov/ , which is free to access. These treatments include:

• Antibodies to TNF (certolizumab pegol)
• 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.

Traditional Crohn's treatment pyramid

What is the role of surgery in treating Crohn’s disease?

Although medical therapy is considered first line in the treatment of Crohn’s disease, there are certain situations in which surgery is necessary.  In fact, up to 75% of patients with Crohn’s disease will require surgery at some point in the course of their disease.  Surgery should not be looked at as a failure of therapy, but as a complement to medical therapy that is necessary in particular circumstances. Indications for surgery include: 

• Perforation of intestine
• Abcess
• Fistula that is symptomatic and cannot be medically managed
• Uncontrollable bleeding from the intestine
• Symptomatic stricture
• Cancer or precancer (dysplasia)
• Toxic megacolon (a potentially lethal form of acute colitis)
• Failure of medical therapy

Steroid dependence

In some situations, such as when a patient has a short segment of small intestine involved or a superficial perianal fistula, a limited surgery may be preferable to long-term therapy with an anti-TNF inhibitor.  The risks and benefits of both the medical and surgical option must be considered.  It is important to remember that surgery is not a cure for Crohn’s disease.  In fact, it is common that patients will have a recurrence of their disease and symptoms at some point in the future, although in some patients this may not occur for a long period of time.  The recurrence of the disease usually occurs at the area of intestine that was removed at surgery (anastomosis).  For this reason, surgeons will remove the least amount of intestine possible. 

Bowel resection

The most common type of surgery is an intestinal resection.  The surgeon removes just the area of affected intestine and reattaches the two healthy pieces of intestine.  The area of the reattachment is called the anastomosis.  As stated above, most patients who undergo bowel resection will have a recurrence of the Crohn’s disease at the anastomosis.  By five years after surgery, approximately 50% of patients will be symptomatic again.  However, some patients may go years after surgery without any symptoms.  Approximately 20% of patients will require another surgery by 10 years after the first. 

After surgery, physicians may prescribe medications to help prevent or delay a recurrence of the Crohn’s disease.  6MP/azathioprine is probably the most effective medication in this situation.  There is also short-term data on metronidazole and mixed results with mesalamine.  Many gastroenterologists will perform a colonoscopy at six to 12 months after surgery to assess the anastomosis and terminal ileum.  If there is significant endoscopic evidence of Crohn’s disease in the small intestine proximal to the anastomosis, patients are at higher risk for recurrence of symptoms, and many physicians will recommend therapy with 6mp/AZA in this situation.

Proctocolectomy and Ostomy

Unfortunately some patients have involvement of their entire colon and require total proctocolectomy (removal of the colon and rectum) and ileostomy.  An ileostomy is where the ileum (small intestine) is brought through the abdominal wall to the skin’s surface (stoma).  The stoma is now where the stool exits the body and requires the patient to wear a pouch or bag to collect the waste.  This pouch is emptied as needed multiple times a day.  The stoma is usually located in the lower right abdomen above the belt-line and is not visible to other people.  Patients with stomas enjoy a good quality of life and can have an active lifestyle.  Additionally, if prior to surgery patients only had involvement of the colon and not the small intestine, the vast majority will not have a recurrence of the Crohn’s disease.  Those patients whose rectum is unaffected with Crohn’s can have their small intestine attached to the rectum (ileorectal anastomosis) and continue to pass stool normally although with an increased frequency.  In some cases of acute perforation of the intestine, a stoma may be created temporarily.  Once the inflammation and infection has resolved, the stoma can be taken down and the bowel reattached.  

Stricturoplasty

In some cases where people have strictures (scarred narrowings) of the intestines, bowel does not even have to be removed.  The surgeon can perform a stricturoplasty, in which the lumen of the intestine is widened without cutting away a portion of the intestine.  The strictured area of the intestine is cut lengthwise and then sewn up widthwise.  This type of surgery preserves bowel length, but still accomplishes the goal of allowing the intestinal contents to pass by the restricted area.

What are the implications for fertility and pregnancy?

In general, women with well-controlled Crohn’s disease appear to have similar fertility rates and birth outcomes to women without the disease.  Some studies have shown an increaed risk of premature birth (before 37 weeks) and low-birth weight infants.  It is felt that those women with active disease are at greatest risk for these negative outcomes.  For women with Crohn’s disease, we usually recommend that the disease be in remission and that patients discuss their plans for pregnancy with their physician before attempting to conceive.  We also recommend consultation with a high-risk obstetrician in a number of cases.   

The risk of a disease flare during pregnancy is similar to the non-pregnant population.  As mentioned, it is important to maintain the disease in remission prior to attempting pregnancy, as there may be a higher risk of low birth weights infants in women with active disease due to pre-term labor. Physicians need to ensure that they are not undertreating a female patient simply because she is pregnant.  In fact, the same treatment principles apply to pregnant and nonpregnant patients alike.  Studies of women who were pregnant while taking either 5-ASA, azathioprine/6MP, steroids, cyclosporin, or infliximab have not shown any increase risk of birth defects or detrimental birth outcomes. Thus, continuing those medications that keep the disease quiet is important in women prior to and throughout the pregnancy.  The only exceptions to this are the use of methotrexate, thalidomide, and certain antibiotics which must be stopped prior to pregnancy because they can cause birth defects. 

In most cases, the type of delivery, C-section versus vaginal delivery, is up to the obstetrician.  Only in cases of active perianal disease will a gastroenterologist recommend C-section over a vaginal delivery. 

Sulfasalazine can lower sperm counts and adversely affect sperm function, although these effects are reversible with discontinuation of the drug.  If men are on sulfasalazine, they can consider tests of sperm count if they are having difficulty with conception.  Mesalamine drugs do not affect the sperm and are an option for those men with abnormal semen analyses.  While some studies have suggested that men taking azathioprine or 6-MP have a higher rate of birth defects in their offspring, this has not been convincingly confirmed and most physicians will continue 6MP in this situation.

Should patients with Crohn’s disease receive immunizations?
Since many patients with Crohn’s disease are on immunomodulators or may eventually end up on immunomodulators, routine vaccination against influenza, pneumococcus, tetanus, and hepatitis B is recommended.  The HPV vaccine is recommended for young women.  For those patients not previously exposed to varicella (chicken pox) and not currently on immunomodulators, the varicella vaccine is also advised.  Unfortunately, despite these recommendations, most patients are not receiving routine vaccinations.  Patients who are already on immunomodulators or high doses of prednisone should not receive live vaccines, such as varicella, yellow fever, measles-mumps-rubella, and oral typhoid. 

What should patients with Crohn’s disease avoid?

1.  Smoking - Smoking has been shown not only to increase the risk for Crohn’s disease but also worsen the course of Crohn’s disease.  Smokers may be less responsive to certain treatments and are more likely to develop a recurrence of Crohn’s disease after surgery.  Quitting smoking is one of the best things a patient with Crohn’s disease can do to avoid exacerbating their condition.

2.  Nonsteroidal anti-inflammatories (NSAIDs) – Studies have suggested that NSAIDs, such as ibuprofen and naproxen, can cause flares of IBD in approximately 25% of patients.  These flares tend to occur within one week of starting regular use of the drug.  Acetaminophen (Tylenol) and aspirin appear to be  safe.  Celebrex (celecoxib) is a specific type of NSAID called a cox-2 inhibitor that appears to be safe, at least in short-term studies of patients in remission and on medicine for their Crohn’s disease.