Crohn's Disease

What is Crohn’s disease?

Crohn’s disease is a chronic disorder of unknown origin characterized by inflammation of the gastrointestinal (GI) tract.  The disease is named for Dr. Burrill B. Crohn, who first described the disease in the medical literature in 1932 with his colleagues, Dr. Leon Ginzberg and Dr. Gordon D. Oppenheimer.  The disease was originally termed “terminal ileitis” which was frightening to patients who wrongly assumed they had a fatal (terminal) disease.  “Regional ileitis” was used for a time, but has since given way to the name, “Crohn’s disease”. 

 Although any part of the GI tract can be affected, from the mouth to the anus, the area where the small intestine (terminal ileum) and colon (cecum) meet is the site most commonly involved.   This inflammation can affect all the layers of the bowel wall (transmural) and can lead to a variety of symptoms including abdominal pain, diarrhea, intestinal bleeding, and weight loss.  These symptoms are non-specific and can be present in many other disorders including ulcerative colitis and gastrointestinal infection.   A physician will make the diagnosis of Crohn’s disease after speaking with and examining the patient and getting a number of diagnostic tests: blood tests, x-rays, and often a colonoscopy.   

 After the diagnosis is made, patients are treated with a variety of medications, often anti-inflammatory or immunomodulatory (drugs that affect the immune system) with the goal of controlling the patients’ symptoms and making them feel well.  In a number of situations, surgery is required.

 There is no cure for Crohn’s disease; it is a chronic illness, so the goals of therapy are to get the patient feeling back to normal, keep the patient feeling normal, and reduce the number of recurrent flares.  The hope is that by achieving those goals patients are able to live normal lives without any limitations related to their disease.

 Because Crohn’s is a chronic disease, patients need to take an active role in their treatment.  Most importantly, they should not be afraid to ask questions.  One important goal of this knol is to provide patients with the information they need to do so effectively.

Who gets Crohn’s disease and how common is it?

Crohn’s disease is not uncommon.  Recent estimates suggest that up to 600,000 people in the United States alone are afflicted with Crohn’s disease, evenly affecting males and females.  It is more common in developed countries and is seen most commonly in North America and Western Europe.  It also appears to be more common in urban rather than rural areas and in the northern rather than the southern areas.  Although Crohn’s disease can develop at any age, it most commonly presents between ages 20-30 years.  One-quarter of patients present before the age of 20.  Although less common, elderly patients can still develop Crohn’s disease. 

 The disease does tend to run in certain families and up to 20% of patients will have a first-degree relative (parent, sibling, or child) with the disease. Crohn’s is more common among Caucasians, particularly Ashkenazi Jews, but is becoming more common among Hispanics, Asians, and African Americans.

What causes Crohn’s disease?

The cause of Crohn’s disease remains uncertain. Although there are a number of theories, none have yet been proven.  What is known is that factors like a person’s genetic makeup, the environment in which one lives, and an individual’s immune system all play a role in the development of the disease, but exactly how this occurs is not clearly understood at this time.  However, many potential mechanisms for how Crohn’s disease may develop are currently under study.

 The most widely accepted theory is that a person’s immune system abnormally overreacts to some type of substance in the gut, which is most likely the bacteria that normally reside in the intestines, and that this overactive immune response is somehow triggered by exposure to something in the person’s environment.   Why one person develops this type of immune response while another person does not is thought to relate to an individual’s genetic makeup or genetic susceptibility; in other words, the person who develops Crohn’s disease has inherited some type of defective gene or genes that causes their immune system to react in this abnormal way. This activation of the immune system leads to an influx of inflammatory cells to the intestine.  In patients with Crohn’s disease, once the immune system is activated, it does not properly shut itself off, which results in the chronic inflammation that is characteristic of Crohn’s disease.  This is why many of the current treatments for Crohn’s disease focus on suppressing the body’s overactive immune response.

Genetic factors

There is a substantial amount of evidence that genetic factors contribute to the development of Crohn’s disease.  Crohn’s disease is more commonly seen among certain racial and ethnic groups; Caucasians, particularly persons of Jewish descent whose relatives come from eastern Europe (Ashkenazim) are especially at risk.   Additionally, there is a higher risk for Crohn’s disease if one has a first degree relative with Crohn’s disease.  In fact, as mentioned previously, up to 20% of patients with Crohn’s disease also have a first degree relative affected with the disease.

 Some of the major recent advances in the field have been in the area of the genetics of Crohn’s disease.  A number of genes have been discovered in the past several years that have been shown to increase the risk for developing Crohn’s disease.  It should be emphasized that not one genetic defect will cause Crohn’s disease; there are a number of genes that can predispose a person to develop the disease.  Currently, there is no role for genetic testing outside of clinical studies, but this may change in the future 

  The hope is that once the Crohn’s susceptibility genes are discovered, scientists can begin to discover their function, which will provide insight into what actually causes Crohn’s disease.  Once we understand what causes the disease, the next step will be to design better medications to help control the symptoms, and even potentially cure the disease.

Environmental factors

Environmental factors appear to combine with an individual’s genetic predisposition to lead to the development of Crohn’s disease.   Certain environmental factors also affect the course of the disease.  Unfortunately the environmental factors are not well studied.  However, it is likely that they either cause the lining (mucosa) of the intestine to become more permeable – a characteristic associated with smoking and the use of nonsteroidal anti-inflammatory drugs (NSAIDs) – or alter the bacteria that normally live in the colon, a situation that can occur with the introduction of antibiotics or gastrointestinal infections. 

 The two best studied environmental factors are smoking and NSAIDs.  Smoking has been shown not only to increase the risk for Crohn’s disease but also worsen the course of the 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 can do.

 NSAIDs (e.g., ibuprofen, naproxen) may trigger the development of Crohn’s disease, although the data in the medical literature is not overwhelming.  Additionally, these drugs can cause flares of established inflammatory bowel disease (Crohn’s or ulcerative colitis) in approximately 25% of patients.  Studies suggest that these flares occur within a week of starting regular use of the NSAIDs.  Acetaminophen (Tylenol) and aspirin appear to be safe and do not lead to exacerbations of Crohn’s disease.  Celecoxib (Celebrex) 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 inflammatory bowel disease (IBD). 

 Diet – does it play a role?

Diet likely has a role as a risk factor for Crohn’s disease, but little is known.  Certainly, there is no one compelling dietary factor that has been shown to cause the disease or cause a flare of the disease.  The most consistent factor identified as a risk factor for Crohn’s disease is a diet high in refined sugars.  Once Crohn’s disease is established, there are no specific foods that a patient should definitely eat or should try to avoid, and usually patients are just advised to just follow a healthy, balanced diet.

 No special diet has been shown to be effective for ameliorating the symptoms of Crohn’s disease.  Many patients mistakenly restrict dairy products and fruit and vegetables in their diet, which can compound nutritional  deficiencies without any reduction in the risk of disease flares.  Only those patients with tight small bowel strictures (narrowings) or recent small bowel obstructions need to follow a low residue diet.  Patients on a low residue diet are instructed to avoid foods that cannot be readily digested such as skins of fruits, nuts, seeds, pineapple, mushrooms, and raw vegetables.  Additonally, only those patients with a concomitant lactose intolerance need to avoid  milk products. 

 What is the effect of stress?

A lot of chronic illnesses are blamed on stress, and many patients with Crohn’s disease will associate flares of their disease to  a particular stress in their life.  There is no evidence demonstrating that stress causes Crohn’s disease.  Although some medical studies have suggested that stress may trigger a flare of Crohn’s disease, other studies have come to the opposite conclusion.  At least one of the reasons for these disparate findings is that stress is a very difficult variable to measure. As a result, it becomes quite challenging to design a study examining how stress affects the course of a disease.  Although the data is conflicting, we nonetheless will recommend stress reduction or relaxation techniques for patients who feel that stress worsens their symptoms. 

What are the symptoms of Crohn’s disease?

The symptoms of Crohn’s disease can vary from mild to severe.  Abdominal pain and diarrhea are the most common symptoms of Crohn’s disease.  However, GI bleeding, nausea, weight loss, fever, and fatigue can also be seen.  Crohn’s disease can also affect other parts of the body, including the joints, skin, liver, and eye.  These are called extraintestinal manifestations (see below) and are rarely the first symptom with which a Crohn’s disease patient presents.  Children can present with delayed development and growth.  Approximately 1/3 of Crohn’s patients will develop symptoms around the anus (perianal), including skin tags, fissures (tears in the anal skin), fistulae (abnormal connection between the intestine and the anus), or abscesses. 

                                                 Common symptoms of Crohn's Disease

 The symptoms described above, however, are not specific for Crohn’s disease and can be seen in many other conditions.  The following is a partial list of other conditions that may mimic Crohn’s disease, also known as a list of differential diagnoses.

•          Infectious causes – bacterial, viral, or parasitic infection.

•          Ischemia – low blood flow to the small intestine or colon, usually seen in older patients

•          Medication – non-steroidal anti-inflammatories, antibiotics, birth control pills

•          Diverticulitis – infection of a diverticulum (outpouching of colon) that can present with left lower quadrant pain and fever

•          Appendicitis – usually presents with right lower quadrant abdominal pain and fever

•          Irritable bowel syndrome – can cause severe diarrhea and abdominal pain

•          Lactose intolerance – can cause diarrhea, bloating, and abdominal pain.  Patients with Crohn’s disease can also have lactose intolerance.

•          Celiac disease – sensitivity to gluten (wheat) which can cause diarrhea and bloating.

•          Gallstones

•          Cancer, lymphoma

•          Diseases that affect other organs in the abdomen also need to be considered such as:

•          Endometriosis, pelvic inflammatory disease, ectopic pregnancy, ruptured ovarian cyst

•          Kidney stones, bladder or kidney infections

 Therefore, symptoms alone are not enough to diagnose someone with Crohn’s disease.  Patients require further workup or testing (see below - How is Crohn’s diagnosed?).  It is also important to remember that even in patients with well established Crohn’s disease, not all abdominal symptoms are related to their disease.  Patients with Crohn’s disease are just as susceptible to the development of GI infections, kidney stones, gallstones, etc., as are patients without Crohn’s disease.   It is important for patients and physicians to keep this in mind at all times. 

 Because Crohn’s disease can affect any part of the GI tract and any layer of the intestinal wall (transmural), the symptoms are quite variable and often depend on the location (See below - Types of Crohn’s disease (location)) and type of Crohn’s disease (See below - Types of Crohn’s disease (disease pattern)) Although the location of Crohn’s disease varies from patient to patient, it often remains constant within a given patient. In other words, it would be extremely rare for a patient with pure ileitis to suddenly develop Crohn’s disease involvement in their colon as well.  While the location of disease tends to remain constant, the type and severity of Crohn’s disease can change over time as a result of persistent inflammation.  For example, many patients with inflammatory disease will eventually go on to develop either fibrostenosing or perforating disease.  (Again, see below - Types of Crohn’s disease (disease pattern))

Types of Crohn’s disease (location)

1. Gastroduodenal Crohn’s disease – also known as upper GI Crohn’s disease:

• Uncommon – symptoms in approximately 5% of patients.
• Affects the stomach and first part of the small intestine (duodenum)
• Symptoms include nausea, loss of appetite, weight loss, vomiting, and pain in the upper abdomen

2. Jejunoileitis – inflammation of the second part of the small intestine (jejunum):

• Uncommon
• Symptoms include diarrhea, abdominal pain (usually after eating), malnutrition due to malabsorption of nutrients, and weight loss      

3. Ileitis – inflammation of the last part of the small intestine (ileum)

• Occurs in approximately 30% of patients
• Symptoms include diarrhea, abdominal pain (often in the right lower quadrant), and weight loss

4. Ileocolitis – inflammation of the ileum and colon (most often the right side of the colon):

• Most common type of disease, affecting approximately 50% of patients
• Symptoms similar to Crohn’s ileitis: diarrhea, abdominal pain (often in the right lower quadrant), and weight loss

5. Crohn’s colitis – inflammation of the colon only:

• Not uncommon.  Approximately 20% of patients with Crohn’s
• Symptoms include diarrhea, rectal bleeding, and abdominal pain 
• Perianal disease and the extraintestinal manifestations of Crohn’s disease are more common in patients with involvement of the colon. Unlike in ulcerative colitis, where the inflammation is continuous and almost always starts in the rectum, working its way back into the colon, Crohn’s disease often spares the rectum.  In addition, Crohn’s disease is often not continuous; there can be a healthy segment of bowel between diseased segments.  This type of involvement is typical of Crohn’s disease and is referred to as a “skip lesion.”

6. Perianal disease

• Affects up to 1/3 of patients with Crohn’s disease. 
• Patients can present with fistulae, fissures, skin tags, or abscesses

a)       Perianal fistulas: perianal fistulas result from small collections of inflammation and infection that tunnel their way from the anal muscle (sphincter) to the skin around the anus.  This leads to drainage of mucus, stool, or pus from openings around the perianal area.  If the external opening closes, an abscess may develop, which characteristically will present with swelling and pain in the perianal area, and associated fever.  Typically, this requires treatment with antibiotics and, often, surgical drainage. 

b)       Fissures: fissures are sores or ulcerations in the lining of the skin that crosses the anal canal; often, these can be quite painful. 

c)       Skin tags: patients with Crohn’s can develop fleshy growths just outside the anus which are known as skin tags. Occasionally, these can be confused with hemorrhoids.  They are usually not painful or clinically relevant.

                          Distribution of Crohn's Disease in the intestinal tract

 Types of Crohn’s disease (disease pattern)

The symptoms and signs of Crohn’s disease are a function of not only the location of disease, but of the pattern of disease.

1. Inflammatory: A form of Crohn’s disease that is due to inflammation of the intestine.  Symptoms include diarrhea, abdominal pain, weight loss, fever, bleeding, fatigue, loss of appetite, and growth retardation (children).  Patients can also develop small bowel obstructions (see below) or a mass in their right lower quadrant.  These patients respond best to medical therapy. This pattern is typical early in the course of Crohn’s disease.

2. Fibrostenotic:  A form of Crohn’s disease that is usually seen in patients with Ileal disease.  Over time, persistent inflammation can lead to scarring within the intestinal wall.  Continued build-up of scar tissue within the intestinal wall causes narrowing of the intestine itself. Eventually the gut becomes so narrow that even a small amount of inflammation causes closure of the lumen, resulting in a small bowel obstruction. These small bowel obstructions are characterized by severe abdominal pain, nausea, vomiting, and lack of passing bowel movements (constipation) or gas from below.  Patients with known stricturing disease will likely be asked to follow a low-residue diet (see below).  Most small bowel obstructions resolve quickly with conservative therapy (nothing to eat, intravenous fluids).   Eventually, patients with fibrostenotic disease are likely to require surgery to remove the scarred section of bowel to prevent recurrent small bowel obstructions in the future.

                      Barium study showing (arrows) narrowing in the small bowel from Crohn's disease

3. Perforating/Fistulizing: Because Crohn’s disease can affect all layers of the bowel wall (transmural), patients can develop a perforation of the intestine, leading to leakage of bowel contents into the abdominal cavity, or they can develop a fistula, which is an abnormal connection or tunnel from one loop of bowel to another or even to another organ.

a)       Perforation – can present acutely with severe abdominal pain, rigid abdomen (“surgical abdomen”), fever, and chills.  The symptoms can be similar to those of appendicitis.  Alternatively, it can present more indolently with a mass in the abdomen, fever, chills, and less severe pain.  A perforation usually results in an intraabdominal abscess (collection of bacteria and inflammatory cells) that requires antibiotics and drainage, either surgically or via a radiologically-placed drain. 

b)       Fistula - The symptoms of a fistula depend on the organ to which the fistula connects: Examples of different types of fistula include bladder (entero-vesical), vagina (entero-vaginal), skin (entero-cutaneous), and intestine (entero-enteric).  The most common type of fistula is actually a perianal fistula, but this entity will be considered separately below.

·           Entero-vesical fistulae often lead to recurrent urinary tract infections.  Patients may also complain of passing gas, blood, or stool when they urinate. 

·                     Entero-vaginal fistulae may present with passage of gas or stool through the vagina. 

·                     Entero-cutaneous fistulae cause drainage of the bowel contents through the skin’s surface.

·                Entero-enteric fistulae can be asymptomatic or may present with diarrhea or an abdominal mass. 

How do you diagnose Crohn’s disease?

There is no single test to establish the diagnosis of Crohn’s disease.  The diagnosis of Crohn’s disease is made using a combination of modalities:

•          Clinical history

•          Physical examination

•          Laboratory tests

•          Endoscopy (Gastroscopy/Colonoscopy)

•          X-ray findings (small bowel series, computed tomography (CT scan), magnetic resonance imaging (MRI))

•          Tissue biopsy (pathology)

 History and physical exam

There is no substitute for a good history and physical exam.  The physician will ask a number of questions regarding the patient’s symptoms to narrow down the possible diagnoses.  The details of the medical history help the physician decide what testing is necessary.  The physician will ask about the chronicity, acuity, and severity of the symptoms.  They will ask questions regarding palliative (things that ease symptoms) and provocative (things that make symptoms worse) factors, particularly whether food or bowel movements improve or worsen the symptoms.   Recent antibiotic or NSAID use, sick contacts, travel, smoking history, and family history of GI disorders are all important clues. 

 The physical exam is also critical in making a definitive diagnosis.  The physician will assess for mouth ulcers, abdominal discomfort when pressing on the abdomen, masses in the abdomen, rashes, joint swelling, and perianal disease.  Often times, a primary care physician will refer to a gastroenterologist for a specialty opinion if, at the conclusion of the exam, the concerns about Inflammatory Bowel Disease remain.  

 Blood tests

There are a number of blood tests that may be helpful in making the diagnosis of Crohn’s disease.  A compete blood count (CBC) may show an anemia (low red blood cells) or may demonstrate an elevated white blood cell or platelet count, the latter of which are both markers of inflammation or infection.  Sedimentation rate (ESR) and C-reactive protein (CRP) are other non-specific markers of inflammation that are often measured during the work-up of Crohn’s disease.  Low albumin (blood protein) can also be seen in patients with long-standing or severe symptoms.  These tests just confirm that there is ongoing inflammation, but do not diagnose specifically what is causing the inflammation.  The stool can also be tested for bacteria and parasites, both of which can cause infections that can mimic the symptoms of Crohn’s disease.   There are some newer stool tests available that test for the presence of intestinal inflammation, but like the serum (blood) tests these are not specific for Crohn’s disease and can be seen with other intestinal diseases and infections. 

 The CBC, ESR, and CRP are blood tests that are often followed serially in patients with well established Crohn’s disease to assess for inflammation, particularly when a patient is complaining of symptoms that may indicate a flare of their disease.  If a patient having symptoms gives a history of any recent international travel, consumption of undercooked or raw foods, or administration of recent antibiotics for an unrelated illness, stool studies to assess for the presence of bacteria or parasites may be checked to ensure that there is not a accompanying GI infection,.  

 There are a number of newer serologic markers (ASCA, ANCA, ompC, anti-CBir1) that may assist in making the diagnosis of Crohn’s disease.  As of yet, these markers still are not accurate enough to make a diagnosis of Crohn’s disease on their own.  However, they may be helpful if used in combination with the history, physical exam, radiologic, and endoscopic findings; they should be considered an adjunct to conventional testing. 

Endoscopy

Very often, inspection of the lining of the intestines with colonoscopy, sigmoidoscopy, or endoscopy using a fiberoptic endoscope is necessary to help establish the diagnosis of Crohn’s disease.  A long, flexible tube with a light source and an attached camera is inserted into the anus (“sigmoidoscopy” if only the lower third of the colon is examined, “colonoscopy” if the full colon is examined). Colonsocopy is often preferred when Crohn’s disease is being considered because it is often possible to advance the scope into the end of the small intestine known as the terminal ileum, a common site for Crohn’s disease involvement.  In Crohn’s disease, the lining of the colon and/or terminal ileum appears swollen, inflamed, with frequent ulcerations.  The inflammation is often patchy and discontinuous,unlike ulcerative colitis. 

                                    Normal small bowel                 Small bowel in Crohn's disease

                                       Normal colon                            Crohn's ulcer in colon

 
Tiny samples, or biopsies, of the lining of the colon are taken during the procedure, so that a pathologist may examine them under the microscope  to look for signs of inflammation.   A specific type of inflammation known as non-caeseating granulomas can be seen in up to 20% of patients with Crohn’s disease and is very helpful in confirming the diagnosis.  The combination of endoscopy and pathology  is almost always necessary to make the diagnosis of Crohn’s disease. This procedure may be postponed in patients with signs of severe colitis, as the lining of the colon becomes very fragile and easy to damage with the endoscope.  Occasionally, if patients have many upper GI symptoms such as upper abdominal pain, reflux, and/or nausea, a gastroscopy or upper endoscopy may be performed to examine the esophagus, the stomach, and the first part of the small bowel (duodenum). 

Radiology

Because endoscopy and colonoscopy can only see the very beginning and end of the small intestine, there are a number of radiologic tests that are used to evaluate the small intestine.  The test that has been most used to evaluate the small intestine is the small bowel series (also called upper GI series or small bowel follow through), In this test, a patient will drink barium and then undergo a series of x-rays that will demonstrate inflammation, fistulas, or strictures of the small intestine, if present.  Often, other radiologic tests such as CT scans and MRIs are also necessary to provide a complete evaluation of the intestines and to rule out complications of Crohn’s disease such as perforations, abscesses, and fistulas.  CT scans and MRIs mainly are used to look outside the bowel wall for complications of Crohn’s disease, but new oral contrast dyes and specialized techniques are enabling these tests to look closely at the walls of the small intestine as well. 

                    CT scan of patient with narrowing (arrow) of small bowel due to Crohn's disease

Capsule endoscopy

Capsule endoscopy is a novel imaging modality that permits the inspection of the small bowel. Patients will swallow a pill that contains a camera embedded inside. The camera then transmits pictures to a recording device and thereby permits inspection of most of the internal lining (mucosa) of the small bowel in a relatively non-invasive manner.  It is mainly used for patients with GI bleeding when no source can be found on upper endoscopy and colonoscopy.   

Care must be used in patients with known Crohn’s disease due to the risk of capsule retention (capsule getting stuck in the intestine).  A retained capsule will often require surgical removal.  Additionally, these studies must be evaluated carefully to avoid misdiagnoses; for example, NSAIDS can cause ulcerations in the small intestines which may be mistaken for the similar-appearing lesions of Crohn’s disease, and asymptomatic ulcerations can actually be seen in up to 15% of the general, otherwise healthy population.  Currently, capsule endoscopy does not examine the esophagus, stomach or colon and does not take biopsies; therefore it is not a substitute for endoscopic procedures, but it may be useful in specific circumstances.   

What are the complications of Crohn’s disease?

There are a number of disease complications that may occur with Crohn’s disease.

1. Small bowel obstruction

The most common complication of Crohn’s disease is a blockage of the intestine, usually the small intestine. The obstruction occurs because the inflammation in the intestinal wall eventually leads to scar tissue and narrowing of the lumen of the intestine (the cavity where digested material passes through).  Over time, the lumen of the gut becomes so narrow that even a small amount of inflammation can lead to closing of the lumen and result in a small bowel obstruction.  The patient will often present with crampy abdominal pain, abdominal distention, nausea and, if severe enough, vomiting, lack of bowel movements, or inability to pass gas from below.  In this situation, patients are usually told to stop eating, also known as bowel rest, which often leads to improvement.  Intravenous fluids may be necessary.  If the obstruction does not resolve or continues to recur despite medical therapy, surgery is usually indicated. 

2. Fistulae

Crohn’s disease may also cause inflammation and ulcers that tunnel through the affected intestine into surrounding organs, such as the skin (entero-cutaneous), bladder (entero-vesicle), vagina (rectovaginal), or other parts of the intestine (entero-enteric).  The most common type of fistula is perianal, but that should be considered separately.  Depending on the organ involved, fistulae are either defined as internal (bladder, intestine) or external (skin).  Some fistulae that occur between the intestine and other parts of the intestine may not require any therapy.  Fistulae to other organs may respond to medical therapy (immunomodulators), but may require surgery.  Abscesses, or collections of pus, require drainage via surgery or via a drain placed by a radiologist.  Sudden (acute) perforation is an indication for surgery.  These patients present acutely with severe abdominal pain, rigid abdomen (“surgical abdomen”), fever, and chills.  The symptoms can be similar to those of appendicitis.

3. Perianal fistulae

These are the most common type of fistulae.  Sometimes fistulas can be treated with medical therapy, but in some cases surgery may be necessary.

4.Osteopenia/Osteoporosis
Mild thinning of the bones (osteopenia) occurs in up  to 50% of patients with Crohn’s disease, and more severe thinning of the bones (osteoporosis) can occur in as many as 15% of patients.  This complication is more common in those who have required steroid therapy, as well as in smokers, patients with more active disease, and those with low calcium and vitamin D intake. As a consequence, a special x-ray  called a bone mineral density testing is recommended for patients who have been on steroids, are postmenopausal, have had a low-trauma fracture, or who have moderate-to-severe Crohn’s diease.  Patients with osteopenia/osteoporosis need to have a workup to rule out other causes of bone loss,  including an overractive thyroid and low blood levels of vitamin D.  All patients with Crohn’s disease should be instructed to take supplemental calcium and vitamin D on a daily basis.  Some patients may require the addition of special medications such as bisphosphonates to prevent further bone loss.  Consultation with an endocrinologist or rheumatologist may be necessary.

5. Colon cancer

There is an increased risk of colon cancer in patients with Crohn’s colitis.  Risk factors include:  more extensive disease, longer duration of disease, family history of colon cancer, or the concomitant presence of a disease called primary sclerosing cholangitis (PSC).  Surveillance colonoscopies and biopsies are recommended every one to two years after the patient has had the disease for eight to ten years.  The exception to this rule is in patients with PSC, who should start undergoing surveillance colonoscopies at the time of diagnosis.

6. Small bowel cancer

There is a clear increased risk of small bowel adenocarcinoma in patients with Crohn’s disease, but it still remains an exceedingly rare complication.  This type of cancer usually arises in areas of long-term active disease or strictured bowel.  There is no screening test that is currently recommended due to the rarity of this complication

7. Anal cancer

This is a rare complication of long-standing perianal Crohn’s disease.

8. Bacterial overgrowth

This complication typically presents with diarrhea, bloating, and abdominal cramping.  It is caused by excessive growth of bacteria in the small intestine, often in the setting of strictures, fistulas, or loss of the valve between the small intestine and colon (ileocecal valve).  It is treated with antibiotics.

9. Nutritional Deficiencies

Nutritional complications can also be seen in patients with Crohn’s disease, including deficiencies of proteins, calories, or vitamins. These deficiencies are caused by inadequate dietary intake, intestinal loss of protein, or poor absorption of nutrients as a consequence of the underlying inflammation. Vitamin B12 deficiency is often seen in patients with Crohn’s disease who have undergone resection of a portion of their terminal ileum, the portion of the intestine that absorbs vitamin B12.  Those same patients can also develop diarrhea from malabsorption of bile salts.  Bile salts cause the colon to secrete instead of absorb water, resulting in diarrhea. Patients who undergo extensive ileal resection are at risk for fat malabsorption, which can lead to deficiencies of fat-soluble vitamins such as Vitamins A, D, E, and K.  Vitamin D deficiency is also not uncommon in patients with Crohn’s disease, often related to self-imposed restriction of dairy products due to perceived lactose intolerance.  Malabsorption is another cause of vitamin D deficiency.

10. Kidney stones

Diarrhea and fat malabsorption can lead to the development of kidney stones, which usually present with severe flank (lower lateral back) pain and blood in the urine.

11. Gallstones

Bile acid malabsorption may predispose to the formation of gallstones.  Gallstones often remain asymptomatic, but can present with intermittent right sided upper abdominal pain.  Patients with gallstones can also develop inflammation of the gallbladder (cholecystitis), infection of the ducts of the liver (ascending cholangitis), or inflammation of the pancreas (pancreatitis).  Once gallstones become symptomatic, the gallbladder is usually surgically removed (cholecystectomy).

12. Extra-intestinal manifestations of Crohn’s disease (EIM)

 Crohn’s disease can affect organs outside the GI tract in up to 25% of patients.  They are usually divided by organ system and by association with disease activity.  The EIM are more common in patients whose disease involves the colon. Following is a list of possible sites that can be affected:

Joints – Crohn’s can affect the lower part of the spine or the peripheral joints (knees, ankles, etc).

Skin - two of the most common rashes associated with Crohn’s disease are (1) erythema nodosum, which presents as painful raised red bumps, and (2) pyoderma gangrenosum, in which the skin develops ulcerations.

                       Pyoderma gangrenosum (skin complication) in a patient with Crohn's disease

Eyes – uveitis presents with eye pain and/or changes in vision and requires evaluation by an ophthalmologist.  Episcleritis is painless redness of the conjunctiva and sclera (white part of the eye).

Liver – Fatty liver is the most common liver disease in patients with Crohn’s disease, but primary sclerosing cholangitis (PSC) is the more severe associated form of liver disease.  PSC is an inflammation of ducts in the liver that can eventually cause the liver to fail (cirrhosis).  Patients with PSC are also at higher risk for cancer of the ducts of the liver. 

Oral Sores

What is the course of Crohn’s disease?

The course of Crohn’s disease is quite variable.  Most patients have intermittent flares between periods of remission.  Over the course of their disease, 75% of patients will require surgery at some point.  Mortality rates in patients with Crohn’s disease appear to be slightly higher than that of the general population. 

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.

                                                 Traditional Crohn's treatment pyramid 

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.

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

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. 

References

1.      Lichtenstein GR, Abreu MT, Cohen R, Tremaine W.  American Gastroenterological Association Institute technical review on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology 2006;130(3):940-987.

1. Langmead L, Rampton DS. Review article: complementary and alternative therapies for inflammatory bowel disease. Aliment Pharmacol Ther. 2006 Feb 1;23(3):341-9.

3.      Caprilli R, Gassull MA, Escher JC, et al. European evidence based consensus on the diagnosis and management of Crohn’s disease: special situations. Gut 2006;55, Suppl 1:i36-58.

4.      Travis SP, Stange EF, Lemann M, et al. European evidence based consensus on the diagnosis and management of Crohn’s disease: current management. Gut 2006;55, Suppl 1:i16-35.

5.      Stange EF, Travis SP, Vermeire S, et al. European evidence based consensus on the diagnosis and management of Crohn’s disease: definitions and diagnosis. Gut 2006;55, Suppl 1:i1-15

6.      Lichtenstein GR, Sands BE, Pazianas M. Prevention and treatment of osteoporosis in inflammatory bowel disease. Inflamm Bowel Dis 2006;12(8):797-813.

1. Vermeire S, Rutgeerts P. Current status of genetics research in inflammatory bowel disease. Genes Immun. 2005 Dec;6(8):637-45

8.      Carter, MJ, Lobo AJ, Travis SP. Guidelines for the management of inflammatory bowel disease in adults. Gut 2004; 53 Suppl 5:v1-16.

9.      Sands BE, Cuffari C, Katz J, et al. Guidelines for immunizations in patients with inflammatory bowel disease. Inflamm Bowel Dis;10(5):677-92.

10.  Egan LJ, Sandborn WJ. Advances in the treatment of Crohn's disease. Gastroenterology. 2004;126(6):1574-81.

11.  Hommes DW, van Deventer SJ. Endoscopy in inflammatory bowel diseases. Gastroenterology. 2004;126(6):1561-73.

12.  Sartor RB. Therapeutic manipulation of the enteric microflora in inflammatory bowel diseases: antibiotics, probiotics, and prebiotics. Gastroenterology. 2004;126(6):1620-33.

13.  Sandborn WJ, Fazio VW, Feagan BG, Hanauer SB; American Gastroenterological Association Clinical Practice Committee. AGA technical review on perianal Crohn's disease. Gastroenterology. 2003;125(5):1508-30

14.  Pearson DC, May GR, Fick GH et al.  Azathioprine and 6-mercaptopurine in Crohn’s disease. A meta-analysis. Ann Intern Med. 1995;123:132-142.

Links

There are a lot of websites with information on ulcerative colitis, but many are simply selling or promoting a product, or have unverified information. The sites below provide reliable information for patients.

Crohn’s & Colitis Foundation of America

http://www.ccfa.org/

European Federation of Crohn's & Ulcerative Colitis Associations

http://www.efcca.org/

Clinical trials conducted in the United States and around the world

http://clinicaltrials.gov/

National Digestive Diseases Information Clearinghouse (NDDIC) for patient information on Crohn’s disease

http://digestive.niddk.nih.gov/ddiseases/pubs/crohns/index.htm

National Library of Medicine’s patient information page on Crohn’s disease

http://www.nlm.nih.gov/medlineplus/crohnsdisease.html

National Health Service (United Kingdom) – patient information on Crohn’s disease

http://www.nhsdirect.nhs.uk/articles/article.aspx?articleId=115

Health On the Net (HON) – a United Nations resource for searching health-related websites that comply with a code of practice in distributing health information to patients

http://www.hon.ch/individuals.html