What is Crohn’s disease

Crohn’s disease is a chronic (long lasting), progressive, and disabling inflammatory bowel disease (IBD) ¹. Ulcerative colitis and microscopic colitis are other common types of inflammatory bowel disease (IBD). Crohn’s disease causes inflammation and irritation in your digestive tract and can involve any site of your gastrointestinal tract from your mouth to your anus, and the inflammation caused by Crohn’s disease often spreads deep into the layers of affected bowel tissue. Most commonly, Crohn’s disease affects your small intestine and the beginning of your large intestine. Crohn’s disease sometimes may lead to life-threatening complications, such as bowel strictures, perforations, and fistula formation. Crohn’s disease causes inflammation of your digestive tract, which can lead to abdominal pain, severe diarrhea, fatigue, fever, weight loss, abdominal masses, anemia and malnutrition ². Inflammation caused by Crohn’s disease can involve different areas of the digestive tract in different people. Extraintestinal manifestations of Crohn’s disease include osteoporosis, arthritis (inflammation of one or more joints, causing pain and stiffness), scleritis (inflammation involving the white part of the eye [sclera]), kidney stones (nephrolithiasis), gallstones (cholelithiasis) and erythema nodosum (an inflammatory disorder affecting subcutaneous fat, it presents as tender red bumps found symmetrically on the shins). Crohn’s disease most often begins gradually and can become worse over time. You may have periods of remission that can last for weeks or years.

Crohn’s disease affects about 500,000 Americans ³. Men and women appear to be affected equally. Symptoms usually start between the ages of 15-35 but can develop at any time during one’s lifetime. Studies show that, over time, Crohn’s disease has become more common in the United States and other parts of the world ⁴. It used to be thought that Crohn’s disease predominantly affects Caucasians in North America and Western Europe, however, experts now see individuals being diagnosed with Crohn’s disease in populations from South America, Africa and Asia where the disease was unheard of 20 years ago. Experts do not know the reason for this increase.

Crohn’s disease can run in families and having a sibling or another first degree relative afflicted with the disease can increase the risk of developing the disease by ten to fifteen times as compared to the general population. Children who have one parent with Crohn’s disease have approximately a 7-10% lifetime risk of developing this disease. If both parents have the disease then the lifetime risk increases to 35%. Some important genetic mutations have been identified in this disease including the NOD2/CARD 15 genes. However, more than 80% of patients with Crohn’s disease do not have a recognized genetic disposition. Given the complex genetic makeup the disease it is not inherited in the classic sense.

Smoking is an important controllable risk factor in Crohn’s disease. People who smoke with this disease tend to have more severe forms of the disease and are at higher risk of needing surgery. People who live in industrialized countries and urban areas are also at elevated risk of having the disease. Some other factors including the use of medications such as non-steroidal anti-inflammatory drugs (aspirin-like drugs) and particular infections have been theorized to exacerbate or cause the disease although none have been shown in a consistent fashion to be the cause.

If you have Crohn’s disease in your large intestine, you may be more likely to develop colon cancer ⁵. If you receive ongoing treatment for Crohn’s disease and stay in remission, you may reduce your chances of developing colon cancer ⁶. Talk with your doctor about how often you should get screened for colon cancer. Screening is testing for diseases when you have no symptoms. Screening for colon cancer can include colonoscopy with biopsies. Although screening does not reduce your chances of developing colon cancer, it may help to find cancer at an early stage and improve the chance of curing the cancer.

While there’s no known cure for Crohn’s disease, therapies can greatly reduce its signs and symptoms and even bring about long-term remission. With treatment, many people with Crohn’s disease are able to function well.

Who is more likely to develop Crohn’s disease?

Crohn’s disease can develop in people of any age and is more likely to develop in people:

• between the ages of 20 and 29 ⁴
• who have a family member, most often a sibling or parent, with IBD
• who smoke cigarettes

Crohn’s disease life expectancy

Most people with Crohn’s disease with the proper medical care tend to live healthy, productive lives with a normal life span. Maintenance of remission and surveillance for complications are the major goals which lead to maintaining quality of life in patients with Crohn’s disease. Regular visits with a gastroenterologist and developing a longstanding relationship are vital to managing this disease.

Types of Crohn’s Disease

If you are diagnosed with Crohn’s disease, it’s important to know and understand which part of your GI tract is affected and how this may affect the symptoms and complications you experience.

The following are five types of Crohn’s disease, together with their presenting symptoms:

Ileocolitis

The most common form of Crohn’s, ileocolitis affects the end of the small intestine (the ileum) and the large intestine (the colon). Symptoms include diarrhea and cramping or pain in the right lower part or middle of the abdomen. This type is often accompanied by significant weight loss.

Ileitis

This type affects only the ileum. Symptoms are the same as ileocolitis. In severe cases, complications may include fistulas or inflammatory abscess in right lower quadrant of abdomen.

Gastroduodenal Crohn’s disease

This type affects the stomach and the beginning of the small intestine(the duodenum). Symptoms include loss of appetite, weight loss, nausea, and vomiting.

Jejunoileitis

This type is characterized by patchy areas of inflammation in the upper half of the small intestine (the jejunum). Symptoms include mild to intense abdominal pain and cramps following meals, as well as diarrhea. In severe cases or after prolonged periods, fistulas may form.

Crohn’s (granulomatous) colitis

This type affects the colon only. Symptoms include diarrhea, rectal bleeding, and disease around the anus (abscess, fistulas, ulcers). Skin lesions and joint pains are more common in this form of Crohn’s than in others

Classification of Crohn’s disease

The International Working Party that issued its report in Rome in 1991 proposed a classification based on anatomical distribution, operative history, and clinical behavior (inflammatory, fistulising, or stenotic disease). However, this classification was felt inappropriate for clinical application in the following years, and the World Congress of Gastroenterology in Vienna in 1998 provided an opportunity for reconsidering and reanalysis of this classification ⁷. The resulting Vienna classification of Crohn’s disease considered age of onset (A), disease location (L), and disease behavior (B) as the predominant phenotypic elements. Although the Vienna classification is still not widely used in clinical practice, researchers have increasingly returned to it and have assessed its applicability and utility. The Montreal classification ⁸ (Table 1) proposed in 2005 is now used as the standard classification method for Crohn’s disease in adult patients. The Montreal classification was proposed through modification and supplementation of the Vienna classification ⁹. Because younger age at diagnosis was known to be highly related to genetic mutation, the age of 40 years was subdivided again into ≤16 years or >16 years in the Montreal classification. As for the involved site, upper gastrointestinal disease (L4) can be added to L1–L3, whereas for disease behavior, the presence of perianal fistula or perianal abscess (p) can be added to B1–B3. In adult Crohn’s disease, it has been known that the site of disease involvement generally does not change over time, but disease behavior is known to progress from the inflammatory to the stricturing or fistulizing type in a substantial number of patients ¹⁰.

With respect to age of onset, the Montreal classification allows for early onset of disease to be categorised separately as a new A1 category for those with age of diagnosis at 16 years or younger, whereas A2 and A3 account for age of diagnosis at 17–40 years and >40 years, respectively (Table 1) ¹¹. This change reflects numerous studies demonstrating that specific serotypes or genotypes are more frequently found in early onset Crohn’s disease ¹². These findings may reflect the presence of specific biomarkers in this subset of patients but equally likely may illustrate the importance of this cohort in identification of novel genetic and serological markers.

Crohn’s disease can also be classified according to the degree of inflammatory lesion involvement in the gastrointestinal tract. Localized disease is defined as intestinal involvement <30 cm in length regardless of the anatomical location. This is usually the case when the ileocecal area is involved, and the sum of the length of the involved ileum and ascending colon is the criterion. Meanwhile, extensive disease is defined as a total length of involvement of ≥100 cm regardless of the anatomical location ¹³.

Finally, two critical issues were identified for integration into the Montreal classification regarding disease behavior. There are now substantial data that perianal fistulising disease is not necessarily associated with intestinal fistulising disease, and it was felt that perianal disease alone required separate subclassification ¹⁴. A further issue with regard to classification of disease behavior is the observation that disease behavior is dynamic over time. Recent studies have reinforced this, demonstrating that patients with predominantly inflammatory disease at diagnosis are very likely to develop either fistulising or stricturing complications within 5, 10, and 20 years ¹⁴. The authors of the Montreal classification considered at length whether a stipulated time point should be given before disease behavior might be classified. This approach was seen to have both benefit as well as limitations, particularly in comparing studies from different centers, and also in retrospective analyses. The consensus statement allows for a stipulated time to be set in studies of this aspect of disease. It should also be noted that these changes to disease location and behaviour are supported by an evolving body of evidence demonstrating that site of disease, behavior, and disease progression are all variables that are likely to be identified by genetic and serological markers ¹⁵.

Table 1. Montreal Classification for Crohn’s disease

Variable
Age at diagnosis (year)	A1, ≤16
	A2, 17-39
	A3, ≥40
Location	L1, ileal
	L2, colonic
	L3, ileocolonic
	L4, isolated upper diseasea
Behavior	B1, non-stricturing, non-penetrating
	B2, stricturing
	B3, penetrating
	p, perianal disease modifierb

Footnotes:
^aL4 is a modifier that can be added to L1–L3 when concomitant upper gastrointestinal disease is present.
^bp is added to B1–B3 when concomitant perianal disease (perianal fistula or perianal abscess) is present.

[Source ⁸ ]

What causes Crohn’s disease?

The exact cause of Crohn’s disease remains unknown. Previously, diet and stress were suspected, but now doctors know that these factors may aggravate but don’t cause Crohn’s disease. A number of factors, such as heredity and a malfunctioning immune system, likely play a role in its development.

Experts think the following factors may play a role in causing Crohn’s disease:

• Immune system. It’s possible that a virus or bacterium may trigger Crohn’s disease. When your immune system tries to fight off the invading microorganism, an abnormal immune response causes the immune system to attack the cells in the digestive tract, too. One cause of Crohn’s disease may be an autoimmune reaction when your immune system attacks healthy cells in your body. Experts think bacteria in your digestive tract can mistakenly trigger your immune system. This immune system response causes inflammation, leading to symptoms of Crohn’s disease.
• Heredity. Crohn’s disease is more common in people who have family members with the disease, so genes may play a role in making people more susceptible. Research has shown that if you have a parent or sibling with Crohn’s disease, you may be more likely to develop the disease. However, most people with Crohn’s disease don’t have a family history of the disease. Scientists continue to study the link between genes and Crohn’s disease.

Risk factors for Crohn’s disease

Some studies suggest that other factors may increase your chance of developing Crohn’s disease. Risk factors for Crohn’s disease may include:

• Age. Crohn’s disease can occur at any age, but you’re likely to develop the condition when you’re young. Most people who develop Crohn’s disease are diagnosed before they’re around 30 years old.
• Ethnicity. Although Crohn’s disease can affect any ethnic group, whites and people of Eastern European (Ashkenazi) Jewish descent have the highest risk. However, the incidence of Crohn’s disease is increasing among blacks who live in North America and the United Kingdom.
• Family history. You’re at higher risk if you have a close relative, such as a parent, sibling or child, with the disease. As many as 1 in 5 people with Crohn’s disease has a family member with the disease.
• Cigarette smoking. Cigarette smoking is the most important controllable risk factor for developing Crohn’s disease ¹⁶. Smoking also leads to more-severe disease and a greater risk of having surgery. If you smoke, it’s important to stop.
• Nonsteroidal anti-inflammatory drugs (NSAIDs). These include aspirin, ibuprofen (Advil, Motrin IB, others), naproxen sodium (Aleve), diclofenac sodium (Voltaren) and others. While they do not cause Crohn’s disease, they can lead to inflammation of the bowel that makes Crohn’s disease worse.
• Antibiotics and birth-control pills may slightly increase the chance of developing Crohn’s disease ¹⁷.
• A high-fat diet may also slightly increase your chance of getting Crohn’s disease ¹⁸.
• Where you live. If you live in an urban area or in an industrialized country, you’re more likely to develop Crohn’s disease. This suggests that environmental factors, including a diet high in fat or refined foods, may play a role in Crohn’s disease.

Complications of Crohn’s disease

Crohn’s disease may lead to one or more of the following complications:

• Bowel obstruction. Crohn’s disease affects the thickness of the intestinal wall. Over time, the thickened areas of your intestines can scar and narrow, which may block the flow of digestive contents. A partial or complete intestinal obstruction, also called a bowel blockage, can block the movement of food or stool through your intestines. You may require surgery to remove the diseased portion of your bowel.
• Ulcers. Chronic inflammation can lead to open sores (ulcers) anywhere in your digestive tract, including your mouth and anus, and in the genital area (perineum).
• Fistulas. Sometimes ulcers can extend completely through the intestinal wall, creating a fistula (a tunnel)— an abnormal connection between different body parts. Fistulas can develop between your intestine and skin on the outside of your body, or between your intestine and another organ. Fistulas near or around the anal area (perianal fistula) are the most common kind. Fistulas may become infected.

When fistulas develop in the abdomen, food may bypass areas of the bowel that are necessary for absorption. Fistulas may occur between loops of bowel, into the bladder or vagina, or out through the skin, causing continuous drainage of bowel contents to your skin.

In some cases, a fistula may become infected and form an abscess, which can be life-threatening if not treated. Abscesses are painful, swollen, pus-filled pockets of infection.

• Anal fissure. This is a small tear in the tissue that lines your anus or in the skin around your anus where infections can occur. Anal fissure is often associated with painful bowel movements, itching, pain, or bleeding and may lead to a perianal fistula.
• Malnutrition. Malnutrition develops when your body does not get the right amount of vitamins, minerals, and nutrients it needs to maintain healthy tissues and organ function. Diarrhea, abdominal pain and cramping may make it difficult for you to eat or for your intestine to absorb enough nutrients to keep you nourished. It’s also common to develop anemia due to low iron or vitamin B-12 caused by Crohn’s disease.
• Colon cancer. Having Crohn’s disease that affects your colon increases your risk of colon cancer. General colon cancer screening guidelines for people without Crohn’s disease call for a colonoscopy every 10 years beginning at age 50. Ask your doctor whether you need to have this test done sooner and more frequently.
• Other health problems. Crohn’s disease can cause problems in other parts of the body. Among these problems are anemia, skin disorders, osteoporosis, arthritis, and gallbladder or liver disease.
• Inflammation in other areas of your body. You may have inflammation in your joints, eyes, and skin.
• Medication risks. Certain Crohn’s disease drugs that act by blocking functions of the immune system are associated with a small risk of developing cancers such as lymphoma and skin cancers. They also increase risk of infection.

Corticosteroids can be associated with a risk of osteoporosis, bone fractures, cataracts, glaucoma, diabetes and high blood pressure, among others. Work with your doctor to determine risks and benefits of medications.

Crohn’s disease signs and symptoms

The main symptoms of Crohn’s disease are abdominal pain, diarrhea, and weight loss. It occurs mainly in the 10 to 20 years age group and lasts throughout a lifetime, as well as causes complications such as bowel stenosis, fistula, and perforation.

In some people with Crohn’s disease, only the last segment of the small intestine (ileum) is affected. In others, the disease is confined to the colon (part of the large intestine). The most common areas affected by Crohn’s disease are the last part of the small intestine and the colon.

Signs and symptoms of Crohn’s disease can range from mild to severe. They usually develop gradually, but sometimes will come on suddenly, without warning. You may also have periods of time when you have no signs or symptoms (remission).

When the disease is active, signs and symptoms may include:

• Diarrhea
• Fever
• Fatigue
• Abdominal pain and cramping
• Blood in your stool
• Mouth sores
• Reduced appetite and weight loss
• Nausea
• Anemia
• Pain or drainage near or around the anus due to inflammation from a tunnel into the skin (fistula)

Other signs and symptoms:

People with severe Crohn’s disease also may experience:

• Inflammation of skin (skin changes that involve red, tender bumps under the skin), eyes (eye redness or pain) and joints (joint pain or soreness)
• Inflammation of the liver or bile ducts
• Delayed growth or sexual development, in children

Your symptoms may vary depending on the location and severity of your inflammation.

Some research suggests that stress, including the stress of living with Crohn’s disease, can make symptoms worse. Also, some people may find that certain foods can trigger or worsen their symptoms.

Crohn’s disease diagnosis

Your doctor will likely diagnose Crohn’s disease only after ruling out other possible causes for your signs and symptoms. There is no one test to diagnose Crohn’s disease.

Your doctor will likely use a combination of tests to help confirm a diagnosis of Crohn’s disease, including:

Blood tests

• Tests for anemia or infection. Your doctor may suggest blood tests to check for anemia — a condition in which there aren’t enough red blood cells to carry adequate oxygen to your tissues — or to check for signs of infection. Expert guidelines do not currently recommend antibody or genetic testing for Crohn’s disease.
• Fecal occult blood test. You may need to provide a stool sample so that your doctor can test for hidden (occult) blood in your stool.

Crohn’s disease test

Intestinal endoscopies are the most accurate methods for diagnosing Crohn’s disease and ruling out other possible conditions, such as ulcerative colitis, diverticular disease, or cancer. Intestinal endoscopies include the following:

• Colonoscopy. This test allows your doctor to view your entire colon and the very end of your ileum (terminal ileum) using a thin, flexible, lighted tube with an attached camera on one end, called a colonoscope or endoscope. During the procedure, your doctor can also take small samples of tissue (biopsy) for laboratory analysis, which may help confirm a diagnosis. You won’t feel the biopsies. Clusters of inflammatory cells called granulomas, if present, help confirm the diagnosis of Crohn’s disease.
• Upper GI endoscopy and enteroscopy. In an upper GI endoscopy, your doctor uses an endoscope to see inside your upper digestive tract, also called your upper GI tract. A trained specialist performs the procedure at a hospital or an outpatient center. You should not eat or drink before the procedure. A health care professional will tell you how to prepare for an upper GI endoscopy. You most often receive a liquid anesthetic to numb your throat and a light sedative to help you stay relaxed and comfortable during the procedure. During the procedure, the doctor carefully feeds the endoscope down your esophagus and into your stomach and duodenum.
  • During an enteroscopy, a doctor examines your small intestine with a special, longer endoscope using one of the following procedures:
    • push enteroscopy, which uses a long endoscope to examine the upper portion of your small intestine
    • single- or double-balloon enteroscopy, which uses small balloons to help move the endoscope into your small intestine
    • spiral enteroscopy, which uses a tube attached to an endoscope that acts as a corkscrew to move the instrument into your small intestine.

• Computerized tomography (CT). You may have a CT scan — a special X-ray technique that provides more detail than a standard X-ray does. This test looks at the entire bowel as well as at tissues outside the bowel. CT enterography is a special CT scan that provides better images of the small bowel. This test has replaced barium X-rays in many medical centers.

• Magnetic resonance imaging (MRI). An MRI scanner uses a magnetic field and radio waves to create detailed images of organs and tissues. MRI is particularly useful for evaluating a fistula around the anal area (pelvic MRI) or the small intestine (MR enterography).

• Capsule endoscopy. For this test, you swallow a capsule that has a camera in it. The camera takes pictures of your small intestine, which are transmitted to a recorder you wear on your belt. The images are then downloaded to a computer, displayed on a monitor and checked for signs of Crohn’s disease. The camera exits your body painlessly in your stool. You may still need endoscopy with biopsy to confirm the diagnosis of Crohn’s disease. The test begins in a doctor’s office, where you swallow the capsule. You can leave the doctor’s office during the test. As the capsule passes through your digestive tract, the camera will record and transmit images to a small receiver device that you wear. When the recording is done, your doctor downloads and reviews the images. The camera capsule leaves your body during a bowel movement, and you can safely flush it down the toilet.

• Balloon-assisted enteroscopy. For this test, a scope is used in conjunction with a device called an overtube. This enables the doctor to look further into the small bowel where standard endoscopes don’t reach. This technique is useful when capsule endoscopy shows abnormalities, but the diagnosis is still in question.

Crohn’s disease treatment

There is currently no cure for Crohn’s disease, and there is no one treatment that works for everyone. The goal of medical treatment is to reduce the inflammation that triggers your signs and symptoms. It is also to improve long-term prognosis by limiting complications. In the best cases, this may lead not only to symptom relief but also to long-term remission.

The treatment of patients with Crohn disease depends on disease severity, patient risk stratification, patient preference, and clinical factors, including age of onset and penetrating complications, and includes treatment with steroids, monoclonal antibody therapies, immunomodulators, and surgery ¹⁹.

Historically, treatment of Crohn’s disease has relied mainly on corticosteroids and immunosuppressive medication with thiopurines (azathioprine/6-mercaptopurine [6-MP]) or methotrexate (MTX) ²⁰. Though the introduction of corticosteroids achieved reduction of mortality in Crohn’s disease patients, this treatment is associated with many well-known undesired adverse effects and therefore not useful for long-term treatment. Two decades ago, the treatment armamentarium was extended by infliximab, the first tumor necrosis factor (TNF)-inhibitor, especially for patients with severe disease course and those who were refractory or intolerant to immunosuppressives ²¹. However, therapy with TNF-inhibitors is still challenging as 20–40% of patients have primary nonresponse to the drug and 23–46% experience secondary loss of response over time ²². In addition, approximately 5% of patients suffer from anti-TNF induced psoriasis or lupus-like syndrome ²³. Challenges also remain in treating elderlies who have significant comorbidities (e.g., heart failure) or patients with a history of malignancy.

Over the last couple of years, a number of new drugs have been developed and approved based either on inhibition of immune cell trafficking or on inhibition of cytokine signaling ²⁴. Vedolizumab, a monoclonal antibody directed against α4β7 integrin, has been approved for the treatment of patients with moderate-to-severe ulcerative colitis or Crohn’s disease who have inadequate response, loss of response or intolerance to conventional therapy with corticosteroids, immunosuppressives, or anti-TNF therapy. It is effective in the induction and maintenance of remission in refractory and luminal Crohn’s disease ²⁵. In real-world Crohn’s disease cohorts, clinical remission and response rates after induction therapy (usually evaluated at week 14) ranged from 24–36% to 49–64%, respectively ²⁶. Vedolizumab prevents circulating immune cells from homing to the mucosa and is gut-selective through interactions with mucosal adhesion molecules. This may be a specific advantage in long-term safety and may also explain the longer period of time to induce remission (12–16 weeks), compared to TNF-inhibitors ²⁷. Therefore, vedolizumab is not the ideal choice in patients with severe Crohn’s disease who are acutely ill where fast response to treatment is needed ²⁰. In the latest European Crohn’s and Colitis Organisation (ECCO) guideline ²⁸, the position of vedolizumab is adapted as it is now also clearly recommended to be used for induction and remission in patients with moderate to severe Crohn’s disease with inadequate response to conventional therapy with immunosuppressives. In other words, it is recommended as a first-line biological. However, the European Crohn’s and Colitis Organisation (ECCO) guideline does not discuss in detail which patients should be commenced on vedolizumab or anti-TNF inhibitors. According to some experts opinion, vedolizumab is suitable as a first choice biological in elderlies with comorbidities and elevated risk of infection and patients with history of malignancy, where safety is of particular concern ²⁰.

Ustekinumab is a monoclonal IgG1 antibody against the p40 subunit of interleukin-12 (IL-12) and IL-23 that targets T-helper cell pathways which promote the accumulation of inflammatory cells within the intestine ²⁹. It was approved for the treatment of patients with moderate-to-severe Crohn’s disease who have failed or were intolerant to treatment with corticosteroids, immunosuppressives, or anti-TNF therapy. Ustekinumab has shown to be effective in inducing and maintaining remission ³⁰, with higher response rates in TNF-naïve than in TNF-experienced patients (54–58% vs. 34%, respectively) ³¹. In the updated ECCO guideline ²⁸, ustekinumab has an expanded position within the approved biologicals as it can also be used as a first-line biological – such as vedolizumab. Again, the ECCO guideline does not give recommendation where to prefer ustekinumab over TNF-inhibitors or over vedolizumab as first-line option. According to some experts opinion, ustekinumab has its particular place as first-line biological, especially in patients with psoriasis and Crohn’s disease. Furthermore, this drug is a suitable option in patients who have developed severe TNF-induced psoriasiform disease ²³.

However, at least to date, TNF-inhibitors are less expensive (especially since biosimilars are available), and the clinical experience with TNF-inhibitors is much greater compared to the new biologicals. The safety profile of both ustekinumab and vedolizumab seems favorable, but long-term safety still needs to be confirmed in postmarketing studies ²⁰.

Crohn’s disease medications

Many people with Crohn’s disease need medicines. Which medicines your doctor prescribes will depend on your symptoms.

Although no medicine cures Crohn’s disease, many can reduce symptoms.

Anti-inflammatory drugs

Anti-inflammatory drugs are often the first step in the treatment of inflammatory bowel disease. They include:

• Corticosteroids also known as steroids. Corticosteroids such as prednisone, budesonide (Entocort EC), hydrocortisone and methylprednisolone can help reduce inflammation in your body, but they don’t work for everyone with Crohn’s disease. Doctors generally use them only if you don’t respond to other treatments. Budesonide is a steroid that is quickly metabolized by the liver thereby reducing corticosteroid-related side effects.

Corticosteroids may be used for short-term (three to four months) symptom improvement and to induce remission. Corticosteroids may also be used in combination with an immune system suppressor.

Side effects of corticosteroids include:

• acne
• bone mass loss
• high blood glucose
• high blood pressure
• a higher chance of developing infections
• mood swings
• weight gain

In most cases, doctors do not prescribe corticosteroids for long-term use.

• Oral 5-aminosalicylates also called 5-aminosalicylic acid (5-ASA). These drugs include sulfasalazine (Azulfidine), which contains sulfa, and mesalazine also known as mesalamine, balsalazide and olsalazine. Oral 5-aminosalicylates have been widely used in the past to control inflammation but now are generally considered of limited benefit. Some of the common side effects of aminosalicylates include: diarrhea, headaches, heartburn, nausea and vomiting, pain in your abdomen.

Immune system suppressors

These drugs also reduce inflammation, but they target your immune system, which produces the substances that cause inflammation. Doctors prescribe these medicines to help you go into remission or help you if you do not respond to other treatments. For some people, a combination of these drugs works better than one drug alone. Immunosuppressants can take several weeks to 3 months to start working. Immunosuppressant drugs include:

• Azathioprine (Azasan, Imuran) and 6-mercaptopurine (Purinethol, Purixan). These are the most widely used immunosuppressants for treatment of inflammatory bowel disease. Taking them requires that you follow up closely with your doctor and have your blood checked regularly to look for side effects, such as a lowered resistance to infection and inflammation of the liver. They may also cause nausea and vomiting.
• Infliximab (Remicade), adalimumab (Humira) and certolizumab pegol (Cimzia). These drugs, called TNF inhibitors or biologics, work by neutralizing an immune system protein known as tumor necrosis factor (TNF).
• Methotrexate (Trexall). This drug is sometimes used for people with Crohn’s disease who don’t respond well to other medications. You will need to be followed closely for side effects.
• Natalizumab (Tysabri) and vedolizumab (Entyvio). These drugs work by stopping certain immune cell molecules — integrins — from binding to other cells in your intestinal lining. Because natalizumab is associated with a rare but serious risk of progressive multifocal leukoencephalopathy — a brain disease that usually leads to death or severe disability — you must be enrolled in a special restricted distribution program to use it.
• Vedolizumab recently was approved for Crohn’s disease. It works like natalizumab but appears not to carry a risk of brain disease.
• Ustekinumab (Stelara). This drug is used to treat psoriasis. Studies have shown that it’s useful in treating Crohn’s disease as well and may be used when other medical treatments fail.
• Cyclosporine and cyclosporine (modified) are also sometimes used to treat Crohn’s disease. Doctors most often prescribe cyclosporine only if you have severe Crohn’s disease because of the medicine’s serious side effects. Talk with your doctor about the risks and benefits of cyclosporine.

Immunosuppressants may have the following side effects:

• a low white blood cell count, which can lead to a higher chance of infection
• feeling tired
• nausea and vomiting
• pancreatitis

Antibiotics

Antibiotics can reduce the amount of drainage and sometimes heal fistulas and abscesses in people with Crohn’s disease. Some researchers also think antibiotics help reduce harmful intestinal bacteria that may play a role in activating the intestinal immune system, leading to inflammation. Frequently prescribed antibiotics include ciprofloxacin (Cipro) and metronidazole (Flagyl).

Biologic therapies

Biologic therapies target proteins made by the immune system. Neutralizing these proteins decreases inflammation in the intestines. Biologic therapies work to help you go into remission, especially if you do not respond to other medicines. Biologic therapies include:

• Anti-tumor necrosis factor-alpha (anti-TNF-α) therapies, such as adalimumab, certolizumab and infliximab
• Anti-integrin therapies, such as natalizumab and vedolizumab
• Anti-interleukin-12 and interleukin-23 therapy, such as ustekinumab

Doctors most often give patients infliximab every 6 to 8 weeks at a hospital or an outpatient center. Side effects may include a toxic reaction to the medicine and a higher chance of developing infections, particularly tuberculosis.

Other medications

In addition to controlling inflammation, some medications may help relieve your signs and symptoms, but always talk to your doctor before taking any over-the-counter medications. Depending on the severity of your Crohn’s disease, your doctor may recommend one or more of the following:

• Anti-diarrheals. A fiber supplement, such as psyllium powder (Metamucil) or methylcellulose (Citrucel), can help relieve mild to moderate diarrhea by adding bulk to your stool. For more severe diarrhea, loperamide (Imodium A-D) may be effective. Loperamide to help slow or stop severe diarrhea. In most cases, people only take this medicine for short periods of time because it can increase the chance of developing megacolon.
• Pain relievers. For mild pain, your doctor may recommend acetaminophen (Tylenol, others). You should avoid using ibuprofen (Advil, Motrin IB, others), naproxen sodium (Aleve) and aspirin because these medicines can make your symptoms worse and can make your disease worse as well.
• Iron supplements. If you have chronic intestinal bleeding, you may develop iron deficiency anemia and need to take iron supplements.
• Vitamin B-12 shots. Crohn’s disease can cause vitamin B-12 deficiency. Vitamin B-12 helps prevent anemia, promotes normal growth and development, and is essential for proper nerve function.
• Calcium and vitamin D supplements. Crohn’s disease and steroids used to treat it can increase your risk of osteoporosis, so you may need to take a calcium supplement with added vitamin D.

Mild to Moderate Crohn’s disease

1. Sulfasalazine can be used to induce remission of mild colonic Crohn’s disease (quality of evidence, high; classification of recommendation, strong).
• Level of agreement: strongly agree 24%, agree 67%, uncertain 7%, disagree 2%, strongly disagree 0%

2. Although the efficacy of 5-aminosalicylic acid (5-ASA) for the remission induction of mild Crohn’s disease is limited, the use of this drug may be considered because of its fewer adverse effects and ease of administration (quality of evidence, high; classification of recommendation, weak).
• Level of agreement: strongly agree 20%, agree 72%, uncertain 8%, disagree 0%, strongly disagree 0%

3. Systemic corticosteroids are indicated for mild active Crohn’s disease that is refractory to 5-ASA (quality of evidence, high; classification of recommendation, strong).
• Level of agreement: strongly agree 36%, agree 53%, uncertain 9%, disagree 0%, strongly disagree 2%

4. Budesonide (9 mg/day) is preferred for induction therapy of mild to moderate Crohn’s disease confined to the terminal ileum or ileocecal area (quality of evidence, high; classification of recommendation, strong).
• Level of agreement: strongly agree 9%, agree 87%, uncertain 4%, disagree 0%, strongly disagree 0%

5. Systemic corticosteroid should be used if budesonide is not effective (quality of evidence, high; classification of recommendation, strong).
• Level of agreement: strongly agree 38%, agree 58%, uncertain 4%, disagree 0%, strongly disagree 0%

For decades, mesalazine also known as mesalamine or 5-aminosalicylic acid (5-ASA), has been used to achieve remission in Crohn’s disease ²⁰. Still nowadays, mesalazine is often prescribed; up to one-third of patients in the Epi-IBD cohort was treated with mesalazine ³². However, the latest European Crohn’s and Colitis Organisation (ECCO) guidelines ²⁸ suggest not to use mesalazine (or sulphasalazine) for Crohn’s disease treatment due to lack of supporting data. The working group performed a meta-analysis of 7 randomized trials comparing mesalazine (5 studies) and sulphasalazine (2 studies), published in the supplements. The Cochrane Network meta-analyses are inconsistent: A recent Cochrane Network meta-analysis by Coward et al. ³³ demonstrated a significant benefit for high-dose mesalazine or mesalamine (above 2.4 g daily) over placebo. However, another Network meta-analysis could not confirm such a dose effect ³⁴. It has to be mentioned that the European Crohn’s and Colitis Organisation (ECCO) recommendation is stated as “weak” and based only on moderate evidence. Furthermore, a risk-benefit analysis has not been performed. According to the meta-analysis, mesalazine is well tolerated ²⁸. According to some experts opinion, mesalazine may still be a treatment option and may be offered to patients who refuse repetitive steroids or do not want to escalate therapy toward immunosuppressives or biologicals ²⁰.

In several placebo-controlled trials conducted in the 1990s, it was reported that mesalamine, is efficacious for mild ileocecal Crohn’s disease ³⁵. Because of not only these evidences but also its fewer adverse effects and ease of administration, mesalamine has been widely used in the treatment of Crohn’s disease. Meanwhile, in a meta-analysis of three large-scale trials that evaluated the efficacy of 4 g/day mesalamine for active Crohn’s disease, high-dose mesalamine showed a statistically significant difference in the reduction of the Crohn’s Disease Activity Index (CDAI) in patients with active Crohn’s disease compared with placebo ³⁶; however, the difference in the mean value of decreased Crohn’s Disease Activity Index (CDAI) (mesalamine group, −63; placebo group, −45; difference of CDAI value between the two groups, -18) was small between the two groups, and its clinical usefulness is limited.

In a meta-analysis ³⁷ of randomized controlled trials, sulfasalazine is only modestly effective with a trend towards benefit over placebo and is inferior to corticosteroids for the treatment of mildly to moderately active Crohn’s disease. Olsalazine and low dose mesalamine (1 to 2 g/day) are not superior to placebo. High dose mesalamine (3.2 to 4 g/day) is not more effective than placebo for inducing response or remission. However, trials assessing the efficacy of high dose mesalamine (4 to 4.5 g/day) compared to budesonide yielded conflicting results and firm conclusions cannot be made. Future large randomized controlled trials are needed to provide definitive evidence on the efficacy of aminosalicylates in active Crohn’s disease. And efficacy was seen only in patients with colonic involvement but not in patients with disease limited to the small intestine ³⁸.

Local mesalazine (rectal foam/enema) in left-sided Crohn’s disease colitis is not recommended by the ECCO guidelines, due to lack of convincing data ²⁸. This treatment has not been studied in randomized controlled studies. To date, budesonide multi matrix with a colonic delivery technology is not (yet) approved for Crohn’s disease.

According to the European Crohn’s and Colitis Organisation (ECCO) guidelines ³⁹, budesonide (initially 9 mg) orally is the best treatment option for mildly active localized ileo-cecal disease to induce remission which can be achieved in up to 60% of patients after a therapy course over 8 weeks ⁴⁰. For moderately active localized ileo-cecal disease, either budesonide or systemic oral corticosteroids are recommended. Usually, budesonide 9 mg daily is somewhat less effective than oral systemic steroids (relative risk [RR] 0.85), especially in severe disease (RR 0.52); however, oral budesonide is associated with less side effects (RR 0.64) ⁴¹. Systemic corticosteroids are suitable in colonic and small bowel Crohn’s disease to induce remission ³⁹.

Budesonide controlled ileal release capsules are used for the treatment of patients with Crohn’s disease mainly involving the ileocecal area, because the drug starts to be released at pH 5.5 or higher and is mostly released and exert actions in the terminal ileum and proximal colon ⁴². In the Cochrane review ⁴³, budesonide is more effective than placebo for induction of remission in Crohn’s disease. Although short-term efficacy with budesonide is less than with conventional steroids, particularly in those with severe disease or more extensive colonic involvement, the likelihood of adverse events and adrenal suppression with budesonide is lower. The current evidence does not allow for a firm conclusion on the relative efficacy of budesonide compared to 5-ASA products ⁴³. Budesonide has fewer adverse effects than conventional systemic corticosteroids, as it undergoes a high first-pass metabolism in the pharmacokinetics of the body. The recommended dose of budesonide is 9 mg/day orally, and is usually reduced by 3 mg every 2 to 4 weeks after 6 weeks of administration. Meanwhile, in patients with high disease activity, systemic corticosteroids are more effective in inducing remission than budesonide. According to the analysis of two individual studies, the pooled risk ratio of remission induction was 0.52, indicating that systemic corticosteroids were superior to budesonide ⁴⁴. Therefore, budesonide is preferred in patients with mild to moderate Crohn’s disease localized to the terminal ileum or ileocecal area, whereas systemic corticosteroids are recommended for patients with higher disease activity. If sufficient efficacy is not achieved even after administration of budesonide for an adequate period, the use of systemic corticosteroids is considered.

Generally, the response of induction therapy should be clinically assessed after 2 weeks. Usually, tapering of corticosteroids starts after 2 weeks. In selected cases (first flare and mild localized disease), no further therapy may be considered (ECCO statement) ³⁹. A population-based study investigated the outcome of first steroid treatment in Crohn’s disease patients and revealed that 80% of the patients had a primary response within 30 days of therapy (48% with complete remission; 32% with partial response). Of those, 55% had prolonged response within 1 year. However, 45% had either a course of relapses or stayed steroid dependent ⁴⁵. Therefore, in around half of the patients, a concomitant therapy with either immunosuppressive agents [azathioprine/6-mercaptopurine (6-MP) or methotrexate (MTX)] or biological treatment must be considered as a steroid-sparing concept. Patients with several indicators predictive for a severe disease course should be early commenced on a biological treatment. When TNF-inhibitors have become available, early start of anti-TNF therapy in these patients increasingly became common practice, given the fact that continued treatment with either infliximab or adalimumab has been associated with a substantial reduction in hospitalisation (with adalimumab every other week: 52 and 48% relative reductions in 12-month risk of all-cause and Crohn’s disease-related hospitalisation, respectively) and surgery for Crohn’s disease (major surgery rate in the adalimumab every other week arm almost 7 times lower than that in the placebo arm ⁴⁶. The literature shows that combined treatment with infliximab and azathioprine (at least 6 months) is more effective than infliximab alone to induce and maintain remission without steroids (SONIC trial) ⁴⁷. Of course, the treating physician has to bear in mind the patient’s individual situation ­including safety profile. However, it must be stated that a significant reduction of surgery rates up to 40% has also been shown for thiopurines ⁴⁸.

Generally, treatment in patients with extensive small bowel disease (defined as involvement of >100 cm small bowel) should be more aggressive ⁴⁹ and TNF-inhibitors should be early started, also in combination with immunosuppressives, if possible ⁵⁰. Early start of anti-TNF therapy is more effective in extensive disease than a late start ⁵¹. The CHARM trial with adalimumab could show that 60% of patients with Crohn’s disease <2 years of duration reached clinical remission, compared to 40% of patients who had a longer duration of disease ⁵².

The updated ECCO guideline recommends them to be used also as first-choice biologicals. Vedolizu­mab (and also ustekinumab) may be preferred over TNF-inhibitors in elderly patients or in patients with history of malignancy, as these drugs have a very good safety profile ²⁸. However, one needs to bear in mind that vedolizumab is not effective against extraintestinal manifestations and is also not suitable when a fast response should be expected. Furthermore, ustekinumab is the preferred biological agent in ­patients with coexistent psoriasis.

It is important to recognize patients who are steroid-dependent (defined as relapse within 12 weeks during tapering or tapering within 16 weeks impossible) or refractory to steroids (defined as nonresponse within 4 weeks). In those patients, biological therapy should be initiated ⁵³.

Patients with early relapses and frequent flares during immunosuppressive therapy should be commenced on biological treatment. Alternatively, surgical resection can be discussed or evaluated, especially in localized disease and in those patients who still have active inflammation despite experience with all TNF-inhibitors and other biologicals.

Monitoring of patients with Crohn’s disease is important and is recommended by the ECCO guidelines ⁵⁴. In patients who reached clinical and biochemical remission, monitoring aims at early flare recognition ⁵⁴. According to the ECCO guidelines fecal calprotectin can be used to detect relapse before clinical symptoms occur. The monitoring time interval should be between 3 and 6 months depending upon duration of remission and current therapy ⁵⁴. Other than in North America, in Europe, especially in Germany and Switzerland, monitoring of IBD patients with ultrasound is much more common and frequently performed by many gastroenterologists in clinical practice. A German prospective multicenter study found that bowel ultrasound can be used to monitor disease activity in patients with active Crohn’s disease ⁵⁵. This method seems to be a useful follow-up method to evaluate early transmural changes in disease activity, in response to medical therapy ⁵⁵.

In case of inadequate response or loss of response, different options can be chosen to optimize the treatment: Serum trough levels of biologicals, especially of TNF-inhibitors, can be monitored and dosage adapted if required, also called therapeutic drug monitoring. It is also possible to optimize the TNF-inhibitor therapy based on clinical judgement only, without measuring drug trough levels or anti-TNF antibodies. The updated ECCO guideline commented on this aspect that there is currently no evidence to recommend for or against the use of therapeutic drug monitoring to improve the clinical outcome ²⁸. This statement is based on the only randomized controlled, multicenter study with 69 patients that showed no significant difference in improving clinical response between the therapeutic drug monitoring-group and the symptom-based group (57.6 vs. 52.8%) ⁵⁶. Overall, despite the limited evidence, therapeutic drug monitoring might bring a cost-saving benefit ⁵⁷. Adding azathioprine/6-mercaptopurine (6-MP) or methotrexate (MTX) could be another step to increase efficacy of TNF-inhibitors, especially in patients treated with infliximab. In case of antibody formation against the TNF-inhibitor which was used (e.g., infliximab), a switch to another one (e.g., adalimumab or certolizumab pegol; certolizumab pegol approved for Crohn’s disease in Switzerland and United States) would be recommended (switch within class).

In patients with primary nonresponse despite adequate dosage or intolerance to the drug, an alternative TNF-inhibitor or another class of biologicals (vedolizu­mab or ustekinumab) must be selected. The preference should be given to change the mechanism of action.

Especially in localized ileo-cecal disease, surgery is also a reasonable option in patients who deny medical treatment options (due to any reason) or in those who are not compliant toward medical therapy.

Esophageal and gastroduodenal disease: According to the ECCO statement 5 H ³⁹, mild esophageal or gastroduodenal disease may be treated with proton pump inhibitors only. However, it needs to be mentioned that Crohn’s disease in the proximal gut is associated with a worse prognosis ⁵⁸. Therefore, in general, more aggressive treatment should be recommended. Evidence-based therapy is mainly based on case series ⁵⁹. Many clinicians add a proton pump inhibitor to conventional induction therapy and have a low threshold for starting anti-TNF therapy than for disease elsewhere.

Moderate to Severe Crohn’s disease

6. Systemic corticosteroid (prednisolone 0.5 to 1 mg/kg/day or 40 to 60 mg/day) is the first-line induction therapy for moderate to severe Crohn’s disease (quality of evidence, moderate; classification of recommendation, strong).
• Level of agreement: strongly agree 38%, agree 60%, uncertain 2%, disagree 0%, strongly disagree 0%

7. Systemic corticosteroid should be reduced gradually according to disease severity and patient response, generally over 8 weeks (quality of evidence, low; classification of recommendation, strong).
• Level of agreement: strongly agree 39%, agree 61%, uncertain 0%, disagree 0%, strongly disagree 0%

8. Anti-TNF (anti-tumor necrosis factor) therapy is indicated if systemic corticosteroid therapy fails (quality of evidence, high; classification of recommendation, strong).
• Level of agreement: strongly agree 48%, agree 48%, uncertain 4%, disagree 0%, strongly disagree 0%

9. Thiopurine monotherapy is not recommended for induction therapy of moderate to severe Crohn’s disease (quality of evidence, moderate; classification of recommendation, weak).
• Level of agreement: strongly agree 19%, agree 65%, uncertain 14%, disagree 2%, strongly disagree 0%

10. Anti-TNF agents may be used to induce remission of moderate to severe Crohn’s disease (quality of evidence, moderate; classification of recommendation, weak).
• Level of agreement: strongly agree 37%, agree 63%, uncertain 0%, disagree 0%, strongly disagree 0%

11. When anti-TNF is used for induction therapy of thiopurine-naïve patients, combined therapy with anti-TNF and thiopurine is more effective than anti-TNF alone (quality of evidence, moderate; classification of recommendation, weak).
• Level of agreement: strongly agree 34%, agree 62%, uncertain 2%, disagree 2%, strongly disagree 0%

12. Intramuscular methotrexate (MTX) may be used to induce remission for moderate to severe Crohn’s disease (quality of evidence, high; classification of recommendation, weak).
• Level of agreement: strongly agree 11%, agree 85%, uncertain 4%, disagree 0%, strongly disagree 0%

According to the Cochrane reviews ⁶⁰ of randomized controlled trials that tested the efficacy of systemic corticosteroid therapy in active Crohn’s disease, systemic corticosteroids showed a significantly higher efficacy of remission induction than did placebo. Looking at the individual studies included in this Cochrane review, Summers et al. ⁶¹ randomly assigned 162 patients with active Crohn’s disease to either prednisone (0.5–0.75 mg/kg/day, gradual reduction) or placebo, and remission was induced in 30% of the control group but in 60% of the corticosteroid group at 17 weeks (number needed to treat [NNT], 3) ⁶¹. Meanwhile, in a study conducted by Malchow et al. ³⁸ (including 105 patients with active Crohn’s disease), remission was induced in 38% of the control group and in 83% of the 6-methylprednisolone (48 mg/day, dose tapered every week) group during an 18-week period (number needed to treat, 2).

To date, there has been no dose-response study for prednisolone. Prednisolone 0.5 to 1 mg/kg/day or 40 to 60 mg/day is usually recommended for induction therapy of moderate to severe Crohn’s disease. Moreover, there have been no studies on the effect of the route of corticosteroid administration, which is generally determined according to the severity of the disease of the patient. Intravenous corticosteroid therapy is considered in severe patients requiring hospitalization, whereas in other cases, corticosteroids are administered orally. Assessment of the therapeutic response to corticosteroids is generally done within 2 to 4 weeks for oral administration and within 1 to 2 weeks for intravenous administration. After the administration of systemic corticosteroids, the treatment response is assessed according to the severity of the patient, and if it is determined that sufficient therapeutic response has been achieved, the corticosteroid dose should be reduced. As rapid reduction is associated with early relapse, gradual tapering of corticosteroids over 8 weeks is recommended ⁶². Although systemic corticosteroids are highly effective in inducing remission of active Crohn’s disease, they are not effective in maintaining remission and can cause many adverse effects during long-term use ⁶³.

Infliximab is a chimeric IgG1 anti-TNF monoclonal antibody that was the first anti-TNF agent tried for the treatment of Crohn’s disease. In a randomized controlled study on the efficacy of infliximab for remission induction, 108 patients with moderate to severe Crohn’s disease who did not respond to 5-ASA, steroids, or immunomodulators (59% of patients at the start of the study used systemic corticosteroids) were randomly assigned to the infliximab (5, 10, or, 20 mg/kg) or placebo group. In this study, the response rates at week 4 in the 5, 10, 20 mg/kg infliximab groups were 81%, 50%, and 64%, respectively, and the infliximab groups (overall response rate, 65%) showed a higher response rate than the placebo group (overall response rate, 17%) ⁶⁴. Moreover, the remission rate at 4 weeks was also significantly different between the infliximab (33%) and placebo (4%) groups. Although the duration of the infliximab treatment response varied somewhat among patients, the response rate of the infliximab group at 12 weeks was 41%, which was higher than that of the placebo group (12%) and this confirms the persistence of drug efficacy ⁶⁴.

Adalimumab is a fully human anti-TNF agent administered subcutaneously. In the Clinical Assessment of Adalimumab Safety and Efficacy Studied as Induction Therapy in Crohn’s Disease (CLASSIC)-I study, 299 patients with moderate to severe Crohn’s disease (20% of patients at the beginning of the study used systemic corticosteroids) who had not received prior infliximab were randomized to receive 40/20 mg adalimumab, 80/40 mg adalimumab, 160/80 mg adalimumab, and placebo, respectively, at weeks 0 and 2. The remission rates in the adalimumab groups at 4 weeks were 18%, 24%, and 36%, respectively, and the rate was significantly higher in the 160/80 mg group than in the placebo group (12%) ⁶⁵. In the above infliximab and adalimumab studies, as the treatment results for patients who failed systemic corticosteroids therapy were not presented separately, the efficacy of anti-TNF agents in these patients are not known exactly. Certolizumab pegol (certolizumab), another anti-TNF agent, is a type of polyethylene glycol attached to anti-TNF Fab′. Unlike infliximab or adalimumab, certolizumab does not cause apoptosis of T cells and monocytes, and it did not consistently show a definite effect in the placebo-controlled studies of patients with moderate to severe Crohn’s disease ⁶⁶.

Although thiopurine (azathioprine [AZA] or 6-mercaptopurine [6-MP]) had been reported to be effective in inducing remission of active Crohn’s disease in an earlier meta-analysis, the latest Cochrane review ⁶⁷ azathioprine and 6-mercaptopurine offer no advantage over placebo for induction of remission or clinical improvement in active Crohn’s disease. Antimetaboilte therapy may allow patients to reduce steroid consumption. Adverse events were more common in patients receiving antimetabolites although differences with placebo were not statistically significant. Azathioprine therapy is inferior to infliximab for induction of steroid-free remission. However, the combination of azathioprine and infliximab was superior to infliximab alone for induction of steroid-free remission ⁶⁷. Therefore, the use of thiopurine alone for the induction of moderate to severe Crohn’s disease lacks clinical evidence.

The Study of Biologic and Immunomodulator Naive Patients in Crohn’s Disease (SONIC) was conducted by randomly assigning infliximab plus AZA, infliximab alone, or AZA alone to patients with moderate to severe Crohn’s disease who had never received AZA or infliximab. The primary end point of the study was the proportion of patients who reached a steroid-free remission at week 26, which was significantly higher in the group with the combination therapy of infliximab and AZA than in the infliximab-alone group (56.8% vs. 44.4%) or AZA-alone group (56.8% vs. 30.0%) ⁶⁸. In addition, concerning the mucosal healing rate at 26 weeks, the combination therapy group showed a higher trend of mucosal healing rate than the infliximabalone group (43.9% vs. 30.1%), and demonstrated a significantly higher mucosal healing rate than the AZA-alone group (43.9% vs. 16.50%) ⁶⁸. Meanwhile, according to the meta-analysis that evaluated the efficacy of immunomodulator combination therapy for adalimumab in Crohn’s disease, adalimumab monotherapy was less effective than the combination therapy of adalimumab and immunomodulator in the remission induction of Crohn’s disease. However, there was no difference in the maintenance efficacy between the two groups ⁶⁹. The previous SONIC study was conducted on thiopurine-naïve patients; however, the individual studies included in the aforementioned meta-analysis of adalimumab were performed on patients regardless of the history of immunomodulatory use. Thus, caution is needed in the comparative interpretation of the results from those two studies.

Methotrexate (MTX) is an antimetabolite that competitively inhibits dihydrofolate reductase, and exerts its effect by blocking the action of dihydrofolate in the cells for DNA synthesis and cell division ⁷⁰. However, the effect of methotrexate in inflammatory diseases such as rheumatoid arthritis is not explained by the cytotoxic mechanism, and it is presumed that its action through inhibition of interleukin or an eicosanoid compound may be involved in the suppression of inflammatory response ⁷¹. According to the placebo-controlled study on the efficacy of methotrexate in inducing remission in 141 patients with active Crohn’s disease, patients receiving intramuscular methotrexate 25 mg/week had significantly higher remission rates at week 16 than those who received placebo (39% vs. 19%; NNT, 5) ⁷². On the other hand, in placebo-controlled studies evaluating the treatment response to oral administration of low-dose methotrexate (12.5–22.5 mg/week) in active Crohn’s disease, methotrexate did not demonstrate a superior efficacy over placebo ⁷³. However, further investigation for the appropriate dose and route of methotrexate in active Crohn’s disease is needed, because of the limited number of patients included in these studies.

Crohn’s disease Refractory to Medical Treatment

13. Surgical treatment should be considered in cases that are refractory to medical therapy. Surgical decision making should be done with full communication with gastroenterologists, surgeons, and the patient (quality of evidence, very low; classification of recommendation, weak).
• Level of agreement: strongly agree 61%, agree 34%, uncertain 5%, disagree 0%, strongly disagree 0%

14. In case of primary nonresponse to anti-TNF, reevaluation of symptoms and change of treatment are necessary (quality of evidence, low; classification of recommendation, no specific recommendation).
• Level of agreement: strongly agree 42%, agree 58%, uncertain 0%, disagree 0%, strongly disagree 0%

15. Although testing of the serum anti-TNF trough level or antibodies to anti-TNF were reported to be useful for optimizing anti-TNF therapy or identifying cause of primary nonresponse or secondary loss of response, further study is required (quality of evidence, low; classification of recommendation, weak).
• Level of agreement: strongly agree 13%, agree 83%, uncertain 4%, disagree 0%, strongly disagree 0%

16. In patients who are intolerant or not responsive to one anti-TNF therapy, a different anti-TNF agent may be used (quality of evidence, infliximab [high], adalimumab [low]; classification of recommendation, infliximab [strong], adalimumab [weak]).
• Level of agreement: strongly agree 7%, agree 80%, uncertain 13%, disagree 0%, strongly disagree 0%

The primary treatment for Crohn’s disease is medical therapy, and surgical treatment is usually performed to improve symptoms of complications ⁷⁴. Surgery should be decided after thorough communication among the gastroenterologists, patient, and surgeons.

Biologics including anti-TNF agents are the most potent among the currently available drugs and very effective in inducing remission in patients with Crohn’s disease who are not responsive to corticosteroids or immunomodulators. Therefore, failure of biologic treatments may mean failure of medical treatment. There is no consensus about the definition of primary nonresponse, although it is generally accepted as the absence of a response to anti-TNF induction therapy. Concerning the time point for defining nonresponse, it is recommended that primary nonresponse should not be assessed before 8 to 12 weeks following the initial dosing of anti-TNF agents ⁷⁵. The incidence of primary nonresponse was reported to be 20% to 40% in clinical studies and 10% to 20% in observational studies ⁷⁶. Several factors are known to predict primary nonresponse, including a disease duration of >2 years, small-bowel involvement, smoking, and normal CRP. Several genetic polymorphism (IBD5 , etc.) were also reported as associated factors. Therefore, smoking cessation is mandatory before treatment to prevent primary nonresponse to anti-TNF therapy. Moreover, it is necessary to evaluate whether there is indeed any evidence of active inflammation, such as endoscopic ulcers or elevated CRP, and the association between inflammatory activity and patient symptoms. Nonresponse to anti-TNF therapy is more likely to occur when symptoms are associated with other noninflammatory causes, such as a fibrotic stricture ⁷⁷. Change to other anti-TNF drug may be an appropriate choice in case of primary nonresponse, as 50% to 60% of those patients respond to other anti-TNF drugs.

Although the mechanism of primary nonresponse has not yet been clearly been identified, pharmacokinetic factors may play an important role, which means that the lack of response is caused by the accelerated clearance of the drug from systemic circulation and/or local tissue ⁷⁸. Immunogenicity, the formation of anti-drug antibody (ADA), has been in the spotlight because it has been reported that binding of anti-drug antibody to the drug results in increased clearance of the drug, leading to unfavorable clinical outcomes. In fact, in many studies, the response to treatment was poor with lower serum concentrations of anti-TNF drug and in the presence of anti-drug antibody. In comparison with patients who received 80/40 mg, those who received 160/80 mg for the induction of remission showed higher adalimumab serum concentration at week 4 (11.6 vs. 3.6 µg/mL) and lower incidence of primary nonresponse ⁷⁹. However, further study is required on the usefulness of anti-drug antibody detection and anti-TNF drug serum level in the treatment, prevention, or prediction of primary nonresponse ⁸⁰. Other suggested mechanisms of primary nonresponse include non-TNF inflammatory pathway, rapid consumption of anti-TNF drug owing to severe inflammation, and presence of inherent antibodies to the anti-TNF drug before exposure to the drug ⁷⁸.

Vedolizumab, a monoclonal antibody to α4β7 integrin, has a totally different mechanism to the previous anti-TNF drugs, and has an anti-inflammatory effect by blocking lymphocyte migration to the gastrointestinal tract. In the GEMINI 3 study on vedolizumab induction therapy for patients with moderate to severe Crohn’s disease who failed treatment with previous anti-TNFs, vedolizumab induction therapy did not show a difference at 6 weeks in comparison with placebo (15.2% vs. 12.1%), but the remission rate at 10 weeks was significantly higher than with placebo (26.6% vs. 12.1%) ⁸¹. Another biologic agent, ustekinumab, is a monoclonal antibody to the p40 subunit of interleukin-12 and interleukin-23, which was approved for the treatment of psoriasis but has recently been shown to be efficacious in intractable Crohn’s disease. In the UNITI-1 study, in which 741 patients with moderate Crohn’s disease who had a history of anti-TNF use (primary nonresponse, secondary loss of response, or intolerance to anti-TNF) were randomized to ustekinumab 130 mg, 6 mg/kg or placebo, the response rates of ustekinumab 130 mg and 6 mg/kg group were 34.3% and 33.7% at 6 weeks respectively, which was higher than that of the placebo group (21.5%) (according to the dosage group ⁸². These results suggest that vedolizumab and ustekinumab may be used as a second-line therapy in patients with primary nonresponse or intolerance to anti-TNF therapy.

For cases that are intolerant to a specific anti-TNF drug, other anti-TNF drugs may show effectiveness. The Gauging Adalimumab Efficacy in Infliximab Nonresponders (GAIN) study including patients with Crohn’s disease who were intolerant or nonresponsive to infliximab demonstrated significantly higher remission and response rates (21% vs. 7%, 52% vs. 34%) at week 4 in patients who received adalimumab 160/80 mg for induction of remission in comparison with the placebo group, and a similar effect was observed across the infliximab-intolerant and infliximab-nonresponse groups ⁸³.

Bowel rest

If your Crohn’s disease symptoms are severe, you may need to rest your bowel for a few days to several weeks. Bowel rest involves drinking only certain liquids or not eating or drinking anything. During bowel rest, your doctor may:

• ask you to drink a liquid that contains nutrients
• give you a liquid that contains nutrients through a feeding tube inserted into your stomach or small intestine
• give you intravenous (IV) nutrition through a special tube inserted into a vein in your arm

You may stay in the hospital, or you may be able to receive the treatment at home. In most cases, your intestines will heal during bowel rest.

Surgery

Even with medicines, many people will need surgery to treat their Crohn’s disease. One study found that nearly 60 percent of people had surgery within 20 years of having Crohn’s disease ⁸⁴. Although surgery will not cure Crohn’s disease, it can treat complications and improve symptoms. Doctors most often recommend surgery to treat:

• fistulas
• bleeding that is life threatening
• intestinal obstructions
• side effects from medicines when they threaten your health
• symptoms when medicines do not improve your condition

A surgeon can perform different types of operations to treat Crohn’s disease.

For any surgery, you will receive general anesthesia . You will most likely stay in the hospital for 3 to 7 days following the surgery. Full recovery may take 4 to 6 weeks.

Small bowel resection

Small bowel resection is surgery to remove part of your small intestine. When you have an intestinal obstruction or severe Crohn’s disease in your small intestine, a surgeon may need to remove that section of your intestine. The two types of small bowel resection are:

• laparoscopic—when a surgeon makes several small, half-inch incisions in your abdomen. The surgeon inserts a laparoscope—a thin tube with a tiny light and video camera on the end—through the small incisions. The camera sends a magnified image from inside your body to a video monitor, giving the surgeon a close-up view of your small intestine. While watching the monitor, the surgeon inserts tools through the small incisions and removes the diseased or blocked section of small intestine. The surgeon will reconnect the ends of your intestine.
• open surgery—when a surgeon makes one incision about 6 inches long in your abdomen. The surgeon will locate the diseased or blocked section of small intestine and remove or repair that section. The surgeon will reconnect the ends of your intestine.

Subtotal colectomy

A subtotal colectomy, also called a large bowel resection, is surgery to remove part of your large intestine. When you have an intestinal obstruction, a fistula, or severe Crohn’s disease in your large intestine, a surgeon may need to remove that section of intestine. A surgeon can perform a subtotal colectomy by:

• laparoscopic colectomy—when a surgeon makes several small, half-inch incisions in your abdomen. While watching the monitor, the surgeon removes the diseased or blocked section of your large intestine. The surgeon will reconnect the ends of your intestine.
• open surgery—when a surgeon makes one incision about 6 to 8 inches long in your abdomen. The surgeon will locate the diseased or blocked section of large intestine and remove that section. The surgeon will reconnect the ends of your intestine.

Proctocolectomy and ileostomy

A proctocolectomy is surgery to remove your entire colon and rectum. An ileostomy is a stoma, or opening in your abdomen, that a surgeon creates from a part of your ileum. The surgeon brings the end of your ileum through an opening in your abdomen and attaches it to your skin, creating an opening outside your body. The stoma is about three-quarters of an inch to a little less than 2 inches wide and is most often located in the lower part of your abdomen, just below the beltline.

A removable external collection pouch, called an ostomy pouch or ostomy appliance, connects to the stoma and collects stool outside your body. Stool passes through the stoma instead of passing through your anus. The stoma has no muscle, so it cannot control the flow of stool, and the flow occurs whenever occurs.

If you have this type of surgery, you will have the ileostomy for the rest of your life.

Crohn’s disease complications treatment

Your doctor may recommend treatments for the following complications of Crohn’s disease:

• Intestinal obstruction. A complete intestinal obstruction is life threatening. If you have a complete obstruction, you will need medical attention right away. Doctors often treat complete intestinal obstruction with surgery.
• Fistulas. How your doctor treats fistulas will depend on what type of fistulas you have and how severe they are. For some people, fistulas heal with medicine and diet changes, whereas other people will need to have surgery.
• Abscesses. Doctors prescribe antibiotics and drain abscesses. A doctor may drain an abscess with a needle inserted through your skin or with surgery.
• Anal fissures. Most anal fissures heal with medical treatment, including ointments, warm baths, and diet changes.
• Ulcers. In most cases, the treatment for Crohn’s disease will also treat your ulcers.
• Malnutrition. You may need IV fluids or feeding tubes to replace lost nutrients and fluids.
• Inflammation in other areas of your body. Your doctor can treat inflammation by changing your medicines or prescribing new medicines.

Nutrition therapy

Your doctor may recommend a special diet given via a feeding tube (enteral nutrition) or nutrients injected into a vein (parenteral nutrition) to treat your Crohn’s disease. This can improve your overall nutrition and allow the bowel to rest. Bowel rest can reduce inflammation in the short term.

Your doctor may use nutrition therapy short term and combine it with medications, such as immune system suppressors. Enteral and parenteral nutrition are typically used to get people healthier prior to surgery or when other medications fail to control symptoms.

Your doctor may also recommend a low residue or low-fiber diet to reduce the risk of intestinal blockage if you have a narrowed bowel (stricture). A low residue diet is designed to reduce the size and number of your stools.
Surgery

If diet and lifestyle changes, drug therapy, or other treatments don’t relieve your signs and symptoms, your doctor may recommend surgery. Nearly half of those with Crohn’s disease will require at least one surgery. However, surgery does not cure Crohn’s disease.

During surgery, your surgeon removes a damaged portion of your digestive tract and then reconnects the healthy sections. Surgery may also be used to close fistulas and drain abscesses.

The benefits of surgery for Crohn’s disease are usually temporary. The disease often recurs, frequently near the reconnected tissue. The best approach is to follow surgery with medication to minimize the risk of recurrence.

Crohn’s disease diet

Changing your diet can help reduce symptoms. Your doctor may recommend that you make changes to your diet such as:

• avoiding carbonated, or “fizzy,” drinks
• avoiding popcorn, vegetable skins, nuts, and other high-fiber foods
• drinking more liquids
• eating smaller meals more often
• keeping a food diary to help identify foods that cause problems

Depending on your symptoms or medicines, your doctor may recommend a specific diet, such as a diet that is:

• high calorie
• lactose free
• low fat
• low fiber
• low salt

Talk with your doctor about specific dietary recommendations and changes. Your doctor may recommend nutritional supplements and vitamins if you do not absorb enough nutrients. For safety reasons, talk with your doctor before using dietary supplements, such as vitamins, or any complementary or alternative medicines or medical practices.

Patients have strong beliefs about the role of diet in the cause of inflammatory bowel disease (Crohn’s disease & ulcerative colitis) and in exacerbating or alleviating ongoing symptoms from inflammatory bowel disease ⁸⁵. The rapid increase in the incidence and prevalence of inflammatory bowel disease in the past several decades strongly suggests an environmental trigger for inflammatory bowel disease, one of which may be dietary patterns. There are several pathways where diet may influence intestinal inflammation such as direct dietary antigens, altering the gut microbiome, and affecting gastrointestinal permeability. However, data that altering diet can change the natural history of inflammatory bowel disease are scarce and evidence based dietary guidelines for patients with inflammatory bowel disease are lacking. Patients therefore seek non-medical resources for dietary guidance such as patient support groups and unverified sources on the internet.

Various dietary components have been proposed to increase the risk of developing or exacerbating symptoms of inflammatory bowel disease. One of the first dietary components associated with developing inflammatory bowel disease was intake of sugar and refined carbohydrates ⁸⁶. However, an ecological study in North America, Europe and Japan failed to show an association between refined sugar intake and Crohn’s disease incidence rates ⁸⁷. There are consistent associations between both fatty acid and protein composition in the diet with the development of inflammatory bowel disease in both ecological and prospective cohort studies ⁸⁸, ⁸⁹. Furthermore, dietary fiber intake has been associated with a lower risk of developing Crohn’s disease, but not ulcerative colitis ⁹⁰.

Two studies ⁹¹, ⁹² of patients who underwent ileocolonic resection provide the strongest evidence for the role of intestinal contents on the course of Crohn’s disease. Both studies demonstrated that recurrence of inflammation after ileal resection is dependent on exposure of the neo-terminal ileum to the fecal contents. Inflammation recurred within 8 days of exposure to the luminal contents ⁹¹, ⁹². However, the fecal stream is a complex mixture of bacteria, other microorganisms, digested food content, and the metabolic products of digestion of food components by the host and microbiota. This makes it very challenging to identify the components of the luminal content that drives the underlying inflammation. Furthermore, these components are not independent of each other.

There is a potential link between diet and the composition of the gut microbiome. Long term agrarian dietary patterns are associated with an enterotype characterized by Prevotella ⁹³, a genera more commonly observed in people from rural Africa where inflammatory bowel disease and particularly Crohn’s disease is uncommon ⁹⁴. Prevotella and related bacteria are efficient at fermenting dietary fiber, thereby leading to higher concentrations of short chain fatty acids (SCFA) ⁹⁵ which may protect against bowel inflammation ⁹⁶. In contrast, high fat diets, through dietary induced changes in the gut microbiota, may increase bowel permeability, a hallmark of Crohn’s disease ⁹⁷. High fat diets also worsen dextran sodium sulfate induced colitis in mice, possibly by increasing colonic epithelial non-classical natural killer T cells and reducing regulatory T cells ⁹⁸. In animal models, consumption of milk derived saturated fat alters bile acid composition, allowing for a bloom of sulfate-reducing bacteria, which in turn can produce greater amounts of the potentially mucosal toxic hydrogen sulfide ⁹⁹. A major source of hydrogen sulfide (H2S) in the bowel is bacterial fermentation of sulfur amino acids which are found in high protein foods such as meats ¹⁰⁰. Hydrogen sulfide has been proposed as contributing to bowel inflammation through a variety of mechanisms, including impaired utilization of short-chain fatty acids (SCFAs) and direct toxic effects ¹⁰¹. However, other research suggests that hydrogen sulfide (H2S) has anti-inflammatory properties and contributes to mucosal healing ¹⁰². These are but a few of the proposed mechanisms by which diet can affect the course of inflammatory bowel disease. Unfortunately, it is currently unknown whether these findings in animal models translate to humans with inflammatory bowel disease.

There are surprisingly few observational studies examining the association of diet with the natural history of inflammatory bowel disease. Jowett et al. ¹⁰³ conducted a prospective study of patients with ulcerative colitis. Jowett observed that patients who reported higher levels of meat, eggs, protein and alcohol consumption were more likely to have a relapse of ulcerative colitis ¹⁰³. Importantly, the association was much stronger for red and processed meats than for other meats and there was no association with fish consumption. Jowett hypothesized that these dietary patterns resulted in higher intestinal concentration of sulfate which in turn led to disease relapse. Another study found a correlation between sulfite consumption and endoscopic activity in ulcerative colitis ¹⁰⁴.

Scientific evidence regarding special diets for inflammatory bowel disease

There are no formal published studies on the benefits of either the specific carbohydrate diet ¹⁰⁵, ¹⁰⁶ or Paleo diets in the management or prevention of inflammatory bowel disease. Only a few small pilot studies have evaluated the FODMAP diet in inflammatory bowel disease patients. Both the specific carbohydrate diet and FODMAP diets purport that carbohydrates lead to bacterial overgrowth. Detecting bacterial overgrowth (i.e. an increase in the abundance of bacteria) is difficult and standard tests are fraught with misclassification. Furthermore, dietary composition is correlated with the composition of the gut microbiome as measured in terms of relative abundance. For example, Wu demonstrated that consumption of carbohydrates was positively correlated with the relative abundance of most but not all firmicutes within human feces ⁹³. Similarly, Hoffman ¹⁰⁷ found that consumption of carbohydrates is positively correlated with the proportional abundance of Candida and the methanogen archaea Methanobrevibacter. The link between diet and abundance of certain bacteria, yeast and archaea is complex, but may represent a syntrophic relationship ¹⁰⁷. For example, Candida may utilize starch, liberating simple carbohydrates that are used by bacteria such as Prevotella and Ruminococcus, which in turn produce substrates for fermentation that can be used by Methanobrevibacter to produce CH4 (methane) and or CO2.

How bacterial overgrowth may result in intestinal inflammation is unclear. The specific carbohydrate diet postulates that bacterial overgrowth results in fermentation and subsequent production of short-chain organic acids that are injurious to the small intestinal mucosa. However Breaking the Viscous Cycle references only case studies on systemic D-lactic acidosis, not mucosal concentrations of organic acids or mucosal injury ¹⁰⁸. The FODMAP authors hypothesize bacterial overgrowth may result in increased intestinal permeability, which has been associated with the pathogenesis of Crohn’s disease ¹⁰⁹.

There have been two small pilot studies evaluating the FODMAP diet in inflammatory bowel disease ¹¹⁰, ¹¹¹. The first was performed in 8 ulcerative colitis patients who had undergone colectomy. Median stool frequency per day dropped from 8 to 4 after initiation of the low FODMAP diet in the retrospective analyses, however no benefit was observed in 5 patients who were studied prospectively ¹¹¹. In the second study, 72 inflammatory bowel disease patients were retrospectively evaluated after education regarding a low FODMAP diet. Based on self-report, 70% of patients remained adherent on the diet after 3 months, and symptoms of pain, bloating, and diarrhea improved among those adherent to the diet ¹¹⁰. These limited retrospective studies are supportive of dietary interventions to improve inflammatory bowel disease symptoms but may be biased due to their retrospective nature and lack objective data regarding inflammatory changes associated with dietary intervention. Symptomatic response in inflammatory bowel disease patients to these dietary interventions may also suggest a component of functional gastrointestinal symptoms or non-celiac gluten intolerance.

The existing data on dietary risk factors are not clear regarding the role of carbohydrates in the development of inflammatory bowel disease. A systematic review of dietary risk factors for inflammatory bowel disease included 5 studies reporting the association of carbohydrate intake and risk of developing inflammatory bowel disease showing conflicting results ¹¹². The two most recent and largest cohort studies showed no association between carbohydrate intake and ulcerative colitis risk ¹¹³, ¹¹⁴. None of the included studies specifically differentiated mono-saccharides from other carbohydrates which could limit it’s applicability to specific carbohydrate diet recommendations. However, the existing data does not strongly support the role of carbohydrates in the development of inflammatory bowel disease or in perpetuating intestinal inflammation.

The carbohydrate malabsorption/bacterial overgrowth theory does not incorporate observations of increased risks of inflammatory bowel disease associated with high protein or high fats. As discussed earlier, Chiba et al. ¹¹⁵ demonstrated a reduction in disease relapse for Crohn’s disease patients on a semi-vegetarian diet compared to a control omnivorous diet. The semi-vegetarian diet included brown rice, soybeans, seaweed, yam, potato, onion and corn- foods restricted by both the specific carbohydrate diet and FODMAP diets. In a prospective cohort study, Jantchou et al. ¹¹³ observed a positive association of high animal protein intake with the development of inflammatory bowel disease. Similarly, high fat diets have been associated with an increased risk of development of both Crohn’s disease and ulcerative colitis ¹¹⁶. Although therapeutic trials of omega-3 PUFA (polyunsaturated fatty acid) to treat inflammatory bowel disease have not proven successful, there are signals that the balance of omega-6: omega-3 PUFA (polyunsaturated fatty acid) may affect inflammatory bowel disease risk ¹¹⁶. The concept of balance between PUFA does correspond conceptually with the Paleo diet; however means to assess ratios of PUFA (polyunsaturated fatty acid) in a practical manner in the modern diet are challenging.

Both the specific carbohydrate diet and Paleo diets advocate a high fiber diet but restrict cereal grain based fiber. Fermentation of dietary fiber in the colon produces short-chain fatty acids (SCFAs), which act as an energy source for colonocytes, modulate the local immune response (attenuate IL-6, IL-8 and TNF-a) and modify the intestinal microbial flora ¹¹⁷. Interventions using grain-based fiber have demonstrated potential therapeutic benefits in ulcerative colitis. Hallert et al. ¹¹⁸ performed a pilot study of 22 ulcerative colitis patients in remission, demonstrating that an increase of dietary fiber intake of 60 g of oat bran daily can increase fecal butyrate levels by 36% without an exacerbation in symptoms ¹¹⁸. Kanauchi et al. ¹¹⁹ performed an open-label control trial of 18 patients with mild-to-moderate ulcerative colitis, treated with 20–30 g/day of germinated barley foodstuff ¹¹⁹. An improvement of bowel related symptoms benefit was observed in the germinated barley foodstuff-treated group as were increased fecal concentrations of Bifidobacterium and Eubaterium limosum. In contrast to the specific carbohydrate diet and Paleo diets, these data suggest that inclusion of cereal-based grains may be beneficial to ulcerative colitis patients in particular. Further study in the role of both cereal grain and non-cereal grain based fiber in inflammatory bowel disease are required.

Both the specific carbohydrate diet and Paleo diets have the potential to contribute to vitamin D deficiency. This is a particular concern given the association of vitamin D deficiency and increased risk of surgery and hospitalization ¹²⁰. In patients expressing interest in either of these diets, assessment of vitamin D status may be important.

Anti-Inflammatory Diet (IBD-AID)

In studies involving people with chronic inflammatory bowel diseases (IBD) like Crohn’s disease and ulcerative colitis, the anti-Inflammatory diet (IBD-AID) has been used as an adjunct dietary therapy for the treatment of inflammatory bowel diseases (IBD) ¹²¹. The goal of the anti-Inflammatory diet (IBD-AID) is to assist with a decreased frequency and severity of flares, obtain and maintain remission in people with inflammatory bowel diseases (IBD). Dysbiosis, or altered bacterial flora, is one of the theories behind the development of anti-Inflammatory diet (IBD-AID), in that certain carbohydrates in the lumen of the gut provide pathogenic bacteria a substrate on which to proliferate ¹²², ¹²³.

The anti-Inflammatory diet (IBD-AID) has five basic components:

1. The first of which is the modification of certain carbohydrates, (including lactose, and refined or processed complex carbohydrates)
2. The second places strong emphasis on the ingestion of pre- and probiotics (e.g.; soluble fiber, leeks, onions, and fermented foods) to help restore the balance of the intestinal flora ¹²⁴, ¹²⁵, ¹²⁶
3. The third distinguishes between saturated, trans, mono- and polyunsaturated fats ¹²⁷, ¹²⁸,
4. The fourth encourages a review of the overall dietary pattern, detection of missing nutrients, and identification of intolerances.
5. The last component modifies the textures of the foods (e.g.; blenderized, ground, or cooked) as needed (per patient symptomology) to improve absorption of nutrients and minimize intact fiber.

The phases indicated in Table 2 are examples of the modification of texture complexity, so that dietitian and patient can expand the diet as the patient’s tolerance and absorption improves. Some sensitivities common to many patients (not just those with IBD), are eased through supplementation of digestive enzymes or avoidance. A senior dietitian advised the patient and either family or spouse regarding the details of the diet during regular clinic visits. Patients taking supplements (probiotics, vitamin/minerals, omega-3 fatty acids) were advised to continue or discontinue, depending on the needs of the individual and the dietary intake ¹²⁹.

The anti-inflammatory diet (IBD-AID) consists of lean meats, poultry, fish, omega-3, eggs, particular sources of carbohydrate, select fruits and vegetables, nut and legume flours, limited aged cheeses (made with active cultures and enzymes), fresh cultured yogurt, kefir, miso and other cultured products (rich with certain probiotics) and honey. Prebiotics, in the form of soluble fiber (containing beta-glucans and inulin, such as bananas, oats, blended chicory root, and flax meal) are suggested. In addition, the patient is advised to begin at a texture phase of the diet matching with symptomology, starting with phase one if in an active flare. Many patients require foods to be softened and textures mechanically altered by pureeing the foods, and avoiding foods with stems and seeds when starting the diet (see phases 1–3 of Table 2), as intact fiber can be problematic for those with strictures and highly active mucosal inflammation. Some patients will require lifelong avoidance of intact fiber. Food irritants are not limited to intact fiber, but may include certain foods, processing agents and flavorings to which IBD patients may be reactive.

Table 2. The Anti-Inflammatory Diet (IBD-AID) Food Phase chart

Phase type	Phase I	Phase II	Phase III	Phase IV
	Soft, well-cooked or cooked then pureed foods, no seeds	Soft Textures: well-cooked or pureed foods, no seeds, choose floppy or tender foods	May still need to avoid stems, choose floppy greens or other greens depending on individual tolerance	If in remission with no strictures
Vegetables	Butternut Squash, Pumpkin, Sweet Potatoes, Onions	Carrots, Zucchini, Eggplant, Peas, Snow peas, Spaghetti squash, Green beans, Yellow beans, Microgreens (2 week old baby greens), Watercress, Arugula, Fresh flat leaf parsley and cilantro, Seaweed, Algae	Butter lettuce, Baby spinach, Peeled cucumber, Olives, Leeks Bok Choy, Bamboo shoots, Collard greens, Beet greens, Sweet peppers, Kale, Fennel bulb	Artichokes, Asparagus, Tomatoes, Lettuce, Brussels sprouts, Beets, Cabbage, Kohlrabi, Rhubarb, Pickles, Spring onions, Water chestnuts, Celery, Celeriac, Cauliflower, Broccoli, Radish, Green pepper, Hot pepper
	Pureed vegetables: Mushrooms, Phase II vegetables (pureed)	Pureed vegetables: all except cruciferous	Pureed vegetables: all from Phase IV, Kimchi
Fruits	Banana, Papaya, Avocado, Pawpaw	Watermelon (seedless), Mangoes, Honeydew, Cantaloupe, May need to be cooked: Peaches, Plums, Nectarines, Pears, (Phase III fruits are allowed if pureed and seeds are strained out)	Strawberries, Cranberries, Blueberries, Apricots, Cherries, Coconut, Lemons, Limes, Kiwi, Passion fruit, Blackberries, Raspberries, Pomegranate (May need to strain seeds from berries)	Grapes, Grapefruit, Oranges, Currants, Figs, Dates, Apples (best cooked), Pineapple, Prunes
Meats and fish	All fish (no bones), Sardines (small bones ok), Turkey and ground beef, Chicken, Eggs	Scallops	Lean cuts of Beef, Lamb, Duck, Goose	Shrimp, Prawns, Lobster
Non dairy unsweetened	Coconut milk, Almond milk, Oat milk, Soy milk
Dairy, unsweetened	Yogurt, Kefir	Farmers cheese (dry curd cottage cheese), Cheddar cheese	Aged cheeses
Nuts/Oils/Legumes/Fats	Miso (refrigerated), Tofu, Olive oil, Canola oil, Flax oil, Hemp oil, Walnut oil, Coconut oil	Almond flour, Peanut flour, Soy flour, Sesame oil, Grapeseed oil, Walnut oil, Pureed nuts, Safflower oil, Sunflower oil	Whole nuts, Soybeans, Bean flours, Nut butters, Well-cooked lentils (pureed), Bean purees (e.g. hummus)	Whole beans and lentils
Grains	Ground flax or Chia Seeds (as tolerated)	Steel cut oats (well-cooked as oatmeal)	Rolled well-cooked oats
Spices	Basil, Sage, Oregano, Salt, Nutmeg, Cumin, Cinnamon, Turmeric, Saffron, Mint, Bay leaves, Tamari (wheat free soy sauce), Fenugreek tea, Fennel tea, Vanilla	Dill, Thyme, Rosemary Tarragon, Cilantro, Basil, Parsley	Mint, Ginger, Garlic (minced), Paprika, Chives, Daikon, Mustard	Wasabi, Tamarind, Horseradish, Fenugreek, Fennel
Sweeteners	Stevia, Maple syrup, Honey (local), Unsweetened fruit juice	Lemon and lime juice
Misc.	Capsule or liquid supplements, Cocoa powder	Baking powder (no cornstarch), Baking soda, Unflavored gelatin	Ghee, Light mayonnaise, Vinegar	Ketchup (sugar free), Hot sauce (sugar free)

[Source ¹²¹ ]

Inflammatory bowel disease dietary guidelines

To help patients navigate their nutritional questions, the International Organization of Inflammatory Bowel Diseases recently reviewed the best current evidence to develop expert recommendations regarding dietary measures that might help to control and prevent relapse of inflammatory bowel disease ¹³⁰. In particular, the International Organization of Inflammatory Bowel Diseases focused on the dietary components and additives that they felt were the most important to consider because they comprise a large proportion of the diets that inflammatory bowel disease patients may follow. Furthermore, the recent International Organization of Inflammatory Bowel Diseases guidelines are an excellent starting point for discussions between patients and their doctors about whether specific dietary changes might be helpful in reducing symptoms and risk of relapse of inflammatory bowel disease. However, all patients with inflammatory bowel disease (IBD) should work with their doctor or a nutritionist, who will conduct a nutritional assessment to check for malnutrition and provide advice to correct deficiencies if they are present.

The International Organization of Inflammatory Bowel Diseases recommendations were developed with the aim of reducing symptoms and inflammation ¹³⁰. The ways in which altering the intake of particular foods may trigger or reduce inflammation are quite diverse, and the mechanisms are better understood for certain foods than others. For example, fruits and vegetables are generally higher in fiber, which is fermented by bacterial enzymes within the colon. This fermentation produces short-chain fatty acids (SCFAs) that provide beneficial effects to the cells lining the colon. Patients with active IBD have been observed to have decreased short-chain fatty acids, so increasing the intake of plant-based fiber may work, in part, by boosting the production of short-chain fatty acids. However, it is important to note disease-specific considerations that might be relevant to your particular situation. For example, about one-third of Crohn’s disease patients will develop an area of intestinal narrowing, called a stricture, within the first 10 years of diagnosis. Insoluble fiber can worsen symptoms and, in some cases, lead to intestinal blockage if a stricture is present. So, while increasing consumption of fruits and vegetable is generally beneficial for Crohn’s disease, patients with a stricture should limit their intake of insoluble fiber.

Table 3. The International Organization of Inflammatory Bowel Diseases guidelines

Food	If you have Crohn’s disease	If you have ulcerative colitis
Fruits	increase intake	insufficient evidence
Vegetables	increase intake	insufficient evidence
Red/processed meat	insufficient evidence	decrease intake
Unpasteurized dairy products	best to avoid	best to avoid
Dietary fat	decrease intake of saturated fats and avoid trans fats	decrease consumption of myristic acid (palm, coconut, dairy fat), avoid trans fats, and increase intake of omega-3 (from marine fish but not dietary supplements)
Food additives	decrease intake of maltodextrin-containing foods	decrease intake of maltodextrin-containing foods
Thickeners	decrease intake of carboxymethylcellulose	decrease intake of carboxymethylcellulose
Carrageenan (a thickener extracted from seaweed)	decrease intake	decrease intake
Titanium dioxide (a food colorant and preservative)	decrease intake	decrease intake
Sulfites (flavor enhancer and preservative)	decrease intake	decrease intake

[Source ¹³⁰ ]

What are specific diets for inflammatory bowel disease?

A number of specific diets have been explored for inflammatory bowel disease (IBD), including the Mediterranean diet, specific carbohydrate diet, Crohn’s disease exclusion diet, autoimmune protocol diet, and a diet low in fermentable oligo-, di-, monosaccharides, and polyols (FODMAPs). Although the International Organization of Inflammatory Bowel Diseases group initially set out to evaluate some of these diets, they did not find enough high-quality trials that specifically studied them ¹³⁰. Therefore, they limited their recommendations to individual dietary components. Stronger recommendations may be possible once additional trials of these dietary patterns become available. For the time being, patients are to monitor for correlations of specific foods to their symptoms. In some cases, patients may explore some of these specific diets to see if they help.

Summary

There is scientific evidence that dietary factors may influence both the risk of developing inflammatory bowel disease and intestinal mucosal inflammation. However, there is lack of  large prospective controlled trials to provide the dietary recommendations patients’ desire. Taken together, studies of exclusive enteral nutrition, exclusion diets, and semi-vegetarian diets suggest that minimizing exposure of the intestinal lumen to selected food items may prolong the remission state of patients with inflammatory bowel disease ¹³¹. Even less evidence exists for the efficacy of the specific carbohydrate diet, FODMAP, or Paleo diet. Furthermore, the practicality of maintaining these interventions over long periods of time is doubtful. Patient-targeted dietary recommendations focus on food restrictions and are highly conflicting. High quality dietary intervention studies are needed to facilitate creation of evidence-based dietary guidelines for patients with inflammatory bowel disease. At a practical level, adherence to defined diets may result in an unnecessary financial burden or reduction in overall caloric intake in patients who are already at risk for protein-calorie malnutrition.

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