ETIOLOGY AND THE DISEASE PROCESS

Crohn’s disease (CD) belongs to the group of inflammatory bowel diseases (IBDs), a generic term for disorders characterized by inflammation in the small and large bowels. Other IBDs are ulcerative colitis (UC) and indeterminate colitis (lymphocytic and collagenous colitis).

Crohn’s disease affecting the colon is associated with a higher risk of developing colorectal cancer.

There are many theories about the etiology of Crohn’s disease, but the exact cause is unknown. Crohn’s disease is known to run in families and be more common in certain ethnicities, suggesting a genetic predisposition. First-degree relatives have a 13 to 18 percent increase in incidence, and there are concordance rates of 50 percent in identical twins. However, no specific reason or factor consistently explains the origin of the disease. All available evidence links Crohn’s disease to abnormally regulated inflammatory processes. The human immune system protects people from harmful foreign substances (antigens) in the environment, such as bacteria, viruses, and parasites. This protection is provided by cells and various proteins (such as antibodies) through an inflammatory reaction that responds to antigens or cell injuries. In Crohn’s disease, the immune system reacts abnormally against the affected part of the gastrointestinal (GI) tract and damages it. This inappropriate inflammation leads to the clinical manifestations of Crohn’s disease.

Studies have shown that the inflammation related to Crohn’s disease is multifactorial and may depend on genetic factors, immune reactions, and environmental cues. Mutations in one gene found on chromosome 16, NOD2/CARD15, are more common in Crohn’s disease patients than in general. The NOD2 protein binds to intracellular bacterial cell wall components and activates the transcription factor NF-κB (nuclear factor-kappaB). NF-κB activates the expression of a host of inflammation-associated genes. The GI cells of patients with Crohn’s disease show increased NF-κB activation. NOD might prevent excessive immune activation and combat microbes in the Gi tract. Mutations in the NOD gene cause the synthesis of a NOD protein that seems to have trouble responding modestly against GI tract bacteria. This defect somehow causes the immune system to turn against its GI microbes and vigorously attack them, injuring the GI tissues. Other genes associated with susceptibility to Crohn’s disease are ATG16L1 (autophagy-related 16-like), IRGM (immunity-related GTPase M), and IL23R (interleukin-23 receptor). Both ATG16L1 and IRGM are involved in autophagy, a process by which the cell recycles its internal components. Autophagy might also affect the clearance of intracellular bacteria. IL23R encodes a regulatory cytokine receptor that helps initiate the innate and adaptive immune activation in the intestines.

Tumor necrosis factor-alpha (TNF-alpha) is a protein produced by specific white blood cells called “macrophages.” TNF is involved in various biological processes. It enhances the ability of white blood cells to defend against infections and other foreign substances. TNF is implicated in many diseases, including autoimmune diseases such as Crohn’s disease. TNF may cause the inflammation associated with Crohn’s disease. Crohn’s disease patients have abnormally elevated TNF levels, causing excessive inflammation with its related adverse effects.

IBDs (Crohn’s disease and ulcerative colitis) have similar symptoms but differ significantly. Crohn’s disease can affect any part of the GI tract, cause inflammation deeply penetrating through the tract linings (full thickness), and show radiographic results suggestive of Crohn’s disease. Ulcerative colitis affects the colon and rectum; it can also cause a “backwash” ileitis in the junction of the small and large intestines. Ulcerative colitis inflammation affects the superficial linings of the affected colon, confined to a part of or all the colon. The latter part of the colon (the rectum) is usually the most affected. Tissue sampling can identify the difference between Crohn’s disease and ulcerative colitis.

RISK FACTORS

Those with a family history of Crohn’s disease, a genetic predisposition, or a smoking history are at the highest risk for this disease. Appendectomies, which decrease susceptibility to ulcerative colitis, do not affect susceptibility to Crohn’s disease.

Crohn’s disease can cause inflammation and ulceration within any region of the digestive tract, but most often in the ileum.

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INCIDENCE

Crohn’s disease affects approximately one in 300 adults in Europe and North America. In North America, the incidence of Crohn’s disease is 3.1 to 20.2 cases per 100,000 person-years. Based on health insurance claims for 9 million Americans in 2007, the prevalence of Crohn’s disease in children younger than 20 years was 43 per 100,000 and in adults was 201 per 100,000. About 20 percent of Crohn’s disease cases run in families. Men and women are affected equally, but with slight female predominance in late adolescence and early adulthood. Crohn’s disease is more common in people of European and Jewish heritage than those of other ethnicities. The onset of Crohn’s disease has two peaks: between the ages of fifteen and thirty and sixty and eighty. However, most patients are diagnosed before the age of thirty.

SYMPTOMS

There are many manifestations of Crohn’s disease, including symptoms within the GI tract and outside of it (extraintestinal). Constitutional symptoms of Crohn’s disease are fatigue, fever, loss of appetite, and weight loss. The most common GI tract symptoms are prolonged diarrhea, with or without rectal bleeding, and abdominal pain (tenderness), typically in the lower right area. Sometimes the abdominal pain caused by Crohn’s disease can mimic appendicitis pain. Malabsorption in the GI tract can lead to malnutrition and weight loss, related to delayed development and poor growth in children. Mouth ulcers may manifest along with pain in the mouth and gums. Problems of the throat, such as pain or difficulty with swallowing, can occur if the esophagus is involved.

Patients with Crohn’s disease may develop perianal conditions such as “fissure-in-ano” or anal fissures (fissures or tears in the lining of the anus) and “fistula-in-ano” (an abnormal connection between the anal intestinal lining and another part of the body, such as the skin, bladder, vagina, or another part of the GI tract). Fistulas are most common in the anal region; abscesses (pockets of pus) may be present as a complication. Blockage (obstruction) and perforation of the GI tract may occur. Extraintestinal symptoms include eye disorders, skin problems, arthritis, and liver and gallbladder diseases.

Comparison of Cr ohn’s Disease and colitis ulcerosa.

Image via Wikimedia Commons. [Public domain.]

SCREENING AND DIAGNOSIS

Screening begins with comprehensive patient history and physical examination. Blood tests include a complete blood count for anemia and assessing markers of inflammation such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) for inflammation. A stool test will assess GI tract bleeding, infection, or inflammation (calprotectin fecal test). Special tests for antibodies, such as antineutrophil cytoplasmic antibodies and anti-Saccharomyces cerevisiae antibodies, may be used in the diagnosis of Crohn’s disease is uncertain. Radiographic studies can include the upper and lower GI series (barium enema). Upper or lower GI endoscopy can identify the affected site, allow tissue sampling (biopsy), and confirm the diagnosis of Crohn’s disease. Examples of GI endoscopies that use flexible tubes with a light and a camera at the ends for visualization include upper GI endoscopy (for the mouth, esophagus, stomach, and upper part of the small bowel), enteroscopy (for the small bowel), Ileocolonoscopy (for the lower small bowel and large bowel), colonoscopy (for the large bowel) and capsule endoscopy (which uses a pill-like camera for the whole intestine but mainly for the small bowel visualization). The severity of Crohn’s disease is diverse, and its activity is described as mild-moderate, moderate-severe, severe-fulminant, and in remission.

TREATMENT AND THERAPY

Crohn’s disease has no cure; however, various medications can alleviate its symptoms. Management of Crohn’s disease and its complications may include medications for treating symptoms such as antidiarrheal agents (loperamide and diphenoxylate), nutritional support, surgery, or a combination of these modalities.

Medications for Crohn’s disease include antibiotics such as ciprofloxacin and metronidazole; anti-inflammatory drugs such as corticosteroids, sulfasalazine, and 5-ASA or 5-aminosalicylate (which, though effective in ulcerative colitis, have uncertain benefits in Crohn’s disease), immunomodulators that inhibit the immune response such as azathioprine, 6-mercaptopurine, and methotrexate; and biologic therapies such as infliximab (Remicade), adalimumab (Humira) certolizumab pegol (Cimzia), and golimumab (Simponi), which are monoclonal antibodies that block tumor necrosis factor (TNF)-alpha activity.

A class of biologic therapies called “anti-integrin antibodies,” such as natalizumab (Tysabri) and vedolizumab (Entyvio), are also effective. Gastro- enterologists prescribe these medications when all others are poorly tolerated or fail to provide a satisfactory response. Natalizumab and vedolizumab are “a₄ integrin” inhibitors. Integrins are prominent cell adhesion molecules, and all leukocytes, except neutrophils, express a₄ß₁ integrins on their surfaces. Leukocytes use the a₄ß₁ integrin to bind to blood vessels and squeeze through them to enter the central nervous system or GI tract. Natalizumab, also used to treat multiple sclerosis, inhibits white blood cell migration across the bloodstream into the GI tract, thereby staunching inflammation in the GI tract. Vedolizumab binds to a different integrin, a₄ß₇, which blocks leukocyte migration into the GI tract but not the central nervous system.

Another biologic therapy that effectively treats Crohn’s disease is ustekinumab (Stelara). This monoclonal antibody specifically targets the p40 subunit of interleukin-12 and -23, effectively inhibiting IL-12 and -23. IL-12 and IL-23 support inflammation and immune responses. Ustekinumab is Food and Drug Administration (FDA)-approved for patients with moderately to severely active Crohn’s disease after failure with other medications. A recent study using an early treatment of combined immunosuppression (immunomodulator + antibody to TNF) showed improved clinical outcomes (decreased need for surgery or hospital admissions and decreased Crohn’s disease-related complications). These medications may have side effects ranging from nausea, vomiting, and headaches to infection susceptibility and more serious potential outcomes. The risks and benefits of medicines are assessed, and modifications are implemented individually.

PROGNOSIS, PREVENTION, AND OUTCOMES

Crohn’s disease is a chronic medical condition. It can manifest in recurrent episodes of the active disease (flares) or remain in remission. Patients with Crohn’s disease are monitored closely for related conditions such as associated cancers. Regular cancer screening using colonoscopy is recommended for patients with colonic Crohn’s disease ten years after its diagnosis because of its association with colorectal cancer. Patients on biological treatments must undergo regular screening for tuberculosis and cancer, as biologics can increase the patient’s susceptibility to both diseases.

Stem cell therapies may revolutionize the treatment of fistulas. Adipose-derived mesenchymal stem cells (ADSCs) quell inflammation in the fistulas and facilitate tissue healing, often with minimal scarring. While such treatments are not yet part of standard care protocols, they show remarkable efficacy in animal and clinical trials.