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Gastroenterology - Inflammatory Bowel Disease - Fast Facts | NEJM Resident 360

Inflammatory bowel disease (IBD) describes a range of idiopathic, chronic inflammatory diseases of the gastrointestinal (GI) tract. Patients with IBD are usually managed as outpatients but can present with severe disease and complications. Although the etiology of IBD is unknown, it is likely a combination of genetic, immunologic, and environmental factors. In this section, we review the three primary subtypes of IBD:

• Crohn disease (CD) involves any part of the GI tract; classically, the mucosa of the bowel is “cobblestoned” in appearance. CD is a transmural disease involving the entire wall of the bowel. Histologically, granulomas may occur but are not required to make the diagnosis. Perianal disease is also common in CD.

• Ulcerative colitis (UC) involves only the colon (large bowel); UC may start in the rectum as proctitis and spread proximally to involve the entire colon (pancolitis). Rectal bleeding and diarrhea are typical presenting symptoms. Histologically, UC is a mucosal disease.

• Indeterminate colitis includes features of both UC and CD (up to 15% of all cases).

Clinical Features

Clinical features of IBD depend on the areas of the GI tract that are affected, the extent of disease, and the severity of the inflammatory process. However, most patients with IBD present with abdominal pain and diarrhea, with or without blood. Patients with proctitis may report constipation and tenesmus. Patients may also present with systemic symptoms (e.g., low-grade fever, reduced appetite, and unintentional weight loss).

• Crohn disease: Patients with CD may also present with GI fistulas, characterized by abnormal tracts between adjacent loops of bowel (enteroenteric fistula), between intestine and bladder (enterovesical), the intestine and abdominal wall (enterocutaneous), or the intestine and the area around the anus and buttocks (perianal).

• Ulcerative colitis: A small proportion of patients with UC present with catastrophic manifestations such as toxic megacolon (transverse or right colon diameter >6 cm) or catastrophic hemorrhage.

Differentiating between CD and UC has important clinical implications, particularly with regards to treatment and follow-up. The following table summarizes the key clinical differences:

Key Clinical Differences Between Crohn Disease and Ulcerative Colitis

Clinical Feature	Crohn Disease	Ulcerative Colitis
Bright blood in stool	Sometimes	Yes
Mucus	Sometimes	Yes
Systemic symptoms	Frequently	Sometimes
Pain	Frequently	Sometimes
Abdominal mass	Sometimes	Rarely
Perianal disease	Yes	No
Fistulas	Yes	No
Small-bowel obstruction	Yes	No

Extraintestinal manifestations (EIMs) associated with IBD:

• Eyes:

  • Episcleritis is more common in CD and usually does not require specific treatment other than that for IBD.

  • Scleritis can cause visual impairment and requires disease-specific treatment and topical steroids.

  • Uveitis is less common than episcleritis and requires prompt treatment with topical and systemic glucocorticoids to prevent blindness.

• Mouth:

  • aphthous ulcers

  • gingivitis

• Joints: Seronegative peripheral and axial arthropathies. Arthritis in IBD has been classified into two types:

• • type 1: pauciarticular (affects less than five joints and often involves large joints)

  • type 2: polyarticular (usually affects at least five small joints)

• Skin:

  • Pyoderma gangrenosum is characterized by deep ulcers that involve the low anterior leg and occasionally the arm. It affects 5% of UC cases and 1% of CD cases and is more likely to develop in patients with severe disease and colonic involvement. The condition may resolve with IBD treatment, but surgical debridement may be required in severe cases.

  • Erythema nodosum is characterized by tender, red nodules on the legs and occasionally arms. Although it can affect patients with UC and CD, it is more prevalent in females and patients with CD.

View an interactive summary of EIM of IBD.

Certain EIMs (e.g., pauciarticular arthritis, oral aphthous ulcers, erythema nodosum, and episcleritis) are more prevalent in patients with increased intestinal disease activity and improve with IBD treatment. However, the course of other EIMs (e.g., ankylosing spondylitis and uveitis) is independent of IBD disease activity.

Pyoderma Gangrenosum in Ulcerative Colitis

Pyoderma gangrenosum involving the left leg. (Source: Pyoderma Gangrenosum in Ulcerative Colitis. N Engl J Med 2018.)

Aphthous Ulcers of the Palate and Uvula and Tongue

Aphthous ulcers (arrows) of the palate and uvula (U) and tongue (T). SP denotes soft palate. (Source: Manifestations of Crohn’s Disease – Extraintestinal Manifestations of Crohn’s Disease. N Engl J Med 1994.)

Workup

Diagnosis of IBD relies on the integration of history and clinical findings with investigational findings that include histopathology.

• General laboratory investigations:

  • Albumin is usually reduced, and inflammatory markers such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are typically raised during active disease.

  • If negative, fecal calprotectin may assist in precluding the need for further invasive investigation such as colonoscopy. 

• • Complete blood examination and iron studies may demonstrate anemia related to either iron deficiency or chronic disease and raised white cell count indicative of inflammation.

  • Stool examination: Fecal calprotectin is a neutrophil-derived protein biomarker that is a highly sensitive, noninvasive marker of intestinal inflammation.

  • Stool microscopy and culture evaluates for parasitic, viral, bacterial, and Clostridiodes difficile infection.

• Imaging: Magnetic resonance (MR) enterography or intestinal ultrasound (popular in Europe) can be used to assess for strictures and fistulae.

• • MR enterography is recommended for all patients with new diagnosis of CD and required for monitoring if small-bowel disease is present.

• Mucosal biopsy obtained during colonoscopy or upper endoscopy confirms the diagnosis in most cases of IBD if the duodenum is involved with CD.

Management

IBD is a chronic disease that can have potentially devastating consequences for the patient and requires lifelong treatment. At each stage of disease, management requires careful consideration and tailoring to the individual patient. Broadly speaking, goals of treatment include:

• treating acute disease to reduce symptoms and preventing recurrences and complications

• optimizing patient quality of life and correcting nutritional deficiencies

• identifying patients who require early intensification of therapy due to risk of severe disease (e.g., age <40 years, more-extensive disease)

Treatment

Treatment of IBD includes aminosalicylates to reduce inflammation, immunosuppressive medications, biologic agents, and surgery. IBD treatment has two phases:

1. induction of remission/treatment of flare
2. maintenance treatment

Induction of remission/treatment of flare:

• Crohn disease: Therapy involves a combination of glucocorticoids and immunosuppressive agents, with or without biologics.

• Ulcerative colitis: First-line induction therapy for mild-to-moderate disease is aminosalicylates (5-aminosalicylic acid [5-ASA], mesalamine, sulfasalazine). Topical aminosalicylic acid (ASA) is used primarily for proctitis or left-sided colitis. Short-term glucocorticoids and immunomodulators (e.g., thiopurines) are used for induction of more-severe disease. Biologic agents may also be used for more-severe disease.

Maintenance of disease remission:

• Remission can be achieved with a combination of immunomodulators and biologics.

• Avoid long-term glucocorticoid therapy due to high risk of complications.

Biologic therapy:

• In the past three decades, biologic therapy has become a mainstay of treatment in high-risk patients with severe disease that is unresponsive to mesalamine or immunosuppressive drugs.

• A number of biologic agents are available, and patients are typically maintained on a combination of biologic and immunomodulators for at least 12 to 18 months.

• Due to the immunosuppressive effects of biologics, all patients need to be screened for latent tuberculosis (chest x-ray and interferon-gamma release assay) and hepatitis B status (hepatitis B surface antigen, hepatitis B core antibody, hepatitis B surface antibody) before commencing a biologic agent.

Biologic Agents for IBD

Biologic Agent	Target of Action	Indication
Infliximab	Tumor necrosis factor (TNF) inhibitor	CD and UC
Adalimumab	TNF inhibitor	CD and UC
Vedolizumab	α4β7 integrin inhibitor (prevents lymphocyte migration into intestinal tissue)	CD and UC
Ustekinumab	Interleukin (IL)-12 and IL-23 antibodies	CD
Tofacitinib	Janus kinase (JAK) inhibitor, modulating cytokine signaling	UC (small effect in CD)

Surgery:

• Crohn disease: Approximately 50% of patients will need an operation to relieve a bowel obstruction or to treat fistulizing disease within the first 10 years of diagnosis. Surgery is not curative in CD; recurrence of symptoms and bowel inflammation is common within several years.

• Ulcerative colitis: Total colectomy is required in 15%–20% of patients. Surgery is curative in UC.

Monitoring:

IBD can be associated with a range of complications, including colon cancer and increased risk of infection. As part of disease management, careful monitoring for complications is needed. Colonoscopies should be performed every 1 to 2 years to evaluate for signs of colon dysplasia, a precursor of colorectal cancer.

Complications of IBD

• Crohn disease:

  • Small-bowel obstruction (SBO):

    • SBO often results from strictures due to inflammation or adhesions from prior surgery, rarely from lymphoma.

    • Conservative management of SBO includes bowel rest, intravenous hydration, nasogastric tube decompression, and treatment of bowel inflammation.

  • Perianal disease:

    • Treatment includes antibiotics, systemic treatment of CD, and surgery to drain abscess or open fistula.

  • Fistulas:

    • Enterocutaneous fistulas (bowel-to-skin) may involve the abdominal wall or gluteal area.

    • Fistulas can also involve segments of intestine or between the bowel and urinary bladder, ureters, or vagina.

    • Management requires aggressive therapy for CD, usually with antibiotics.

    • Surgery may be required for chronic, nonhealing fistulas to divert the fecal stream and allow the intestine to heal and fistulas to close.

  • Intra-abdominal abscess:

    • These are often related to small, walled-off perforations or fistulizing CD.

    • Management involves antibiotics, interventional radiology–guided drainage, and stepped-up treatment of CD. Refractory cases may require surgery.

Intra-abdominal Abscess

A large abdominal-wall abscess with enterocutaneous fistulas (straight arrow)
(Source: Fistulizing Crohn’s Disease. N Engl J Med 2002.)

• Ulcerative colitis**:**

  • Toxic megacolon (rare):

    • Dilated colon can be seen on plain abdominal film or CT scan.

    • Treatment involves surgical consultation, nasogastric suction, intravenous (IV) antibiotics, fluid hydration, and anti-inflammatory drugs to reduce bowel inflammation.

    • If patients deteriorate or do not improve with conservative management, total colectomy is warranted to prevent perforation.

  • Acute severe colitis:

    • The severity of UC can be classified based on the Truelove and Witts criteria

Modified Truelove and Witts Criteria for Classification of Acute Severe Colitis

	Acute severe colitis
Bloody stools per day	>6
Pulse	>90 beats/minute
Temperature	>37.8 °C (100°F)
Hemoglobin	<10.5 gm/dL
Erythrocyte sedimentation rate (ESR)
or
C-reactive protein (CRP)	>30 mm/hour

30 mg/dL |

• • Management involves IV glucocorticoids and reassessment at day 3.

  • Patients who do not respond to treatment require rescue therapy (biologic) or colectomy.

• Primary sclerosing cholangitis (PSC):

• • PSC affects approximately 5% of patients with UC and is more common in males; typical findings include extensive colitis, rectal sparing, and backwash ileitis.

  • Patients are often positive for antineutrophil cytoplasmic antibodies with cytoplasmic staining (c-ANCA).

  • PSC increases the risk for both colorectal cancer and cholangiocarcinoma.

  • The natural course of PSC is independent of IBD.

  • Treatment is discussed in the section on biliary disease.

• Other complications of IBD:

• • Venous thromboembolism: Patients with IBD are at increased risk of deep-vein thrombosis and pulmonary embolism. All patients with IBD flares require chemoprophylaxis with subcutaneous or low-molecular-weight heparin.

  • Patients are at risk for malnutrition with nutritional deficiencies that can result in osteoporosis and peripheral neuropathy.

  • B-cell lymphomas have been independently associated with use of thiopurine and TNF inhibitors.

  • Colorectal cancer (CRC): Patients with long-standing colitis from CD or UC have 5 to 9 times higher risk of CRC than the general population and therefore require surveillance.

    • The American Gastroenterological Association (AGA) and European Crohn’s and Colitis Organisation (ECCO) recommend the following screening protocol for patients with IBD at risk of CRC:

Suggested Algorithm for Colorectal Cancer Surveillance in Inflammatory Bowel Disease

(Source: Cancers Complicating Inflammatory Bowel Disease. N Engl J Med 2015.)

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