Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) describes a range of idiopathic, chronic inflammatory diseases of the gastrointestinal (GI) tract. Patients with IBD are usually cared for 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, most commonly the terminal ileum and colon; classically, the mucosa of the bowel is cobblestoned in appearance. CD is a transmural disease involving the entire wall of the bowel, but it is also typically asymmetrical and segmental, often described as skip lesions in reference to its noncontiguous nature. 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 contiguously to involve the entire colon (pancolitis). Rectal bleeding and diarrhea are typical presenting symptoms. Histologically, UC is a mucosal disease rather than having the transmural nature of CD.

• Indeterminate colitis includes features of both UC and CD and accounts for up to 15% of all cases of IBD.

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, tenesmus, incontinence, or fecal urgency. Patients may also present with systemic symptoms (e.g., low-grade fever, reduced appetite, and unintentional weight loss) or symptoms related to complications (e.g., bowel obstruction from strictures). Lastly, a number of extraintestinal manifestations (EIMs) are associated with IBD.

• 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), between the intestine and abdominal wall (enterocutaneous), or between the intestine and the area around the anus and buttocks (perianal). Other complications include strictures and abscesses.

• 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 distinction between the two is made using a combination of clinical, endoscopic, imaging, and histologic findings. The following table summarizes the key clinical differences:

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 glucocorticoids.

  • 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.

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.

(Source: Pyoderma Gangrenosum in Ulcerative Colitis. N Engl J Med 2018.)

(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) are typically raised during active disease.

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

  • Stool examination: Fecal calprotectin is a neutrophil-derived protein biomarker that is a highly sensitive, noninvasive marker of intestinal inflammation. If negative, fecal calprotectin may assist in precluding the need for further invasive investigation such as colonoscopy

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

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

  • 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.

  • Upper endoscopy is recommended in patients with CD and upper GI symptoms.

  • Ileocolonoscopy is recommended for all patients with suspected IBD.

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)

Severe IBD flares: Patients with severe IBD flares are often hospitalized. The following are general principles for evaluation and management of such patients:

• Provide supportive care with fluids and pain management as needed.

• Initial laboratory testing should include evaluation of anemia and kidney function, albumin, and CRP.

• In patients with CD and suspected intra-abdominal abscesses or fistulizing disease, abdominal imaging (e.g., MR enterography, CT enterography, or ultrasound) is necessary to determine the extent of disease.

  • Abdominal imaging can also be used to determine the extent of colitis and other complications (e.g., fibrostenosis).

• In patients with acute severe UC, infectious colitis (especially if caused by C. difficile) should be excluded with stool testing. Infectious colitis can mimic a flare or overlap with a flare.

• Endoscopic assessment can examine disease activity and enables biopsies that are needed to exclude active cytomegalovirus (CMV) infection in patients on immunosuppressive agents for IBD.

• Venous thromboembolism (VTE) prophylaxis should be administered; an IBD flare is an independent risk factor for VTE.

• Intravenous (IV) glucocorticoids are often used as first-line therapy in acute, severe flares to rapidly improve symptoms and allow bridging to biologic therapy.

  • Response to glucocorticoids should be assessed after 3-5 days of therapy (e.g., decline in CRP).

  • Patients who do not have a response to glucocorticoids should be considered for biologics as “rescue” therapies or surgical intervention. Surgery must always be considered in patients who do not respond to glucocorticoids, especially those with acute, severe UC.

• Multidisciplinary care involving surgery is often needed for patients with worsening CD who present with fistulizing disease, intraabdominal abscesses, or fibrostenosis.

Treatment

Treatment of IBD includes aminosalicylates to reduce inflammation, immunosuppressive medications, biologic agents, and surgery.

IBD treatment has two phases:

• induction of remission/treatment of flare

• maintenance of disease remission

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 UC 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 the 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.

Surgery:

• Crohn disease: Approximately 50% of patients with CD will require surgery 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

• The goal of treatment is sustained remission. Monitoring for remission involves continued evaluation of not only symptoms but also biomarkers (CRP, fecal calprotectin).

• Colonoscopy or sigmoidoscopy are also utilized on occasion to assess for disease activity if symptoms, biomarkers, or both begin to suggest that a patient may no longer be in sustained remission.

• Careful monitoring for complications is another component of disease management. IBD can be associated with a range of complications, including colon cancer and increased risk of infection. 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, IV hydration, nasogastric tube decompression, and treatment of bowel inflammation.

  • Perianal disease:

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

  • Fistulas:

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

    • Fistulas can also involve segments of intestine or occur 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.

(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, 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

      Criteria	Acute Severe Colitis
      Bloody stools per day	>6
      Pulse	>90 beats/minute
      Temperature	>37.8°C (100°F)
      Hemoglobin	<10.5 g/dL
      Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP)	>30 mm/hr >30 mg/dL

    • Management involves IV glucocorticoids and reassessment at day 3.

    • Patients who do not have a response to treatment require rescue therapy (biologics; infliximab, cyclosporine, tofacitinib) 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.

  • Malnutrition: 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 five to nine 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 who are at risk for CRC:

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