Inflammatory Bowel Disease

General Principles

  • Ulcerative colitis (UC) is an idiopathic chronic inflammatory disease of the colon and rectum, characterized by continuous mucosal inflammation from the rectum to varying extents proximally.
  • Crohn disease (CD) is characterized by transmural inflammation of the gut wall and can affect any part of the tubular GI tract.

Diagnosis

Clinical Presentation

  • Both disorders can present with diarrhea, weight loss, and abdominal pain. UC typically presents with bloody diarrhea. CD can also present with fistula formation, strictures, abscesses, or bowel obstruction.
  • Extracolonic manifestations of inflammatory bowel disease (IBD) include arthritis, primary sclerosing cholangitis, and ocular and skin lesions.

Diagnostic Testing

  • Endoscopy remains the preferred method for diagnosis. UC is characterized by continuous inflammation from the rectum and extending varying distances into the colon. Endoscopy may demonstrate colonic involvement in CD (erosions or ulcers with a patchy distribution and skip lesions); ileoscopy during colonoscopy may demonstrate terminal ileal involvement. Video capsule endoscopy may help identify small bowel CD. Histopathology demonstrates chronic mucosal inflammation with crypt abscesses and cryptitis in UC. Noncaseating granulomas are classic for CD but are not always seen.
  • Cross-sectional imaging studies (CT and MRI scans) as well as contrast radiography (small bowel follow-through series, barium enema) are useful to evaluate for complications of CD such as strictures, fistulas, and abscesses.
  • Serologic markers play a limited role as adjuncts for diagnosis. Anti-Saccharomyces cerevisiae antibodies are typically seen in CD, and perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) are seen in UC. C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) may be elevated but do not always correlate with disease activity.
  • C. difficile colitis is more frequent in IBD patients compared with non-IBD populations; therefore, stool studies are warranted to look for this organism with disease flares. CMV superinfection can occur in patients on immunosuppressive agents and can be diagnosed by histopathology during endoscopy.

Treatment

Medications

Treatment is based on the severity of disease, location, and associated complications. Management aims are to resolve the acute presentation and reduce future recurrences. Both UC and CD can be categorized into three categories of severity for management purposes.

  • Mild to moderate disease: Patients have little to no weight loss and good functional capacity and are able to maintain adequate oral intake. UC patients have less than four bowel movements daily with no rectal bleeding or anemia, whereas CD patients have little or no abdominal pain. Aminosalicylates (5-ASA) should be used to induce remission in patients with mild to moderate UC (see Table 18-4).1 Patients with left-sided colitis may respond to topical therapies. Patients who achieve remission with 5-ASAs should continue to take them but may be able to use a lower dose. This class of medications has not been consistently shown to be effective in CD.2 Ileal-release budesonide may be required to induce remission in patients with mild-moderate CD.
  • Moderate to severe disease refers to CD patients who fail to respond to treatment for mild to moderate disease or those with significant weight loss, anemia, fever, abdominal pain or tenderness, and intermittent nausea and vomiting without bowel obstruction. In UC, moderate to severe disease manifests with more than six bloody bowel movements daily, fever, mild anemia, and elevated ESR.1 Risk factors for severe CD include age <30 years at initial diagnosis, extensive anatomic involvement, perianal and/or severe rectal disease, deep ulcers, prior surgical resection, and stricturing or penetrating behavior.2 The goal of therapy is to induce remission rapidly with corticosteroids and to maintain remission with immunosuppressive agents and/or biologic agents as appropriate. Treatment is typically continued until the patient fails to respond to a particular agent or the agent is no longer tolerated. Glucocorticoids are often required to induce remission in patients with moderate to severe UC or CD; however, they carry significant side effects and should not be used to maintain remission. Azathioprine, 6-mercaptopurine, or methotrexate can be used to maintain remission but are not effective at inducing remission. Anti–tumor necrosis factor-α (anti–TNF-α) monoclonal antibodies are used to induce and maintain remission. Anti-TNF-α in combination with azathioprine is more effective at inducing remission than anti-TNF-α alone.2 Other biologics are now available for inducing and maintaining remission, including vedolizumab, natalizumab, ustekinumab, and tofacitinib.
  • Severe or fulminant disease patients are typically hospitalized because of the severity of their symptoms. Fulminant CD patients have persistent symptoms despite conventional glucocorticoids or anti–TNF-α therapy or have high fevers, persistent vomiting, intestinal obstruction, intra-abdominal abscess, peritoneal signs, or cachexia. Fulminant colitis (both CD and UC) can present with profuse bloody bowel movements, significant anemia, and systemic signs of toxicity (fever, sepsis, electrolyte disturbances, dehydration). Toxic megacolon occurs in 1%–2% of UC patients, wherein the colon becomes atonic and dilated, with significant systemic toxicity.
    • Supportive therapy consists of NPO status with NG suction if there is evidence of small bowel ileus or obstruction. Dehydration and electrolyte disturbances are treated vigorously. Anticholinergic and opioid medications should be discontinued.
    • Initial investigation includes cross-sectional imaging to evaluate for intra-abdominal abscess. Blood cultures and stool studies to exclude C. difficile colitis should be performed. Cautious flexible sigmoidoscopy with minimal insufflation and only with CO2 may be done to determine severity of colonic inflammation and for biopsies to exclude CMV colitis.
    • Once infection is excluded, intensive medical therapy with IV corticosteroids (methylprednisolone 60 mg/day or hydrocortisone 100 mg three or 4 times per day).
    • Patients who fail to improve with 3–5 days of steroids should be treated with infliximab (5–10 mg/kg).1 Cyclosporine infusion (2–4 mg/kg/d, to achieve blood levels of 200–400 ng/mL) is used in some centers.
    • Early surgical consultation for possible colectomy should be obtained in case medical therapy is unsuccessful.
    • Nutritional support is administered as appropriate after 5–7 days; TPN is often indicated if enteral nutrition is not tolerated.
    • Early surgical consultation should be obtained in case medical therapy is unsuccessful. Clinical deterioration/lack of improvement despite 7–10 days of intensive medical management, evidence of bowel perforation, and peritoneal signs are indications for urgent total colectomy.
    • Patients who respond to infliximab should continue it. Patients who respond to cyclosporine should transition to azathioprine or vedolizumab.1
Table 18-4: Medications for Inflammatory Bowel Disease
MedicationDosingMechanism of ActionComments
5-ASA

Not consistently effective for CD
Sulfasalazine0.5 g bid-1.5 g qidMetabolized to 5-ASA and a sulfapyridine moietySignificant side effects from sulfapyridine moiety; especially effective for IBD arthropathy
MesalamineVaries by brandActive component of sulfasalazineAlso available in suppository or enema for distal UC
Rarely can cause paradoxical worsening of colitis
Asacola800–1600 mg PO tidReleased at a pH of 7 in the distal ileum
Pentasaa0.5–1.0 g PO qidTime- and pH-dependent release mechanism distributes in the small bowel and colon
Aprisoa1.5 g PO qdaypH-dependent release distributes throughout the colon
Lialdaa (multimatrix delivery system)1.2–2.4 g PO qday–bidSustained release throughout the colon despite decreased frequency of administration
Balsalazide (Colazal)1.5 g bid–2.25 tidBacterial cleavage to mesalamine by colonic bacteria
Olsalazine (Dipentum)500 mg bid5-ASA dimer cleaved by colonic bacteria
Antibiotics

Used to treat fistulizing CD and abscesses
Metronidazole250–500 mg PO tid
Risk of neuropathy
Ciprofloxacin500 mg PO bid
Risk of tendon rupture
Corticosteroids
Multiple immunosuppressing effectsShould NOT be used as maintenance therapy. Topical therapy can be used for distal disease
Methylprednisolone60 mg IV qday

Prednisone40–60 mg qday

Budesonide9 mg qdaypH-controlled release delivers drug to ileum and ascending colon (Entocortb)
Multimatrix system preferentially acts on colon (Ucerisb)
Topical formulations can be used for distal disease		May reduce side effects due to first-pass metabolism
Immunomodulators
6-Mercaptopurine1.0–1.5 mg/kg/d POPurine analog, causes preferential suppression of T-cell activation and antigen recognitionChecking thiopurine methyltransferase (TPMT) enzyme activity prior to starting therapy identifies patients at risk for dangerous cytopenias
6-Thioguanine (6-TG) metabolite levels assess adequacy of dosing; high 6-methyl mercaptopurine (6-MMP) levels predict hepatotoxicity
Azathioprine1.5–2.5 mg/kg/d POS-imidazole precursor of 6-MPRisk of hepatosplenic T-cell lymphoma with thiopurines, especially in young men
Methotrexate15–25 mg IM or PO weeklyInhibits DNA synthesisMay cause nausea/vomiting, hepatotoxicity
Biologics
Infliximab (Remicade)5 mg/kg IV infusions at weeks 0, 2, and 6, followed by maintenance infusions every 4–8 weeksMonoclonal antibody against tumor necrosis factor-alpha (anti–TNF-α)Risk of opportunistic infections, reactivation of TB and HBV with all anti–TNF-α agents
Adalimumab (Humira)160 mg SC at week 0, then 80 mg SC at week 2, followed by 40 mg SC every 1–2 weeksAnti–TNF-α
Certolizumab pegol (Cimzia)400 mg SC at weeks 0, 2, and 4, followed by maintenance doses every 4 weeksAnti–TNF-α
Golimumab (Simponi)200 mg SC at week 0, then 100 mg SC at week 2 and every 4 weeks thereafterAnti–TNF-αOnly approved for UC
Vedolizumab (Entyvio)300-mg infusions at weeks 0 and 2, followed by infusions every 4–8 weeksMonoclonal antibody against α4β7 integrin, prevents T cell migration to inflammation. α4β7 is specific to GI tractGood safety profile because of gut specificity
Natalizumab (Tysabri)300-mg infusions at weeks 0, 4, and 8, followed by monthly infusions thereafterMonoclonal antibody to α-4 integrin. In contrast to α4β7, α-4 is found in and outside the GI tractRisk of JC polyomavirus reactivation causing progressive multifocal leukoencephalopathy has limited its use
Ustekinumab (Stelara)Weight-dependent dosing of 260–520-mg infusion at week 1, followed by 90-mg subcutaneous maintenance injections every 8 weeksMonoclonal antibody to the p40 subunit of interleukin-12 and interleukin-23Good safety profile. Also approved for psoriasis, so good option for IBD patients with psoriasis or psoriaform reactions to anti–TNF-α
Tofacitinib (Xeljanz)5 mg or 10 mg oral twice a dayJanus kinase inhibitorRisk of thromboembolic events; use with caution in patients with CV risk factors

5-ASA, 5-aminosalicylates; 6-MP, 6-mercaptopurine; anti–TNF-α, anti–tumor necrosis factor-α; CD, Crohn disease; CV, cardiovascular; GI, gastrointestinal; HBV, hepatitis B virus; IBD, inflammatory bowel disease; UC, ulcerative colitis.

aBrand name formulation of mesalamine.

bBrand name formulation of budesonide.

Surgical Management

  • Surgery in CD is generally reserved for fistulas, obstruction, abscess, perforation, or bleeding; medically refractory disease; and neoplastic transformation. Stricturoplasty is an option for focal tight strictures; biopsies should be obtained to rule out cancer at stricture sites.
  • In CD, recurrence close to the resected margins is common after bowel resection. Efforts should be made to avoid multiple resections in CD because of the risk of short bowel syndrome.
  • In UC, total colectomy is generally curative, though some patients may develop inflammation in the small intestinal pouch created after colectomy.

Lifestyle/Risk Modification

  • CD patients with a stricture should consume a low-roughage diet to avoid precipitating a bowel obstruction.
  • Patients with Crohn ileitis or ileocolonic resection may need vitamin B12 supplementation. Specific oral replacement of calcium, magnesium, folate, iron, vitamins A and D, and other micronutrients may be necessary in patients with small bowel CD.
  • TPN may be necessary food intolerance for greater than 4 or 5 days or to improve nutrition prior to surgery.

Special Considerations

  • Patients with both UC and Crohn colitis longer than 8 years should undergo annual or biennial colonoscopic surveillance for neoplasia, ideally using chromoendoscopy.1
  • Consistent histopathologic evidence of any grade of dysplasia is an indication for total colectomy.
  • Smoking cessation is warranted for all patients with IBD. There is epidemiologic evidence of a protective effect on a limited number of patients with UC, but the overall health risks of smoking outweigh the risks of disease exacerbation.
  • Venous thromboembolism: Patients with IBD are at increased risk for venous thromboembolism and should treated with prophylaxis when admitted to the hospital.1
  • Family planning is important in women with active disease as there is an increased risk of premature delivery, low birth weight, and congenital abnormalities. Active inflammation, rather than biologic medications, increase the risk of complications.3 Thus, biologics should NOT be discontinued.
  • Symptom control is an important adjunct to therapy but must be used cautiously.
    • Antidiarrheal agents may be useful as an adjunctive therapy in selected patients with mild exacerbations or postresection diarrhea. They are contraindicated in severe exacerbations and in toxic megacolon.
    • Narcotics should be used sparingly for pain control.

References

  1. Rubin DT, Ananthakrishnan AN, Siegel CA, et al. ACG clinical guideline: ulcerative colitis in adults. Am J Gastroenterol. 2019;114:384-413.  [PMID:30840605]
  2. Lichtenstein GR, Loftus EV, Isaacs KL, et al. ACG clinical guideline: management of Crohn’s disease in adults. Am J Gastroenterol. 2018;113:481-517.  [PMID:29610508]
  3. Mahadevan U, Long MD, Kane SV, et al. Pregnancy and neonatal outcomes after fetal exposure to biologics and thiopurines among women with inflammatory bowel disease. Gastroenterology. 2021;160:1131-1139.  [PMID:33227283]

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