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Overview of Inflammatory Bowel Disease
Inflammatory bowel disease (IBD), which includes Crohn disease and ulcerative colitis (UC), is a relapsing and remitting condition characterized by chronic inflammation at various sites in the GI tract, which results in diarrhea and abdominal pain.
Inflammation results from a cell-mediated immune response in the GI mucosa. The precise etiology is unknown, but evidence suggests that the normal intestinal flora trigger an abnormal immune reaction in patients with a multifactorial genetic predisposition (perhaps involving abnormal epithelial barriers and mucosal immune defenses). No specific environmental, dietary, or infectious causes have been identified. The immune reaction involves the release of inflammatory mediators, including cytokines, interleukins, and TNF.
Although Crohn disease and UC are similar, they can be distinguished in most cases (see Differentiating Crohn Disease and Ulcerative Colitis). About 10% of colitis cases are considered indeterminate. The term colitis applies only to inflammatory disease of the colon (eg, ulcerative, granulomatous, ischemic, radiation-induced, infectious). Spastic (mucous) colitis is a misnomer sometimes applied to a functional disorder, irritable bowel syndrome (see Irritable Bowel Syndrome (IBS)).
Differentiating Crohn Disease and Ulcerative Colitis
IBD affects people of all ages but usually begins before age 30, with peak incidence from 14 to 24. IBD may have a second smaller peak between ages 50 and 70; however, this later peak may include some cases of ischemic colitis.
IBD is most common among people of Northern European and Anglo-Saxon origin and is 2 to 4 times more common among Ashkenazi Jews than non-Jewish whites. The incidence is lower in central and southern Europe and lower still in South America, Asia, and Africa. However, the incidence is increasing among blacks and Latin Americans living in North America. Both sexes are equally affected. First-degree relatives of patients with IBD have a 4- to 20-fold increased risk; their absolute risk may be as high as 7%. Familial tendency is much higher in Crohn disease than in UC. Several gene mutations conferring a higher risk of Crohn disease (and some possibly related to UC) have been identified.
Cigarette smoking seems to contribute to development or exacerbation of Crohn disease but decreases risk of UC. Appendectomy done to treat appendicitis also appears to lower the risk of UC. NSAIDs may exacerbate IBD. Oral contraceptives may increase the risk of Crohn disease, and isotretinoin may increase the risk of UC. Some data suggest that perinatal illness and the use of antibiotics in childhood may be associated with an increased risk of IBD.
Crohn disease and UC both affect organs other than the intestines. Most extraintestinal manifestations are more common in UC and Crohn colitis than in Crohn disease limited to the small bowel. Extraintestinal manifestations are categorized in 3 ways:
1. Disorders that usually parallel (ie, wax and wane with) IBD flare-ups: These disorders include peripheral arthritis, episcleritis, aphthous stomatitis, erythema nodosum, and pyoderma gangrenosum. Arthritis tends to involve large joints and be migratory and transient. One or more of these parallel disorders develops in more than one third of patients hospitalized with IBD.
2. Disorders that are clearly associated with IBD but appear independently of IBD activity: These disorders include ankylosing spondylitis, sacroiliitis, uveitis, and primary sclerosing cholangitis. Ankylosing spondylitis occurs more commonly in IBD patients with the HLA-B27 antigen. Most patients with spinal or sacroiliac involvement have evidence of uveitis and vice versa. Primary sclerosing cholangitis, which is a risk factor for cancer of the biliary tract, is strongly associated with UC or Crohn colitis. Cholangitis may appear before or concurrently with the bowel disease or even 20 yr after colectomy. Liver disease (eg, fatty liver, autoimmune hepatitis, pericholangitis, cirrhosis) occurs in 3 to 5% of patients, although minor abnormalities in liver function tests are more common. Some of these conditions (eg, primary sclerosing cholangitis) may precede IBD by many years and, when diagnosed, should prompt an evaluation for IBD.
3. Disorders that are consequences of disrupted bowel physiology: These disorders occur mainly in severe Crohn disease of the small bowel. Malabsorption may result from extensive ileal resection and cause deficiencies of fat-soluble vitamins, vitamin B 12 , or minerals, resulting in anemia, hypocalcemia, hypomagnesemia, clotting disorders, and bone demineralization. In children, malabsorption retards growth and development. Other disorders include kidney stones from excessive dietary oxalate absorption, hydroureter and hydronephrosis from ureteral compression by the intestinal inflammatory process, gallstones from impaired ileal reabsorption of bile salts, and amyloidosis secondary to long-standing inflammatory and suppurative disease.
Thromboembolic disease may occur as a result of multiple factors in all 3 categories.
Several classes of drugs are helpful for IBD. Details of their selection and use are discussed under each disorder.
5-ASA blocks production of prostaglandins and leukotrienes and has other beneficial effects on the inflammatory cascade. Because 5-ASA is active only intraluminally and is rapidly absorbed by the proximal small bowel, it must be formulated for delayed absorption when given orally. Sulfasalazine, the original agent in this class, delays absorption by complexing 5-ASA with a sulfa moiety, sulfapyridine. The complex is cleaved by bacterial flora in the lower ileum and colon, releasing the 5-ASA. The sulfa moiety, however, causes numerous adverse effects (eg, nausea, dyspepsia, headache), interferes with folate (folic acid) absorption, and occasionally causes serious adverse reactions (eg, hemolytic anemia or agranulocytosis and, rarely, hepatitis or pneumonitis). Reversible decreases in sperm count and motility occur in up to 80% of men. If used, sulfasalazine should be given with food, initially in a low dosage (eg, 0.5 g po bid) and gradually increased over several days to 1 to 2 g bid to tid. Patients should take daily folate supplements (1 mg po) and have CBC and liver tests every 6 to 12 mo. Acute interstitial nephritis secondary to mesalamine occurs rarely; periodic monitoring of renal function is advisable because most cases are reversible if recognized early.
Newer drugs that complex 5-ASA with other vehicles seem almost equally effective but have fewer adverse effects. Olsalazine (a 5-ASA dimer) and balsalazide (5-ASA conjugated to an inactive compound) are cleaved by bacterial azoreductases (as is sulfasalazine). These drugs are activated mainly in the colon and are less effective for proximal small-bowel disease. Olsalazine dosage is 500 to 1500 mg po bid, and balsalazide is 2.25 g po tid. Olsalazine sometimes causes diarrhea, especially in patients with pancolitis. This problem is minimized by gradual escalation of dose and administration with meals.
Other forms of 5-ASA use delayed-release coatings. Asacol (typical dose 800 to 1200 mg po tid) is 5-ASA coated with an acrylic polymer whose pH solubility delays release of the drug until entry into the distal ileum and colon. Pentasa (1 g po qid) is 5-ASA encapsulated in ethylcellulose microgranules that release 35% of the drug in the small bowel. Two once/day formulations of mesalamine (Lialda, Apriso) are available; this less frequent dosing may improve adherence.
5-ASA is also available as a suppository (500 or 1000 mg at bedtime or bid) or enema (4 g at bedtime or bid) for proctitis and left-sided colon disease. These rectal preparations are effective for both acute treatment and long-term maintenance in proctitis and left-sided colon disease and they have incremental benefit in combination with oral 5-ASA.
Corticosteroids are useful for acute flare-ups of most forms of IBD when 5-ASA compounds are inadequate. However, corticosteroids are not appropriate for maintenance. IV hydrocortisone 300 mg/day or methylprednisolone 60 to 80 mg/day by continuous drip or in divided doses (eg, 30 to 40 mg po bid) is used for severe disease; oral prednisone or prednisolone 40 to 60 mg once/day may be used for moderate disease. Treatment is continued until symptoms remit (usually 7 to 28 days) and then tapered by 5 to 10 mg weekly to 20 mg once/day. Treatment is then further tapered by 2.5 to 5 mg weekly while instituting maintenance therapy with 5-ASA or immunomodulators. Adverse effects of short-term corticosteroids in high doses include hyperglycemia, hypertension, insomnia, hyperactivity, and acute psychotic episodes.
Hydrocortisone enemas or foam may be used for proctitis and left-sided colon disease; as an enema, 100 mg in 60 mL of isotonic solution is given once/day or bid. The enema should be retained in the bowel as long as possible; instillation at night, with the patient lying on the left side with hips elevated, may prolong retention and extend distribution. Treatment, if effective, should be continued daily for about 2 to 4 wk, then every other day for 1 to 2 wk, and then gradually discontinued over 1 to 2 wk.
Budesonide is a corticosteroid with a high (> 90%) first-pass liver metabolism; thus, oral administration may have a significant effect on GI tract disease but minimal adrenal suppression. Oral budesonide has fewer adverse effects than prednisolone but is not as rapidly effective and is typically used for less severe disease. Budesonide may be effective in maintaining remission for 3 to 6 mo but has not yet proved effective for long-term maintenance. Dosage is 9 mg once/day. It is also available outside the US as an enema.
Azathioprine and its metabolite 6-mercaptopurine inhibit T-cell function. They are effective long-term and may diminish corticosteroid requirements and maintain remission for years. These drugs often require 1 to 3 mo to produce clinical benefits, so corticosteroids cannot be withdrawn until at least the 2nd month. Dosage of azathioprine is usually 2.5 to 3.0 mg/kg po once/day and 6-mercaptopurine is 1.5 to 2.5 mg/kg po once/day but varies depending on individual metabolism. Signs of bone marrow suppression must be monitored with regular WBC count (biweekly for 1 mo, then every 1 to 2 mo). Pancreatitis or high fever occurs in about 3 to 5% of patients; either is an absolute contraindication to rechallenge. Hepatotoxicity is rarer and can be screened by blood tests every 6 to 12 mo. Newly available blood tests that measure the activity of one of the enzymes that metabolize azathioprine and 6-mercaptopurine and that directly measure metabolite levels may sometimes be helpful in ensuring safe and effective drug dosages.
Methotrexate 15 to 25 mg po or sc weekly is of benefit to many patients with corticosteroid-refractory or corticosteroid-dependent Crohn disease, even those who have not responded to azathioprine or 6-mercaptopurine. Adverse effects include nausea, vomiting, and asymptomatic liver function test abnormalities. Folate 1 mg po once/day may diminish some of the adverse effects. Women taking methotrexate should be using at least one form of birth control. Additionally, women and perhaps men should stop methotrexate for at least 3 mo before trying to conceive. Monthly CBCs and liver function tests with albumin should be done for the first 3 mo of therapy then every 8 to 12 wk during therapy. Alcohol use, obesity, diabetes, and possibly psoriasis are risk factors for hepatotoxicity. Preferably, patients with these conditions should not be treated with methotrexate. Pretreatment liver biopsies are not recommended; liver biopsies are done if the results of 6 of 12 tests done in a 1-yr period show elevated levels of AST. Myelosuppression, pulmonary toxicity, and nephrotoxicity can also occur with methotrexate therapy.
Cyclosporine, which blocks lymphocyte activation, may benefit patients with severe UC unresponsive to corticosteroids and who may otherwise require colectomy. Its only well-documented use in Crohn disease is for patients with refractory fistulas or pyoderma. Initial dose is 4 mg/kg IV in continuous infusion over 24 h; responders are converted to an oral dose of 6 to 8 mg/kg once/day with early introduction of azathioprine or 6-mercaptopurine. Long-term use (> 6 mo) is contraindicated by multiple adverse effects (eg, renal toxicity, seizures, opportunistic infections, hypertension, neuropathy). Generally, patients are not offered cyclosporine unless there is a reason to avoid the safer curative option of colectomy. If the drug is used, trough blood levels should be kept between 200 to 400 ng/mL and Pneumocystis jirovecii prophylaxis should be considered during the period of concomitant corticosteroid, cyclosporine, and antimetabolite treatment. Tacrolimus, an immunosuppressant also used in transplant patients, seems as effective as cyclosporine.
Infliximab, certolizumab, and adalimumab are antibodies to TNF. These agents are useful in Crohn disease; additionally infliximab and, likely, adalimumab are beneficial in UC for refractory or corticosteroid-dependent disease. Several anti-interleukin antibodies and interleukins may decrease the inflammatory response and are being studied for Crohn disease. An antibody to leukocyte adhesion molecules (natalizumab) has been approved as a 2nd-line agent through a restricted prescribing program for the most refractory cases of Crohn disease; other analogs (eg, vedolizumab, tofacitinib) are also being studied.
Infliximab is given as a single IV infusion of 5 mg/kg over 2 h. It is followed by repeat infusions at wk 2 and 6. Subsequently, it is given every 8 wk. To maintain remission in many if not most patients, the dose needs to be increased or the interval needs to be shortened within a year or so. Adalimumab is given with an initial loading dose of 160 mg sc and then 80 mg sc at wk 2. After that dose, 40 mg sc is given every 2 wk. A third anti-TNF agent, certolizumab, is also approved for use in Crohn disease. Monotherapy with anti-TNF agents is clearly effective for both induction and maintenance of remission, but some studies suggest better results when anti-TNF agents are initiated in combination with a thiopurine (eg, azathioprine). Nevertheless, given the possible increase in adverse effects with combination therapy, treatment recommendations should be individualized. Corticosteroid tapering may begin after 2 wk. Adverse effects during infusion (infusion reaction) include immediate hypersensitivity reactions (eg, rash, itching, sometimes anaphylactoid reactions), fever, chills, headache, and nausea. Delayed hypersensitivity reactions have also occurred. Anti-TNF drugs given subcutaneously (eg, adalimumab) do not cause infusion reactions, although they may cause local erythema, pain, and itching (injection site reaction). Patients who are intolerant or who have lost their initial response to infliximab may respond to adalimumab therapy.
Several patients have died of sepsis after anti-TNF use, so these drugs are contraindicated when uncontrolled bacterial infection is present. Furthermore, TB reactivation has been attributed to these drugs; therefore, screening with PPDs and/or interferon-gamma release assay and chest x-ray is required before its use.
Lymphoma, demyelinating disease, and liver and hematologic toxicity are other potential concerns with anti-TNF antibody treatment. Other anticytokine, anti-integrin, and growth factors are under investigation, as is leukopheresis therapy to deplete activated immunocytes.
Antibiotics may be helpful in Crohn disease but are of limited use in UC. Metronidazole 500 to 750 mg po tid for 4 to 8 wk may control mild Crohn disease and help heal fistulas. However, adverse effects (particularly neurotoxicity) often preclude completion of treatment. Ciprofloxacin 500 to 750 mg po bid may prove less toxic. Many experts recommend metronidazole and ciprofloxacin in combination. Rifaximin, a nonabsorbable antibiotic, at a dose of 200 mg po tid or 800 mg po bid may also be beneficial as treatment for active Crohn disease.
Various nonpathogenic microorganisms (eg, commensal Escherichia coli, Lactobacillus species, Saccharomyces) given daily serve as probiotics and may be effective in preventing pouchitis (see Inflammatory Bowel Disease (IBD):Surgery), but other therapeutic roles have yet to be clearly defined. Therapeutic infestation with the parasite Trichuris suis has been tried in an effort to stimulate T2-helper cell immunity and may decrease disease activity in UC.
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