Inflammatory bowel disease in adults

Inflammatory bowel diseases, including Crohn's disease and ulcerative colitis, are relapsing diseases with periods of remission and are characterized by chronic inflammation of various parts of the gastrointestinal tract, leading to diarrhea and abdominal pain.

Inflammation is the result of a cell-mediated immune response in the gastrointestinal mucosa. The exact etiology is unknown; some studies suggest that normal intestinal flora triggers an immune reaction in patients with a multifactorial genetic predisposition (possibly impaired epithelial barrier 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 tumor necrosis factor (TNF).

Although the symptoms of Crohn's disease and ulcerative colitis are similar, they can be differentiated in most cases. Approximately 10% of colitis cases are considered nonspecific. The term "colitis" applies only to inflammatory diseases of the colon (e.g., ulcerative, granulomatous, ischemic, radiation, infectious). The term "spastic (mucous) colitis" is sometimes used incorrectly, since it refers not to inflammatory but to functional bowel disease.

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Epidemiology of inflammatory bowel diseases

Inflammatory bowel disease affects people of all ages but typically manifests before age 30, with a peak incidence between 14 and 24 years. Ulcerative colitis may have a second but smaller peak incidence between 50 and 70 years; however, this later peak incidence may include some cases of ischemic colitis.

Inflammatory bowel disease in adults is most common in people of Northern European and Anglo-Saxon descent and several times more common in Jews. The incidence of inflammatory bowel disease is lower in central and southern Europe and lower in South America, Asia, and Africa. However, the incidence is increased in blacks and Hispanics living in North America. Both sexes are affected equally. In first-generation relatives of patients with inflammatory bowel disease, the risk of developing the disease increases by 4- to 20-fold; the absolute risk of developing the disease may be greater than 7%. Family history is much higher in Crohn's disease than in ulcerative colitis.

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What causes inflammatory bowel disease in adults?

A specific gene mutation has been identified that determines a high risk of developing Crohn's disease (but not ulcerative colitis).

Smoking may contribute to the development or worsening of Crohn's disease, but it reduces the risk of ulcerative colitis. Nonsteroidal anti-inflammatory drugs (NSAIDs) may worsen inflammatory bowel disease.

Symptoms of Inflammatory Bowel Disease

Crohn's disease and ulcerative colitis affect organs other than the intestine. Most extraintestinal manifestations are more common in UC and Crohn's colitis than in Crohn's disease limited to the small intestine. Extraintestinal symptoms of inflammatory bowel disease fall into three categories:

1. Disorders that typically co-occur (i.e. wax and wane) with flares of inflammatory bowel disease. They include peripheral arthritis, episcleritis, aphthous stomatitis, erythema nodosum, and pyoderma gangrenosum. The arthritis is usually migratory, transient, and involves large joints. One or more of these co-occurring disorders develop in more than one-third of patients hospitalized with inflammatory bowel disease.
2. Disorders that are probably secondary to inflammatory bowel disease but occur independently of flares of inflammatory bowel disease. They include ankylosing spondylitis, sacroiliitis, uveitis, and primary sclerosing cholangitis. Ankylosing spondylitis is more common in patients with inflammatory bowel disease and the HLA-B27 antigen. Most patients with spinal or sacroiliac disease have features of uveitis and vice versa. Primary sclerosing cholangitis is a risk factor for biliary tract cancer, which may occur even 20 years after colectomy. Liver disease (eg, fatty liver, autoimmune hepatitis, pericholangitis, cirrhosis) occurs in 3% to 5% of patients, although mild abnormalities in liver function tests are more common. Some of these disorders (eg, primary sclerosing cholangitis) may precede inflammatory bowel disease and, if diagnosed, should be assessed for the possibility of inflammatory bowel disease progression.
3. Disorders that result from destructive changes in the intestine. They develop mainly in severe Crohn's disease of the small intestine. Malabsorption may result from extensive resection of the ileum and cause vitamin B ₁₂ and mineral deficiencies, leading to anemia, hypocalcemia, hypomagnesemia, blood clotting disorders, bone demineralization, and, in children, growth and developmental delays. Other disorders include kidney stones due to excessive absorption of oxalates, hydroureter and hydronephrosis due to compression of the ureter, inflammatory bowel disease, cholelithiasis due to impaired reabsorption of bile salts in the ileum, and amyloidosis due to a long-term purulent-inflammatory process.

All three groups may develop thromboembolic disease as a result of various factors.

Treatment of inflammatory bowel disease

Several classes of medications are effective in treating inflammatory bowel disease. Details of their selection and use are discussed for each condition.

5-aminosalicylic acid

(5-ASA, mesalamine). 5-ASA blocks the production of prostaglandins and leukotrienes and has other beneficial effects on the inflammatory cascade. Since 5-ASA is only active intraluminally and is rapidly absorbed in the proximal small intestine, this must be taken into account when creating conditions for delayed absorption when administered orally. Sulfasalazine, the original drug in this class, delays the absorption of the complex of 5-ASA with the sulfa group of sulfapyridine. The complex is cleaved by bacterial flora in the terminal ileum and colon, releasing 5-ASA. The sulfa group, however, causes numerous undesirable effects (eg, nausea, dyspepsia, headache), impairs folate absorption, and occasionally causes severe adverse reactions (eg, hemolytic anemia and agranulocytosis and, rarely, hepatitis or pneumonitis).

A reversible decrease in sperm count and motility occurs in 80% of men. When sulfasalazine is used, it should be taken with food, initially at a low dose (e.g., 0.5 g orally twice daily) and gradually increased over several days to 1-2 g 2-3 times daily. Patients should additionally take 1 mg of folate orally daily and have complete blood counts and liver function tests monitored every 6-12 months.

Newer preparations that combine 5-ASA with other transporters are also effective but have fewer adverse effects. Olsalazine (a 5-ASA dimer) and balsalazine (5-ASA conjugated to an inactive component) are broken down by bacterial azoreductase (as is sulfasalazine). These preparations are activated primarily in the colon and are less effective in proximal small bowel lesions. The dosage of olsalazine is 500-1500 mg twice daily and balsalazine 2.25 g three times daily. Olsalazine sometimes causes diarrhea, especially in patients with pancolitis. This problem is minimized by gradually increasing the dosage and taking the preparation with food.

Other formulations of 5-ASA contain coatings to delay release of the drug. Asacol (usual dose 800-1200 mg 3 times daily) is 5-ASA coated with an acrylic polymer whose pH solubility delays release of the drug to the distal ileum and colon. Pentasa (1 g 4 times daily) is 5-ASA encapsulated in ethylcellulose microgranules, and only 35% of the drug is released in the small intestine. Secondary acute interstitial nephritis due to mesalamine is rare; periodic monitoring of renal function is desirable, since most cases are reversible if complications are recognized early.

In case of proctitis and lesions of the left half of the colon, 5-ASA can be used in the form of suppositories (500 mg 2-3 times a day) or in the form of enemas (4 g before bedtime or 2 times a day). Rectal use of the drug is effective in the acute course of the disease and long-term use and may be advisable in combination with oral administration of 5-ASA.

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Glucocorticoids

Glucocorticoids are indicated in acute cases of most forms of inflammatory bowel disease if 5-ASA preparations are insufficient, but they are not intended for maintenance treatment. In severe cases, intravenous hydrocortisone 300 mg/day or methylprednisolone 60-80 mg/day continuously by drip or in divided doses is used; in moderate cases, oral prednisolone or prednisolone 40-60 mg once a day can be used. Treatment of inflammatory bowel disease continues until symptoms disappear (usually 7-28 days) and the dose is gradually reduced from 5 to 10 mg weekly to 20 mg once a day, followed by a decrease from 2.5 to 5 mg weekly with the appointment of maintenance therapy with 5-ASA or immunomodulators. Adverse effects of short-term glucocorticoid therapy in high doses include hyperglycemia, hypertension, insomnia, increased activity, and acute episodes of psychotic disorders.

Hydrocortisone enemas or irrigations may be used for proctitis and lesions of the left flank of the colon; 100 mg of the preparation in 60 ml of isotonic solution is administered as an enema 1-2 times a day. This composition should be retained in the intestine as long as possible; instillations before bedtime with the patient lying on the left side with the thighs drawn up to the abdomen prolong the retention time of the solution and increase the area of action. If effective, daily treatment should be extended for approximately 2-4 weeks, then every other day for 1-2 weeks, followed by gradual withdrawal over more than 1-2 weeks.

Budesonide is a glucocorticoid with high (>90%) hepatic metabolism during the first cycle; thus, oral administration may have significant effects on GI disease but minimal adrenal suppression. Oral budesonide has fewer adverse effects than prednisone, but it is not as effective and is generally used in less severe cases. Its dosage is 9 mg once daily. It is also available outside the United States as an enema. Like other glucocorticoids, budesonide is not recommended for long-term use.

Immunomodulatory drugs

Azathioprine and its metabolite 6-mercaptopurine inhibit T-cell function. They are effective in the long term and can reduce the need for glucocorticoids and maintain remission for many years. Treatment with these drugs for 1-3 months is often necessary to achieve a clinical effect, so glucocorticoids cannot be withheld for at least 2 months. The usual dosage of azathioprine is 2.5-3.0 mg/kg orally once a day and 6-mercaptopurine 1.5-2.5 mg/kg orally once a day, but individual dosage may vary depending on metabolism. Evidence of bone marrow suppression should be monitored regularly by white blood cell counts (every two weeks in the first month, then every 1-2 months). Pancreatitis or high fever occurs in approximately 3-5% of patients; any of them is an absolute contraindication to repeated use. Hepatotoxicity develops less frequently and can be monitored by biochemical blood tests every 6-12 months.

In some patients who are unresponsive to glucocorticoids, methotrexate 15–25 mg orally, intramuscularly, or subcutaneously may be given successfully, even in patients who have been unresponsive to azathioprine or 6-mercaptopurine. Nausea, vomiting, and asymptomatic changes in liver function tests are common. Oral folate 1 mg once daily may reduce some of the adverse effects. Alcohol consumption, obesity, and diabetes are risk factors for hepatotoxicity. Patients with these risk factors should have a liver biopsy after the full 1.5 g dose.

Cyclosporine, which blocks lymphocyte activation, may be effective in patients with severe ulcerative colitis that is refractory to glucocorticoids and requires colectomy. Its use is absolutely indicated in patients with Crohn's disease and intractable fistulas or pyoderma.

Initial dose is 4 mg/kg IV once daily; if effective, patients are switched to 6-8 mg/kg orally once daily and then rapidly switched to azathioprine or 6-mercaptopurine. Numerous adverse effects (eg, renal toxicity, seizures, opportunistic infections) contraindicate long-term use (> 6 months). In general, patients are not offered cyclosporine unless there is a reason to avoid a safer treatment than colectomy. When using the drug, blood levels should be maintained between 200-400 ng/mL and it should be considered for prophylaxis against Pneumocystis jiroveci (formerly P. carinii). Tacrolimus, an immunosuppressant used in transplantation, is as effective as cyclosporine.

Anti-cytokine drugs

Infliximab, CDP571, CDP870, and adalimumab are anti-TNF antibodies. Natalizumab is an anti-leukocyte adhesion molecule antibody. These agents may be effective in Crohn's disease, but their effectiveness in UC is unknown.

Infliximab is administered as a separate intravenous infusion at a dose of 5 mg/kg over 2 hours. Some clinicians initiate therapy with concomitant 6-mercaptopurine, using infliximab as a maintenance drug until the initial drug has achieved peak efficacy. A gradual tapering of the glucocorticoid dose can be initiated after 2 weeks. If necessary, infliximab can be repeated every 8 weeks. Adverse effects include delayed hypersensitivity reactions, headache, and nausea. Several patients have died from sepsis after using infliximab, so generalized bacterial infection is a contraindication to the drug. In addition, reactivation of tuberculosis has been reported with the use of this drug; therefore, a tuberculin skin test with PPD and chest radiography should be performed before initiating the drug.

Thalidomide reduces the production of aTNF and interleukin 12 and to some extent suppresses angiogenesis. The drug may be effective in Crohn's disease, but teratogenicity and other adverse effects (e.g., rash, hypertension, neurotoxicity) limit its use to research studies. The efficacy of other anticytokines, antiintegrin antibodies, and growth factors is being studied.

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Antibiotics and probiotics

Antibiotics are effective in Crohn's disease, but their use is limited in ulcerative colitis. Metronidazole 500-750 mg orally 3 times a day for 4-8 weeks relieves moderate disease and is quite effective in the development of fistulas. However, adverse effects (especially neurotoxicity) may prevent a full course of treatment. Ciprofloxacin 500-750 mg orally 2 times a day appears to be less toxic. Some experts recommend the combined use of metronidazole and ciprofloxacin.

Various non-pathogenic microorganisms (e.g. commensal Escherichia coli, Lactobacillus species, Saccharomyces) are used daily as probiotics and may be effective in the prevention of pouchitis syndrome, but their other roles in treatment must be clearly defined.

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Replacement therapy

Most patients and their families are concerned about diet and the impact of stress. Although there are isolated reports of clinical benefit from certain diets, including one with severe carbohydrate restriction, controlled studies have not shown any effectiveness. Avoiding stress overload may be effective.