There are two forms of idiopathic inflammatory bowel disease (IBD): ulcerative colitis, a mucosal inflammatory condition confined to the rectum and colon, and Crohn’s disease, a transmural inflammation of gastrointestinal (GI) mucosa that may occur in any part of the GI tract. The etiologies of both conditions are unknown, but they may have a common pathogenetic mechanism.
The major theories of the cause of inflammatory bowel disease involve infectious or immunologic causes. Microorganisms are a likely factor in the initiation of inflammation in inflammatory bowel disease. The immunologic theory assumes that inflammatory bowel disease is caused by an inappropriate reaction of the immune system (both autoimmune and nonautoimmune phenomenon) Proposed etiologies for inflammatory bowel disease are found in Table 1.
Smoking appears to be protective for ulcerative colitis but associated with increased frequency of Crohn’s disease.
Ulcerative colitis and Crohn’s disease differ in two general respects: anatomic sites and depth of involvement within the bowel wall. There is, however, overlap between the two conditions, with a small fraction of patients showing features of both diseases (Table 2).
|TABLE 1. Proposed Etilogies for Inflammatory Bowel Disease|
|Viruses (e.g., measles)|
|L-Forms of bacteria|
|Connective tissue disorders|
|Smoking (Crohn’s disease)|
|Altered host suceptibility|
|Immune-mediated mucosal damage|
|Emotional or physical trauma|
|TABLE 2. Comparison of the Clinical and Pathologic Features of Crohn’s Disease and Ulcerative Colitis|
|Feature||Crohn’s Disease||Ulcerative Colitis|
|Abdominal tenderness||Common||May be present|
|Abdominal wall and internal fistulas||Common||Absent|
|Aphthous or linear ulcers||Common||Rare|
|Ileal involvement||Very common||Rare|
|Crypt abscesses||Rare||Very common|
Ulcerative colitis is confined to the colon and rectum and affects primarily the mucosa and the submucosa. The primary lesion occurs in the crypts of the mucosa (crypts of Lieberkuhn) in the form of a crypt abscess.
Local complications (involving the colon) occur in the majority of ulcerative colitis patients. Relatively minor complications include hemorrhoids, anal fissures, or perirectal abscesses.
A major complication is toxic megacolon, a severe condition that occurs in up to 7.9% of ulcerative colitis patients admitted to hospitals. The patient with toxic megacolon usually has a high fever, tachycardia, distended abdomen, elevated white blood cell count, and a dilated colon.
The risk of colonic carcinoma is much greater in patients with ulcerative colitis as compared with the general population.
Approximately 11% of patients with ulcerative colitis have hepatobiliary complications including fatty liver, pericholangitis, chronic active hepatitis, cirrhosis, sclerosing cholangitis, cholangiocarcinoma, and gallstones.
Arthritis commonly occurs in inflammatory bowel disease patients and is typically asymptomatic and migratory. Arthritis typically involves one or a few large joints such as the knees, hips, ankles, wrists, and elbows.
Ocular complications (iritis, episcleritis, and conjunctivitis) occur in up to 10% of patients. Five percent to 10% of patients experience dermatologic or mucosal complications (erythema nodosum, pyoderma ganrenosum, aphthous stomatitis).
Crohn’s disease is a transmural inflammatory process. The terminal ileum is the most common site of the disorder but it may occur in any part of the GI tract.
About two thirds of patients have some colonic involvement, and 15% to 25% of patients have only colonic disease.
Patients often have normal bowel separating segments of diseased bowel; that is, the disease is often discontinuous.
Complications of Crohn’s disease may involve the intestinal tract or organs unrelated to it. Small-bowel stricture and subsequent obstruction is a complication that may require surgery. Fistula formation is common and occurs much more frequently than with ulcerative colitis.
Systemic complications of Crohn’s disease are common and similar to those found with ulcerative colitis. Arthritis, iritis, skin lesions, and liver disease often accompany Crohn’s disease.
Nutritional deficiencies are common with Crohn’s disease.
There is a wide range of ulcerative colitis presentation. Symptoms may range from mild abdominal cramping with frequent small-volume bowel movements to profuse diarrhea (Table 3).
Most patients with ulcerative colitis experience intermittent bouts of illness after varying intervals of no symptoms.
Mild disease has been defined as fewer than four stools daily, with or without blood, with no systemic disturbance and a normal erythrocyte sedimentation rate (ESR).
Patients with moderate disease have more than four stools per day but with minimal systemic disturbance.
With severe disease, the patient has more than six stools per day with blood, with evidence of systemic disturbance as shown by fever, tachycardia, anemia, or ESR greater than 30.
|TABLE 3. Clinical Presentation of Ulcerative Colitis|
|Signs and symptoms|
|Frequent bowel movements, often with blood in the stool|
|Fever and tachycardia in severe disease|
|Blurred vision, eye pain, and photophobia with ocular involvement|
|Raised, red, tender nodules that vary in size from 1 cm to several centimeters|
|Hemorrhoids, and fissures, or perirectal abscesses may be present|
|Iritis, uveitis, episcleritis, and conjunctivitis with ocular involvement|
|Dermatologic findings with erythema nodosum, pyoderma gangrenosum, or aphthous ulceration|
|Increased erythrocyte sedimentation rate|
|Leukocytosis and hypoalbuminemia with severe disease|
As with ulcerative colitis, the presentation of Crohn’s disease is highly variable (Table 4). A single episode may not be followed by further episodes, or the patient may experience continuous, unremitting disease. A patient may present with diarrhea and abdominal pain or a perirectal or perianal lesion.
The course of Crohn’s disease is characterized by periods of remission and exacerbation. Some patients may be free of symptoms for years, while others experience chronic problems in spite of medical therapy.
|TABLE 4. Clinical Presentation of Crohn’s Disease|
|Signs and symptoms|
|Malaise and fever|
|Frequent bowel movements|
|Abdominal mass and tenderness|
|Perianal fissure or fistula|
|Increased white blood cell count and erythrocyte sedimentation rate|
Goals of treatment include resolution of acute inflammatory processes, resolution of attendant complications (e.g., fistulas, abscesses), alleviation of systemic manifestations (e.g., arthritis), maintenance of remission from acute inflammation, or surgical palliation or cure.
Treatment of inflammatory bowel disease centers on agents used to relieve the inflammatory process. Salicylates, glucocorticoids, antimicrobials, and immunosuppressive agents such as azathioprine and mercaptopurine are commonly used to treat active disease and, for some agents, to lengthen the time of disease remission.
In addition to the use of drugs, surgical procedures are sometimes performed when active disease is not adequately controlled or when the required drug dosages pose an unacceptable risk of adverse effects.
Patients with moderate to severe disease inflammatory bowel disease are often malnourished.
The nutritional needs of the majority of patients can be adequately addressed with enteral supplementation. Patients who have severe disease may require a course of parenteral nutrition.
Probiotic formulas have been effective in maintaining remission in ulcerative colitis.
For ulcerative colitis, colectomy may be performed when the patient has disease uncontrolled by maximum medical therapy or when there are complications of the disease such as colonic perforation, toxic dilatation (megacolon), uncontrolled colonic hemorrhage, or colonic strictures.
The indications for surgery with Crohn’s disease are not as well established as they are for ulcerative colitis, and surgery is usually reserved for the complications of the disease. There is a high recurrence rate of Crohn’s disease after surgery.
The major types of drug therapy used in inflammatory bowel disease include aminosalicylates, glucocorticoids, immunosuppressive agents (azathioprine, mercaptopurine, cyclosporine, and methotrexate), antimicrobials (metronidazole and ciprofloxacin), and agents to inhibit tumor necrosis factor О± (TNF О±) (anti-TNFО± antibodies).
Sulfasalazine, an agent that combines a sulfonamide (sulfapyridine) antibiotic and mesalamine (5-aminosalicylic acid) in the same molecule, has been used for many years to treat inflammatory bowel disease. Mesalamine-based products are listed in Table 5.
Glucocorticoids and adrenocorticotropic hormone (ACTH) have been widely used for the treatment of ulcerative colitis and Crohn’s disease and are used in moderate to severe disease. Prednisone is most commonly used. Budesonide is an oral controlled-release formulation that minimizes systemic effects.
Immunosuppressive agents such as azathioprine and mercaptopurine (a metabolite of azathioprine) are sometimes used for the treatment of inflammatory bowel disease. These agents are generally reserved for cases that are refractory to steroids and may be associated with serious adverse effects such as lymphomas, pancreatitis, or nephrotoxicity. Cyclosporine has been of short-term benefit in acute, severe ulcerative colitis when used in a continuous infusion.
Methotrexate given 15 to 25 mg intramuscularly once weekly is useful for treatment and maintenance of Crohn’s disease.
Antimicrobial agents, particularly metronidazole, are frequently used in attempts to control Crohn’s disease particularly when it involves the perineal area or fistulas.
Infliximab is useful in steroid-dependent or fistulizing disease but the cost far exceeds that of other regimens.
Mild to Moderate Disease
The first line of drug therapy for the patient with mild to moderate colitis is oral sulfasalazine or an oral mesalamine derivative, or topical mesalamine or steroids for distal disease.
When given orally, usually 4 g/day, up to 8 g/day of sulfasalazine is required to attain control of active inflammation. Sulfasalazine therapy should be instituted at 500 mg/day and increased every few days up to 4 g/day or the maximum tolerated.
Oral mesalamine derivatives (such as those listed in Table 5) are reasonable alternatives to sulfasalazine for treatment of ulcerative colitis but they are not more effective than sulfasalazine.
Steroids have a place in the treatment of moderate to severe ulcerative colitis that is unresponsive to maximal doses of oral and topical mesalamine. Prednisone up to 1 mg/kg/day may be used for patients who do not have an adequate response to sulfasalazine or mesalamine.
Steroids and sulfasalazine appear to be equally efficacious; however, the response to steroids may be evident sooner.
Rectally administered steroids or mesalamine can be used as initial therapy for patients with ulcerative proctitis or distal colitis.
Transdermal nicotine in the highest tolerated dose improved symptoms of patients with active ulcerative.
|TABLE 5. Mesalamine Derivatives for Treatment of Inflammatory Bowel Disease|
|Product||Trade Name(s)||Formulation||Dose/Day||Site of Action|
|Mesalamine||Rowasa, Salofalk, Claversal, Pentasa||Enema||1—4 g||Rectum, terminal colon|
|Asacol||Mesalamine tablet coated with Eudragit-S (delayed-release acrylic resin)||2.4—4.8 g||Distal ileum and colon|
|Pentasa||Mesalamine capsules encapsulated in ethylcellulose microgranules||2—4 g||Small bowel and colon|
|Olsalazine||Dipentum||Dimer of 5-aminosalicylic acid oral||1.5—3 g||Colon|
Severe or Intractable Disease
Patients with uncontrolled severe colitis or incapacitating symptoms require hospitalization for effective management. Most medication is given by the parenteral route.
With severe colitis, there is a much greater reliance on parenteral steroids and surgical procedures. Sulfasalazine or mesalamine derivatives have not been proven beneficial for treatment of severe colitis.
Steroids have been valuable in the treatment of severe disease because the use of these agents may allow some patients to avoid colectomy. A trial of steroidsis is warranted in most patients before proceeding to colectomy, unless the condition is grave or rapidly deteriorating.
Continuous intravenous infusion of cyclosporine (4 mg/kg/day) is recommended for patients with acute severe ulcerative colitis refractory to steroids.
Maintenance of Remission
Once remission from active disease has been achieved, the goal of therapy is to maintain the remission.
The major agents used for maintenance of remission are sulfasalazine (2 g/day) and the mesalamine derivatives, although mesalamine is not as effective as sulfasalazine.
Steroids do not have a role in the maintenance of remission with ulcerative colitis because they are ineffective. Steroids should be gradually withdrawn after remission is induced (over 3 to 4 weeks). If they are continued, the patient will be exposed to steroid side effects without likelihood of benefits.
Maintenance of remission is well documented up to 1 year and may last as long as 3 years.
Azathioprine is effective in preventing relapse of ulcerative colitis for periods of up to 2 years. However, 3 to 6 months may be required for beneficial effect.
Active Crohn’s Disease
The goal of treatment for active Crohn’s disease is to achieve remission; however, in many patients, reduction of symptoms so that the patient may carry out normal activities or reduction of the steroid dose required for control is a significant accomplishment.
In the majority of patients, active Crohn’s disease is treated with sulfasalazine, mesalamine derivatives, or steroids, although azathioprine, mercaptopurine, or metronidazole is frequently used.
Sulfasalazine is more effective when Crohn’s disease involves the colon.
Mesalamine derivatives (such as Pentasa or Asacol) that release mesalamine in the small bowel may be more effective than sulfasalazine for ileal involvement.
Steroids are frequently used for the treatment of active Crohn’s disease, particularly with more severe presentations. Steroids are preferred for treatment of severe Crohn’s disease, mainly because these agents can be given parenterally and response to therapy may occur sooner than with other agents. Once remission is achieved, however, it may prove difficult to reduce steroid dosage without reintroduction of active disease.
Metronidazole (given orally up to 20 mg/kg/day) may be useful in some patients with Crohn’s disease, particularly in patients with colonic involvement or those with perineal disease.
The immunosuppressive agents (azathioprine and mercaptopurine) are generally limited to use in patients not achieving adequate response to standard medical therapy, or to reduce steroid doses when toxic doses are required. The usual dose of azathioprine is 2 to 2.5 mg/kg/day and 1 to 1.5 mg/kg/day for mercaptopurine. Up to 6 months may be required to observe a response.
A genetic polymorphism causes deficiency of the enzyme thiopurine S-methyltransferase in some people, reduces mercaptopurine metabolism and increases the risk of bone marrow suppression.
Cyclosporine is not recommended for Cronn’s disease except for patients with symptomatic and severe perianal or cutaneous fistulas. The dose of cyclosporine is important in determining efficacy. An oral dose of 5 mg/kg/day was not effective, whereas 7.9 mg/kg/day was effective. However, toxic effects limit application of the higher dosage.
Methotrexate, given as a weekly injection of 5 to 25 mg has demonstrated efficacy for induction of remission in Crohn’s disease as well as for maintenance therapy.
Infliximab, 5 mg/kg single infusion, is effective for refractory or fistulizing Crohn’s disease when given everyday for 8 weeks.
Maintenance of Remission
Prevention of recurrence of disease is clearly more difficult with Crohn’s disease than with ulcerative colitis. Sulfasalazine and oral mesalamine derivatives are effective in preventing acute recurrences in quiescent Crohn’s disease.
Steroids also have no place in the prevention of recurrence of Crohn’s disease; these agents do not appear to alter the long-term course of the disease.
Although the published data are not consistent, there is evidence to suggest that azathioprine and mercaptopurine are effective in maintaining remission in Crohn’s disease.
The treatment required for toxic megacolon includes general supportive measures to maintain vital functions, consideration for early surgical intervention, and antimicrobials.
Aggressive fluid and electrolyte management are required for dehydration.
When the patient has lost significant amounts of blood (through the rectum), blood replacement is also necessary.
Steroids in high dosages should be administered intravenously to reduce acute inflammation. Doses as high as 2 mg/kg/day of prednisone equivalent have been recommended (generally administered as hydrocortisone).
Antimicrobial regimens that are effective against enteric aerobes and anaerobes (e.g., aminoglycoside with clindamycin or metronidazole, imipenem, meropenem, or extended-spectrum penicillin with a ОІ -lactamase inhibitor) should be administered from the time of diagnosis and continued until patient improvement is assured.
The common systemic manifestations of inflammatory bowel disease include arthritis, anemia, skin manifestations such as erythema nodosum and pyoderma gangrenosum, uveitis, and liver disease.
Anemia may be a common problem where there is significant blood loss from the GI tract. When the patient can consume oral medication, ferrous sulfate should be administered. Vitamin B12 or folic acid may also be required.
Drug therapy for inflammatory bowel disease is not a contraindication for pregnancy, and most pregnancies are well managed in patients with these diseases. The indications for medical and surgical treatment are similar to those in the nonpregnant patient. If a patient has an initial bout of inflammatory bowel disease during pregnancy, a standard approach to treatment should be initiated.
Metronidazole or methotrexate should not be used during pregnancy.
ADVERSE DRUG REACTIONS TO AGENTS USED FOR TREATMENT OF IBD
Sulfasalazine is often associated with either dose-related or idiosyncratic adverse drug effects. Dose-related side effects usually include GI disturbances such as nausea, vomiting, diarrhea, or anorexia, but may also include headache and arthralgia.
Patients receiving sulfasalazine should receive oral folic acid supplementation since sulfasalazine inhibits folic acid absorption.
Non-dose-related adverse effects of sulfasalazine include rash, fever, or hepatotoxicity most commonly, as well as relatively uncommon but serious reactions such as pancreatitis and hepatitis.
Oral mesalamine derivatives may impose a lower frequency of adverse effects compared with sulfasalazine. Eighty percent to 90% of patients who are intolerant to sulfasalazine will tolerate oral mesalamine derivatives.
The well-appreciated adverse effects of glucocorticoids include hyperglycemia, hypertension, osteoporosis, fluid retention and electrolyte disturbances, myopathies, psychosis, and reduced resistance to infection. In addition, glucocorticoid use may cause adrenocortical suppression. Specific regimens for withdrawal of glucocorticoid therapy have been suggested.
Immunosuppressants such as azathioprine and mercaptopurine have a significant potential for adverse reactions, including bone marrow suppression, and have been associated with lymphomas (in renal transplant patients) and pancreatitis. Myelosuppression resulting in leucopenia is related to a deficiency in thiopurine S-methyltransferase in some patients.
Infliximab has been associated with infusion reactions, serum sickness, sepsis, and tuberculosis.
EVALUATION OF THERAPEUTIC OUTCOMES
The success of therapeutic regimens to treat IBDs can be measured by patient-reported complaints, signs and symptoms, direct physician examination (including endoscopy), history and physical examination, selected laboratory tests, and quality of life measures.
To create more objective measures, disease-rating scales or indices have been created. The Crohn’s Disease Activity Index (CDAI) is a commonly used scale, particularly for evaluation of patients during clinical trials. The scale incorporates eight elements: (1) number of stools in the past 7 days; (2) sum of abdominal pain ratings from the past 7 days; (3) rating of general well-being in the past 7 days; (4) use of antidiarrheals; (5) body weight; (6) hematocrit; (7) finding of abdominal mass; and (8) a sum of symptoms present in the past week. Elements of this index provide a guide for those measures that may be useful in assessing the effectiveness of treatment regimens.
Standardized assessment tools have also been constructed for ulcerative colitis. Elements in these scales include (1) stool frequency; (2) presence of blood in the stool; (3) mucosal appearance (from endoscopy); and (4) physician’s global assessment based on physical examination, endoscopy, and laboratory data.