Drugs for Inflammatory Bowel Disease
Several classes of drugs are helpful for inflammatory bowel disease (IBD). Details of their selection and use are discussed under each disorder (see Crohn disease treatment and ulcerative colitis treatment).
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, pneumonitis, or myocarditis). 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 the dose and frequency gradually increased over several days to 1 to 1.5 g qid. 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.
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 1000 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 formulations of 5-ASA use delayed-release and/or extended-release coatings. Asacol HD® (typical dose 1600 mg po tid) and Delzicol® (800 mg tid) are delayed-release forms of 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 an extended-release 5-ASA encapsulated in ethylcellulose microgranules that release 35% of the drug in the small bowel. Lialda® (2400 to 4800 mg po once/day) and Apriso® (1500 mg po once/day) are combination delayed-release and extended-release formulations that may be given once/day; their less frequent dosing may improve adherence. All of these formulations of 5-ASA are therapeutically roughly equivalent.
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. Patients who cannot tolerate enemas due to rectal irritation should be given 5-ASA foam.
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 16 to 20 mg tid 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 depending upon clinical response, 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 8 wk but has not yet proved effective for long-term maintenance. The drug is approved for small-bowel Crohn disease, and an enteric-coated, delayed-release form is available for ulcerative colitis. Dosage is 9 mg once/day. It is also available outside the US as an enema.
All patients started on corticosteroids (including budesonide) should be given oral vitamin D 400 to 800 units/day and calcium 1200 mg/day. Corticosteroids should be used with caution in patients with chronic liver disease including cirrhosis because bioavailability and clinical effects may be enhanced.
The antimetabolites azathioprine, 6-mercaptopurine, and methotrexate are also used in combination therapy with biologic agents.
Azathioprine and its metabolite 6-mercaptopurine inhibit T-cell function and may induce T-cell apoptosis. 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 completely 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 to 1.5 mg/kg po once/day but varies depending on individual metabolism. The dose of azathioprine or 6-mercaptopurine should be reduced by 50% and adjusted accordingly based on clinical response and hematologic monitoring in patients who are intermediate metabolizers.
The most common adverse effects are nausea, vomiting, and malaise. 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. These drugs are associated with increased risk of lymphoma and nonmelanoma skin cancers.
Before starting these drugs, patients should have tests to measure the activity of thiopurine methyltransferase (TPMT), an enzyme that converts azathioprine and 6-mercaptopurine to their active metabolites 6-thioguanine (6-TG) and 6-methylmercaptopurine (6-MMP). Patients should also have genotype testing for known low-activity variants of this enzyme. After starting these drugs, it is useful to measure levels of 6-TG and 6-MMP to help ensure safe and effective drug dosages. Therapeutic efficacy correlates with 6-TG levels between 230 and 400 picomoles per 8 x 108RBCs. Myelotoxicity can occur when 6-TG levels are > 400. Hepatotoxicity can occur when 6-MMP levels are > 5700 picomoles per 8 x 108 RBCs. The concentrations of metabolites are also useful in nonresponding patients to distinguish lack of adherence from resistance.
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. Both women and men taking methotrexate should ensure the female partner uses an effective contraceptive method such as an intrauterine device, a contraceptive implant, or an oral contraceptive. Less effective methods of contraception, such as condoms, spermicides, diaphragms, cervical caps, and periodic abstinence, should be discouraged. 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, hepatitis B and C, 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 biologic agents 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 2 to 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 with severe UC unresponsive to corticosteroids and biologics 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 and may be considered for use in patients with severe or refractory UC who do not require hospitalization.
Infliximab, certolizumab, adalimumab, and golimumab are antibodies to tumor necrosis factor (TNF). Infliximab, certolizumab, and adalimumab are useful in Crohn disease, particularly in preventing or retarding postoperative recurrence. Infliximab, adalimumab, and golimumab are beneficial in UC for refractory or corticosteroid-dependent disease.
Infliximab is approved for Crohn disease and UC and 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. The accepted therapeutic serum level is 6 to 10 μg/mL.
Adalimumab is approved for Crohn disease and UC. It 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. The dose should be adjusted to achieve a therapeutic serum level of 8 to 12 μg/mL. Patients who are intolerant or who have lost their initial response to infliximab may respond to adalimumab therapy.
Certolizumab is approved for Crohn disease. It is given as 400 mg sc q 2 wk for three doses and then q 4 wk for maintenance. Patients who are intolerant of or who have lost their initial response to infliximab may respond to certolizumab.
Golimumab is approved for use in patients with UC. It is given with an initial loading dose of 200 mg sc and then 100 mg at wk 2. After that dose, 100 mg is given every 4 wk. Patients who are intolerant or who have lost their initial response to infliximab may respond to golimumab therapy.
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) or methotrexate. 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).
Several patients have died of sepsis after anti-TNF use, so these drugs are contraindicated when uncontrolled bacterial infection is present. Also, TB and hepatitis B reactivation has been attributed to anti-TNF drugs; therefore, screening for latent TB (with PPDs and/or interferon-gamma release assay) and for hepatitis B is required before therapy.
Lymphoma, demyelinating disease, and liver and hematologic toxicity are other potential concerns with anti-TNF antibody treatment.
Several immunosuppressive interleukins and anti-interleukin antibodies also may decrease the inflammatory response and are being studied for Crohn disease.
Vedolizumab and natalizumab are antibodies to leukocyte adhesion molecules. Vedolizumab has been approved for moderate to severe UC and Crohn disease. The recommended dose of IV vedolizumab is 300 mg at 0, 2, and 6 wk and then every 8 wk. Its effect is believed to be limited to the gut, making it safer than natalizumab, which is used only as a 2nd-line drug through a restricted-prescribing program for the most refractory cases of Crohn disease.
Ustekinumab, an anti-IL-12/23 antibody, is approved for patients with moderate to severe Crohn disease who have failed conventional therapy. The initial loading dose is a single IV dose based on weight:
After the loading dose, patients are given a maintenance dose of 90 mg sc every 8 wk.
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, except in toxic colitis). 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, 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.