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Drugs for Inflammatory Bowel Disease

By

Aaron E. Walfish

, MD, Mount Sinai Medical Center;


Rafael Antonio Ching Companioni

, MD, Digestive Diseases Center

Last full review/revision Jun 2020| Content last modified Jun 2020
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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-Aminosalicylic Acid (5-ASA, Mesalamine)

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 orally 2 times a day) and the dose and frequency gradually increased over several days to 1 to 1.5 g 4 times a day. Patients should take daily folate supplements (1 mg orally) and have complete blood count and liver tests every 6 to 12 months. 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 orally 2 times a day, and balsalazide is 2.25 g orally 3 times a day (capsule form) or 3.3 g orally 2 times a day (tablet form). The effectiveness of the tablet form of balsalazide in female patients has not been shown in clinical studies. 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 orally 3 times a day) and Delzicol® (800 mg orally 3 times a day) 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 orally 4 times a day) 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 orally once a day) and Apriso® (1500 mg orally once a day) are combination delayed-release and extended-release formulations that may be given once a 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 2 times a day) or enema (4 g at bedtime or 2 times a day) for proctitis and left-sided colon disease. These rectal preparations are effective for both acute treatment and long-term maintenance in proctitis and proctosigmoiditis 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

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 3 times a day is used for severe disease; oral prednisone or prednisolone 40 to 60 mg once a 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 a day. Treatment is then further tapered by 2.5 to 5 mg weekly depending on 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 a day or twice a day. 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 weeks, then every other day for 1 to 2 weeks, and then gradually discontinued over 1 to 2 weeks.

Budesonide is a corticosteroid with a high (> 90%) first-pass liver metabolism; thus, oral administration may have a significant effect on gastrointestinal 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 weeks 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 a 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.

Immunomodulating Drugs

The antimetabolites azathioprine, 6-mercaptopurine, and methotrexate are also used in combination therapy with biologic agents.

Azathioprine and 6-mercaptopurine

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 months 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 orally once a day and 6-mercaptopurine is 1 to 1.5 mg/kg orally once a 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 white blood cell counts (biweekly for 1 month, then every 1 to 2 months). 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 months. 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 450 picomoles per 8 × 108 red blood cells (RBCs). Myelotoxicity can occur when 6-TG levels are > 450. Hepatotoxicity can occur when 6-MMP levels are > 5700 picomoles per 8 × 108 RBCs. The concentrations of metabolites are also useful in nonresponding patients to distinguish lack of adherence from resistance.

Methotrexate

Methotrexate 15 to 25 mg orally or subcutaneously 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 test abnormalities. Folate 1 mg orally once a 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 months before trying to conceive. Monthly complete blood counts and liver tests with albumin should be done for the first 3 months of therapy then every 8 to 12 weeks 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-year period show elevated levels of aspartate aminotransferase (AST). Myelosuppression, pulmonary toxicity, and nephrotoxicity can also occur with methotrexate therapy.

Cyclosporine and tacrolimus

Cyclosporine, which blocks lymphocyte activation, may benefit patients with severe ulcerative colitis 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 hours; responders are converted to an oral dose of 6 to 8 mg/kg once a day with early introduction of azathioprine or 6-mercaptopurine. Long-term use (> 6 months) is contraindicated by multiple adverse effects (eg, renal toxicity, seizures, opportunistic infections, hypertension, neuropathy). Generally, patients with severe ulcerative colitis 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 (166 to 333 nmol/L) 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 ulcerative colitis who do not require hospitalization. The trough blood levels should be kept between 10 to 15 ng/mL (12 to 25 nmol/L). Tacrolimus can be given for short-term treatment of perianal and cutaneous fistulas in Crohn disease.

Biologic Agents

Anti-TNF drugs

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 ulcerative colitis for refractory or corticosteroid-dependent disease.

Infliximab is approved for Crohn disease and ulcerative colitis and is given as a single IV infusion of 5 mg/kg over 2 hours. It is followed by repeat infusions at weeks 2 and 6. Subsequently, it is given every 8 weeks. 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 > 5 mcg/mL.

Adalimumab is approved for Crohn disease and ulcerative colitis. It is given with an initial loading dose of 160 mg subcutaneously and then 80 mg subcutaneously at week 2. After that dose, 40 mg subcutaneously is given every 2 weeks. The dose should be adjusted to achieve a therapeutic serum level of > 7.5 mcg/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 subcutaneously every 2 weeks for three doses and then every 4 weeks for maintenance. Patients who are intolerant of or who have lost their initial response to infliximab may respond to certolizumab. The accepted therapeutic serum level is > 20 mcg/mL.

Golimumab is approved for use in patients with ulcerative colitis. It is given with an initial loading dose of 200 mg subcutaneously and then 100 mg at week 2. After that dose, 100 mg is given every 4 weeks. 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 weeks. 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, tuberculosis (TB) and hepatitis B reactivation has been attributed to anti-TNF drugs; therefore, screening for latent TB (with tuberculin skin tests and/or interferon-gamma release assay) and for hepatitis B is required before therapy. Documenting immunity to varicella is advised. Some physicians also recommend serologic testing for Epstein-Barr virus and cytomegalovirus.

Lymphoma and possibly other cancers (eg, non-melanoma skin cancer), demyelinating disease (eg, multiple sclerosis, optic neuritis), heart failure, and liver and hematologic toxicity are other potential concerns with anti-TNF drug treatment.

Other biologic agents

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 ulcerative colitis and Crohn disease. The recommended dose of IV vedolizumab is 300 mg at 0, 2, and 6 weeks and then every 8 weeks. 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. The accepted therapeutic serum level of vedolizumab is > 20 mcg/mL.

Ustekinumab, an anti-IL-12/23 antibody, is approved for patients with moderate to severe Crohn disease or ulcerative colitis who have failed conventional therapy. The initial loading dose is a single IV dose based on weight:

  • < 55 kg: 260 mg

  • 55 to 85 kg: 390 mg

  • > 85 kg: 520 mg

After the loading dose, patients are given a maintenance dose of 90 mg subcutaneously every 8 weeks. The accepted therapeutic serum level is > 5 mcg/mL.

Other anticytokine, anti-integrin, small-molecule agents, and growth factors are under investigation, as is leukopheresis therapy to deplete activated immunocytes.

Small-molecule agents

Small-molecule agents are drugs with molecular weight < 1 kilodalton. Some of these are now in use or under development for the management of IBD. They are given orally and lack the immunogenicity associated with monoclonal antibodies.

Tofacitinib is a small-molecule agent that inhibits Janus kinase 1–3 and is approved for adult patients with moderate to severe ulcerative colitis. The initial dosage of the immediate-release form is 10 mg orally 2 times a day for at least 8 weeks, followed by 5 or 10 mg orally 2 times a day. The initial dosage of the extended-release form is 22 mg orally once a day for at least 8 weeks, followed by 11 mg orally once a day. Potential adverse effects include elevated cholesterol levels, diarrhea, headache, shingles (herpes zoster), augmented blood creatine phosphokinase, nasopharyngitis, rash, and upper respiratory tract infection. Other uncommon adverse effects include cancer and opportunistic infections. In addition, the U.S. Food and Drug Administration warned of an increased risk of fatal pulmonary embolism and death in patients with rheumatoid arthritis.

Antibiotics and Probiotics

Antibiotics

Antibiotics may be helpful in Crohn disease but are of limited use in ulcerative colitis, except in toxic colitis. Metronidazole 500 to 750 mg orally 3 times a day for 4 to 8 weeks may control mild Crohn disease and help heal fistulas. However, adverse effects (particularly neurotoxicity) often preclude completion of treatment. Ciprofloxacin 500 to 750 mg orally 2 times a day may prove less toxic. Many experts recommend metronidazole and ciprofloxacin in combination. Rifaximin, a nonabsorbable antibiotic, at a dose of 200 mg orally 3 times a day or 800 mg orally 2 times a day may also be beneficial as treatment for active Crohn disease.

Probiotics

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 ulcerative colitis.

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