gastrointestinal disorders
Medications for Inflammatory Bowel Disease
Biologic Agents
Infliximab, certolizumab,adalimumab, andgolimumabare antibodies to tumor necrosis factor (TNF).Infliximab, certolizumab, andadalimumabare useful in Crohn disease, particularly in preventing or retarding postoperative recurrence.Infliximab,adalimumab, andgolimumabare beneficial in ulcerative colitis for refractory or corticosteroid-dependent disease. Infliximabis useful 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. Adalimumabis useful 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 accepted therapeutic serum level is > 7.5 mcg/mL. Patients who are intolerant or who have lost their initial response toinfliximabmay respond toadalimumabtherapy. Certolizumabis useful 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 toinfliximabmay respond to certolizumab. The accepted therapeutic serum level is > 20 mcg/mL. Golimumabis beneficial for 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 toinfliximabmay respond togolimumabtherapy. 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) ormethotrexate. 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 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, nonmelanoma 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. Several immunosuppressive interleukins and anti-interleukin antibodies also may decrease the inflammatory response and are being studied for Crohn disease. is currently available only through a restricted-use program because it increases the risk of Progressive Multifocal Leukoencephalopathy (PML) (PML). Ustekinumab,an anti-IL-12/23 antibody, is available for patients with moderate to severe Crohn disease or ulcerative colitis. 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. Other anticytokine, anti-integrin, small-molecule agents, and growth factors are under investigation, as is leukopheresis therapy to deplete activated immunocytes. Risankizumab, an anti-IL-23 antibody, is available for patients with moderate to severe Crohn disease. The induction dose is 600 mg IV at weeks 0, 4, and 8. The maintenance dose is 180 to 360 mg subcutaneous at week 12 and every 8 weeks thereafter. Using the lowest dose that maintains endoscopic remission is recommended. Liver tests should be done at baseline and during the induction period. Biosimilars are biologic medications that are very similar to a reference biologic product. Biosimilars of the anti-TNF drugs have been commercialized. Small-molecule agents are medications 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. Tofacitinibis a small-molecule agent that inhibits Janus kinase 1–3 and is available 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. Upadacitinibis a small-molecule agent that selectively inhibits Janus kinase 1. This inhibits IL-6- and IFN-gamma–related signaling, resulting in less effect on natural killer cell depletion than other small molecule agents such astofacitinib. The induction dose is 45 mg once daily for 8 weeks for ulcerative colitis and 45 mg once daily 12 weeks for Crohn disease; the maintenance dose for both ulcerative colitis and Crohn disease is 15 mg once daily and can be titrated to 30 mg once daily in patients with refractory, severe, or extensive disease. The medication should be discontinued if remission is not achieved with the 30-mg dose. The most common side effects are acne vulgaris, folliculitis, upper respiratory tract infection, hypersensitivity, nausea, and abdominal pain. In general the side effects are similar to those of other Janus kinase (JAK) inhibitors (eg,tofacitinib). Ozanimodis a sphingosine 1-phosphate (S1P) receptor modulator and is used for adults with moderate to severe active ulcerative colitis. The initial dosage is 0.23 mg orally once a day on days 1 to 4, then 0.46 mg orally once a day on days 5 to 7. The maintenance dosage is 0.92 mg orally once a day starting on day 8. If a dose is missed during the first 14 days of treatment, the titration regimen with 0.23 mg orally once a day should be restarted. If a dose is missed after 14 days of treatment, treatment should be continued as recommended.Ozanimodis contraindicated in people with myocardial infarction within the last 6 months or other cardiac issues such as unstable angina or heart failure. This drug is also contraindicated in people with the following cardiac conduction system disorders: Mobitz type II 2nd-degree block, 3rd-degree atrioventricular block, sick sinus syndrome, or sinoatrial block unless they have a functioning pacemaker.Ozanimodshould be avoided in people who have had a stroke or transient ischemic attack within the last 6 months.Ozanimodalso should be avoided in people with severe untreated sleep apnea and in people taking a monoamine oxidase inhibitor.Ozanimodcan increase the risk of infections, cause bradyarrhythmia, lower the number of lymphocytes, and cause liver injury. ECG and varicella zoster virus antibody testing should be done before starting treatment withozanimod. 