Overview of dosing and monitoring of biologic agents and small molecules for treating ulcerative colitis in adults

INTRODUCTION — Ulcerative colitis (UC) is a chronic inflammatory disease of the colon characterized by bloody diarrhea. Biologic agents and small molecules are used for treating patients with moderately to severely active UC.

Dosing, monitoring, and adverse effects of biologic agents and small molecules for the treatment of UC in adults will be reviewed here. Selecting a specific biologic agent or small molecule is influenced by the indication, disease severity, disease prognosis, patient's medical history, extraintestinal manifestations, patient preference, availability in individual countries, and insurance coverage/cost. Medical management of UC is discussed separately:

●(See "Medical management of low-risk adult patients with mild to moderate ulcerative colitis".)

●(See "Management of moderate to severe ulcerative colitis in adults".)

●(See "Management of the hospitalized adult patient with severe ulcerative colitis".)

An overview of thiopurine therapy (azathioprine and mercaptopurine) in inflammatory bowel disease (IBD) is discussed separately. (See "Overview of azathioprine and mercaptopurine use in inflammatory bowel disease".)

An overview of budesonide therapy for IBD is discussed separately. (See "Overview of budesonide therapy for adults with inflammatory bowel disease".)

Adjustments to medication regimens for patients with IBD and suspected or known coronavirus disease 19 (COVID-19) are discussed separately. (See "COVID-19: Issues related to gastrointestinal disease in adults", section on 'Inflammatory bowel disease'.)

TUMOR NECROSIS FACTOR INHIBITORS

Pharmacology and use — Infliximab, adalimumab, and golimumab are monoclonal antibodies directed against anti-tumor necrosis factor (TNF)-alpha. The efficacy of TNF agents for treating Crohn disease provided the rationale for clinical trials of infliximab (and other anti-TNF agents) in patients with UC, a disorder in which TNF also has an important role. TNF-alpha is expressed at high levels in the colonic mucosa of patients with UC [1].

The basis for using these agents is that TNF-alpha has several biologic activities that may be directly related to the pathogenesis of inflammatory bowel disease (IBD) and to the dysregulation of the immune system that occurs in patients with IBD. (See "Overview of biologic agents in the rheumatic diseases", section on 'Anticytokine approaches' and "Treatment of Crohn disease in adults: Dosing and monitoring of tumor necrosis factor-alpha inhibitors".)

●Infliximab – Infliximab is a chimeric monoclonal antibody comprised of 75 percent human and 25 percent murine sequences, which has a high specificity for and affinity to TNF-alpha. Infliximab neutralizes the biologic activity of TNF-alpha by inhibiting binding to its receptors. Infliximab is used by most clinicians in combination with an immunomodulator (azathioprine, 6-mercaptopurine, or methotrexate).

●Adalimumab – Adalimumab is a recombinant, fully human monoclonal antibody that binds to TNF-alpha, thereby interfering with binding to TNF-alpha receptor sites and subsequent cytokine-driven inflammatory processes. The humanized construction of adalimumab is presumed to lower the risk of forming antidrug antibodies compared with infliximab. (See "Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases", section on 'Adalimumab-induced human anti-human antibodies'.)

●Golimumab – Golimumab is a fully human monoclonal antibody that neutralizes TNF-alpha activity. Golimumab has a longer half-life than adalimumab. (See 'Golimumab' below and "Overview of biologic agents in the rheumatic diseases", section on 'Golimumab'.)

Pretreatment screening — Prior to starting a biologic agent, it is important to review each patient's vaccination and exposure history. Ideally, this review should be performed before the start of immunosuppressive therapy, when the likelihood of developing a protective immune response to any needed vaccine is highest and when live vaccines can be given safely. (See "Medical management of low-risk adult patients with mild to moderate ulcerative colitis", section on 'Approach to vaccination'.)

Pretreatment screening includes:

●Hepatitis B surface antigen (HbsAg), hepatitis B surface antibody, and hepatitis B core antibody (anti-HBc).

Patients with serologic evidence of hepatitis B virus (HBV) infection (HbsAg-positive or anti-HBc-positive) are at risk for HBV reactivation if they receive immunosuppressive therapy. Prevention, diagnosis, and treatment of HBV reactivation are discussed separately. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

●Hepatitis C virus (HCV) antibody. For patients with HCV antibodies, we obtain HCV RNA. If HCV RNA is detected, we refer the patient to a hepatologist for consideration of treatment. (See "Screening and diagnosis of chronic hepatitis C virus infection" and "Overview of the management of chronic hepatitis C virus infection".)

However, chronic HCV infection is not a contraindication for immunosuppressive therapy [2,3].

●Interferon-gamma release assay such as QuantiFERON-TB Gold In-Tube assay (preferred) or tuberculin skin test.

If the screening test for latent tuberculosis is indeterminate or positive, a chest radiograph is obtained, and the patient is referred to an infectious disease specialist for further evaluation.

•(See "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)".)

•(See "Risk of mycobacterial infection associated with biologic agents and JAK inhibitors", section on 'Screening'.)

•(See "Use of interferon-gamma release assays for diagnosis of tuberculosis infection (tuberculosis screening) in adults".)

●Documenting immunity to varicella (eg, varicella zoster virus [VZV] IgG, clinician diagnosis of disease). (See "Diagnosis of varicella-zoster virus infection", section on 'Serologic testing'.)

For patients with evidence of immunity who are ≥19 years old, we assess the need for and timing of zoster (shingles) vaccination, and this is discussed separately. (See "Immunizations in autoimmune inflammatory rheumatic disease in adults", section on 'Zoster vaccines'.)

For patients without evidence of immunity, we assess the need for VZV vaccination based on patient age and risk status, and this is discussed separately. (See "Important health maintenance issues for children and adolescents with inflammatory bowel disease", section on 'Immunizations' and "Immunizations in autoimmune inflammatory rheumatic disease in adults".)

●Serologic testing for Epstein-Barr virus (EBV) and cytomegalovirus (CMV). We obtain anti-EBV and anti-CMV antibodies to assess for evidence of prior infection and thus the patient's risk of reactivation [2]. (See "Clinical manifestations and treatment of Epstein-Barr virus infection" and "Overview of diagnostic tests for cytomegalovirus infection".)

Contraindications — Contraindications to the use of anti-TNF therapies (briefly summarized) include the following (see "Treatment of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults", section on 'Use of TNF inhibitors'):

●Active, untreated infection

●Latent (untreated) tuberculosis

●Demyelinating disease (eg, multiple sclerosis, optic neuritis)

●Uncontrolled heart failure (New York Heart Association [NYHA] class III or IV)

●Active malignancy

The safety of anti-TNF therapies and risk of recurrent malignancy in patients with a history of malignancy is less well established than in patients without such a history; the available data are discussed in detail separately. (See "Tumor necrosis factor-alpha inhibitors: Risk of malignancy".)

Dosing and administration — This section describes induction and maintenance dosing for infliximab, adalimumab, and golimumab. In addition, options for dose escalation are included for patients with loss of response while on maintenance therapy. The approach to the patient with UC who is not responding to induction anti-TNF therapy is discussed separately. (See "Management of moderate to severe ulcerative colitis in adults" and "Management of the hospitalized adult patient with severe ulcerative colitis".)

Decisions regarding dose adjustments for patients on maintenance therapy who lose response can be guided by therapeutic drug monitoring (table 1). (See 'Therapeutic drug monitoring' below.)

Infliximab — The induction dose of infliximab for treatment of patients with moderately to severely active UC is 5 mg/kg intravenously at zero, two, and six weeks [4,5].

Patients who achieve an adequate response (based on clinical, endoscopic, and laboratory findings) to initial therapy will require repeat infusions of 5 mg/kg, usually every eight weeks, to maintain remission. Beginning at week 10 of infliximab therapy, an alternative to intravenous administration is subcutaneous injection [6-9]. Infliximab 120 mg is given subcutaneously once every two weeks.

Patients who have active inflammation while on maintenance dosing can be managed by dose escalation and/or initiation of immunomodulator treatment [10,11]. Dose escalation can be accomplished by either decreasing the dosing interval (eg, from eight weeks to six weeks) or by increasing the dose (eg, from 5 mg/kg to 7.5 mg/kg or 10 mg/kg). The maximal dose of infliximab is 10 mg/kg every four weeks.

Adalimumab — Induction therapy with adalimumab is given subcutaneously with the following regimen [12]:

●Week zero, initial dose – 160 mg, given over one or two days

●Week two – 80 mg once

●Week four and thereafter – 40 mg every other week (maintenance dose)

We suggest the same induction regimen for patients who are being switched to adalimumab from another anti-TNF agent.

For patients who have a disease flare while on maintenance dosing, the dosing interval can be shortened to every week, or the dose may be increased to 80 mg every other week [13-15]. An alternative to dose escalation is adding an immunomodulator.

Golimumab — The recommended induction dose for golimumab is 200 mg subcutaneously at week zero, then 100 mg at week two, followed by weight-based maintenance therapy [16,17]:

●For patients with actual body weight ≥80 kg – 100 mg every four weeks

●For patients with actual body weight <80 kg – 50 mg every four weeks

For patients who have loss of response while on maintenance dosing and who are candidates for dose escalation, options include increasing the maintenance dose to 100 mg every four weeks, irrespective of body weight, or, alternatively, initiating an immunomodulator [18].

Monitoring — In addition to clinical observation, monitoring the response to anti-TNF agents may include therapeutic drug monitoring (checking drug levels, antidrug antibodies) and biomarker levels (C-reactive protein [CRP], fecal calprotectin). Time intervals for follow-up evaluations, including colonoscopy to assess for endoscopic remission, are discussed separately. (See "Management of moderate to severe ulcerative colitis in adults".)

Therapeutic drug monitoring — Therapeutic drug monitoring involves measuring serum drug concentrations (induction or trough) [19] and antidrug antibodies to optimize the use of anti-TNF agents for patients with IBD. Selecting patients for therapeutic drug monitoring and modifying anti-TNF therapy based on monitoring is discussed separately. (See "Treatment of Crohn disease in adults: Dosing and monitoring of tumor necrosis factor-alpha inhibitors", section on 'Therapeutic drug monitoring'.)

The suggested target drug trough concentrations are primarily based on cross-sectional studies of patients on maintenance therapy; however, some patients require higher drug concentrations to achieve remission [20,21]:

●Infliximab: ≥5 mcg/mL

●Adalimumab: ≥7.5 mcg/mL

●Golimumab: >1 mg/L [22]

Biomarkers of inflammation — In addition to therapeutic drug monitoring, obtaining biomarkers of inflammation (eg, fecal calprotectin or lactoferrin, CRP) can help guide therapy to achieve endoscopic and clinical remission in patients with UC [23,24].

●Stool inflammatory markers – Fecal calprotectin can be used to monitor response to anti-TNF therapy in patients with UC, because fecal calprotectin levels correlate with endoscopic disease activity [25-28]. Fecal calprotectin levels are also more accurate than serum inflammatory markers (eg, CRP) for detecting active disease [29]. Calprotectin is a calcium binding protein complex, found in abundance in neutrophilic granulocytes, and fecal calprotectin levels are increased in patients with mucosal inflammation [27]. (See "Approach to the adult with chronic diarrhea in resource-abundant settings", section on 'General laboratory tests'.)

●CRP – A high baseline CRP level that normalizes with treatment has been associated with a higher chance of having a response to infliximab [11,30]. However, up to 15 percent of patients do not have an elevated CRP despite active inflammation [29].

Adverse events — The TNF-alpha inhibitors have multiple potential adverse events that are listed below and discussed in more detail separately [31] (see "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects"):

●Infection. (See "Risk of mycobacterial infection associated with biologic agents and JAK inhibitors" and "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections".)

●Malignancy. (See "Tumor necrosis factor-alpha inhibitors: Risk of malignancy".)

●Induction of autoimmunity. (See "Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases".)

●Demyelinating disease.

●Worsening or new onset heart failure.

●Injection site reactions.

●Neutropenia.

●Infusion reactions. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects", section on 'Infusion reactions'.)

●Cutaneous reactions, including psoriasiform lesions.

The risk of combination therapy (ie, anti-TNF agent plus an immunomodulator) in patients with IBD is discussed separately. (See "Treatment of Crohn disease in adults: Dosing and monitoring of tumor necrosis factor-alpha inhibitors", section on 'Risks with combination therapy'.)

ANTI-INTEGRIN ANTIBODIES

Pharmacology and use — Vedolizumab is a recombinant humanized, monoclonal antibody, developed as a gut-selective anti-integrin specifically targeting alpha-4-beta-7 integrin in the gastrointestinal tract [32]. Integrins are proteins involved in regulating cellular movement including migration of leukocytes to the gut. Vedolizumab is not typically associated with systemic immunosuppression because it interferes with lymphocyte trafficking limited to the gastrointestinal tract.

Pretreatment screening — Prior to starting a biologic agent, it is important to review each patient's vaccination and exposure history, as discussed above. (See 'Pretreatment screening' above.)

Dosing and administration — The induction dose of vedolizumab for treatment of patients with moderately to severely active UC is 300 mg intravenously at zero, two, and six weeks, then every eight weeks thereafter for maintenance [33,34]. Beginning with the third vedolizumab dose, an alternative to intravenous administration is subcutaneous administration [35,36]. At week 6 of therapy and thereafter, vedolizumab 108 mg is given subcutaneously once every two weeks.

Patients who achieve an adequate response (based on clinical and endoscopic findings) to initial therapy usually require long-term therapy to maintain remission. For patients who have active inflammation while on maintenance therapy, the dose can be escalated by decreasing the vedolizumab dosing interval (eg, 300 mg intravenously every four or six weeks) [37].

Monitoring — In addition to clinical observation, monitoring the response to vedolizumab may include checking biomarker levels (C-reactive protein [CRP], fecal calprotectin). Time intervals for follow-up evaluations, including colonoscopy to assess for endoscopic remission, are discussed separately. (See 'Biomarkers of inflammation' above and "Management of moderate to severe ulcerative colitis in adults".)

Adverse events — Vedolizumab use is associated with low incidence of serious infection or infusion-related reactions, although mild nasopharyngitis is a common side effect [33,38]. In an analysis of safety data from four trials including 1256 patients with UC, treatment with vedolizumab was not associated with a higher rate of serious infections compared with placebo (2.7 per 100 person-years [95% CI 1.9-3.4] versus 5.0 per 100 person-years [95% CI 0.1-10.0]) [39]. In an analysis of six studies including 2830 patients with inflammatory bowel disease (IBD), the rate of infusion-related reactions was ≤5 percent, and most were mild or moderate in intensity and rarely resulted in discontinuation of the drug [39].

Data suggest that for patients with UC, the risk of serious infection is lower with vedolizumab compared with other biologic agents. In a study including three population-based cohorts with mean follow-up of 1.1 years, patients with UC had lower risk of serious infection with vedolizumab compared with anti-tumor necrosis factor (TNF) agents (incidence rate: 17.6 versus 20.4 per 1000 person-years; hazard ratio [HR] 0.68, 95% CI 0.50-0.93) [38].

ANTI-INTERLEUKIN ANTIBODIES

Pharmacology and use — Anti-interleukin antibody-based therapy (eg, ustekinumab, mirikizumab) is used for treating patients with moderate to severe UC [40,41]. Ustekinumab is an anti-interleukin 12/23 antibody, whereas mirikizumab targets the p19 subunit of interleukin-23.

Pretreatment screening — Prior to starting a biologic agent, it is important to review each patient's vaccination and exposure history, as discussed above. (See 'Pretreatment screening' above.)

Dosing and administration

Ustekinumab — Induction therapy with ustekinumab is given as a single intravenous infusion with weight-based dosing. Maintenance dosing is 90 mg subcutaneously eight weeks after the initial dose, then every eight weeks thereafter [40].

For patients who do not have symptomatic improvement (ie, those with persistent diarrhea and/or rectal bleeding) within four to six weeks after the first dose of ustekinumab, we may give the next dose at that time rather than at eight weeks [42,43]. For patients without symptomatic improvement after an additional 8 to 12 weeks of four-to-six-week dosing, we typically switch to an alternative agent with a different mechanism of action. For patients with worsening symptoms, we may switch to an alternative agent sooner than 8 to 12 weeks. In addition to dose optimization to every four to six weeks, repeat induction dosing (ie, intravenously administered, weight-based therapy) has been effective for patients with Crohn disease, but the data for treating UC are lacking [44-47].

Mirikizumab — The induction dose of mirikizumab is 300 mg intravenously at zero, four, and eight weeks [48]. Maintenance dosing is 200 mg subcutaneously at 12 weeks after the initial dose, then every four weeks thereafter.

For patients with inadequate response at week 12, we may extend induction dosing by administering 300 mg intravenously every four weeks for three additional doses, followed by 200 mg, subcutaneously, every two weeks until week 52.

For patients with loss of response after week 12, we may escalate the dose by administering 300 mg intravenously every four weeks for three additional doses [49]. Studies on dose optimization of mirikizumab are limited.

Monitoring and adverse events — In addition to clinical observation, monitoring the response to anti-interleukin antibodies may include checking levels of biomarkers (C-reactive protein [CRP], fecal calprotectin). Time intervals for follow-up evaluations, including colonoscopy to assess for endoscopic remission, are discussed separately. (See 'Biomarkers of inflammation' above and "Management of moderate to severe ulcerative colitis in adults".)

Anti-interleukin antibodies have been associated with low risk of serious infection, although mild nasopharyngitis is a common side effect with ustekinumab and mirikizumab [41,50,51].

SMALL MOLECULES

Janus kinase (JAK) inhibitors

Pharmacology and use — The oral JAK inhibitors that are available for treating moderate to severe UC include tofacitinib and upadacitinib. JAK inhibitors decrease signaling by a number of cytokine and growth factor receptors [52,53]:

●Tofacitinib is a nonselective JAK inhibitor that inhibits JAK1, JAK2, and JAK3 enzymes

●Upadacitinib is a selective JAK inhibitor that inhibits JAK1 enzyme

Pretreatment screening — Prior to starting a JAK inhibitor, we review each patient's vaccination and exposure history (as discussed above), and we check total cholesterol and high density lipoprotein levels because JAK inhibition has been associated with increased cholesterol levels [54-56]. (See 'Pretreatment screening' above.)

Pretreatment screening includes documenting immunity to varicella (eg, varicella zoster virus [VZV] IgG, clinician diagnosis of disease). (See "Diagnosis of varicella-zoster virus infection", section on 'Serologic testing'.)

For patients with evidence of immunity who are ≥19 years old, we assess the need for and timing of zoster (shingles) vaccination, because JAK inhibition is associated with higher rates of herpes zoster infection [57,58]. These issues are discussed separately. (See "Immunizations in autoimmune inflammatory rheumatic disease in adults", section on 'Zoster vaccines' and 'Adverse events' below.)

Contraindications — We do not use JAK inhibitors in patients with active serious infections (eg, tuberculosis) or severe liver impairment. In addition, for patients with a history of thromboembolic disease (eg, history of pulmonary embolism, deep venous thrombosis), JAK inhibitors should be used with caution because of concern for increased risk of thromboembolic events and mortality in patients with rheumatoid arthritis treated with tofacitinib [59]. (See 'Dosing and administration' below and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Tofacitinib'.)

However, following studies in patients with inflammatory bowel disease (IBD) suggested that tofacitinib and upadacitinib were not associated with an increased risk of venous thromboembolism or major cardiovascular events [60,61].

Dosing and administration — Dosing for JAK inhibitors is informed by the specific agent:

●Tofacitinib – We use a tofacitinib induction dose of 10 mg twice daily (or tofacitinib XR 22 mg once daily) for eight weeks, followed by a maintenance dose of 5 mg twice daily (or tofacitinib XR 11 mg once daily) [52,59,62]. For patients with inadequate response to initial therapy after eight weeks, induction dosing may be extended for a total of 16 weeks [61]. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'Tofacitinib'.)

●Upadacitinib – We use an upadacitinib induction dose of 45 mg once daily for eight weeks, followed by a maintenance dose of 15 mg once daily [63,64]. For patients with refractory, severe, or extensive disease, a maintenance dose of 30 mg once daily may be appropriate.

Monitoring — Obtaining biomarkers of inflammation, including fecal calprotectin and C-reactive protein (CRP), can help guide therapy to achieve endoscopic and clinical remission in patients with UC [23]. Time intervals for follow-up evaluations, including colonoscopy to assess for endoscopic remission and monitoring lipid levels, are discussed separately. (See "Management of moderate to severe ulcerative colitis in adults", section on 'Janus kinase (JAK) inhibitors' and 'Biomarkers of inflammation' above.)

Adverse events — The relative safety of JAK inhibitors has generally appeared similar to that of biologic agents used for treating UC; however, additional concerns that require attention include risk of herpes zoster infection and thromboembolism [57,58,61,65,66]. (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Tofacitinib' and 'Contraindications' above.)

Risk factors for thrombosis or cardiovascular events include history of inherited hypercoagulable disorder, thromboembolism, cardiovascular disease, hyperlipidemia, or malignancy; use of combined estrogen-progestin oral contraceptives or hormone replacement therapy; or patients undergoing major surgery. (See "Overview of the causes of venous thrombosis" and "Overview of established risk factors for cardiovascular disease" and "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use".)

Tofacitinib and upadacitinib have been associated with higher rates of herpes zoster infection, particularly for patients receiving higher maintenance doses [57,58,63]. As an example, in a study including 592 patients with UC, the incidence rate of herpes zoster was higher for patients on maintenance therapy with tofacitinib 10 mg twice daily versus placebo (6.6 per 100 person-years [95% CI 3.2-12.2] versus 1 per 100 person-years [95% CI 0.0-5.4]) [57]. However, the rate of herpes zoster was not significantly different for patients on tofacitinib 5 mg twice daily versus placebo. (See 'Pretreatment screening' above.)

Sphingosine 1-phosphate (S1P) receptor modulators — Sphingosine-1-phosphate (S1P) receptor modulators for treating moderate to severe UC include ozanimod and etrasimod. (See "Clinical use of oral disease-modifying therapies for multiple sclerosis", section on 'Ozanimod' and "Management of moderate to severe ulcerative colitis in adults", section on 'Sphingosine-1-phosphate (S1P) receptor modulators'.)

●Pharmacology and use – Ozanimod and etrasimod are both S1P receptor modulators but have slightly different target receptors. Ozanimod is a S1P receptor 1 and 5 modulator, whereas etrasimod is a S1P 1, 4 and 5 receptor modulator. S1P is a signaling molecule for immune activation. S1P receptors play an important role in lymphocyte trafficking and immune activation.

●Pretreatment evaluation – Prior to initiating an oral S1P receptor modulator, we obtain complete blood count including lymphocyte count, liver biochemical tests, and an electrocardiogram to screen for cardiac conduction abnormalities. Prior to starting ozanimod, patients at risk (ie, those with a history of diabetes or uveitis) undergo ophthalmic evaluation to screen for uveitis or macular edema. Prior to initiating etrasimod, all patients undergo ophthalmic evaluation and dermatologic evaluation. Patients should also be tested for antibodies to varicella zoster virus (VZV), and seronegative patients who are not yet immunosuppressed should have VZV vaccination. (See "Immunizations in autoimmune inflammatory rheumatic disease in adults".)

S1P receptor modulators are contraindicated in patients with myocardial infarction, unstable angina, stroke, transient ischemic attack, or heart failure in the last six months. Additional contraindications include patients with Mobitz type II second- or third-degree atrioventricular block, sick sinus syndrome, sinoatrial block (unless the patient has a functioning pacemaker), and severe, untreated sleep apnea. These agents are also contraindicated for patients taking a monoamine oxidase inhibitor.

We advise patients using ozanimod to avoid foods and beverages that contain high levels of tyramine. (See "Monoamine oxidase inhibitors (MAOIs): Pharmacology, administration, safety, and side effects", section on 'Prescribing MAOIs'.)

●Dosing and administration – Ozanimod is titrated slowly during the first week. We use an initial ozanimod dose of 0.23 mg daily on days 1 through 4, then 0.46 mg once daily on days 5 through 7 [67]. The maintenance dose is 0.92 once daily starting on day 8.

The induction and maintenance dose for etrasimod is 2 mg orally once daily [68].

●Monitoring – Obtaining biomarkers of inflammation, including fecal calprotectin and CRP, can help guide therapy to achieve endoscopic and clinical remission in patients with UC [23]. Time intervals for follow-up colonoscopy to assess for endoscopic remission are discussed separately. (See 'Biomarkers of inflammation' above.)

●Adverse effects – In randomized trials including patients with UC who were treated with ozanimod, the most commonly reported adverse effects were anemia, nasopharyngitis, and headache [69]. In trials involving etrasimod, the most commonly reported adverse events were anemia, headache, and worsening of UC [70]. Cardiovascular events were reported infrequently and included hypertension and bradycardia.

PREGNANCY — The use of biologic agents during pregnancy and lactation is discussed elsewhere. (See "Fertility, pregnancy, and nursing in inflammatory bowel disease", section on 'Medications during pregnancy and lactation'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ulcerative colitis in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Ulcerative colitis (Beyond the Basics)" and "Patient education: Sulfasalazine and the 5-aminosalicylates (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Tumor necrosis factor inhibitors – Tumor necrosis factor (TNF)-alpha inhibitors, including infliximab, adalimumab, and golimumab, are biologic agents used for treating patients with ulcerative colitis (UC). The decision whether to use infliximab, adalimumab, or golimumab in patients requiring anti-TNF therapy is influenced by the indication, patient preference, and availability in individual countries. (See 'Introduction' above.)

•Pretreatment screening – Prior to starting a biologic agent, we review each patient's vaccination and exposure history. Ideally, this review should be performed before the start of immunosuppressive therapy, when the likelihood of developing a protective immune response to any needed vaccine is highest, and when live vaccines can be given safely. (See 'Pretreatment screening' above and "Medical management of low-risk adult patients with mild to moderate ulcerative colitis", section on 'Approach to vaccination'.)

•Contraindications – Contraindications to the use of anti-TNF therapies (briefly summarized) include (see 'Contraindications' above and "Treatment of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults", section on 'Use of TNF inhibitors'):

-Active, uncontrolled infection

-Latent (untreated) tuberculosis

-Demyelinating disease (eg, multiple sclerosis, optic neuritis)

-Uncontrolled heart failure (NYHA classes III or IV)

-Active malignancy

The safety of anti-TNF therapies and risk of recurrent malignancy in patients with a history of malignancy is less well established than in patients without such a history; these issues are discussed separately. (See "Tumor necrosis factor-alpha inhibitors: Risk of malignancy".)

•Monitoring – In addition to clinical observation, monitoring the response to anti-TNF agents may include therapeutic drug monitoring (checking drug trough levels, antidrug antibodies), biomarker levels (eg, fecal calprotectin, C-reactive protein [CRP]), and colonoscopy with biopsies. (See 'Monitoring' above.)

•Adverse events – Potential adverse events associated with TNF-alpha inhibitors include (see 'Adverse events' above and "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects"):

-Infection

-Malignancy

-Induction of autoimmunity

-Demyelinating disease

-Heart failure

-Injection site reactions

-Infusion reactions

-Neutropenia

-Cutaneous reactions, including psoriasiform lesions

●Anti-integrin antibodies – For treating patients with moderately to severely active UC, vedolizumab is a recombinant humanized, monoclonal antibody, developed as a gut-selective anti-integrin specifically targeting alpha-4-beta-7 integrin in the gastrointestinal tract. Vedolizumab is not typically associated with systemic immunosuppression because it interferes with lymphocyte trafficking limited to the gastrointestinal tract. (See 'Anti-integrin antibodies' above.)

●Anti-interleukin antibodies – Anti-interleukin antibody-based therapy (eg, ustekinumab, mirikizumab) is used for treating patients with moderate to severe UC. Ustekinumab is an anti-interleukin 12/23 antibody, whereas mirikizumab targets the p19 subunit of interleukin-23. Anti-interleukin antibodies have been associated with durable efficacy and overall low risk of serious infection.

●Small molecules – For treating patients with moderately to severely active UC, tofacitinib and upadacitinib are orally-administered JAK inhibitors that decrease signaling by a number of cytokine and growth factor receptors. Potential adverse events associated with JAK inhibitors include herpes zoster infection and thromboembolism in at-risk patients. Other small molecules for treating UC include the sphingosine 1-phosphate (S1P) receptor modulators, ozanimod and etrasimod, which play a role in lymphocyte tracking and activation of the immune system. Adverse events are uncommon, but it is important that patients undergo pretreatment testing. (See 'Small molecules' above.)

ACKNOWLEDGMENTS

The UpToDate editorial staff acknowledges Yousif I A-Rahim, MD, who contributed to earlier versions of this topic review.

The UpToDate editorial staff acknowledges Paul Rutgeerts, MD, who contributed as a section editor for UpToDate in Gastroenterology.