Management of moderate to severe ulcerative colitis in adults

INTRODUCTION — Ulcerative colitis (UC) is a chronic inflammatory condition of the large intestine that is limited to the mucosal layer of the colon. It almost always involves the rectum, and may extend in a proximal and continuous fashion to involve other portions of the colon. The pattern of disease activity is characterized by periods of active inflammation alternating with periods of remission.

Most patients with UC are treated with pharmacologic therapy, and multiple drugs are available. Therapies can be grouped as induction therapies (ie, relatively rapid onset of action) and maintenance therapies (ie, appropriate for long-term use). Some therapies (eg, biologic agents, small molecules) are used for both induction and maintenance of remission. While glucocorticoids may be used for inducing remission, they are not effective or suitable for maintaining remission. As a result, the term "maintenance of remission" refers to glucocorticoid-free remission.

The focus of this topic is the medical management of adult patients with moderate to severe UC in an ambulatory setting. The management of patients who require hospitalization for management of severe UC is discussed separately. (See "Management of the hospitalized adult patient with severe ulcerative colitis".)

The surgical management of UC is discussed separately. (See "Surgical management of ulcerative colitis".)

Medical management of adult patients with mild to moderate UC is discussed separately. (See "Medical management of low-risk adult patients with mild to moderate ulcerative colitis".)

DISEASE ACTIVITY, SEVERITY, AND RISK

Defining overall disease activity — Clinical trials of UC often use formal grading systems to describe disease activity. The severity of UC is generally classified as mild, moderate, or severe disease; however, the definition of moderate to severe disease activity may vary in the literature depending on the specific index or score being used (eg, Truelove and Witts severity index [1], Mayo Clinic score [2], Montreal classification [3]).

In clinical practice, the following definitions of moderate and severe disease may be more useful:

●Mild – Patients with mild clinical disease have ≤4 stools per day with or without small amounts of blood, no signs of systemic toxicity (eg, no tachycardia), and a normal C-reactive protein (CRP) and/or erythrocyte sedimentation rate (ESR). Mild crampy abdominal pain, tenesmus, and periods of constipation are also common, but severe abdominal pain, profuse bleeding, fever, and weight loss are not part of the spectrum of mild disease.

●Moderate – Patients with moderate clinical disease may have frequent (four to six per day) loose, bloody stools, mild anemia not requiring blood transfusions (hemoglobin >10 g/dL [100 g/L]), and abdominal pain that is not severe. Patients have no or minimal signs of systemic toxicity. Adequate nutrition is usually maintained and weight loss is not associated with moderate clinical disease.

●Severe – Patients with severe clinical disease typically have frequent loose bloody stools (≥6 per day) with severe cramps and evidence of systemic toxicity as demonstrated by a fever (temperature ≥37.8°C), tachycardia (heart rate ≥90 beats per minute), anemia (hemoglobin <10.0 g/dL [100 g/L]), and/or an elevated CRP or ESR. Patients may have weight loss. Management of hospitalized patients with severe UC is discussed separately. (See "Management of the hospitalized adult patient with severe ulcerative colitis".)

In addition, patients may have moderate to severe disease at the time of presentation, or they may have progressive disease that was initially mild.

Defining disease extent — We use the following terminology to describe the extent of involvement of UC (see "Endoscopic diagnosis of inflammatory bowel disease in adults", section on 'Differentiating ulcerative colitis from Crohn disease'):

●Ulcerative proctitis – Ulcerative proctitis refers to disease limited to the rectum, often extending 15 to 20 cm proximal to the anal verge and distal to the rectosigmoid junction

●Ulcerative proctosigmoiditis – Ulcerative proctosigmoiditis refers to disease limited to the rectum and sigmoid colon and not involving the descending colon

●Left-sided colitis – Left-sided colitis refers to disease that extends beyond the sigmoid colon and as far proximally as the splenic flexure or 60 cm from the anal verge.

●Extensive colitis or pancolitis – Extensive colitis refers to disease extending proximal to the splenic flexure (or beyond 60 cm from the anal verge); when disease affects the entire colon, the term "pancolitis" is often used.

Colonoscopy with biopsy is required to determine the extent of involvement, as the distribution of mucosal inflammation may progress or recede over time and histologic involvement can predict risk for glucocorticoid use, hospitalization, and dysplasia [4-6].

Assessing endoscopic disease activity — The degree of disease inflammation can be assessed with endoscopic evaluation for mucosal ulcerations and disease extent. Different scores have been used to assess severity of endoscopic lesions, and the Mayo endoscopic score of activity is commonly used in drug studies [2]. The Mayo endoscopic subscore ranges from 0 to 3, while the Mayo score for assessing UC activity ranges from 0 to 12 (calculator 1). For example, endoscopic features of moderately active UC include marked erythema, absent vascular pattern, friability, and erosions, while features of severely active disease include spontaneous bleeding and ulceration [2]. The endoscopic appearance of UC is discussed in more detail separately. (See "Endoscopic diagnosis of inflammatory bowel disease in adults", section on 'Differentiating ulcerative colitis from Crohn disease'.)

The severity of the endoscopic appearance of the colonic mucosa is included in the assessment of risk for disease relapse and need for hospitalization or colectomy [7]. (See 'Assessing risk for long-term sequelae' below.)

Assessing risk for long-term sequelae — For patients with moderate to severe UC, any of the following features may predict a higher risk for long term sequelae (eg, colectomy) [6,8,9]:

●Extensive colitis (see 'Defining disease extent' above).

●Deep colonic ulcers (see "Endoscopic diagnosis of inflammatory bowel disease in adults", section on 'Differentiating ulcerative colitis from Crohn disease').

●Age <40 years.

●Elevated CRP [10] and/or ESR.

●Glucocorticoid requirement to maintain remission [11].

●History of hospitalization for UC [12].

●Co-existing infection (Clostridioides difficile infection or cytomegalovirus infection).

Definitions based on glucocorticoid use — We use the following definitions of UC based on clinical response (ie, fewer episodes of diarrhea, no bleeding) to oral glucocorticoid therapy [6,13,14]:

●Glucocorticoid-responsive disease – UC is glucocorticoid-responsive if there is a clinical response to oral prednisone (40 to 60 mg daily or equivalent) within 30 days.

●Glucocorticoid-dependent disease – UC is glucocorticoid-dependent if glucocorticoids cannot be tapered to less than 10 mg per day within three months of starting therapy without disease recurrence, or if relapse occurs within three months of stopping glucocorticoids.

●Glucocorticoid-refractory disease – UC is glucocorticoid-refractory if there is no clinical response to oral prednisone (40 to 60 mg per day or equivalent) within 30 days.

Assessing clinical response with intravenous glucocorticoid therapy is discussed separately. (See "Management of the hospitalized adult patient with severe ulcerative colitis", section on 'Inpatient management'.)

PRETREATMENT EVALUATION — Therapy for UC is guided by pretreatment evaluation (laboratory studies and lower endoscopy), and the goals are to exclude alternative or co-existing conditions and determine the extent and severity of disease. The approach to the pretreatment evaluation for ambulatory patients with UC is discussed separately. (See "Medical management of low-risk adult patients with mild to moderate ulcerative colitis", section on 'Pretreatment evaluation'.)

INDUCTION OF REMISSION

Goals of therapy — The treatment goal for patients with active UC is to achieve glucocorticoid-free remission (endoscopic and clinical remission) by demonstrating complete mucosal healing [6]. Evidence is still evolving for histologic remission in UC, but it is not yet supported as a primary treatment target. Response to therapy can be determined by assessing symptoms, laboratory testing, and supplemented by endoscopy with biopsies as needed.

Our therapeutic approach for induction of remission for patients with moderate to severe UC reflects society guidance [6,15].

Selecting induction therapy — Selecting induction therapy for patients with moderate to severe UC takes into account several factors including coexisting inflammatory conditions (ie, inflammatory arthritis, psoriasis, multiple sclerosis, or enteropathic arthritis), patient preferences, patient characteristics (eg, age), risk of adverse events (eg, infection, malignancy), other medication use, prior therapy for UC, accessibility to an infusion center, patient compliance, and coverage of medication costs by payers [16]. The plan for long-term maintenance therapy is also factored into choosing an induction regimen.

Because multiple factors inform the decision to begin a specific induction regimen, the choice is individualized and decision-making is shared with the patient. This selection process results in treatment variability among patients with UC. For the patient with moderate to severe UC, first-line induction therapy options include biologic agents (with or without an immunomodulator [eg, azathioprine, 6-mercaptopurine]), oral sphingosine-1-phosphate (S1P) receptor modulators, or glucocorticoids. (See 'Specific initial regimens' below.)

As an example, we typically use an induction regimen of an anti-TNF agent (with or without an immunomodulator) for patients who have coexisting inflammatory disease such as rheumatoid arthritis, ankylosing spondylitis, or other conditions treated with anti-TNF therapy [17]. For patients with psoriasis or psoriatic arthritis, we may use ustekinumab or mirikizumab as initial induction therapy. For patients with multiple sclerosis or other demyelinating condition, we may initiate a S1P receptor modulator (eg, ozanimod, etrasimod) and avoid anti-TNF therapy.

For most patients who are ≥65 years old or who have a history of recent infection (eg, pneumonia within the previous three months), we typically use vedolizumab or an anti-interleukin agent (ustekinumab or mirikizumab) for induction therapy because these agents have not been associated with increased risk of serious infection. (See 'Specific initial regimens' below.)

Product labeling indicates that use of oral JAK inhibitors is limited to second-line therapy after an anti-TNF agent. This is in contrast to clinical trial design and the initial regulatory approval of a JAK inhibitor for UC. (See 'Nonresponders to initial therapy' below.)

Specific initial regimens

Anti-tumor necrosis factor (TNF) agent-based therapy — Anti-TNF therapy with or without an immunomodulator (eg, azathioprine, 6-mercaptopurine) is used to induce remission in patients with moderate to severe UC [18-20]. The expected time frame for a clinical response ranges from a few days to up to eight weeks [21].

The pretreatment screening, dosing, monitoring, and adverse effects of anti-TNF agents are discussed separately. (See "Overview of dosing and monitoring of biologic agents and small molecules for treating ulcerative colitis in adults".)

The pretreatment screening, dosing, monitoring and adverse effects of thiopurines are discussed separately. (See "Overview of azathioprine and mercaptopurine use in inflammatory bowel disease".)

For patients who do not tolerate thiopurines (azathioprine or 6-mercaptopurine), we use methotrexate as an alternative immunomodulator [22]. For patients taking methotrexate, folic acid (1 mg daily) is given because folic acid supplementation may reduce gastrointestinal symptoms and aminotransferase elevations associated with the drug. Further discussion regarding prevention and management of adverse effects related to methotrexate, including hepatotoxicity, is found elsewhere. (See "Major side effects of low-dose methotrexate" and "Hepatotoxicity associated with chronic low-dose methotrexate for nonmalignant disease" and "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Precautions and prevention of adverse effects'.)

Combination therapy with an anti-TNF agent (infliximab) and an immunomodulator (eg, azathioprine) was more effective for inducing remission when compared with anti-TNF monotherapy or thiopurine monotherapy [20,23]. In a trial of 239 patients with moderate to severe UC who had not previously received anti-TNF agents, patients received treatment with infliximab, azathioprine, or combination therapy. At 16 weeks, patients who were treated with infliximab plus azathioprine had higher rates of glucocorticoid-free clinical remission compared with those receiving infliximab alone or azathioprine alone (40 versus 22 and 24 percent, respectively). Serious infections were not more common in patients receiving combination versus monotherapy.

Anti-TNF monotherapy (infliximab, adalimumab, golimumab) was effective for inducing remission in patients with UC; however, no trials directly compared agents to one another [24,25]. In a meta-analysis of six studies including 1823 patients with UC, patients treated with anti-TNF agent monotherapy were more likely to achieve remission compared with patients given placebo (relative risk [RR] 2.45, 95% CI 1.72-3.47) [24].

Vedolizumab — We use vedolizumab (an anti-integrin antibody) to induce remission for patients with moderate to severe UC, and the pretreatment screening, dosing, administration, and adverse effects of vedolizumab are discussed separately. (See "Overview of dosing and monitoring of biologic agents and small molecules for treating ulcerative colitis in adults", section on 'Anti-integrin antibodies'.)

In addition, we prefer vedolizumab to an anti-TNF for initial therapy for patients who are at higher risk for infection or malignancy (eg, older patients, those with history of malignancy, or those with recent history of serious infection [eg, pneumonia]) because vedolizumab is gut-selective and is not associated with an increased risk of serious infection or malignancy [26,27].

Most patients will have symptomatic improvement within six weeks of the initial vedolizumab dose [26].

Vedolizumab was effective for inducing remission in patients with moderately to severely active UC [26,27]. In a systematic review of three studies including over 600 patients with UC, patients given vedolizumab were less likely to fail to achieve clinical remission after six weeks of therapy compared with placebo (48 versus 72 percent, RR 0.68, 95% CI, 0.59 to 0.78) [27].

Whether or not vedolizumab is more effective than anti-TNF agent monotherapy (adalimumab) for inducing and maintaining clinical remission is unclear. In a randomized trial including 769 patients with moderate to severe UC, patients assigned vedolizumab had higher rates of clinical remission (defined as total Mayo score ≤2 and no subscore >1 (calculator 1)) compared with patients assigned adalimumab (31 versus 22 percent; difference 9 percent, 95% CI 2-15) [28]. However, rates of glucocorticoid-free clinical remission were lower in the vedolizumab group (13 versus 22 percent; difference -9 percent, 95% CI -18.9 to 0.4), although this was not statistically significant. Serious adverse events were numerically lower with vedolizumab (11 versus 14 percent), but rates of serious infections were similar (2 percent in each group).

Anti-interleukin antibody-based therapy — Anti-interleukin antibody-based therapy (eg, ustekinumab, mirikizumab) is used to induce remission in patients with moderate to severe UC:

●Ustekinumab — Ustekinumab (an anti-interleukin 12/23 antibody) has been approved by the US Food and Drug Administration (FDA) for the treatment of moderate to severe UC [29]. Ustekinumab may be used for patients who are naïve to biologics and for patients who have not responded to other immunosuppressants [29,30]. However, failure to respond to an anti-TNF agent is not required prior to using ustekinumab. We typically use ustekinumab as monotherapy, although we may use it in combination with an immunomodulator for some patients (eg, those who have not responded to other biologic therapy).

Induction therapy with ustekinumab is given intravenously with weight-based dosing. Maintenance dosing is 90 mg subcutaneously every eight weeks. 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 next dose at that time rather than at eight weeks. For patients without symptomatic improvement after an additional 8 to 12 weeks of every four-to-six-week dosing, we typically switch to an alternative agent. For patients with worsening symptoms, we may switch to an alternative agent sooner than 8 to 12 weeks.  

We typically use ustekinumab as monotherapy because reported rates of antidrug antibody formation in patients with ulcerative colitis have been low (ie, <5 percent) [29].

Pretreatment screening is similar to testing performed prior to initiating anti-TNF therapy (eg, hepatitis B surface antigen, screening for latent tuberculosis), and this is discussed separately. (See "Overview of dosing and monitoring of biologic agents and small molecules for treating ulcerative colitis in adults", section on 'Pretreatment screening'.)

Ustekinumab was effective for inducing remission in patients with moderate to severe UC. In a trial including 961 patients with moderate to severe UC, patients assigned ustekinumab (either 130 mg or 6 mg/kg) had higher rates of clinical remission (defined as total Mayo score ≤2 and no subscore >1 (calculator 1)) at week 8 compared with placebo (16 and 16 percent, respectively, versus 5 percent) [31]. Rates of endoscopic improvement (defined as Mayo endoscopic subscore ≤1) were also higher in the ustekinumab group (26 and 27 percent, respectively, versus 14 percent). Rates of serious adverse events were not numerically higher for patients on ustekinumab compared with placebo.

●Mirikizumab — Mirikizumab (a monoclonal antibody that targets the p19 subunit of interleukin-23) was approved by the FDA for patients with moderate to severe UC who are naïve to biologics or have not responded to other immunosuppressants [32]. We typically use mirikizumab as monotherapy, although we may use it in combination with an immunomodulator for some patients (eg, those who have not responded to other biologic therapy).

The induction dose of mirikizumab is 300 mg, intravenously, at zero, four, and eight weeks [33]. Maintenance dosing is 200 mg subcutaneously at 12 weeks after the initial dose, then every four weeks thereafter.

Pretreatment screening is similar to testing that is performed prior to initiating anti-TNF therapy (eg, hepatitis B surface antigen, screening for latent tuberculosis). These issues are discussed separately. (See "Overview of dosing and monitoring of biologic agents and small molecules for treating ulcerative colitis in adults", section on 'Pretreatment screening'.)  

Mirikizumab was effective for inducting remission in patients with moderate to severe UC [32]. In a trial including 1281 patients with moderate to severe UC who did not respond to prior therapy, mirikizumab (300 mg, administered intravenously at weeks 0, 4, and 8) resulted in higher rates of clinical remission at week 12 compared with placebo (24.2 versus 13.3 percent; absolute difference 11.1 percentage points, 99.9% CI 3.2-19.1) [32]. Rates of serious adverse events were numerically similar in both groups.

Sphingosine-1-phosphate (S1P) receptor modulators — Two oral S1P receptor modulators (ozanimod and etrasimod) have been approved in the United States for treating adults with moderate to severe UC [34-36]. Use of S1P receptor modulators does not require previous failure of immunosuppressants, glucocorticoids, biologics, or other small molecules. Data have suggested that most patients have symptomatic improvement (fewer stools, less rectal bleeding) within two weeks of initiating therapy [37].

Prior to initiating an oral S1P receptor modulator, we obtain complete blood count including lymphocyte count, liver biochemical and function tests, and an electrocardiogram to screen for preexisting cardiac conduction abnormalities. Prior to starting ozanimod, patients with a history of diabetes or uveitis undergo ophthalmic evaluation. For etrasimod, all patients undergo ophthalmic evaluation, and they also have a dermatologic examination prior to or shortly after starting therapy. The pretreatment evaluation before initiating S1P receptor modulators and drug dosing are discussed separately. (See "Overview of dosing and monitoring of biologic agents and small molecules for treating ulcerative colitis in adults", section on 'Sphingosine 1-phosphate (S1P) receptor modulators' and "Clinical use of oral disease-modifying therapies for multiple sclerosis", section on 'Ozanimod'.)

General laboratory monitoring for patients on maintenance therapy is discussed below. (See 'Monitoring' below.)

Ozanimod was effective for inducing remission for patients with UC. In a randomized trial including 645 patients with moderate to severe UC, clinical remission rates at ten weeks were higher with ozanimod (1 mg daily) compared with placebo (18 versus 6 percent, absolute difference 12 percentage points, 95% CI 8-17) [37]. Overall rates of adverse events were numerically similar in both groups. The most commonly reported adverse events in the ozanimod group were anemia (4 percent), nasopharyngitis (4 percent), and headache (3 percent). Cardiovascular events were reported infrequently in the ozanimod group and included hypertension (1 percent) and bradycardia (0.5 percent).

Etrasimod was effective for inducing remission for patients with moderate to severe UC [38,39]. In two trials (ELEVATE UC 52 and ELEVATE UC 12), a total of 787 patients with moderate to severe UC who had inadequate or loss of response to at least one prior therapy were randomized to receive etrasimod 2 mg daily or placebo [38]. After 12 weeks, etrasimod resulted in higher rates of clinical remission (ELEVATE UC 52: 27 versus 7 percent and ELEVATE UC 12: 25 versus 15 percent). Nine patients receiving etrasimod developed bradycardia within two days of starting therapy, whereas no bradycardia occurred in the placebo group. Seven patients with bradycardia were asymptomatic, and bradycardia resolved in the symptomatic patients after discontinuing treatment.

Glucocorticoids — Systemic oral glucocorticoids are used for inducing remission in patients with moderate to severe UC or may be given to provide more immediate symptom relief for patients who are started on a biologic agent for induction therapy. Glucocorticoids should not be used long-term because of the side effect profile and also because they are not used for maintaining disease remission. (See "Major adverse effects of systemic glucocorticoids" and 'Maintenance of remission' below.)

We typically start oral prednisone at a dose of 40 mg daily, and most patients who respond to oral glucocorticoids have symptomatic improvement (fewer bowel movements, less or no bleeding) within one week. After clinical remission has been achieved (ie, formed stools, no blood), we generally taper prednisone by either 5 mg or 10 mg increments on a weekly or semiweekly basis. If symptoms recur during the glucocorticoid taper, the last effective dose may be resumed. The pretreatment evaluation for glucocorticoid-sparing therapy (eg, thiopurine, biologic agent) is performed, if it had not been done previously. (See "Overview of azathioprine and mercaptopurine use in inflammatory bowel disease" and "Overview of dosing and monitoring of biologic agents and small molecules for treating ulcerative colitis in adults".)

The duration of glucocorticoid therapy depends on clinical response as well as ability to successfully taper without symptom recurrence. If clinical response is not achieved after one to four weeks of therapy, or if symptoms worsen despite glucocorticoid therapy, we evaluate for potential causes of nonresponse (eg, co-existing infection), and some patients may require inpatient hospitalization. (See "Management of the hospitalized adult patient with severe ulcerative colitis".)

For patients who have been treated with glucocorticoids for greater than three months, a slower taper may be needed to avoid adrenal insufficiency, and this is discussed separately [40]. (See "Glucocorticoid withdrawal".)

Glucocorticoids were effective for inducing remission for patients with moderately to severely active UC. In a meta-analysis of five trials including 445 patients with active UC, patients given systemic glucocorticoids had a lower risk of failing to achieve remission compared with patients on placebo (RR 0.65; 95% CI 0.45-0.93) [41].

The use of budesonide for patients with mildly to moderately active UC is discussed separately. (See "Medical management of low-risk adult patients with mild to moderate ulcerative colitis", section on 'Induction of remission'.)

Nonresponders to initial therapy

Choosing subsequent therapy — For most patients who do not respond to initial biologic therapy and who have active inflammation (confirmed by endoscopy) in the absence of infection, we switch to an alternative agent from a different biologic class or a small molecule. (See 'Specific initial regimens' above and 'Small molecules' below.)

As examples:

●For patients who do not respond to infliximab despite adequate drug levels, we switch to a biologic agent from a different class (eg, ustekinumab, vedolizumab, mirikizumab) or a small molecule (eg, tofacitinib, upadacitinib, ozanimod, etrasimod) [23]. Data from clinical trials in patients who did not respond or lost response to anti-TNF agents suggested that JAK inhibitors were effective as second-line therapy in such patients, whereas third-line options include vedolizumab or an oral S1P receptor modulator [42,43]. Therapeutic drug monitoring for patients with inflammatory bowel disease on anti-TNF therapy is discussed separately. (See "Treatment of Crohn disease in adults: Dosing and monitoring of tumor necrosis factor-alpha inhibitors", section on 'Therapeutic drug monitoring'.)

●For patients who do not respond to injectable anti-TNF therapy monotherapy (eg, adalimumab, golimumab), we typically switch to a biologic agent from a different class or a small molecule. However, for nonresponders with severe UC, we may first try switching the injectable anti-TNF agent to infliximab infusion and adding azathioprine (provided that the patient is not at increased risk for thiopurine-related adverse effects [eg, young male patients], and this is discussed separately). (See "Overview of azathioprine and mercaptopurine use in inflammatory bowel disease", section on 'Adverse effects' and 'Anti-tumor necrosis factor (TNF) agent-based therapy' above.)

●For most patients who do not respond to initial biologic therapy with vedolizumab or anti-interleukin-based therapy, we typically use a regimen of infliximab combined with an immunomodulator (eg, azathioprine). (See 'Anti-tumor necrosis factor (TNF) agent-based therapy' above.)

Small molecules

Janus kinase (JAK) inhibitors — Two oral JAK inhibitors (tofacitinib and upadacitinib) were approved in the United States for treating adults with moderate to severe UC who have not responded or are intolerant to anti-TNF agent-based therapy [42,44-47]. The onset of action of JAK inhibitors varies greatly. For example, some patients have a relatively rapid response (within one week), while for other patients, response may take up to 16 weeks [43,48-50]. (See 'Selecting induction therapy' above.)

We also use JAK inhibitors for patients with another approved indication (eg, rheumatoid arthritis, ankylosing spondylitis, other spondyloarthropathies, psoriatic arthritis, atopic dermatitis) and for patients with enteropathic arthritis [47].

The following are important aspects of pretreatment screening and initiating therapy (see "Overview of dosing and monitoring of biologic agents and small molecules for treating ulcerative colitis in adults", section on 'Small molecules'):

●Caution should be used when prescribing JAK inhibitors for patients with a history of thromboembolic disease, cardiovascular disease, or those ≥50 years old with at least one cardiovascular risk factor because of data showing a higher risk of thromboembolic events and mortality in patients with rheumatoid arthritis who have those risk factors and were treated with tofacitinib compared with those treated with an injectable anti-TNF agent [51-54].

The FDA issued a safety report on the risk of serious adverse events (ie, cardiovascular events, thrombosis, and malignancy) related to the use of tofacitinib [52]. In an open-label trial with median follow-up of four years that included 4362 patients with rheumatoid arthritis who were at least 50 years of age and had at least one cardiac risk factor, tofacitinib (5 or 10 mg twice daily) resulted in an increased risk of malignancy, particularly lung cancer and lymphoma, (HR 1.48, 95% CI 1.04-2.09) and a nonsignificant trend toward increased risk of major adverse cardiovascular events (defined as cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke; HR 1.33, 95% CI 0.91-1.94) compared with anti-TNF agents [52,54]. The FDA advised screening patients with inflammatory disorders for cardiovascular and malignancy risk factors and limiting use of tofacitinib to patients with inadequate response to anti-TNF agents. (See "Overview of the Janus kinase inhibitors for rheumatologic and other inflammatory disorders", section on 'Adverse effects'.)

We use JAK inhibitors in patients with UC, although with more caution in those with relevant risk factors, and we monitor such patients for symptoms and signs of thromboembolic events. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism" and "Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity".)

●Prior to initiating JAK inhibitors or shortly after starting therapy, we advise administration of the non-live recombinant zoster (shingles) vaccine to adult patients with evidence of immunity to varicella because JAK inhibitors are associated with higher rates of herpes zoster infection [42]. (See "Immunizations in autoimmune inflammatory rheumatic disease in adults", section on 'Zoster vaccines'.)

●We check total cholesterol and high-density lipoprotein cholesterol levels within four to eight weeks after initiating tofacitinib and within 12 weeks after initiating upadacitinib because both are associated with increased cholesterol [55]. However, whether the increase in lipids is clinically significant is uncertain.

General laboratory monitoring for patients on maintenance therapy is discussed below. (See 'Monitoring' below.)

Tofacitinib was effective for induction of remission for patients with UC. In two randomized trials (OCTAVE Induction 1 and 2 trials of 598 and 541 patients, respectively), patients with moderate to severe UC who received tofacitinib 10 mg twice daily experienced remission at eight weeks more frequently compared with those receiving placebo; for OCTAVE 1, 18 versus 8 percent (absolute difference 10, 95% CI 4-16) and for OCTAVE 2: 17 versus 4 percent (absolute difference 13, 95% CI 8-18) [42].

Upadacitinib was effective for inducing remission in patients with UC who have not responded to biologic therapy [43,56,57]. In the U-ACHIEVE trial, including 474 patients with moderate to severe UC, clinical remission rates at week 8 were higher with upadacitinib (45 mg once daily) compared with placebo (26 versus 5 percent) [43]. Upadacitinib also resulted in higher rates of endoscopic improvement (36 versus 7 percent). In another trial (U-ACCOMPLISH), including 522 patients, clinical remission rates at week 8 were higher with upadacitinib (45 mg once daily) compared with placebo (34 versus 4 percent) [43]. In both trials, patients given upadacitinib had higher rates of improvement in stool frequency and absence of rectal bleeding. These data show promise for using upadacitinib for patients who do not respond to biologic agents while further studies on efficacy and safety are anticipated.

Intravenous glucocorticoids — Some patients who do not respond to oral glucocorticoids (eg, prednisone 40 to 60 mg per day) within one to four weeks of initiating therapy may respond to intravenous glucocorticoids [58-60]. The management of patients with severe UC who require hospitalization for intravenous glucocorticoids is discussed separately. (See "Management of the hospitalized adult patient with severe ulcerative colitis".)

SURGERY — Patients with moderate to severe UC who have persistent symptoms (or glucocorticoid dependence) despite medical therapy or who do not tolerate the drug regimen due to adverse effects are candidates for surgery. Surgical management of UC including specific procedures (eg, total proctocolectomy with ileal pouch anal anastomosis) is discussed separately. (See "Surgical management of ulcerative colitis".)

MAINTENANCE OF REMISSION

Goals of therapy — After clinical remission has been achieved, the goal of management is to maintain glucocorticoid-free remission and prevent clinical and endoscopic relapse, and most patients with moderate to severe UC are given long-term medical therapy. The choice of therapy to maintain remission depends on the specific agent used to achieve remission, patient preferences, clinician preferences, and insurance coverage/cost.

Monitoring — Patients in clinical remission are monitored by assessing symptoms, physical examination, laboratory studies (eg, fecal calprotectin), and endoscopic assessment of inflammatory activity (eg, flexible sigmoidoscopy or colonoscopy with mucosal biopsies). The timing of reassessment varies depending upon the specific therapy (and its onset of action) and the specific monitoring tool (eg, symptoms are reassessed prior to follow-up endoscopic evaluation).

For example, we generally use the following monitoring schedule for patients who have achieved clinical remission:

●Routine laboratory monitoring:

•Complete blood count with differential and liver biochemical tests every three to four months

•Electrolytes and renal function test annually

●Endoscopic evaluation: Colonoscopy (or flexible sigmoidoscopy) with mucosal biopsies in six months, while subsequent interval depends on endoscopic findings and duration of disease. (See 'Health maintenance' below.)

●Inflammatory markers: C-reactive protein (CRP) and fecal calprotectin are obtained in three to four months [61]. Monitoring serum CRP may be particularly useful in patients who have a history of an elevated CRP level with active disease that normalized after achieving remission. (See "Medical management of low-risk adult patients with mild to moderate ulcerative colitis", section on 'Monitoring during remission'.)

Patients who relapse — Some patients will experience disease relapse (eg, recurrent symptoms, laboratory or endoscopic evidence of inflammation) after achieving remission, and we evaluate such patients for co-existing conditions (eg, infectious colitis), exacerbating factors (eg, recent antibiotic use, life stress), and medication non-compliance. (See 'Pretreatment evaluation' above.)

For patients who initially responded to biologic therapy but then relapse (confirmed by endoscopic exam), options include optimizing the drug dose, switching to an alternative biologic agent in the same drug class, or switching to an agent from a different drug class (table 1). The preferred approach depends on the available alternatives for subsequent therapy, drug levels, and antidrug antibody levels [6,15,62]. For example (see 'Specific initial regimens' above):

●For patients with low drug levels and no (or low) antidrug antibody levels, the drug dose is typically escalated.

●For most patients with high levels of neutralizing antidrug antibodies, we switch to another biologic agent within the same therapeutic class if available (eg, a different anti-tumor necrosis factor (TNF) agent and add an immunomodulator). If there are no alternatives within the same biologic class, we switch to a drug from a different class.

Therapeutic drug monitoring and suggested drug levels for patients with inflammatory bowel disease are discussed in greater detail separately. (See "Overview of dosing and monitoring of biologic agents and small molecules for treating ulcerative colitis in adults", section on 'Therapeutic drug monitoring'.)

Specific regimens based on induction response

Anti-TNF agent-induced remission — For patients who achieved clinical and endoscopic remission with an anti-TNF-based regimen, the approach to maintenance therapy is as follows:

●For patients on combination therapy (anti-TNF agent plus an immunomodulator), we continue long-term anti-TNF therapy. Prior to withdrawing immunomodulator therapy, we perform colonoscopy with biopsies to confirm mucosal healing and histologic remission, and we obtain anti-TNF drug trough levels to confirm that the anti-TNF drug level is optimized. (See "Overview of dosing and monitoring of biologic agents and small molecules for treating ulcerative colitis in adults", section on 'Therapeutic drug monitoring'.)

The duration of immunomodulator therapy depends on the patient's previous response to biologic therapy (see 'Thiopurines' below and "Overview of azathioprine and mercaptopurine use in inflammatory bowel disease"):

•For patients on combination therapy who have not failed other biologic agents previously, we may attempt to discontinue the immunomodulator after they have sustained clinical and endoscopic remission for a minimum of six months (typically much longer).

•For patients who had failed one other biologic agent (in the absence of antidrug antibodies) before achieving remission with combination therapy, we continue the immunomodulator for a minimum of 12 months before discussing whether to discontinuing it.

•For patients who failed more than one biologic agent and/or have made antidrug antibodies to a previous biologic, we usually continue combination therapy for >12 months.

●For patients on anti-TNF monotherapy, we continue long-term anti-TNF therapy to maintain remission.

Standard maintenance dosing, options for dose escalation, and laboratory monitoring for patients with UC on anti-TNF maintenance therapy are discussed separately. (See "Overview of dosing and monitoring of biologic agents and small molecules for treating ulcerative colitis in adults", section on 'Tumor necrosis factor inhibitors'.)

Anti-TNF agents were effective for maintaining remission for patients with UC who achieved remission with an anti-TNF agent. In a systematic review of three trials including over 1000 patients with UC, patients on long term anti-TNF therapy were more likely to maintain clinical remission compared with placebo (relative risk [RR] 2.00, 95% CI 1.52-2.62) [24].

Vedolizumab-induced remission — For patients who achieved remission with vedolizumab, we continue long-term vedolizumab therapy to maintain remission. Standard maintenance dosing, options for dose escalation, and laboratory monitoring for patients on vedolizumab is discussed separately. (See "Overview of dosing and monitoring of biologic agents and small molecules for treating ulcerative colitis in adults", section on 'Anti-integrin antibodies'.)

If disease relapse occurs during vedolizumab therapy, dose escalation (typically by shortening intravenous dosing interval to every four weeks) is reasonable, in addition to evaluating for co-existing conditions or exacerbating factors [63]. We do not routinely check antidrug antibodies because they rarely occur with vedolizumab use. (See 'Monitoring' above and 'Patients who relapse' above.)

If dose escalation does not result in clinical response, patients are switched to an alternative therapy from another biologic class (eg, anti-TNF agent). (See 'Specific initial regimens' above.)

Vedolizumab was effective for maintaining remission for patients with UC. In a 52-week maintenance trial including 373 patients with UC, patients on vedolizumab were less likely to have clinical relapse compared with patients on placebo (54 versus 84 percent, RR 0.67, 95% CI 0.59-0.77) [26,27].

Anti-interleukin agent-induced remission — For patients who achieved clinical and endoscopic remission with an anti-interleukin agent, the approach to maintenance therapy is as follows:

●Ustekinumab-induced remission – For patients who achieve remission with ustekinumab, it is continued for long-term maintenance therapy. For patients who relapse on ustekinumab, dose escalation (typically by shortening the dosing interval to every four to six weeks) is reasonable in addition to evaluating for co-existing conditions or exacerbating factors (see 'Pretreatment evaluation' above). We do not routinely check antidrug antibodies, which rarely occur with ustekinumab therapy. (See 'Patients who relapse' above.)

Ustekinumab was effective for maintaining remission for patients with moderate to severe UC who achieved remission with ustekinumab. In a trial including 523 patients with moderate to severe UC who had an initial response to ustekinumab, patients on ustekinumab (90 mg every 8 weeks or every 12 weeks) had higher rates of maintaining clinical remission at 44 weeks compared with placebo (44 and 38 percent, respectively, versus 24 percent) [31]. Rates of glucocorticoid-free remission were also higher in the ustekinumab groups compared with placebo (42 and 38 percent, respectively, versus 23 percent). (See 'Anti-interleukin antibody-based therapy' above.)

●Mirikizumab-induced remission – For patients who achieved remission with mirikizumab, it is continued for long-term maintenance therapy. For patients who relapse on mirikizumab, it is unclear whether adjusting the dose will result in clinical response or remission because data are lacking.  

Mirikizumab was effective for maintaining remission for patients with moderate to severe UC who achieved remission with mirikizumab. In a trial including 544 patients with moderate to severe UC who had initial response to mirikizumab at week 12, mirikizumab, 200 mg administered subcutaneous every four weeks, resulted in higher rates of clinical remission compared with placebo after 40 weeks (49.9 versus 25.1 percent) [32]. Rates of glucocorticoid-free remission were also higher in the mirikizumab group (44.9 versus 21.8 percent).

Glucocorticoid-induced remission — Glucocorticoids are not used for maintaining remission in UC and should be tapered while a thiopurine (eg, azathioprine) is initiated for long-term therapy. Alternatively, a biologic agent (eg, anti-TNF agent) may be used as long-term maintenance therapy for patients who achieved remission with glucocorticoid monotherapy. (See 'Anti-TNF agent-induced remission' above.)

Thiopurines — Thiopurines have a very slow onset of action, and typically take up to 12 weeks to achieve a full therapeutic effect [64]. The pretreatment screening, dosing, and adverse effects of thiopurines are discussed separately. (See "Overview of azathioprine and mercaptopurine use in inflammatory bowel disease".)

With the availability of biologic therapy, there are fewer patients with UC who are treated with thiopurines as maintenance monotherapy. In addition, thiopurines are not good options for patients who are unlikely to comply with regular laboratory monitoring or are unwilling to accept the risk of adverse effects (eg, malignancy, bone marrow suppression).

Patients with UC on thiopurine maintenance therapy had a lower risk of disease relapse or colectomy [65,66]. In a meta-analysis of six studies including 236 patients with UC, patients on a thiopurine were more likely to maintain remission compared with patients on placebo (odds ratio [OR] 2.56, 95% CI 1.51-4.34) [66]. In a cohort study of 253 patients with UC who were started on a thiopurine, patients who continued therapy were less likely to undergo colectomy within 10 years compared with patients who stopped treatment within 12 months of drug initiation (20 versus 29 percent, adjusted hazard ratio [HR] 0.39, 95% CI 0.21-0.73).

Small molecule-induced remission — For patients who achieved clinical and endoscopic remission with a small molecule, the approach to maintenance therapy is as follows:

●JAK inhibitor-induced remission – For patients who achieved remission with a JAK inhibitor, we continue long-term therapy at the lowest effective dose to maintain remission [51,67]:

•Tofacitinib – For patients who achieved clinical remission on tofacitinib (immediate release) with 10 mg twice daily (or with tofacitinib [extended-release] 22 mg once daily), drug labeling advises that clinicians reduce the dose to 5 mg twice daily (or tofacitinib extended-release, 11 mg, once daily) to minimize the risk of adverse events [68-70]. If disease relapse occurs at the lower dose, increasing the tofacitinib dose to 10 mg twice daily (or extended-release, 22 mg once daily) is reasonable. However, in our experience, most patients cannot lower the dose to 5 mg twice daily without developing relapse. Thus, most clinicians with expertise in UC do not lower the dose below 10 mg twice daily.

For patients who achieved remission with 5 mg twice daily, the same dose (or tofacitinib extended-release, 11 mg once daily) is continued for long-term maintenance.

Tofacitinib is effective for maintenance of remission in patients with UC. In a trial including 593 patients who had clinical response to tofacitinib and were followed 52 weeks, rates of sustained remission were higher in patients receiving tofacitinib 5 mg or 10 mg daily (34.5 and 40.6 percent, respectively) compared with placebo (11.1 percent); absolute percent difference for 5 mg dose was 23.2 (95% CI 15.3-31.2) and for 10 mg, 29.5 (95% CI 21.4-37.6) [42]. As compared with placebo, tofacitinib was associated with more overall infections and more cases of herpes zoster, although the absolute risk differences were low. (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Tofacitinib'.)

•Upadacitinib – For patients who achieved clinical remission with upadacitinib 45 mg daily, the dose is reduced after eight weeks of therapy to minimize risk of adverse events. For patients who had extensive, severe, or refractory disease prior to achieving clinical remission, the upadacitinib maintenance dose is 30 mg daily; for other patients, the maintenance dose is 15 mg daily [47,71].

In our experience, some patients relapse when the upadacitinib dose is lowered to less than 45 mg once daily. For such patients, we increase the dose back to 45 mg once daily for four weeks. For patients who achieve clinical remission, we resume a lower dose of upadacitinib 30 mg once daily and continue it for long-term maintenance.

Data suggest that upadacitinib is effective for maintaining remission in patients with UC. In a trial of 451 adults with moderate to severe UC who achieved clinical response with upadacitinib and were followed for 52 weeks, rates of sustained clinical remission were higher for patients receiving upadacitinib, 15 mg or 30 mg, compared with placebo (42 and 52 percent, respectively, versus 12 percent) [43]. Similarly, rates of glucocorticoid-free clinical remission were higher with upadacitinib, 15 mg or 30 mg, compared with placebo (57 and 68 percent, respectively, versus 22 percent). In addition, upadacitinib resulted in higher rates of endoscopic improvement (49 and 62 percent, respectively, versus 14 percent) and in higher scores on health-related quality of life measures [43]. The rates of adverse events were similar in the treatment and placebo groups. In a subsequent analysis from the maintenance trial (U-ACHIEVE), upadacitinib 30 mg daily resulted in a longer duration of sustained remission compared with upadacitinib 15 mg daily (34.4 versus 30.5 weeks) [71].

●S1P receptor modulator-induced remission

•Ozanimod – For patients who achieved remission with ozanimod, we continue long-term ozanimod therapy as data showed that ozanimod was effective for maintaining remission. In a trial including 457 patients with moderate to severe UC who achieved clinical response with ozanimod and were followed through week 52, rates of clinical remission were higher with ozanimod compared with placebo (37 versus 18 percent; absolute difference 19, 95% CI 11-26) [37]. Increased alanine aminotransferase levels were reported more frequently in the ozanimod group (4.8 versus 0.4 percent), although statistical analysis was not provided. Rates of serious infection were numerically similar in both groups (ie, less than 2 percent). In an open-label, extension study with >4 years of follow-up, ozanimod, 1 mg daily, was associated with long-term clinical, endoscopic, and histologic efficacy with no new safety signals [36].

•Etrasimod – For patients who achieved remission with etrasimod, we continue long-term etrasimod therapy because data showed that etrasimod was effective for maintaining remission. In a trial including 409 patients with moderate to severe UC who achieved remission with etrasimod and were followed through week 52, rates of clinical remission were higher with etrasimod compared with placebo (32 versus 7 percent) [38]. In the maintenance trial, rates of serious adverse events were numerically similar in both groups.

NUTRITION — The use of nutrition and dietary therapy in patients with inflammatory bowel disease is discussed separately. (See "Nutrition and dietary management for adults with inflammatory bowel disease".)

HEALTH MAINTENANCE — It is important to address routine health maintenance, including screening and prevention of other diseases as well as monitoring for side effects of therapy in patients with IBD. Patients with longstanding IBD affecting the colon also require endoscopic surveillance for dysplasia. These issues are discussed separately. (See "Medical management of low-risk adult patients with mild to moderate ulcerative colitis", section on 'Health maintenance' and "Surveillance and management of dysplasia in patients with inflammatory bowel disease".)

INVESTIGATIONAL THERAPIES — Other therapies have been examined for treating patients with UC, but none has been sufficiently studied or approved to recommend its routine use:

●Other anti-integrin antibodies – In addition to vedolizumab, other molecules have been developed to block the interaction between alpha-4 beta-7 integrin and mucosal addressin cell adhesion molecule-1 (MAdCAM), and these have demonstrated favorable short-term safety profiles and efficacy. These include monoclonal antibodies to block MAdCAM-1 and monoclonal antibodies against beta 7 [72-75].

●Other Janus kinase (JAK)-inhibitors – Other JAK-inhibitors are being studied for treating UC (or other inflammatory or autoimmune diseases). (See "Treatment of psoriatic arthritis".)

Filgotinib is an oral, selective JAK1 inhibitor that has been studied for treating moderate to severe UC. In two induction phase 2b/3 trials including 659 biologic therapy-naïve patients and 689 biologic therapy-experienced patients with moderate to severe UC, patients were randomized to receive filgotinib 100 mg, 200 mg, or placebo once daily [76]. Filgotinib 200 mg daily resulted in higher rates of clinical remission compared with placebo after 10 weeks (biologic therapy-naïve patients: 26.1 versus 15.3 percent, absolute difference 10.8 percent; 95% CI 2.1-19.5; and biologic therapy-experienced patients: 11.5 versus 4.2 percent, absolute difference 7.2 percent; 95% CI, 1.6-12.8). However, rates of clinical remission after 10 weeks were not significantly different for patients given filgotinib 100 mg daily compared with placebo. In the induction trials, the incidence of serious adverse events was numerically similar for patients given filgotinib 100 mg or 200 mg daily compared with placebo, but statistical analysis was not provided (5.0 and 4.3 percent, respectively, versus 4.7 percent). In the maintenance trial including 664 patients, filgotinib 200 mg daily resulted in higher rates of clinical remission compared with placebo after 58 weeks of therapy (37.2 versus 11.2 percent; absolute difference 26.0 percent, 95% CI 16.0-35.9). Filgotinib has been approved for moderate to severe ulcerative colitis in Japan and the European Union. Further studies and regulatory approval are needed before incorporating filgotinib into routine clinical practice in the United States.

●Fecal microbiota transplantation – Preliminary data suggest that fecal microbiota transplantation (FMT) has the potential to be an effective treatment for UC when standard treatments have failed. However, FMT is associated with potential risk for transmission of infectious agents, and the optimal dosing schedule and delivery method for FMT remain unclear [77-83]. Strategies to reduce infection risk and the pretreatment evaluation are discussed in more detail separately. (See "Fecal microbiota transplantation for treatment of Clostridioides difficile infection".)

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".)

SUMMARY AND RECOMMENDATIONS

●Pretreatment evaluation – Therapy for UC is guided by pretreatment evaluation (laboratory studies and lower endoscopy), and the goals are to exclude alternative or co-existing conditions and determine the extent and severity of disease. (See "Medical management of low-risk adult patients with mild to moderate ulcerative colitis", section on 'Pretreatment evaluation'.)

●Goals of medical therapy – Patients with moderate to severe UC are at increased risk for colectomy as well as complications of long-term systemic glucocorticoids. The goal of therapy in such patients is to achieve complete mucosal healing and increase the likelihood of sustained glucocorticoid-free remission and prevent hospitalizations and surgery. This typically requires both an induction phase of therapy and steroid-sparing maintenance therapy. (See 'Goals of therapy' above.)

●Induction therapy – While systemic glucocorticoids were once the mainstay of therapy, there are a growing number of effective biologic agents for moderate to severe UC, including anti-tumor necrosis factor (TNF) therapy, anti-integrin therapy, and others. There are limited data comparing one induction strategy with another, and treatment is individualized. (See 'Induction of remission' above.)

For most patients who are hospitalized with acute severe UC, intravenous glucocorticoids with or without topical glucocorticoids remain the cornerstone of initial inpatient medical therapy to achieve rapid disease stabilization. The management of these patients is discussed separately. (See "Management of the hospitalized adult patient with severe ulcerative colitis".)

For ambulatory patients with moderate to severe UC, options for initial induction therapy include the following (all of which have been shown to be more effective than placebo in randomized trials):

•Anti-TNF therapy (infliximab, adalimumab, golimumab) with or without an immunomodulator,

•Anti-integrin therapy (vedolizumab),

•Anti-interleukin-based therapy (ustekinumab, mirikizumab)

•Sphingosine-1-phosphate (S1P) receptor modulator therapy (ozanimod, estrasimod)

The choice of a specific therapy is individualized based on patient age and comorbidities, side effect profiles, prior therapies received, patient preferences with regard to route and frequency of administration, and insurance coverage/cost.

Small molecules including oral Janus kinase [JAK] inhibitors (tofacitinib and upadacitinib) have been effective as induction therapies in UC. However, regulatory labeling requires that we reserve JAK inhibitors for patients who did not respond or were intolerant to an anti-TNF-based therapy or for patients in whom anti-TNFs cannot be given. (See 'Small molecules' above.)

●Maintenance therapy – For patients with moderate to severe UC, we recommend maintenance glucocorticoid-sparing therapy after initial remission has been achieved with an induction regimen, rather than no maintenance therapy (Grade 1B). The choice of maintenance therapy depends on the specific agent used to induce remission, patient preferences, clinician preferences, and insurance coverage/cost. (See 'Maintenance of remission' above.)

●Patients who relapse – For patients who initially responded to biologic therapy but then have disease relapse (confirmed by endoscopy), options include optimizing the drug dose, switching to an alternative biologic agent in the same class, or switching to an agent from a different drug class. The preferred approach depends on the available alternatives for subsequent therapy, drug levels, and antidrug antibody levels. As examples (see 'Patients who relapse' above):

•For patients on biologics with low drug levels and no (or low) antidrug antibody levels, the drug dose is typically escalated.

•For most patients with high levels of neutralizing antidrug antibodies, we switch to another biologic agent within the same therapeutic class if available (eg, a different anti-TNF agent and add an immunomodulator). If there are no alternatives within the same biologic class, we switch to a drug from a different class or a small molecule.

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Paul Rutgeerts, MD (deceased), who contributed as a section editor for UpToDate in Gastroenterology.