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Management of moderate to severe ulcerative colitis in adults

Management of moderate to severe ulcerative colitis in adults
Authors:
Russell D Cohen, MD, FACG, AGAF
Adam C Stein, MD
Section Editor:
Sunanda V Kane, MD, MSPH
Deputy Editor:
Kristen M Robson, MD, MBA, FACG
Literature review current through: Feb 2022. | This topic last updated: Oct 13, 2021.

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) 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 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]) or glucocorticoids. (See 'Specific initial regimens' below.)

For example, we prefer an induction regimen of infliximab combined with azathioprine for most patients who have failed other biologic therapies (eg, vedolizumab), who are not compliant with self-injections (eg, adalimumab), or whose insurance coverage does not support the use of self-injectable medications. (See 'Anti-tumor necrosis factor (TNF) agent-based therapy' below.)

Alternatively, we prefer vedolizumab for induction therapy for most patients who are ≥65 years old or who have a history of recent infection (eg, pneumonia within the previous three months) because vedolizumab is not associated with increased risk of serious infection. (See 'Vedolizumab' below.)

Specific initial regimens

Anti-tumor necrosis factor (TNF) agent-based therapy — TNF therapy with or without an immunomodulator (eg, azathioprine) is used to induce remission in patients with moderate to severe UC [17-19]. The expected time frame for a clinical response ranges from a few days to up to eight weeks [20].

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 [21]. 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 [19,22]. 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 [23,24]. 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) [23].

Biosimilars — Biosimilars are biologic products that are highly similar to a reference product [25], and biosimilars of the anti-TNF agents have been marketed and are under development. (See "Overview of biologic agents and kinase inhibitors in the rheumatic diseases", section on 'Biosimilars for biologic agents'.)

Commercially available biosimilars of anti-TNF agents are described in the drug information monograph (Lexicomp) for the reference product. (See "Infliximab (including biosimilars): Drug information" and "Adalimumab (including biosimilars): Drug information".)

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 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).

Ustekinumab — Ustekinumab (an anti-interleukin 12/23 antibody) was approved by the US Food and Drug Administration (FDA) for the treatment of moderate to severe UC in 2019 [29]. Ustekinumab may be used as first-line biologic therapy for some patients (eg, those who have not responded to other therapies [ie, mesalamine and/or glucocorticoids and/or immunosuppressants]); however, failure to respond to an anti-TNF agent is not required prior to using ustekinumab [29,30].

Induction therapy with ustekinumab is given intravenously with weight-based dosing. Maintenance dosing is 90 mg subcutaneously every eight weeks. (See "Overview of medical management of high-risk, adult patients with moderate to severe Crohn disease", section on 'Ustekinumab'.)

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.

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 side 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 [32]. (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) [33].

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.)

For example:

For patients who do not respond to infliximab infusion despite adequate drug levels, we switch to a biologic agent from a different class (eg, ustekinumab) or a small molecule [22]. 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), 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.)

Small molecules

Tofacitinib — Tofacitinib, an oral small molecule Janus kinase (JAK) inhibitor, is used for treating adults with moderate to severe UC who have failed or are intolerant to anti-TNF agent-based therapy [34-37]. The onset of action of tofacitinib varies greatly. For example, some patients have a relatively rapid response (within one week), while for other patients, response may take up to eight weeks. (See 'Selecting induction therapy' above.)

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 tofacitinib 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 an increased risk of thromboembolic events and mortality in patients with rheumatoid arthritis [38-40].

The US Food and Drug Administration (FDA) issued a safety report on the risk of serious adverse events (ie, cardiovascular events, thrombosis, and malignancy) related to the use of tofacitinib [39]. In a postmarketing, unpublished, 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 [39]. 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 "Janus kinase inhibitors for rheumatologic and other inflammatory disorders: Biology, principles of use, and adverse effects", section on 'Adverse effects'.)

We use tofacitinib in patients with ulcerative colitis who do not have 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 tofacitinib or shortly after starting therapy, we give the non-live recombinant zoster (shingles) vaccine to adult patients with evidence of immunity to varicella, because tofacitinib is associated with higher rates of herpes zoster infection [35]. (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 because it is associated with increased cholesterol [41]. 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) [35].

Ozanimod — Ozanimod is an oral sphingosine-1-phosphate (S1P) receptor modulator that is used for treating adult patients with moderate to severe UC [42-44]. Ozanimod use does not require previous failure of immunosuppressants, glucocorticoids, biologics, or other small molecules.

Prior to initiating ozanimod, we obtain complete blood count including lymphocyte count, liver biochemical and function tests, an electrocardiogram to screen for cardiac conduction abnormalities, and ophthalmic evaluation to screen for uveitis or macular edema. Patients should also be tested for antibodies to varicella zoster virus (VZV), and seronegative patients should have VZV vaccination. (See "Disease-modifying therapies for multiple sclerosis: Pharmacology, administration, and adverse effects", section on 'Ozanimod'.)

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, 95% CI 8-17) [45]. Overall rates of adverse events were numerically similar in both groups, although statistical analysis was not provided. 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). These data are promising, while further studies will help inform positioning of ozanimod in clinical practice.

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 [46-48]. 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. 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.

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 anti-drug antibody levels [6,15,49]. 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 anti-drug 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 typically try to discontinue the immunomodulator after they have sustained clinical and endoscopic remission for a minimum of six months.

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 discontinuing it.

For patients who failed more than one biologic agent and/or have made antidrug antibodies to a previous biologic, we may 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) [23].

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'.) In addition, a dosage form of vedolizumab given by self-injection is expected but not yet commercially available [50].

If disease relapse occurs during vedolizumab therapy, dose escalation (typically by shortening dosing interval to every four weeks) is reasonable, in addition to evaluating for co-existing conditions or exacerbating factors [51]. We do not routinely check anti-drug 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].

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 weeks) is reasonable in addition to evaluating for co-existing conditions or exacerbating factors. (See 'Pretreatment evaluation' above.) We do not routinely check anti-drug antibodies, which rarely occur with ustekinumab therapy.

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 'Ustekinumab' above.)

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 [52]. 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 [53,54]. 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) [54]. 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:

Tofacitinib – For patients who achieved remission with tofacitinib, we continue long-term tofacitinib therapy at the lowest effective dose to maintain remission (ie, 5 mg twice daily) [38]:

For patients who achieved clinical remission with 10 mg twice daily, the dose is reduced to 5 mg twice daily to minimize the risk of adverse events [55,56]. If disease relapse occurs at the lower dose, resuming the 10 mg twice daily dose for a maximum of 16 weeks is reasonable.

For patients who achieved remission with 5 mg twice daily, the same dose is continued for long-term maintenance.

Tofacitinib is effective for maintenance of remission for 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) [35]. 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'.)

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) [45]. 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).

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 to recommend its routine use:

Other anti-interleukin (IL) antibodies: In addition to ustekinumab (which targets both IL-12 and IL-23), therapies that target IL-23 through the p19 protein are available for treating patients with psoriasis and are also being studied for treating inflammatory bowel disease. (See "Treatment of psoriasis in adults", section on 'Inhibitors of IL-23 and related cytokines'.)

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 [57-60].

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 [61]. 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). Further studies and regulatory approval are needed before incorporating filgotinib into routine clinical practice. (See "Investigational therapies for rheumatoid arthritis", section on 'Janus kinase inhibitors'.)

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 [62-68]. 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

For patients with UC, defining disease activity and severity includes the assessment of the inflammatory burden, disease course, risk of long-term sequelae, and patient symptoms as part of a patient-centered management approach. (See 'Disease activity, severity, and risk' above.)

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'.)

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 (see 'Induction of remission' above):

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.

For most patients who are hospitalized with acute severe UC, intravenous glucocorticoids with or without topical glucocorticoids remain the backbone 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), or

Anti-interleukin 12/23 therapy (ustekinumab)

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 tofacitinib (an oral Janus kinase [JAK] inhibitor) and ozanimod (an oral sphingosine-1-phosphate [S1P] receptor modulator), have also shown effectiveness as induction therapies in UC. However, due to possible risks associated with these medications (thromboembolic, cardiovascular, and malignancy risks with tofacitinib, and cardiovascular risks with ozanimod), we reserve small molecules as second-line options in patients who do not achieve remission with anti-TNF-based therapy. (See 'Small molecules' above.)

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.)

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 anti-drug antibody levels. For example (see 'Patients who relapse' 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 anti-drug 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.

Patients with longstanding inflammatory bowel disease affecting the colon and/or comorbid primary sclerosing cholangitis require endoscopic surveillance for dysplasia. (See "Surveillance and management of dysplasia in patients with inflammatory bowel disease".)

ACKNOWLEDGMENT — We are saddened by the death of Paul Rutgeerts, MD, who passed away in September 2020. UpToDate gratefully acknowledges Dr. Rutgeerts' work as our Section Editor for Gastroenterology.

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Topic 4060 Version 46.0

References

1 : Cortisone in ulcerative colitis; final report on a therapeutic trial.

2 : Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study.

3 : Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal World Congress of Gastroenterology.

4 : Changes in extent of ulcerative colitis: a study on the course and prognostic factors.

5 : The natural history of pediatric ulcerative colitis: a population-based cohort study.

6 : ACG Clinical Guideline: Ulcerative Colitis in Adults.

7 : Early mucosal healing with infliximab is associated with improved long-term clinical outcomes in ulcerative colitis.

8 : Clinical predictors of colectomy in patients with ulcerative colitis: systematic review and meta-analysis of cohort studies.

9 : Natural History of Adult Ulcerative Colitis in Population-based Cohorts: A Systematic Review.

10 : Clinical course and prognosis in ulcerative colitis: results from population-based and observational studies.

11 : Early corticosteroids requirement after the diagnosis of ulcerative colitis diagnosis can predict a more severe long-term course of the disease - a nationwide study of 1035 patients.

12 : History of medical hospitalization predicts future need for colectomy in patients with ulcerative colitis.

13 : Review article: the management of steroid dependency in ulcerative colitis.

14 : Review article: the management of steroid dependency in ulcerative colitis.

15 : Ulcerative Colitis Care Pathway.

16 : Advocating for Patients With Inflammatory Bowel Disease: How to Navigate the Prior Authorization Process.

17 : Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis.

18 : Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial.

19 : Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis.

20 : Time to clinical response and remission for therapeutics in inflammatory bowel diseases: What should the clinician expect, what should patients be told?

21 : The role of DMARDs in reducing the immunogenicity of TNF inhibitors in chronic inflammatory diseases.

22 : AGA Clinical Practice Guidelines on the Management of Moderate to Severe Ulcerative Colitis.

23 : Systematic review with network meta-analysis: the efficacy of anti-tumour necrosis factor-alpha agents for the treatment of ulcerative colitis.

24 : Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis.

25 : Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis.

26 : Vedolizumab as induction and maintenance therapy for ulcerative colitis.

27 : Vedolizumab for induction and maintenance of remission in ulcerative colitis.

28 : Vedolizumab versus Adalimumab for Moderate-to-Severe Ulcerative Colitis.

29 : Vedolizumab versus Adalimumab for Moderate-to-Severe Ulcerative Colitis.

30 : Vedolizumab versus Adalimumab for Moderate-to-Severe Ulcerative Colitis.

31 : Ustekinumab as Induction and Maintenance Therapy for Ulcerative Colitis.

32 : Guidelines for the management of inflammatory bowel disease in adults.

33 : Glucocorticosteroid therapy in inflammatory bowel disease: systematic review and meta-analysis.

34 : Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis.

35 : Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis.

36 : Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis.

37 : Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis.

38 : Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis.

39 : Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis.

40 : Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis.

41 : Tofacitinib Treatment Is Associated With Modest and Reversible Increases in Serum Lipids in Patients With Ulcerative Colitis.

42 : P030 Ozanimod Efficacy, Safety, and Histology in Patients with Moderate-to-Severe Ulcerative Colitis During Maintenance in the Phase 3 True North Study.

43 : Ozanimod Induction and Maintenance Treatment for Ulcerative Colitis.

44 : Long-Term Efficacy and Safety of Ozanimod in Moderately to Severely Active Ulcerative Colitis: Results From the Open-Label Extension of the Randomized, Phase 2 TOUCHSTONE Study.

45 : Ozanimod as Induction and Maintenance Therapy for Ulcerative Colitis.

46 : Intensive intravenous regimen for severe attacks of ulcerative colitis.

47 : Further experience in the treatment of severe attacks of ulcerative colitis.

48 : Intensive intravenous treatment of ulcerative colitis.

49 : American Gastroenterological Association Institute Guideline on Therapeutic Drug Monitoring in Inflammatory Bowel Disease.

50 : Efficacy and Safety of Vedolizumab Subcutaneous Formulation in a Randomized Trial of Patients With Ulcerative Colitis.

51 : Loss of Response to Vedolizumab and Ability of Dose Intensification to Restore Response in Patients With Crohn's Disease or Ulcerative Colitis: A Systematic Review and Meta-analysis.

52 : Ulcerative Colitis.

53 : Impact of thiopurines on the natural history and surgical outcome of ulcerative colitis: a cohort study.

54 : Meta-analysis: the efficacy of azathioprine and mercaptopurine in ulcerative colitis.

55 : Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis.

56 : Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis.

57 : The mucosal addressin cell adhesion molecule antibody PF-00547,659 in ulcerative colitis: a randomised study.

58 : A randomised phase I study of etrolizumab (rhuMAbβ7) in moderate to severe ulcerative colitis.

59 : Etrolizumab as induction therapy for ulcerative colitis: a randomised, controlled, phase 2 trial.

60 : Anti-MAdCAM antibody (PF-00547659) for ulcerative colitis (TURANDOT): a phase 2, randomised, double-blind, placebo-controlled trial.

61 : Filgotinib as induction and maintenance therapy for ulcerative colitis (SELECTION): a phase 2b/3 double-blind, randomised, placebo-controlled trial.

62 : Systematic review: faecal microbiota transplantation in the management of inflammatory bowel disease.

63 : Step-up fecal microbiota transplantation strategy: a pilot study for steroid-dependent ulcerative colitis.

64 : Fecal Microbiota Transplantation for Ulcerative Colitis: A Systematic Review and Meta-Analysis.

65 : Fecal Microbiota Transplantation Induces Remission in Patients With Active Ulcerative Colitis in a Randomized Controlled Trial.

66 : Findings From a Randomized Controlled Trial of Fecal Transplantation for Patients With Ulcerative Colitis.

67 : Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial.

68 : Effect of Fecal Microbiota Transplantation on 8-Week Remission in Patients With Ulcerative Colitis: A Randomized Clinical Trial.