What is the recommended treatment approach for a patient with ulcerative colitis?

Treatment of Ulcerative Colitis

Treatment for ulcerative colitis must be stratified by disease severity and extent, with standard-dose mesalamine (2-3 grams/day) plus rectal mesalamine as first-line therapy for mild-to-moderate disease, oral corticosteroids for moderate-to-severe disease requiring induction, and advanced biologics (infliximab, vedolizumab, ustekinumab, or JAK inhibitors) for moderate-to-severe disease or corticosteroid-dependent/refractory cases. 1, 2

Mild-to-Moderate Disease

Extensive or Left-Sided Disease

• Initiate standard-dose oral mesalamine 2-3 grams/day combined with rectal mesalamine as first-line therapy, which achieves superior remission rates compared to either agent alone 1, 2, 3
• Once-daily dosing of oral mesalamine is preferred over multiple daily doses to improve adherence 1
• For suboptimal response to standard dosing or moderate disease activity, escalate to high-dose mesalamine (>3 grams/day) with rectal mesalamine 1, 2
• If inadequate response after 4-6 weeks of optimized mesalamine therapy, advance to oral prednisolone 40 mg daily for induction 2, 3

Distal Disease (Proctosigmoiditis or Proctitis)

• Use mesalamine suppositories 1 gram daily for proctitis as the preferred initial treatment, delivering medication more effectively to the rectum 2
• For proctosigmoiditis, mesalamine enemas are preferred over oral mesalamine alone 1
• Topical mesalamine is more effective than topical corticosteroids for distal disease 2
• Combining topical with oral mesalamine is more effective than monotherapy 2

Important Caveats for Mild-to-Moderate Disease

• Patients already on sulfasalazine in remission or those with prominent arthritic symptoms may continue sulfasalazine 2-4 grams/day if cost is prohibitive, though it has higher intolerance rates 1, 2
• Do not use probiotics, curcumin, or fecal microbiota transplantation as these lack sufficient evidence and risk delaying proven effective therapy 1, 2

Moderate-to-Severe Disease

Corticosteroid Induction

• Initiate oral prednisolone 40 mg daily for induction of remission in patients with inadequate response to optimized 5-ASA therapy 2, 3
• After successful induction, transition to maintenance therapy—do not continue corticosteroids long-term 2, 3

Advanced Therapies (Biologics and Small Molecules)

The AGA strongly recommends the following agents over no treatment for moderate-to-severe UC 1:

Preferred first-line biologics in biologic-naïve patients:

• Infliximab (5 mg/kg IV at weeks 0,2,6, then every 8 weeks) 1, 3, 4
• Vedolizumab 1, 3

Other strongly recommended options:

• Golimumab, ustekinumab, risankizumab, guselkumab 1
• Tofacitinib, upadacitinib (JAK inhibitors—see restrictions below) 1
• Ozanimod, etrasimod (sphingosine-1-phosphate modulators) 1

Conditionally recommended options:

• Adalimumab, filgotinib, mirikizumab 1

JAK Inhibitor Restrictions

• The FDA restricts JAK inhibitors (tofacitinib, upadacitinib, filgotinib) to patients with prior failure or intolerance to TNF antagonists 1
• Use cautiously in patients ≥65 years, current/long-term smokers, or those with cardiovascular disease or cancer history 1

Combination Therapy

• Combine TNF antagonists with immunomodulators (azathioprine or methotrexate) rather than using TNF antagonist monotherapy, as combination therapy achieves superior remission rates 1, 3
• The UC-SUCCESS trial demonstrated 39.7% corticosteroid-free remission with infliximab plus azathioprine versus 22.1% with infliximab alone 5
• For non-TNF biologics (vedolizumab, ustekinumab), there is insufficient evidence to recommend combination therapy over monotherapy 1

Immunomodulator Monotherapy

• Do not use thiopurine monotherapy for inducing remission in active moderate-to-severe disease 1
• Do not use methotrexate monotherapy for inducing or maintaining remission 1
• Thiopurine monotherapy may be used for maintaining remission typically induced with corticosteroids, though advanced therapies are preferred 1

Acute Severe Ulcerative Colitis (Hospitalized Patients)

Immediate Management

• Joint management by gastroenterologist and colorectal surgeon is mandatory 2, 3, 5
• Daily physical examination to assess for abdominal tenderness and rebound 2, 3
• Initiate IV methylprednisolone 40-60 mg/day or hydrocortisone 400 mg/day as first-line therapy 2, 3, 5

Supportive Care

• IV fluid and electrolyte replacement 2, 3, 5
• Maintain hemoglobin >10 g/dL with transfusion if needed 2, 3, 5
• Administer subcutaneous low-molecular-weight heparin for thromboprophylaxis 2, 3, 5
• Daily abdominal radiography to monitor for toxic megacolon 5

Rescue Therapy for Steroid-Refractory Disease

• Assess response by day 3—approximately 67% respond to IV corticosteroids alone 5
• For patients refractory to IV corticosteroids, use infliximab or cyclosporine as rescue therapy 2, 3, 5
• Patients responding to cyclosporine should transition to oral cyclosporine with azathioprine/6-mercaptopurine 6
• Colectomy is indicated for patients who fail rescue therapy 5, 6

Maintenance Therapy

General Principles

• Lifelong maintenance therapy is recommended for all patients, especially those with left-sided or extensive disease, to reduce relapse risk and potentially reduce colorectal cancer risk 2, 3, 5
• Maintenance options include aminosalicylates, thiopurines, and biologics depending on disease severity and prior response 5

De-escalation Considerations

• Patients in remission on biologics and/or immunomodulators after prior 5-ASA failure may discontinue 5-ASA 1, 2, 3
• In patients achieving corticosteroid-free remission for ≥6 months on combination TNF antagonist plus immunomodulator therapy, do not withdraw the TNF antagonist 1
• There is insufficient evidence to guide withdrawal of immunomodulators in patients on combination therapy 1

High-Risk Features Requiring Aggressive Therapy

Patients with the following features predict aggressive disease and may benefit from earlier advanced therapy 2:

• Age <40 years at diagnosis 2
• Extensive disease 2
• Severe endoscopic activity 2
• Extra-intestinal manifestations 2
• Elevated inflammatory markers (CRP, fecal calprotectin) 2

Monitoring and Treatment Adjustment

• Confirm disease activity endoscopically and exclude infectious causes before initiating therapy 5
• Monitor using stool frequency, rectal bleeding, inflammatory markers (CRP, fecal calprotectin), and endoscopic assessment 5
• Adjust treatment if symptoms deteriorate, rectal bleeding persists beyond 10-14 days, or sustained relief is not achieved after 40 days of appropriate 5-ASA therapy 2
• Patients who do not respond to advanced therapy by week 14 are unlikely to respond with continued dosing and should be considered for alternative therapy or surgery 4
• For patients losing response to infliximab 5 mg/kg, consider dose escalation to 10 mg/kg 4

Critical Safety Considerations

Infliximab and TNF Antagonists

• Screen for latent tuberculosis and initiate treatment prior to starting TNF antagonists 4
• Monitor closely for invasive fungal infections (histoplasmosis, coccidioidomycosis) and opportunistic infections 4
• Risk of lymphoma and hepatosplenic T-cell lymphoma (HSTCL), particularly in adolescent and young adult males receiving combination therapy with azathioprine or 6-mercaptopurine 4

Sulfasalazine

• Monitor complete blood counts with differential and liver function tests every 2 weeks for the first 3 months, then monthly for the next 3 months, then every 3 months 7
• Maintain adequate fluid intake to prevent crystalluria 7
• May cause oligospermia and infertility in men, which reverses upon discontinuation 7