Medical therapy of ulcerative colitis (UC) follows a two-phase paradigm: induction of remission followed by maintenance of remission. The agent and route are selected according to disease extent (proctitis, left-sided colitis, or extensive colitis) and disease activity (mild-to-moderate, moderate-to-severe, or acute severe).^[1] The current treatment target is corticosteroid-free remission with endoscopic (mucosal) healing rather than symptom control alone.^[2][3] 5-aminosalicylic acid (5-ASA) is first-line for mild-to-moderate disease. Moderate-to-severe disease is managed with early initiation of an advanced therapy (biologic or oral small molecule), with corticosteroids used only as a short-term bridge.^[1][4] Acute severe UC requires hospitalization, intravenous corticosteroids, and an early decision about rescue therapy or colectomy.^[5]

• Assess disease extent and activity at each encounter using clinical, biochemical (CRP, fecal calprotectin), and endoscopic parameters. Reassess response after starting a new therapy, ideally at about 8 weeks.^[1]
• Fecal calprotectin is recommended to assess response to therapy, to evaluate suspected relapse, and for monitoring during maintenance.^[1]
• Exclude C. difficile infection during flares before escalating therapy. In severe or refractory disease, also exclude cytomegalovirus colitis.^[1]
• Corticosteroids induce remission but do not maintain it. Each course should be prescribed together with a plan for steroid-sparing maintenance therapy.^[6][1]

• Dose: For mildly active disease of any extent, low-dose oral 5-ASA (2.0–2.4 g/day) is as effective as 4.8 g/day. Patients with moderately active disease may benefit from 4.8 g/day.^[1] High-dose mesalamine combined with rectal mesalamine is recommended for a suboptimal response to standard-dose therapy.^[7]
• Frequency: Once-daily oral 5-ASA dosing is as effective as divided dosing and improves adherence.^[1][7]
• Formulation: Oral mesalamine formulations and the diazo-bonded agents (balsalazide, olsalazine, sulfasalazine) are all treatment options.^[3] Switching between 5-ASA formulations for 5-ASA failure is not recommended; escalate to another drug class instead (ACG: conditional, low).^[1]
• 5-ASA–refractory disease:
  • Budesonide MMX 9 mg/day is recommended for disease not responding to optimized 5-ASA.^[1]
  • Oral systemic corticosteroids (typically prednisone 40–60 mg/day) are recommended for UC of any extent that fails 5-ASA.^[1][8]
  • For proctitis refractory to topical 5-ASA, tacrolimus or beclometasone suppositories are suggested alternatives (ACG: conditional, low).^[1]
  • Failure of optimized 5-ASA warrants management as moderate-to-severe disease.^[1]

• Proctitis: Rectal 5-ASA 1 g/day (ACG: strong, moderate).^[1]
• Left-sided or extensive colitis: Oral 5-ASA ≥1.5 g/day (ACG: strong, moderate).^[1]
• Oral 5-ASA is superior to placebo for maintenance (high-certainty evidence), and once-daily dosing has a benefit and harm profile similar to conventional dosing.^[9] In pooled trials, sulfasalazine was more effective than 5-ASA for maintenance. However, 5-ASA preparations were developed to avoid sulfasalazine-related adverse effects.^[9]
• Patients who achieve remission with combined oral and rectal 5-ASA should continue oral 5-ASA. Intermittent rectal 5-ASA can be added for patients at high risk of relapse.^[3]
• Corticosteroids (systemic, budesonide MMX, or topical) should not be used for maintenance (ACG: strong, moderate).^[1]

Moderate-to-severe activity is broadly defined by:^[5]

• ≥6 stools/day
• Frequent urgency and hematochezia
• Elevated inflammatory markers (ESR ≥30 mm/h)
• Mayo endoscopic subscore 2–3 or UCEIS 5–8

• Systemic corticosteroids (prednisone 40–60 mg/day) induce remission (number needed to treat approximately 3) but serve only as a bridge to a maintenance agent.^[1][6]
• The AGA advises early use of advanced therapies rather than a traditional step-up approach, to limit cumulative corticosteroid exposure.^[4]
• ACG strongly recommends all of the advanced therapies listed below for induction of remission.^[1]
• Thiopurine monotherapy and methotrexate monotherapy are not recommended for induction.^[4][1]
• Combination therapy is preferred over monotherapy for anti-TNF agents:
  • Infliximab combined with an immunomodulator is suggested over either agent alone.^[4]
  • Adalimumab or golimumab combined with an immunomodulator is also suggested over monotherapy.^[4]
• When an advanced therapy is started after 5-ASA failure, adding 5-ASA provides no additional efficacy (ACG: conditional, very low).^[1]

The AGA living guideline positions agents by relative efficacy:^[4]

• Advanced-therapy–naïve patients: Use a higher-efficacy agent or an intermediate-efficacy agent rather than lower-efficacy adalimumab.
  • Higher efficacy: infliximab, vedolizumab, ozanimod, etrasimod, upadacitinib, risankizumab, guselkumab.
  • Intermediate efficacy: golimumab, ustekinumab, tofacitinib, filgotinib, mirikizumab.
• Prior advanced-therapy exposure (especially anti-TNF): Prefer tofacitinib, upadacitinib, or ustekinumab (higher efficacy), or filgotinib, mirikizumab, risankizumab, or guselkumab (intermediate efficacy). These are preferred over adalimumab, vedolizumab, ozanimod, or etrasimod.
• Filgotinib is not approved in the United States.^[4]

Comparative data are limited:

• In a post hoc analysis of trial data in biologic-naïve patients, infliximab and vedolizumab produced similar clinical remission.^[13]
• Infliximab achieved higher 1-year endoscopic remission (36.0% vs. 25.6%) and corticosteroid-free remission (29.5% vs. 15.0%).^[13]

• Continue the agent that successfully induced remission. This applies to anti-TNF agents, vedolizumab (IV or SC), ustekinumab, IL-23p19 inhibitors, S1P receptor modulators, and JAK inhibitors (ACG: strong, moderate).^[1]
• Thiopurine monotherapy (azathioprine or 6-mercaptopurine) is suggested for maintenance of remission that was typically induced by corticosteroids.^[4] Supporting evidence is low certainty.^[14]
• For patients in corticosteroid-free remission for ≥6 months on anti-TNF plus immunomodulator combination therapy, the AGA suggests against withdrawing the anti-TNF agent.^[4]
• Methotrexate is not recommended for maintenance.^[4][1]
• Systemic corticosteroids are not recommended for maintenance at any severity (ACG: strong, moderate).^[1]
• In patients on anti-TNF maintenance who previously failed 5-ASA, concomitant 5-ASA offers no benefit and can be stopped.^[1]

Detailed inpatient and surgical management is addressed in separate microchapters.

• Definition (Truelove–Witts): ≥6 bloody stools/day plus ≥1 systemic sign (fever, tachycardia, anemia, or ESR ≥30 mm/h or elevated CRP).^[5]
• Initial management:
  • Hospitalization.
  • IV methylprednisolone 60 mg/day or hydrocortisone 100 mg three to four times daily.
  • Venous thromboembolism prophylaxis.
  • Early surgical consultation.^[5]
• Assessing steroid response: Assess on days 3–5. Steroid-refractory disease (e.g., >8 stools/day, or 3–8 stools/day with CRP >45 mg/L) warrants rescue therapy.^[5]
• Rescue therapy: Infliximab or cyclosporine, which have similar short-term efficacy (response approximately 60–80%).^[5]
• Surgery: Failure to improve within 3–5 days of rescue therapy is an indication for colectomy.^[5]
• Drugs to avoid: Antimotility and anticholinergic agents should be avoided in severe active colitis because of the risk of toxic megacolon.

Management of pouchitis after ileal pouch–anal anastomosis is addressed in the surgery microchapter.

• Corticosteroid taper: The optimal taper is not standardized, and recommendations differ among societies; ACG individualizes tapering.^[1]
• First-line biologic choice: Head-to-head data are limited.
  • Infliximab may achieve higher endoscopic and corticosteroid-free remission than vedolizumab in biologic-naïve patients.^[13]
  • Vedolizumab had lower infection rates than adalimumab in VARSITY.^[11]
• JAK inhibitors: Their high efficacy must be balanced against cardiovascular, thrombotic, malignancy, and infection risks, particularly in older patients and those with cardiovascular risk factors.^[12]
• Thiopurines: Their role is narrowing as advanced therapies expand. Evidence for maintenance remains low certainty, although thiopurines remain widely used.^[14]

• Rectal 5-ASA is underused in distal disease, even though it outperforms both oral 5-ASA and rectal corticosteroids for proctitis and left-sided colitis.^[1]
• Before declaring 5-ASA failure, confirm adequate oral and rectal dosing, adherence, and treatment duration.^[1]
• Steroid dependence or repeated steroid courses should prompt escalation to a steroid-sparing agent rather than further steroid re-treatment.^[6][1]
• Avoid infliximab monotherapy when combination with an immunomodulator is appropriate.^[4]
• Before starting immunosuppressive or advanced therapy, screen for latent tuberculosis and hepatitis B and update vaccinations.^[1]
• Consider cardiovascular and thrombotic risk before prescribing a JAK inhibitor to older or high-risk patients.^[12]