What Has Changed in the Treatment of Ulcerative Colitis?

Ulcerative colitis treatment has moved from a relatively simple ladder of 5-aminosalicylates, corticosteroids, thiopurines and anti-TNF therapy to a crowded field of biologics and oral small molecules. The 2025 American College of Gastroenterology (ACG) guideline and the American Gastroenterological Association (AGA) living guideline now place much greater emphasis on early effective therapy, objective monitoring and treatment positioning. The practical challenge in 2026 is not whether effective therapies exist; it is selecting the right intensity and mechanism for the individual patient while minimizing corticosteroid exposure and preventing hospitalization, colectomy and colorectal neoplasia.

1. The treatment target is broader than symptom relief

The 2025 ACG guideline recommends treating ulcerative colitis to achieve endoscopic improvement, defined as resolution of inflammatory changes to a Mayo endoscopic score of 0 or 1, because objective improvement is associated with more durable steroid-free remission and fewer hospitalizations and surgeries. Symptoms remain important, but stool frequency and rectal bleeding alone do not fully describe inflammatory activity.

Fecal calprotectin (FC) has therefore become a routine management tool. ACG recommends using FC to assess response, investigate suspected relapse and monitor patients during maintenance. A rising FC can prompt earlier evaluation before a severe clinical flare develops, while a low value can help clinicians consider non-inflammatory explanations for ongoing symptoms.

Histologic remission is prognostically interesting and increasingly reported, but routine treatment escalation solely to normalize histology is not yet the universal standard. The primary practical targets remain clinical control, steroid-free remission and endoscopic improvement.

2. Mild distal disease still rewards topical therapy

The explosion of advanced therapies has not made basic pharmacology obsolete. For mildly to moderately active ulcerative proctitis, rectal mesalamine remains highly effective and is recommended by ACG for induction. Topical therapy can deliver high drug concentration directly to inflamed mucosa with limited systemic exposure.

A common failure in practice is not pharmacologic but behavioral: patients may dislike suppositories or enemas, and clinicians may under-explain why route matters. Treatment should therefore include practical adherence discussion. For left-sided disease, combined oral and rectal 5-ASA may outperform oral therapy alone in appropriate patients.

Corticosteroids remain induction drugs, not maintenance drugs. Repeated or prolonged steroid use should be treated as a failure of the maintenance strategy and a reason to reposition therapy.

3. Moderate-to-severe disease now has many advanced options

The 2024 AGA living guideline, reviewed again in 2025 and March 2026 without a need to change its core recommendations, supports multiple advanced therapies for moderate-to-severe UC. These include TNF antagonists, vedolizumab, ustekinumab, Janus kinase (JAK) inhibitors, sphingosine-1-phosphate (S1P) receptor modulators and newer interleukin-23 (IL-23) agents.

The 2025 ACG guideline similarly incorporates a much broader range of mechanisms than older treatment algorithms. Current options include infliximab, adalimumab and golimumab; vedolizumab; ustekinumab; tofacitinib and upadacitinib; ozanimod and etrasimod; and selective IL-23 agents such as guselkumab, mirikizumab and risankizumab, depending on jurisdiction and approval status.

The key change is that these drugs should not be thought of as a simple interchangeable list. Comparative efficacy, prior exposure, speed of onset, comorbidity, infection risk, thrombosis and cardiovascular risk where relevant, pregnancy considerations, age, route preference and access all influence the choice.

4. Earlier advanced therapy is replacing prolonged step-up in the right patient

The AGA living guideline explicitly supports early use of advanced therapy rather than a slow step-up strategy after repeated failure of lower-intensity treatment in moderate-to-severe disease. The reason is analogous to Crohn's disease: repeated uncontrolled inflammation and steroid exposure are not benign waiting periods.

This does not erase the importance of disease severity. Mild proctitis should not be managed like extensive steroid-dependent colitis. The principle is that treatment intensity should reflect disease burden, prognostic risk and the cost of delay.

5. Therapy positioning matters more than ever

Patients and clinicians now ask a question that older guidelines rarely had to answer: Which advanced therapy should be first?

There is no universal first drug for every patient. Infliximab has strong efficacy and remains especially important in acute severe ulcerative colitis and in patients where rapid, potent systemic control is required. Vedolizumab offers a gut-selective mechanism with an attractive safety profile for many patients. Ustekinumab and selective IL-23 agents offer alternative cytokine targets. JAK inhibitors can act rapidly and are orally administered, but require careful risk assessment. S1P modulators provide another oral option with their own monitoring and contraindication considerations.

Network meta-analysis and living guidelines help rank population-level efficacy, but they cannot replace individual clinical judgment. Prior anti-TNF exposure, extraintestinal manifestations, patient age and comorbidities can substantially change the preferred sequence.

6. Acute severe ulcerative colitis remains a distinct emergency

Acute severe ulcerative colitis (ASUC) should not be managed as ordinary outpatient moderate-to-severe disease. Hospitalized patients require rapid exclusion of infection, particularly Clostridioides difficile, intravenous corticosteroids, venous thromboembolism prophylaxis unless contraindicated, nutritional support and early objective assessment of response.

Failure to improve promptly should trigger rescue therapy and surgical involvement rather than prolonged ineffective steroids. Infliximab and cyclosporine remain established rescue strategies. The 2025 ACG guideline also discusses newer rescue approaches, including JAK inhibition in selected circumstances, but institutional expertise and patient-specific risk are important. Early colorectal surgical consultation is not an admission of failure; it is part of high-quality ASUC care.

7. Therapeutic drug monitoring is becoming more selective

Reactive therapeutic drug monitoring can be useful when a patient loses response to a biologic, helping distinguish underexposure or immunogenicity from mechanistic failure. Routine proactive monitoring for every drug and every patient remains more debated and depends on the agent and clinical context. The practical question is whether the result will change the management decision.

8. Preventive care and cancer prevention remain part of disease control

Longstanding colonic inflammation increases colorectal neoplasia risk. High-quality surveillance colonoscopy, modern image-enhanced techniques when indicated, and control of inflammation are part of cancer prevention. Vaccination, skin-cancer prevention, cervical screening, bone health, mental health and infection risk management are also essential because the disease and its therapies both shape long-term outcome.

A practical treatment framework

A practical algorithm

• Define extent and severity, confirm active inflammation and exclude infection before escalating therapy.
• Use rectal and/or oral 5-ASA efficiently for appropriate mild disease; do not skip topical therapy because it is inconvenient.
• Treat corticosteroid dependence as a sign that the maintenance strategy is inadequate.
• For moderate-to-severe disease, consider advanced therapy early rather than requiring repeated lower-efficacy failures.
• Choose among biologic and small-molecule options using comparative efficacy, prior exposure, comorbidities, safety, pregnancy plans, route preference and access.
• Monitor with symptoms plus objective measures, especially fecal calprotectin and endoscopy.
• Treat ASUC as a separate hospital emergency with rapid rescue or surgery when intravenous corticosteroids fail.

What has changed most?

Three changes stand out. First, the number of effective mechanisms has expanded dramatically. Second, objective targets and fecal calprotectin have moved closer to the center of routine management. Third, the concept of waiting through sequential treatment failures has lost ground in moderate-to-severe disease.

What should trainees remember?

Ulcerative colitis treatment is still severity-based. Mild distal disease often responds beautifully to correctly delivered 5-ASA. Moderate-to-severe disease increasingly requires early, effective steroid-sparing therapy. Hospitalized ASUC is a different clinical problem and requires time-sensitive decisions.

For practising gastroenterologists, treatment selection in 2026 is an exercise in positioning. The best drug is not simply the newest drug; it is the therapy whose efficacy, safety profile and delivery fit the patient's disease and risk profile, followed by objective monitoring to confirm that the plan is working.

Free further reading from Dr. Alan B. R. Thomson

Dr. Thomson's Guideline-Based Management in Gastroenterology and Practice Review in Gastroenterology are available as free digital downloads at GIandHepatology.com. They provide the clinical framework; treatment selection should be updated against the 2025 ACG guideline and the AGA living guideline because the therapeutic landscape continues to evolve rapidly.

Frequently asked questions

What is the current treatment target in ulcerative colitis?

Clinical steroid-free remission plus objective improvement, particularly endoscopic improvement, is the practical target; fecal calprotectin is useful for monitoring.

Are 5-ASA drugs obsolete?

No. They remain highly useful for appropriate mild-to-moderate UC, especially rectal therapy for proctitis and distal disease.

Should moderate-to-severe UC patients always fail conventional drugs before biologics or small molecules?

No. Current AGA guidance supports earlier advanced therapy in appropriate moderate-to-severe disease rather than prolonged step-up after repeated failure.

How is acute severe ulcerative colitis different?

ASUC is a hospital emergency requiring infection exclusion, IV corticosteroids, thrombosis prevention and timely rescue therapy or surgical management when response is inadequate.

References

1. Thomson ABR. Guideline-Based Management in Gastroenterology. CAPstone Academic Publishers; 2015. ISBN 978-1515078623.

2. Thomson ABR. Practice Review in Gastroenterology. CAPstone Academic Publishers; 2014. ISBN 978-1500855321.

3. Rubin DT, Ananthakrishnan AN, Siegel CA, Barnes EL, Long MD. ACG Clinical Guideline Update: Ulcerative Colitis in Adults. Am J Gastroenterol. 2025;120(6):1187-1224. doi:10.14309/ajg.0000000000003463.

4. Singh S, Loftus EV Jr, Limketkai BN, et al. AGA Living Clinical Practice Guideline on Pharmacological Management of Moderate-to-Severe Ulcerative Colitis. Gastroenterology. 2024;167(7):1307-1343. doi:10.1053/j.gastro.2024.10.001. Living guideline reviewed through March 2026 with no change to recommendations.

5. Raine T, Bonovas S, Burisch J, et al. ECCO Guidelines on Therapeutics in Ulcerative Colitis: Medical Treatment. J Crohns Colitis. 2022;16(1):2-17.

6. Farraye FA, et al. ACG Clinical Guideline: Preventive Care in Inflammatory Bowel Disease. Am J Gastroenterol. 2025.

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