What is the recommended step‑by‑step treatment algorithm for ulcerative colitis and Crohn’s disease, including drug choices, dosing, and indications based on disease severity?

Treatment of Inflammatory Bowel Disease

For moderate-to-severe ulcerative colitis, start advanced therapies (biologics or JAK inhibitors) early rather than stepping up from 5-aminosalicylates, and for Crohn's disease, use oral prednisone 40–60 mg daily for moderate-to-severe disease while reserving high-dose mesalamine only for mild ileocolonic presentations. 1

Ulcerative Colitis Treatment Algorithm

Mild-to-Moderate Disease (Outpatient)

Distal Disease (Proctitis/Proctosigmoiditis):

• Initiate mesalamine 1 g suppository once daily for proctitis—suppositories deliver medication more effectively than foam or enemas 2, 3
• For proctosigmoiditis, use mesalamine enemas 1–4 g daily 4
• Add oral mesalamine ≥2.4 g daily if topical therapy alone fails or if relapse occurs more than once yearly 4, 2, 3
• Topical mesalamine is superior to topical corticosteroids for distal disease 2, 3

Left-Sided or Extensive Colitis:

• Start combination therapy: mesalamine enema ≥1 g daily plus oral mesalamine ≥2.4 g daily (once-daily dosing improves adherence) 4, 2, 3
• This combination is more effective than either topical or oral therapy alone 2, 3
• If inadequate response after 2–4 weeks, escalate to oral prednisone 40 mg daily with gradual taper over 8 weeks 4, 3
• Critical pitfall: Rapid tapering (<8 weeks) precipitates early relapse 4, 2

Moderate-to-Severe Disease (Advanced Therapy Candidates)

The 2024 AGA guideline represents a paradigm shift—early advanced therapy is now preferred over traditional step-up from 5-ASA:

• Suggest early use of advanced therapies rather than gradual step-up after 5-ASA failure 1
• This applies to patients with moderate-to-severe symptoms (Mayo endoscopy subscore 2–3), mild symptoms with high inflammatory burden, or corticosteroid-dependence 1

Drug Selection by Efficacy Tier:

Higher Efficacy Options:

• Infliximab (biosimilars equivalent to originator; subcutaneous formulation available for maintenance) 1
• Adalimumab (biosimilars equivalent) 1
• Ustekinumab (biosimilars equivalent) 1

Intermediate Efficacy Options:

• Vedolizumab (subcutaneous formulation available for maintenance) 1
• Tofacitinib (JAK inhibitor) 1
• Ozanimod (S1P receptor modulator) 1

Prioritize higher or intermediate efficacy medications over lower efficacy options, both in advanced therapy-naïve patients and those with prior TNF antagonist exposure 1

Combination Therapy Considerations:

• Combine TNF antagonists with immunomodulators (thiopurines) rather than TNF monotherapy—this improves outcomes 1
• For non-TNF biologics, there is insufficient evidence to recommend combination with immunomodulators 1

Severe Disease (Hospitalization Required)

Immediate Management:

• Start intravenous hydrocortisone 400 mg/day or methylprednisolone 60 mg/day immediately—do not delay for stool culture results 4
• Provide supportive care: IV fluids, electrolyte replacement, blood transfusion to maintain hemoglobin >10 g/dL, subcutaneous heparin for VTE prophylaxis 4
• Joint management by gastroenterology and colorectal surgery from admission 4
• Counsel patients about 25–30% colectomy risk 4

Rescue Therapy Triggers (by Day 3):

• 8 stools/day or 3–8 stools/day with CRP >45 mg/L predicts ≈85% colectomy rate 4

• Rescue options: infliximab 5 mg/kg IV at weeks 0,2,6 or cyclosporine 2 mg/kg/day IV 4

Surgical Indications:

• Toxic megacolon not improving after 24–48 hours, colonic perforation, massive hemorrhage with hemodynamic instability, or failure of rescue therapy after 4–7 days 4
• Peritoneal signs (rebound tenderness, guarding, rigidity) mandate immediate surgical consultation 4

Maintenance Therapy

• Continue aminosalicylates (mesalamine ≥2 g daily), azathioprine 1.5–2.5 mg/kg/day, or mercaptopurine 0.75–1.5 mg/kg/day indefinitely to reduce relapse risk and potentially lower colorectal cancer risk 4, 2
• Do not withdraw TNF antagonists in patients on combination therapy who achieve corticosteroid-free remission for ≥6 months 1
• Discontinue 5-ASA in patients who escalated to advanced therapies after 5-ASA failure 1
• Monitor renal function (eGFR) before starting mesalamine, at 2–3 months, then annually 3

Monitoring on Advanced Therapy

• Assess symptomatic response within 3 months of initiation 1
• Assess symptomatic and biochemical remission within 3–6 months 1
• Assess endoscopic improvement/remission within 6–12 months 1
• Perform periodic monitoring of hemogram, chemistries, and transaminases per drug label 1

---

Crohn's Disease Treatment Algorithm

Mild Ileocolonic or Colonic Disease

• High-dose mesalamine 4 g daily is appropriate first-line therapy for mild ileocolonic Crohn's disease 1, 2
• For mild colonic disease limited to the colon, sulfasalazine 4–6 g daily can be used, though side effects are common 1
• Evaluate symptomatic response between 2–4 months to determine need for therapy modification 1
• Critical distinction: Mesalamine has limited efficacy in Crohn's disease compared to ulcerative colitis—reserve for truly mild disease only 2

Mild-to-Moderate Ileal/Right Colonic Disease

• Oral budesonide 9 mg daily is first-line therapy for isolated ileocecal disease 1, 2
• Budesonide is marginally less effective than prednisone but has fewer systemic side effects 1, 2
• Evaluate symptomatic response between 4–8 weeks 1
• Do not use budesonide for maintenance—it is ineffective 1

Moderate-to-Severe Disease

Induction Therapy:

• Oral prednisone 40–60 mg daily is recommended for moderate-to-severe Crohn's disease 1, 2
• This is a strong recommendation for moderate-to-severe presentations 1
• Taper gradually over 8 weeks—rapid tapering (<8 weeks) causes early relapse 1, 2
• Evaluate symptomatic response between 2–4 weeks to determine need for therapy modification 1

Steroid-Sparing Agents:

• Add azathioprine 1.5–2.5 mg/kg/day or mercaptopurine 0.75–1.5 mg/kg/day as adjunctive therapy and steroid-sparing agents 1, 2
• Critical limitation: Thiopurines have slow onset (8–12 weeks) and should not be used as monotherapy for active disease 1
• Evaluate response at 12–16 weeks; modify therapy if corticosteroid-free remission not achieved 1

Alternative for Steroid-Dependent/Resistant Disease:

• Parenteral methotrexate can induce and maintain remission in corticosteroid-dependent/resistant patients 1

Severe Disease (Hospitalization Required)

• Administer intravenous hydrocortisone 400 mg/day or methylprednisolone 60 mg/day 1, 2
• Add intravenous metronidazole because distinguishing active disease from septic complications is difficult 1, 4, 2
• Evaluate symptomatic response within 1 week to determine need for therapy modification 1

Biologic Therapy:

• Infliximab 5 mg/kg is effective for moderate-to-severe disease 1
• Critical contraindication: Avoid infliximab in patients with obstructive symptoms 1, 4, 2
• Screen for tuberculosis before initiating anti-TNF therapy 4
• Active sepsis (e.g., intra-abdominal abscess) is an absolute contraindication to anti-TNF therapy 4

Maintenance Therapy

• Thiopurine monotherapy (azathioprine or mercaptopurine) can maintain remission induced with corticosteroids in selected patients 1
• Parenteral methotrexate maintains remission in patients who achieved remission on corticosteroids plus methotrexate 1
• Do not use oral corticosteroids for maintenance—this is a strong recommendation 1

Special Considerations

Before escalating therapy, exclude alternative causes of symptoms:

• Bacterial overgrowth 1, 2
• Bile salt malabsorption 1, 2
• Fibrotic strictures 1, 2
• Dysmotility 1

Surgical Considerations:

• Consider surgery for patients who fail medical therapy 1
• Surgery may be appropriate as primary therapy in limited ileal or ileocecal disease 1

---

Critical Pitfalls to Avoid

• Never delay intravenous corticosteroids while awaiting stool microbiology in suspected severe colitis 4
• Never taper prednisone faster than 8 weeks—this precipitates early relapse 1, 4, 2
• Never use infliximab in Crohn's disease patients with obstructive symptoms 1, 4, 2
• Never use corticosteroids for long-term maintenance in either condition 1, 4
• Never use thiopurine or methotrexate monotherapy to induce remission in active Crohn's disease—onset is too slow 1
• Never overlook topical therapy in ulcerative colitis—combination topical plus oral mesalamine is significantly more effective than oral alone 2, 3