What is the recommended workup and treatment algorithm for Crohn’s disease, including first‑line therapy, biologic agents, and surgical considerations?

Crohn's Disease: Workup and Treatment Algorithm

Initial Diagnostic Workup

The diagnostic evaluation of Crohn's disease requires ileocolonoscopy with biopsies from at least five sites (including ileum and rectum, two specimens per site) to confirm diagnosis, assess disease extent, and differentiate from ulcerative colitis. 1

Essential Diagnostic Modalities

• Ileocolonoscopy with biopsy is the gold standard, allowing direct visualization of mucosal inflammation, assessment of disease extent, and histologic confirmation of transmural inflammation or granulomas 2
• MR-enterography is complementary to ileocolonoscopy for complete small bowel assessment, particularly important since up to 20% of Crohn's patients have isolated proximal small bowel disease beyond endoscopic reach 2
• Fecal calprotectin serves as a validated surrogate marker for intestinal inflammation, useful for distinguishing active inflammation from functional symptoms 2
• Contrast-enhanced CT abdomen/pelvis should be obtained if acute abdominal symptoms are present to evaluate for bowel wall thickening, pneumatosis, or perforation 3

Disease Phenotyping and Risk Stratification

Before initiating therapy, assess the following high-risk features that warrant early biologic consideration 4:

• Complex disease behavior: stricturing or penetrating disease at presentation 4
• Perianal fistulizing disease: associated with more aggressive course and higher treatment intensity needs 4
• Young age at diagnosis (typically under 40 years): tends toward more aggressive progression 4
• Steroid dependency: indicates severe disease activity requiring early biologic consideration 4
• Extensive small bowel disease (including jejunal involvement): increases complication risk and warrants early biologics 4

Pre-Treatment Laboratory Assessment

• Baseline C-reactive protein and fecal calprotectin to establish inflammatory markers 4
• Thiopurine methyltransferase (TPMT) activity if considering combination therapy with azathioprine 4
• Tuberculosis screening before initiating anti-TNF therapy 3
• Stool cultures for bacterial pathogens, Clostridioides difficile toxin, and parasites to exclude infectious etiologies 3

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Treatment Algorithm by Disease Severity and Location

Mild Ileocolonic or Colonic Disease

For mild ileocolonic Crohn's disease, initiate high-dose mesalazine 4 g daily as first-line therapy. 1, 3

• Sulfasalazine 4 g daily is effective for active colonic disease but has higher side-effect rates; reserve for selected patients with reactive arthropathy 3
• Topical mesalazine may be effective in left-sided colonic Crohn's disease of mild-to-moderate activity 3

Moderate-to-Severe Ileocolonic or Colonic Disease

Oral prednisolone 40 mg daily with an 8-week taper is recommended for moderate-to-severe disease or for patients who failed mesalazine. 1, 3

• For isolated ileocecal moderate disease, budesonide 9 mg daily is an alternative, though marginally less effective than prednisolone 1, 3
• Critical pitfall: Rapid tapering of prednisolone (< 8 weeks) is associated with early relapse 3
• In steroid-dependent disease (requiring > 1 course/year), initiate azathioprine 1.5–2.5 mg/kg/day or mercaptopurine 0.75–1.5 mg/kg/day as steroid-sparing agents 1, 3
• These thiopurine agents have a slow onset of action (8–12 weeks) and should be used adjunctively, not as sole therapy for active disease 3

Severe Disease Requiring Hospitalization

Administer intravenous hydrocortisone 400 mg/day or methylprednisolone 60 mg/day plus intravenous metronidazole immediately, because active disease is difficult to distinguish from septic complications. 3

• Provide supportive care: IV fluids, electrolyte replacement, blood transfusion to keep hemoglobin > 10 g/dL, and subcutaneous heparin for venous-thromboembolism prophylaxis 3
• Offer enteral or parenteral nutritional support if the patient is malnourished 3
• Infliximab 5 mg/kg is effective for severe disease but must be avoided in patients with obstructive symptoms 3
• Active sepsis (e.g., intra-abdominal abscess) is an absolute contraindication to anti-TNF therapy 3

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First-Line Biologic Therapy for Moderate-to-Severe Disease

For newly diagnosed isolated ileal Crohn's disease with poor-prognostic features, infliximab or adalimumab should be used as the first-line biologic (strong recommendation, high-quality evidence). 4

Biologic Selection Algorithm

• Anti-TNF agents (infliximab or adalimumab) are the preferred initial biologic for moderate-to-severe ileal disease with risk-factor-driven poor prognosis 4
• Vedolizumab may be preferred in patients with concurrent eczema due to its gut-selective mechanism 4
• Ustekinumab is optimal for patients with eczema or other extraintestinal manifestations where TNF antagonists may worsen skin disease 4

Combination Therapy

When initiating anti-TNF therapy, combine the anti-TNF agent with a thiopurine (azathioprine) or methotrexate rather than using anti-TNF monotherapy (high-quality evidence). 4

Early Assessment of Anti-TNF Response

• At 2 weeks: Assess clinical response and/or fecal calprotectin to allow timely escalation if needed 4
• At 8–12 weeks: Evaluate symptomatic response to determine whether therapy should be modified 4

Treatment Goals

Treatment aims for clinical remission, endoscopic healing, and prevention of complications in moderate-to-severe disease 4

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Maintenance Therapy After Remission

Once remission is achieved, long-term maintenance therapy is necessary to prevent relapse, though the optimal duration remains uncertain. 1

Maintenance Options

• Azathioprine 1.5–2.5 mg/kg/day or mercaptopurine 0.75–1.5 mg/kg/day are effective for maintaining remission (grade A evidence) 1
• Methotrexate 15–25 mg IM weekly is effective for patients whose active disease has responded to IM methotrexate; appropriate for those intolerant of or who have failed azathioprine/mercaptopurine therapy 1
• Infliximab 5–10 mg/kg every 8 weeks is effective in patients who have responded to an initial infusion 1
• Mesalazine has limited benefit and is ineffective at doses < 2 g/day, or for those who have needed steroids to induce remission 1

Monitoring Before Therapy Withdrawal

Before withdrawal of any maintenance IBD therapy is considered 1:

• Confirm clinical remission using a combination of clinical, biochemical, endoscopic/histological and/or radiological investigations 1
• Raised CRP and calprotectin, persistent inflammation on radiological imaging, and endoscopic inflammation at the time of drug withdrawal have all been reported to be associated with increased relapse risk 1
• Withdrawal of purine analogues or anti-TNF therapy (monotherapy or combination) is associated with significant risk of relapse; shared decision-making should be undertaken before withdrawal 1

Post-Withdrawal Monitoring

• Monitor clinical symptoms, objective markers of inflammation (CRP/fecal calprotectin), and/or endoscopy and/or radiology for reassessment 1

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Fistulizing and Perianal Crohn's Disease

Infliximab is recommended as first-line advanced therapy for perianal Crohn's disease. 1

Assessment Modalities

• Pelvic MRI scan and examination under anesthesia by a colorectal surgeon experienced in evaluation of fistulizing perianal Crohn's disease 1
• Endoscopic assessment of the rectal mucosa should be undertaken 1
• Depending on local availability and expertise, endoanal ultrasound may have a role 1

Medical Management

• Metronidazole 400 mg tds (grade A) and/or ciprofloxacin 500 mg bd (grade B) are appropriate first-line treatments for simple perianal fistulae 1
• Azathioprine 1.5–2.5 mg/kg/day or mercaptopurine 0.75–1.5 mg/kg/day are potentially effective for simple perianal fistulae or enterocutaneous fistulae where distal obstruction and abscess have been excluded 1
• Infliximab (three infusions of 5 mg/kg at 0,2, and 6 weeks) should be reserved for patients whose perianal or enterocutaneous fistulae are refractory to other treatment and should be used as part of a strategy that includes immunomodulation and surgery 1
• Medical therapies should be started promptly after adequate surgical drainage of perianal abscesses 1

Surgical Management

• Setons should be placed to prevent sepsis in fistulizing perianal Crohn's disease; the optimal timing of seton removal is uncertain, factoring patient preferences and complexity of the fistulae 1
• Surgical repair (advancement flap, ligation of intersphincteric fistula tract [LIFT]) may be considered for selected patients in a multidisciplinary setting 1
• Patients with severe perianal Crohn's disease refractory to medical therapy and affecting quality of life should be offered faecal stream diversion surgery 1

Management of Intra-Abdominal Abscesses

• Intra-abdominal abscesses should be treated by antibiotics and, if possible, radiologically guided percutaneous drainage 1
• Following treatment of an abdominal abscess in the setting of non-perianal fistulizing Crohn's disease, joint medical and surgical discussion is required, but interval surgical resection is not always necessary 1

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Surgical Management

It is estimated that intestinal resection surgery is required in 18–31% of patients with Crohn's disease within 5 years of diagnosis and 25–40% within 10 years. 1

Indications for Surgery

Surgery is most commonly performed for 1:

• Stricture formation
• Fistulizing disease
• Medically refractory disease
• Perforation
• Persisting or recurrent obstruction
• Abscess not amenable to percutaneous drainage
• Intractable hemorrhage
• Dysplasia or cancer

Timing of Surgery

• Acute emergency abdominal surgery in Crohn's disease should be avoided unless there is peritonism or ischemia 1
• Deferred surgery when the patient is optimized results in lower complication rates and lower rates of stoma formation 1
• There is sufficient evidence to propose delaying surgery when possible to allow a multimodal approach to management, including nutrition, corticosteroid weaning, and management of any abscesses 1

Surgical Options for Stricturing Disease

Patients with symptomatic stricturing small bowel Crohn's disease should have joint medical and surgical assessment to optimize medical therapy and plan requirement for surgical resection or strictureplasty. 1

• Strictureplasty is an alternative to resection in patients with small bowel Crohn's disease strictures shorter than 10 cm and is useful where there are multiple strictures or a need to preserve gut length; longer strictures can be treated using non-standard strictureplasty techniques 1
• If there are multiple strictures close to each other in a segment of bowel and there is adequate remaining healthy bowel, a single resection may be preferable to multiple strictureplasties 1
• For localized ileocecal Crohn's disease with obstructive symptoms but no significant evidence of active inflammation, surgery is the preferred option 2
• Laparoscopic resection of stricturing, fibrotic disease of the terminal ileum (<40 cm) can be offered as a sound therapeutic option with a benefit and risk profile comparable to medical therapy 2
• Wide lumen stapled ileocolic side-to-side (functional end-to-end) anastomosis is the preferred technique, reducing overall postoperative complications, clinical recurrence, and reoperation rates 2

Surgical Approach

• Laparoscopic approach is preferred for ileocolic resections where appropriate expertise is available 2
• For segmental colonic disease, segmental colectomy is appropriate for patients with a single involved colonic segment 2

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Post-Surgical Management

Assessment of Crohn's disease activity to guide medical therapy should be performed 6 months after surgery, preferably with ileocolonoscopy. 1

Post-Operative Prophylaxis

• Endoscopic recurrence (Rutgeert's score i2-i4) occurs in 30-90% of patients at the neoterminal ileum within 12 months of surgery 5
• In high-risk patients (multiple prior surgeries, resection for penetrating Crohn's disease, history of perianal disease, or active smoker), biologics should be initiated within 90 days of surgery 4
• Infliximab significantly reduces endoscopic recurrence at 76 weeks compared with placebo (31% vs 60%, p<0.001) 1
• Adalimumab may have a large effect in preventing clinical and endoscopic relapses (low certainty evidence) 1
• Vedolizumab probably has a large effect in preventing endoscopic relapse (moderate certainty evidence) 1

Monitoring Post-Surgery

• MR-enterography and intestinal ultrasound may be used with sensitivities of 89% to 100% and specificities of 69% to 86% 1

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Critical Pitfalls to Avoid

• Do not taper prednisolone faster than 8 weeks, as rapid tapering precipitates early relapse 3
• Do not use infliximab in Crohn's disease patients with obstructive symptoms 3
• Never use corticosteroids for long-term maintenance in Crohn's disease 3
• Do not delay corticosteroid therapy while awaiting stool microbiology results in suspected severe inflammatory disease 3
• Before escalating therapy, consider alternative causes of symptoms such as bacterial overgrowth, bile-salt malabsorption, or fibrotic strictures 3
• Active sepsis (e.g., intra-abdominal abscess) is an absolute contraindication to anti-TNF therapy 3