What is the treatment approach for Crohn's disease?

Crohn's Disease: Comprehensive Management Overview

Disease Characteristics and Natural History

Crohn's disease is a chronic inflammatory bowel disease affecting any part of the gastrointestinal tract, characterized by transmural inflammation that leads to progressive bowel damage in most patients if inadequately treated. 1

• Up to one-third of patients present with complicated disease (strictures, fistulas, abscesses) at diagnosis 1, 2
• Approximately 50% of patients require surgery within 10 years of diagnosis 1, 2
• The disease follows an unpredictable course with periods of exacerbation and remission 1
• Clinical symptoms often disconnect from underlying inflammation, making objective monitoring essential 1

Disease Assessment and Severity Classification

Disease severity must be categorized as mild, moderate, or severe based on clinical symptoms, inflammatory markers (CRP, fecal calprotectin), and extent of disease involvement before selecting treatment 2. Disease location (ileal, colonic, ileocolonic) and pattern (inflammatory, stricturing, penetrating) determine appropriate therapeutic approach 2.

Regular monitoring with objective markers including endoscopy, C-reactive protein, fecal calprotectin, and imaging is crucial for tight disease control and preventing progression. 1, 3

Treatment Approach for Active Disease

Mild to Moderate Disease

For mild to moderate disease limited to the ileum and/or ascending colon, budesonide 9 mg daily is the first-line treatment, offering superior efficacy to placebo (RR for remission: 1.93; 95% CI: 1.37-2.73) with fewer systemic side effects than conventional steroids. 1, 2

• Budesonide demonstrates high topical anti-inflammatory activity with low systemic absorption and better safety profile compared to prednisolone 1
• For colonic disease, sulfasalazine shows modest efficacy (RR: 1.38; 95% CI: 1.00-1.89), though benefit is limited to colonic involvement 1
• 5-aminosalicylates (mesalamine) are NOT recommended for Crohn's disease as they show no clear benefit over placebo (RR: 1.28; 95% CI: 0.79-2.03) for inducing remission 1

Moderate to Severe Disease

For moderate to severe disease, systemic corticosteroids (prednisone or methylprednisolone 40-60 mg/day) effectively induce remission (RR: 1.99; 95% CI: 1.51-2.64 vs placebo) but should never be used for maintenance therapy. 1, 2

• Evaluate response to prednisone at 2-4 weeks to determine need for therapy modification 2
• Taper prednisone gradually over 8 weeks, as rapid reduction increases early relapse risk 2
• For hospitalized patients with severe disease, IV methylprednisolone 40-60 mg/day (typically 40 mg every 8 hours) provides more predictable drug delivery 2
• Evaluate response to IV therapy within 1 week to determine if therapy modification is needed 2

Early Biologic Therapy Strategy

The AGA suggests early introduction of biologic therapy with or without an immunomodulator rather than delaying until after failure of mesalamine and/or corticosteroids in moderate to severe disease. 1

This recommendation is based on:

• The TOP-DOWN trial showing early combination therapy (infliximab + immunosuppressant) achieved 61.5% corticosteroid-free remission vs 42.2% with step-up therapy at 52 weeks (RR: 0.67; 95% CI: 0.46-0.97) 1
• The REACT study demonstrating lower rates of major adverse complications at 24 months with early combination therapy (HR: 0.73; 95% CI: 0.62-0.86) 1
• Step-up therapy delays appropriate treatment and risks disease progression, while early biologic therapy may overtreat some patients but prevents complications 1

Biologic Therapy Options

Anti-TNF Agents (Infliximab, Adalimumab)

Anti-TNF therapy is strongly recommended as first-line or after conventional therapy failure for moderate to severe disease, particularly in patients with risk factors for poor prognosis. 2, 3

• Infliximab dosing: 5 mg/kg IV at weeks 0,2, and 6, then every 8 weeks for maintenance 4
• For patients who respond then lose response, consider increasing to 10 mg/kg 4
• Patients not responding by week 14 are unlikely to benefit from continued dosing 4
• Combination with immunomodulators (azathioprine/mercaptopurine) reduces immunogenicity and increases drug concentrations 4

Critical safety considerations:

• Screen for latent tuberculosis before initiating and during therapy 4
• Increased risk of serious infections, including opportunistic infections (histoplasmosis, coccidioidomycosis, listeriosis) 4
• Risk of lymphoma and other malignancies, particularly hepatosplenic T-cell lymphoma in young males receiving concomitant thiopurines 4
• Avoid live vaccines during therapy and for 6 months after in utero exposure 4

Vedolizumab

Vedolizumab is recommended for patients who fail corticosteroids, thiopurines, methotrexate, or anti-TNF therapy. 2, 3

• Evaluate response between 10-14 weeks 2
• Maintenance dosing: 300 mg IV every 8 weeks achieves 39.0% clinical remission vs 21.6% with placebo at week 52 3
• Gut-selective mechanism offers favorable safety profile with less systemic immunosuppression 3

Ustekinumab

Ustekinumab is recommended for moderate to severe disease after failure of other therapies. 2, 3

• Evaluate response between 6-10 weeks 2
• Maintains clinical remission in 51% vs 35.9% with placebo over 44 weeks 3

Maintenance Therapy

Patients who achieve remission with biologic therapy should continue the same agent for maintenance. 2, 3

Immunomodulators

Azathioprine (1.5-2.5 mg/kg/day) or mercaptopurine (0.75-1.5 mg/kg/day) are recommended for maintenance when:

• Previously used with corticosteroids to induce remission 2
• Patients have adverse prognostic factors 2
• Maintaining remission after surgery in high-risk patients 2
• As monotherapy for steroid-dependent or steroid-resistant patients 2

Methotrexate should be considered for maintenance only when:

• Needed to induce remission initially 2
• Patient tried but did not tolerate azathioprine/mercaptopurine 2
• Contraindications exist to thiopurines 2

Combination Therapy Considerations

While combination therapy (biologic + immunomodulator) increases efficacy, it carries higher complication risk 1. The risk of losing response after stopping the immunomodulator may be mitigated with therapeutic drug monitoring 1. Discontinuing the biologic while continuing the immunomodulator leads to high relapse rates (44% at 1 year, 52% at 2 years) 1.

Perianal Fistulizing Disease

For simple perianal fistulae, metronidazole 400 mg three times daily and/or ciprofloxacin 500 mg twice daily are appropriate first-line treatments. 3

• Azathioprine or mercaptopurine are effective when antibiotics are insufficient 3
• Infliximab should be reserved for perianal or enterocutaneous fistulae refractory to other treatments 3, 4

Treatments NOT Recommended

The following have no role in Crohn's disease management:

• 5-aminosalicylates for moderate to severe disease 1
• Antibiotics for luminal disease (no consistent efficacy demonstrated) 1
• Corticosteroids for maintenance therapy 1, 2
• Long-term opioid use (associated with poor outcomes) 2
• Probiotics, omega-3 fatty acids, marijuana, or naltrexone for induction or maintenance 2
• Enteral nutrition or dietary modification alone in adults 2

Critical Pitfalls and Monitoring

Common pitfalls to avoid:

• Delaying biologic therapy with ineffective step-up approach using mesalamine 1
• Using corticosteroids for maintenance (leads to steroid dependency) 1, 2
• Failing to screen for tuberculosis before anti-TNF therapy 4
• Combining anti-TNF with azathioprine/mercaptopurine in young males (hepatosplenic T-cell lymphoma risk) 4
• Administering live vaccines during or within 6 months after biologic therapy 4
• Relying on symptoms alone without objective disease monitoring 1

Essential monitoring parameters:

• Endoscopy for mucosal healing assessment 1
• CRP and fecal calprotectin for inflammation monitoring 1, 3
• Therapeutic drug monitoring for biologics, especially when losing response 1
• Regular tuberculosis screening during anti-TNF therapy 4

Adjunctive Measures

Smoking cessation is the single most important factor in maintaining remission and should be strongly encouraged. 3

Additional health maintenance includes:

• Correction of nutritional deficiencies 1
• Osteoporosis screening and prevention 1
• Age-appropriate vaccinations (avoiding live vaccines during immunosuppression) 1, 4
• Cancer surveillance in long-term immunosuppression 1

Treatment Algorithm Summary

For newly diagnosed or active disease:

1. Assess severity and disease location
2. Mild-moderate ileal/right colon → Budesonide 9 mg daily 1, 2
3. Mild-moderate colonic → Sulfasalazine 1
4. Moderate-severe or high-risk features → Early biologic ± immunomodulator 1, 2, 3
5. Severe hospitalized → IV methylprednisolone, evaluate at 1 week 2

For maintenance:

1. Continue the agent that induced remission 2, 3
2. Monitor with objective markers every 3-6 months 1
3. Adjust therapy based on objective disease activity, not symptoms alone 1