AGA Living Guideline on Pharmacologic Management of Moderate-to-Severe Crohn’s Disease

The American Gastroenterological Association (AGA) Living Guideline on the pharmacologic management of moderate-to-severe Crohn’s disease provides evidence-based recommendations to guide clinical decision-making for adult outpatients with moderate-to-severely active luminal Crohn’s disease. The guideline focuses on using advanced therapies to achieve disease remission and improve patient outcomes while minimizing risks. Below is a detailed breakdown of the guideline:

### **Scope and Approach**

• **Patient Population**: Adult outpatients with moderate-to-severely active luminal Crohn’s disease.
• **Development Framework**: Recommendations are based on the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) framework, incorporating evidence synthesis and network meta-analysis to position therapies according to efficacy and safety.
• **Patient-Centered Focus**: Emphasis on tailoring therapy to individual patient needs, preferences, and clinical circumstances.

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### **Key Recommendations**

#### **Pretreatment Considerations**

1. **Confirm Active Inflammation**: Before initiating advanced therapy, confirm active inflammation through biomarkers (e.g., C-reactive protein, fecal calprotectin), endoscopic evaluation, or imaging studies.

2. **Core Pretreatment Screening**:

• Screen for **hepatitis B** and **tuberculosis** prior to starting biologic or small molecule therapies.
• Optimize vaccination status (e.g., influenza, pneumococcal, herpes zoster) before initiating immunosuppressive therapy to reduce the risk of serious infections.

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#### **Advanced Therapy Recommendations**

1. **Strong Recommendations**:

• AGA strongly recommends using **advanced therapies** such as infliximab, adalimumab, ustekinumab, risankizumab, mirikizumab, guselkumab, or upadacitinib over no treatment.

2. **Conditional Recommendations**:

• **Certolizumab pegol** and **vedolizumab** are suggested over no treatment, reflecting lower certainty or benefit compared to higher-efficacy options.

3. **Biosimilars**:

• Biosimilars of infliximab, adalimumab, and ustekinumab are considered equivalent to their originator biologics in terms of efficacy and can be used interchangeably.

4. **Subcutaneous Maintenance Therapy**:

• Subcutaneous formulations of infliximab and vedolizumab offer comparable efficacy to intravenous (IV) maintenance regimens.

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#### **Efficacy-Based Positioning**

1. **Therapy-Naïve Patients**:

• For patients who have not previously received advanced therapy, AGA suggests starting with **higher-efficacy options** rather than lower-efficacy ones.
• Higher-efficacy grouping is determined based on predefined criteria, including absolute benefit thresholds and network meta-analysis rankings.

2. **Advanced Therapy–Exposed Patients**:

• For patients previously exposed to one or more advanced therapies, AGA suggests using higher- or intermediate-efficacy agents rather than lower-efficacy agents.

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#### **Special Considerations**

1. **Dose Optimization**:

• Extended induction or dose escalation may benefit partial responders, particularly those with a higher disease burden.

2. **Safety Concerns with JAK Inhibitors**:

• **Upadacitinib** (a Janus kinase [JAK] inhibitor) requires careful risk assessment due to potential cardiovascular and thrombotic risks. JAK inhibitors are generally avoided in patients planning pregnancy in the near term.

3. **Thiopurine Therapy**:

• Thiopurine monotherapy (e.g., azathioprine, mercaptopurine) is **not recommended** for inducing remission in moderate-to-severe Crohn’s disease.
• Thiopurine monotherapy is suggested over no treatment for **maintenance of remission**, particularly after steroid-induced remission.

4. **Methotrexate**:

• Subcutaneous or intramuscular methotrexate is suggested for induction and maintenance therapy.
• Oral methotrexate is **not recommended** for either induction or maintenance therapy.

5. **Combination Therapy**:

• For patients naïve to thiopurines starting infliximab, **infliximab + thiopurine** is suggested over infliximab monotherapy to reduce the risk of immunogenicity.
• No recommendations are made for infliximab + methotrexate, adalimumab + immunomodulator, or non-TNF biologic + immunomodulator due to insufficient evidence.

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#### **Treatment Strategies**

1. **Earlier Use of Advanced Therapy**:

• The guideline suggests initiating advanced therapy upfront rather than relying on step-up approaches involving corticosteroids and/or immunomodulator monotherapy.

2. **Induction and Maintenance**:

• Advanced therapies are positioned to induce remission and maintain it long-term, with dose optimization strategies for partial responders.

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### **Knowledge Gaps**

• Evidence is insufficient to recommend combination therapies involving infliximab + methotrexate, adalimumab + immunomodulators, or non-TNF biologics + immunomodulators.
• Long-term comparative data on efficacy and safety for newer agents like risankizumab, mirikizumab, and guselkumab are still evolving.

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### **Practical Implications**

This guideline emphasizes the importance of:

• Early use of advanced therapies for moderate-to-severe Crohn’s disease.
• Confirming active inflammation and optimizing pretreatment screening and vaccination.
• Selecting therapies based on efficacy rankings and individual patient factors.
• Careful risk assessment for therapies with specific safety concerns (e.g., JAK inhibitors).

Overall, the AGA guideline provides a structured framework to help clinicians navigate the complex landscape of Crohn’s disease management, prioritizing evidence-based, patient-centered care.