A Phenotype-Driven Guide to Biologic Selection in Crohn's Disease

The management of Crohn's disease has undergone a paradigm shift, moving away from a reactive model focused on symptom control towards a proactive, treat-to-target strategy. This modern approach aims to alter the natural history of the disease by achieving deep, objective remission, thereby preventing complications like strictures, fistulas, and the need for surgery. A systematic, evidence-based approach is paramount, beginning with accurate disease classification and risk stratification to tailor the selection of advanced therapies to the individual patient's disease phenotype.

1.0 Foundational Principles of Modern Crohn's Disease Management

Before selecting a specific agent, a clinician must establish a foundational understanding of the patient's disease, their risk profile, and the overarching therapeutic goals. This ensures that treatment is not only effective but also safe and aligned with long-term objectives.

1.1 Disease Classification: The Montreal System

Accurate classification is the first step in developing a therapeutic strategy. The Montreal system is the most widely used framework for categorizing Crohn's disease based on age at diagnosis, disease location, and disease behavior.

Montreal Classification System:

• Age at Diagnosis (A):
  • A1: Below 17 years
  • A2: Between 17-40 years
  • A3: Above 40 years
• Disease Location (L):
  • L1: Ileal (terminal ileum)
  • L2: Colonic
  • L3: Ileocolonic
  • L4: Isolated upper disease (modifier)
• Disease Behavior (B):
  • B1: Non-stricturing, non-penetrating (inflammatory)
  • B2: Stricturing
  • B3: Penetrating
  • p: Perianal disease modifier

The behavioral phenotype (B1, B2, or B3), often with a perianal modifier ("p"), is the primary determinant of therapeutic strategy and prognosis.

1.2 Risk Stratification and the Treat-to-Target (T2T) Model

Identifying patients at high risk for a complicated disease course is critical for deciding when to initiate aggressive, early therapy. High-risk features predict a greater likelihood of future surgeries, hospitalizations, and disability.

Characteristics of High-Risk Patients:

• Young age at diagnosis (<17 years)
• Extensive small bowel disease
• Deep ulcerations on endoscopy
• Stricturing (B2) or penetrating/fistulizing (B3) disease behavior
• History of previous surgery for Crohn's disease
• Perianal disease

For these patients, a Treat-to-Target (T2T) model is essential. This model moves beyond symptom control to pursue objective evidence of healing. The therapeutic goals are hierarchical:

• Clinical Remission: Resolution of symptoms such as abdominal pain and diarrhea.
• Biomarker Normalization: Normalization of inflammatory markers like C-reactive protein (CRP) and fecal calprotectin (FC).
• Endoscopic Healing: Resolution of mucosal ulcerations, which is associated with better long-term outcomes, including fewer hospitalizations and surgeries.

1.3 The Essential Pre-Biologic Checklist

Before initiating any advanced therapy, a thorough safety screen is mandatory to minimize the risk of infectious complications and ensure the patient is prepared for immunosuppressive treatment.

Pre-Initiation Safety Checklist:

• Tuberculosis (TB) Screening: All patients must be screened for latent TB infection with an Interferon-Gamma Release Assay (IGRA) blood test, supplemented by a chest x-ray as needed.
• Hepatitis B (HBV) Screening: Screening with HBsAg, anti-HBs, and anti-HBc is crucial. Biologic therapy can suppress the immune system's control over the virus, leading to HBV reactivation, which can cause severe hepatitis and liver failure. Patients with active or past infection require monitoring and may need prophylactic antiviral therapy.
• Vaccination Update: All age-appropriate vaccinations should be brought up to date before starting therapy. This includes influenza, pneumococcal, COVID-19, and shingles (Shingrix). Importantly, live vaccines must be administered at least four weeks before starting a biologic and must be avoided during treatment.

With these foundational principles established, the next step is to understand the available therapeutic agents and their distinct mechanisms of action.

2.0 The Therapeutic Armamentarium for Crohn's Disease

The landscape of advanced therapies for Crohn's disease has expanded significantly, offering a range of agents with distinct mechanisms of action. Understanding these differences is crucial for making an informed initial selection and for rationally sequencing therapies in the event of treatment failure.

Major Classes of Advanced Therapies for Crohn's Disease:

• Anti-TNF Agents (TNF Inhibitors):
  • Infliximab (IV infusion)
  • Adalimumab (subcutaneous injection)
  • Certolizumab pegol (subcutaneous injection)
• Anti-Integrin Agents:
  • Vedolizumab (IV infusion) - gut-selective
• Anti-IL-12/23 Agents:
  • Ustekinumab (IV induction, then subcutaneous maintenance)
• Anti-IL-23 Agents:
  • Risankizumab (IV induction, then subcutaneous maintenance)
• JAK Inhibitors:
  • Upadacitinib (oral)

Applying this powerful armamentarium effectively requires tailoring the choice of agent to the patient's specific disease presentation, or phenotype.

3.0 Phenotype-Guided Biologic Selection

The most effective treatment strategies are those tailored to the patient's specific disease behavior. While many agents are effective for uncomplicated inflammatory disease, the presence of strictures or penetrating complications significantly influences the choice of therapy. This section provides evidence-based recommendations for the three primary Crohn's disease phenotypes.

3.1 Management of Inflammatory (B1) Crohn's Disease

The B1 phenotype is characterized by luminal inflammation without the presence of strictures or fistulas. While all major classes of advanced therapies are effective for moderate-to-severe B1 disease, anti-TNFs, ustekinumab, and risankizumab are often favored as initial therapy in biologic-naïve patients. The choice is further guided by patient-specific factors and therapeutic priorities.

• Need for Rapid Onset: For hospitalized patients or those with severe symptoms and deep ulcerations, agents with a rapid onset of action are preferred. Anti-TNFs (Infliximab, Adalimumab) and JAK inhibitors (Upadacitinib) are preferred.
• Safety-First Approach: For patients who are elderly, have a high baseline risk of infection, or have a history of malignancy, agents with a more favorable safety profile are prioritized. Vedolizumab (gut-selective) and Ustekinumab are preferred.
• Strong Mucosal Healing Priority: Achieving deep endoscopic remission is a primary goal to alter the long-term course of the disease. Risankizumab and Ustekinumab have demonstrated particularly strong outcomes in endoscopic healing.
• Oral Route Preference: For patients who prefer to avoid injections or infusions, an oral small molecule is the only option. Upadacitinib is the preferred agent.

3.2 Management of Stricturing (B2...