Treat-to-Target Approach to Crohn's Disease Management

• Disease Activity: This is a measure of the current inflammatory burden, categorized as mild, moderate, or severe. We assess this using a combination of patient-reported symptoms, objective biomarkers (CRP, fecal calprotectin), and endoscopic or imaging findings that reveal the extent and depth of ulceration, with deep ulcers signifying a higher-risk disease course.
• Disease Behavior: This describes the long-term pattern of the disease and is critical for predicting its course and selecting appropriate therapy. The primary phenotypes are:
  • Inflammatory (B1): Characterized by inflammation of the bowel wall without narrowing or perforations.
  • Stricturing (B2): Characterized by chronic inflammation leading to fibrosis and narrowing of the bowel, which can cause obstructive symptoms.
  • Penetrating (B3): The most aggressive form, where inflammation extends through the entire bowel wall, leading to complications like fistulas (abnormal connections between the bowel and other organs or the skin) or abscesses (walled-off collections of pus).

1. First-Line Induction: The standard of care is controlled-ileal-release (CIR) budesonide. The typical dose is 9 mg daily for approximately 8 weeks. This formulation is designed to release the medication directly in the terminal ileum and right colon, minimizing systemic side effects. It is crucial to emphasize that this is for induction only and is not an appropriate maintenance therapy.
2. Alternative Induction: Exclusive Enteral Nutrition (EEN) is a well-established and effective induction therapy, particularly in the pediatric population, but it remains a valid option for motivated adults.
3. Therapies to Avoid: Certain treatments are not appropriate for this scenario and represent undertreatment. These include 5-ASA compounds (mesalamine), which have proven ineffective for ileal Crohn's, and routine antibiotics (e.g., ciprofloxacin, metronidazole) for uncomplicated luminal inflammation.

• Remission Achieved (Normal CRP ≤5 mg/L and Fecal Calprotectin trending <250 µg/g): The goal has been met. Stop budesonide and continue to monitor the patient closely with clinical check-ins and periodic biomarkers.
• Partial Response (Improved but abnormal biomarkers): The patient has ongoing, objective inflammation. Stop budesonide and escalate to an advanced, steroid-sparing therapy. Continuing steroids in this scenario fosters steroid dependency, constitutes undertreatment, and fails to alter the disease course.
• No Response (Unchanged or worse): This indicates a primary non-response to steroid induction. Stop budesonide and immediately switch to an advanced therapy.

• TNF-α Inhibitors
  • Infliximab (IV and SC Zymfentra), Adalimumab, Certolizumab pegol
  • This class has the longest track record, a deep evidence base for mucosal healing, and the unique utility of Therapeutic Drug Monitoring (TDM) to guide treatment.
• IL-12/23 (p40) Blocker
  • Ustekinumab
  • This agent offers an excellent safety and tolerability profile, making it a strong choice for older or comorbid patients, or in any scenario where minimizing infection risk is a priority.
• IL-23 (p19) Blockers
  • Risankizumab, Mirikizumab
  • These newer agents offer strong efficacy as monotherapy, have very low immunogenicity, and feature convenient subcutaneous maintenance dosing.
• Integrin Blockers
  • Vedolizumab (gut-selective α4β7), Natalizumab (systemic α4)
  • Vedolizumab is a gut-selective therapy with an excellent safety profile, while Natalizumab is a highly effective but last-line option due to specific safety concerns.
• JAK Inhibitors
  • Upadacitinib (oral)
  • This oral small molecule provides a very rapid onset of action and high efficacy, but its use requires careful patient selection and monitoring due to class-specific warnings.

• The Top Contenders: Risankizumab vs. Infliximab
  • Risankizumab (IL-23 Blocker): This is often a preferred first choice due to its strong monotherapy efficacy, convenient every-8-week subcutaneous maintenance dosing, and minimal immunogenicity, which eliminates the need for combination immunosuppression or routine TDM.
  • Infliximab (Anti-TNF): This agent remains a top-tier choice, backed by the deepest evidence base for inducing mucosal healing. It offers a rapid onset of action and the significant advantage of allowing for Therapeutic Drug Monitoring (TDM), which enables precise, data-driven optimization of therapy.

• Ustekinumab (IL-12/23 Blocker): This is an excellent safety-leaning alternative. Its superb tolerability makes it a strong choice for older patients, those with comorbidities, or anyone for whom minimizing infection risk is a top priority.
• Upadacitinib (JAK1 Inhibitor): This oral agent is highly effective and acts very quickly. It is typically reserved for patients with steroid-refractory or high-urgency disease or those who have failed other biologics. Its use requires a thorough discussion of class-specific boxed warnings (e.g., VTE, MACE) and an established laboratory monitoring plan.
• Vedolizumab (α4β7 Integrin Blocker): As a gut-selective therapy, this agent has a superior safety profile. However, it is often de-prioritized for purely ileal disease due to a slower onset of action compared to anti-TNF or IL-23 agents.

• If the first-line agent was an Anti-TNF (e.g., Infliximab):
  • The next best step is Risankizumab (IL-23). This is supported by head-to-head data from the SEQUENCE trial, which demonstrated superiority over ustekinumab for endoscopic remission at week 48 in patients who had failed anti-TNF therapy. Ustekinumab and Upadacitinib are also strong subsequent alternatives.
• If the first-line agent was an IL-23 Blocker (e.g., Risankizumab):
  • The next best step is an Anti-TNF (e.g., Infliximab). Switching to this class leverages a different mechanism of action and brings the powerful tool of TDM into play for precise optimization. Upadacitinib is another highly effective option.
• If the first-line agent was Vedolizumab:
  • The best rescue agents are Ustekinumab or an IL-23 blocker like Risankizumab, which have demonstrated superior efficacy in real-world cohorts of patients who have previously failed therapy.

1. Imaging and Surgical Control: All patients require cross-sectional imaging, typically an MRI, to fully delineate the anatomy of the fistula tracts and identify any associated abscesses. This must be followed by an Exam Under Anesthesia (EUA), during which a surgeon can drain any abscesses and place draining setons through the fistula tracts. Setons keep the tracts open, allowing them to drain and preventing recurrent abscess formation while medical therapy takes effect.
2. Adjunctive Antibiotics: A short course of antibiotics, such as ciprofloxacin with or without metronidazole, can be used as an adjunct to help control septic symptoms while the primary advanced therapy is initiated.

• The clear, evidence-based first-line agent for fistulizing Crohn's disease is Infliximab (Anti-TNF). It has the strongest and most extensive randomized controlled trial data demonstrating its ability to induce fistula closure.
• Adalimumab (Anti-TNF) is a reasonable alternative if infliximab is not feasible.

1. Ustekinumab (IL-12/23 Blocker): This is the best next choice. It is supported by the most robust real-world data demonstrating meaningful rates of fistula improvement and closure in patients who have previously failed anti-TNF therapy.
2. Upadacitinib (JAK1 Inhibitor): This is a strong subsequent option with rapidly growing data supporting its efficacy for fistula improvement. Its fast onset of action is particularly valuable when rapid control of concurrent luminal inflammation is also needed.
3. Vedolizumab (α4β7 Integrin Blocker): This agent can be considered a safety-first alternative. However, it is important to set expectations that its effect on fistulas is generally slower and less potent compared to the other options.

• Therapeutic Drug Monitoring (TDM): TDM, which involves measuring drug levels and anti-drug antibodies, is an established and invaluable tool for anti-TNF agents (Infliximab, Adalimumab). It guides optimization to overcome low drug levels and confirms mechanistic failure when levels are adequate but the disease is active. TDM is not routinely used for IL-23 blockers or JAK inhibitors.
• Managing a Rectal Flare: For a patient on stable systemic therapy who develops new rectal symptoms (proctitis), the first step is to rule out infection (e.g., C. difficile). The next step is to add a topical therapy, such as budesonide foam or a hydrocortisone enema, as a local bridge while simultaneously assessing and optimizing the underlying systemic agent. Topical mesalamine is only a minor adjunct in this setting and is ineffective for ileal Crohn's.
• Pregnancy Considerations: While most biologics can be used safely in pregnancy, Certolizumab pegol is often preferred among the anti-TNFs. Due to its unique structure lacking an Fc region, it has minimal placental transfer, reducing fetal exposure in late gestation.
• Natalizumab's Niche Role: Natalizumab is a highly effective integrin blocker but is reserved as a last-line therapy due to the risk of Progressive Multifocal Leukoencephalopathy (PML), a rare but serious brain infection. Its use is restricted to patients who are negative for the JC virus (JCV) and requires enrollment in the mandatory TOUCH REMS safety program. Crucially, treatment should be discontinued if there is no evidence of clinical benefit by 12 weeks.

1. Phenotype Dictates Strategy. Treatment begins with a fundamental classification of the disease. The distinction between luminal inflammatory disease and complicated penetrating/fistulizing disease determines the entire therapeutic pathway, from the urgency of intervention to the choice of the first-line agent.
2. Embrace Treat-to-Target. The goal is not merely to make patients feel better, but to achieve objective, steroid-free remission. This requires setting clear biomarker and endoscopic targets at the outset and escalating therapy in a timely manner—typically at the 12-16 week checkpoint—if those T2T targets are not met.
3. Sequence Intelligently. When a treatment fails, switch to a drug with a different mechanism of action based on the best available evidence. For luminal disease, this most commonly involves switching between the anti-TNF and IL-23 classes. For fistulizing disease, the sequence is clear: start with anti-TNF, and if that fails, move to ustekinumab.
4. Control the Source. For any penetrating complication, such as an abscess or fistula, the absolute and non-negotiable priority is procedural control. Drainage of abscesses and placement of setons must occur before or in concert with medical escalation to ensure patient safety and therapeutic success.