Crohn’s disease is a chronic inflammatory condition of the gastrointestinal tract causing persistent inflammation anywhere from the mouth to the anus. For patients with moderate to severe disease, biologic medications are the standard treatment, suppressing the overactive immune response by blocking specific proteins that drive inflammation. These therapies include anti-tumor necrosis factor (TNF) agents like adalimumab and infliximab. While effective for many, a significant number of patients will eventually experience a time when their medication no longer controls their disease. This non-response requires a systematic approach to identify the cause and explore alternative, non-biologic, and surgical pathways to achieve sustained remission.
Defining Treatment Failure
When a biologic treatment fails to achieve or maintain disease control, it is categorized into two types. Primary Non-Response (PNR) occurs when the medication never produces a satisfactory clinical improvement after the initial induction phase, typically within the first few months of starting the drug. PNR often suggests the drug’s mechanism does not address the specific inflammatory pathway driving the patient’s disease. The second type is Secondary Loss of Response (SLR), which happens when a patient initially responds well but then experiences a return of symptoms over time. Both PNR and SLR are confirmed by clinical markers, such as persistent diarrhea or abdominal pain, and objective evidence of inflammation, including elevated C-reactive protein (CRP) or fecal calprotectin.
Investigating the Cause of Non-Response
Determining the specific reason for non-response is essential before switching treatments, as the cause dictates the next step. The first step involves Therapeutic Drug Monitoring (TDM), which measures the drug concentration (trough level) in the blood before the next dose. Low trough levels suggest the medication is being cleared too quickly and may indicate a need for dose intensification. TDM also checks for anti-drug antibodies (ADAs), immune-mediated proteins that neutralize the biologic. High ADA levels clear the drug quickly, leading to low trough levels and treatment failure.
If TDM shows adequate drug levels and no ADAs, the non-response is a mechanistic failure, meaning the drug’s target is no longer the main driver of inflammation. In this case, switching to a biologic with a different mechanism of action is the preferred strategy. Objective assessment is also critical to rule out non-inflammatory complications mimicking a flare. Imaging, such as Magnetic Resonance Enterography (MRE) or CT Enterography, and endoscopy can confirm active inflammation or identify structural issues. Structural complications, like strictures or abscesses, often require surgical intervention rather than increased biologic dosing.
Strategies for Switching Biologics
When a biologic fails, the most common strategy is to switch to another targeted therapy that works through a different mechanism. This swap targets an alternate inflammatory pathway driving the patient’s disease. If a patient fails an anti-TNF agent, the next step is often to use a drug from a completely different class.
Alternative Biologic Classes
Anti-integrins: These agents, such as vedolizumab, block inflammatory white blood cells from entering the gut tissue.
Anti-interleukin (IL) inhibitors: These drugs, such as ustekinumab, target the IL-12 and IL-23 proteins to disrupt the inflammatory cascade.
Switching to a new class is generally preferred over switching to a different drug within the same class, especially after a primary non-response, as it engages a different biological target. While switching within the anti-TNF class can be effective in cases of secondary loss of response with high ADAs, the success rate is typically lower than switching mechanisms. The selection of the next biologic is a personalized decision based on the patient’s disease characteristics and the potential for lasting remission.
Small Molecule and Immunosuppressive Options
Other drug classes offer alternatives for patients who have failed one or more injectable biologics. The newer small molecule inhibitors offer a different chemical structure and often an oral route of administration. These include Janus Kinase (JAK) inhibitors, such as upadacitinib, which block specific enzymes inside immune cells to interrupt inflammatory signaling. JAK inhibitors are a targeted synthetic therapy that works quickly and has shown efficacy even after anti-TNF treatment failure. Their oral administration offers an alternative to the injections or intravenous infusions required for biologics, providing a distinct mechanism of action when large protein-based biologics have not worked.
Older traditional immunosuppressants, such as thiopurines (azathioprine or 6-mercaptopurine) and methotrexate, also continue to play a role. These drugs suppress the overall immune system to reduce inflammation. They are sometimes used in combination with biologics to help reduce anti-drug antibodies, or they can be utilized as monotherapy in specific situations where targeted therapies have failed or are inappropriate.
Surgical Management as a Therapeutic Option
When medical therapy, including multiple biologics and small molecules, is insufficient to control the disease or when complications arise, surgical management becomes a necessary therapeutic option. Surgery is not a failure of treatment but a targeted intervention to address areas of irreversible damage caused by chronic inflammation. It is indicated when medical therapy cannot resolve complications such as bowel obstruction from strictures, persistent fistulas, or abscesses.
The most common procedure is a bowel resection, where the diseased segment is removed and the healthy ends are reconnected. This provides significant symptom relief and improves quality of life, especially for patients with localized disease. Another technique is stricturoplasty, which involves widening a narrowed section of the bowel without removing it, preserving intestinal length. While surgery can be highly effective and offer a long period of remission, it does not cure Crohn’s disease. Inflammation can recur in other parts of the digestive tract over time, so patients often continue medical therapy afterward to maintain remission and prevent recurrence.