Navigating treatment options when first-line anti-TNF therapy fails
For millions living with Crohn's disease, anti-TNF (tumor necrosis factor) medications like infliximab and adalimumab have been revolutionary, offering significant relief from this chronic inflammatory bowel condition 2 . However, the journey is often not straightforward. A striking reality in gastroenterology is that a significant number of patients—up to 30%—do not respond to initial anti-TNF treatment (primary non-response), and many others who initially benefit later lose that response (secondary loss of response) 7 .
Up to 30% of patients with Crohn's disease experience treatment failure with anti-TNF therapies, requiring alternative treatment strategies.
Finding yourself at this therapeutic crossroads can be daunting. The good news is that the landscape of Crohn's treatment has expanded dramatically. This article serves as your guide to the world of second-line therapies, explaining the science behind the options and offering clear, evidence-based insights to help you and your doctor navigate this critical decision.
To understand the second-line options, it's helpful to know why first-line treatments can fail. Anti-TNF agents work by targeting and neutralizing TNF-alpha, a key pro-inflammatory cytokine that drives the damaging inflammation in Crohn's disease 2 4 . However, the body can fight back in two main ways:
Crohn's disease is complex and involves multiple inflammatory pathways. Even if TNF is successfully blocked, other pathways, such as those involving interleukins (IL) like IL-12 and IL-23, can continue to drive the disease process 6 .
A major shift in clinical guidelines has occurred. Historically, doctors followed a "step-up" approach, reserving advanced therapies for only the most severe cases. The 2025 American College of Gastroenterology (ACG) clinical guideline now suggests that for patients with moderate-to-severe Crohn's disease, it is not necessary to fail conventional therapies before starting advanced treatments 1 . This "top-down" or early intervention strategy recognizes that getting the right treatment early can lead to better long-term outcomes by preventing disease complications.
Step-up Therapy: Start with milder treatments, escalate to biologics only if necessary
Top-down Therapy: Early intervention with advanced treatments for better long-term outcomes
When anti-TNF therapy fails, the next step is to switch to an agent with a different mechanism of action. The main classes of second-line biologics and small molecule drugs work in distinct ways.
| Drug Class | Example Agents | Mechanism of Action | Key Characteristics |
|---|---|---|---|
| IL-12/23 Inhibitors | Ustekinumab 1 6 | Blocks interleukin (IL)-12 and IL-23, two cytokines involved in inflammatory pathways distinct from TNF 6 . | An established option after anti-TNF failure; administered by IV infusion or subcutaneous injection 6 7 . |
| IL-23 Inhibitors | Risankizumab 1 6 | Specifically targets the p19 subunit of IL-23, providing a more precise blockade of this pathway 1 . | Newer class; shown to be highly effective in patients with prior anti-TNF exposure 1 6 . |
| Anti-Integrins | Vedolizumab 1 7 | Targets α4β7 integrin, blocking lymphocytes from migrating from the bloodstream into the gut lining 7 . | Gut-selective mechanism; may have a favorable safety profile as it minimizes systemic immune suppression 7 . |
| JAK Inhibitors | Upadacitinib 1 | A small-molecule pill that inhibits Janus kinase (JAK) enzymes, blocking intracellular signaling of multiple cytokines 1 . | The only oral advanced therapy for Crohn's; provides a convenient administration route 1 . |
Large molecule drugs typically administered by injection or infusion
Oral medications that work inside cells to block signaling pathways
Precision medicine approaches targeting specific inflammatory pathways
While guidelines provide direction, nothing influences clinical practice more than a well-designed, head-to-head study. The SEQUENCE trial was a pivotal phase 3b study designed to answer a crucial question: in patients who have failed anti-TNF therapy, which is more effective—ustekinumab (an IL-12/23 inhibitor) or risankizumab (an IL-23 inhibitor)? 6
The trial directly compared the standard dosing regimens of risankizumab and ustekinumab in patients with moderate-to-severe Crohn's disease. It had two primary goals: to assess clinical remission at week 24 and endoscopic response at week 48 6 .
This trial provided strong evidence that IL-23 inhibition with risankizumab may be more effective than IL-12/23 inhibition with ustekinumab in this specific patient population 6 . This has led many clinicians to favor risankizumab for patients after anti-TNF failure.
| Outcome Measure | Risankizumab (IL-23 Inhibitor) | Ustekinumab (IL-12/23 Inhibitor) | Statistical Significance |
|---|---|---|---|
| Clinical Remission (Week 24) | 57.1% | 40.6% | p = 0.004 |
| Endoscopic Response (Week 48) | 47.5% | 30.4% | p = 0.003 |
The development of these advanced therapies relies on a sophisticated understanding of the immune system. The table below details some of the key "research reagents" — often biological molecules themselves — that scientists use to study and develop treatments for Crohn's disease.
| Research Tool / Molecule | Function in Research | Relevance to Drug Development |
|---|---|---|
| Cytokines (TNF-α, IL-12, IL-23) | Purified proteins used to stimulate inflammatory pathways in cell cultures and animal models of colitis 2 4 . | Used to screen and test potential drug candidates for their ability to block these specific cytokines. |
| Monoclonal Antibodies | Laboratory-produced antibodies designed to bind with high specificity to a single target, like a cytokine or its receptor 2 4 . | The basis for most biologic drugs (e.g., infliximab, ustekinumab, risankizumab). Research versions are first tested in pre-clinical models. |
| Lamina Propria Mononuclear Cells | Immune cells isolated from the intestinal lining of patients or animal models 4 . | Allow researchers to study the direct effects of drugs on the specific inflammatory cells present in the gut of a person with Crohn's. |
| Cell Lines (e.g., Jurkat T-cells) | Immortalized human immune cells that can be grown continuously in the lab 4 . | Provide a standardized and readily available model to study mechanisms like T-cell activation and apoptosis (programmed cell death) induced by drugs. |
| Animal Models (e.g., murine colitis) | Genetically modified or chemically treated mice that develop IBD-like inflammation 4 . | Essential for testing the efficacy and safety of new drug candidates in a whole living system before human trials. |
With several effective options available, the choice is no longer one-size-fits-all. The decision is increasingly personalized, based on a combination of factors 6 7 .
The SEQUENCE trial strongly supports the use of IL-23 inhibitors like risankizumab after anti-TNF failure 6 . However, other options like ustekinumab and vedolizumab remain effective for many.
For complex fistulizing disease, while infliximab remains first-line, other options like upadacitinib are now considered reasonable 1 .
A patient's overall health profile may make one drug's safety profile more attractive than another's. This is a critical discussion to have with your gastroenterologist.
In many healthcare systems, the cost of medication and the rules of insurance coverage can influence which drug is chosen 6 .
Ultimately, the 2025 ACG guidelines and contemporary research emphasize an individualized, patient-centered approach. The goal is a shared decision between you and your doctor, selecting a therapy that not only targets your inflammation effectively but also aligns with your life and preferences.
Hitting a roadblock with your first biologic treatment for Crohn's disease is a challenge, but it is far from the end of the road. The growing arsenal of second-line therapies, backed by robust head-to-head clinical trials and updated guidelines, provides more hope and options than ever before.
By understanding the science, the evidence, and the factors that guide personalized treatment, you can move from a place of uncertainty to one of informed confidence, ready to collaborate with your healthcare team on the next best step in your journey to wellness.