Infliximab (Remicade) is a biologic medication used to treat several chronic autoimmune diseases, including Crohn’s disease, ulcerative colitis, rheumatoid arthritis, and ankylosing spondylitis. As a monoclonal antibody, infliximab works by targeting and neutralizing tumor necrosis factor-alpha (TNF-α), a protein that drives inflammation in these conditions. This medication is administered through a slow intravenous infusion in a clinical setting. Because the body processes this drug differently from person to person, the amount of infliximab remaining in the blood can vary widely. Monitoring these circulating levels is necessary to maintain the drug’s effectiveness over time.
Why Levels Are Measured (Therapeutic Drug Monitoring)
The process of measuring drug concentration in the blood is known as Therapeutic Drug Monitoring (TDM). The primary purpose of TDM is to personalize treatment, ensuring each patient maintains an optimal level of medication for their specific needs. TDM helps clinicians navigate the significant variability in how quickly individuals clear the drug from their system, which is influenced by factors like body weight, disease burden, and the presence of antibodies.
TDM focuses on measuring the “trough level,” which is the concentration of infliximab in the blood immediately before the next scheduled infusion. This timing represents the lowest point of drug concentration in the patient’s system. If the trough level is below a certain threshold, there may not be enough medication to suppress inflammation effectively.
Ensuring adequate drug concentration is crucial for efficacy, safety, and cost management. If levels are too low, the patient’s disease may flare up, leading to worse outcomes. Conversely, if levels are unnecessarily high, the patient is exposed to potential risks, such as infection, without added therapeutic benefit, while also increasing healthcare costs. TDM helps clinicians optimize the balance between achieving a sustained treatment response and minimizing unnecessary drug exposure.
Target Trough Levels for Maintenance and Healing
The recommended concentration of infliximab depends heavily on the patient’s specific treatment goal, such as clinical remission or mucosal healing. For a patient who is already in clinical remission and is on maintenance therapy, the standard therapeutic trough range is typically cited between 3 to 7 micrograms per milliliter (µg/mL). Maintaining levels within this range is generally associated with sustained control of symptoms and prevention of disease relapse.
When the treatment goal is more ambitious, such as achieving mucosal healing in inflammatory bowel disease, higher trough levels are often required. Mucosal healing refers to the absence of active inflammation visible on an endoscopy, which is a stronger predictor of long-term remission than symptom relief alone. For this intensive goal, many clinical guidelines suggest aiming for infliximab trough levels of 8 µg/mL or higher.
In cases of active or severe disease, especially during the initial induction phase or when treating complications like fistulizing Crohn’s disease, even higher levels may be necessary to overcome the inflammatory burden. Some data suggest trough levels exceeding 10 µg/mL are needed for optimal fistula healing. These higher targets reflect the need for a greater drug concentration during periods of high disease activity.
When Levels Are Too Low: Loss of Response and Immunogenicity
A significant challenge in long-term infliximab therapy is the Loss of Response (LOR), where a patient who was previously stable begins to experience a return of symptoms. When TDM reveals a trough level below the therapeutic range, it is often due to the body’s immune system mistakenly recognizing the drug as a foreign invader. This is known as immunogenicity, and it leads to the production of Anti-Drug Antibodies (ADAs).
These ADAs, which are essentially antibodies against infliximab, bind directly to the drug molecule. The binding action neutralizes the infliximab, preventing it from attaching to and blocking the inflammatory TNF-α protein. This neutralization renders the medication ineffective, even if a standard dose is administered.
The formation of ADAs also accelerates the clearance of the drug from the body, leading to the rapid removal of infliximab from the circulation. Consequently, the measured trough level drops, and the drug’s effectiveness diminishes quickly. If a patient experiences LOR and is found to have low or undetectable infliximab trough levels coupled with high concentrations of ADAs, the mechanism of failure is considered immune-mediated. This scenario requires a change in treatment strategy to either suppress the immune response or switch to a different class of medication.
Optimizing Treatment: Adjusting Dosage Based on Results
Once TDM results are available, the clinician can implement a strategy to optimize the patient’s therapy. If the infliximab trough level is low, but Anti-Drug Antibodies are undetectable or very low, the problem is likely pharmacokinetic, meaning the patient is clearing the drug faster than expected. In this situation, the primary strategy is dose intensification, which involves either increasing the amount of drug given at each infusion or shortening the time interval between infusions.
Conversely, if TDM reveals a consistently high infliximab trough level, the clinician may consider frequency reduction. This involves decreasing the dose or lengthening the interval between treatments. This de-escalation strategy maintains the drug’s effectiveness while potentially reducing cost and long-term risk of infection.
If the TDM results show low drug levels alongside high Anti-Drug Antibodies, the first action may be to introduce or intensify an immunomodulator medication, such as methotrexate or azathioprine, alongside the infliximab. These agents can help suppress the immune system’s production of ADAs, allowing the infliximab concentration to rise back into the therapeutic range. If this strategy fails or if the ADA levels are extremely high, the patient is typically switched to a biologic medication with a different mechanism of action to avoid the immune response entirely.