Biologic therapy has been a beacon of hope for people living with autoimmune diseases. They have helped many achieve more symptom-free days and get a new lease on life. But for a proportion of biologic users, treatment failure is a nerve-wracking possibility. For others, biologics may not work at all. So, what gives, and what are your options?
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What Is Biologic Treatment Failure?
In simple terms, biologic failure is a situation wherein a biologic does not work or stops working. Treatment failure is most often associated with tumour necrosis factor inhibitors (TNFi). Infliximab (Remicade) and adalimumab (Humira), in particular, have a higher risk of failing compared with other biologics.
Biologics are a type of monoclonal antibody. They work by blocking specific proteins of the immune system. Proteins like TNF are the fuel that drives the inflammatory cycle. By blocking inflammation promoters, biologics like TNFi stop the immune system from attacking your body.
There are currently four classes of biologics used as a second line of treatment for autoimmune disease. But, in Canada, reimbursement policies can limit your options. For example, in Ontario, only Remicade and Humira are reimbursed for the treatment of IBD.
Types of Biologic Failure
Biologics are far from the perfect miracle drug. Sometimes, the mechanism that makes them work well is also their weakness. The numbers vary, but an estimated 30% of biologic users stop treatment due to non-response.
Primary non-response (PNR) is the failure to respond to a first biologic after 14 weeks of treatment. For example, if you have IBD, you have PNR if after 14 weeks:
- You are not showing any symptomatic improvement
- Your inflammatory markers are not decreasing
- Your bowel tissue is not displaying any signs of healing on endoscopy
In a secondary non-response scenario, a patient responds adequately to the treatment. They might experience vast improvements in symptoms, energy levels, and quality of life. Some even achieve remission. But without warning, they progressively lose this response and their gains. Loss of response can happen anytime from months to years after starting therapy.
Possible Reasons for Biologic Treatment Failure
Identifying a treatment that works for the long term is often the hardest part of any illness. As much as possible, doctors try to make sure that biologics are the most cost-effective option for you. But in the real-world setting, a lot of factors can influence your treatment response. Successful treatment hinges on how well these factors are managed.
Different classes of biologics work through different mechanisms. For example, infliximab targets TNFs. But if your inflammation involves a different pathway, you will probably not respond to infliximab or any other TNFi.
Sometimes, your inflammation can switch to a different pathway during your treatment. This can render your biologic ineffective and can cause secondary non-response.
Low Drug Levels
Biologics, like all other drugs, need to reach therapeutic levels to work. If you don’t have enough biologics in your system, you’re simply not going to feel better. One major cause of low drug levels and poor response is elevated body weight. High body weight increases the rate of metabolism and elimination of biologics.
Drug leakage through the gut can also cause less-than-ideal biologic levels. This is a problem particularly in IBD because damaged intestinal walls allow drugs to leak through.
Development of Antibodies
The development of anti-drug antibodies (ADAs) is a major cause of secondary non-response. Much like a vaccine, biologics are “immunogenic.” This means they can induce an immune response and antibody production. The problem is that these antibodies target the biologic drug itself.
ADAs contribute to treatment failure by directly affecting biologic efficacy. A type of ADA called neutralizing antibodies binds to a drug molecule, preventing it from hitting its target protein. In one meta-analysis, ADAs were found to reduce clinical response to TNFis by 68%. Moreover, ADAs cause your body to clear out the drug faster than it can start working.
Overall, TNFis are more likely than others to cause ADA production. Among the TNFis, infliximab and adalimumab have the most neutralizing effect. Newer classes of biologics like ustekinumab (Stelara) and vedolizumab (Entyvio) rarely have this problem.
Aside from drug type, intermittent dosing and subcutaneous injections can also contribute to ADA development.
Some people are genetically hard-wired to respond poorly to biologic treatment. To be more specific, people carrying an HLA-DQA1*05 mutation are more likely to develop ADAs. In some studies, 92% of people with the mutation developed ADAs within a year of treatment.
Progression to Severe Disease
Although early treatment with biologics can stop disease progression, some patients may still develop complications. For example, if you have Crohn’s disease, you may develop bowel obstruction despite biologic treatment. In cases like these, surgery may be necessary in addition to biologic therapy.
Signs That Your Biologic Treatment Might Be Failing
Here are some red flags to watch out for.
- You feel no symptomatic improvement after 12 to 14 weeks of treatment.
- You develop new symptoms in other parts of your body.
- Your health deteriorates quickly.
- You still find basic activities like dressing, eating, and grooming challenging.
- You start developing allergic reactions to your injections or infusions.
- Normal doses don’t seem to make you feel better for as long as they used to.
- You were starting to feel better, and now you feel symptoms returning.
Next Steps to Take When Your Biologic Stops Working
If you feel that your biologic is not helping, you should discuss your concerns with your doctor. Periodic checkups are typical, especially at the beginning of your treatment.
Periodic assessments are necessary because they can catch early signs of biologic failure. More importantly, they can determine why the treatment failed and guide the next treatment decisions.
1. Determining the source of symptoms
Worsening symptoms don’t necessarily indicate biologic failure. Instead, they could mean that your body is fighting off an infection. Infections caused by C. difficile and cytomegalovirus are common in patients with IBD. Similarly, people with asthma are more vulnerable to viral respiratory infections.
Infections can both worsen your symptoms and mimic flares. Also, they are often indistinguishable from your autoimmune disease. Because of this, your doctor has to rule out infections before anything else. If you turn out to have an infection, you will have to pause your biologic treatment and undergo treatment for the infection.
2. Determining whether there is active inflammation
After infections are ruled out as a source of your symptoms, your doctor will determine whether there is active inflammation. To do this, your doctor will test for a variety of inflammatory markers. C-reactive protein and erythrocyte sedimentation rate (EST) are highly sensitive markers.
Fecal calprotectin for IBD and rheumatoid factor for rheumatoid arthritis can assess the degree of inflammation.
Ideally, you’re also going to undergo a series of imaging tests (e.g., endoscopy, MRI, or ultrasonography). These tests provide direct visualization of your response or non-response to treatment.
3. Testing drug and antibody levels
If your doctor finds an objective increase in inflammation, your drug and antibody levels are tested next. Testing is done in three ways:
- Enzyme-linked immunosorbent assay (ELISA)
- Radio-immunoassay (RIA)
- Fluid phase mobility shift assay
There is currently no standardized test, so different laboratories use different methods. Your drug and antibody levels will determine the next steps.
4. Optimizing dose and frequency
If you test positive for low drug levels and antibodies, your doctor might increase your dose, increase your dosing frequency, or both. For example:
- Infliximab could be increased from 5 mg/kg every 8 weeks to 10 mg/kg every 4 weeks.
- Adalimumab could be increased from 40 mg every 2 weeks to 40 mg every week.
You’ll likely be on this new dosing regimen for at least 12 weeks. To counteract your antibodies, your doctor might also start you on methotrexate. Methotrexate has been found to decrease antibody formation. Moreover, it increases drug levels and improves outcomes. In a 2013 study, methotrexate helped non-responders regain their response to their biologic.
If you still don’t improve, your doctor might switch you to other drugs in the same class or to an entirely new class. Patients who fail on a TNFi may respond well to another TNF drug. In a study of patients with ulcerative colitis, 16 out of 24 patients achieved remission on another TNF drug after infliximab failed.
5. Switching to another class with a different mechanism of action
Having active disease symptoms despite adequate or high drug levels and negative antibodies indicates PNR. Mechanism incompatibility is most likely the cause. Mechanism of action refers to the biochemical interaction through which a drug produces its effect on the body.
If you have PNR, you’re unlikely to respond to dose escalation. Instead, you may be switched to a biologic class with a different mechanism of action as early as possible.
For example, if you have been on Remicade, your doctor may switch you to Stelara or Enytvio. For rheumatoid arthritis and psoriatic arthritis, Health Canada has approved the small molecule drug tofacitinib.
6. Switching from Subcutaneous to IV Infusions
Because subcutaneous injections are immunogenic, you may opt to switch to IV infusions. Switching to IV infusions could help you regain your biologic response. In a 2019 study, 73% of primary non-responders achieved remission after they switched injections to IV infusions.
Make the Most of Your Biologic Treatment with Precision Medicine
Biologics have helped countless lives in the past two decades. However, just like each experience of autoimmune disease is unique, biologics also impact each person differently.
Precision medicine helps SRx take autoimmune care a step further. By using your genetic data and unique environmental and health circumstances, we can help you find the most promising treatments for you, not for everyone else.
Biomarkers are biochemical signatures found in the blood, tissues, or body fluids. They reveal information about your health status and unique biological processes. They can be anything from blood pressure and blood cholesterol to inflammatory proteins and the unique genetic expressions of your synovial joint.
In autoimmune management, biomarkers can be used to:
- Detect early signs of disease activity
- Predict individual treatment response
- Predict prognosis
- Monitor disease or health status
Therapeutic drug monitoring
Therapeutic drug monitoring (TDM) is the periodic measurement of drug levels in the blood. Often, TDA is combined with ADA detection. Together, TDA and antibody testing can personalize your treatment plan and improve therapeutic outcomes by:
- Fine-tuning drug dosage according to your needs
- Detecting under-treatment at early stages before signs of clinical recurrence appear
- Promoting proactive patient care
- Guiding treatment decisions
Pharmacogenomics lets us tap into your genetic code to find gene variations that will affect your biologic response. For example, one gene variation associated with poor treatment response is HLA-DQA1*05. As explained, this allele increases ADA development against TNFi drugs.
Through pharmacogenomics, we can learn whether you carry this allele. This will help to:
- Personalize your treatment plan
- Allow the targeted and pre-emptive use of methotrexate
- Minimize risk and optimize response
- Prevent frustrating trial-and-errors
- Reduce costs
Precision medicine shows us a safer, more cost-effective way of managing autoimmune diseases. At SRx, we strive to employ precision medicine to guide all aspects of our practice. With precision medicine, SRx delivers targeted, personalized, and patient-centred care. Reach out to us today to learn more about our personalized services.