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Infliximab and Adalimumab Drug and Anti-drug Antibody TestingTest code(s) 36294, 36295, 36296, 36297, 36298, 36299, 36301, 36302, 36303, 36310, 36311, 36312
Question 1. What are infliximab and adalimumab?
Infliximab and adalimumab are therapeutic monoclonal antibodies that target tumor necrosis factor-alpha (TNF-a), a specific proinflammatory molecule. They are mostly prescribed to treat rheumatic diseases, inflammatory bowel disease, and certain dermatologic conditions.1-3
Question 2. How common is treatment failure in patients on infliximab or adalimumab therapy, and when does it tend to occur?
Approximately one-third of patients receiving these biologics experience primary treatment failure (no response to induction therapy) (Table 1).4 In addition, up to about 50% of patients who initially respond to induction therapy with either infliximab or adalimumab later lose the effect and experience disease flares during ongoing maintenance therapy (secondary failure) (Table 2).5,6
Treatment failure rates can vary depending on the drug and clinical indication. Table 1 summarizes studies of nonresponse rates for patients with IBD when treated with adalimumab or infliximab. For instance, nonresponse has been observed in 46% of Crohn disease patients after 26 weeks of adalimumab therapy, while only 31% to 38% of patients with ulcerative colitis show no clinical response after 8 weeks of infliximab therapy.
Table 2 summarizes studies of treatment failure rates in patients with rheumatic diseases who are taking adalimumab or infliximab.
Question 3. What causes treatment failure for patients receiving infliximab or adalimumab?
Several factors can predispose to primary and secondary treatment failure. In patients with primary treatment failure, subtherapeutic levels may indicate poor adherence or increased drug clearance, or other pharmacokinetic issues.
In patients with secondary failure, subtherapeutic drug levels may also be caused by the development of anti-drug antibodies; that is, antibodies that target and lower the bioavailability of TNF-alpha inhibitors. The immunogenicity of TNF-alpha inhibitors (adalimumab, infliximab, etanercept, golimumab, and certolizumab) was investigated in a meta-analysis of 68 studies (14,651 patients) performed from 1966 to 2013. In that study, anti-drug antibodies were detected more often in patients treated with infliximab (25%) than in those treated adalimumab (14%), certolizumab (6.9%), golimumab (3.8%), or etanercept (1.2%).9 Development of anti-drug antibodies reduced the odds of clinical response by 67% overall, although nearly half of the data were derived from articles involving infliximab or adalimumab.
Question 4. How can testing of infliximab and adalimumab drug and anti-drug antibody levels help manage treatment failure?
Although empiric treatment changes can be used to manage treatment failure, a testing-based strategy (ie, testing drug levels and/or anti-drug antibody levels) can help clinicians determine the mechanism of failure and provide an evidence-based approach to evaluating these patients instead of treating them empirically.10 Testing-based strategies help characterize the mechanism of treatment failure as being pharmacodynamic (eg, presence of drug but lack of effect) or pharmacokinetic (ie, low bioavailability of drug due to metabolism issues or anti-drug antibodies) in nature. This information may be helpful in deciding between options to address failure, which may include dosage intensification or switching to a different TNF-alpha inhibitor or drug class.
Question 5. How are drug levels and anti-drug antibody results interpreted?
Table 3 provides a general interpretation of what biologic drug levels and anti-drug antibody detection can mean in relation to one another.
Question 6. Do current guidelines address the role of infliximab and adalimumab drug-level testing?
Yes. The American Gastroenterological Association (AGA) guidelines recommend reactive monitoring (ie, in response to suboptimal disease control) of trough drug levels to guide treatment changes in patients receiving biologics for management of active inflammatory bowel disease.3 Recommended trough drug levels are 5.0 µg/mL for infliximab and ≥7.5 µg/mL for adalimumab.1 Recommendations for drug level testing are not specified in guidelines from the American College of Rheumatology1 or the American Academy of Dermatology.2
Question 7. Why would you measure TNF-alpha inhibitor drug and anti-drug antibody levels at the same time for patients with treatment failure?
Measuring both drug and anti-drug antibody levels at the same time may speed determination of bioavailability and the cause of treatment failure. Measuring only drug levels is appropriate if a sequential approach is preferred. Measuring only anti-drug antibody levels may be appropriate if insufficient bioavailability has already been established.
Question 8. What tests are available for infliximab and adalimumab drug levels and anti-drug antibody levels?
Table 4 outlines the Quest Diagnostics tests available for infliximab and adalimumab therapeutic monitoring. Drug and anti-drug antibody levels are available individually and as panels for 2 types of patient populations: those being treated for inflammatory bowel disease, and those being treated for rheumatic diseases.
Question 9. Do all laboratories use the same test methods for infliximab and adalimumab drug monitoring?
No. Many comparable and widely accepted protein assay methods are used to measure biologic drug levels and detect anti-drug antibodies (eg, fluid-phase radioimmunoassay, solid-phase enzyme-linked immunosorbent assay, reporter gene assay, and enzyme immunoassay); Quest Diagnostics offers enzyme-linked immunosorbent assays, or ELISAs. Performance of various assays tends to be comparable.12 However, infliximab concentrations and anti-infliximab antibody titers may show slight systematic differences. Therefore, it is recommended to use the same assay for a given patient.10
Some ELISA-based tests for adalimumab or infliximab anti-drug antibody are susceptible to false-negative results caused by cross-reactivity with rheumatoid factor. Because our anti-drug antibody level assays measure both free and bound anti-drug antibody, serum rheumatoid factor will not cause false-negative anti-drug antibody results.
Question 10. Is there a test for monitoring patients receiving a biosimilar to infliximab?
Infliximab monitoring assays from Quest Diagnostics were originally designed to detect the reference drug infliximab and its anti-drug antibody, Inflectra® (infliximab-dyyb), an FDA-approved biosimilar of infliximab (exact same amino acid sequence), has become commercially available. Because of the similarities in molecular structures of biosimilars and its reference compounds, the infliximab assays have subsequently been validated for the detection of Inflectra and its anti-drug antibody. The American College of Rheumatology (ACR)1, the American Gastroenterological Association (AGA)3, and the FDA13 all advocate applying infliximab clinical guidance to the use of its biosimilars.14,15
- Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2016;68:1-26.
- Menter A, Gottlieb A, Feldman SR, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis, section 1: overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol. 2008;58:826-850.
- Feuerstein JD, Nguyen GC, Kupfer SS, et al. American Gastroenterological Association Institute Guideline on therapeutic drug monitoring in inflammatory bowel disease. Gastroenterology. 2017;153:827-834.
- Ford AC, Sandborn WJ, Khan KJ, et al. Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis. Am J Gastroenterol. 2011;106:644–659.
- Allez M, Karmiris K, Louis E, et al. Report of the ECCO pathogenesis workshop on anti-TNF therapy failures in inflammatory bowel diseases: definitions, frequency and pharmacological aspects. J Crohns Colitis. 2010;4:355–366.
- Yanai H, Hanauer SB. Assessing response and loss of response to biological therapies in IBD. Am J Gastroenterol. 2011;106:685–698.
- Remicade [package insert]. Horsham, PA: Janssen Biotech Inc; 2015.
- Humira [package insert]. North Chicago, IL: AbbVie Inc; 2016.
- Thomas SS, Borazan N, Barroso N, et al. Comparative immunogenicity of TNF inhibitors: impact on clinical efficacy and tolerability in the management of autoimmune diseases: a systematic review and meta-analysis. BioDrugs. 2015;29:241-258.
- Lázár-Molnár E, Delgado JC. Immunogenicity assessment of tumor necrosis factor antagonists in the clinical laboratory. Clin Chem. 2016;62:1186-1198.