Infliximab, Adalimumab, Vedolizumab, and Ustekinumab in Autoimmune Diseases
Biologic agents (e.g. infliximab, adalimumab, vedolizumab, or ustekinumab) are used to treat multiple inflammatory conditions, including rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis; inflammatory bowel disease (eg, Crohn disease, ulcerative colitis), ankylosing spondylitis, and plaque psoriasis. These agents are generally given to individuals who fail conventional medical therapy, and they are typically highly effective for the induction and maintenance of clinical remission. However, not all individuals respond, and a high proportion of individuals lose response over time. It is estimated that 1 in 3 individuals do not respond to induction therapy (primary nonresponse); further, among initial responders, response wanes over time in approximately 20% to 60% of individuals (secondary nonresponse). The reasons for therapeutic failures remain a matter of debate but include accelerated drug clearance (pharmacokinetics) and neutralizing agent activity (pharmacodynamics) due to antidrug antibodies (ADA). ADA is also associated with injection-site reactions and acute infusion reactions and delayed hypersensitivity reactions.
Detection of Antidrug Antibodies
The detection and quantitative measurement of ADA is difficult, owing to drug interference and identifying when antibodies likely have a neutralizing effect. First-generation assays (i.e., enzyme-linked immunosorbent assays [ELISA]) can measure only ADA in the absence of detectable drug levels, due to the interference of the drug with the assay. Other techniques available for measuring antibodies include the radioimmunoassay method and, more recently, the homogenous mobility shift assay using high-performance liquid chromatography. Disadvantages of the radioimmunoassay method are associated with the complexity of the test and prolonged incubation time, along with safety concerns related to the handling of radioactive material. The homogenous mobility shift assay measures ADA when infliximab is present in serum. Studies evaluating the validation of results among different assays are lacking, making interstudy comparisons difficult. One retrospective study by Kopylov et al (2012), which evaluated 63 individuals, demonstrated comparable diagnostic accuracy between 2 different ELISA methods in individuals with inflammatory bowel disease(ie, double-antigen ELISA and antihuman lambda chain-based ELISA). This study did not include an objective clinical and endoscopic scoring system for validation of results.
Treatment Options for Secondary Nonresponse to Biologic Agents
A diminished or suboptimal response to infliximab, adalimumab, vedolizumab, or ustekinumab can be managed in several ways: shortening the interval between doses, increasing the dose, switching to a different biologic agent (in individuals who continue to have a loss of response after receiving the increased dose), or switching to a non- biologic agent.
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.
Prometheus Laboratories, a College of American Pathologists-accredited lab under the Clinical Laboratory Improvement Amendments, offers 4 non-radio-labeled, fluid-phase homogenous mobility shift assay tests: called Anser IFX (for infliximab), Anser ADA (for adalimumab), Anser VDZ (for vedolizumab), and Anser UST (for ustekinumab). The tests measure both serum drug concentrations and ADA. They are not based on an ELISA test, and can measure ADA in the presence of detectable drug levels, improving on a major limitation of the ELISA method.