Description
Infliximab, Adalimumab, Vedolizumab, and Ustekinumab in Autoimmune Diseases
Biologic agents used to treat autoimmune diseases include infliximab, adalimumab, vedolizumab, and ustekinumab. Infliximab (Remicade) is an intravenous tumor necrosis factor α blocking agent approved by the U.S. Food and Drug Administration (FDA) for the treatment of rheumatoid arthritis, Crohn disease, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, and ulcerative colitis. Adalimumab (Humira) is a subcutaneous tumor necrosis factor α inhibitor that is FDA approved for the treatment of rheumatoid arthritis, Crohn disease, ulcerative colitis, ankylosing spondylitis, plaque psoriasis, psoriatic arthritis in adults and those with juvenile idiopathic arthritis, hidradenitis suppurativa, and uveitis. Vedolizumab (Entyvio) is an intravenous integrin receptor antagonist that is FDA approved for treatment of ulcerative colitis and Crohn disease in adults. Ustekinumab (Stelara) is an intravenous and subcutaneous human interleukin-12 and -23 antagonist that is FDA approved for the treatment of, Crohn disease and ulcerative colitis in adults, and psoriatic arthritis and plaque psoriasis in children and adults. Following the primary response to these medications, some patients become secondary nonresponders. The development of antidrug antibodies is considered a cause of this secondary nonresponse.
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 two (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.
Regulatory Status
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 four (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.
Summary of Evidence
For individuals who have rheumatoid arthritis, psoriatic arthritis, or juvenile idiopathic arthritis; inflammatory bowel disease (e.g., Crohn disease, ulcerative colitis); ankylosing spondylitis; or plaque psoriasis who receive evaluation for serum antibodies to infliximab, adalimumab, vedolizumab, or ustekinumab, the evidence includes multiple systematic reviews, randomized controlled trials, and observational studies. Relevant outcomes are test validity, change in disease status, health status measures, quality of life, and treatment-related morbidity. Antibodies to biologic agents develop in a substantial proportion of treated individuals and are believed to neutralize or enhance clearance of the drugs. Considerable evidence has demonstrated an association between antidrug antibodies and secondary nonresponse as well as injection-site and infusion-site reactions. The clinical usefulness of measuring antidrug antibodies hinges on whether test results inform management changes, thereby leading to improved outcomes, compared with management directed by symptoms, clinical assessment, and standard laboratory evaluation. Limited evidence has described management changes after measuring antidrug antibodies. A randomized controlled trial did not find a difference in relapse rates with therapeutic drug monitoring of inflximab using trough levels and antidrug antibodies compared to standard therapy without monitoring these levels. A small randomized controlled trial in individuals with Crohn disease and other inflammatory diseases comparing antidrug antibody-informed management of relapse with standard dose escalation did not demonstrate improved outcomes with the antidrug antibody-informed approach. Additionally, many assays, some having significant limitations, have been used in studies; antidrug antibody threshold values that are informative for discriminating treatment responses have not been established. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.
