Measurement of Serum Antibodies to Selected Biologic Agents

POLICY NUMBER

A.2.04.84

DESCRIPTION

Biologic agents used to treat autoimmune diseases include infliximab, adalimumab, vedolizumab, and ustekinumab. Infliximab (Remicade) is an intravenous tumor necrosis factor alpha 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 alpha 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.

Infliximab, Adalimumab, Vedolizumab, and Ustekinumabin 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 patients who fail conventional medical therapy, and they are typically highly effective for the induction and maintenance of clinical remission. However, not all patients respond, and a high proportion of patients lose response over time. It is estimated that one in three patients do not respond to induction therapy (primary nonresponse); further, among initial responders, response wanes over time in approximately 20% to 60% of patients (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). Antidrug antibodies are also associated with injection-site reactions and acute infusion reactions and delayed hypersensitivity reactions.

Detection of Antidrug Antibodies

The detection and quantitative measurement of antidrug antibodies is difficult, owing to drug interference and identifying when antibodies likely have a neutralizing effect. First-generation assays (i.e., enzyme-linked immunosorbant assays [ELISA]) can only measure antidrug antibodies 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 antidrug antibodies when infliximab is present in serum. Studies evaluating the validation of results among different assays are lacking, making interstudy comparisons difficult. One retrospective study in 63 patients demonstrated comparable diagnostic accuracy between two different ELISA methods in patients 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 patients 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 (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Laboratories that offer LDTs 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 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 enzyme-linked immunosorbent assay (ELISA) test, and can measure antidrug antibodies in the presence of detectable drug levels, improving on a major limitation of the ELISA method.

POLICY

Measurement of antidrug antibodies in an individual receiving treatment with a biologic agent, either alone or as a combination test, which includes the measurement of serum TNF blocking agent levels, is considered investigational.

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Selected U.S. Food and Drug Administration approved biologic agents include infliximab, adalimumab, vedolizumab, and ustekinumab.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting. 

POLICY HISTORY

11/15/2012: Approved by Medical Policy Advisory Committee.

12/13/2013: Added Adalimumab to the policy title and description. Added the following policy statement: Measurement of antibodies to adalimumab in a patient receiving treatment with adalimumab, either alone or as a combination test which includes the measurement of serum adalimumab levels, is considered investigational.

01/06/2015: Policy reviewed; description updated. Policy statement unchanged.

07/31/2015: Code Reference section updated for ICD-10.

01/12/2016: Policy description updated regarding reasons for therapeutic failures and to add laboratory testing information. Policy statements unchanged. Investigative definition updated in policy guidelines section.

06/07/2016: Policy number A.2.04.84 added.

12/05/2016: Policy description updated. Policy statements unchanged.

01/08/2018: Policy description updated. Policy statements unchanged.

01/08/2019: Policy description updated. Policy statements unchanged.

12/19/2019: Code Reference section updated to add new CPT codes 80145 and 80230 effective 01/01/2020.

07/07/2020: Policy title changed from "Measurement of Serum Antibodies to Infliximab and Adalimumab" to "Measurement of Serum Antibodies to Selected Biologic Agents." Policy description updated to include vedolizumab (Entyvio) and ustekinumab (Stelara). Removed investigational statements for infliximab and adalimumab and added that the measurement of antibodies to tumor necrosis factor (TNF) blocking agents in a patient receiving treatment with a TNF blocking agent, either alone or as a combination test, which includes the measurement of serum TNF blocking agent levels, is considered investigational. Policy Guidelines updated to list current FDA-approved TNF blocking agents. Code Reference section updated to add CPT codes 80280 and 80299.

03/25/2021: Policy revised to update terminology to reflect the addition of the interleukin-2 and -23 antagonist ustekinumab.

01/27/2022: Policy description updated regarding indications for Adalimumab (Humira). Policy statement unchanged.

01/18/2023: Policy reviewed. Policy statement updated with minor wording change.

12/06/2023: Policy reviewed; no changes.

01/04/2024: Policy description updated. Policy statement unchanged. Policy Guidelines updated to change "Currently" to "Selected."

10/01/2024: Code Reference section updated to add new CPT codes 0514U and 0515U.

12/16/2024: Policy reviewed; no changes.

01/30/2025: Policy reviewed; no changes.

SOURCE(S)

Blue Cross Blue Shield Association policy # 2.04.84 

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

Investigational Codes

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