Testing for John Cunningham Virus (JCV) is critical for managing progressive multifocal leukoencephalopathy (PML) risk in natalizumab-treated multiple sclerosis (MS) patients. Natalizumab effectively reduces MS disease activity but increases PML risk, particularly in JCV seropositive individuals. The introduction of natalizumab biosimilars has exacerbated this issue, revealing inconsistencies between assays from different manufacturers. Our clinic observed varying JCV test results after switching patients to a biosimilar, undermining clinician confidence and complicating risk management. This highlights the urgent need for standardized, validated JCV testing practices to ensure reliable risk stratification, enhance patient safety, and maintain effective MS treatment protocols.
Natalizumab, a humanized monoclonal antibody targeting the α4-integrin receptor, has shown significant efficacy in the treatment of relapsing forms of multiple sclerosis (MS) by inhibiting the migration of leukocytes across the blood–brain barrier, thus preventing inflammatory damage in the central nervous system.1 Despite its therapeutic benefits, natalizumab is associated with an increased risk of PML, a rare but potentially fatal brain infection caused by the reactivation of the JCV.2 The incidence of PML in patients treated with natalizumab is notably influenced by their anti-JCV antibody status, with seropositive patients facing a significantly higher risk.3
Monitoring JCV antibody status or index values is crucial for managing MS patients on natalizumab therapy. This allows clinicians to identify individuals at increased risk for PML and make informed treatment decisions, which has contributed to a marked decrease in PML incidence among treated patients.4 Specifically, the risk of PML is considerably lower in patients who test negative for anti-JCV antibodies or low index values, emphasizing the importance of routine screening.3 Recent studies have highlighted that the combination of anti-JCV antibody status or index value with other risk factors, such as prior immunosuppressive therapy and duration of natalizumab treatment, can further refine risk stratification.5
The expiration of natalizumab’s patent has led to the emergence of biosimilar alternatives, which present both opportunities and challenges in clinical practice.6 While biosimilars can reduce treatment costs, the natalizumab case involves the proprietary assay for anti-JCV antibody detection, complicating the risk assessment process.7 The availability of different tests for anti-JCV antibodies, each associated with either the reference natalizumab or its biosimilar, raises concerns regarding the comparability and reliability of these assays. This situation exemplifies the concept of “companion diagnostics,”8 where specific tests are required for the initiation and continuation of treatment, predominantly in oncology but increasingly relevant in MS management.
In our MS clinic, we began administering the biosimilar natalizumab in April 2024. Following this transition, we observed discrepancies in anti-JCV antibody test results among two out of eight patients previously treated with the original natalizumab. These 2 patients displayed inconsistent anti-JCV antibody test results depending on the laboratory used. A stable 34-year-old female, on natalizumab since 2016, showed consistently negative JCV index, measured every 6 months using the original manufacturer’s assay. After switching to the biosimilar in April 2024, she received an inconclusive anti-JCV test result in May (index 0.28), followed by a clearly positive result in June (index 0.44). However, a subsequent test in July, conducted using the original manufacturer’s laboratory, returned a negative result.
Similarly, a stable 33-year-old female on natalizumab since 2011 had consistently tested negative via the original manufacturer’s assay. After switching to the biosimilar in April 2024, and she had a positive JCV index in July (index 0.71), which was confirmed with a follow-up test in August from the same laboratory (index 0.73). However, an additional test conducted in August 2024 using the original manufacturer’s assay returned a negative result.
The discrepancies in companion diagnostics due to different assays present significant challenges for clinicians, particularly when interpreting divergent results from various tests. In the concrete cases, we opted to continue natalizumab therapy, but reverted to the original product to ensure consistent testing from a single (original) provider. The issue extends beyond inconsistent results (negative/positive); disparities in JCV index values can alter the perceived PML risk for individual patients. Such inconsistencies can undermine confidence in the reliability of diagnostic tools and complicate risk management strategies for conditions like PML. The reliance on proprietary assays can restrict access to essential diagnostic tools, ultimately impacting patient safety and treatment outcomes.
To address these challenges, it is crucial to advocate for greater transparency and independent validation of tests, as well as to consider centralized testing in accredited independent laboratories. This approach could standardize testing procedures and results, thereby enhancing the reliability of risk stratification for PML. Furthermore, integrating findings from validation studies into clinical guidelines will ensure that healthcare providers have access to evidence-based recommendations for managing patients effectively. This will ultimately improve patient safety and treatment outcomes in the management of conditions like PML.