Proteomic Biomarker Panel for Gauging Multiple Sclerosis Disease Activity: A Case Series From Real-World Use Free

Multiple sclerosis (MS) is an autoimmune, neurodegenerative disease affecting the central nervous system. It affects approximately 900,000 individuals in the United States,¹  typically with age of onset and/or diagnosis in individuals between the ages of 20 to 40 years. MS is characterized by inflammatory demyelination and degradation of the axon. Although it is thought to be mediated by genetic and environmental factors, the etiology has not been elucidated.² 

Currently, MS is assessed and monitored using MRI measures (eg, new T2 lesions of gadolinium-enhancing [Gd+] lesions) and clinical assessments (eg, Expanded Disability Status Scale and clinical relapses). However, there is a critical unmet need for accurate, reliable, objective, and trackable biomarkers^3,4  that are more sensitive, cost-effective, and noninvasive to monitor and assess MS disease activity.⁵  Furthermore, these biomarkers could inform treatment decisions and advance the field toward precision medicine.^6,7 

The Octave Multiple Sclerosis Disease Activity (MSDA) test is a serum-based proteomic assay that utilizes an algorithm consisting of 18 biomarkers to produce 4 disease pathway scores (ie, immunomodulation, neuroinflammation, myelin biology, and neuroaxonal integrity; FIGURE 1) and an overall disease activity (DA) score. It has been analytically⁸  and clinically validated⁹  and controls for age and sex. The DA score is scaled from 1.0 to 10.0 in intervals of 0.5. The categories are defined as low, moderate, and high with ranges of 1.0 to 4.0, 4.5 to 7.0, and 7.5 to 10.0, respectively. The 3 categories (ie, low, moderate, high) reflect the likelihood of developing 0, 1, or 2 or more Gd+ lesions. The validated MSDA test was initially piloted in select Multiple Sclerosis Centers of Excellence, Centers for Comprehensive MS Care, and private MS clinics. It is now broadly available for routine clinical use.

The objective of this case series was to describe the real-world clinical experience using the MSDA test with 2 exploratory aims: (1) to reconcile longitudinal MSDA results with patient history, clinical presentation, and radiographic changes; and (2) to gain insights into the underlying biology of MS to support clinical decisions.

Four women with MS of various ages with different disease durations, disease-modifying therapy (DMT) use, and radiographic presentations were examined (TABLE). Individuals were monitored between 2022 and 2023 with 2 MSDA testing points. Analytical and clinical validations of the MSDA test are reported in prior publications.^8,9  Clinical and radiographic data were collected from the patients' medical records.

Patient 1 was 35 years of age, White, and female with a disease duration of 7 years who experienced an MS relapse on natalizumab. She initially presented with optic neuritis in 2016. She subsequently underwent MRIs and lumbar puncture that revealed demyelination and positive oligoclonal bands consistent with a diagnosis of MS. She was initially prescribed glatiramer acetate, but she discontinued therapy for unknown reasons. In June 2021, she developed left-hand weakness and full-body numbness. Brain MRI revealed an enhancing lesion and development of new white matter lesions in the bilateral cerebral hemispheres when compared with scans from 2018. A cervical spine MRI revealed a new enhancing lesion. She started natalizumab in October 2021. She had breakthrough disease on a subsequent brain MRI in August 2022 that revealed several new, nonenhancing lesions. Further testing revealed natalizumab-neutralizing antibodies. Her MSDA score was 8 (high). Natalizumab was discontinued on August 2, 2022. She started ocrelizumab on October 3, 2022. A second MSDA on April 5, 2023, was scored at 1.5 (low). Clinically, she was doing well. A brain MRI, also on April 5, 2023, revealed stable demyelination (FIGURE 2A).

Patient 2 was 50 years of age, White, and female with a disease duration of 9 years. She transitioned from diroximel fumarate to ofatumumab in June 2021 after breakthrough disease activity on brain and cervical spine MRI. Her MSDA score was 1 (low). She continued ofatumumab. Follow-up testing on June 8, 2023, revealed an MSDA score of 1 (low). Clinically, she was doing well. An updated brain MRI was ordered but not completed at the time of the study (FIGURE 2B).

Patient 3 was 29 years of age and female with a disease duration of 22 years. She chose other as her ethnicity/race. She was on dimethyl fumarate but did not adhere to treatment. She then stopped DMT completely due to her pregnancy; in June 2021, she had breakthrough disease on brain MRI during her second trimester. She resumed taking dimethyl fumarate and her MSDA score was 5 (moderate) at this time. After she initially decided to transition to ocrelizumab, she later opted to continue on dimethyl fumarate with reported adherence. Follow-up testing on April 26, 2023, revealed an MSDA score of 4.5 (moderate). Updated brain and cervical spine MRIs on the same day showed likely stable demyelination after accounting for changes in technology (1.5T to 3T) (FIGURE 2C). Clinically, she was doing well.

Patient 4 was 46 years of age, White, and female with a disease duration of 1 year. She presented with paresthesia in spring of 2022. A brain MRI revealed demyelination. No demyelination was seen in the cervical or thoracic spinal cord. A lumbar puncture was positive for oligoclonal bands. Prior to initiation of therapy, her MSDA score was 6 (moderate). She decided to start high-efficacy therapy with natalizumab. After 6 infusions of natalizumab, follow-up testing on April 13, 2023, revealed an MSDA score of 4 (low), and an updated brain MRI on the same day showed stable demyelination (FIGURE 2D). Clinically, she was doing well.

This case series examined 4 people with MS and their disease states to identify, interpret, and follow their MSDA test scores. Each patient received a baseline MSDA test and a follow-up test. Data demonstrated that MSDA test scores were consistent with the radiographic and clinical status of patients, as revealed by clinical examination, patient report, and MRI. These examples support using the MSDA test to establish baseline disease activity and response to DMT, and then longitudinal monitoring of disease activity and stability.

Recent guidelines have indicated the importance of research and development of fluid biomarkers in MS.^10-12  In the management of MS and other neurological diseases, identifying and quantifying axonal damage could allow for more accuracy in diagnosis and prognosis predictions.¹³  In addition, fluid biomarkers could be used to identify individuals at risk of treatment failure and further personalize treatment plans.¹⁴ 

While neurofilament light chain (NfL) is one of the most widely studied biomarkers, it can be elevated in a number of other inflammatory, neurodegenerative, traumatic, and cerebrovascular diseases.¹³  NfL can also be confounded by age, which is controlled in the MSDA test.³  In addition, recent evidence regarding the phenomenon of smoldering MS points to the possibility of other biomarkers such as C-X-C motif chemokine ligand 10,¹⁵  and C-X-C motif chemokine ligand 13,¹⁶  glial fibrillary acidic protein,¹⁴  B-cell activating factor,¹⁴  osteopontin,¹⁴  and IL-12β.¹⁴  The MSDA test uses NfL and 17 other proteins to create an algorithm of disease activity that controls for age and sex, providing a more comprehensive assessment of MS disease biology. Furthermore, the MSDA's multiprotein panel outperformed NfL in terms of identifying risk of developing Gd+ lesions, new and enlarging T2 lesions, and active vs stable status.⁹ 

As described by Paul et al, a quality biomarker must be easily and reliably measured, have high sensitivity and specificity, correlate to disease activity, and be cost-effective.¹⁴  This case series supports the finding that the MSDA test is a quality biomarker measure. In addition, the MSDA test can potentially reduce health care costs by reducing unnecessary imaging and alterations in DMT.¹⁷  The possible reduction of health care utilization by using the MSDA test in MS is currently being investigated in a randomized, controlled trial.¹⁸ 

Study limitations include small sample size and potential selection bias, which may impact generalizability of the results. Moreover, the absence of greater follow-up data restricts our ability to assess the test's utility over an extended period of time. Despite these limitations, the findings provide preliminary insights, and further studies with larger cohorts are needed to better establish the clinical utility of the MSDA test.

This case series illustrates that disease activity scores appear to correlate with clinical relapses, radiographic brain and/or spinal disease, and efficacy of therapy. The MSDA test may be used to verify stability and may support the clinical decision to alter therapy. The initial baseline results from the case studies reported here provide snapshot MSDA scores that may change with both clinical and subclinical disease activity. Therefore, the ability to follow patients longitudinally will provide additional insights into patient disease activity and may impact clinical decision-making. In short, the MSDA test is a quality biomarker assay panel due to not only its specificity, reliability, and sensitivity,^8,9  but also its clinical relevance, response to treatment, and clinical utility. Future directions include additional longitudinal following of patients, MSDA scores through disease activity cycle (pre- and post relapse), and DMT response signatures and predictors.