Patients with multiple sclerosis (MS) who have been stable for many years may wish to stop disease-modifying treatment because of its cost and potential adverse effects. However, the risk of future disease activity is unknown, and there’s no consensus on which patients are candidates for treatment discontinuation.

Serum biomarkers are becoming increasingly investigated for risk profiling in MS. Researchers at Brigham and Women’s Hospital have found that changes in two of them after treatment is stopped can signal impending disease activity.

Tanuja Chitnis, MD, the Cindy Larsen Chugg distinguished chair in the Department of Neurology, Howard L. Weiner, MD, director of the Brigham Multiple Sclerosis Clinic, and colleagues report in Neurology: Neuroimmunology & Neuroinflammation.

Methods

The researchers reviewed data from the Comprehensive Longitudinal Investigation of MS at the Brigham (CLIMB), a real-world observational cohort that has been following patients with MS since 2000. Patients have clinical examinations every six months, and MRI scans and blood sample collections every year, even if MS treatment has been stopped.

This analysis included 78 adults (92% female) who were enrolled between January 1, 2000, and December 9, 2021, had no clinical attacks of MRI activity for more than two years while on treatment, discontinued treatment after more than two years, and had blood samples obtained within two years before and after treatment discontinuation.

Serum samples were assayed for two intermediate filaments that revealed different pathologies:

• Serum neurofilament light chain (sNfL) is released from neurons into cerebrospinal fluid during neuroaxonal injury and nearly proportionally into the blood, and has been associated with inflammatory activity, treatment response, and long-term clinical and MRI outcomes.

• Serum glial fibrillary acidic protein (sGFAP), primarily expressed in astrocytes, is released during astrogliosis, and higher levels have been correlated with progressive MS and brain T2 lesion volume and atrophy.

Outcomes After Treatment Discontinuation

The median follow-up time was 6.3 years. The team investigated three outcomes after the treatment stop date:

• Confirmed disability worsening (CDW, primary outcome), defined as an increase in Expanded Disability Status Scale (EDSS) by 1.5 if the EDSS was 0 at treatment discontinuation; by 1.0 if the discontinuation EDSS was between 1.0 and 5.0; and by 0.5 if the discontinuation EDSS was 5.5 or higher—27 patients (35%) met one of these criteria at a median 5 years after treatment stop

• New attack, defined as new or worsening neurologic symptoms lasting ≥24 hours without fever or infection—19 patients (24%) at a median 3 years

• New MRI activity, defined as new or enlarging T2 lesions or contrast-enhancing lesions on brain or spinal cord MRI—26 patients (33%) at a median 2 years

Pretreatment Measurements

In themselves, biomarker levels obtained before stopping treatment did not predict any outcome.

Posttreatment Measurements

The posttreatment results suggested increases in sNfL and sGFAP levels after treatment is stopped may identify patients at risk of future MS activity:

• Higher posttreatment sNfL—Higher risk of disability (CDW) (adjusted HR, 2.80; P=0.005) and higher risk of new MRI activity (aHR, 3.09; P=0.004)
• 100% increase in sNfL from pre- to post-treatment: Higher risk of disability (CDW) (HR, 3.87; P=0.009) and new MRI activity (HR, 4.02; P=0.005)
• >50% increase in sGFAP: Higher risk of disability (CDW) (HR, 5.34; P=0.012) and new MRI activity (HR, 5.16; P=0.004)

Laying the Groundwork for Risk Stratification

These findings support the practice of measuring sNfL and sGFAP both before and after treatment discontinuation to potentially allow the resumption of therapy before disease activity recurs. However, an independent study is needed to validate that hypothesis and determine whether resuming treatment when biomarker levels increase can prevent eventual disease activity.