Increasing levels of neurofilament-light chain (NfL) and glial fibrillary acidic protein (GFAP) after drug discontinuation may identify previously stable MS patients at risk of new disease activity, according to Comprehensive Longitudinal Investigation of MS at the Brigham and Women’s Hospital (CLIMB) investigators (Bose et al. Neurol Neuroimmunol Neuroinflamm 2023;10:e200167; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC10574823/pdf/NXI-2023-000383.pdf ).

The study obtained serum NfL and GFAP levels before and after drug discontinuation in 78 MS patients. Patients were younger than those enrolled in recent discontinuation trials. Median age was 48.5 years, and median disease duration was 12.3 years. All participants had no clinical attacks or MRI activity for two years before and after drug discontinuation. Most patients were taking a first-line injectable DMT (71%); 18% were on an oral DMT and 14% were receiving an infusion drug. The duration of follow-up was 4-9 years.

Overall, 35% of patients experienced 6-month confirmed disability worsening. The median time to CDW was 5.1 years after stopping treatment.

Prior to stopping treatment, the median sNfL level was 10.1 pg/mL; the median GFAP level was 109.7 pg/mL. Neither measure was predictive of future disease activity. However, an increase in either biomarker was predictive of 6-month CDW and new MRI activity. Patients had a significantly higher risk of CDW if there was a 100% increase in sNfL (hazard ratio 3.87) and a 50% increase in sGFAP (HR 5.34). Neither biomarker predicted relapse activity. However, a higher post-treatment sNfL level (HR 3.09) or GFAP level (HR 4.88) was associated with new MRI activity. The average time to new disease activity was two years.

The authors noted that in this younger population, increasing sNfL and GFAP levels after drug discontinuation may herald a recurrence of disease activity 2-5 years before it manifests. This would enable clinicians to reinitiate treatment in at-risk patients.

It should be noted that it is not known if restarting treatment in patients with rising biomarker levels will prevent future disability worsening. It is also unclear if the CLIMB findings would be generalizable to older patients who stop treatment or were on a higher-efficacy DMT. Two of three previous discontinuation trials enrolled patients aged 55+ years (DISCOMS) or >50 years (STOP-I-SEP).