The Faces of "Too Late"-A Surprisingly Progressive Cohort of "Stable" Relapsing Remitting Multiple Sclerosis Patients

Abstract

Background and Objectives: Although available therapies have changed the natural evolution of multiple sclerosis (MS), in time some patients assume a progressive course and no longer respond to treatment. There is no definitive clinical or laboratory parameter to certify MS progression from relapsing remitting MS (RRMS) to secondary progressive MS (SPMS) in early phases of transition. Our study aims to evaluate the value of clinical parameters and serum neurofilament light chain levels (sNfLs) as early warning signs of conversion to SPMS. Materials and Methods: The Expanded Disability Status Scale (EDSS), Nine-Hole Peg Test (9HPT), 25-foot walk test (25FWT) and Symbol Digit Modalities Test (SDMT) were evaluated at 12 months apart in a cohort of 83 RRMS treated patients. sNfLs were evaluated at the second time point. Results: sNfLs correlate with EDSS and SDMT, with EDSS change and disease duration. Clinical parameters correlate among themselves and perform well in supporting the diagnosis of SPMS in logistic regression and ROC curves analysis. Eighty percent of the RRMS patients in our study (of which 65% are treated with high-efficacy disease-modifying drugs) showed some type of progression independent of relapses (PIRA) after 12 months, with one in five patients experiencing isolated cognitive worsening and almost two-thirds some type of motor worsening. We found no differences in terms of progression between patients treated with platform drugs versus high-efficacy drugs. Conclusions: An elevated level of progression independent of relapses (PIRA) was found in our cohort, with high-efficacy drugs providing no supplementary protection. As sNfL levels were correlated with the progression of EDSS (the main clinical progression marker), they may be considered potential prognostic markers, but further studies are necessary to precisely define their role in this direction. The lack of early sensitive markers for risk of progression may contribute to therapeutic delay and failure.

Keywords: 25FWT; 9HPT; EDSS; PIRA; SDMT; multiple sclerosis; neurofilament light chains.

Figure 1

Population pyramid count of sNfL values in relation to presence of EDSS change at T1 compared to T0 (Bars represent number of patients with a specific sNfL value). Values were rounded to the nearest integer for this graphic. Mean ranks for patients without EDSS change were 38.34 (N = 58) and for patients with EDSS change 50.5 (N = 25)—Mann–Whitney U test was significant p = 0.035. Abbreviations: sNfL: serum neurofilament light chain; EDSS: Expanded Disability Status Scale.

Figure 2

Distribution of EDSS differences: (A), 25FWT differences (B), SDMT differences (C) and 9HPT differences (D) across treatment type (0 represents platform treatment; 1 represents high-efficacy treatment). Abbreviations: 9HPT: 9 Hole Peg Test, 25FWT: 25 Foot Walk Test; EDSS: Expanded Disability Status Scale; SDMT: Single Digit Modalities Test.