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. 2019 May;85(5):653-666.
doi: 10.1002/ana.25463. Epub 2019 Mar 30.

Silent progression in disease activity-free relapsing multiple sclerosis

University of California, San Francisco MS-EPIC Team; Bruce A C Cree  1 , Jill A Hollenbach  1 , Riley Bove  1 , Gina Kirkish  1 , Simone Sacco  1 , Eduardo Caverzasi  1 , Antje Bischof  1 , Tristan Gundel  1 , Alyssa H Zhu  1 , Nico Papinutto  1 , William A Stern  1 , Carolyn Bevan  1 , Andrew Romeo  1 , Douglas S Goodin  1 , Jeffrey M Gelfand  1 , Jennifer Graves  1 , Ari J Green  1 , Michael R Wilson  1 , Scott S Zamvil  1 , Chao Zhao  1 , Refujia Gomez  1 , Nicholas R Ragan  1 , Gillian Q Rush  1 , Patrick Barba  1 , Adam Santaniello  1 , Sergio E Baranzini  1 , Jorge R Oksenberg  1 , Roland G Henry  1 , Stephen L Hauser  1
Affiliations

Silent progression in disease activity-free relapsing multiple sclerosis

University of California, San Francisco MS-EPIC Team et al. Ann Neurol. 2019 May.

Abstract

Objective: Rates of worsening and evolution to secondary progressive multiple sclerosis (MS) may be substantially lower in actively treated patients compared to natural history studies from the pretreatment era. Nonetheless, in our recently reported prospective cohort, more than half of patients with relapsing MS accumulated significant new disability by the 10th year of follow-up. Notably, "no evidence of disease activity" at 2 years did not predict long-term stability. Here, we determined to what extent clinical relapses and radiographic evidence of disease activity contribute to long-term disability accumulation.

Methods: Disability progression was defined as an increase in Expanded Disability Status Scale (EDSS) of 1.5, 1.0, or 0.5 (or greater) from baseline EDSS = 0, 1.0-5.0, and 5.5 or higher, respectively, assessed from baseline to year 5 (±1 year) and sustained to year 10 (±1 year). Longitudinal analysis of relative brain volume loss used a linear mixed model with sex, age, disease duration, and HLA-DRB1*15:01 as covariates.

Results: Relapses were associated with a transient increase in disability over 1-year intervals (p = 0.012) but not with confirmed disability progression (p = 0.551). Relative brain volume declined at a greater rate among individuals with disability progression compared to those who remained stable (p < 0.05).

Interpretation: Long-term worsening is common in relapsing MS patients, is largely independent of relapse activity, and is associated with accelerated brain atrophy. We propose the term silent progression to describe the insidious disability that accrues in many patients who satisfy traditional criteria for relapsing-remitting MS. Ann Neurol 2019;85:653-666.

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Conflict of interest statement

Companies that make MS disease‐modifying therapies mentioned in this article include Bayer, Biogen, EMD Serono, Novartis, Pfizer, F. Hoffman La Roche, Sanofi Genzyme, and Teva. The following authors disclosed financial relationships with these companies. B.A.C.C.: consultancy, Biogen, EMD Serono, Novartis. R.B.: consultancy, F. Hoffmann‐La Roche, Novartis, Sanofi Genzyme. J.M.G.: consultancy, Biogen. J.G.: speaker honoraria, Biogen, Sanofi Genzyme. D.S.G.: consultancy, Novartis; speaker honoraria, EMD, Serono, Novartis, Sanofi Genzyme. M.R.W.: grant support, F. Hoffman La Roche, Genentech. A.J.G.: consultancy, Novartis. S.S.Z.: consultancy, Biogen, F. Hoffman La Roche, Novartis, Sanofi Genzyme, Teva; grant support, Biogen, Teva. S.E.B.: speaker honoraria, Bayer, Biogen, EMD Serono, Novartis, Pfizer, F. Hoffman La Roche, Sanofi Genzyme, Teva. R.G.H.: grant support, F. Hoffman La Roche, Sanofi Genzyme; advisory boards, F. Hoffman La Roche, Novartis; educational programs, Sanofi Genzyme, Teva. S.L.H., travel reimbursement and writing assistance, F. Hoffmann‐La Roche for CD20‐related meetings and presentations. The other authors have nothing to report.

Figures

Figure 1
Figure 1
Factors that contribute to or correlate with relapse occurrence and the subsequent impact of relapses on disability. Check marks indicate significant associations, and x marks indicate that associations were not identified. 9HPT = 9‐Hole Peg Test; EDSS = Expanded Disability Status Scale; MRI = magnetic resonance imaging; PASAT = Paced Auditory Serial Addition Test; SDMT = Symbol Digit Modalities Test; T25FW = Timed 25‐Foot Walk.
Figure 2
Figure 2
Factor analysis for mixed data clustering individuals by shared clinical and genetic attributes (from Table 3) that contribute to relapse frequency. Participants appear to cluster together based on annual relapse frequency. Participants with no relapses cluster separately from participants with more than one relapse. Even participants with a single relapse appear to cluster together as a subset of participants with no relapses.
Figure 3
Figure 3
Relative brain atrophy is attenuated in clinically stable patients. Longitudinal response plots show the impact of relapses and disability on relative brain volume loss. Plots of individual data are depicted in addition to the regression lines that are adjusted for covariates (sex, disease duration, age, and HLA‐DRB1*15:01). CSF = cerebrospinal fluid.
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