Intrathecal Inflammatory Profile and Gray Matter Damage Predict Progression Independent of Relapse Activity in Early Multiple Sclerosis

Abstract

Background and objectives: The objective of this study was to determine, at the time of diagnosis, a CSF and MRI profile of intrathecal compartmentalized inflammation predictive of progression independent of relapse activity (PIRA) in early relapsing-remitting multiple sclerosis (RRMS).

Methods: This five-year prospective study included 80 treatment-naïve patients with RRMS enrolled at time of diagnosis. All patients underwent a lumbar puncture, regular neurologic evaluations including an Expanded Disability Status Scale (EDSS) assessment every 6 months, and an annual 3T brain MRI. PIRA was defined as having a confirmed disability progression independent of relapse activity. CSF levels of 68 inflammatory molecules were evaluated in combination with white matter and cortical lesion number (CLn) and volume, and regional gray matter thickness and volume.

Results: During the follow-up, 23 patients with RRMS (28.8%) experienced PIRA. At diagnosis, participants with PIRA were older (44.0 ± 10.7 vs 37.4 ± 12.4, p = 0.017) and with more disability (median EDSS score [interquartile range] of 3 [range 2-4] for PIRA vs 1.5 [range 1-2] for no PIRA group, p < 0.001). Random forest selected LIGHT, CXCL13, sTNFR1, sTNFR2, CCL7, MIF, sIL6Rbeta, IL35, CCL2, and IFNβ as the CSF markers best associated with PIRA. sTNFR1 (hazard ratio [HR] 10.11 [2.61-39.10], p = 0.001), sTNFR2 (HR 5.05 [1.63-15.64], p = 0.005), and LIGHT (HR 1.79 [1.11-2.88], p = 0.018) were predictors of PIRA at regression analysis. Baseline thalamus volume (HR 0.98 [0.97-0.99], p = 0.005), middle frontal gyrus thickness (HR 0.05 [0.01-0.72], p = 0.028), and CLn (HR 1.15 [1.05-1.25], p = 0.003) were MRI predictors of PIRA.

Discussion: A specific intrathecal inflammatory profile associated with TNF superfamily markers, CLn, and atrophy of several cortical and deep gray matter regions, assessed at time of diagnosis, is predictive of PIRA in early MS.

Figure 1. CSF Markers and PIRA

(A) CSF markers increased in patients with PIRA events. (B) Markers differentially increased in the subgroup of patients with PIRMA. CCL20 = chemokine (C-C motif) ligand 20; IL22 = interleukin-22; IL27 = interleukin-27; IL35 = interleukin-35; LIGHT = tumor necrosis factor superfamily member 14; OPN = osteopontin; PIRA = progression independent of relapse activity; PIRMA = progression independent of relapse and MRI activity; sTNFR1 = soluble-tumor necrosis factor-receptor 1. *p < 0.05, **p < 0.01

Figure 2. CSF Markers Associated With PIRA

(A) Multiway importance plot: most important variables associated with PIRA. Minimal depth and times a root measures are shown. Lower minimal depth values indicate higher predictive accuracy while higher times a root measure indicates a higher predictive power. (B) Multiway importance plot: most important variables associated with PIRMA. CCL2 = chemokine (C-C motif) ligand 2; CCL25 = chemokine (C-C motif) ligand 25; CCL7 = chemokine (C-C motif) ligand 7; CXCL11 = chemokine (C-X-C motif) ligand 11; CXCL13 = chemokine (C-X-C motif) ligand 13; IL35 = interleukin-35; INFbeta = interferon beta; LIGHT = tumor necrosis factor superfamily member 14; MIF = macrophage migration inhibitor factor; PIRA = progression independent of relapse activity; PIRMA = progression independent of relapse and MRI activity; sCD163 = soluble-CD163 (cluster of differentiation 163); sIL6Rbeta = soluble interleukin-6 receptor beta; sTNFR1 = soluble-tumor necrosis factor-receptor 1; sTNFR2 = soluble-tumor necrosis factor-receptor 2.

Figure 3. MRI Markers Associated With PIRA

Multiway importance plot with the most important MRI variables associated with PIRA (A) and in a subgroup of patients with PIRMA (B). Minimal depth and times a root measures are shown. Lower minimal depth values indicate higher predictive accuracy while higher times a root measure indicates a higher predictive power. PIRA = progression independent of relapse activity; PIRMA = progression independent of relapse and MRI activity.

Figure 4. ROC Analysis

ROC analysis curves showing combined models with CSF and MRI markers. AUC = area under the curve; CI = confidence interval; CM = combined model; FBR = false-positive rate; ROC = receiver operating characteristic; TPR = true-positive rate.