Immunological and short-term brain volume changes in relapsing forms of multiple sclerosis treated with interferon beta-1a subcutaneously three times weekly: an open-label two-arm trial

Abstract

Background: Brain volume atrophy is observed in relapsing-remitting multiple sclerosis (RRMS).

Methods: Brain volume changes were evaluated in 23 patients with RRMS treated with interferon β-1a 44 μg given subcutaneously (SC) three times a week (tiw) and 15 healthy controls. Percentages of whole brain and tissue-specific volume change were measured from baseline (0 months) to 3 months, from 3 to 6 months, and from baseline to 6 months using SIENAX Multi Time Point (SX-MTP) algorithms. Immunological status of patients was also determined and correlations between subsets of T cells and changes in brain volume were assessed.

Results: Interferon β-1a 44 μg SC tiw in 23 patients with RRMS resulted in significant reductions in whole brain and gray matter tissue volume early in the treatment course (baseline to 3 months; mean change; -0.95%; P = 0.030, -1.52%; P = 0.004, respectively), suggesting a short-term treatment-induced pseudoatrophy effect. From baseline to 6 months, there were significant correlations observed between decreased T- cell expression of IL-17 F and decreased whole brain and brain tissue-specific volume.

Conclusions: These findings are consistent with the interpretation of the pseudoatrophy effect as resolution of inflammation following treatment initiation with interferon β-1a 44 μg SC tiw, rather than disease-related tissue loss.

Trial registration: ClinicalTrials.gov; NCT01085318.

Figures

Fig. 1

Brain volume changes in RRMS patients vs HCs. Percent change in whole brain volume in RRMS patients treated with IFN β-1a SC tiw and in HCs was measured. No P-values remained significant after adjustment for multiple comparisons. *P < 0.05, within-group difference from zero (Wilcoxon signed-rank test). †P < 0.05, patients versus HCs (Wilcoxon rank-sum test). In the box plots, the bold line represents the median; the boxes represent the middle 50 % of data; the top and bottom of the box represent the third and first quartiles; the open circles are outliers. The whisker lines above and below the boxes represent the largest and smallest values that are not considered to be outliers. Means are denoted by a ‘+’ sign. HC healthy control; IFN interferon; RRMS relapsing–remitting multiple sclerosis; SC subcutaneously; tiw three times weekly

Fig. 2

Gray matter volume changes in RRMS patients and HCs. Percent change in GM volume in RRMS patients treated with IFN β-1a SC tiw and in HCs was assessed. P-values were for the difference from zero within groups from the Wilcoxon signed-rank test. P-values in parentheses are those remaining significant after Holm–Bonferroni correction for multiple comparisons. *P < 0.05. **P < 0.01. ***P < 0.001. In the box plots, the bold line represents the median; the boxes represent the middle 50 % of data; the top and bottom of the box represent the third and first quartiles; the open circles are outliers. The whisker lines above and below the boxes represent the largest and smallest values that are not considered to be outliers. Means are denoted by a ‘+’ sign. GM gray matter; HC healthy control; IFN interferon; RRMS relapsing–remitting multiple sclerosis; SC subcutaneously; tiw three times weekly

Fig. 3

White matter volume changes in RRMS and HCs. Percent change in WM volume in RRMS patients treated with IFN β-1a SC tiw and in HCs was measured. Changes in WM volume were not significant at any timepoint. In the box plots, the bold line represents the median; the boxes represent the middle 50 % of data; the top and bottom of the box represent the third and first quartiles; the open circles are outliers. The whisker lines above and below the boxes represent the largest and smallest values that are not considered to be outliers. Means are denoted by a ‘+’ sign. HC healthy control; IFN interferon; RRMS relapsing–remitting multiple sclerosis; SC subcutaneously; tiw three times weekly; WM white matter

Fig. 4

IL-17 F–expressing CD4+ T cells and brain volume changes in RRMS patients and HCs. Decreased percentage of IL-17 F–expressing CD4+ T cells from baseline to 6 months correlated with decreased whole brain volume from baseline to 6 months in RRMS patients treated with IFN β-1a SC tiw. HC healthy control; IFN interferon; IL interleukin; RRMS relapsing–remitting multiple sclerosis; SC subcutaneously; tiw three times weekly

Fig. 5

IL-17 F–expressing CD8+ T cells and GM volume changes in RRMS. Higher percentage of IL-17 F–expressing CD8+ T cells from baseline to 6 months correlated with smaller decreases in GM volume from baseline to 6 months in treated patients with RRMS. GM gray matter; IL interleukin; RRMS relapsing–remitting multiple sclerosis

Fig. 6

IL-17 F-expressing CD4+ T cells and WM volume changes in RRMS. Decreased percentage of IL-17 F-expressing CD4+ T cells from baseline to 6 months correlated with decreased WM volume from baseline to 6 months in treated patients with RRMS. IL interleukin; RRMS relapsing–remitting multiple sclerosis; WM white matter

Fig. 7

IL-22–expressing CD4+ T cells and GM volume changes in RRMS. Higher percentage of IL-22–expressing CD4+ T cells at baseline correlated with smaller decreases in GM volume from baseline to 6 months in treated patients with RRMS. GM gray matter; IL interleukin; RRMS relapsing–remitting multiple sclerosis