Disease-modifying therapies modulate retinal atrophy in multiple sclerosis

Abstract

Objective: To retrospectively investigate whether disease-modifying therapies (DMTs) exert differential effects on rates of retinal atrophy in relapsing-remitting multiple sclerosis (RRMS), as assessed using optical coherence tomography (OCT).Methods: A total of 402 patients with RRMS followed at the Johns Hopkins MS Center who underwent Cirrus-HD OCT were assessed for eligibility. Inclusion criteria included at least 1 year of OCT follow-up and adherence to a single DMT during the period of follow-up. Combined thickness of the ganglion cell 1 inner plexiform (GCIP) and other retinal layers was computed utilizing automated macular segmentation. Retinal thickness changes were analyzed using mixed-effects linear regression.Results: The effects of glatiramer acetate (GA; n 5 48), natalizumab (NAT; n 5 46), and interferonb-1a subcutaneously (IFN SC ; n 5 35) and intramuscularly (IFN IM ; n 5 28) were assessed. Baseline analyses revealed no significant differences between groups in terms of age, sex, optic neuritis history, or follow-up duration. During follow-up, relative to NAT-treated patients, IFN SC -and GAtreated patients exhibited 0.37 mm/y (p , 0.001) and 0.14 mm/y (p 5 0.035) faster rates of GCIP thinning, respectively, adjusting for the interval between initiation of DMT and OCT monitoring (gap time), age, sex, relapses, and disease duration. In the IFN SC group, GCIP thinning was 1.53 mm/y faster during the first year of therapy vs during the time interval afterwards (p , 0.001).Conclusions: Rates of GCIP atrophy in patients with RRMS vary according to DMT utilization. Our findings support OCT for monitoring neurodegenerative treatment effects in the retina, an easily accessible tissue, and as a practical outcome measure in RRMS clinical trials. Neurology ® 2017;88:525-532 GLOSSARY AMT 5 average macular thickness; DMT 5 disease-modifying therapy; GA 5 glatiramer acetate; GCIP 5 ganglion cell 1 inner plexiform layer; HC 5 healthy control; IFN 5 interferon; IFN IM 5 intramuscular interferon-b-1a; IFN SC 5 subcutaneous interferon-b-1a; INL 5 inner nuclear layer; MME 5 microcystic macular edema; MS 5 multiple sclerosis; NAT 5 natalizumab; OCT 5 optical coherence tomography; ON 5 optic neuritis; ONL 5 outer nuclear layer; pRNFL 5 peripapillary retinal nerve fiber layer thickness; RRMS 5 relapsing-remitting multiple sclerosis.Although multiple sclerosis (MS) is conventionally regarded as an autoimmune, inflammatory, demyelinating disorder of the CNS, neurodegeneration resulting from these processes is recognized as the principal substrate of long-term disability.1,2 Currently available disease-modifying therapies (DMTs) for relapsing-remitting MS (RRMS) modulate or suppress the immune system, reducing the risk for future inflammation and associated neurodegeneration.3 Accordingly, the effect of DMTs on MRI-derived estimates of brain atrophy is a common outcome in MS trials. [4][5][6][7] Recent studies reveal that retinal atrophy mirrors brain atrophy over time in MS. 8 However, it remains unclear wh...

Retinal layer thinning predicts treatment failure in relapsing multiple sclerosis

“…Although it is already established that loss of both GCIPL and pRNFL indicates neuroaxonal damage and that is slowed in patients treated with high‐efficacy DMT (natalizumab or alemtuzumab) compared to patients with moderate‐efficacy DMT (interferon β, glatiramer acetate), the present study is the first prospectively investigating retinal layer thinning as a marker of future DMT failure [7–11] Consistent with previous results, the effect size was larger measuring GCIPL than pRNFL, underlining that GCIPL is better suited for measuring DMT response [7–10] GCIPL thinning is more specific for MS, displays superior structure‐function correlation, and reflects neuroaxonal damage faster than pRNFL, while being less prone to a flooring effect in more advanced MS or to confounding by swelling from acute ON [6] In accordance with earlier studies, we found disease duration weakly inversely correlated with annual loss of both GCIPL and pRNFL, whereas baseline GCIPL and pRNFL thickness were weakly correlated with the degree of annual GCIPL and pRNFL thinning [6] This is likely because patients with shorter disease duration and higher baseline retinal thickness have more tissue to lose.…”

Retinal layer thinning predicts treatment failure in relapsing multiple sclerosis

“…Although it is already established that loss of both GCIPL and pRNFL indicates neuroaxonal damage and that is slowed in patients treated with high‐efficacy DMT (natalizumab or alemtuzumab) compared to patients with moderate‐efficacy DMT (interferon β, glatiramer acetate), the present study is the first prospectively investigating retinal layer thinning as a marker of future DMT failure [7–11] Consistent with previous results, the effect size was larger measuring GCIPL than pRNFL, underlining that GCIPL is better suited for measuring DMT response [7–10] GCIPL thinning is more specific for MS, displays superior structure‐function correlation, and reflects neuroaxonal damage faster than pRNFL, while being less prone to a flooring effect in more advanced MS or to confounding by swelling from acute ON [6] In accordance with earlier studies, we found disease duration weakly inversely correlated with annual loss of both GCIPL and pRNFL, whereas baseline GCIPL and pRNFL thickness were weakly correlated with the degree of annual GCIPL and pRNFL thinning [6] This is likely because patients with shorter disease duration and higher baseline retinal thickness have more tissue to lose.…”

Progressive Multiple Sclerosis Is Associated with Faster and Specific Retinal Layer Atrophy

“…Our demonstration that INL and ONL thicknesses are lower cross‐sectionally, and exhibit faster thinning longitudinally in PMS, raises the possibility that a progressive neuronopathy may ensue as the MS disease course progresses into a more neurodegenerative and less inflammatory phase, and that this may be tracked in vivo by OCT. This is further supported by the lack of effect of DMTs (including high‐potency therapies primarily targeting the adaptive immune system) on atrophy within these layers in PMS, although interestingly we did observe slower thinning of the INL and ONL in RRMS patients treated with natalizumab, as previously demonstrated in a smaller cohort . Notably, natalizumab is linked to greater brain atrophy in the first year of treatment, but less in subsequent years, a phenomenon that has been attributed to “pseudoatrophy” due to resolution of inflammation and edema .…”

Modulation of Retinal Atrophy With Rituximab in Multiple Sclerosis

“…Our study expands upon prior work by Button et al, 7 in which natalizumab-treated patients with RRMS demonstrated slower rates of GCIPL atrophy, as compared to patients treated with interferon-β and GA, and similar rates to HCs. Despite being an off-label treatment for RRMS, based on phase 2 clinical trial data, rituximab is considered to be a highly effective treatment for RRMS.…”

Retinal layer thinning predicts treatment failure in relapsing multiple sclerosis

“…Although it is already established that loss of both GCIPL and pRNFL indicates neuroaxonal damage and that is slowed in patients treated with high‐efficacy DMT (natalizumab or alemtuzumab) compared to patients with moderate‐efficacy DMT (interferon β, glatiramer acetate), the present study is the first prospectively investigating retinal layer thinning as a marker of future DMT failure [7–11] Consistent with previous results, the effect size was larger measuring GCIPL than pRNFL, underlining that GCIPL is better suited for measuring DMT response [7–10] GCIPL thinning is more specific for MS, displays superior structure‐function correlation, and reflects neuroaxonal damage faster than pRNFL, while being less prone to a flooring effect in more advanced MS or to confounding by swelling from acute ON [6] In accordance with earlier studies, we found disease duration weakly inversely correlated with annual loss of both GCIPL and pRNFL, whereas baseline GCIPL and pRNFL thickness were weakly correlated with the degree of annual GCIPL and pRNFL thinning [6] This is likely because patients with shorter disease duration and higher baseline retinal thickness have more tissue to lose.…”

Progressive Multiple Sclerosis Is Associated with Faster and Specific Retinal Layer Atrophy

“…Our demonstration that INL and ONL thicknesses are lower cross‐sectionally, and exhibit faster thinning longitudinally in PMS, raises the possibility that a progressive neuronopathy may ensue as the MS disease course progresses into a more neurodegenerative and less inflammatory phase, and that this may be tracked in vivo by OCT. This is further supported by the lack of effect of DMTs (including high‐potency therapies primarily targeting the adaptive immune system) on atrophy within these layers in PMS, although interestingly we did observe slower thinning of the INL and ONL in RRMS patients treated with natalizumab, as previously demonstrated in a smaller cohort . Notably, natalizumab is linked to greater brain atrophy in the first year of treatment, but less in subsequent years, a phenomenon that has been attributed to “pseudoatrophy” due to resolution of inflammation and edema .…”

Modulation of Retinal Atrophy With Rituximab in Multiple Sclerosis

“…Our study expands upon prior work by Button et al, 7 in which natalizumab-treated patients with RRMS demonstrated slower rates of GCIPL atrophy, as compared to patients treated with interferon-β and GA, and similar rates to HCs. Despite being an off-label treatment for RRMS, based on phase 2 clinical trial data, rituximab is considered to be a highly effective treatment for RRMS.…”

Retinal layer thinning predicts treatment failure in relapsing multiple sclerosis

“…Although it is already established that loss of both GCIPL and pRNFL indicates neuroaxonal damage and that is slowed in patients treated with high‐efficacy DMT (natalizumab or alemtuzumab) compared to patients with moderate‐efficacy DMT (interferon β, glatiramer acetate), the present study is the first prospectively investigating retinal layer thinning as a marker of future DMT failure [7–11] Consistent with previous results, the effect size was larger measuring GCIPL than pRNFL, underlining that GCIPL is better suited for measuring DMT response [7–10] GCIPL thinning is more specific for MS, displays superior structure‐function correlation, and reflects neuroaxonal damage faster than pRNFL, while being less prone to a flooring effect in more advanced MS or to confounding by swelling from acute ON [6] In accordance with earlier studies, we found disease duration weakly inversely correlated with annual loss of both GCIPL and pRNFL, whereas baseline GCIPL and pRNFL thickness were weakly correlated with the degree of annual GCIPL and pRNFL thinning [6] This is likely because patients with shorter disease duration and higher baseline retinal thickness have more tissue to lose.…”

Progressive Multiple Sclerosis Is Associated with Faster and Specific Retinal Layer Atrophy

“…Our demonstration that INL and ONL thicknesses are lower cross‐sectionally, and exhibit faster thinning longitudinally in PMS, raises the possibility that a progressive neuronopathy may ensue as the MS disease course progresses into a more neurodegenerative and less inflammatory phase, and that this may be tracked in vivo by OCT. This is further supported by the lack of effect of DMTs (including high‐potency therapies primarily targeting the adaptive immune system) on atrophy within these layers in PMS, although interestingly we did observe slower thinning of the INL and ONL in RRMS patients treated with natalizumab, as previously demonstrated in a smaller cohort . Notably, natalizumab is linked to greater brain atrophy in the first year of treatment, but less in subsequent years, a phenomenon that has been attributed to “pseudoatrophy” due to resolution of inflammation and edema .…”

Modulation of Retinal Atrophy With Rituximab in Multiple Sclerosis

“…Our study expands upon prior work by Button et al, 7 in which natalizumab-treated patients with RRMS demonstrated slower rates of GCIPL atrophy, as compared to patients treated with interferon-β and GA, and similar rates to HCs. Despite being an off-label treatment for RRMS, based on phase 2 clinical trial data, rituximab is considered to be a highly effective treatment for RRMS.…”