From the Department of Neurology (H.E., J.L., H.M., E.S.V., G.K., O.C.M., A.G.F., N.P., M.D., S.D., N.N., A.Q., C.H., A.Z.L., A.D., K.C.F., P.A.C., E.S.S., S.S.), Johns Hopkins University School of Medicine; Department of Electrical and Computer Engineering (J.L.P.), Johns Hopkins University, Baltimore, MD; and Mellen Center for Multiple Sclerosis (R.B.), Cleveland Clinic, OH.
Neurology. 2023 Sep 5;101(10):e1014-e1024. doi: 10.1212/WNL.0000000000207551. Epub 2023 Jul 17.
Ganglion cell + inner plexiform layer (GCIPL) thinning, measured by optical coherence tomography (OCT), reflects global neurodegeneration in multiple sclerosis (MS). Atrophy of the inner (INL) and outer nuclear layer (ONL) may also be prominent in progressive MS (PMS). The phase 2, SPRINT-MS trial found reduced brain atrophy with ibudilast therapy in PMS. In this post hoc analysis of the SPRINT-MS trial, we investigate (1) retinal atrophy (2) differences in response by subtype and (3) associations between OCT and MRI measures of neurodegeneration.
In the multicenter, double-blind SPRINT-MS trial, participants with secondary progressive MS (SPMS) or primary progressive MS (PPMS) were randomized to ibudilast or placebo. OCT and MRI data were collected every 24 weeks for 96 weeks. Extensive OCT quality control and algorithmic segmentation produced consistent results across Cirrus HD-OCT and Spectralis devices. Primary endpoints were GCIPL, INL, and ONL atrophy, assessed by linear mixed-effects regression. Secondary endpoints were associations of OCT measures, brain parenchymal fraction, and cortical thickness, assessed by partial Pearson correlations.
One hundred thirty-four PPMS and 121 SPMS participants were included. GCIPL atrophy was 79% slower in the ibudilast (-0.07 ± 0.23 µm/y) vs placebo group (-0.32 ± 0.20 µm/y, = 0.003). This effect predominated in the PPMS cohort (ibudilast: -0.08 ± 0.29 µm/y vs placebo: -0.60 ± 0.29 µm/y, a decrease of 87%, < 0.001) and was not detected in the SPMS cohort (ibudilast: -0.21 ± 0.28 µm/y vs placebo: -0.14 ± 0.27 µm/y, = 0.55). GCIPL, INL, and ONL atrophy rates correlated with whole brain atrophy rates across the cohort ( = 0.27, = 0.26, and r = 0.20, respectively; < 0.001). Power calculations from these data show future trials of similar size and design have ≥80% power to detect GCIPL atrophy effect sizes of approximately 40%.
Ibudilast treatment decreased GCIPL atrophy in PMS, driven by the PPMS cohort, with no effect seen in SPMS. Modulated atrophy of retinal layers may be detectable in sample sizes smaller than the SPRINT-MS trial and correlate with whole brain atrophy in PMS, further highlighting their utility as outcomes in PMS.
This study provides Class II evidence that ibudilast reduces composite ganglion cell + inner plexiform layer atrophy, without reduction of inner or outer nuclear layer atrophy, in patients with primary progressive MS but not those with secondary progressive MS.
通过光学相干断层扫描（OCT）测量的神经节细胞+内丛状层（GCIPL）变薄反映了多发性硬化症（MS）中的整体神经退行性变。内层（INL）和外层核层（ONL）的萎缩在进展性 MS（PMS）中也可能很明显。第 2 阶段，SPRINT-MS 试验发现，在 PMS 中，用伊布地尔治疗可减少脑萎缩。在 SPRINT-MS 试验的这项事后分析中，我们研究了（1）视网膜萎缩，（2）亚型反应的差异，以及（3）OCT 和 MRI 神经退行性变测量之间的关联。
在这项多中心、双盲 SPRINT-MS 试验中，将继发性进展性 MS（SPMS）或原发性进展性 MS（PPMS）患者随机分配至伊布地尔或安慰剂组。每隔 24 周采集 OCT 和 MRI 数据，共采集 96 周。Cirrus HD-OCT 和 Spectralis 设备均采用广泛的 OCT 质量控制和算法分割，得出一致的结果。主要终点是 GCIPL、INL 和 ONL 萎缩，通过线性混合效应回归进行评估。次要终点是 OCT 测量值、脑实质分数和皮质厚度之间的关联，通过部分 Pearson 相关性进行评估。
纳入了 134 例 PPMS 和 121 例 SPMS 患者。伊布地尔组（-0.07±0.23 µm/y）的 GCIPL 萎缩速度比安慰剂组（-0.32±0.20 µm/y）慢 79%（ = 0.003）。这种效果主要在 PPMS 队列中（伊布地尔：-0.08±0.29 µm/y 比安慰剂：-0.60±0.29 µm/y，减少 87%，<0.001），而在 SPMS 队列中未检测到（伊布地尔：-0.21±0.28 µm/y 比安慰剂：-0.14±0.27 µm/y， = 0.55）。GCIPL、INL 和 ONL 萎缩率与整个队列的全脑萎缩率相关（ = 0.27、 = 0.26 和 r = 0.20，均<0.001）。从这些数据进行的功效计算显示，未来具有类似规模和设计的试验具有≥80%的功效，可检测到大约 40%的 GCIPL 萎缩效应大小。
在 PMS 中，伊布地尔治疗降低了 GCIPL 萎缩，主要是在 PPMS 队列中，而在 SPMS 中则没有这种作用。视网膜层的调制性萎缩在样本量小于 SPRINT-MS 试验的情况下可能是可检测的，并且与 PMS 中的全脑萎缩相关，进一步强调了它们作为 PMS 结局的效用。
本研究提供了 II 级证据，表明伊布地尔可减少原发性进展性 MS 患者的复合神经节细胞+内丛状层萎缩，但不减少继发性进展性 MS 患者的内或外核层萎缩。
