Knier Benjamin, Leppenetier Gildas, Wetzlmair Carmen, Aly Lilian, Hoshi Muna-Miriam, Pernpeintner Verena, Biberacher Viola, Berthele Achim, Mühlau Mark, Zimmer Claus, Hemmer Bernhard, Korn Thomas
Department of Neurology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany2Department of Experimental Neuroimmunology, Technische Universität München, Munich, Germany.
Department of Neurology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
JAMA Neurol. 2017 Jul 1;74(7):847-856. doi: 10.1001/jamaneurol.2017.0377.
Biomarkers to estimate long-term outcomes in patients with multiple sclerosis (MS) and to assign patients to individual treatment regimens are urgently needed.
To assess whether retinal layer volumes are correlated with immune cell subsets and immunoglobulin indices in the cerebrospinal fluid and whether retinal layer volumes alone or in combination with intrathecal variables are associated with worsening of disease in patients with relapsing-remitting MS.
DESIGN, SETTING, AND PARTICIPANTS: This observational cohort study included 312 patients with relapsing-remitting MS in 2 independent cohorts (72 patients with short disease duration [cohort 1] and 240 patients with longer disease duration [cohort 2]) treated at a single German university hospital from April 15, 2013, through November 11, 2015.
The common ganglion cell and inner plexiform layer (GCIPL) and inner nuclear layer (INL) volumes were tested for association with the immunoglobulin indices and the frequencies of immune cells in the cerebrospinal fluid (including B cells, T cells, and natural killer cells) (cohort 1). Volumes of GCIPL alone (cohorts 1 and 2) or GCIPL corrected for intrathecal B-cell frequencies (cohort 1) were tested for their association with worsening disability.
A total of 312 patients (212 women [67.9%] and 100 men [32.1%]; median age, 34.0 years [interquartile range (IQR), 28.0-42.0 years]) were available for analysis. In cohort 1 (50 women [69.4%] and 22 men [30.6%]; median age, 31.0 years [IQR, 26.3-38.3 years]), with short disease durations (median, 1.0 months [IQR, 1.0-2.0 months]), low GCIPL volumes were associated with increased intrathecal B-cell frequencies (median, 1.96% [IQR, 1.45%-4.20%]) and intrathecal IgG synthesis (median cerebrospinal fluid/serum IgG index, 0.78 [IQR, 0.53-1.07]). The INL volumes correlated with the frequencies of intrathecal CD56bright natural killer cells (r = 0.28; P = .007). Individuals with low GCIPL volumes (<1.99 mm3) had a 6.4-fold risk for worsening disability during follow-up compared with patients with higher GCIPL values (95% CI, 1.7-24.2; P = .007). This finding was reproduced in cohort 2 (162 women [67.5%] and 78 men [32.5%]; median age, 34.0 years [IQR, 29.0-42.0 years]) consisting of patients with longer disease durations (median, 36.0 months [IQR, 21.0-60.0 months]) (hazard ratio, 2.4; 95% CI, 1.2-4.8; P = .02). In both cohorts, INL volumes correlated with the prospective increase in T2 lesion load and the number of gadolinium-enhancing lesions.
Retinal layers reflect different aspects of disease activity during MS. Loss of GCIPL is associated with intrathecal B-cell immunity and constitutes an independent risk factor for worsening disability, whereas high INL volumes are associated with activity on magnetic resonance imaging in the brain parenchyma. Thus, retinal optical coherence tomography might be a means to support stratification of patients with MS for different therapeutic regimens.
迫切需要生物标志物来评估多发性硬化症（MS）患者的长期预后，并为患者制定个体化治疗方案。
评估视网膜层体积是否与脑脊液中的免疫细胞亚群和免疫球蛋白指标相关，以及单独的视网膜层体积或与鞘内变量相结合是否与复发缓解型MS患者的疾病恶化相关。
设计、设置和参与者：这项观察性队列研究纳入了2个独立队列中的312例复发缓解型MS患者（72例病程短的患者[队列1]和240例病程长的患者[队列2]），这些患者于2013年4月15日至2015年11月11日在德国一家大学医院接受治疗。
测试共同神经节细胞和内丛状层（GCIPL）以及内核层（INL）体积与免疫球蛋白指标和脑脊液中免疫细胞频率（包括B细胞、T细胞和自然杀伤细胞）的相关性（队列1）。测试单独的GCIPL体积（队列1和2）或校正鞘内B细胞频率后的GCIPL体积（队列1）与残疾恶化的相关性。
共有312例患者（212例女性[67.9%]和100例男性[32.1%]；中位年龄34.0岁[四分位间距（IQR），28.0 - 42.0岁]）可供分析。在队列1（50例女性[69.4%]和22例男性[30.6%]；中位年龄31.0岁[IQR，26.3 - 38.3岁]）中，病程短（中位值1.0个月[IQR，1.0 - 2.0个月]），低GCIPL体积与鞘内B细胞频率增加（中位值1.96%[IQR，1.45% - 4.20%]）和鞘内IgG合成增加（中位脑脊液/血清IgG指数，0.78[IQR，0.53 - 1.07]）相关。INL体积与鞘内CD56bright自然杀伤细胞频率相关（r = 0.28；P = 0.007）。与GCIPL值较高的患者相比（95%CI，1.7 - 24.2；P = 0.007），GCIPL体积低（<1.99 mm3）的个体在随访期间残疾恶化的风险高6.4倍。这一发现在队列2（162例女性[67.5%]和78例男性[32.5%]；中位年龄34.0岁[IQR，29.0 - 42.0岁]）中得到重现，该队列由病程较长（中位值36.0个月[IQR，21.0 - 60.0个月]）的患者组成（风险比，2.4；95%CI，1.2 - 4.8；P = 0.02）。在两个队列中，INL体积均与T2病变负荷的前瞻性增加和钆增强病变数量相关。
视网膜层反映了MS疾病活动的不同方面。GCIPL的丧失与鞘内B细胞免疫相关，是残疾恶化的独立危险因素，而高INL体积与脑实质磁共振成像上的活动相关。因此，视网膜光学相干断层扫描可能是支持MS患者进行不同治疗方案分层的一种手段。
