Institute of Neuropathology, University Medical Center Goettingen, Goettingen, Germany.
Department of Medical Statistics, University Medical Center Goettingen, Goettingen, Germany.
JAMA Neurol. 2018 Apr 1;75(4):428-435. doi: 10.1001/jamaneurol.2017.4842.
Plasma exchange and immunoadsorption are second-line apheresis therapies for patients experiencing multiple sclerosis relapses. Early active multiple sclerosis lesions can be classified into different histopathological patterns of demyelination. Pattern 1 and 2 lesions show T-cell- and macrophage-associated demyelination, and pattern 2 is selectively associated with immunoglobulin and complement deposits, suggesting a humoral immune response. Pattern 3 lesions show signs of oligodendrocyte degeneration. Thus it is possible that pathogenic heterogeneity might predict therapy response.
To evaluate the apheresis response in relation to histopathologically defined immunopathological patterns of multiple sclerosis.
DESIGN, SETTING AND PARTICIPANTS: This single-center cohort study recruited 69 patients nationwide between 2005 and 2016. All included patients had a diagnosis of early active inflammatory demyelination consistent with multiple sclerosis; were classified into patterns 1, 2, or 3 based on brain biopsy analysis; and underwent apheresis treatments. Patients who had concomitant severe disease, neuromyelitis optica, or acute disseminated encephalomyelitis were excluded.
The primary therapy outcome was a functionally relevant improvement of the relapse-related neurological deficit. Radiological and Expanded Disability Status Scale changes were secondary outcome parameters.
The mean (SD) age of patients was 36.6 (13.3) years; 46 of the 69 participants (67%) were female. Overall, 16 patients (23%) exhibited pattern 1 lesions, 40 (58%) had pattern 2 lesions, and 13 (19%) had pattern 3 lesions. A functional therapy response was observed in 5 of the 16 patients with pattern 1 disease (31%) and 22 of the 40 patients with pattern 2 disease (55%), but none of the 13 patients with pattern 3 disease exhibited improvement (pattern 2 vs 3 P < .001). Radiological improvements were found in 4 (25%), 22 (56%), and 1 (11%) of patients with patterns 1, 2, and 3, respectively. The respective rates of response measured by changes in Expanded Disability Status Scale scores were 25%, 40%, and 0%. Brainstem involvement was a negative predictive factor for the functional therapy response (logarithmic odds ratio [logOR], -1.43; 95% CI, -3.21 to 0.17; P = .03), while immunoadsorption (as compared with plasma exchange) might be a positive predictive factor (logOR, 3.26; 95% CI, 0.75 to 8.13; P = .01).
This cohort study provides evidence that the response to apheresis treatment is associated with immunopathological patterns. Patients with both patterns 1 and 2 improved clinically after apheresis treatment, but pattern 2 patients who showed signs of a humoral immune response benefited most. Apheresis appears unlikely to benefit patients with pattern 3 lesions.
血浆置换和免疫吸附是多发性硬化症患者发生多次复发时的二线血浆清除治疗方法。早期活动的多发性硬化症病灶可分为不同的脱髓鞘组织病理学模式。模式 1 和 2 病变显示 T 细胞和巨噬细胞相关脱髓鞘，而模式 2 选择性地与免疫球蛋白和补体沉积相关，提示存在体液免疫反应。模式 3 病变显示少突胶质细胞变性的迹象。因此，致病异质性可能预测治疗反应。
评估与多发性硬化症的组织病理学定义的免疫病理学模式相关的血浆清除反应。
设计、地点和参与者：本单中心队列研究于 2005 年至 2016 年期间在全国范围内招募了 69 名患者。所有纳入的患者均有符合多发性硬化症的早期活跃性炎症性脱髓鞘诊断；根据脑活检分析分为模式 1、2 或 3；并接受了血浆清除治疗。排除同时患有严重疾病、视神经脊髓炎或急性播散性脑脊髓炎的患者。
主要治疗结局是与复发相关的神经功能缺损的功能相关改善。影像学和扩展残疾状况量表的变化是次要结局参数。
患者的平均（SD）年龄为 36.6（13.3）岁；69 名参与者中有 46 名（67%）为女性。总体而言，16 名患者（23%）表现为模式 1 病变，40 名（58%）表现为模式 2 病变，13 名（19%）表现为模式 3 病变。16 名模式 1 疾病患者中有 5 名（31%）和 40 名模式 2 疾病患者中有 22 名（55%）出现功能治疗反应，但 13 名模式 3 疾病患者均无改善（模式 2 与 3 相比，P<0.001）。分别有 4（25%）、22（56%）和 1（11%）名患者出现影像学改善。通过扩展残疾状况量表评分变化测量的相应反应率分别为 25%、40%和 0%。脑干受累是功能治疗反应的负预测因素（对数比值[logOR]，-1.43；95%CI，-3.21 至 0.17；P=0.03），而免疫吸附（与血浆置换相比）可能是正预测因素（logOR，3.26；95%CI，0.75 至 8.13；P=0.01）。
本队列研究提供的证据表明，血浆清除治疗的反应与免疫病理学模式相关。接受血浆清除治疗后，模式 1 和 2 的患者均在临床上得到改善，但表现出体液免疫反应迹象的模式 2 患者获益最大。血浆清除治疗似乎对模式 3 病变的患者无益。
