Abstract

Interleukin-6 (IL6) expression increases in atrophying muscles and lung tissue during compromised function. Considering ALS patients undergo these same pathological changes, IL6 levels may be relevant for prognostication and treatment. The amount of soluble IL6 receptor, dictated by the IL6R³⁵⁸Ala variant, and local tissue environment in which IL6 signaling occurs is known to influence the ultimate effects of IL6 in multiple diseases. In this longitudinal study, we show that serum IL6 levels negatively correlate both with the patient’s functional status as measured by the overall ALSFRS-R and subscores, and with respiratory function as measured by the percent predicted FVC (ppFVC). The correlations are only present in the two-thirds of patients who carry the IL6R³⁵⁸Ala variant that mediates pro-inflammatory transsignaling in the cases of ALSFRS-R limb and respiratory subscores and ppFVC. These results suggest that some observed associations between IL6 and ALS are driven by the subset of patients carrying the IL6R³⁵⁸Ala variant and thus that any IL6-targeted therapeutic approaches may be more advantageous when aimed at this group. Specifically, with relation to respiratory decline, these patients may benefit from closer respiratory follow-up and early initiation of noninvasive ventilation.

摘要

在功能受损期间，萎缩的肌肉和肺组织中白细胞介素 6 (IL6) 的表达增加。考虑到 ALS 患者经历这些相同的病理变化，IL6 水平可能与预后和治疗相关。已知由 IL6R ³⁵⁸ Ala 变体决定的可溶性 IL6 受体的量以及发生 IL6 信号传导的局部组织环境会影响 IL6 在多种疾病中的最终作用。在这项纵向研究中，我们表明血清 IL6 水平与患者的功能状态（通过整体 ALSFRS-R 和子评分测量）以及呼吸功能（通过预测 FVC 百分比 (ppFVC) 测量）呈负相关。^{相关性仅存在于携带 IL6R 358}的三分之二的患者中在 ALSFRS-R 肢体和呼吸亚评分和 ppFVC 的情况下介导促炎转信号的 Ala 变体。这些结果表明，一些观察到的 IL6 和 ALS 之间的关联是由携带 IL6R ³⁵⁸ Ala 变体的患者亚群驱动的，因此任何针对 IL6 的治疗方法在针对该群体时可能更有利。具体而言，与呼吸衰退有关，这些患者可能受益于更密切的呼吸随访和早期开始无创通气。