Freedman Mark S, Comi Giancarlo, Coyle Patricia K, Aldridge Julie, Chen Liang, Marhardt Kurt, Kappos Ludwig
University of Ottawa and the Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8l6, Canada.
Università Vita Salute San Raffaele, Ospedale San Raffaele, Milan, Italy.
Mult Scler Relat Disord. 2020 Apr;39:101891. doi: 10.1016/j.msard.2019.101891. Epub 2019 Dec 9.
Clinically isolated syndrome (CIS) is defined as a monophasic clinical episode highly suggestive of multiple sclerosis (MS). Regardless, studies have shown that treatment at this early stage of MS can delay a second event and prolong the transition to clinically diagnosed MS. The objective of this post-hoc analysis was to determine the effect of early CIS treatment with once weekly (qw) or three times weekly (tiw) subcutaneous interferon (scIFN) β-1a vs. delayed treatment (DT) on the composite endpoint of no evidence of disease activity (NEDA)-3.
In REFLEX, patients with CIS were randomized to double-blind scIFN β-1a 44 µg tiw, qw, or placebo for 24 months. Upon clinically-definite MS, patients switched to open-label scIFN β-1a tiw. Patients who completed REFLEX entered an extension (REFLEXION). Patients initially randomized to placebo switched to tiw (DT); scIFN β-1a patients continued their initial qw/tiw regimen for up to 60-months post-randomization. This post-hoc analysis was conducted in the integrated intent-to-treat REFLEX plus REFLEXION population (tiw, n = =171; qw, n = =175; DT, n = =171). All p values are nominal. CIS was defined using the McDonald 2010 criteria.
Patients receiving early treatment (ET) with scIFN β-1a tiw and qw were more likely to achieve NEDA-3 than DT at year 2 (tiw vs. DT: OR 4.26, 95% CI 2.02-8.98, p = =0.0001; qw vs. DT: OR 2.99, 95% CI 1.39-6.43, p = =0.005). Compared with DT, ET with scIFN β-1a tiw was more likely to achieve NEDA-3 at year 3 (OR 3.73, 95% CI 1.63-8.55, p = =0.002) and year 5 (OR 12.96, 95% CI 1.66-101.04, p = =0.015). Between ET regimens, the odds of achieving NEDA-3 were not significantly improved by scIFN β-1a 44 µg tiw at year 2 (OR 1.42, 95% CI 0.81-2.50, p = =0.22) but were at year 3 (OR 2.26, 95% CI 1.11-4.60, p = =0.024) and year 5 (OR 3.22, 95% CI 1.01-10.22, p = =0.048), indicating that the beneficial effects of more frequent scIFN β-1a dosing become more apparent over time in patients with CIS. In the subgroup of patients with Gd+ lesions at baseline the odds for achieving NEDA-3 were higher for ET up to year 2 compared with DT (tiw: OR 10.21, 95% CI 1.23-84.82, p = =0.03; qw: OR 8.97, 95% CI 1.08-74.28, p = =0.04). In patients without Gd+ lesions at baseline, those receiving ET were more likely to achieve NEDA-3 at year 2 (OR 3.56, 95% CI 1.56-8.10, p = =0.003), year 3 (OR 2.54, 95% CI 1.05-6.18, p = =0.04) and year 5 (OR 9.63, 95% CI 1.19-77.79, p = =0.034) than patients who received DT.
ET with scIFN β-1a tiw was associated with a higher likelihood of achieving NEDA-3 not only at 2 but also at 3 and 5 years.
临床孤立综合征（CIS）被定义为高度提示多发性硬化症（MS）的单相临床发作。尽管如此，研究表明，在MS的这一早期阶段进行治疗可以延迟第二次发作，并延长向临床确诊MS的转变时间。这项事后分析的目的是确定每周一次（qw）或每周三次（tiw）皮下注射干扰素（scIFN）β-1a的早期CIS治疗与延迟治疗（DT）对无疾病活动证据（NEDA）-3复合终点的影响。
在REFLEX研究中，CIS患者被随机分为双盲皮下注射44μg的scIFNβ-1a，每周三次（tiw）、每周一次（qw）或安慰剂，为期24个月。一旦确诊为临床确诊的MS，患者转为开放标签的scIFNβ-1a，每周三次（tiw）。完成REFLEX研究的患者进入延长期（REFLEXION）。最初随机分配到安慰剂组的患者转为每周三次（tiw）（延迟治疗）；scIFNβ-1a组患者在随机分组后继续其初始的qw/tiw方案，最长可达60个月。这项事后分析是在综合意向性治疗的REFLEX加REFLEXION人群中进行的（每周三次（tiw），n = 171；每周一次（qw），n = 175；延迟治疗（DT），n = 171）。所有p值均为名义值。CIS采用2010年麦克唐纳标准定义。
接受早期治疗（ET）的皮下注射scIFNβ-1a每周三次（tiw）和每周一次（qw）的患者在第2年比延迟治疗（DT）更有可能达到NEDA-3（每周三次（tiw）与延迟治疗（DT）：OR 4.26，95%CI 2.02-8.98，p = 0.0001；每周一次（qw）与延迟治疗（DT）：OR 2.99，95%CI 1.39-6.43，p = 0.005）。与延迟治疗（DT）相比，皮下注射scIFNβ-1a每周三次（tiw）的早期治疗（ET）在第3年（OR 3.73，95%CI 1.63-8.55，p = 0.002）和第5年（OR 12.96，95%CI 1.66-101.04，p = 0.015）更有可能达到NEDA-3。在早期治疗方案之间，皮下注射44μg的scIFNβ-1a每周三次（tiw）在第2年达到NEDA-3的几率没有显著提高（OR 1.42，95%CI 0.81-2.50，p = 0.22），但在第3年（OR 2.26，95%CI 1.11-4.60，p = 0.024）和第5年（OR 3.22，95%CI 1.01-10.22，p = 0.048）有提高，这表明随着时间的推移，更频繁的皮下注射scIFNβ-1a给药对CIS患者的有益效果变得更加明显。在基线时有钆增强（Gd+）病变的患者亚组中，与延迟治疗（DT）相比，早期治疗（ET）在第2年达到NEDA-3的几率更高（每周三次（tiw）：OR 10.21，95%CI 1.23- 84.82，p = 0.03；每周一次（qw）：OR 8.97，95%CI 1.08-74.28，p = 0.04）。在基线时无钆增强（Gd+）病变的患者中，接受早期治疗（ET）的患者在第2年（OR 3.56，95%CI 1.56-8.10，p = 0.003）、第3年（OR 2.54，95%CI 1.05-6.18，p = 0.04）和第5年（OR 9.63，95%CI 1.19-77.79，p = 0.034）比接受延迟治疗（DT）的患者更有可能达到NEDA-3。
皮下注射scIFNβ-1a每周三次（tiw）的早期治疗（ET）不仅在第2年，而且在第3年和第5年达到NEDA-3的可能性更高。
