系统性硬化症(SSc)是一种罕见的致残结缔组织疾病,几乎没有可用的治疗选择。弥漫性皮肤系统性硬化症(dcSSc)与高死亡率相关。先前的实验表明,JAK2抑制剂可以显着改善博来霉素(BLM)诱导的小鼠模型的皮肤纤维化,包括减少真皮增厚和胶原蛋白积累。我们旨在描述口服JAK1/2抑制剂baricitinib在SSc患者中的疗效,特别是关注皮肤纤维化和微血管表现。
我们描述了口服选择性JAK1、JAK2或JAK3抑制剂治疗在BLM诱导的皮肤纤维化小鼠模型中的不同作用。此外,10例dcSSc成人患者接受了baricitinib治疗。我们评估了12周和24周时改良的rodman皮肤评分(mRSS)和数字溃疡净负荷相对于基线的变化。我们还比较了24周内硬皮病健康评估问卷(SHAQ)和圣乔治呼吸问卷(SGRQ)总分的绝对变化。
在皮肤纤维化的实验小鼠模型中,JAK1和JAK2抑制剂改善皮肤纤维化,以JAK2抑制剂效果最明显。用JAK2抑制剂处理也减弱了毛细血管稀疏。我们证明,在接受baricitinib治疗的10例SSc患者中,皮肤纤维化和数字溃疡显着缓解。mRSS在第12周从基线显著改善,mRSS的平均变化为-8.3[95%置信区间(CI),-12.03至-4.574;p=0.0007],在第24周时改善更大,至-11.67(95%CI,-16.84至-6.496;p=0.0008)。在四名数字溃疡(DU)患者中,三个在第24周完全愈合,另一个患者的溃疡数量显着减少,也没有新的溃疡患者.仅观察到一个带状疱疹不良事件(AE)。
我们的结果表明,选择性JAK1和JAK2抑制剂减轻皮肤纤维化,和口服JAK1/2抑制剂baricitinib是一种潜在的有效治疗dcSSc患者皮肤纤维化和DU。在这项研究中,大多数患者对Baricitinib的耐受性良好。需要更多的大型临床试验来证实我们的初步发现。
ChiCTR2000030995。
Systemic sclerosis (SSc) is a rare disabling connective tissue disease with few available treatment options. Diffuse cutaneous systemic sclerosis (dcSSc) is associated with high mortality. A previous experiment has shown that JAK2 inhibitor can significantly improve skin fibrosis in bleomycin (BLM)-induced murine model, including reducing dermal thickening and collagen accumulation. We aimed to describe the efficacy of oral JAK1/2 inhibitor baricitinib in SSc patients, especially focusing on skin fibrosis and microvascular manifestations.
We described the different effects of oral selective JAK1, JAK2, or JAK3 inhibitor treatment in a BLM-induced skin fibrosis mouse model. Furthermore, 10 adult patients with dcSSc were treated with baricitinib. We assessed the changes in modified rodman skin score (mRSS) and digital ulcer net burden at week 12 and 24 from baseline. We also compared the absolute changes in scores on the Scleroderma Health Assessment Questionnaire (SHAQ) and a total score on the St. George\'s Respiratory Questionnaire (SGRQ) over a 24-week period.
In the experimental mouse model of skin fibrosis, a JAK1 and JAK2 inhibitor ameliorated skin fibrosis, and a JAK2 inhibitor had the most obvious effect. Treatment with the JAK2 inhibitor also blunted the capillary rarefaction. We demonstrated that skin fibrosis and digital ulcers were significantly relieved in 10 SSc patients treated with baricitinib. The mRSS significantly improved at week 12 from baseline, with a mean change in mRSS of -8.3 [95% confidence interval (CI), -12.03 to -4.574; p = 0.0007] and improved greater at week 24 to -11.67 (95% CI, -16.84 to -6.496; p = 0.0008). Among the four patients with digital ulcers (DU), three were completely healed at week 24, the number of ulcers in another patient was significantly reduced, and there was no patient with new ulcers. Only one adverse event (AE) of herpes zoster was observed.
Our results indicate that selective JAK1 and JAK2 inhibitor alleviates skin fibrosis, and oral JAK1/2 inhibitor baricitinib is a potentially effective treatment for dcSSc patients with skin fibrosis and DU. Baricitinib was well-tolerated by most patients in this study. Additional large clinical trials are needed to confirm our pilot findings.
ChiCTR2000030995.