目的:免疫检查点抑制剂(ICI)治疗可显著改善多种癌症的预后。ICI的作用机制涉及免疫系统激活以增强抗肿瘤免疫力。预先存在自身免疫性疾病的患者,如系统性硬化症(SSc),被排除在最初的ICI临床试验中,因为担心这种免疫系统激活可能导致自身免疫性疾病发作或新的疾病,严重免疫相关不良事件(irAE)。在本研究中,我们报告了我们在已有SSc患者中使用ICIs的经验.
方法:接受ICI治疗的SSc患者来自约翰霍普金斯硬皮病中心研究注册中心。通过图表审查和预先指定的定义,我们确定了患者是否经历了SSc活性恶化或新的irAE。SSc疾病活动恶化预先定义为改良Rodnan皮肤评分(mRSS)增加,新出现的硬皮病肾危象,间质性肺病(ILD)的CT扫描进展,增加雷诺现象的频率或严重程度,新的肺动脉高压,或者肌炎发作。IrAE还包括活动性炎性关节炎和皮炎。
结果:纳入了8例接受ICI治疗的SSc患者。总的来说,在ICI治疗期间和之后,SSc症状保持稳定。长期正弦或有限皮肤SSc(lcSSc)的患者在ICI治疗后均未出现进行性皮肤增厚。一个病人,他在弥漫性皮肤SSc(dcSSc)病程早期,经历了恶化的皮肤增厚和肾脏危象。三名患者(38%)总共经历了五次irAE(2级:腹泻,粘膜炎和皮炎;3级:肺炎,和4级:肾炎)。4级肾炎患者同时出现硬皮病肾危象和免疫检查点相关性肾炎。没有人因irAE而死亡。
结论:在这项研究中,ICI治疗在长期患者中耐受性良好,正弦或lcSSc。IrAE很常见,但通常是可控的。早期患者,活动性SSc可能因ICI治疗而面临更大的风险,但是需要更多的研究。
OBJECTIVE: Immune checkpoint inhibitor (ICI) therapies have dramatically improved outcomes in multiple cancers. ICI\'s mechanism of action involves immune system activation to augment anti-tumor immunity. Patients with pre-existing autoimmune diseases, such as systemic sclerosis (SSc), were excluded from initial ICI clinical trials due to concern that such immune system activation could precipitate an autoimmune disease flare or new, severe immune related adverse events (irAE). In the present study, we report our experience with ICIs in patients with pre-existing SSc.
METHODS: Patients with SSc who received ICI therapy for cancer were identified from the Johns Hopkins Scleroderma Center Research Registry. Through chart review and prespecified definitions, we identified whether patients experienced worsening SSc activity or new irAEs. SSc disease activity worsening was pre-defined as an increase in modified Rodnan skin score (mRSS), new scleroderma renal crisis, progression of interstitial lung disease (ILD) on CT scan, increased Raynaud\'s phenomenon frequency or severity, new pulmonary hypertension, or myositis flare. IrAEs also included active inflammatory arthritis and dermatitis.
RESULTS: Eight patients with SSc who received ICI therapy for cancer were included. Overall, SSc symptoms remained stable during and after ICI therapy. None of the patients with long-standing sine or limited cutaneous SSc (lcSSc) had progressive skin thickening after ICI therapy. One patient, who was early in his diffuse cutaneous SSc (dcSSc) disease course, experienced worsening skin thickening and renal crisis. Three patients (38 %) experienced a total of five irAEs (grade 2: diarrhea, mucositis and dermatitis; grade 3: pneumonitis, and grade 4: nephritis). The patient with grade 4 nephritis developed scleroderma renal crisis and immune checkpoint related nephritis simultaneously. There were no deaths due to irAEs.
CONCLUSIONS: In this study, ICI therapy was well tolerated in patients with longstanding, sine or lcSSc. IrAE were common but generally manageable. Patients with early, active SSc may be at greater risk from ICI therapy, but more research is needed.