Comparing and Combining Bortezomib and Mycophenolate in SSc Pulmonary Fibrosis

 描述（由申请人提供）：系统性硬化症（SSc）是一种慢性、多系统结缔组织疾病，估计患病率高达75/100，000。肺纤维化发生在约40%的患者中，并且是死亡的主要原因，而皮肤纤维化是发病的重要原因。没有治疗显示出对SSc相关的肺和皮肤纤维化的持续作用。然而，霉酚酸酯（MMF）已成为许多SSc中心的一线治疗。我们发表的数据显示，博来霉素诱导肺损伤后7或14天给予硼替佐米（一种FDA批准的用于治疗多发性骨髓瘤的蛋白酶体抑制剂）可预防肺和皮肤纤维化。硼替佐米已用于全球超过350，000例多发性骨髓瘤患者，毒性和耐受性可接受。然而，在SSc患者中没有硼替佐米的此类数据。我们的体外和动物数据为检测硼替佐米治疗肺和皮肤纤维化提供了令人信服的病理生理学依据。因此，在这项资助中，我们提出了一项试点临床试验，在SSc肺纤维化患者中将硼替佐米加入吗替麦考酚酯（MMF）。该试验的目的是评估硼替佐米与MMF联合治疗具有肺部疾病进展高风险的SSc患者的安全性、耐受性和疗效。

 DESCRIPTION (provided by applicant): Systemic sclerosis (SSc) is a chronic, multisystem connective tissue disease with an estimated prevalence as high as 75 per 100,000. Pulmonary fibrosis occurs in ~40% of patients and is the leading cause of death while skin fibrosis is a significant cause of morbidity. There are no therapies that have shown a sustained effect in SSc associated pulmonary and skin fibrosis. Nevertheless, mycophenoalate mofetil (MMF) has become 1st line therapy at many SSc centers. Our published data shows that bortezomib, an FDA approved proteasomal inhibitor for the treatment of multiple myeloma, administered 7 or 14 days after the induction of lung injury by bleomycin prevented lung and skin fibrosis. Bortezomib has been used in more than 350,000 multiple myeloma patients worldwide with acceptable toxicity and tolerability. There is, however, no such data for bortezomib in SSc patients. Our in vitro and animal data provide a compelling pathophysiologic rationale for testing bortezomib for pulmonary and skin fibrosis. Thus in this grant we propose a pilot clinical trial of adding bortezomib to mycophenolate mofeteil (MMF) in patients with SSc Pulmonary Fibrosis. The objective of the trial is to assess safety, tolerability & efficacy of bortezomib in combination wih MMF in SSc patients at high risk of pulmonary disease progression.