Haddon D James, Wand Hannah E, Jarrell Justin A, Spiera Robert F, Utz Paul J, Gordon Jessica K, Chung Lorinda S
From the Division of Immunology and Rheumatology, Stanford University School of Medicine; Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford; Department of Rheumatology, Palo Alto VA Health Care System, Palo Alto, California; Department of Rheumatology, Hospital for Special Surgery, New York, New York, USA.
D.J. Haddon, PhD, Research Associate, Immunology and Rheumatology, Division of Immunology and Rheumatology, Stanford University School of Medicine; H.E. Wand, BS, Genetic Counseling Candidate, Division of Immunology and Rheumatology, Stanford University School of Medicine; J.A. Jarrell, PhD Candidate, Immunology, Division of Immunology and Rheumatology, Stanford University School of Medicine; R.F. Spiera, MD, Professor of Clinical Medicine, Rheumatology and Director, Vasculitis and Scleroderma Program, Department of Rheumatology, Hospital for Special Surgery; P.J. Utz, MD, Professor of Medicine, Immunology and Rheumatology, Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine; J.K. Gordon, MD, Assistant Professor of Medicine, Rheumatology, Department of Rheumatology, Hospital for Special Surgery, New York; L.S. Chung, MD, MS, Associate Professor of Medicine, Immunology and Rheumatology, Division of Immunology and Rheumatology, Stanford University School of Medicine, and Department of Rheumatology, Palo Alto VA Health Care System.
J Rheumatol. 2017 May;44(5):631-638. doi: 10.3899/jrheum.160833. Epub 2017 Mar 15.
Imatinib has been investigated for the treatment of systemic sclerosis (SSc) because of its ability to inhibit the platelet-derived growth factor receptor and transforming growth factor-β signaling pathways, which have been implicated in SSc pathogenesis. In a 12-month open-label clinical trial assessing the safety and efficacy of imatinib in the treatment of diffuse cutaneous SSc (dcSSc), significant improvements in skin thickening were observed. Here, we report our analysis of sera collected during the clinical trial.
We measured the levels of 46 cytokines, chemokines, and growth factors in the sera of individuals with dcSSc using Luminex and ELISA. Autoantigen microarrays were used to measure immunoglobulin G reactivity to 28 autoantigens. Elastic net regularization was used to identify a signature that was predictive of clinical improvement (reduction in the modified Rodnan skin score ≥ 5) during treatment with imatinib. The signature was also tested using sera from a clinical trial of nilotinib, a tyrosine kinase inhibitor that is structurally related to imatinib, in dcSSc.
The elastic net algorithm identified a signature, based on levels of CD40 ligand, chemokine (C-X-C motif) ligand 4 (CXCL4), and anti-PM/Scl-100, that was significantly higher in individuals who experienced clinical improvement than in those who did not (p = 0.0011). The signature was validated using samples from a clinical trial of nilotinib.
Identification of patients with SSc with the greatest probability of benefit from treatment with imatinib has the potential to guide individualized treatment. Validation of the signature will require testing in randomized, placebo-controlled studies. Clinicaltrials.gov NCT00555581 and NCT01166139.
伊马替尼因其能够抑制血小板衍生生长因子受体和转化生长因子-β信号通路而被研究用于治疗系统性硬化症（SSc），这些信号通路与SSc的发病机制有关。在一项评估伊马替尼治疗弥漫性皮肤型SSc（dcSSc）的安全性和有效性的12个月开放标签临床试验中，观察到皮肤增厚有显著改善。在此，我们报告我们对临床试验期间收集的血清的分析。
我们使用Luminex和酶联免疫吸附测定法（ELISA）测量dcSSc患者血清中46种细胞因子、趋化因子和生长因子的水平。使用自身抗原微阵列测量免疫球蛋白G对28种自身抗原的反应性。弹性网络正则化用于识别一个特征，该特征可预测伊马替尼治疗期间的临床改善情况（改良Rodnan皮肤评分降低≥5）。还使用尼洛替尼（一种与伊马替尼结构相关的酪氨酸激酶抑制剂）治疗dcSSc的临床试验中的血清对该特征进行了测试。
弹性网络算法基于CD40配体、趋化因子（C-X-C基序）配体4（CXCL4）和抗PM/Scl-100的水平识别出一个特征，在经历临床改善的个体中该特征显著高于未经历临床改善的个体（p = 0.0011）。该特征使用尼洛替尼临床试验的样本进行了验证。
识别最有可能从伊马替尼治疗中获益的SSc患者有潜力指导个体化治疗。该特征的验证将需要在随机、安慰剂对照研究中进行测试。Clinicaltrials.gov标识符：NCT00555581和NCT01166139。
