Abstract
Objective. 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.
Methods. 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.
Results. 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.
Conclusion. 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.
Footnotes
Supported by Novartis (investigator-initiated grant), the Rudolph Rupert Scleroderma Program at the Hospital for Special Surgery, the Donald E. and Delia B. Baxter Foundation (Career Development Award to PJU), the Floren Family Trust (gift to PJU), the Ben May Charitable Trust (gift to PJU), the National Heart Lung and Blood Institute (Proteomics Contract 268201000034C to PJU), the National Institutes of Health (grant numbers T32GM007365, U19-AI082719, U19-AI110491, UH2-AR067676, UM2-AR067678, UM1-AI110498, and U19-AI090019 all to PJU), the Alliance for Lupus Research (grant number 21858 to PJU), the Canadian Institutes for Health Research (Fellowship to DJH), the Stanford Translational Research and Applied Medicine Program (Pilot Grant to DJH), the Scleroderma Research Foundation (to LSC), the Scleroderma Foundation (to LSC and New Investigator Grant to JKG), the Scleroderma Clinical Trials Consortium (to LSC), the Hospital for Special Surgery/Kellen Family Foundation (Clinician Scientist Development Award to JKG), and the US National Institute of Arthritis and Musculoskeletal and Skin Diseases (5U19AI056363-10 to RFS). The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 261382.
- Accepted for publication January 25, 2017.