Session Type: Abstract Submissions (ACR)
Tyrosine kinase inhibitors (TKIs), including imatinib mesylate, have been studied for the treatment of diffuse cutaneous Systemic Sclerosis (dcSSc). In a previously reported single center, open-label study of imatinib for dcSSc, a significant improvement in the modified Rodnan skin score (MRSS) was observed. In this study, we analyzed the patient serum samples collected during the trial by Luminex and autoantigen microarray to investigate the mechanism of action of imatinib in dcSSc, and to identify biomarkers that are predictive of response to imatinib.
Thirty patients who fulfilled ACR criteria for SSc, with dcSSc, were enrolled in the trial, and 24 completed 12 months of treatment with oral imatinib 400 mg daily. Serum samples were collected at -1, 0, 6, 12, and 15 (post-treatment follow-up) months. Twenty-six patient serum samples were available for analysis at screening/baseline, 25 at 6 months, 20 at 12 months, and 15 at the follow-up time point.
Luminex immunoassays were used to measure the levels of 44 cytokines, chemokines and growth factors in each serum sample in duplicate. Autoantigen microarrays were used to measure the levels of 30 autoantigens known to be associated with dcSSc, in parallel. Luminex and microarray results were analyzed by Significance analysis of microarrays (SAM), a statistical technique that uses permutation to adjust for multiple testing. SAM was used to identify Luminex analytes and autoantibodies that were present at significantly different levels: 1) in healthy controls vs. patients with dcSSc at baseline, 2) during treatment with imatinib vs. baseline; and 3) in the baseline samples of responders vs. non-responders. For this analysis, a decrease in MRSS ≥ 5, previously defined as the minimal clinically important difference, was considered a response to treatment.
Luminex analysis identified 18 analytes that were present at significantly higher levels in the serum of patients with dcSSc than in healthy control serum, including previously reported factors IL-6, MCP-1, VEGF, IL-17 and MIP-1β (fold-change > 2, q < .001). Autoantigen microarray analysis revealed 7 autoantibodies present at significantly higher levels in dcSSc patient sera than in healthy control sera, including Scl-70 and RNA Pol III (fold-change > 1.5, q < .001). We observed significant reductions in 5 autoantibodies following 6 months of treatment with imatinib, including Scl-70 and RNA Pol III, compared to baseline (q < .001). Imatinib treatment was also associated with reductions in 8 Luminex analytes, including VEGF, IL-17, MCP-1, PDGF-AA, and PDGF-BB (q < .001). Levels of VEGF, IL-17, and MIP-1β were significantly higher in responders than non-responders at baseline.
Treatment with imatinib was associated with a reduction in the serum levels of VEGF and IL-17. Increased serum levels of VEGF, IL-17 and MIP-1β in dcSSc patients at baseline were associated with an increased likelihood of clinical improvement in MRSS with imatinib treatment. Investigation of the utility of the baseline levels of IL-17, VEGF and MIP-1β for patient stratification in the context of future randomized controlled trials of TKIs in SSc is warranted.
D. J. Haddon,
P. J. Utz,
R. F. Spiera,
Novartis Pharmaceutical Corporation,
J. K. Gordon,
« Back to 2014 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/luminex-and-autoantigen-microarray-analysis-of-sera-from-patients-with-diffuse-cutaneous-systemic-sclerosis-reveals-changes-associated-with-imatinib-mesylate-treatment/