Hsp90 Levels in Idiopathic Inflammatory Myopathies and Their Association With Muscle Involvement and Disease Activity: A Cross-Sectional and Longitudinal Study

Abstract

BackgroundHeat shock proteins (Hsp) are chaperones playing essential roles in skeletal muscle physiology, adaptation to exercise or stress, and activation of inflammatory cells. We aimed to assess Hsp90 in patients with idiopathic inflammatory myopathies (IIM) and its association with IIM-related features.MethodsHsp90 plasma levels were analyzed in a cross-sectional cohort (277 IIM patients and 157 healthy controls [HC]) and two longitudinal cohorts to assess the effect of standard-of-care pharmacotherapy (n=39 in early disease and n=23 in established disease). Hsp90 and selected cytokines/chemokines were measured by commercially available ELISA and human Cytokine 27-plex Assay.ResultsHsp90 plasma levels were increased in IIM patients compared to HC (median [IQR]: 20.2 [14.3–40.1] vs 9.8 [7.5–13.8] ng/mL, p<0.0001). Elevated Hsp90 was found in IIM patients with pulmonary, cardiac, esophageal, and skeletal muscle involvement, with higher disease activity or damage, and with elevated muscle enzymes and crucial cytokines/chemokines involved in the pathogenesis of myositis (p<0.05 for all). Plasma Hsp90 decreased upon pharmacological treatment in both patients with early and established disease. Notably, Hsp90 plasma levels were slightly superior to traditional biomarkers, such as C-reactive protein and creatine kinase, in differentiating IIM from HC, and IIM patients with cardiac involvement and interstitial lung disease from those without these manifestations.ConclusionsHsp90 is increased systemically in patients with IIM. Plasma Hsp90 could become an attractive soluble biomarker of disease activity and damage and a potential predictor of treatment response in IIM.

Hsp90 as a Myokine: Its Association with Systemic Inflammation after Exercise Interventions in Patients with Myositis and Healthy Subjects

“…In the IG, we observed a significant improvement ( p < 0.05 in all) in muscle strength by 26% from baseline (assessed by MMT-8), endurance by 135% from baseline (assessed by FI-2), stability by 11% from baseline (assessed by FVA), and reduced disability by 39% from baseline (assessed by HAQ), which was clinically meaningful in a substantial proportion of patients [ 31 ]. In contrast to another recent study from our group where we described a significant decrease in plasma levels of Hsp90 from baseline to 24 weeks in the CG (baseline: 15.7 [9.8–29.5], week 24: 12.9 [9.7–16.6] ng/mL, p = 0.042) [ 20 ], in the present study we observed a stabilization of the plasma Hsp90 levels over 24 weeks in the IG (baseline: 12.5 [8.9–16.8], week 24: 12.0 [8.0–16.1] ng/mL, p = 0.969; difference between IG and CG: p = 0.014) ( Figure 1 A). Of particular interest, the change in plasma Hsp90 in the IG over the first 12 weeks was able to predict the improvement in muscle endurance (FI-2) over the entire 24-week intervention period (r = 0.510, p = 0.008) ( Figure 1 B).…”

“…It is also worth mentioning that the longitudinal IIM cohort with established disease from that study was further analyzed in this study and served as the control cohort for the IIM IG, as originally designed in our 24-week exercise intervention study [ 31 ]. In the CG of this study, although we did not find any significant changes in the mean serum levels of LD and CK at week 24 compared to baseline after continued immunosuppressive therapy (LD: −9%, p = 0.897; CK: +5%, p = 0.154) [ 20 ], we observed a significant increase in IL-2 and IL-6 and a significant decrease in IL-9, MIP-1β, MCP-1, RANTES, and TNF. Meanwhile, systemic levels of all of these cytokines have been shown to correlate with several IIM-specific features [ 33 , 36 , 37 , 38 , 39 , 40 ].…”

“…Thus far, systemic levels of Hsp90 have never been reported in either IIM patients or healthy subjects after exercise interventions. Nonetheless, our recently published cross-sectional study demonstrated increased Hsp90 plasma levels in IIM patients compared with healthy controls, which were associated with muscle involvement, higher disease activity, and several cytokines/chemokines (IL-1b, IL-6, IL-8, IL-17, interferon γ (IFN-γ), C-X-C motif chemokine ligand 10 (CXCL10), MCP-1, MIP-1α, MIP-1β, vascular endothelial growth factor (VEGF), and platelet-derived growth factor-(PDGF)-BB) previously implicated in the pathogenesis of IIM [ 20 , 21 , 22 , 33 , 34 , 35 ]. In that study, a decrease in Hsp90 levels after standard-of-care immunosuppressive therapy in IIM patients with both early and established disease was described [ 20 ].…”

“…Nonetheless, our recently published cross-sectional study demonstrated increased Hsp90 plasma levels in IIM patients compared with healthy controls, which were associated with muscle involvement, higher disease activity, and several cytokines/chemokines (IL-1b, IL-6, IL-8, IL-17, interferon γ (IFN-γ), C-X-C motif chemokine ligand 10 (CXCL10), MCP-1, MIP-1α, MIP-1β, vascular endothelial growth factor (VEGF), and platelet-derived growth factor-(PDGF)-BB) previously implicated in the pathogenesis of IIM [ 20 , 21 , 22 , 33 , 34 , 35 ]. In that study, a decrease in Hsp90 levels after standard-of-care immunosuppressive therapy in IIM patients with both early and established disease was described [ 20 ]. It is also worth mentioning that the longitudinal IIM cohort with established disease from that study was further analyzed in this study and served as the control cohort for the IIM IG, as originally designed in our 24-week exercise intervention study [ 31 ].…”

“…Additionally, Hsp90 elicits immune response via cytokines and is upregulated under acute or chronic inflammatory conditions [ 18 , 19 ]. In particular, our recent study demonstrated elevated systemic Hsp90 levels in patients with idiopathic inflammatory myopathies (IIM) compared with healthy controls, especially their association with muscle involvement, as well as a reduction in systemic Hsp90 levels upon standard-of-care immunosuppressive treatment [ 20 ].…”