We appreciate the letter by Honore et al. and agree that a selective pharmacological approach is more rational than unspecific/non-selective medications. With regard to interleukin-6 (IL-6) targeting, we believe that current research, including the sgp130(fc) development, is rightly going towards this direction. Nevertheless, we wish to point out some considerations. Firstly, owing to the need of identifying promptly approaches for managing the COVID-19-related acute respiratory distress syndrome (ARDS), our article focused on drugs currently approved for other therapeutic indications, where they target cytokines involved in the COVID-19 inflammatory storm [1]. Secondly, we are well aware that IL-6 acts through both transmembrane IL-6 receptors (tmIL-6R; mainly regenerative or anti-inflammatory functions) and soluble IL-6 receptors (sIL-6R; trans-signaling pathway with pro-inflammatory actions). However, this anti-inflammatory/pro-inflammatory balance of the IL-6 receptor axis can be affected by several variables, such as proteases, other cytokines, concomitant drugs, genetic factors (up/down-regulation of tmIL-6R, sIL-6R, and gp130 expression), with relevant consequences on IL-6 signaling [5]. In this context, a specific/personalized therapeutic approach could be a good option, but it might be more suitable for chronic than acute conditions, such as the COVID-19-related ARDS. Moreover, even though IL-6 trans-signaling can be inhibited selectively, some detrimental conditions resulting from IL-6 blockade, such as serum increments of liver transaminases, lipids, cholesterol, and C-reactive protein, may still occur [6]. Thirdly, current evidence on the benefit of blocking the IL-6 pathway in COVID-19-related ARDS is encouraging. For instance, in a case series, 100 COVID-19 patients with ARDS displayed a prompt improvement after tocilizumab administration, in the setting of both intensive care (74%) and non-intensive care (65%) [7]. We agree with Honore et al. that sgp130(fc) could be a promising therapeutic approach. However, this novel biological drug exerts its inhibiting action on the IL-6 trans-signaling in a dose-dependent manner, and in an in vivo model, when administered at high dosage, it was shown to interfere also with the classical signaling pathway of tmIL-6R [8]. Thus, additional studies are required to identify the most appropriate anti-inflammatory dose of sgp130(fc) that could allow to achieve optimal benefits in the management of hyperinflammation associated with COVID-19-related ARDS. In conclusion, adequate clinical trials are required to assess whether a more favorable risk/benefit profile is associated with the inhibition of IL-6 trans-signaling, as compared with the overall blockade of IL-6 receptor pathways. While waiting for such evidence, we must continue to rely on currently available pharmacological approaches.
Authors’ response: Inhibiting IL-6 in COVID-19: we are not sure that sgp130(fc) can affect only the trans-signaling receptor pathway of IL-6
Irma ConvertinoPrimo
;Marco Tuccori;Corrado Blandizzi
2020-01-01
Abstract
We appreciate the letter by Honore et al. and agree that a selective pharmacological approach is more rational than unspecific/non-selective medications. With regard to interleukin-6 (IL-6) targeting, we believe that current research, including the sgp130(fc) development, is rightly going towards this direction. Nevertheless, we wish to point out some considerations. Firstly, owing to the need of identifying promptly approaches for managing the COVID-19-related acute respiratory distress syndrome (ARDS), our article focused on drugs currently approved for other therapeutic indications, where they target cytokines involved in the COVID-19 inflammatory storm [1]. Secondly, we are well aware that IL-6 acts through both transmembrane IL-6 receptors (tmIL-6R; mainly regenerative or anti-inflammatory functions) and soluble IL-6 receptors (sIL-6R; trans-signaling pathway with pro-inflammatory actions). However, this anti-inflammatory/pro-inflammatory balance of the IL-6 receptor axis can be affected by several variables, such as proteases, other cytokines, concomitant drugs, genetic factors (up/down-regulation of tmIL-6R, sIL-6R, and gp130 expression), with relevant consequences on IL-6 signaling [5]. In this context, a specific/personalized therapeutic approach could be a good option, but it might be more suitable for chronic than acute conditions, such as the COVID-19-related ARDS. Moreover, even though IL-6 trans-signaling can be inhibited selectively, some detrimental conditions resulting from IL-6 blockade, such as serum increments of liver transaminases, lipids, cholesterol, and C-reactive protein, may still occur [6]. Thirdly, current evidence on the benefit of blocking the IL-6 pathway in COVID-19-related ARDS is encouraging. For instance, in a case series, 100 COVID-19 patients with ARDS displayed a prompt improvement after tocilizumab administration, in the setting of both intensive care (74%) and non-intensive care (65%) [7]. We agree with Honore et al. that sgp130(fc) could be a promising therapeutic approach. However, this novel biological drug exerts its inhibiting action on the IL-6 trans-signaling in a dose-dependent manner, and in an in vivo model, when administered at high dosage, it was shown to interfere also with the classical signaling pathway of tmIL-6R [8]. Thus, additional studies are required to identify the most appropriate anti-inflammatory dose of sgp130(fc) that could allow to achieve optimal benefits in the management of hyperinflammation associated with COVID-19-related ARDS. In conclusion, adequate clinical trials are required to assess whether a more favorable risk/benefit profile is associated with the inhibition of IL-6 trans-signaling, as compared with the overall blockade of IL-6 receptor pathways. While waiting for such evidence, we must continue to rely on currently available pharmacological approaches.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
