Tocilizumab is a humanized monoclonal antibody to IL-6 widely used in Rheumatology. Indications include RA, GCA, & Takayasu's arteritis.
There are some reports of it being useful in COVID19. This is not surprising, as there are similar reports of its use with the original SARS virus.
Presumably, in some of these cases, Tocilizumab helps turn down the cytokine storm, characterised by high levels of IL-6. It is important to mention that IL-6 plays an important role in infections, where it is instrumental in priming B cells, among its other functions.
However, IL-6 can also damage normal tissues quite quickly, which might be innocent bystanders not germane to the ongoing inflammatory process.
Viruses can increase the production of IL-6 through the aforementioned TLRs. TLR3 and TLR9 (cognate receptors for dsRNA and DNA respectively) act through an adapter protein called MyD88. The latter leads to two divergent pathways. While one pathway downstream of MyD88 proceeds to activate kinases IRAK1 & IRAK4 and subsequently through IRF 5&7, turns on the class I interferon genes in the nucleus, the other pathway proceeds down IRAK4 & IRAK2 to activate nuclear factor kappa B, and thus increases the production of cytokines such as TNF alpha and IL-6.
Normally, the interferon producing pathway dominates the inflammatory pathway, and most subjects overcome their viral infections through the viricidal effect of interferons.
For reasons not best understood though, in some subjects, the inflammatory pathway dominates, thus quickly leading to tissue damage, and sometimes, death. It is for these subjects that Tocilizumab might be useful.
In a similar vein, it is worth mentioning here that the IL-6 receptor activates JAK1 and JAK2 (also TYK2), which in turn, switches on STAT3. It is not inconceivable therefore that JAK inhibitors such as Tofacitinib, Baricitinib and Upadicitinib would be useful in patients with cytokine storm.
One curious effect of Tocilizumab is that it makes CRP virtually useless as a marker of inflammation. Subjects on Tocilizumab markedly reduce the production of CRP by liver, and ongoing inflammation may proceed with a normal CRP.
There are some reports of it being useful in COVID19. This is not surprising, as there are similar reports of its use with the original SARS virus.
Presumably, in some of these cases, Tocilizumab helps turn down the cytokine storm, characterised by high levels of IL-6. It is important to mention that IL-6 plays an important role in infections, where it is instrumental in priming B cells, among its other functions.
However, IL-6 can also damage normal tissues quite quickly, which might be innocent bystanders not germane to the ongoing inflammatory process.
Viruses can increase the production of IL-6 through the aforementioned TLRs. TLR3 and TLR9 (cognate receptors for dsRNA and DNA respectively) act through an adapter protein called MyD88. The latter leads to two divergent pathways. While one pathway downstream of MyD88 proceeds to activate kinases IRAK1 & IRAK4 and subsequently through IRF 5&7, turns on the class I interferon genes in the nucleus, the other pathway proceeds down IRAK4 & IRAK2 to activate nuclear factor kappa B, and thus increases the production of cytokines such as TNF alpha and IL-6.
Normally, the interferon producing pathway dominates the inflammatory pathway, and most subjects overcome their viral infections through the viricidal effect of interferons.
For reasons not best understood though, in some subjects, the inflammatory pathway dominates, thus quickly leading to tissue damage, and sometimes, death. It is for these subjects that Tocilizumab might be useful.
In a similar vein, it is worth mentioning here that the IL-6 receptor activates JAK1 and JAK2 (also TYK2), which in turn, switches on STAT3. It is not inconceivable therefore that JAK inhibitors such as Tofacitinib, Baricitinib and Upadicitinib would be useful in patients with cytokine storm.
One curious effect of Tocilizumab is that it makes CRP virtually useless as a marker of inflammation. Subjects on Tocilizumab markedly reduce the production of CRP by liver, and ongoing inflammation may proceed with a normal CRP.
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