General Updates | The role of inflammation in SCD pathophysiology and potential avenues for targeting it

I think inflammation is a key aspect of sickle cell disease that perhaps people tend to overlook a little bit when you think about sickle cell. Primarily the main event that happens in sickle cell is the precipitation of the, you know, the actual sickling of the hemoglobin molecule, which then forms these fibers and then causes the change of the red cell shape, which then eventually leads to sickling and hemolysis and all the downstream effects of that. Now, although this particular event, where the polymerization of the hemoglobin molecule is the cardinal event in sickle, there is more to it. There’s more to the process of vaso occlusion that we see in sickle cell. Generally speaking, the very important physiological thing to remember in this process of sickling is that, from the hemoglobin becoming hypoxic or being exposed to hypoxic environment to the actual precipitation of these insoluble fibers within the red cell cytosol, there is a lag time. And this lag time could be milliseconds. And if you are able to rescue the red cell from this hypoxic environment before that lag time ends then you’re not actually getting the the polymerization; it does not happen because, you know, immediately it then becomes soluble because it exposes itself to oxygen again. And what happens is that the lag time increases. So you, by definition, need an increased lag time for this polymerization to happen in the first place, and the more inflammation there is, the more lag time there is. In fact, if there was no inflammation at all, there would not perhaps be that any or minimal sickling, as it were.

So in some ways inflammation plays a very important role in kind of increasing the time that the red cell spends in an hypoxic environment by causing it to slow down, by causing the blockage in the blood flow, and thereby continuing to expose the red blood cell to hypoxemia. And how does this happen? So it could be that the triggering incident is a precipitation of the insoluble fibers within the red cell cytosol. But, sometimes what happens is these red cells they’re hemolyzed, they break down, they are activated, they cause endothelial activation, they cause white cell activation. They cause upregulation of these sticky molecules also within the endothelium as well as within the surface of the white cells and platelets are activated as well just through this cardinal event of the polymerization. And all of these are part of inflammation, sort of the hyper inflamed scenario that you’re seeing within the red cell within the circulation of a patient with sickle cell. And actually all of these contribute towards this increased sickling.

In terms of, you know, what can be done in reducing the inflammation. So traditionally Hydroxycarbamide is very well known to reduce this inflammation through reducing, for example, because it’s a cytoreductive treatment, it’ll reduce the white cells, overall the white cell count of the patient and therefore there’ll be less white cells to become activated and less white cells to cause sort of, you know, the clogging and the inflammation within the microcirculation. So that’s one way hydroxycarbamide directly can cause reduction in inflammation as such.

But there are new treatments happening, you know, there are some new treatments that directly address that, not just now, but in the past it has been used. For example, you know, people have experimented on using steroids, for example, in sickle cell patients, under scoring the fact that inflammation is such an important aspect of sickling and that maintenance of the of the sickling process. But of course, steroids come with their own sort of plethora of challenges, of side effects, etc., and was never really taken up as a potential option for patients with sickle cell. But, you know, we had an interesting discussion about a new molecule, which is a Bruton tyrosine kinase inhibitor that has been used in the context of immune thrombocytopenia as a sort of immune suppressive treatment, which does not affect T-cell function or B-cell function, it just is an anti-inflammatory molecule. Because it has it is now approved to be used in ITP, the company are very interested – this was a company that we were talking to – they were very interested in exploring whether this could be used in sickle cell. So they have currently proposed a phase three study. They’re kind of bypassing the phase one and two, because the dose and the safety aspect of the studies have already been established through the ITP experience.

So it will be interesting to see whether this sort of global reduction of inflammation through these kind of molecules, which look at suppression of immunity, you know, across all the key immune players within the sickling environment and see if that would result in reduced polymerization and all the downstream effects of polymerization that I’ve just mentioned.

So it’s exciting times ahead. We have had some recent difficulty with being able to continue to use approved drugs. So two drugs were withdrawn from the market in the last couple of years. And so it will be very helpful both to clinicians and as well as to patients if new drugs that are coming through actually are shown to be effective and can be used. But we are a few years hence for these drugs to become part of standard of care.

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