Changing Treatment Approaches in the Management of Plaque Psoriasis - Episode 5
George Han, MD, PhD, guides a discussion on the mechanism of action of TNF-alpha inhibitors used to treat plaque psoriasis.
Brad Glick, DO, MPH: Let’s discuss some of the mechanisms of action of the available biologic therapies. I’ll start with you, George. Talk to us about the TNF [tumor necrosis factor] inhibitors. What is available, and what are their indications? Where do you use them?
George Han, MD, PhD: TNF-alpha inhibitors were the first class of biologics used for psoriasis. They are well described now as crucial pathogenic drivers of psoriasis. There are 2 cell membrane receptors, TNF receptor type 1 and 2. These induce the maturation of dendritic cells. We talked about that first point of activation. Directly, it activates dendritic cells that then go on to proceed through the rest of the inflammatory cascade. We mentioned IL-23 [interleukin-23] and Th17 [T helper 17 cells], IL-17 afterward, but there are some other effects of TNF alpha as well. You are talking about looking at increasing cell adhesion molecules—ICAM [intercellular adhesion molecules], VCAM [vascular cell adhesion molecules]. Basically, in an area of inflammation, that allows more permeability, and more inflammation to enter the tissue. This all builds upon it each other. Third of all, on the keratinocytes themselves, TNF alpha actually stimulates this forward loop of inflammation.
There are a couple of different parts that TNF-alpha inhibitors do influence in psoriasis. There are a number of TNF-alpha inhibitors that have been developed, and they are all slightly different. If look at infliximab, or you look at adalimumab, etanercept, and certolizumab pegol, there are very different medicines here, which is interesting. Infliximab is infused; adalimumab is injected, but it binds soluble membrane bound TNF alpha. Etanercept is a little different; it is a fusion protein. It binds free TNF alpha more. That is one slight differentiator between them. There are some subtle difference in effects. I think those are called out a little more when you use them off-label, but that is not the subject of this talk. Certolizumab pegol is a fragment that is pegylated to increase the time in circulation. There are a lot of interesting TNFs there. We see a long track record of these being effective for psoriasis as well as psoriatic arthritis.
There are some downsides as well. With TNF antagonists, we want to look for some comorbidities that we want to rule out—certainly demyelinating diseases, congestive heart failure. It is a little worse for tuberculosis, and a little worse in terms of general immunosuppression. Also, we are starting to see a signal in increased nonmelanoma skin cancer. Those are things to look out for with TNF-alpha inhibitors, as well as this TNF-alpha induced psoriatic formed inflammation. Usually, we will see that in patients who are on a TNF-alpha inhibitor for inflammatory bowel disease [IBD]. Interestingly, those patients had increased interferon signal driving their psoriatic formed skin inflammation. The solution is to take them off the TNF-alpha inhibitor. It is a class effect; we do not want to switch them to another one. We want to switch them to something else that may cover both the IBD and psoriasis, for example.
Brad Glick, DO, MPH: Great details.
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Transcript edited for clarity.