Biologics for Plaque Psoriasis: IL-12/23 and IL-17 Inhibitors

Brad Glick, DO, MPH: Neal, what about interleukin [IL]-12/23 inhibitors? Also, comment as well on the IL-23 inhibitors. What do we have in our toolbox?

Neal Bhatia, MD: I always remember when ustekinumab came to market and IL-12/23 was a subject. The funny example I heard was that these are the synchronized swimmers of the Olympics of psoriasis, IL-12 and 23, because you see them constantly swimming and playing together in the sandbox to work on the effector T cells, on CD4 cells, on other interleukins, and important cytokine balances. Also, as George brought up inflammatory bowel disease, IL-12 and 23 play a strong role in the pathogenesis of Crohn disease as well as, again, psoriatic arthritis and psoriasis in terms of the progression of damage. It is involved in tissue damage as well as the promotion of other inflammatory mediators.

We like to use the word upstream to sound important when we are talking about immunology, but in many ways, the 23 part of TH23 [T helper 23] cell division as well as interleukin-23, where it acts, is much more upstream in comparison to some of the other cytokines we know about with psoriasis. IL-12 also plays a very important role; it is almost a quarterback of the TH1 [T helper cell type 1] inflammatory cascades. Most of them, again, act not only in tandem, but they talk to each other a lot in terms of promotion of keratinocyte dysplasia and differentiation change, which cell lines are coming into the fold of tissue. Of course, there is the promotion of other cytokines and chemokines that go along with it. I mentioned the word faucet before. If there is a faucet to turn off, turning off the faucet of interleukin-23 is a very significant one.

There is the same concept of, again, shutting down the conversion of the activation of interleukin-17 where it does its primary mechanisms of action. The idea is to be thinking about pathways that are driven toward psoriasis; IL-12 and IL-23 have a very strong pathway there. One thing I remember—and Erin and George, you guys can correct me if I’m wrong—was a lot of the talk about congestive heart failure slowing down or impeding the activity of the tumor necrosis factor [TNF] and negative inotropic effects were always thought to be a function of IL-12 and 23 balancing out. I remember, in some of the early days when those cytokines were being inhibited, there was concern about that. I think that those concerns are probably behind us now. Anyway, that is just kind of a synopsis there.

Brad Glick, DO, MPH: With upstream inhibition of interleukin-23, you get downregulation of some other very important cytokines, as you mentioned, one of them being interleukin-17. Erin, talk to us about interleukin-17 blockers. What is out there and how do they work?

Erin Boh, MD, PhD, FAAD: I like to say that the IL-17 cytokine is the driver for psoriasis, but it is not the start. IL-23 is really, like Neal was saying, that really starts everything going. But the effector cytokine is IL-17. We have a number of agents in that class. There are secukinumab, ixekizumab and brodalumab on the market. All of them block IL-17A as well as a few other component IL-17s. There is IL-17A, there is C, there is E, and there is even an F. We will talk about that in a second, but the predominate one that the current IL-17 inhibitors block is IL-17A. With the blockade of that, we then see that is the effector cytokine for going in and upregulating not only TNF and other inflammatory cytokines, but that is the driver for making your psoriatic plaque. It upregulates keratinocyte proliferation, angiogenesis, and the like. They are very effective in inhibiting the psoriasis plaque, but just like all the other drugs, we do have to be concerned about certain comorbidities. As I mentioned earlier, we have this whole class of diseases—the immune-mediated inflammatory diseases—and they share cytokines. Inflammatory bowel disease is mediated in part with IL-17. If you block IL-17, you can make inflammatory bowel disease worse. We do want to watch for people who have a history of inflammatory bowel disease. We do not want to give them these IL-17 inhibitors because it can worsen their disease process. Going back to your history, find out the comorbidities. There is a theoretical concern, and actually, a practical concern. IL-17 is used for maturation in terms of handling candidiasis. 

We do see a slight uptick in candidiasis in patients who have IL-17 inhibitors on board, not enough that we necessarily have to stop the drug, but we have to be aware and cognizant of that. You can have an increased incidence of candidiasis with the IL-17 class of drugs. You may also see a little uptick in herpetic infections, so we do want to be a little bit careful about them. IL-17 is one of the pivotal cytokines, along with TNF, that are involved in psoriatic joint disease. We look at the synovium, you look at osteoclasts, osteoblast formation in psoriatic arthritis, and IL-17 is one of the big players. TNF alpha is also. We can see that that might be a useful treatment in patients who have concomitant psoriasis and psoriatic arthritis who did not improve on the TNFs. I think we need to still think about comorbidities. 

There will be a new IL-17 player on the block sometime later this summer or in the early fall. It is going to be a little bit different in that it blocks both IL-17A and F. It is going to be interesting because there are some interesting data looking at comorbid states, particularly atherosclerosis. I think that is going to be a new avenue for us to go down, and we can think about impacting other comorbidities and disease states. I am excited about that one coming out. Again they all, as a class, have certain things we need to watch for, but they are very effective. They block the IL-17 cytokine and pull them out. I think it is very exciting that we have all these different types of classes of drugs that we can choose from depending on what the patient’s baggage is.

Brad Glick, DO, MPH: If you enjoyed the content, please subscribe to our e-newsletters to receive upcoming Peer Exchanges and other great content right in your inbox. Thank you, everyone. Have a great evening.

Transcript edited for clarity.