Psound Bytes™ Transcript: Episode 180

Release date: Nov. 15, 2022

“Welcome to this episode of Psound Bytes™, a podcast series produced by the National Psoriasis Foundation, the nation’s leading organization for individuals living with psoriasis and psoriatic arthritis. In each episode someone who lives with psoriatic disease, a loved one or an expert will share insights with you on living well. If you like what you hear today, please subscribe to our podcast and join us every month at Psound Bytes™ for more insights on understanding, managing, and thriving with psoriasis and psoriatic arthritis.”

Shiva: My name is Shiva Mozaffarian and here today for a discussion about the IL-17/IL-23 pathways and how important it is to the pathogenesis of psoriasis and psoriatic arthritis is dermatologist Dr. Jason Hawkes, Associate Professor of Dermatology at the University of California, Davis. Dr. Hawkes is very familiar with this topic since he receives numerous questions in his clinic and from providers, in addition to publishing articles about the IL-17/1L-23 pathways. Dr. Hawkes has a background in translational immunology and has served as a Principal Investigator and Co-Investigator for a number of pharmaceutical-sponsored and investigator-initiated clinical trial protocols which includes IL-17 and IL-23 treatments. Dr. Hawkes is also a member of the National Psoriasis Foundation’s Medical Board as well as the Scientific Advisory Committee.

Welcome Dr. Hawkes! It’s so great to have you back on Psound Bytes™. I’m excited to talk about the IL-17 and IL-23 axis with you today. But to help provide a basis for our discussion, we now know that psoriasis is a systemic, chronic immune-mediated disease that’s more than just a skin disease. Can you explain the inflammatory process that prompts the development of plaque psoriasis?

Dr. Hawkes: Thanks for having me. I'm excited to talk about this topic. When I talk to patients this is probably one of the most common questions that we get in the clinic, and I like to explain that it's a little easier to start with the big picture and work backwards. It seems to make a little bit more sense that way. So when we think about psoriasis and we really boil it down to some big easy buckets to understand, we know that psoriasis is caused by increased level of inflammation or inflammatory signals. Those signals work together to really sustain the inflammation which therefore makes it a chronic disease, it sort of keeps perpetuating itself. Some of the key players that we found to be involved in this process are signals that stimulate inflammation like interferon or tumor necrosis factor like TNF, IL-17 and IL-23. And these are those signals that are trying to keep that inflammation ongoing. We often call this feed forward mechanism. So once the process gets started, it really sustains itself. And one of the ways that sustains the disease process is there are permanent cells. So once this immune system gets set off, there are cells that we call resident memory T cells which stay in the skin or the joints, for example, and they're there, continually perpetuating this disease. I say it's easier from the big picture because when we get down to the very factors that start disease, why do patients get psoriasis from the very beginning? We actually don't really understand that process. We have a pretty good idea of what happens downstream and how does the process continue. We don't know exactly what triggers it and some patients have genes that are more common in multiple members of their family. Some people may have it start with an infection for example as we see in guttate psoriasis. Medications can trigger disease but either way, this process once it gets started, it creates a framework by which it can sort of sustain this process. So we're certainly seeing this link between the immune system being upregulated and then maintaining disease. And of course as our patients know, it's more than just a skin problem. We see this inflammation throughout the body happening in both the skin and the joints. And of course these other conditions that are associated with psoriasis like obesity, liver disease, chronic kidney disease and cardiovascular disease. We are seeing these diseases come as a result of the chronic inflammation. So as I explain that to patients, I want them to understand that there's a inflammatory process, the immune system running on high. And our goal is to try to bring the inflammation down. Which is a really important concept because the treatments that work for psoriasis are things that ultimately suppress the immune system. And that's a scary concept to patients to think about “my immune system being suppressed” but that's what we want to do. So I would say “your immune systems at a 10 and it should be down at a two or a three. So we need to bring it down. We don't wanna make you 0, but we wanna bring it back down to that level, which is normal because yours is running too high.” So that's really the big picture of what's happening in psoriasis as a chronic systemic inflammatory disease.

Shiva:  So given what you just explained about how psoriasis develops, what's the history behind the development of selective targeted treatments used today? And how do early disease models compare with what we know now?

Dr. Hawkes: Yeah, early on in this disease, obviously it was a visible disease. So physicians or providers could see that the patients had psoriasis, but we really didn't understand what the cause of psoriasis was. Probably some of the most fundamental observations that were made early in this disease was a link between psoriasis and the immune system and that sort of came indirectly from multiple medical observations. So for example, cancer patients who have psoriasis who went through chemotherapy treatments, their disease went away following chemotherapy. Patients who were transplant patients that were put on immunosuppressive medications, their disease went away. Bone marrow transplants and the bone marrow effectively changes the immune system. Their disease when away.  So this led to this sort of association between psoriasis and the immune system. Now there’s early thoughts that maybe suggested that could this be an autoimmune disease but trying to tease those out early on was difficult.  Another important observation was that the patients who were put on (including these transplant patients or cancer patients) these immunosuppresive medications like cyclosporine or methotrexate which are very effective at inhibiting the immune response, patient’s psoriasis went away. And that really created this link that there’s a problem with the immune system. And then actually my early clinical mentor Dr. Gerry Krueger at the University of Utah, had shown this concept in mouse models where they put psoriasis skin and transplanted them on mice who did not have an immune system and what they found is that human psoriasis kind of melted away and it wasn’t able to sustain itself.  But if you gave those mice back their immune cells or injected the immune system back into it the psoriasis would flare back up. And so we had these clinical observations, these mouse models, showing the link between the immune system and psoriasis. And later one of my other mentors at Rockville University showed that when you destroy specifically the T-cells in the immune response you can also shut down psoriasis. So this started narrowing down really the key cells driving psoriasis.  And I think the final key observation was the development of a medication, the biologic blocking TNF but they were studying it in patients with inflammatory bowel disease. There were patients that had inflammatory bowel disease and psoriasis who were treated with this medication and their psoriasis got better. And this sort of set the stage for really looking at developing targeted therapies that could block very specific signals from the immune system or very specific cells like the T cells in the immune system and shut down psoriasis. And as the research continued, we ultimately were able to really tie this down to a very specific pathway which is what we talked about the IL-23 and theIL-17 pathway as being the real central player to the development of psoriatic disease.                                                                                              

Shiva: So Dr. Hawkes you mentioned TNF earlier, where in this paradigm do the TNF alpha inhibitors, IL-17 and IL-23 inhibitors interact in the development of psoriatic disease?

Dr. Hawkes: Yeah, this is an important question because it leads to some confusion. I hear this both from patients and also dermatology residents. The question is if IL-23 and IL-17 are the central drivers of the immune response that lead to psoriatic disease then why do other drugs that don't block IL-23 and 17 work? For example, the TNF inhibitors or also ustekinumab which blocks IL-12 and 23. And the answer is that the immune system interacts with itself, right? So there are signals that even though it's not the primary IL-23 or 17 signal, there are other signals that feed into that pathway. And also there are signals that respond. So if we take TNF for example, the reason we think TNF inhibitors work is that TNF, the signal from dendritic cells are sort of upstream of the IL-23 and 17 pathway. So as you make more TNF, it starts to promote the IL-23, IL-17 pathway in the skin but TNF also works with IL-17. So IL-17, the reason it's so central is that it's really driving a lot of the phenotype of psoriasis. So it makes more inflammation. It makes our skin cells divide and then as the skin cells, the keratinocytes, start to become overactive and hyperproliferate, that sends a signal back to the T cells which start making more IL-23 and 17. So TNF, in addition to helping promote more IL-23 and 17, it also works with IL-17 so that the effects that IL-17’s having on the skin when it's with TNF, it has a greater impact. And so we talked about that being a synergistic effect. So by blocking TNF, we're doing two things. We're eliminating it’s sort of indirect effect on IL 23 and IL-17. And then we're also eliminating the synergistic effect and so we think of the TNF inhibitors as being really kind of indirect inhibitors of the IL-17 and 23 pathway.  When we talk about IL-12 and 23 or ustekinumab, which is one of our early therapies in psoriasis, it's primary impact is by the inhibition of IL-23. So we'll talk about this a little bit later where I ustekinumab blocks p40, it's a subunit of the cytokine that's shared between IL-12 and 23, so when you block p40, you block both cytokines. Now IL-23 probably its main impact on psoriasis and there's actually some evidence that IL-12 probably protects against psoriasis so by blocking it may not be helping us. And I think that's supported by the success of the newer therapies that block IL-23 by p19, which means it doesn't have an impact on IL-12. And those newer therapies are actually more effective and quite a bit more effective in psoriasis compared to ustekinumab. So there's a lot of complexity in how these different signals interact with one another.

Shiva: So I’ve heard about natural killer cells. Do these contribute to the development of psoriasis?

Dr. Hawkes: Yeah, there's been an exciting area as we've started to tease out some of the non-traditional T lymphocytes and their role in psoriasis. So when we talk about natural killer cells, we're really talking about a bigger group of immune cells called the innate lymphoid cells which includes natural killer cells. And even though they're a minority of the immune cells that contribute to psoriasis. So when you compare natural killer cells to T cells, for example, the traditional lymphocytes, the natural killer cells are very, very small percentage, but they do contribute to disease, and they can make the traditional cytokines like TNF, IL-17 or IL-22 for example. And what's interesting about these cells is while they're making these signals, they don't appear to be under the same control as the traditional T-cell. So, for example, these IL-17 producing T cells are very responsive to IL-23, which is really helping to sustain the IL-17 pathway. But these innate lymphoid cells, they appear to lack expression of the IL-23 receptor, so they're not under the same control. And that raises the question that different stimuli in the environment, infections etcetera, may also sort of stimulate them differently than the traditional T-cells. This ultimately could have an impact on how the treatments work. So for example, if we use ah traditional IL-23 or IL-17 blocker, which is commonly used in practice today, theoretically, there are some of these cells which may still be making signals that contribute to psoriasis that are not responding to the same treatments. Are these traditional treatments? So we're still trying to tease out exactly what role these non-traditional immune cells play in psoriasis and looking at ways to also inhibit or consistently block their signal as a way to achieving better disease control in psoriasis.

Shiva:  Interesting. So given all that you've said, it seems that the IL-17/ IL-23 signaling pathway is important to the development of psoriasis. Is that correct?

Dr. Hawkes: So as I mentioned, we have this chronic stage of psoriasis, we have a system which is overactive. We're making high levels of signals that are telling our immune system to stay on and active. And obviously that has collateral damage. It impacts the skin. It impacts the joint. It impacts other organs like our heart, our blood vessels, etcetera. And the IL-17 signals and the IL-23 signals are really the key players in that story. They're not the only players, but they appear to have the greatest impact, and we learned that from looking at other therapies. So, for example, TNF plays a role, but it clearly doesn't play the predominant role because the success of the TNF inhibitors wasn't nearly as effective in the skin as some of these newer therapies. And also, signals like interferon for example which we traditionally think of the Type 1 inflammation, these signals when we've tried to block them in early clinical trials as a monotherapy. So just blocking that and not blocking other signals in patients with psoriasis, it wasn't very effective clinically. So these cells and these signals that are all involved in psoriasis, you can try to tease out their impact or their contribution to psoriasis by saying what if we just block signal X versus signal Y and then see how much better we do in disease control.  When you do that, what we find is that blocking IL-17 or IL-23 is by far the most effective when we're talking about plaque psoriasis. But there's some really subtle differences that we need to be aware of. So if you take the TNF inhibitors and you block TNF and you compare that to blocking IL-17 or 23 with regards to the skin response, they're much more effective if you block IL-17 and 23. So there's no difference in these treatments when we really kind of look at the joint disease. So that's kind of an interesting and important thing to tease out that we have huge improvements from the TNF inhibitors to where we are now without 17 and 23 medications. But in the joints, we really haven't pushed the needle very much. So in skin, we're looking at PASI 100, which is 100% improvement in disease and for skin a lot of these newer medications, that's the new standard because we've made such progress in the skin. But when you're talking about the joints we're still talking about ACR 20 or ACR 50, which is a 20% or a 50% improvement in the joint. So you know we haven't even cracked into ACR 70, ACR 100 for example. So the difference is between skin and joint are still a huge gap that we have in our treatment of disease. And so the story that plays out in the skin is subtly different than what's playing out in the joints and so some of these signals, while they may not play a prominent role in the skin, may have more of a central role in the joints. But we still know that IL-17 and 23 are central because we have therapies that can block one of those two signals that appears to work pretty well for a lot of patients in both skin and joint disease. And that's what keeps them very central.                                                                                        

Shiva: So we know with the release of the newer biologics, they tend to focus on IL-17 and IL-23 for reasons you've already stated. How effective are such therapies in treating moderate to severe plaque psoriasis or psoriatic arthritis?

Dr. Hawkes: These therapies that we have now particularly for the skin have been highly effective. It's not uncommon for nine out of 10 patients to get 90% improvement. Some of these medications are getting six or seven out of 10 patients, 100% clear. So from the skin perspective, we've made enormous progress and we're seeing large percentages of patients who come in and have either minimal disease or completely clear. So we talked about them being clear or almost clear and I'd say for patients that have uncomplicated skin disease like plaque psoriasis without joint disease or other significant health problems for the most part these therapies can keep most of those patients clear. Now joint disease as I mentioned, we're not seeing those same results in success. The joint disease can be quite complicated, and the TNF inhibitors compared to that of IL-17 or 23 inhibitors there hasn't been a big change. So when I explain this to patients, I explain that if you take a TNF inhibitor and say an IL-23 inhibitor for example, we see about the same or very similar responses in the joints, but huge differences and improvements with using the IL-17 or 23 inhibitors. And so there's no advantage with these medications in the joints alone. But when you take joints and skin some of these newer therapies have tremendous advantages. Now those patients that have really bad joint disease for example that have minimal skin disease. They don't always respond to these therapies and occasionally we have to revert back to more broad acting medications like methotrexate or cyclosporine for example. Methotrexate’s sort of been a very common medication that a lot of rheumatologists use and in fact, a lot of rheumatologists will continue to use low doses of prednisone in these patients because they need that broad acting immunosuppression to keep the joint disease down. So we have a lot of progress that still needs to be made in the treatment of psoriatic arthritis, but for the most part we've really cracked into the development of highly effective treatments of the skin and whether these treatments are also going to eliminate the development of comorbidities like cardiovascular disease or diabetes, etcetera, in patients with psoriasis is an ongoing research effort which has had some mixed results. So it's still to be determined there.

Shiva:  We’ve spoken a lot about IL-17 and Il-23. Can you provide some examples of the IL-17 and IL-23 treatments?

Dr. Hawkes: Yeah, when we think about the IL-17 class, we’re really thinking about three medications. So secukinumab and ixekizumab, different medications but they block IL-17 in the same way. So they block IL-17A, which is one of the predominant signals driving psoriasis. So, two different medications that have really the same mechanism of action in terms of how they work. And then we have brodalumab, which rather than blocking out 17A, blocks the IL-17 receptor. The advantage to blocking the IL-17 receptor is that it blocks the pro-inflammatory signal for more than just IL-17A. And so this has theoretically a broader impact on the immune response in terms of blocking the signals that can drive psoriasis. The latter brodalumab is probably not as clinically used mostly because of the black box warning which came with this medication relating to suicidal ideation. And I think this scared a lot of patients and quite frankly practitioners from using this. So I think in this group of IL- 17 medications probably has the lowest utilization. But I will say that studies afterwards have shown that patients on this medication we don't see this suicidal ideation, which was noted in early trials, but what we do see is a very highly effective medication. And so brodalumab is certainly a treatment that both patients and practitioners should be aware of because of its broader action on the IL-17 pathway can have a very high efficacy in the skin. The trials didn't finish in psoriatic arthritis, but it is a treatment that we do utilize for even some of our most severe patients because of its high effectiveness. When we move to the IL-23 class we're talking about risankizumab, guselkumab and tildrakizumab. And as I mentioned earlier, the way that the IL-23 class differs from the IL-12 and 23 classes that with the IL-23 cytokine being composed of two subunits, the p40 and the p19, blocking p19 only blocks IL-23 and it doesn't have an impact on IL-12. So these newer medications all have the same mechanism of action of just blocking p19 and therefore having a selective impact on IL-23. Now tildrakizumab like brodalumab has had a lower utilization as well, and there's been two main reasons for that. One is that tildrakizumab is physician or in office administered, so that limits its use for patients who maybe don't have access or have limited access to the physician to have these medications administered. And also, it appears to have a slower onset of action. So I think for those reasons has more limited use in the community. But these are the current FDA approved treatments in the IL-17 and the IL-23 class.

Shiva: And are there any head-to-head clinical trials comparing older biologic treatments to IL-17 and IL- 23 therapies?

Dr. Hawkes: Yes, there are many clinical trials which have compared the newer therapies to the older therapies. I would say we have more than 20 head-to-head trials. The head-to-head trials with the IL-17 and 23 inhibitors most frequently use the TNF inhibitors like adalimumab, or ustekinumab, which was kind of the newer generation. And there were reasons for that. Adalimumab or the TNF inhibitors were really our first line therapy historically in psoriasis. So kind of comparing to the old guard I think makes sense. But because of the difference in the mechanism of action, there was a shift to the second generation, so ustekinumab comparing IL-17 and 23 as a head-to-head made more sense because we had advanced clinically. So as we've moved away from some of the TNF inhibitors, for example, to ustekinumab, which was very appealing to a lot of patients because it could be administered every three months once you're on maintenance therapy. So alot fewer injections with better disease control. It made sense to compare the newer IL-17 and 23 inhibitors to the older class, which had become in some ways a standard of care for many patients. Now, they're interestingly have been a lot of comparisons between the IL-17 and the 23 class, and the reason for that was these two classes have shown really I think superiority in terms of treatment especially of skin disease. So the question would come up as to which one is better, IL-23 or IL-17 and we do have several studies that have compared these different classes. Probably the most recognized was the ECLIPSE trial comparing guselkumab and secukinumab. We had the IXORA-R trial which also then showed a comparison of guselkumab to ixekizumab and I think the sort of take away from these trials that when you get right down to it they're pretty similar in terms of their efficacy. There's this subtlety that maybe the IL-17 class is a little bit faster, has a faster onset. Once you get down the road with treatment, the idea of  these therapies personally as being quite similar and there's some advantages and disadvantages to both classes. One requires more frequent injection, the other less frequent injection. But for those patients looking for that maybe that slight edge of slightly faster disease treatment response then we may kind of go one direction.  And talking about the elephant in the room is the fact that a lot of these head-to-head trials, while they're interesting, we don't always get our choice of saying, well, I want drug A versus drug B and the insurance definitely plays a role. But in concept I view the IL-17 and 23 classes being pretty similar with regards to the joint or with regard to the skin treatment and the joints gets a little bit messier as we've talked about earlier.

Shiva: Are there any cautions associated with use of the IL-17 and IL 23 therapies?

Dr. Hawkes: For the most part, these class of medications really come with very few limitations and warnings. I think the primary concern we have with IL-17 inhibitors is sort of the development of inflammatory bowel disease. This has been sort of a contentious topic and one that's really left a lot of patients confused. The background here is that the IL-17 inhibitors obviously were studied for the treatment of psoriasis, but also were being studied for the potential treatment of inflammatory bowel disease, so ulcerative colitis or Crohn's disease, for example. And what we found in those inflammatory bowel disease trials is that there were some patients who actually had worsening of their inflammatory bowel disease and those patients that were treated in the psoriasis trials, there were some patients who developed inflammatory bowel disease. So in general, we talk about trying to avoid this class in patients with inflammatory bowel disease. Now one really important distinction is that if we look at most of the research data, there's good evidence that a patient with psoriasis who does not have inflammatory bowel disease, there's really not any evidence to support that the IL-17 inhibitors will cause them to develop inflammatory bowel disease. The reason for that is that patients with psoriasis on no treatments already have an increased risk of inflammatory bowel disease. So patients at any time during their natural course of the disease might go on to develop other conditions. We talked about these as being the comorbidities. So a patient may go on to develop inflammatory bowel disease and that happens even when they're not on a biologic. So what we want to distinguish from the main caution with IL-17 inhibitors is that these are not an ideal choice for patients who have a pre-existing history of inflammatory biology. So I tend to avoid these medications in somebody that already has inflammatory bowel disease. But I don't worry about the new development of inflammatory bowel disease as a result of this medication in our psoriasis patients. But if they do develop inflammatory bowel disease, at some point on therapy, then we usually switch them. We don't have that same concern with the IL-23 inhibitors. They don't appear to  impact or worsen inflammatory bowel disease and indeed they're being studied for the potential treatment of inflammatory bowel disease. So that's a very common one that comes up. There are a lot of other situations where we may prefer these two classes of medications over the TNF inhibitors. So we think about situations where we wanna be less immunosuppressive. So immune patients with malignancy, we wanna have less of an impact on their immune system and there's good evidence that the IL-17 and 23 class are can be safe in patients who have psoriasis and also malignancy. We don't have a lot of data in pregnancy but sort of the same thing that we think because of their narrow effects that these therapies will likely be safe in patients with pregnancy although we don't have that data. There's a clear first line choice with the TNF inhibitor, certolizumab, for pregnancy because it isn't transferred across the placenta to impact the fetus for example. And so, that's a clear first line choice. But we start to think about the IL-17 to 23 inhibitors as being safe options for a lot of these situations where we want to minimize the impact on the immune system. So for the most part these are highly effective and very safe medications where we have a lot fewer contraindications than we do with some of the first generation treatments.

Shiva:  So we’ve heard a lot about an upcoming treatment—bimekizumab which differs from current IL-17 inhibitors. Can you please talk about the differences, and do you have any updates on its release?

Dr. Hawkes: Yeah, bimekizumab’s a very interesting medication. And this gets into some of the specifics as to how IL-17 contributes to disease. One of the aspects that you've already heard about is that IL-17 is really central to driving inflammation in the skin and making the skin cells hyperproliferate and make their own signals, which contribute to chronic psoriasis. The main signal that is blocked by the traditional IL-17 inhibitors by secukinumab and ixekizumab, is blocking IL-17A. But as I mentioned with Brodalumab, which blocks the IL- 17 receptor, it's advantages that it blocks multiple IL-17 signals. So not just IL-17A for example. So we have this family of IL-17 signals A through F which can really promote inflammation. So instead of blocking just IL-17A, bimekizumab acts differently in that it blocks both IL-17A and IL-17F. So again, I sort of think of this medication as being a little bit in between the IL-17A selective blockers like secukinumab, ixekizumab and in between brodalumab, which is blocking the receptor which is going to block even more than just A and F. And so when we think about bimekizumab, we're talking about a medication that blocks both IL-17A and IL-17F. The concept behind the development of this medication is that IL-17A clearly contributes to psoriatic disease. But IL-17F  which can be at higher levels and really drive disease in psoriasis may also be contributing. So by blocking both A and F, the thought is that we can get a better disease control by shutting down that feed forward inflammation pathway. And so, it acts differently in this way, but would still fall within this IL-17 class. Now we had hoped to have this medication approved this year, but from my understanding, the approval of this medication was delayed, and it was delayed not because of clinical concerns, but from my understanding due to some sort of inspection in the facilities producing this medication. So there was some additional information that was required. So unfortunately, we had a delay on this medication, but from the results from the trial, looks like this is going to be a highly effective therapy in psoriasis. Now one of the unique aspects that will be talked about I think among patients and clinicians with this medication is that it does tend to have a higher rate of candidiasis. Candidiasis or if you’ll think about oral thrush, for example, is definitely a side effect or an impact of blocking IL-17 because IL-17 in our body naturally helps protect us against these candida infections. So when you block it, you take away that protection and you can develop candida and because bimekizumab blocks we think this more effectively in the body by blocking IL-17A and F it does appear that there are even higher levels of this oral candidiasis that we see with this new therapy. So it'll be something that we'll need to have discussions with patients about and see if this increased rate of candidiasis is going to impact its clinical use compared to the traditional IL-17A inhibitors like secukinumab and ixekizumab.

Shiva: Thank you, Doctor Hawkes for being here with us today and for such an interesting discussion about the IL-17/IL-23 pathways. Do you have any final thoughts about recent research developments and innovations for the treatment of psoriatic disease?

Dr. Hawkes: Yeah, it's always fun to see some of the new developments that are coming out in psoriasis. Particularly because not every patient responds to the current existing biologic therapies. If we had a treatment that worked for 100% of patients then we wouldn't need new therapies. And the fact is we don't, and we need options for these patients. The biologics have proven to be very safe, very effective, well tolerated. A lot of advantages over the traditional systemic immunosuppressants like methotrexate for example, because they don't have lab monitoring for the most part, we really don't see major side effects. Most people tolerate biologics very, very well. But there are those aspects of how they work that make them very, very targeted. And sometimes people's disease isn't really targeted. They have multiple pathways feeding into their disease development or for example, they're just unwilling or unable to do the injections that come with biologics. So there's been a lot of interest in the development of small molecules or oral pills that are not injections. Which rather than do injections, you know every couple of weeks or once a month or every three months or two months, then these pills would be sort of daily treatments that would be like methotrexate, but without some of the drawbacks. So apremilast, for example, was the first small molecule that we saw that was not really a broad acting immunosuppressant that had some benefit for psoriasis. But there's been developments in other areas and one of the class of medications that are very interesting are the JAK inhibitors and as a lot of our patients have seen these JAK inhibitors are being approved for the treatment of multiple conditions. So eczema, for atopic dermatitis, alopecia areata, psoriatic arthritis, so inflammatory bowel disease, we're starting to see treatments here. And so, we're looking at this class as having an impact and again calming down or suppressing the immune system. But they work very, very differently. So the biologics work by binding to the outside of the cell and then getting a signal down to the inside of the cell to change how the immune systems activated. And that passage from the outside of the cell where the big proteins bind like the cytokines and the antibodies, the signal to the inside of the cell is really the JAK stat pathways. So we're really talking about breaking this link from the outside of cells to the inside of cells where the immune system is turned on. And so they're developing these medications that can go inside cells and block that pathway, which is shutting off the immune system response. And when we talk about JAK inhibitors, as these treatments of these other conditions, there has been concern in this class because there are these black box warnings of things like serious infection, potential malignancies that have scared patients away from these medications. One of the really exciting developments in the psoriasis world is that we have a medication called deucravacitinib which blocks TYK2 which is one of the four enzymes in the JAK family. But what's very interesting about this medication is that by blocking it, you can have a very specific effect on TYK2 which is this isoform that it blocks, and it really doesn't impact the other members of the JAK family. So we have JAK1, JAK2, JAK3 and TYK2. And by blocking JAK1 for example, you can have an impact on multiple of these other members of the family. But the medication deucravacitinib, which has been developed, just blocks TYK2, and what we know with TYK2 is that it's a very important signaling pathway for IL-12 and 23. So this will be reminiscent to ustekinumab. So we know that blocking of IL-12 and 23 can be very effective in psoriasis. But now we have a pill that can also by blocking this intermediary, intracellular signaling pathway can also disrupt the IL-12 and 23 signaling. And it really doesn't have the drawbacks from some of the traditional JAK inhibitors that we're hearing about on the market. So this is going to be a very interesting medication for the treatment of psoriasis potentially for both skin and joints as being a very effective inhibitor of the IL-23 and IL-12 signaling pathways. So this is a new development that gives potentially another small molecule oral medication with a relatively safe treatment profile and it'll be very exciting to see how this fares compared to some of the biologics. And so I think this will be an interesting area as we've now just seen this approved and start to get some comparison from some of these patients that have maybe been on biologics that haven't fully worked, or they wanted to kind of move away from injections and to see how this oral medication works. So as we see more of these small molecules and these oral medications approved in psoriasis, it gives patients even more control as to how they want to treat their disease. So this is an exciting development that's come out this year.

Shiva: Definitely sounds exciting! Lots of hope for the future! Thank you, Dr. Hawkes, for taking time to address this important pathway that really drives treatment development. It’ll be so interesting to see what the future holds for this target area. For more information about the “ins and outs” of treatment options contact our Patient Navigation Center by email at education@psoriasis.org or call (800) 723-9166, option 1 today. Thank you to our sponsors who provided support on behalf of this Psound Bytes™ episode through unrestricted educational grants from AbbVie, Amgen, Bristol Myers Squibb and Janssen. 

We hope you enjoyed this episode of Psound Bytes™ for people with psoriasis and psoriatic arthritis. If you or someone you love has ever struggled with psoriatic disease, our hope is that through this series you’ll gain information to help you lead a healthier life and inspire you to look to the future. Please join us for another inspiring podcast. You can find this or all future episodes of Psound Bytes™ on Apple Podcasts, Spotify, iHeart Radio, Google Play, Gaana, and the National Psoriasis Foundation web page. To learn more about this topic or others please visit psoriasis.org or contact us with your questions or comments by email at podcast@psoriasis.org.  

This transcript has been created by a computer and edited by an NPF Volunteer.