Psound Bytes™ Transcript: Episode 182

Release date: Dec. 6, 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 I’m here today with renowned rheumatologist Dr. Sergio Schwartzman for a discussion about the JAK STAT pathway and treatments associated with this pathway for psoriatic disease. In addition to a practice in the Upper East Side of Manhattan in New York, Dr. Schwartzman is a Clinical Associate Professor of Medicine at Weill Cornell Medical Center, an Associate Attending Physician at New York Presbyterian Hospital and an Associate Attending Physician at the Hospital for Special Surgery where he is also the Franchellie M. Cadwell Chair Emeritus. Dr. Schwartzman’s clinical and research interests include psoriatic disease, the spondyloarthritis group of diseases such as ankylosing spondylitis, rheumatoid arthritis, inflammatory bowel disease associated arthritis, and autoimmune diseases of the eye. He has been a member of  the American College of Rheumatology, the Spondyloarthritis Research and Treatment Network (SPARTAN), the American Uveitis Society, and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA). He is also on the medical board of the National Psoriasis Foundation.                                                               

Welcome Dr. Schwartzman! Thank you for joining us on Psound Bytes™. To help provide a framework for our discussion, can you please describe what is the role of a Janus tyrosine kinase or the JAK family of enzymes in the development of inflammatory diseases such as psoriasis and psoriatic arthritis?           

Dr. Schwartzman: Janus is the Greek God of doorways looking both outside and inside of the room. The Janus kinase family signal from the cell surface or outside of the cell into the cell and ultimately into the nucleus, activating a cell which then causes psoriasis and inflammatory arthritis. The JAK inhibitors are not new therapies. The FDA first approved JAK inhibitors in 2012. A medication called ruxolitinib was the first JAK inhibitor to be approved then and is currently used to treat graft-versus-host disease, myelofibrosis and polycythemia vera. These are all hematological illnesses. Interestingly though, it was also recently approved for vitiligo as a cream. So these are not new medications. Now the way that they work has been known for about 2 to 3 decades. They inhibit a group of enzymes that are important in immune regulation. So the JAK inhibitors inhibit four different enzymes and these are JAK 1, JAK 2, JAK 3 and TYK2. It is important to understand that diseases such as psoriatic disease are the consequence of overproduction of cytokines like TNF, interleukin-17 (IL-17) and interleukin-23 (IL-23) which then bind to the outside of the cell and then through the JAK pathway result in the production of phosphate groups that bind another molecule, called the signal transducer and activator of transcription, or STAT, which then enters the nucleus of the cell and causes over production and stimulation of that cell, which then causes the disease in question. So in summary, the JAK STAT pathway translates the signal from outside of the cell through four different enzyme systems, the JAK’s that then activates a cell and causes a disease.                                                                                                                                                                        

Shiva: So given what you just said, it sounds like the JAK STAT signaling axis plays an important role in the intracellular cross talks that signal the cascade of psoriatic disease and inflammation. So how does this axis impact development of therapies for psoriatic disease?                                                          

Dr. Schwartzman: Interesting question. Strategically, one can either create a medication such as a biologic agent that targets the actual cytokine outside of the cell and be very specific or block Janus kinase pathways and depending upon the Janus Kinase inhibitor, a number of different signaling molecules that are outside of the cells that can no longer signal into the cell nucleus. So technically JAK inhibitors may be less specific than biologics such as anti-TNF agents, anti-interleukin-17 agents and anti-interleukin-23 agents.                                                                                                                                                  

Shiva: And can you provide examples of JAK inhibitors for psoriatic disease and how they act within the framework that you've described?

Dr. Schwartzman: So for example, Tofacitinib is a pan JAK inhibitor, meaning that it inhibits JAK 1, JAK 2 and JAK 3. Upadacitinib is a very selective JAK inhibitor and it predominantly inhibits JAK 1. Deucravacitinib is brand new and this is a TYK inhibitor but is only approved for psoriasis (that one’s not approved for psoriatic arthritis). So as we look then at three of the JAK inhibitors that are used in psoriatic disease, they all have different selectivity of the different four JAK’s that we described in the first question.                                                                                                                                            

Shiva: So you mentioned some other diseases already,  but are JAK inhibitors used to treat diseases beyond what you've mentioned already?                                                                                                               

Dr. Schwartzman: Absolutely. In fact, JAK inhibitors were first approved for other diseases. Tofacitinib was the first JAK inhibitor for autoimmune diseases and that was approved initially for rheumatoid arthritis. It's also approved for psoriatic arthritis, ankylosing spondylitis, ulcerative colitis and polyarticular juvenile arthritis. So tofacitinib is not approved for psoriasis alone.  Upadacitinib is also approved for rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and ulcerative colitis like tofacitinib, but in addition is approved for atopic dermatitis and non-radiographic axial spondyloarthritis.  It is not approved in psoriasis.  A third JAK inhibitor called baricitinib is approved for rheumatoid arthritis, alopecia areata, and interestingly for people who are very sick with COVID-19 and are hospitalized. So the diseases or the indications for the different JAK inhibitors, vary significantly and interestingly are quite broad.                                                                                                                                       

Shiva: That’s so interesting. So how do JAK inhibitors compare to other treatments for psoriatic disease such as biologics? And are they as effective in controlling the disease?                                                                    

Dr. Schwartzman: So if you look at the diseases that I've just mentioned, the JAK inhibitors in some of these diseases, particularly rheumatoid arthritis, have been studied in head-to-head studies and that is the only way to tell whether a therapy is as effective or more effective. In psoriatic arthritis, for example, tofacitinib did a head-to-head study against adalimumab and it was noninferior to adalimumab. Upadacitinib, on the other hand, has also done a head-to-head study, again in rheumatoid arthritis, only neither of these were in psoriatic arthritis. Upadacitinib against adalimumab was superior and against another drug that's actually a biologic that's approved for psoriatic arthritis called abatacept, upadacitinib was also superior.                                                                                                                                  

Shiva: And Dr. Schwartzman, just how safe are JAK inhibitors? We've heard there are side effects associated with use of JAK inhibitors, which includes placement of a box warning by the FDA on use of tofacitinib.                                                                                                                                                                     

Dr. Schwartzman: So, all medications have potential risks and potential benefits. So the keyword there is potential. So obviously everything that's written as a risk does not happen in every patient who has the disease. But these are some adverse events that are seen in some of the patients in clinical trials and in the real world. The box warning includes the entire JAK class, except for deucravacitinib. However, it is not known as to whether they all behave in a similar way. The reason for that is that the box warning, for example, came out due to a study called the Oral Surveillance Study in which tofacitinib was studied head-to-head in patients over the age of 50, with at least one cardiovascular risk factor, and were treated over a four-year period of time. So this was an FDA mandated study to look at whether or not these two drugs without a placebo were equally safe or different. And what was found was that tofacitinib had major adverse cardiovascular events and cancers that were higher than in the patients with tofacitinib, then in the patients treated with adalimumab. Once this happened, the FDA decided to apply the box warning to all of the JAK inhibitors except for the TYK2 inhibitor. Now the list of adverse events is long, and it does include if you read it critically, infections and this includes serious infections and opportunistic infections, things like fungus, TB is in there as well, although it's not very high. It does include malignancies and depending on which group you're looking at the type of malignancy could be very different. It includes abnormal laboratory tests including blood counts, including liver function tests, including lipids. These drugs have not been studied in pregnancy or in women who are lactating, so they shouldn't be used there. No live vaccines should be given to patients who are on these drugs because the effects of that are unknown and clearly combinations of therapies should not be utilized, meaning that these drugs should not be combined with either other biologics or two different JAK inhibitors, for example, what are called too targeted synthetics. So allergic reactions can happen with any medication, so those are included as well.                                                                                                                                    

Shiva: So, given what you just said, should the safety concerns apply to all JAK inhibitors you mentioned?                                                                                                                                                                   

Dr. Schwartzman: If you’re the FDA, the answer from their perspective is yes because they're major role is to protect the population. I think for us, and I probably should have mentioned this in terms of adverse events, I think that for tofacitinib, the adverse events that I mentioned including cardiovascular events should be considered as well as malignancies to be greater than they are in the anti-TNF groups. But I think applying what we learned in that study to every single one of the JAK inhibitors is probably unfair. Those head-to-head studies were not performed with the other JAK inhibitors. But nonetheless I think that we should be cognizant that these adverse events can occur and probably the ones that have gained the most notoriety has been the issue of serious infections, malignancies, death, cardiovascular events and also clotting events. So those have been seen across the JAK class. We just don't know whether it's equally applicable to every single one of the JAKS that are currently in the marketplace or being studied.                                                                                                                                                                   

Shiva: That brings me to my next question. You mentioned deucravacitinib earlier which was recently approved to treat psoriasis and doesn’t have a lot of adverse effects. So how does it work compared to other JAK inhibitors and do you anticipate that this treatment will be approved for psoriatic arthritis?  

Dr. Schwartzman: Well, the data’s still being gathered, and we know the phase two data that was recently presented. If we look at that and we look at the traditional outcome measures for psoriatic arthritis, like the ACR 20 and the MDA, all of those do seem to indicate that deucravacitinib statistically will be superior to placebo from the phase two data, but we gotta see the phase three data. So if you asked me the question, is it likely to get approved for psoriatic arthritis, I would say yes, but likely doesn't mean definite.                                                                                                                                                  

Shiva: So Dr. Schwartzman, are there other JAK inhibitors that you think will be approved in the future for the treatment of psoriatic disease?                                                                                                                         

Dr. Schwartzman: It's a great question. So what's happening now in the field and in psoriatic arthritis -  as well as in straight psoriasis, is that we have so many therapies available to treat patients with psoriatic arthritis. Our major challenge now is not so much that we don't have drugs, but that we have to decide which drug to use in a specific patient. And sometimes the individual patient’s characteristics will dictate which drug you use. So as we look at some of the therapies that have been studied in psoriatic disease, there's a drug, for example, that Lilly has that's an interleukin-23 inhibitor that looked very good in psoriatic disease, but the company decided not to market it in psoriatic disease because the marketplace was too crowded, and they moved it to inflammatory bowel disease. So it's being studied in inflammatory bowel disease. So I think if you ask the question will there be new JAK inhibitors? The answer is that it's easy to make JAK inhibitors. I mean, they're chemicals. So it's basically done in the lab. It's not as intensive a process as it is to create biologics. The cost and the time is really in the clinical trials. So I do think that there's an unmet need and if there's something that is unusual and has better outcomes than what we see with the current class of drugs there's a need for that. But right now the effort for JAK inhibitors I think continues and you know as you look at what we have available some drugs for example are not approved in autoimmune diseases but are being used in other diseases. We mentioned ruxolitinib when we started that's used for myeloproliferative diseases and is now being, just approved as a cream. But the current panel of JAK inhibitors um could be used for other indications and some that are used for other diseases. There's for example one called abrocitinib that's approved for atopic dermatitis. Potentially that could be studied in psoriatic disease as well. So it's a completely open question.                                                                                                                                                                  

Shiva: And with any new treatment development, we really want to raise that bar from ACR 20 to ACR 50. Isn’t that correct?                                       

Dr. Schwartzman: I think that's a great question and that's exactly what's happening. So, for example, you now look at the current clinical trials, there's IL-17 inhibitor that was just presented at the ACR and in terms of the primary outcome measure for bimekizumab, it's an interleukin 17A and F inhibitor. So it's not a JAK inhibitor, but it is a drug that will be approved for psoriatic disease and other diseases as well. Their primary outcome was an ACR 50 which was gutsy.                                                                                     

Shiva: I’ll say.                                                                                                                                                                           

Dr. Schwartzman: They reached it.                                                                                                                                     

Shiva:  That's amazing. That really is the new goal.                                                                                                         

Dr. Schwartzman: Yep, it's raising the bar as you put it.                                                                                         

Shiva: Well thank you Dr. Schwartzman for such an interesting discussion about JAK inhibitors. Do you have any final comments about the use of JAK inhibitors that you'd like to share with our audience?          

Dr. Schwartzman: I do. I think this is a class that has one huge advantage that we kind of lose track of when we start looking at efficacy and safety, which is appropriate. We have to look at efficacy and safety.  But I think number one, this is a class that's easy to administer. This is a pill. All of our biologics are injections or infusions. And I think number two this is a class of drugs that is easy to make. Again, it's a chemical formula that is required. So if I look at the class as a whole and we now look critically at the efficacy data, you can't argue with the efficacy data. They are very effective therapies. And if we look at the safety data, even though there have been new identified adverse events, if we look at the individual JAK inhibitors, they don't all have comparator trials with other therapies that we have.  And if we look at their data retrospectively, they don't seem to have, at least some of them don't seem to have, the same potential risk. Although again, you still have to keep risk in mind. So I think as we move forward with this class the efficacy is unquestioned. I think the safety is now well defined and as we continue to move forward, more data will be accumulated to further define that risk.                                 

Shiva:  Such great comments for the future. Thank you Dr. Schwartzman for taking time to address JAK inhibitors and their effectiveness in the treatment of psoriatic disease. For more information about the “ins and outs” of treatment options contact our Patient Navigation Center by emailing  education@psoriasis.org or by calling (800) 723-9166, option 1 today. Finally 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.