Managing the Side Effects and Adherence of JAK Inhibitors for Patients With Severe Alopecia Areata

In this podcast, Brett King, MD, PhD, discusses the use of JAK inhibitors for patients with severe alopecia areata and dives into how JAK inhibitors were discovered for the treatment of severe alopecia areata. He provides recommendations on diagnosing severity and highlights the differences between the available JAK inhibitors, side effects to consider when prescribing JAK inhibitors for severe alopecia areata, and managing patient adherence and expectations for hair regrowth.

Dr Brett King: Hello everyone. My name is Brett King, and up until recently I was associate professor of Dermatology at the Yale School of Medicine. And I recently left there to join my wife in private practice in Fairfield, Connecticut. 

I've spent a lot of time in the last decade taking care of patients with alopecia areata and have really, I think, helped to develop the space of treatment in this disease that, prior to two-and-a-half years ago, did not have an FDA-approved therapy. And now that has rapidly evolved so that now, two-and-a-half years after the approval of baricitinib in June 2022, we now have 3 approved JAK inhibitors for the treatment of severe alopecia areata, making this an incredibly exciting time, which brings us to the topic of the conversation today. I will be talking about alopecia areata and its treatment with JAK inhibitors. And I really hope in the next bit of time to really highlight how we got here and where we are today in the context of where we hope to be in the future and to really highlight all of the data, the most important data that we have for treatment of this disease with JAK inhibitors. 

So, diving in, let's talk about how we got here. Without a doubt, JAK inhibitors for the treatment of alopecia areata have forever changed the disease. And it really started with a 2014 publication of a single patient with severe alopecia areata who I treated with tofacitinib. He re-grew his hair—scalp, eyebrows, and eyelashes. In an instant, truly over the course of hours after release of this publication, this single case report made its way into news outlets all around the globe. 

Realizing there was an opportunity, because truly, the amount of interest from, again, news outlets but more importantly from patients around the world in this report led me and my wife, Britt Craiglow, now a pediatric dermatologist, to start an open-label clinical trial of tofacitinib in alopecia areata. 

That clinical trial showed positive results. And in a short time, the pharmaceutical industry became interested in alopecia areata. And 8 years—only 8 years—after the publication of that case report, we had approval of baricitinib, the first medicine approved for alopecia areata, and a year later, approval of ritlecitinib, approved down to age 12, for treatment of alopecia areata. And then just a few months ago, in July 2024, we had approval of deuruxolitinib, the third medicine for alopecia areata. It's really quite a story that in such a short time, a disease is transformed forever. 

So, thinking about this, 3 FDA-approved medicines for alopecia areata—again, baricitinib, ritlecitinib, and deuruxolitinib. In particular, they are approved for severe alopecia areata. And so the question arises, what does severe alopecia areata mean? We are fortunate that in the labels, in the package inserts for these 3 medicines, that severe is not defined. Right? There's not a SALT score. There's not an amount of scalp hair loss that is said to be severe. 

However, it's also true that, at least in my experience and the experience of most people I've spoken with, that very often when we write a prescription for these medicines that payers ask us for a SALT score, which we'll get to in a second, and that they typically want a SALT score of 50 or more in order to approve these medicines for our patients. 

Now, SALT score stands for Severity of Alopecia Tool score. It is a tool that is used in clinical trials in particular, but very clearly, we need to be using this now in clinical practice. Again, it's a tool to assess the amount of scalp hair loss. And in clinical trials to date, patients have had 50% to 100% scalp hair loss or SALT scores of 50 to 100. And so, necessarily or typically, payers are asking us for those SALT scores in the patients for whom we are writing and trying to get approval of these drugs. 

So, because this is new to us, right—the care of these patients is really new to us, right? Before two-and-a-half years ago, we didn't have an approved therapy. So, an important question arises in clinical practice, and that is: How do we take account of all of the aspects of alopecia areata to assess disease severity? I just mentioned the SALT score, which we can certainly adapt to clinical practice and use every day, but for a disease with myriad presentations—because eyebrows can be involved, eyelashes can be involved, the beard can be involved, nails can be involved—because of these different aspects of presentation, we would like a more holistic assessment of disease severity. 

And for that, I would advise people to turn to the Alopecia Areata Scale or AASc. And this was a scale developed together with a large group of alopecia areata experts in the US, and it was really intended to be a simple tool to use in clinical practice. And what the scale gives us is that first we're going to think about scalp hair loss in our severity assessment, where mild alopecia areata is 20% or less scalp hair loss, moderate alopecia areata is 21% to 49% scalp hair loss, and severe alopecia areata is 50% to 100% scalp hair loss. Now, many might argue that you don't need 25% scalp hair loss to have moderate alopecia areata. I think arguably that could be severe alopecia areata. But again, these were the initial scorings, if you will, for mild, moderate, and severe. 

And then the idea is that there are 4 additional items that we can use to change somebody's initial severity rating based on amount of scalp hair loss. So, the first is a negative impact on psychosocial functioning resulting from alopecia areata. The second is noticeable involvement of eyebrows or eyelashes. The third item is an inadequate response after at least 6 months of treatment. And the fourth item is diffuse or multifocal positive hair pull test consistent with rapidly progressive alopecia areata. And the idea is that if any of those 4 items is present in a patient with mild alopecia areata determined by the extent of scalp hair loss, then that patient can be upgraded to moderate alopecia areata, and similarly, if any of those 4 items are present in a patient with moderate alopecia areata as determined by the extent of scalp hair loss, then that patient's disease severity can be changed to severe. And so again, just a very useful tool, very easy to use in a moment in clinical practice, and really where I hope our field is going because, again, this is new to us. And so we need to all speak a common language when we're speaking amongst ourselves. And again, I hope that the alopecia areata scale begins to give us sort of a common language about disease severity. But also, it gives us a tool with which I think we can communicate with payers to say, “No, no, no—this patient may not have a SALT score of 50, but they still have severe disease.”
 
Okay, so now let's move on. So, there are 3 approved medicines for alopecia areata: baricitinib, ritlecitinib, and deuruxolitinib. The question naturally arises: What are the similarities and differences among them? Well, there are several similarities and differences. To begin, baricitinib and deuruxolitinib achieve scalp hair regrowth somewhat faster than ritlecitinib. But this is really important to understand: Approximately 45% to 50% of patients achieve a SALT score less than or equal to 20 or 20% or less scalp hair loss between 1 and 1.5 years of treatment for all 3 medicines. So again, the speed or the rapidity of regrowth is a little bit different, but they all get to the same place in time. And we're going to come back to that later in our discussion when we think about how long patients need to be counseled on the time it takes to get to goal, which is really important for us as providers and really important for patients and their compliance. 

Now, another difference among the 3 medicines. There are 2 doses of baricitinib, 2 milligrams and 4 milligrams, taken once daily. And there is a single dose of ritlecitinib, 50 milligrams once daily, and a single dose of deuruxolitinib, which is 8 milligrams taken twice daily. Again, important to know because as we think about a patient achieving treatment goal—hair regrowth—if we have a thought about changing their dose or tapering, we have to be aware of the doses available in order to construct a tapering algorithm. 

So, another difference: Baricitinib is approved not only for alopecia areata but also for rheumatoid arthritis, for atopic dermatitis in patients ages 2 and older outside the US, and also for treatment of juvenile idiopathic arthritis in patients ages 2 years and older outside the US. Ritlecitinib is approved only in alopecia areata, again down to age 12, but it is in phase 3 clinical trials for vitiligo. 

Now, the last difference: laboratory monitoring. It is similar for all 3 medicines except for the following: Ritlecitinib does not require lipid monitoring. And another difference is that prior to treatment with deuruxolitinib, C-Y-P-2-C-9 or CYP2C9 genotyping is recommended. 

So, now that we know about the similarities and the differences in these medicines, we know about their efficacy, let's talk for a moment about the safety profile of JAK Inhibitors, right? It is impossible to talk about these medicines without having a conversation about their safety, in particular the boxed warning for JAK inhibitors.
 
To begin, JAK inhibitors are well-tolerated overall. The most common adverse events are upper respiratory tract infection, headache, nasopharyngitis, and acne. Acne is an interesting side effect of JAK inhibitors. Typically happens in less than 10% of people with some JAK inhibitors, not the ones approved in alopecia areata, it can occur in up to 20% of patients. But again, acne is in our wheelhouse. We know how to treat it when we see it. 

Now the warnings that give us a bit of anxiety are those in the boxed warning. And these include warnings about serious infection, malignancy, major adverse cardiovascular events—so think myocardial infarction or stroke—and thrombosis. And without going into great detail, and again, we could have a whole conversation about where these warnings emerge from, I just want to say we're going to screen patients appropriately. We're going to discuss potential risks prior to initiating treatment. But I just want to point out that these warnings emerge from JAK inhibitors for treatment of rheumatoid arthritis of very different population than the patients we treat in dermatology and that in that clinical trial that gave us the boxed warnings in rheumatology, the patient profile was very different. And not just that, but patients were also under treatment with methotrexate and, most of the time, prednisone. And so I'm just not sure that it's fair to borrow those risks in that population and overlay them on everybody that we see in dermatology. And lastly, I just want to note that the rates of these events in clinical trials of JAK inhibitors and alopecia areata are low and absolutely consistent with reported background rates in the general alopecia areata population. 

Okay, so now let's move on to the highlights and lessons learned from clinical trials in alopecia areata. Probably the most important lesson we have learned from clinical trials is that patients must be treated for a minimum of 6 months, 9 months even better, before a decision is made regarding switching treatment. This is a really important lesson because, again, this is new to us. The care of patients with severe alopecia areata is new to us in dermatology. Again, baricitinib was only approved less than two-and-a-half years ago. And so we're all getting familiar and comfortable with the care of these patients in a way that we never had an opportunity previously. 

And one thing for sure, right—if you have severe alopecia areata, you wanted your hair yesterday. And so when you show up in a doctor's office and they give you a medicine, baricitinib or ritlecitinib or deuruxolitinib. You go home, start taking the medicine, and in a week, you're looking in the mirror, saying to yourself, "Where's the hair?” Right? “The doctor said I was going to grow hair." And in a month, you're looking in the mirror, "Where's the hair?” But we have to understand, circling back to an earlier point I made, this takes time, right? We don't reach 40% to 50% of patients successfully treated across all 3 of these medicines before a year to a year-and-a-half of treatment. And so, we have to counsel patients out of the gate. Patience is important. We're not going to make a decision about treatment for 6 months or maybe longer. 

And so, let's dive into the data that tells us this, right? This is not just me looking at plots of SALT score less than or equal to 20 responses over time. But there have been analyses, one with baricitinib and the other with ritlecitinib, that really teach us how to think about evaluating patients over the course of treatment. 

In the baricitinib analysis, a 30% improvement from baseline, or 30% scalp hair regrowth, over different time periods was used to predict ultimate scalp hair regrowth. And I like this because 30% regrowth is something that we can evaluate. We can evaluate the patient at month 3, at month 6, looking for that, right? We want complete regrowth, but again, it's nice to have that 30% regrowth predicts, right? To know that that often predicts ultimate complete scalp hair regrowth or near complete scalp hair regrowth. And again, using this 30% improvement from baseline, most responders were identified in the first 12 weeks, but many were identified between weeks 16 and 36. And though a small number, some patients didn't achieve that 30% improvement from baseline until after 36 weeks. And so we have that we can't make a treatment decision in 3 or 4 months. Right? We need, again, a minimum, an absolute minimum of 6 months on a single therapy, probably optimally 9 months, before we would make a decision about doing something different or switching therapies. 

Now, in the ritlecitinib analysis, only about half of patients who ultimately achieved a SALT score less than or equal to 20 over 52 weeks, did so in the first 6 months of treatment, and the other half did so between month 7 and 12. And so again, we can't make a decision about treatment at month 3 or 4. When the patient comes in or calls the office at one of those early times and says, “I'm not doing well, I'm going to stop,” or “I want to change,” the answer is “No, we’ve got to keep going.” And even better, right, to prevent that phone call, when we're sitting with them at the first visit, let's make them aware of this data and say this is a marathon, right? We are in this for 6 to 9 months before we're going to make big decisions about treatment or about changing treatment.
 
So, in the case of baricitinib, right, we want to optimize the dose, preferably out of the gate, right? If we can use 4 milligrams, let's use 4 milligrams. If anything with baricitinib, right, at month 2 or 3, if you started with the 2 milligram dose, you're going to, if anything with baricitinib, just make a decision to increase the dose at that early time point. 

And with ritlecitinib or deuruxolitinib, we're just staying the course with those single doses for 6 to 9 months. And again, really important for patient compliance but ultimately for everybody's satisfaction with this, right? We want to do what's best for the patient. We want the patient to do what's best for them, and ultimately that means we have to have a conversation about this data with our patients. 

Now another lesson learned from clinical trials is that alopecia areata is not necessarily a reversible form of hair loss. Our very early data in patients treated with tofacitinib off-label showed that patients who had no hair for more than 10 years were much less likely to grow hair than patients who had had no hair for 1 or 2 or 5 or 6 or 7 years. Since then, these results have been confirmed in clinical trials, which have informed us that efficacy of treatment is much greater in the first 3 to 4 years of an episode of severe loss than in, say, the second 4 years in an episode of severe loss. And notice I'm being very careful with my language here. It's episode of severe loss and the duration of episode of severe loss that matters, not how long somebody has had disease, right? If I had a spot 30 years ago that regrew, and 4 years ago I lost all my hair, what matters to prognosis of treatment with a JAK inhibitor is that I've had no hair for 4 years, not that I've had disease for 30 years. Really important. 

Now another important lesson from clinical trials is that the efficacy of treating patients with no hair is not the same as efficacy when patients have hair. So again, in clinical trials when we take patients who have a SALT score of 50 to 94– So, right, we open the door to the room, we look at the exam table, the patient sitting there, and there is hair, right? There might be 50% loss, there might be 90% loss. But again, we see some hair on the head, on the scalp. And we think about the difference in efficacy between that group and those with a SALT score of 95 to 100. So now think about patients who historically, we called them alopecia totalis or alopecia universalis. The efficacy of treatments—and it doesn't matter if we're talking about baricitinib, ritlecitinib, or dueruxolitinib—the efficacy of treatment is much greater in the patients who have hair versus those who do not have hair. Now, really important, I don't want anybody walking away from this and saying, "Oh geez, so I'm not supposed to treat patients who have no hair loss." No, absolutely not. Treatment works well in those with a baseline SALT score of 95 to 100, but it's about half of the efficacy seen in patients who have hair at the start of treatment. And so there's a really important lesson to us in this. And that is that when we're sitting with a patient, and maybe they're unsure of whether they want to undergo treatment, and they're sitting there and they have 70% scalp hair loss, but they're rapidly losing, or you do a hair pull test, and everywhere you pull, hair comes out. This is somebody who we think is headed towards no scalp hair. Well, again, the data says we want to undertake treatment as often as we can when patients have hair, because that patient is going to do better. Okay, so a real practical lesson for all of us that emerges from the clinical trial data. 

And then lastly, again, highlights of clinical trials and the lessons learned. In the baricitinib clinical trials, there were two maneuvers that we all need to be aware of. One was treatment withdrawal at 1 year in patients who had regrown their hair. And another treatment maneuver was in patients who had regrown hair with a 4 milligram dose; at 1 year of treatment, many of them were titrated down to the 2 milligram dose. And let's quickly talk about the results of these two maneuvers.
 
So, with treatment withdrawal, 80% to 90% of patients who regrew their hair at 1 year lost treatment benefit in the 1 year after withdrawing treatment, okay? And so this tells us that there are a tiny number of people who will actually maintain their hair regrowth after withdrawing treatment, but the vast majority are going to lose their hair again. This shouldn't surprise us, right? Because this is a chronic disease, especially patients with severe disease. It is a chronic disease. So, we shouldn't be surprised that chronic treatment is necessary. But nevertheless, until we had this clinical trial, we didn't know that for sure. So that's lesson number one. 

And now the lesson from down titration. So again, taking patients who regrew their hair with baricitinib 4 milligrams at 1 year and then changing their dose to 2 milligrams. About 40% of those patients over the next year will flare. And so, meaning they needed the 4 milligram dose. This isn't altogether surprising, because twice as many people succeed with a 4 milligram dose as with the 2 milligram dose. And so really that result simply highlights to us that if you are a 4 milligram person, you need the 4 milligram dose for maintenance. If you are a 2 milligram baricitinib person, you need 2 milligrams daily for maintenance. What makes it tricky is that the label for baricitinib says that once an adequate response is achieved with the 4 milligram dose to titrate down the dose to 2 milligrams. I would urge caution to everybody listening to push back on that label instruction. And if a patient has regrown their hair with 4, let's maintain 4 milligrams daily to maintain hair regrowth. And if you have a thought to down titrate, go much more slowly than today 4 and tomorrow 2 milligrams forever more. 

So, to wrap things up, we've talked about a lot. We've come a long ways in a short period of time in the care of patients with alopecia areata. It's unbelievably exciting. But almost as exciting as where we've come in a short period of time is where we're headed. This is truly the golden age of alopecia areata, and I think in some ways this is the golden age for treatment in dermatology, because there's so much translational research happening, permitting treatment of diseases that we never thought we could treat before or that we couldn't treat before. 

But really, in alopecia areata, we're in the middle of this, and there are many clinical trials happening of new JAK inhibitors but also drugs with very unique mechanisms of action. And the next few years, I think we're going to see advancement even over where we are today that is going to continue to make this space utterly exciting. And really it's just, it's so much fun to take care of these patients, and it's going to continue to be fun and maybe even get more exciting. 

And so, I hope that everybody who's tuned in has taken away a little bit of this excitement, learned something new, something that you're going to really take to clinic tomorrow and bring a new perspective to the patients that you see. And again, just embrace. Embrace where we are. Embrace these patients and their care, and make an incredible difference in the lives of your patients. Thank you so much for tuning in, and I hope to have another opportunity to speak to you in the future.