Janus Kinase Inhibitors and Alopecia Areata: From Data to Dialogue
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Dermatologists treating alopecia areata (AA) with Janus kinase (JAK) inhibitors face a critical challenge: translating complex clinical trial data and US Food and Drug Administration (FDA) boxed warnings into meaningful, patient-centered dialogue. In this in-depth interview, Dr Justin Ko shares his approach to navigating these conversations, including how to individualize risk assessment, frame therapeutic benefits, and foster shared decision-making, offering practical tips for balancing regulatory guidance with real-world care.
The Dermatologist: Can you explain the origin of the boxed warning on JAK inhibitors and its significance for dermatologists prescribing these medications?
Dr Ko: This is a question that we commonly get from both colleagues and patients, and I think it is important to have the context for the data and the study underlying this boxed warning on our JAK inhibitors used for dermatologic disease. The data and the evidence behind the boxed warning stemmed from the ORAL Surveillance trial, which was looking at oral rheumatoid arthritis (RA) treatments. This was a post-marketing study that the FDA had the makers of tofacitinib conduct as a condition of approving their medication for RA around 2021. The trial involved patients with RA who were age 50 years or older and who had at least 1 cardiovascular risk factor.
Those are 2 important points to consider as we think about the data and this study. Patients taking a tumor necrosis factor alpha (TNF-α) inhibitor were compared with those taking tofacitinib at 5 mg twice a day and 10 mg twice a day. Over the course of the trial, the investigators stopped the 10 mg twice a day arm because they were seeing safety signals in increased risk of major adverse cardiovascular events (MACE), thrombosis, and cancer. They concluded that there was risk associated with the use of tofacitinib over TNF-α inhibitors based on these endpoints. As a result, the boxed warning was included, not only on tofacitinib, the medication that was studied, but around the entire class of JAK inhibitors, including baricitinib, upadacitinib, and, interestingly, the topical formulation of ruxolitinib.
The Dermatologist: What does the clinical trial data suggest regarding the frequency and severity of adverse events associated with JAK inhibitors in patients with AA?
Dr Ko: I think the challenge before us as clinicians is given the boxed warning that exists, how do we interpret it clinically? Also, how do we help interpret it for our patients and talk them through what this means and the risks and benefits of medications that we are thinking about prescribing. And then how do we make it relevant for them and their condition, which is sometimes very different from the patients, conditions, circumstances, and risk factors that were part of the study underlying the boxed warning. More specifically, how are our patients with AA either different from or similar to the patients with RA who were in the ORAL Surveillance study of tofacitinib?
We know there are important differences. One is that the patient demographics are very different. Our patients, especially those studied in AA trials, tend to be younger, healthier, and have less cardiovascular risk factors. It is not a surprise that the incidents and rates of MACE, thrombotic events, and malignancy events were much lower than those found in the ORAL Surveillance trial. So, how do we interpret this for our patients? How do we understand this as clinicians and how do we engage in shared decision-making so that we acknowledge what those risks are? But I think equally important is talking about the potential benefits.
What did the trials show in terms of the efficacy of these medications for AA? From a clinical standpoint, how does that translate into an effect and a meaningful impact on a patient's quality of life? We see teenage patients who are in their formative years, or maybe they are in their twenties and making their first career decisions or family planning decisions. These are important times where we can make a difference in the lives of our patients by having a balanced, fair, appropriate conversation about what we expect in terms of benefits and what the risks are, contextualizing it in a way that is relevant for their condition and their risk factors. This is not just saying that the boxed warning is a red flag, but rather going the additional step and asking what does it mean for the patient individually and how do we make the right decision together?
The Dermatologist: Are there any particular risk factors or patient populations that you believe are more susceptible to experiencing adverse events when using JAKs for AA?
Dr Ko: Every patient is an individual patient, and that is how we should think about and have the conversation with them about risks, benefits, and expectations to get to a shared decision-making model. There are patients I see who I have different conversations with. For example, I see patients who are over age 50 who have cardiovascular risk factors like hyperlipidemia and hypertension; maybe they have had a transient ischemic attack or a malignancy in the past. The conversation I have with those patients is very different from my conversations with patients who are young and healthy and do not have those risk factors. I have different conversations with patients who are in the parts of their lives where they are thinking about family planning, or patients who have been longtime smokers, or patients who may be young and healthy but are taking oral contraceptives. We bring all these things into our clinical lens and help interpret the data for the patient and walk them through what it means for them to potentially be on one of these medications. We interpret the available data and all the experience we have as clinicians and bring that to bear on the patient’s care so we can make the best decision together.
The Dermatologist: How do the benefits of JAK inhibitors for treating AA compare with the potential risks, particularly with respect to the boxed warning?
Dr Ko: It is incredibly important to start from the premise that the FDA has a rigorous process around safety and efficacy when approving new medications. These JAK inhibitors have gone through that process and met the bar of evidence for safety and efficacy. I tell my patients that this means something in terms of the weight of the existing evidence and the studies that have been done— there is enough evidence that the FDA approved these medications. The way to contextualize these conversations is to convey that we are not doing something based on an anecdote or a case study; we are doing things based on rigorous randomized controlled trials in large populations of patients. And then we get into talking about the details of what we saw in those trials and what it might mean for the patient. What might we expect for them given what we know about their condition? For example, how long has their current duration of AA been, what medications have they been on before, and how did they respond or not respond? What other comorbidities do they have? Are they an atopic person who has eczema as well, where they have a high eosinophilic count, or do they have other comorbidities or considerations in their health history that we might need to take into account?
It starts from the big picture, and we work our way down to individual factors. As part of that, I do not want to miss the forest for the trees. Yes, there is a lot of this that is purely clinical. How do we monitor labs? How do we ensure safety? But I always come back to what does this mean for the patient. What would getting treatment, or not getting treatment, or pursuing different options mean for them as a person in their life? This is what we do as clinicians, and we should not take it for granted. We can fundamentally change the trajectory of our patients' lives, and that is the power and responsibility we hold in these conversations. We should take it as the sacred interaction and relationship it is. I have so many meaningful experiences that stick with me where I can think back on the first conversation I had with a patient who I am still seeing 10 years later, and I see what we did together and how we made their life better and different. It is about how we get from the boxed warning to a place where we are impacting patients in a meaningful way.
The Dermatologist: What real-world experience have you encountered regarding the safety and tolerability of JAK inhibitors in patients with AA, especially concerning long-term use?
Dr Ko: I find generally that JAK inhibitors for AA are well tolerated. There are things we know that patients will get when taking a JAK inhibitor, such as acne or folliculitis. We also know there are certain things that patients can experience when they are first starting, such as headaches, gastrointestinal symptoms, or fatigue. These tend to go away in a couple of months, so we can counsel patients to stick with it. We know the kinds of laboratory abnormalities we see, and we know they are things that bump in a way where we can follow them safely, but we also know what happens if they bump more. We have the clinical experience to wield these medications in a safe, effective way and we can guide our patients through the things that might happen.
We know that during cold and flu season, patients on a JAK inhibitor may potentially get an extra cold a season. For my patients who are of the age where they are eligible for shingles vaccination, they get vaccinated for shingles before they start a JAK inhibitor. In fact, there is recent evidence about the decrease in dementia risk with shingles vaccinations, so I add that to the conversation. For my patients with severe eczema, especially facial atopic dermatitis, and a history of herpes simplex who I am going to put on a JAK inhibitor, we discuss suppressive therapy. I tell the patient, if you develop an outbreak and you are starting to get it widespread in the areas of eczema, do not wait, call me because that is a skin urgent situation.
All my patients know they can reach me in between our formal interactions. We have ways that patients can message and send photos. This type of relationship, trust, and connectivity gives us confidence we can get through anything that comes up with these medications. If they have signs and symptoms or if we need to do a workup for something, it is a team effort and a longitudinal relationship. These are patients who we continue to monitor both for progress in terms of efficacy and for safety issues that can come up over the course of time.
And then, of course, there are things on the label that we should all be doing. We should be checking QuantiFERON before starting a JAK inhibitor, and we should be asking about a history of hepatitis. We should be checking appropriate levels and titers. JAK inhibitors are just another effective tool in the arsenal of treatments we have; in fact, they are the first approved tool for AA. We have the data, evidence, and clinical knowledge to be able to use these tools appropriately and effectively in the right circumstances and help guide patients through conversations about treatment options and what might be right for them.
The Dermatologist: Are there any specific management strategies or monitoring protocols you follow to minimize the risk of adverse events when prescribing JAK inhibitors for AA?
Dr Ko: In general, if we have made the decision to start, I think about all the things we might do before we start that would be helpful. For example, labs to check for latent infections and making sure that age-appropriate cancer screening has been done. If the patient is a smoker, have they had a computed tomography scan or an X-ray of their lungs? I also think about vaccination status. Sometimes we will have patients come in who are hesitant about certain vaccinations or just the concept of vaccinations, and we play a role in having these conversations with our patients. This is where we step outside our dermatologist role and into our physician role and ask what is relevant for this patient and their health, especially considering we are going to be starting them on a medication that has these kinds of implications.
We also get to talk about where patients are in their life like I mentioned before. Are they thinking about family planning? What does that look like? Are they planning to get pregnant in the next X number of years? And if so, how do we think about the treatment approach and strategy for their medication? I have many patients of childbearing age taking oral contraceptives who frequently fly for work. How do we think about that in the context of being on a JAK inhibitor? We talk about the fact that this potentially slightly elevates their risk for a deep vein thrombosis and the things we might do to mitigate the risk. For a patient who is perimenopausal and thinking about hormone replacement therapy, what does that look like and how do we think about those considerations in the context of maybe a potentially elevated thrombotic risk?
I hope that all of us become comfortable with these conversations and the use of JAK inhibitors. But how do we wield them appropriately? How do we have the right conversations about them? How do we continue to monitor our patients? And then how do we think about those conversations that inevitably come up about when to stop the medication and how to taper it? The good news is that we have data to inform us. There have been great trials that have given us some insight into these kinds of conversations and there are post-marketing registry trials and studies being done that will continue to give us insight into both the safety and efficacy of these medications in the real world, with real patients, and with real experience. I feel incredibly fortunate to be a practicing clinician in the time of medications like JAK inhibitors, which are truly transformational for our patients. How cool is it to be a dermatologist right now and really be able to do things that we could not do before for our patients with AA?
The Dermatologist: In your opinion, how should dermatologist balance shared decision-making with patients when discussing the potential risk of JAK inhibitors in the treatment of AA?
Dr Ko: I think the terminology about balance is so important. Balance is the key. It means presenting the risk but in a way that contextualizes it both against the baseline population risk—the risk of not doing something—with the risk of the treatments we have that are not JAK inhibitors. Risk is not absolute; it is relative. How do we help patients think about that and hold the risk in the right way, in the right place, and make it the right size, if you will? And then how do we help them think about and contextualize what the benefit might be?
What does response mean? What does non-response mean? Is it beyond the patient’s scalp hair? Is it their facial hair or body hair? I think we must get into the nuance to understand what is meaningful to patients. What is their expectation, how do they think about the balance of risk and benefit, and where are they in the course of their life? It is a different conversation with a child and their parents than when you have that conversation with a teenager, a college-age student, or an adult. There are also individual factors around the patient’s life and their health. We have the responsibility to bring the data, but it is not just throwing information at the patient, rather it is having the conversations where we put all that information into the right context.
One of the things I always say, and I teach this to my residents, is that it is not usually a one conversation deal; it is a relationship. Or sometimes there are different conversations that happen. I have some patients who I have had multi-year conversations with and there are others where we align during the first conversation.
We must make sure we are in alignment with our patients and they are not outweighing either the expectation, benefit, or risk part of the equation, that we are in balance. I would say we can rely on our clinical gut and judgment to know when we have had one of those conversations, and I think you feel it when you get there with a patient.
Disclosure: The author reports no relevant financial relationships.
