JAK Inhibitors & Boxed Warnings

Gain expert insight into the origins and implications of the boxed warning on JAK inhibitors for dermatologists treating alopecia areata. Learn about clinical trial data, patient selection, risk mitigation strategies, and the importance of shared decision-making in practice.

Melissa Piliang, MD, FAAD, is chair of dermatology at Cleveland Clinic in Cleveland, OH.

Key Clinical Takeaway

• Origin of Boxed Warning:
  • The boxed warning on JAK inhibitors stems from a study in patients with rheumatoid arthritis, comparing tofacitinib to TNF inhibitors.
  • Study population included high-risk individuals: age >50, obesity, smoking history, diabetes, hypertension.
  • Elevated rates of MACE (major adverse cardiovascular events), malignancies, thrombosis (e.g., DVT, PE), and serious infections were noted in the JAK arm, leading to a class-wide boxed warning—even for topical JAKs.
  • These data were extrapolated to all indications, including alopecia areata, despite differing patient demographics.
• Clinical Trial Data in Alopecia Areata:
  • Incidence of MACE in AA trials was very low, and limited to patients with preexisting risk factors (e.g., older age, metabolic comorbidities, smoking).
  • No MACE events occurred in otherwise healthy individuals, including pediatric and young adult patients.
  • Observed incidence of MACE in AA trial populations was lower than background rates in untreated AA patients—suggesting a favorable safety profile in well-selected patients.
• Identifying High-Risk Populations:
  • JAK inhibitor risks increase in patients with:
    • Age >50
    • Smoking history
    • Obesity
    • Diabetes
    • Hypertension
    • Hyperlipidemia
  • Smoking was highlighted as a particularly important modifiable risk factor.
• Risk-Benefit Consideration in Clinical Practice:
  • Emotional and psychosocial benefits of hair regrowth with JAK inhibitors are substantial—patients often report improved self-esteem, social functioning, and life trajectory.
  • In shared decision-making, the clinical impact of hair regrowth should be weighed against individualized risk assessment.
  • Most patients perceive benefits to outweigh potential risks, especially when informed and engaged in decision-making.
• Long-Term Real-World Safety Experience:
  • Over 10 years of clinical experience, including off-label use of tofacitinib, showed no MACE events in Dr. Piliang’s cohort.
  • Careful patient selection and proactive risk mitigation (e.g., smoking cessation, weight loss) were key to safe prescribing.
• Monitoring and Management Protocols:
  • Pre-treatment labs:
    • CBC, metabolic panel (liver/kidney function)
    • Lipid panel (when relevant)
    • TB and Hepatitis B screening to rule out latent infection
  • Ongoing monitoring includes periodic labs per FDA guidance.
  • Coordination with PCPs or specialists (e.g., cardiology) recommended for optimizing comorbid conditions before initiation.
• Patient Engagement and Shared Decision-Making:
  • Open conversations about personal health status, risk factors, and treatment goals are essential.
  • Patients should be empowered to evaluate benefit-risk ratio in collaboration with their dermatologist.
  • Personalization of care plans and respecting patient autonomy are central to ethical JAK inhibitor use.
• Guidance for Dermatology Colleagues:
  • Understand the context and limitations of the boxed warning.
  • Differentiate between high-risk RA trial populations and typically healthier AA patients.
  • Recognize the transformational impact of treatment access for patients with AA.
  • Educate and monitor thoughtfully rather than avoiding JAK use out of fear—when appropriately prescribed, outcomes can be life-changing.

Transcript

The Dermatologist: Can you explain the origin of the boxed warnings on JAK inhibitors and its significance for dermatologists prescribing these medications?

Dr Piliang: Yes, so I think it's really important to understand where that black box warning came from and especially as we talk about risks and benefits of using these JAK inhibitors. So the black box warning came from a study in patients with rheumatoid arthritis. In this study, they compared one JAK inhibitor called Tofacitinib with a different type of rheumatoid arthritis treatment, a biologic medications that fall into this category of TNF inhibitors. So they compared TNF inhibitors have been around for a long time, 20 years or more to treat rheumatoid arthritis. JAK inhibitors are the new kid on the block. And so they were comparing how the risks in patients who took the TNFs versus those who took the JAK inhibitors, and they were including patients who had risk factors for MACE events. So MACE events are malignancies, blood clots, strokes, heart attacks, and deep vein thrombosis, pulmonary embolism. So it only included people who were older. They had to be over 50 and they had to have risk factors like they were obese, they had diabetes, they smoked, and so they compared those two groups and comparing the two groups of rheumatoid arthritis patients, they found the patients who got the tofacitinib, the JAK inhibitor, had a higher incidence of MACE events than the patients who took the TNFs. Coming from that study one study and only in rheumatoid arthritis patients, they then applied that black box warning to every JAK inhibitor including topical forms.

As dermatologists, we tend to treat a healthier patient population and especially a healthier patient population than the rheumatoid arthritis patients. They tend to be a riskier group to begin with. And when we think about treating our patients, we are more risk averse than some other specialties might be because our patients tend to be healthy and we want to prescribe to the ethic of do no harm to our patients. So I think that's why this black box warning was very impactful for dermatologists. In thinking about how we can treat and manage patients with JAK inhibitors,

The Dermatologist: What does the clinical trial data suggest regarding the frequency in severity of side effects or adverse events associated with JAK inhibitors in patients with alopecia areata?

Dr Piliang: The clinical trial data is actually to me very reassuring. There were a very low incidence of MACE events in the clinical trials, but they did occur when that data was looked at, they occurred. All of the MACE events occurred in patients who had risk factors that I mentioned before. They were older, they were obese, they smoked, they had diabetes, those kind of risk factors. And so in otherwise healthy patients in the clinical trials who didn't have risk factors. So if you're thinking about kids in young adults who have alopecia areata, they did not have any of these MACE events reported. The other thing I think to look at is what would we expect the incidents of MACE events in this population if they weren't on a JAK inhibitor? And so when you look at the incidents in patients who have alopecia areata, it's actually higher than the incidents in the trials. Again, reassuring not saying that these aren't real risks, not saying that we don't have to think about them and talk about them and be aware of them and select carefully which patients we prescribe JAK inhibitors too, but I think the data is reassuring.

The Dermatologist: Are there particular risk factors or patient populations that you believe are more susceptible to experiencing adverse events when using JAK inhibitors for alopecia areata?

Dr Piliang: So if we look at the trial data, yes, it looks like patients who have risk, preexisting risk factors for these MACE events. So somebody for example who is older over 50 who's obese or not all of these, but has one or two of these obese, they smoke or have a history of smoking, they have diabetes, they have high cholesterol, they have high blood pressure, all these risk factors that will increase your risk. I think especially smoking, we need to be careful with patients who smoke.

The Dermatologist: How do the benefits of JAK inhibitors in treating alopecia areata compare with the potential risks, particularly with respect to the boxed warning?

Dr Piliang: Yeah, I think alopecia of patients who go on JAK inhibitors and regrow their hair get incredible benefits. I have patients who I've followed for more than 10 years before we were able to get them a JAK who then were able to go on a jak and I can see the emotional benefits to the patients. It's amazing to me. They come in and bright smiles hopping down the hall so, so happy and doing new things in their lives, getting new jobs, getting married, moving on. And so real benefits to being on these medications and almost any medication you take has risks. And so we have to always think about what's the risk versus the benefit when we prescribe medications and we do need to have a conversation with our patients and patients should have a conversation with their doctors about their individual risk factors and think about what their own individual benefit or risk is for it. And when I talk to my patients, they tend to feel that the benefits far outweigh the risk and in my experience, my patients have done incredibly well.

The Dermatologist: What real world experience have you encountered regarding the safety and tolerability of JAK inhibitors in patients with alopecia areata, especially concerning long-term use?

Dr Piliang: So I have been prescribing JAK inhibitors since the first paper that Dr. Brett King published that was killing two birds with one stone and a young man who we prescribed tofacitinib. When that paper hit, we had over 300 phone calls to our office from patients who we treated over the years who wanted to go on this medication, and so we started prescribing it. So I have more than 10 years experience. Lots of that experience is in this medication that was used in the trial that led to the black box warning. And my patients have done incredibly well. I'm very, they're fortunate. I'm fortunate we haven't had any MACE events in my cohort of patients at this point. I always feel like I should knock wood because I don't want to have one either, but I am very careful about who I prescribed to and I've had a couple of patients who've lost significant amount of weight before they went on a JAK inhibitor to decrease their risk factor. I've had a patient who stopped smoking. So I think if it's really important for a patient to go on this medication and they have risk factors, then we need to do everything we can to mitigate those risk factors so that they can take it as safely as possible.

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 alopecia area?

Dr Piliang: So I check blood work as is recommended in the package insert from the FDA. So I check to make sure that they don't before we start medication that they're healthy. So I'll check their blood cell count, I check a metabolic panel to make sure their liver and kidneys are functioning well. I check if the medication can affect the cholesterol, then I will check a lipid panel before they start and then I want to make sure they don't have an infection that we may not know about. So TB and hepatitis BI also check because those patients can have for a long time before they have symptoms and I wouldn't want to immunosuppress somebody who has one of those infections. So I do check before for those things. And we check labs periodically once the patients are on the medication and if they have some kind of cardiac risk factor, if they have high blood pressure, cholesterol, I might send them to a colleague to tune up their general health. So if they have high cholesterol, I would want them to be seeing their primary care doctor to make sure that their benefiting from their expertise in terms of how to manage their cholesterol. Maybe they need a lipid lowering medication. I want their blood pressure to be under good control and their primary care doctor could help with that. If they have a cardiac history, I would send them to the cardiologist to see what they think their respectives are and kind of get their agreement. Before we started.

The Dermatologist: In your opinion, how should dermatologists balanced shared decision making with patients when discussing the potential risk of JAK inhibitors in the treatment of alopecia areata?

Dr Piliang: I think it's incredibly important for patients to be involved in these decisions. They have significant impact on the patient, on their life. If they get the benefit from treating the medication, they regrow their hair, but also they're the ones that have to take that risk to their health if they were to have an adverse event. So I think it's very important that patients have an open dialogue with their dermatologists about the medications, about their health, about their risks, and make that decision together.

The Dermatologist: Are there any tips or insights you would like to share with your dermatologist colleagues regarding box warnings on JAK inhibitors?

Dr Piliang: So I think it's important for dermatologists to really understand where that black box warning came from. Understand that the trial data and what we actually found in the trials and to also understand really how incredibly important it is for patients with alopecia areata have access to treatment and the enormous impact it can have on their life.