Alopecia areata highlights from AAD 2023

Understanding JAK inhibitor black box warnings: is risk equal across conditions?

By Angela Lorio

Dr Brett King MD, PhD, Professor of Dermatology at Yale School of Medicine recaps the discussion of JAK inhibitors at AAD 2023 including the rationale for the use of JAK inhibitors as targeted therapy for alopecia areata and an in-depth look at JAK inhibitors mechanism of action.

“If we are afraid of them, we are not going to use them. We are not going to change countless lives,” said Brett Andrew King, MD, PhD, associate professor of dermatology, Yale School of Medicine, New Haven, Connecticut, to begin his lecture “Clinical Impact of the JAK-STAT Pathway”¹.

Dr. King noted that the safety profile across all JAK inhibitors is almost identical. The adverse events (AEs) they cause are manageable and expected, but their required black box warnings give healthcare providers pause. FDA-approved JAK inhibitors for rheumatoid arthritis or alopecia areata now carry the same black box risks, including major adverse cardiac events (MACE), venous thromboembolism (VTE) and malignancy.

Dr. King’s lecture was one of nine expert-led discussions on topics relevant to the expanding reach of JAK inhibitors in the field in a session, “JAK Inhibitors: A New Frontier in Dermatology”². The session was held on the opening morning of the the American Academy of Dermatology Annual Meeting in New Orleans, Louisiana, USA.

“We really need to understand where that boxed warning actually comes from to understand how it bears on our patients,” Dr. King explained. His presentation emphasized that the origin of the boxed warning for all JAK inhibitors was a clinical trial of tofacitinib for rheumatoid arthritis.

“Are our risks in dermatology and alopecia areata the same as JAK inhibitor safety risks in rheumatic disease?” asks Dr. King. He proposed that the risk is not the same. Dr. King discussed the basis for the black box warning, reviewed considerations for its interpretation, and presented relevant evidence and clinical application for selecting and managing patients for JAK inhibitor treatment.

JAK inhibitors are used in rheumatoid arthritis, and are now coming into use for dermatological conditions like alopecia areata; AE profiles may not be the same between patients with these two conditions

The black box warning

The US Food and Drug Administration bases the black box warning on findings of the ORAL Surveillance study, which evaluated the JAK inhibitor tofacitinib³. In ORAL Surveillance, approximately 4300 high-risk patients with rheumatoid arthritis (RA) were randomized to receive 5 mg or 10 mg of tofacitinib twice daily or a tumor necrosis factor (TNF) inhibitor. After a median 4 years of follow-up (and approximately 5000 patient-years), the tofacitinib groups demonstrated higher incidence for AEs, including serious infections, MACE, thromboembolic events, and malignancy.

The incidence of MACE was 3.4% among those taking any dose of tofacitinib and 2.5% of those randomized to TNF inhibitor. Rates of malignancy were 4.2% and 2.9%, respectively. Serious infections and thromboembolic events also increased for tofacitinib as compared with TNF inhibitor.

While careful not to dismiss the importance of these data, Dr. King did however underscore differences between the ORAL group and a likely population with dermatologic indications, or more specifically, alopecia areata. The ORAL population had a body mass index of approximately 30 kg/m². All patients in the trial were taking methotrexate, and almost 60% were taking concomitant corticosteroids.

Interpreting the black box warnings in dermatology

The FDA’s charge is to inform the public about risk. Physicians have a more personal mission, involving the benefits and risks of treating individual patients. With that in mind, Dr. King emphasized two facts for consideration in context:

1. The boxed warning for ruxolitinib 1.5% topical cream refers to an oral JAK inhibitor in rheumatoid arthritis patients, not ruxolitinib in patients with dermatologic conditions.
2. The boxed warning of tofacitinib is based on a post-marketing safety study requested by the FDA to help understand its long-term risks associated with specific observations in people taking the drug. A post-marketing study population by nature is enriched with patients allowing you to investigate this risk.

In this second case, the manufacturer was asked to investigate findings of increased dyslipidemia in one-third of patients and 12 malignancies in patients taking tofacitinib. These signals were not present in the original clinical trial population.

Here, study inclusion meant patients 50 years or older with at least one cardiovascular risk factor—cigarette smokers, people with hypertension, diabetes, and/or dyslipidemia, family history or personal history of coronary artery disease.

Are these saying that the risk of these events in rheumatic disease states the same as they are in alopecia areata, atopic dermatitis, vitiligo, and other dermatologic conditions? Dr. King responded, “I would argue that no, it is just not possibly the same.” He clarified that the patients in this study do not come close to the patient profile seen in the dermatology setting.

Evidence

A recent long-term upadacitinib safety study provides one of the closest comparisons available from a real-world dermatology population⁴. Burmester et al. collected safety data on nearly 7000 patients and 15,000 patient years of exposure to the drug across RA, psoriatic arthritis, ankylosing spondylosis, and atopic dermatitis trials.

When safety and, specifically malignancy, MACE and VTE events, were compared across all indications relative to RA, per 100 patient years, the risk was generally lower for atopic dermatitis, although numbers of case of each AE were low and confidence intervals at times overlapped (Table 1).

Table 1. Comparisons in AE rates of upadacitinib in rheumatoid arthritis and atopic dermatitis, Events per 100 person-years (95% confidence interval).

AD, atopic dermatitis; MACE, major adverse cardiovascular event; NMSC, non-melanoma skin cancer; RA, rheumatoid arthritis; UPA, upadacitinib; VTE, venous thromboembolic event.

Clinical application in the alopecia areata population

“I don’t want anybody here to think I’m diminishing the risk of JAK inhibitors,” stresses King.

He recommends caution in specific populations, guided by the population that demonstrated risk in the study on which the black box warning was based. “I’m not recommending hard stops for these patients, just very patient-specific conversations about benefit.”

JAKis continue to provide game-changing results for alopecia areata community

By Angela Lorio

Dr Brett King covers the discussions around the future of alopecia areata management at AAD 2023. Emphasising the need for ongoing treatment for the chronic condition alopecia areata.  Dr King also highlights development of evidence-based treatment guidelines.

Data presented at this year’s second Late-Breaking Research session at the American Academy of Dermatology (AAD) 2023 Annual Meeting is promising as JAK inhibitors pursue a broader reach into alopecia areata⁵. The early JAK inhibitor data that inspired approval of baricitinib, a JAK1/2 inhibitor, last year continues to show reproducibility in other JAK inhibitors and durability over time for patients with alopecia areata, as indicated by two oral presentations during this session.

THRIVE-AA2: Deuruxolitinib shows significant and early hair regrowth

Dr Brett A. King and colleagues reported significant improvements in hair regrowth at 24 weeks for patients with alopecia areata taking 8 mg twice-daily and 12 mg twice-daily doses of deuruxolitinib (CTP-543)⁶.

Both doses resulted in significant regrowth, starting as early as 4 weeks and continuing throughout the 24-week study period.

“These data are highly encouraging and support the potential of deuruxolitinib to regrow hair on the scalp, eyebrows, and eyelashes in patients with alopecia areata, and in many cases with a rapid onset of effect,” said Dr. King while presenting the study⁶.

In this double-blind phase 3 trial of the oral JAK inhibitor deuruxolitinib, investigators randomised 517 patients to receive either the drug at 8 mg (n = 256) or 12 mg (n = 129) twice daily or placebo (n = 130) for 24 weeks. The primary endpoint was a score of 20 or less on the Severity of Alopecia Tool (SALT), meaning patients had 20% or less of hair loss (or 80% or more of hair coverage), by the 24-week endpoint.

In the higher dose (12 mg twice-daily) group, 38% of patients reached the primary endpoint. A smaller number, 33%, did so in the 8-mg twice-daily dose group. The treatment differences between both deuruxolitinib doses and the 1% of patients reaching the primary endpoint in the placebo group was statistically significant (p<.0001; Table 1).

Deuruxolitinib achieved near-complete or complete scalp hair regrowth (SALT ≤10) after 24 weeks in 35% patients taking the 12 mg twice-daily dose and 21% patients taking the 8 mg twice-daily dose.

There was also significant improvement in status for the approximately three-fourths of patients who had eyebrow involvement or eyelash involvement at baseline. More than two-thirds of these patients had regrowth by week 24 (Table 1).

Table 1. SALT, BETA, and BELA results from Thrive-AA2 trial.

BELA, Brigham eyelash tool for alopecia; BETA, Brigham eyebrow tool for alopecia; BID, twice-daily; SALT, severity of alopecia tool; wk, week.

Dr. King emphasised that significant hair regrowth was evident by week 12 of the 24-week randomised trial. At 24 weeks, the improvement (decrease in SALT score) from baseline was 53% in patients taking the 12 mg dose compared to 45% in patients taking the 8 mg dose.

SALT scores of ≤20 at weeks 20, 16, and 12 were statistically significant in both groups.

Furthermore, a total of 47% of patients in the 8 mg twice-daily group and 52% of patients in the 12 mg twice-daily group reported being “satisfied” or “very satisfied”. This compared with only 2% of patients in the placebo group. Patient satisfaction was measured according to the Satisfaction of Hair Patient Reported Outcome (SPRO) scale at week 24.

Regarding safety, treatment-emergent adverse events (TEAEs) were seen in 80.5% on 8 mg and 81.4% of patients on 12 mg deuruxolitinib, compared to 70.0% on placebo; serious TEAEs were seen in 1.2% and 1.6% compared to 0% with placebo; and TEAEs leading to study drug discontinuation were see in 3.1% and 2.3% compared to 0.8% with placebo. The most common TEAEs were COVID-19, nasopharyngitis, blood creatine phosphokinase increase, headache and acne. There we no thromboembolic events or deaths observed in this study.

BRAVE-AA2: 104-week results demonstrates durability for baricitinib

Also presented during the Late-Breaking Research session were 2-year results demonstrating durability of data presented last year from the phase 3 BRAVE-AA randomised trials of the JAK inhibitor baricitinib in alopecia areata⁷.

Phase 3 trial results are also demonstrating the durability of response in alopecia areata treated with JAK inhibitors

“Efficacy of baricitinib for severe alopecia areata was maintained at 104 weeks in week 52 responders,” said presenter Maryanne M. Senna, MD of the Lahey Hair Loss Center of Excellence at Lahey Hospital and Medical Center in Burlington and Harvard Medical School in Boston, Massachusetts, USA⁸.         

Data from the extended BRAVE-AA2 study demonstrated that 90% of adult patients with alopecia areata maintained their 52-week status up to the 104-week endpoint of the trial.

Specifically, 117 (90.7%) receiving 4 mg baricitinib and 58 (89.2%) receiving 2 mg baricitinib maintained a SALT score ≤20 at 104 weeks. In the cohort of patients with SALT scores ≥20 at 52 weeks, 43 (39.1%) patients receiving 4 mg baricitinib reached SALT scores ≤20 by 104 weeks.

“Efficacy increased in patients with SALT scores ≥20 at week 52, illustrating that long-term treatment may be needed to observe maximum benefit in some patients,” explained Dr. Senna.

The 104-week analysis included 65 patients from the 2 mg group, 129 from the 4 mg group, and 110 partial responders. Patients who demonstrated response with baricitinib 2 mg or 4 mg once-daily at 52 weeks continued treatment at the same dose into the extension.

Investigators also evaluated the effect of 4 mg once daily for partial response. A partial response was defined as an unsustained SALT ≤20 at any time during the study, but >20 at 52 weeks. Partial responders also included patients with eyelash/eyebrow involvement who met response criteria (≥2) at some point before 52 weeks, but not at 52 weeks.

Patients with a response were more likely to have a current episode duration shorter than 4 years (76%-83%), whereas more patients with partial response (35%) had a current episode duration of 4 years or longer.

Durable baricitinib results led to SALT ≤20 responses in 40% of patients with moderate/severe alopecia and SALT ≤10 in 30% after 52 weeks of follow-up in the phase 3 BRAVE-AA1 and BRAVE-AA2 trials.

“The follow-up suggests that if you keep patients on treatment, you can get many of them to a meaningful response,” Dr. Senna said.

According to Senna, there were no new safety signals. Major adverse cardiovascular events and thromboembolic events, reported previously with JAK inhibitor use for other diseases, have not been observed in the BRAVE-AA phase 3 studies.

What’s next

Baricitinib’s regulatory approval for alopecia areata last year marked both the first time a JAK inhibitor and the first time systemic therapy of any kind was approved for alopecia. The U.S. Food and Drug Administration approval came just two short months after reports of long-term BRAVE data demonstrating baricitinib’s superiority over placebo at 36 weeks released last year⁷. And the THRIVE data are expected to be submitted in a new drug application for deuruxolitinib for alopecia areata by the middle of the year.

These late-breaking data set the stage for JAK inhibitors to increase patient benefit in alopecia areata, as they have with other dermatologic diseases.

“JAK inhibitors are changing the paradigm of alopecia areata,” Dr. King said. Results like these are, he says, "changing the landscape of how we think about this disease."

Clinical approach to alopecia areata in paediatric populations in the JAK inhibitors era

By Angela Lorio

Dr Brett King provides an overview of advances in treatment discussed at AAD 2023 with a focus on developments in the treatment of paediatric alopecia areata.

The FDA approval of the first systemic treatment for alopecia areata in June 2022 spurred interest in the disease and the advances affecting it. Changes in the field have made dermatologists rethink their approach to treatment and what they can offer patients.

Paediatric dermatologist Brittany Gareth Craiglow talked about how these new therapies have influenced the approach to patients in her paediatric practice in her talk ‘How to treat children with Alopecia Areata?’⁹, part of the session ‘Alopecia Areata: New Therapies’, directed by Natasha Atanaskova Mesinkovska¹⁰.

Medical treatment in children: combining therapies yields best results

When it comes to treatment algorithms in paediatrics, the best results come from choosing the right combination of therapies available. Dr Craiglow likened her process with each new patient to that of a chef: no one-size-fits-all approach. Her top considerations included age of the patient, duration of their alopecia areata, duration of current episode, and the family’s and patient’s level of risk tolerance.

Corticosteroids first-line for mild disease

When patients first present with active disease, or when there is spontaneous hair growth after the disease has been dormant, that is when to think about using corticosteroids. Early shedding might be described as hair on the pillow.

For mild disease, Dr Craiglow uses pulsed corticosteroids, and acknowledged that maximum doses of prednisone may be high, especially when you consider instructions for bedtime administration. But she also advised that “kids really tend to tolerate it quite well”.

Intralesional corticosteroids can also be successful in mild disease, but for teens rather than younger children. Dr Craiglow advised that “only if the patient can tolerate it – you don’t want the treatment to be worse than the disease”.

Dupilumab story evolving

The dual IL-4/IL-13 inhibitor dupilumab is approved by the FDA for five indications, including atopic dermatitis and asthma¹¹. “It is not something you are going to give to everybody and think you’re going to have a lot of success”, Dr Craiglow warned. There are case reports in the literature that demonstrate improvement of alopecia when dupilumab is treating these concomitant conditions¹².

Another study identified a threshold of IgE levels greater than 200 IU/ml to be the basis for ability to achieve increased Severity of Alopecia Tool (SALT) scores¹³. Dr Craiglow suggested considering dupilumab if there is concomitant atopic dermatitis and IgE levels are greater than 200 IU/ml.

While dupilumab is indicated for dermatological conditions like atopic dermatitis, it is not yet approved for treating alopecia areata. It is currently being studied in phase 2 trials¹³.

Oral minoxidil is a useful adjunct

When treating patients, Dr Craiglow says she thinks of herself a bit like Oprah Winfrey: “You get minoxidil. You get minoxidil. And you get minoxidil. Everyone gets minoxidil”. Whatever therapy turns out to be the right one, minoxidil is a useful adjunct and an important component of the overall combination regimen. “It’s a hair fertilizer”, she reminded the audience: “If there is any hair there, it will make more”.

While minoxidil for treating hair loss is formally approved only in adults as over-the-counter topical therapy, a literature review published in 2020 pointed out that it has been examined in paediatric patients, but that such use is off-label and that guidelines for use are lacking¹⁴.

JAK inhibitors as new alopecia treatment options

For severe disease, options in alopecia have been limited, but clinical results with JAK inhibitors are changing that. The approval of baricitinib for alopecia areata has improved access¹⁵, but it is this access that continues to be one of the biggest barriers for treating severe disease, explained Dr Craiglow.

Currently, there are no JAK inhibitors approved for treatment of alopecia areata in children. Ritlecitinib offers the only randomised controlled trial experience of JAK inhibitors for alopecia areata in paediatric patients aged 12 and older¹⁶. Other JAK inhibitors, baricitinib, upadacitinib and abrocitinib have paediatric indications in other dermatologic diseases. Similar to dupilumab, many of these agents show efficacy in treating multiple diseases (Table 1).

Table 1. JAK inhibitor use in dermatologic conditions, including alopecia areata, and FDA-approval status.

Beyond medical treatment: treat the person

Dr Craiglow reminded her audience that one of the most powerful skills a doctor can offer patients with alopecia areata is to just acknowledge that having alopecia areata is hard. “A lot of the patient visit in my practice is just talking to the patient”, she said. “I often first say, ‘How are you holding up?’ and ask them to rank on a scale from one to ten for how much alopecia areata is ruining their life… Before they answer, I always say ‘a lot of my patients aren't doing so well’”.

This gives patients permission to admit how they are actually feeling about having alopecia. Many of these patients feel ashamed of their negative feelings. They feel ashamed that they are unable to identify with the messages they hear: “it’s just hair”, “at least you aren’t sick”, “things could be worse”, and “you should be embracing life”.

Dr Craiglow also focuses on helping her young patients approach questions. “I always ask my patients, ‘when kids at school ask you, what do you say?’ and the majority of them don't have an answer”, she said. “This is something we can help them with that that might make their life a little bit better even beyond medical treatment”.

Encouraging young patients to role play their response to questions from people and other kids about their illness was another suggestion. Dr Craiglow referenced an approach advocated by the Changing Faces website¹⁹: “Give kids the formula: Respond, Reassure, Redirect. First you explain, ‘Oh, I have alopecia.’ Then reassure the person with the question, ‘I'm okay. I'm not sick. It’s not contagious’... whatever seems to be their concern. Then, redirect. Move on to change the subject.”

Dr Craiglow mentioned that she helps her young patients develop a script to practice in order to encourage them to work with family members outside of the office and to create different scenarios. The idea is to help the patient feel prepared and comfortable and to relieve any anxiety about real-life situations that present themselves.

Caring for children with alopecia goes beyond treatment options – managing their reactions to having alopecia is also important