Highlights
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Janus kinase (JAK) inhibitors have ushered in a new era in alopecia areata (AA). Historically, moderate to severe AA was refractory to treatment. JAK inhibitors have changed that; Treatment of moderate to severe AA is now possible.
Alopecia areata (AA) is an autoimmune disease that causes hair loss. It is the second most common form of alopecia, usually causing round patches of alopecia and, less commonly, complete loss of all body hair. Moderate to severe AA is notoriously refractory to treatment.
In June 2014, we reported the first AA patient successfully treated with the Janus kinase (JAK) inhibitor (JAKi) tofacitinib. Subsequently, open clinical trials, case series, and reports of tofacitinib and ruxolitinib supported the use of JAKi for AA. Industry-sponsored clinical trials followed, and in June 2022, history was made with the first Food and Drug Administration approval of a treatment for AA, baricitinib, followed a year later by the second, ritlecitinib.
Rationale for JAKi treatment of AA
Immune activation and attack on the hair follicle in AA involve the cytokines interferon-gamma and interleukin-15. Signaling by interferon-gamma and interleukin-15 requires JAK proteins; Therefore, JAKis modulate the activity of important AA drivers, leading to hair regeneration.
Oral JAKis for AA
There are numerous publications of off-label use of JAKis for AA, generally of tofacitinib and, to a much lesser extent, of ruxolitinib, because these were approved in 2011-2012, several years before other JAKis. Because none of these drugs have been studied in large randomized controlled trials, data on their overall effectiveness in AA are lacking.
To date, results from phase 3 randomized controlled trials of 3 oral JAKis have been published and/or presented: baricitinib, ritlecitinib, and deuruxolitinib (CTP-543). Enrollment criteria and patient characteristics in these trials have been similar. Patients have ≥50% scalp hair loss, with an average scalp hair loss of 80% to 90%; approximately half of patients have almost total or complete loss of scalp hair (i.e., alopecia totalis and alopecia universalis), and between 60% and 70% of patients have involvement of the eyebrows and 60% and 70% of patients have eyelash involvement. The ritlecitinib trial was conducted in patients aged 12 years or older, while the baricitinib and deuruxolitinib trials were conducted only in adults.
Baricitinib
In 2 trials of baricitinib, 39% and 23% of patients treated with baricitinib 4 mg and 2 mg daily, respectively, achieved ≤20% scalp hair loss over 36 weeks of treatment, and the majority those patients achieved ≤10% scalp hair loss. Approximately one-third of patients with severe eyebrow loss achieved normal or near-normal eyebrows and, similarly, one-third of patients with severe eyelash loss achieved normal or near-normal eyelashes during the 36-week period. Over an additional 16 weeks of treatment (52 weeks total), the proportion of patients achieving ≤20% scalp hair loss continued to increase.
Baricitinib was the first drug approved for the treatment of adults with severe AA.
Ritlecitinib
In a trial of ritlecitinib, 23% of patients treated with 50 mg daily of ritlecitinib achieved ≤20% scalp hair loss over 24 weeks of treatment, and the majority of those patients achieved scalp hair loss scalp of ≤10%. Similar proportions of patients with any eyebrow involvement or any eyelash involvement achieved normal or near-normal eyebrows or eyelashes, respectively, over the 24-week period. Over an additional 24 weeks of treatment (48 weeks total), the proportion of patients achieving ≤20% scalp hair loss increased to 40%.
Ritlecitinib is approved for the treatment of patients 12 years of age and older with severe AE.
Deuruxolitinib
In a trial of deuruxolitinib, 30% to 42% of patients treated with 2 doses of deuruxolitinib achieved ≤20% scalp hair loss over 24 weeks of treatment, the majority of whom achieved ≤10% hair loss. scalp hair.
Topical JAKis are ineffective for moderate to severe AA
Although there are case reports of topical JAKi for AA, topical JAKi has not demonstrated efficacy in AA clinical trials of ruxolitinib 1.5% cream, delgocitinib ointment, or tofacitinib 2% ointment.
JAKis Security in AA
JAKis have a boxed warning for malignancy, infection, mortality, major adverse cardiovascular events, and thrombosis. The warning is one born out of a long-term safety study of tofacitinib in rheumatoid arthritis that was enriched in patients with a higher baseline risk of these adverse events. At least in the case of baricitinib, for which there are data in rheumatoid arthritis, atopic dermatitis and AA, the safety profile in AA (and atopic dermatitis) is favorable and better than in rheumatoid arthritis, supporting the notion that the risk is different in different patient populations.
Ultimately, the safety profile of different JAKis in AA will be evaluated in clinical trials and possibly in registries that follow patients long-term. Necessarily, when deciding whether treatment with JAKi is suitable for any patient, possible risk factors such as smoking, obesity, hypertension, etc. will have to be taken into account.
When to consider JAKi AA treatment and optimize efficacy
JAKis clinical trials have involved adolescent and adult patients with 50% to 100% scalp hair loss whose current episode of severe hair loss is 6 months to 7 to 10 years. Certainly, in clinical practice, treatment may also be considered when there is less severe scalp hair loss, such as when there is notable eyebrow /eyelash involvement , disease that is refractory to treatment, significant psychosocial impact, and/or diffuse positive hair pull test or when the current episode of severe hair loss lasts more than 10 years.
Analyzes of clinical trials have revealed 2 patient/disease characteristics that impact efficacy, sometimes dramatically.
- The first is the duration of the current episode of severe illness, that is, the amount of time a patient has had severe scalp hair loss. Treatment in the first 3 to 4 years of severe scalp hair loss greatly improves effectiveness.
- The second characteristic is the presence of hair on the scalp, that is, the effectiveness is much higher for patients who have some hair on the scalp at the time of starting treatment than for those with almost complete hair loss or complete.
It may be possible to improve responses to JAKi treatment with combination therapy. Based on previous data showing that oral minoxidil 5 mg twice daily is sometimes effective as monotherapy for AA, there are limited data showing that JAKis in combination with oral minoxidil 2.5 to 5 mg once or twice daily day increases responses to treatment.15
Summary
JAKis have forever changed AA, providing the first two approved drugs, baricitinib and ritlecitinib, for severe AA, not only with other JAKis but, hopefully, with other treatments with new mechanisms of action to follow. These advances herald a bright future for patients.
Comments
A new type of medication, JAK inhibitors, can effectively treat moderate to severe alopecia areata, a hair loss condition that has historically been difficult to treat. A study of its effectiveness, conducted by Dr. Brett King and Dr. Brittany Craiglow of Yale University, was published in a supplement to the Journal of the American Academy of Dermatology .
"Because alopecia areata is an inflammatory condition, a JAK inhibitor will essentially reduce the inflammation that fuels the disease and restore balance to your immune system," said dermatologist Dr. Sandra Johnson. She is an associate professor at the University of Arkansas for Medical Sciences in Little Rock and was not involved in the study.
"The development of JAK inhibitors has given us another treatment to improve the lives of patients with alopecia areata," Johnson said in a news release from the American Academy of Dermatology.
The condition is most common in children , but can occur at any age. It involves sudden hair loss with affected patches that expand. In some cases, it spreads to the entire head or body.
It is also more common in those who have a close blood relative with the disease and in people who have been treated for cancer with a drug called nivolumab (Opdivo). Medical conditions such as asthma, hay fever, eczema, thyroid disease, vitiligo and Down syndrome also increase the risk of alopecia areata.
The new study credits JAK inhibitors with ushering in a new era , making the treatment of moderate to severe alopecia areata possible. The authors noted that two drugs, baricitinib and ritlecitinib , are approved and a third, deuruxolitinib , is in the approval process. Clinical trials are also ongoing.
Diagnosing alopecia areata involves an examination of the area of hair loss and the person’s nails. Blood tests may be needed to rule out other diseases caused by the immune system.
In addition to JAK inhibitors, contact immunotherapy can be used to change a person’s immune system so that it stops attacking their hair follicles. Other treatment options include the antirheumatic drug methotrexate and anti-inflammatory corticosteroids.
"We now have more treatment options than ever for patients with alopecia areata, and they are providing results for people for whom previous treatments were ineffective," Johnson said. "It’s important to know that no one treatment works for everyone. Your board-certified dermatologist can recommend the treatment options that work best for you."
