NEW YORK — Alopecia areata, an autoimmune condition, is known to be driven by immune cell infiltration and upregulated cytokines that attack hair follicles, but the importance of systemic — not just localized — control of inflammation might be underappreciated, according to one expert.

Therapies with anti-inflammatory effects, particularly JAK inhibitors, are highly effective for alopecia areata and increasingly are used for other inflammatory-related forms of alopecia. However, systemic inflammation, not just inflammation at the scalp, should also be a therapeutic target, according to Natasha Mesinkovska, MD, PhD, vice chair for clinical research in the Department of Dermatology at the University of California Irvine School of Medicine.

“The point is that the inflammation that produces hair loss is not only localized,” said Mesinkovska on November 14 at Sixth Inflammatory Skin Disease Summit.

All three of the oral drugs approved for alopecia areata — baricitinib, ritlecitinib, and deuruxolitinib — are JAK inhibitors, which do act systemically, but Mesinkovska pointed out that not all patients have an adequate response, and relapse is highly likely when these drugs are stopped.

Adjunctive Systemic Drugs Might Accelerate Control

Mesinkovska has been looking for adjunctive therapies, particularly those that can attenuate the low or moderate level of systemic inflammation that is common in patients with alopecia areata.

The frequency with which alopecia areata occurs in patients with another inflammatory skin condition, such as atopic dermatitis, is not a coincidence — even if many clinicians consider these to be unrelated. “We have all learned that these diseases coexist,” Mesinkovska pointed out and said she considers systemic inflammation a common risk.

As a result, Mesinkovska has been evaluating or using adjunctive anti-inflammatories. One example is low-dose oral minoxidil, a therapy approved for androgenic alopecia, which she is routinely offering as a first-line medication to patients with alopecia areata and other forms of hair loss.

“I use the oral formulation specifically for the systemic effect,” said Mesinkovska, who cited evidence that this drug not only suppresses inflammation around the follicles but also can downregulate circulating inflammatory factors. Minoxidil, a drug with potential anti-aging effects because of the correlation between increasing age and inflammation, has a good safety profile if used in low doses, she said.

“The changes in blood pressure can be avoided if the daily dose is kept under 5 mg,” said Mesinkovska, who was a coauthor of a paper on the safe use of minoxidil for hair loss that was published this year.

She has also become interested in GLP-1 agonists and similar drugs for weight loss for their anti-inflammatory effects. Because of their pro-inflammatory activity of adipocytes, body weight reductions lower circulating inflammatory factors. Although these therapies are most attractive for patients with another indication, they have provided encouraging hair regrowth on top of other hair-loss therapies, according to Mesinkovska.

Anti-Inflammatory Effect Sustained With Weight Control

One of the advantages of weight loss for attenuating the inflammatory state is that the effects “persist after body weight is normalized,” Mesinkovska said.

The fact that anti-inflammatory agents can substantially reduce hair loss and even provide complete hair regrowth, is not news, but Mesinkovska said the process is being understood in new detail, and much of this work supports the idea of reducing systemic, not just local, inflammation to provide deeper and more durable remission.

The basic science of alopecia areata, which appears to depend at least in part on T helper 1 effector CD4+ and CD8+t T cells infiltrating the hair follicle, was summarized earlier this year in a research article cited by Mesinkovska. Although much of this research is based on murine models, the authors explain how hair follicles, which are considered to be immune privileged, become the targets of T cell-mediated autoimmunity.

For hair loss, the science supporting systemic inflammation is perhaps strongest for alopecia areata, but Mesinkovska suggested that these principles might be relevant to other inflammatory scalp disorders, such as frontal fibrosing alopecia, which is among the inflammation-related forms of hair loss that have been increasing in prevalence.

Viral infections, such as COVID, are a potential example of stress as a factor in hair loss. Although some hypothesized that the spike in cases of alopecia areata during the COVID pandemic was related to the effect of the disease or the vaccine on immune function, Mesinkovska suggested that stress-induced inflammation cannot be ruled out.

Although Mesinkovska is already offering therapies beyond JAK inhibitors to reduce systemic inflammation in patients with alopecia areata, these are not substitutes. JAK inhibitors are effective and, with the exception of the “very real” risk for herpes zoster, safe and well tolerated, according to Mesinkovska.

She emphasized that anti-inflammatory therapy is best started soon after the onset of hair loss associated with inflammation.

“You have to start JAK inhibitors early and keep patients on them even when they get impatient for a better response,” Mesinkovska said. If JAK inhibitors are stopped early, most patients will lose whatever response they achieved and forgo the opportunity for improvement over time, she warned.

Emma Guttman-Yassky, MD, PhD, chair of the Department of Dermatology at the Icahn School of Medicine at Mount Sinai in New York City, has also become intrigued with the idea that systemic, not just local, control of inflammation might be important. This relates not only to alopecia associated with inflammation but also to inflammation of the skin.

Guttman-Yassky’s attention has also been drawn to GLP-1 agonists as a tool for modifying the risk for immune-mediated conditions. Indeed, she expects to release an announcement about a 1-day symposium devoted to this topic scheduled in the summer. The symposium is being organized by the Inflammatory Skin Disease Summit.

The basis for this meeting is the “growing evidence” that control of inflammation with GLP-1 drugs will not only reduce the risk for obesity and cardiometabolic syndrome but may “also lower inflammation [associated with skin diseases] acting in synergy with anti-inflammatory drugs,” Guttman-Yassky explained at the meeting.

Mesinkovska reported financial relationships with AbbVie, Almirall, Concert, Eli Lilly, Galderma, Incyte, Janssen, L’Oreal, Merck, and Pfizer. Guttman-Yassky reported financial relationships with AbbVie, Almirall, AstraZeneca, Bristol-Myers Squibb, DBV Technologies, Eli Lilly, EMD Serono, Galderma, Incyte, Janssen, Kyowa Kirin, Leo Pharma, Merck, Pfizer, Sanofi Genzyme, and UCB.