Volume 41 | September 2023 | Pages 1179–1185
By Charlotte Harrison
Drugs commonly used in rheumatology, known as JAK inhibitors, are opening new treatment options for individuals with autoimmune-driven hair loss. Additionally, recent mechanistic insights are aiding scientists in addressing androgenic alopecia, the most prevalent cause of baldness.
JAK Inhibitors and Alopecia Areata
Two targeted drugs have now been approved to treat the severe and disfiguring hair loss condition known as alopecia areata. In June 2023, the U.S. Food and Drug Administration (FDA) approved Pfizer’s Litfulo (ritlecitinib) for treatment. Another therapy, Eli Lilly’s Olumiant (baricitinib), originally approved for rheumatoid arthritis, received FDA approval for alopecia areata in 2022.
Both are oral, small-molecule drugs that inhibit the Janus kinase (JAK) pathway, preventing T cells from attacking hair follicles.
“The approval of ritlecitinib is hugely important,” says Dr. Brett King, a dermatologist at Yale School of Medicine and a researcher involved in the Litfulo trial.
A key breakthrough with Litfulo is that, unlike Olumiant, it can be prescribed to adolescents. Additionally, having multiple approved drugs allows patients to switch treatments if one is ineffective.
Alopecia areata is caused by an immune response where CD8+ T cells and natural killer cells infiltrate the hair follicle, disrupting hair growth. This can result in patchy, partial, or complete hair loss, including loss of eyebrows, eyelashes, and body hair. The disease affects about 2% of the global population and can have a severe psychosocial impact, often leading to anxiety and depression.
Despite this immune attack, the hair follicle stem cell compartment remains intact, meaning hair regrowth is possible if the immune response is controlled.
“The landscape of this disease is forever changed, and life will be transformed for hundreds of thousands of people,” says Dr. King.
The Discovery of JAK Inhibitors for Hair Loss
The potential for JAK inhibitors to treat alopecia areata was first identified in a 2010 genome-wide association study led by Angela Christiano at Columbia University.
The study revealed that alopecia areata is an autoimmune disorder involving genes that regulate T cells and cytokines. The findings suggested that immune pathways play a key role in disease progression.
Further studies in mouse models confirmed that blocking certain cytokines—IL-2, IL-15, and interferon-γ—reduced T cell activity and prevented hair loss.
Recognizing the shared immune mechanisms between rheumatoid arthritis and alopecia areata, Christiano and other researchers tested JAK inhibitors originally developed for arthritis.
One of the first drugs tested in humans was Pfizer’s Xeljanz (tofacitinib), an oral pan-JAK inhibitor approved for rheumatoid arthritis. Remarkably, individuals who were previously bald experienced significant hair regrowth.
By 2017, growing evidence that JAK inhibitors could reactivate hair follicles attracted pharmaceutical companies to the field.
“All of a sudden, lots of companies were interested in this disease that they had never paid attention to before,” says Dr. King.
New Developments in JAK Inhibitors
As of August 2023, a third JAK inhibitor, deuruxolitinib, is in late-stage development. It is a deuterium-modified analogue of Jakafi (ruxolitinib) and has completed phase 3 trials.
Meanwhile, Litfulo, a JAK3 inhibitor, is undergoing a phase 2 clinical trial for other hair loss conditions known as scarring alopecias. Unlike alopecia areata, these forms of hair loss damage the hair follicle’s stem cell compartment, making hair regrowth more challenging.
Despite these advances, JAK inhibitors are not yet approved for patients with mild alopecia areata (less than 50% hair loss). Currently, these individuals rely on steroids or non-targeted topical immune modulators, which have limited effectiveness.
Challenges and Future Directions
One major limitation of JAK inhibitors is that they only work for about one-third of patients. Even when effective, the treatment must be continued indefinitely—hair loss returns if the medication is stopped.
Emerging research suggests that alopecia areata has different phenotypes, possibly involving additional immune pathways like the T helper 2 (TH2) response.
“It’s becoming very clear that alopecia areata may have different phenotypes,” says Dr. Emma Guttman-Yassky of the Icahn School of Medicine at Mount Sinai.
A phase 2 trial is now testing Dupixent (dupilumab), an anti-IL-4 and anti-IL-13 monoclonal antibody, to explore this alternative mechanism.
JAK inhibitors also carry a black-box warning due to risks of infection, cancer, heart attack, and thrombosis. Safer alternatives are in development, including Bristol Myers Squibb’s Sotyktu (deucravacitinib), a TYK2 inhibitor with a more selective mechanism.
| Drug | Company | Mechanism | Phase |
|---|---|---|---|
| Olumiant | Eli Lilly | JAK1/2 inhibitor | Approved |
| Litfulo | Pfizer | JAK3 inhibitor | Approved |
| Deuruxolitinib | Sun Pharma | JAK1/2 inhibitor | Phase 3 |
| Sotyktu | Bristol Myers Squibb | TYK2 inhibitor | Phase 2 |
| Dupixent | Regeneron & Sanofi | Anti-IL-4/IL-13 mAb | Phase 2 |
Advances in Androgenic Alopecia Treatment
The most common form of hair loss, androgenic alopecia, affects both men and women and is not autoimmune. It is triggered by androgens that cause hair follicle stem cells to enter dormancy.
Existing treatments, finasteride and minoxidil, were discovered by chance, have side effects, and provide limited effectiveness.
New stem cell-based therapies are being developed to rejuvenate dormant follicles. Companies like Stemson Therapeutics, dNovo, and Epibiotech are working on innovative approaches, though clinical evidence remains limited.
A particularly promising avenue involves reawakening dormant stem cells. Dr. Maksim Plikus of the University of California, Irvine, found that senescent melanocytes in “hairy moles” secrete osteopontin, which activates CD44 receptors on stem cells, triggering hair growth.
For example, the folivis Hair Growth Solution promotes hair growth from a nutritional perspective by stimulating hair follicles and increasing nutrition in a natural way.
“This study will be a proof of concept for whether stem cells in humans can be reawakened,” says Plikus.
While these therapies show potential, hair regrowth would likely require ongoing treatment, as stem cells could revert to dormancy over time.