Going bald can be emotionally upsetting for anyone. But imagine losing all of your hair. Not just the hair on your head – but everywhere.
Attorney Laura Freeman of Phoenix, Arizona has been living with this kind of hair loss since she was 22. She’s among an estimated 6.8 million Americans who have alopecia areata, an autoimmune disease that starts out with small bald patches that can progress to loss of scalp and facial hair (alopecia totalis) and, in rare cases, total loss of body hair (alopecia universalis).1
For Laura, a 41-year-old mother of four young children, periodic patchy hair loss began after a bout with chicken pox when she was a toddler. “Sometimes I would have large bald spots all over my head that were impossible to conceal. Other times, they would be small and hardly noticeable,” she recalls. “Yet, I remember a constant sense of worry about it. I didn’t have hair like the other kids. I never would. Children made fun of me. I remember store clerks asking my mom if I had cancer.”
For several years, Laura tried minoxidil (Rogaine), which produced only peach fuzz hair growth and caused rashes. She also had cortisone injections into her scalp. The shots worked, but they were painful and caused thinning skin, so she was forced to abandon that approach as well.
In the summer of 1998, as she was preparing to go to law school, Laura lost her eyebrows and eyelashes and became totally bald. Her only option: wearing a wig.
“It was expensive and depressing and necessary,” Laura remarks. Her lack of eyelashes and eyebrows are especially noticeable, even with the wig. “After I got my wig, I remember telling friends who asked about it or who wondered if my hair was real. It’s still socially uncomfortable for me even at the age of 41.”
A Yale University study of almost 2,000 patients published online in July finds that alopecia areata causes a negative impact on quality of life, particularly in social functioning, psychological and emotional distress.2 “The results of this study lend further support to the fact that AA [alopecia areata] is not a ‘cosmetic’ problem but rather a medical disorder with important negative health consequences,” the study authors conclude.2
Clinical trials of three drugs FDA-approved for other autoimmune disorders may one day change that outlook for alopecia areata patients.
Roots of the Problem
Our hair follicles cycle between an active growth phase – anagen -- and a resting phase -- telogen. We normally lose 60 to 100 hairs every day, as hair is shed by follicles in telogen to make room for new growth (hair grows around a half inch each month). Excessive hair loss can be triggered by stress, pregnancy, illness, genetics (male pattern baldness, or androgenic alopecia) and autoimmunity.
In autoimmune alopecia areata, killer T-cells (cytotoxic T-lymphocytes), the shock troops of the immune system, target hair follicles. T-cell invasion doesn’t destroy the follicles and hair root, but the resulting inflammation causes the follicles to shrink, forcing them into a dormant state that dramatically slows production of hair.3 Because the follicles are still alive and hair roots are still supplied with stem cells, they have the potential to produce hair again. Indeed, in some people with alopecia areata, hair starts to grow again spontaneously.1
The trio of drugs being tested in clinical trials for alopecia block a family of enzymes called Janus kinases (JAKs) involved in inflammatory cell-signalling, the same pathway that triggers killer T-cells to attack hair follicles. Blocking JAK enzymes shuts off that signal, explains Angela M. Christiano, PhD, a professor in the Departments of Dermatology, Genetics and Development at Columbia University in New York. Dr. Christiano has a personal motivation for her research; she lost her own hair to alopecia areata in 1995 (it has since grown back).
JAK inhibitors not only appear to prevent T-cells from attacking the hair follicle but also seem to act locally, awakening dormant follicles, adds Dr. Christiano. In lab experiments with mouse and human hair follicles, her team found that JAK inhibitors could promote rapid, robust hair growth.4
In 2015, the Columbia researchers reported that the JAK inhibitor ruxolitinib restored almost complete hair growth in three individuals with longstanding and severe disease.5
“The hair follicle is one of a handful of body sites normally protected from the immune system. We call this ‘immune privilege,’” Dr. Christiano explains. T-cells violate the immune privilege of hair follicles in anagen, leading to loss of the growing hair shaft.6 “To treat it we not only need to control the immune response but also restore the immune privileged state of the hair follicle,” she adds. So far, researchers haven’t found a way to do that.
Judging the JAKs
The three JAK inhibitors being tested in alopecia areata are already in use for other disorders.
Tofacitinib (Xeljanz) is approved for rheumatoid arthritis. Ustekinumab (Stelara) is used to treat psoriatic arthritis. A third JAK inhibitor, oral ruxolitinib (Jakafi) is used to treat the bone marrow disorder myelofibrosis. Their FDA-approved status means much is known about the drugs’ safety. However, their effectiveness in alopecia areata has only been tested in small numbers of patients.
A preliminary study of three patients given ustekinumab injected under the skin (subcutaneously) was conducted at Mount Sinai Hospital in New York. Just-published results show that after 20 weeks, hair growth ranged from 25% to 85% in those patients.7 The patient with total hair loss (alopecia universalis) had the greatest amount or hair regrowth -- over 90%. The researchers also reported a decrease in inflammatory markers, and normalization of hair keratin and immune-related genes seen in scalp biopsies after 20 weeks of treatment.7 A larger study is now underway.
Another newly-published study, from researchers at Yale University, reported successful hair regrowth in a patient using topical ruxolitinib.8 A follow-up study with multiple patients is being planned.
Massachusetts-based Concert Pharmaceuticals announced in May that a modified analogue of ruxolitinib, dubbed CTP543, will start Phase 1 clinical evaluation later this year, with efficacy studies expected in 2017.9 CTP543 targets two JAK enzymes: JAK-1 and JAK-2.
As with other drugs that dampen the immune system, oral or injected JAK inhibitors can increase the risk for infection. Topical formulations designed expressly for the scalp may pose less of a risk, but high concentrations will likely be needed to produce an effect, cautions Dr. Christiano.
Larger and longer clinical trials will be needed to establish JAK inhibitors safe and effective for reversing alopecia areata.
The Genetic Connection
Dr. Christiano and her colleagues have identified approximately 14 genes that predispose people to alopecia areata. Among them are genes involved in the activation of JAK enzymes and the resulting inflammation that drives alopecia areata. Those genes are also associated with rheumatoid arthritis, thyroid disease, and celiac disease.
In fact, people with alopecia areata are at higher risk for other autoimmune problems, such as thyroid disease or vitiligo, which produces patches of light or pigment-free skin.
Genetic connections also mean people with alopecia areata are more likely to have family members with autoimmune diseases. Laura was diagnosed with Hashimoto’s thyroiditis in 2013; her mother has rheumatoid arthritis.
“I am constantly worried about taking on another autoimmune disease. I worry about my children developing autoimmune disease as well,” says Laura. “One of my daughters was having gastrointestinal issues this year. Both her gastroenterologist and allergist suggested that with my history of autoimmunity that she was at risk for a GI autoimmune disease -- Crohns, Colitis, or Celiac. So far, she has tested negative, thank goodness.”
According to the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), loss of hair meant to protect the body can also make people vulnerable to infections and allergies. For example, your eyelashes and eyebrows are meant to keep foreign particles from getting in your eyes; hair in your nose is meant to trap dust and germs as well as foreign bodies.
Dr. Christiano is now experimenting with stem cells to promote hair growth, since these cells have the capacity to morph into any type of tissue. The idea is to inject stem cells enriched with growth factors into hair follicles. She’s formed a start-up, aptly named Rapunzel, to gather venture capital funding for the research.11
So far, Dr. Christiano and colleagues have been able to grow hair in tissue culture scaffolding in the lab.11 She hopes one day the strategy may not only help patients with alopecia areata -- but also people with hereditary hair loss.
1 Alopecia Areata Foundation, Alopecia Areata. https://www.naaf.org/alopecia-areata. Accessed July 28, 2016.
2 Liu LY, King BA, and Craiglow BG. Health-related quality of life (HRQoL) among patients with alopecia areata (AA): A systematic review. J Am Acad Dermatol. DOI: http://dx.doi.org/10.1016/j.jaad.2016.04.035. Published online July 16, 2016. 0190-9622. Accessed July 28.
3 Xing L, Dai Z, Jabbari A, et al., Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nature Medicine. 2014;20:1043-1049. doi:10.1038/nm.3645.
4 Harel S, Higgins CA, Cerise JE, et al., Pharmacologic inhibition of JAK-STAT signaling promotes hair growth. Science Advances. 23 Oct 2015:Vol.1, no. 9, e1500973. DOI: 10.1126/sciadv.1500973 http://advances.sciencemag.org/content/1/9/e1500973.
5 Mohammadi D, A Ray of Hope for Alopecia Areata Patients. The Pharmaceutical Journal, May 2016, Vol 296, No 7889, online | DOI:10.1211/PJ.2016.20201092. http://www.pharmaceutical-journal.com/news-and-analysis/features/finding-new-treatments-for-alopecia-areata-patients/20201092.article Accessed August 1, 2016.
6 Villasante Fricke AC, Miteva M. Epidemiology and burden of alopecia areata: a systematic review. Clinical, Cosmetic and Investigational Dermatology. 2015; 8: 397–403. https://dx.doi.org/10.2147/CCID.S53985. Accessed July 28, 2016.
7 Guttman-Yassky E, Ungar B, Noda S, et al., Extensive alopecia areata is reversed by IL-12/IL-23p40 cytokine antagonism. J Allergy Clin Immunol. 2016;137(1):301-304. DOI: http://dx.doi.org/10.1016/j.jaci.2015.11.001
8 Craiglow BG, Daniel Tavares D, King BA. Topical Ruxolitinib for the Treatment of Alopecia Universalis. JAMA Dermatol. 2016;152(4):490-491. doi:10.1001/jamadermatol.2015.4445.
9 Concert Pharmaceuticals Unveils CTP543 for Treatment of Alopecia Areata. Business Wire, May 4, 2016. http://www.businesswire.com/news/home/20160504006458/en/Concert-Pharmaceuticals-Unveils-CTP-543-Treatment-Alopecia-Areata. Accessed August 9, 2016
10 National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). Questions and Answers About Alopecia Areata. April 2015. http://www.niams.nih.gov/health_info/alopecia_areata/ Accessed July 28, 2016.
11 Keshavan M, There’s new hope for treating hair loss – in women, too. STAT News.August 12, 2016. https://www.statnews.com/2016/08/12/hair-loss-biotech-women/ Accessed August 16, 2016.