By Jan Bowers, contributing writer, May 01, 2012
Alopecia areata (AA) presents a thorny challenge to dermatologists searching for an effective treatment. It can resolve spontaneously with no intervention. There are no treatments approved by the Food and Drug Administration (FDA), which has classified the disease as an orphan indication. A variety of off-label treatments are effective in some patients, but few have been rigorously tested in randomized clinical trials. An analysis of 17 trials by the Cochrane Skin Group, published in the online Cochrane Database of Systematic Reviews (2008;Apr16;(2):CD004413), concluded that “overall, none of the interventions showed significant treatment benefit in terms of hair growth when compared with placebo.” But dermatologists are looking to genetic treatments in hopes of offering relief to patients suffering from what Angela M. Christiano, PhD, a professor in the departments of dermatology and genetics and development at Columbia University researching such treatments, called “the most prevalent autoimmune disease in the United States” during her Hot Topics lecture at the American Academy of Dermatology’s recent 70th Annual Meeting in San Diego.
Lacking a wealth of solid evidence, “most dermatologists are at a loss as to how to treat extensive alopecia areata,” said Jerry Shapiro, MD, clinical professor of dermatology at the University of British Columbia and professor of dermatology at New York University. He attributed the dearth of clinical trials for existing treatments to the fact that AA “is a small niche for drug companies in terms of how much money can be garnered from a particular drug. It does affect almost 2 percent of the population, but most people get better on their own.” Maria K. Hordinsky, MD, professor and chair of dermatology at the University of Minnesota, remarked that “it’s very challenging in this day and age, when we’re supposed to treat everything using evidence-based medicine. Other colleagues in medicine follow protocol, standards of care; that’s what you do in 2012. But in alopecia areata, we’re still figuring it out.”
Although there has been no clear path to curing patients with AA, “there are treatments that do work and can help individuals,” Dr. Shapiro said. In addition, investigators are exploring new avenues of treatment with a variety of lasers and with drugs that target the genes associated with the disease.[pagebreak]
AA is an autoimmune disease involving T-lymphocytes whose pathogenesis is not clearly understood, according to a comprehensive, two-part update published in the Journal of the American Academy of Dermatology (2010;62(2):177-202) and co-authored by Dr. Shapiro along with Abdullah Alkhalifah, MD, Adel Alsantali, MD, Eddy Wang, BSc, and Kevin J. McElwee, PhD. It is found worldwide, affecting patients of all ages and all races. Alopecia areata can cause hair loss anywhere on the body, but it affects the scalp in about 90 percent of cases seen in dermatology clinics. The article notes that the disease is classified according to the extent of hair loss: “patchy AA, in which there is a partial loss of scalp hair; alopecia totalis (AT), in which 100 percent of scalp hair is lost; or alopecia universalis (AU), in which there is a 100 percent loss of all scalp and body hair. Approximately 5 percent of cases will progress to AT/AU.” The AA lesions are typically round or oval, with normal-looking skin (although the skin may also have a peachy or reddened appearance). Up to 50 percent of patients will recover within one year even without treatment, but most will have more than one episode of hair loss, according to the JAAD update. In AT and AU, the chance of full recovery is less than 10 percent. In addition to extent of hair loss, factors indicating a poor prognosis include an ophiasis pattern of hair loss, a long duration of hair loss, young age at presentation, atopy, a positive family history, the presence of other autoimmune diseases, and nail involvement.
The choice of treatment depends on the age of the patient and extent of disease, said Antonella Tosti, MD, professor of dermatology at the University of Miami Miller School of Medicine. “With adults, systemic steroids may be my first line, and maybe intralesional steroids if it’s mild or moderate disease,” she said. “I also use high-potency topical steroids with occlusion.” Parents who bring their child to a dermatologist expect the child to receive some kind of treatment, she noted. “If a child has severe disease, my first choice is topical immunotherapy utilizing sensitizers like squaric acid,” Dr. Tosti added. Another key factor is whether the patient is in the process of losing hair or has already lost all scalp or body hair. “If the patient is losing hair, you have to do your best to stop the hair loss,” Dr. Tosti said. “If it’s alopecia totalis, the patient may be willing to wait — it’s a different psychological situation.”
For parents of children with AA, waiting to see if the hair regrows spontaneously can be especially difficult, Dr. Tosti said. “They have a child who is losing hair, so they do their best to get the doctor to treat the child immediately. The dermatologist can give a treatment that we know is probably not effective, like topical steroids, but I try to be honest and tell parents, you can try doing nothing and wait a little bit to see if the hair grows spontaneously.” The JAAD update by Dr. Shapiro and others also notes that “most AA patients are highly motivated and want treatment.” Their recommendation for first-line treatment is:
- For children younger than 10, a combination of 5 percent minoxidil solution twice daily with a midpotent topical steroid.
- For patients older than 10 with less than 50 percent scalp involvement, intralesional injections of triamicinoline acetinoide (5 mg/mL).
- For adult patients with more than 50 percent scalp involvement, topical immunotherapy with diphenylcyclopropenone.
Because AA is associated with high psychiatric comorbidities such as anxiety and depression, the authors cite the need for large-scale randomized controlled trials to evaluate the efficacy of antidepressants. “We don’t really know the association between alopecia areata and psychosocial morbidity,” Dr. Shapiro said. “I suspect a lot of the psychosocial aspects are a result rather than a cause, but we don’t know that. We do know that the disease is psychologically devastating. It’s one of the few conditions in dermatology that causes people to cry in the office. Hair problems are something that bring people to tears.” Dr. Shapiro and Dr. Tosti both emphasized the importance of support groups for patients with AA (see sidebar, "Support groups a lifeline for patients with alopecia areata").[pagebreak]
GWAS yields important clues
One of the most promising areas of AA research has emerged from a genome-wide association study (GWAS) that used DNA from thousands of AA patients. The patients are participants in a registry established in 2000 and funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Eight thousand patients and controls have agreed to be contacted for future clinical trials, and more than 3,000 serum and DNA samples have been collected. (The registry moved under the stewardship of the National Alopecia Areata Foundation at the end of March and is no longer collecting samples.)
In an article published in an issue of Dermatologic Therapy devoted to AA (2011;24(3):364-368), Dr. Hordinsky discussed the findings of the GWAS and their significance. Key genes found in the GWAS include those linked to T-cell proliferation, and hair follicle genes that activate the NKG2D ligand, which can trigger autoimmunity. The findings suggest three avenues of treatment: blocking NK cell innate immunity, halting activated T-cells, and modifying the inflammatory cytokine network. A group of researchers met in 2010 to discuss the results of the GWAS and identify new drug treatment opportunities.
“Except for genes in the HLA region, the others that were identified were in large part new findings,” Dr. Hordinsky said. “Because it’s an immune-mediated disease, it wasn’t a surprise that some of the immune-type genes showed up. But the fact that we could identify specific genes allowed the group to start thinking about what drugs are in development right now that target those pathways or those particular genes.”
Indeed, Dr. Christiano provided an update on the work toward finding such a drug during the Hot Topics session at the AAD’s recent 70th Annual Meeting in San Diego. She said that research has focused on the NKG2D ligand; she and her fellow researchers determined that those ligands were fueled by IL-15. Blocking IL-15 had shown effectiveness in the treatment of rheumatoid arthritis, psoriasis, and celiac disease, she said, so researchers are exploring both topical and infusion treatments that may prove helpful for alopecia patients. Abatacept, now used in the treatment of rheumatoid arthritis, will be tested in patients with AT or AU in a clinical trial at Columbia University after being proven to prevent the onset of alopecia in a mouse study.
“We’ve entered a new era; we can now be more focused and strategic as we try to find a drug that will work for this disease,” Dr. Hordinsky said. “Patients are demanding progress and results, and the community of researchers in dermatology is committed to finding a cure.”
Lasers explored for patchy AA
Although some dermatologists, including Antonella Tosti, MD, professor of dermatology at the University of Miami Miller School of Medicine, use the excimer laser to treat alopecia areata (see main article), laser therapy has not been a focus of AA research in the United States. “I think that’s because lasers are an evolving area,” said Maria K. Hordinsky, MD, professor and chair of dermatology at the University of Minnesota. “There are a number of small published studies looking at the excimer laser in particular, in people with patchy alopecia areata and those who have lost their eyebrows, but there aren’t a lot of large studies. However, there’s a movement in the country now to organize a multi-center study that will really examine the efficacy of the excimer laser. The investigators and the type of laser have been identified, but the protocol still needs to be finalized.”
Outside the U.S., a number of researchers are testing the excimer laser and, in one center, the fractional photothermolysis laser. The 308-nm laser was tested by a group of French dermatologists who reported their results in a letter to the editor of JAAD (2004;51(5):837-838). They treated nine patients twice a week for a maximum of 24 sessions; each treated lesion had an untreated lesion on the opposite side as a control. All five patients with alopecia partialis (patchy AA) showed hair regrowth in the treated patches, compared with none of the four patients with alopecia totalis (AT) or alopecia universalis. None of the five patients who responded lost their hair over a three-month follow-up period. The group concluded that the laser appears to be an effective therapy for patchy AA, but restated the need for more and larger studies.
A Kuwaiti dermatologist, Nawaf Al-Mutairi, MD, tested the 308-nm excimer laser on 18 patients with 42 recalcitrant patches that had not responded to other AA treatments. Each lesion was treated twice a week for a maximum of 24 sessions over three months; each patient had at least one lesion that was left untreated, as a control site. The results, published in Dermatologic Surgery (2007;33(12):1483-1487), showed regrowth of hair in 17 (41.5 percent) treated patches and no control patches. Thirteen of 18 lesions on the scalp showed complete regrowth, although at six-month follow up, two patients who had shown complete regrowth earlier showed a recurrence of hair loss. Dr. Al-Mutairi concluded that this laser “appears to be a good therapeutic option for patchy AA of the scalp and in some cases with patchy AA of the beard area,” but not for AT or for patchy areas on the extremities. He recommended further investigation of the excimer laser in combination with topical agents, and in comparison with other laser systems.
An erbium glass fractional laser was used to treat a patient in South Korea with multiple large AA lesions on the frontal scalp. He had previously been treated with 5 percent minoxidil, topical steroid, and intralesional corticosteroids. After 24 weekly treatment sessions, with two passes of the laser per session, the patient was reported to have complete regrowth in all lesions, with no relapse observed during a six-month follow-up period. In his article describing the case, posted on the laser manufacturer’s website in 2009, Beom Joon Kim, MD, PhD, theorized that the laser’s mechanism of action might be the induction of T-cell apoptosis and enhancement of hair growth. Dr. Kim, who is associate professor of dermatology at Chung-Ang University College of Medicine in Seoul, said he has continued to test both the CO2 and the erbium glass fractional lasers, as well as the excimer laser. “In alopecia totalis and universalis, it was difficult to obtain a good clinical outcome” with fractional thermolysis, he noted. “But in some cases of alopecia areata, patients showed good responses after the first two or three treatments. When new hair is seen on the lesion, I stop irradiating with the erbium glass laser because it can damage the hair shaft and cause breakage. But you could apply the excimer laser to new hair growth.”
In the U.S., a researcher is taking a different approach to investigating laser therapy for alopecia areata, using a low-level (655-nm) laser comb cleared by the FDA and marketed for home treatment of androgenetic alopecia. Joaquin Jimenez, MD, research associate professor of dermatology at the University of Miami Miller School of Medicine, tested the device on six mice with induced AA (a control group of six mice received a sham treatment with the laser turned off). His results, published in Lasers in Medical Science (2012;27(2):431-436), showed hair regrowth in all six of the laser-treated mice and none in the control group. “What I believe has been used in other countries is an attempt to kill or incapacitate the T-lymphocytes,” Dr. Jimenez said. “Our approach is to enhance the hair regrowth. This wavelength has been shown to stimulate ATP in the mitochondria and stimulate the growth of hair and of cells overall.” The next step will be to test the device in combination with a T-cell inhibitor such as an immunosuppressant, again using mice, Dr. Jimenez said. “Depending on how that works out, we would then hope to take that to the clinical setting using human subjects.”
Support groups a lifeline for patients with alopecia areata
Alopecia areata “is a disease that destroys the life of the patient,” exclaimed Antonella Tosti, MD, professor of dermatology at the University of Miami Miller School of Medicine. “Part of my counsel to the patient is that it’s very, very important that they find a support group.” Jerry Shapiro, MD, clinical professor of dermatology at the University of British Columbia and professor of dermatology at New York University, has gone one better, starting his own support group in Vancouver. “Dermatologists can initiate this process; they can even make their offices available for certain nights every few months,” he said. “Because they know all the patients, they can bring them together. Some people don’t want to discuss their disease with other people, but for a lot of patients, it helps.”
The National Alopecia Areata Foundation (www.naaf.org) serves as a resource for patients and physicians, offering a message board, research updates, advice on living with alopecia areata, fundraising events, and a marketplace of products for people with alopecia. The organization’s website lists support groups, with contact information, for 46 states and offers advice for those wanting to start a group. In a Dermatologic Therapy article (2011;24(3):302-304) about AA support groups, Victoria D. Kalabokes, president and CEO of the National Alopecia Areata Foundation, emphasized the impact that diseases of the skin have on an individual’s self-perception. “Support group members tell us there is a tremendous power in sharing experiences with others and gaining support from others who are struggling,” she wrote. “They find their own identity and nurture their own needs.”