Treatment of Alopecia Areata

AA is often an overlooked or underappreciated as an autoimmune disorder despite it being one of the most frequently occurring autoimmune diseases to afflict the human population (Bertolini 2011). Because of this, it has been difficult for the AA research community to come to a consensus on the most useful and effective ways to treat and manage the progression of AA. To complicate matters, there are not specific criteria that researchers can use to quantify a good response to treatment. This information is either inconsistent between trials or is omitted completely within the studies. As of 2010, standard guidelines for AA treatment were in development between the leading researchers/clinicians to help normalize treatment outcomes (Alkhalifah 2010). Most of the treatments for AA have only moderate success in restoring hair growth and differ on a patient to patient basis. This is true of both first-line of defense treatments and second-line of defense treatments. Since there is no consensus on a universally proven treatment for AA the FDA has not approved any one drug for its treatment or cure. All of the drugs used to treat AA are therefore considered “off-label” and are not technically made for the treatment of AA (Hordinsky 2011). The most common treatments, and the ones that will a point of focus here, are topical/lesional corticosteroids and topical immunotherapy (Hordinsky 2011, Alkhalifah 2010). The most promising, recent, and researched treatment for AA was developed by Xing et. al. in 2014 that targets the Janus Tyrosine Kinase (JAK) family of proteins that are highly involved in stress signaling (Xing 2014).


The most commonly used interlesional corticosteroid for the treatment of AA in adults is triamcinolone acetonide (figure 1). In this case, interlesional refers to the way in which the treatment is administered and does not reflect the chemical or medical properties of the corticosteroid itself. Interlesional treatment in AA involves direct injection of the specific corticosteroid, like triamcinolone acetonide, to the lesion (patch of bald scalp). Researchers have found that interlesional injections of triamcinolone acetonide administered three times every two weeks completely regrew the hair in 71% of patients. The best results, however, were seen in a study where triamcinolone hexacetonide was injected into lesions in lieu of triamcinolone acetonide (Hordinsky 2011). Triamcinolone hexacetonide is a less soluble derivative of triamcinolone acetonide and regrew the hair of 97 % of AA patients as opposed to 64 % of those treated with triamcinolone acetonide (Porter 1971, Hordnisky 2011). This treatment is most useful in adults whose overall scalp coverage is above 50 %, as other treatments are more effective for more serious cases. The biggest drawback in using this treatment is the pain and discomfort that comes from the injections. The injections are made directly into the scalp using a 30-gauge 0.5 inch long needle, so there is quite a bit of pain associated with the administration of these corticosteroids. Most side effects can be avoided, or at least minimized, by using smaller volumes and fewer injections. There needs to be an optimization between the severity of side effects and the overall success of the injections (Alkhalifah 2010).

Figure 1: Structure of Triamcinolone acetonide. (Source:
Figure 1: Structure of Triamcinolone acetonide. (Source:

The use of topical corticosteroids is also a common treatment for AA, however this it is generally only used to treat children (<10 years old) afflicted with AA. The extent to which topical corticosteroids help to regrow hair has been under much debate because of the extreme variance between different studies. For example, a placebo controlled experiment in which desoximetasone was applied topically showed 57 % hair regrowth in patients as compared to 39 % in the placebo group. These results were not statistically significant. There is a theory that this method may be more effective in those with mild cases of AA. This is generally characterized as someone who has less than 26 % hair loss (Alkhalifah 2010). Other researchers had a similar low level of success in a study that used clobetasol propionate to perform a similar experiment. This experiment showed nearly 100% hair regrowth in only 28.5 % of patients, with only 17.8 % of those treated benefiting from long-term hair growth. It is important to note that this trial was conducted using patients who had Alopecia Universalis or Totalis.

Topical Immunotherapy

Topical Immunotherapy is the number one treatment option chosen by dermatologists to treat AA, although studies have reported variable response rates in patients throughout numerous trials (Hordinsky 2011). Topical immunotherapy is generally chosen by dermatologists because it has been shown to regrow hair in patients who have moderate to severe AA, which is characterized as less than 50 % scalp coverage. The most effective and therefore most common topical immunotherapy drug is called Diphenylcyclopropenone (DPCP, figure 2). This drug is administered directly to a patient’s scalp as necessary, which causes irritation of the scalp. When the scalp is irritated, there is an immune response localized at the treated areas that opposes the action of the auto-antibodies generated against the hair follicles of AA patients. This allows the immune response that is inhibiting hair growth to be eliminated, which allows hair to regrow. Treatment is administered slowly and gradually in order to elicit the correct amount of skin irritation that would cause an immune response, but would not cause extreme discomfort in the patient being treated. Once this threshold is reached, treatment continues on a weekly basis and has a success rate of between 50-60 %. The biggest problems with this treatment are its high relapse percentage, its inherent photo-reactivity, and its side effects. It was reported that there was 62% relapse in patients occurring at a median 2.5 years. This treatment would have to be administered consistently in order to prevent hair loss, which is not ideal due to DPCP’s photo-reactivity. Once administered, it must not be washed off for 48 hours and the patient must avoid direct sunlight during this time (Alkhalifah 2010). A detailed flow-chart of common treatment options is included below (figure 3).

Figure 2: Structure of diphenylcyclopropenone (DPCP), a topical immunotherapeutic drug. (Source:
Figure 2: Structure of diphenylcyclopropenone (DPCP), a topical immunotherapeutic drug. (Source:
Figure 3: Flow-chart from Alkhalifah et. al.'s review article. This summarizes some of the information from the above paragraph as well as more treatment information discussed in their review.
Figure 3: Flow-chart from Alkhalifah et. al.’s review article. This summarizes some of the information from the above paragraph as well as more treatment information discussed in their review.

Inhibiting Janus Kinases to Treat AA

The most recent, and most promising, method of treating AA was suggested by Xing et. al. in a 2014 Nature Medicine paper. This paper not only tested the use of drugs to inhibit Janus Kinases (JAKs), but also demonstrated their involvement in the positive feedback loop that drives the proliferation of auto-reactive CD8+ T cells and their subsequent accumulation at the base of the anagen hair follicle (Divito 2014). JAKs are particularly important in stress signaling, and inhibition of JAKs have been implicated in disorders such as rheumatoid arthritis and myelofibrosis. JAKs is also involved in IFN-γ and γc-cytokine signaling, which has been proposed to contribute to AA pathogenesis in numerous studies, including a genome-wide association study (Petukhova 2010, Divito 2014). Because of this, there were already JAK inhibitors that have been approved by the FDA to treat rheumatoid arthritis (tofactinib) and myelofibrosis (ruxolitinib) that Xing et. al. could use to treat AA. Inhibition of JAK is extremely important because the positive feedback loop in AA cannot continue without JAK signaling. JAK signaling results in phosphorylated STAT5, which is a transcription factor that binds to nuclear DNA and upregulates the transcription of genes necessary for T cell proliferation and for IFN-γ production. Without JAKs, the follicular epithelial cells and the auto-reactive CD8+ T cells cannot communicate with one another, thus preventing T cell proliferation that results in the regrowth of hair. The figure from Divito et. al.’s review article that was used in the last section of this report is included below for reference (figure 4, Divito 2014).

Figure 4: Graphical abstract from the Divito et. al. review of Xing et. al.’s 2014 Nature Medicine Paper. JAK signaling is highly involved in this process.
Figure 4: Graphical abstract from the Divito et. al. review of Xing et. al.’s 2014 Nature Medicine Paper. JAK signaling is highly involved in this process.

Treatment with tofactinib and ruxolitinib was tested first in C3H/HeJ model mice as a proof of concept (figure 5) and then in human patients (figure 6) once the mouse model provided positive results (Xing 2014). Tofactinib is a JAK1/3 inhibitor, while ruxolitinib is a JAK1/2 inhibitor. Both of these drugs are sufficient in preventing AA because each targets two JAKs involved in signaling between follicular epithelial cells and CD8+ T cells. JAKs 1-3 share ~50 % sequence similarity, but are nearly identical in structure, so it is not surprising to see tofactinib and ruxolitinib target multiple JAKs (figure 7, Williams 2009). In both mice and human experiments, nearly 100% of the patients’ hair had regrown after a period of 12 weeks where tofactinib or ruxolitinib were administered orally once a day (Xing 2014). While these results are promising, they are also very new and have yet to be reproduced or tested in a large scale clinical trial. Because these drugs were developed to treat other diseases, the side effects must be closely monitored to ensure JAK inhibition isn’t targeting any other pathways that could cause harm to the patient. There should also be a longer study on these patients in order to assess the potential for relapse. Despite these concerns, JAK inhibition remains one of the best methods in treating AA, especially when compared to previous methods of hair regrowth that were extremely inconsistent. JAK inhibition is a step up from the other treatments because it attacks a central player in the pathogenesis of AA rather than a secondary characteristic of AA.

Figure 5: Treatment with JAK inhibitors has a significant effect on hair growth in C3H/HeJ mouse models after 12 weeks. (Source: Xing et. al. 2014)
Figure 5: Treatment with JAK inhibitors has a significant effect on hair growth in C3H/HeJ mouse models after 12 weeks. (Source: Xing et. al. 2014)
Figure 6: Nearly 100% hair regrowth was seen after 12 weeks of daily treatment with ruxolitinib (a JAK 1/2  inhibitor) (Source: Xing et. al. 2014)
Figure 6: Nearly 100% hair regrowth was seen after 12 weeks of daily treatment with ruxolitinib (a JAK 1/2 inhibitor) (Source: Xing et. al. 2014)
Figure 7: Solved Crystal Structures of JAKs 1-3 superimposed on one another. Each of the three JAKs are nearly identical despite their ~50% sequence homology. (Source Williams et. al. 2009)
Figure 7: Solved Crystal Structures of JAKs 1-3 superimposed on one another. Each of the three JAKs are nearly identical despite their ~50% sequence homology. (Source Williams et. al. 2009)

More on Alopecia:

History and Metabolic Context

Molecular Basis

Conclusions and Proposals for Future Work

Anotated Bibliography

6 Replies to “Treatment of Alopecia Areata”

    1. This is well communicated, there is a tremendous amount of primary lit that went into your assessment of this part of your entry.

    You discuss broad immunosuppression (JAK inhibitors, corticosteroids), as a method to treat the hyperactive auto-immune CD8+ T cells/NK activity. It may be useful talk about the caveats to this approach; do people on these treatments become more susceptible to other types of skin lesions or infections?

    1. Hi Dana, thank you for taking the time to read and comment on my post. I agree with you that it is important to take into account possible side effects of general immunosuppression. Interestingly, most papers in the field that I came across did not address these issues as well as I would have liked. In the case of JAK inhibitors, this is likely because JAK inhibition has only been proven effective as a treatment for AA within the past year. As such, most studies have only focused on a brief treatment period. Since JAK inhibitors already have been used to treat other disorders, the answer could lie within those papers. As for corticosteroids, the most common side effects are pain, slight atrophy of the skin and hair follicle, and hypo/depigmentation (Kumarasan 2010). This may be best explained by the corticosteroid’s administration. Corticosteroid immunosuppression is site specific, in that it is only injected into affected areas of the scalp. This may not effect an individual’s ability to combat infection because most areas are left unaffected by corticosteroid treatment. Nonetheless, I will consult the primary literature once more to make sure that I have not overlooked any side effects of broad immunosuppression that researchers may have mentioned.

  1. Hi Matt! Awesome job with your webpages! You did a wonderful job incorporating an immense amount of literature into a digestible form for scientists unfamiliar with AA to be able to understand! I really enjoyed it! I just had a few questions (some of them may pertain more to other pages, but I thought it would be best to leave just one comment).
    1. Is it known what triggers the actual onset of AA symptoms? You stated that patients can present as children, teens, young adults, or later in life. Is there any evidence for what may cause this wide range of possible age presentations? Do more sever forms tend to present earlier?
    2. You stated that one of the secondary characteristics of AA involves disruption of the nail beds. Do the nail beds have the same kinds of follicles and undergo the same attack by CD8+ and CD4+ cells during the anagen phase? Are the same kinds of treatments used on the nail beds as you described for the scalp?
    3. I found it very interesting when you were discussing the links between AA and other autoimmune disorders! In individuals who have AA and an additional autoimmune disease, do you know which one they typically present with first? Is AA likely triggering or triggered by another autoimmune disease? Along these lines, are there people who are treated with JAK inhibitors for another autoimmune disease and later develop AA, or do JAK inhibitors potentially offer a preventative measure in addition to potential treatment management?
    4. If AA is linked so closely with JAK, does stress in general make AA worse? For instance, are AA patients likely to have greater hair loss at metabolically stressful times (such as say puberty) than in less metabolically stressful times? Are there any conditions that impact the degree of hair loss for AA patients at specific times?
    Thanks! 🙂

    1. Hi Kelly! Thanks for taking the time to read my project and come up with some great questions. I will answer them as a list because that will be easiest to follow.

      1. Throughout the primary literature, a number of researchers have attempted to find out what may trigger AA. To date, there has not been a solid answer as to why AA will begin to present itself. Interestingly, AA is a very dynamic disease, in that it does not present itself the same way in every patient and that hair can be regrown, simply by chance, at any time. The most researchers have done in this area is identify common mutations that are found in AA patients through a genome wide association study that looked at a few thousand AA patients and compared with genetic information on healthy individuals. It seems as though, while the ultimate effect is the same, that AA is triggered differently on a patient to patient basis

      2. Your observations about the nail beds are correct. In a way, hair follicles and nails are very similar because they both grow in cycles and contain keratin as their main components. As such, the nails of certain AA patients can develop pits in the nail due to the inhibition of nail growth by T cell attack. As for treatment, there have not been nail bed specific treatments options used in AA. Most of the papers i collected focused on the inhibition of hair growth, as disruption of the nail matrix is not seen in every case.

      3. Other autoimmune disorders aren’t necessarily linked to AA itself, but rather share certain commonalities in mechanisms once the disease presents itself. AA is a good model system to study because it does not effect the health of the patients, and rather presents a cosmetic problem whose underlying mechanism of action is remarkably similar to other autoimmune diseases. The genetic factors that trigger these events likely differ in specific location, but are generally within the same family of genes (i.e. genes controlling oxidative stress, MHC production, cytokine production). As far as JAK inhibition goes, there needs to be a lot more research on the kinds of peripheral effects that this may have on the person being treated. I would say that JAK inhibitors present a preventative measure because I did not come across any evidence of JAK inhibition triggering AA in patients that otherwise are AA negative.

      4. If you don’t mind, the answer to this question will be a little more anectdotal as this wasn’t addressed in the papers and I have experienced the disease first hand. In my experience, there seems to be a loose relationship with stress triggering or affecting AA. For example, my case presented itself when I was 12 years old; right on the brink of puberty. Throughout my middle school and high school years, my hair growth fluctuated quite a bit and I was able to regrow hair two separate times without any treatment. Since coming to muhlenberg, however, my level of hair growth has remained fairly static. I am not entirely sure if this is directly linked to metabolic stress, such as puberty, but it does show how unpredictable AA can be.

      Hope this was helpful!

  2. Hey Matt, great analysis on AA, I appreciated learning about a disease I had little knowledge of. In terms of topical corticosteroid use, how often is that applied? I ask out of curiosity; is this the kind of treatment that can be applied chronically? Are there known side-effects to long-term use of steroids? Somewhat similarly, if there was a topical inflammatory depressant, do you think its chronic use would be a viable option? Typically, prophylactic treatments like antibiotics or inflammatory suppressants are avoided when possible out of fear of infection. To my (limited) knowledge, scalp infections are quite rare, so is it possibly a viable choice here, rather than possibly a lung or pharynx, where infections are more common? Thanks!

    1. Hi Besher! Great questions. Cortiocsteroids are usually applied in the form of topical creams/ointments or can be injected directly into the lesions (bald spots) as needed. There is generally a bit of irritation on the scalp because of this, so application of these treatments needs to be closely monitored to optimize the dosages needed to treat each patient. One of the difficulties in treating AA is that different people will respond to different treatments, which suggests that onset of AA can come from a number of different avenues. I agree with you that general immunosuppresants can be tricky to use because it leaves the patient vulnerable to other diseases. The good news for AA is that these treatments generally only act on the microenvironment in which they were applied/injected, so the immunosuppression is not widespread. This is not the case for JAK inhibition, but more research needs to be done in order to assess the risks associated with the suppression of an immune response this way.

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