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).
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 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).
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).
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.
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