How suitable are JAK inhibitors in treating the inflammatory component in patients with alopecia areata and vitiligo?

KEYWORDS:

• Alopecia areata
• autoimmunity
• cytokines
• hair loss
• hypopigmentation
• inflammation
• JAK inhibitors
• ruxolitinib
• tofacitinib

Alopecia areata (AA) and vitiligo are immune-mediated inflammatory skin diseases, which impact the quality of life, psychological health, and societal views of patients. The Janus Kinase (JAK)-signal transducer and activator of transcription (STAT) pathway contribute to the inflammation in both conditions. The JAK/STAT pathway is a conserved signal transduction pathway used by cells to sense and regulate gene expression. Genetic mutations and polymorphisms of this pathway are relevant to the pathophysiology of many immune-related conditions and cancers [1]. JAK inhibitors show promising efficacy and address the need for new, nonsteroidal treatment options for these conditions.

Nonsegmental vitiligo is a chronic autoimmune disease that is clinically characterized by depigmented patches on the skin caused by the destruction of melanocytes. It affects approximately 1% of the individuals worldwide [2]. The pathogenesis of vitiligo includes activation of an inflammatory pathway that ultimately leads to cell-mediated autoimmunity against melanocytes (Figure 1). The JAK/STAT pathway incorporates proinflammatory signaling cytokines and CD8+T cells (Figure 1) [3]. Activated CD8+T cell-mediated autoimmunity causes the destruction of melanocytes (Figure 1) [3]. On the other hand, anti-melanocyte specific antibodies are frequently found in patients with autoimmune vitiligo and are believed to contribute to the pathogenesis as well [4–6].

Figure 1. Mechanism of action for JAK inhibitors in Alopecia Areata (above) and Vitiligo (below). The pathogenesis of vitiligo begins with the activation of JAK ½ in a keratinocyte via binding of IFN-γ secreted by CD8+T cell. The dimerization of JAK1/2 via autophosphorylation activates the STAT protein which, in turn, leads to the production of proinflammatory cytokines. Subsequently, these cytokines lead to the activation and recruitment of more CD8+T cells via JAK 1/3 which target local melanocytes. Similarly, the pathogenesis of alopecia areata involves the activation of a CD8+T cell which causes the secretion of IFN-γ and, subsequently, activates JAK1,2,3 via signaling cascade. This results in the inflammation and destruction of a hair follicle.

Currently, there is no FDA-approved oral or topical medication specifically made to treat vitiligo. However, topical corticosteroids (TCS) have been used. For more sensitive areas, calcineurin inhibitors are a more favorable option. Topical JAK inhibitors provide a safer option, as they reduce the risk of side effects caused by TCS and oral JAK inhibitors [7]. Oral JAK inhibitors have been used to treat other inflammatory skin diseases, including psoriatic arthritis and atopic dermatitis [3].

Tofacitinib and ruxolitinib are JAK inhibitors that provide a targeted approach for the treatment of vitiligo. Each downregulates a distinct step in the JAK/STAT pathway and, in turn, reduces inflammatory cytokines (Figure 1) [8]. Specifically, the inhibitors interfere with the autophosphorylation and activation of the JAK dimers. Subsequently, the STAT protein cannot translocate to the nucleus and initiates production of proinflammatory cytokines [3]. Tofacitinib is a JAK 1/3 inhibitor that induces repigmentation when applied as a 2% topical solution twice daily [8]. Tofacitinib is also available as an oral medication. Recent studies have revealed symptomatic improvement with 5 mg twice daily by mouth [7]. Ruxolitinib is a JAK 1/2 inhibitor that was recently FDA approved as a topical medication for the treatment of atopic dermatitis. Approximately 50% repigmentation was seen in 45–50% of the subjects in a study investigating 1.5% topical ruxolitinib solution applied once and twice daily [8]. In both tofacitinib and ruxolitinib, low-level narrow-band UVB or sun-exposure enhance their effect [9]. However, no specific protocols are set in place, suggesting the need for more controlled studies. Additionally, there have been instances where patients experience disease relapse upon treatment cessation of JAK inhibitors. This highlights the involvement of IL-15 expression and self-reactive memory cells in the skin, which may open doors to another targeted treatment option for individuals with vitiligo [3].

Vitiligo greatly impacts the quality of life of patients with comorbid psychological disorders and societal stigmatization. Since patients need to be on a long-term treatment plan and are dealing with psychological comorbidities, it is also difficult for them to adhere completely to their treatment regimens [10]. Dermatology Life Quality Index (DLQI) scores improve in patients taking JAK inhibitors [11]. A recent study suggested that incorporating psychiatric evaluation may be helpful for vitiligo patients in order to help cope with their skin condition [10]. The use of a combined treatment plan involving topical JAK inhibitors, narrow-band UBV phototherapy, and careful counseling may be needed to ensure repigmentation, improved quality of life, and increased adherence.

JAK inhibitors may also prevent similar cytokine signal transduction, which causes other autoimmune conditions, like AA. AA causes nonscarring, sharply demarcated, round patches of hair loss, and affects approximately 2.1% of the population [9,12]. The disease can result in annular or patchy scalp lesions (AA), complete loss of scalp hair (alopecia totalis), or loss of all body hair (alopecia universalis) [12]. Genome-wide analysis studies (GWAS) reveal multiple chromosomes linked to AA [12]. Expression of CD8⁺NKG2D⁺T causes secretion of interferon-gamma, which subsequently activates JAK-1,2, and 3 via a signaling cascade resulting in inflammation and damage to the hair follicle and hair loss (Figure 1).

To date, there is no FDA approved therapy specific to AA [13]. Traditional AA treatments include corticosteroids, light therapy, and immunotherapy. Topical and intralesional corticosteroids are first-line AA treatments as they reduce inflammation and thus allow for the recovery of damaged hair follicles [9]. Though effective, their use increases the risk of cutaneous atrophy. In the refractory AA cases, systemic corticosteroids demonstrate full hair regrowth in 62% of the patients [12]. Yet, the relapse rate of AA with corticosteroids is between 33% and 75%.⁶ The second-line AA treatment includes immunotherapeutic agents such as squaric acid dibutylester and diphencyclopropenone, which function via antigenic competition to distract CD4+T-cells from attacking hair follicles [12]. Its effectiveness is variable with 9% to 87% response rates [9]. Methotrexate is used for treatment in severe AA [14]. Less common traditional AA treatments include minoxidil combined with psoralen plus ultraviolet A (PUVA) light therapy [9].

Several different JAK inhibitors target signaling pathways specific to AA, including tofacitinib, ruxolitinib, and baricitinib. The method of treatment delivery is important as oral JAK inhibitors appear to have four times higher odds (95% CI 1.56–10.45) of generating a treatment response, and seven times higher odds (95% CI 2.07–29.41) of complete response in AA than topical JAK inhibitors [15]. Oral JAK inhibitors appear to be safe and well tolerated in AA patients. The most common adverse effects are infections, particularly the urinary tract (UTI) and upper respiratory infections (URI) [13]. Rarely changes in blood cell counts, cholesterol levels, and liver transaminases are observed [13]. Oral JAK inhibitors are associated with an increased risk of some cancers and infections, but no hospitalizations or increased risk of malignancies have been reported with their use for AA treatment [13]. Limitations of the use of JAK inhibitors in AA treatment include recurrence of AA after stopping JAK inhibitors, suggesting the need for AA patients to continue oral JAK inhibitors indefinitely, which increases concern for long-term effects of JAK inhibitor use [13].

The use of oral JAK inhibitors is a promising treatment as they are effective in AA and vitiligo patients. JAK inhibitor use for the treatment of these conditions is associated with a low rate of adverse effects, making it a more attractive treatment option than the current first-line option of TCS [16] A limitation of JAK inhibitor includes cost as the annual expense of treatment in an AA patient is approximately $50,000 [16]. The need for long-term treatment with JAK inhibitors presents another limitation, as discontinuation is associated with disease relapse. Similar to AD patients treated with JAK inhibitors, it is likely that AA and vitiligo patients will need to fail first- and second-line treatments to meet the qualifications for prior authorization from insurance companies [17]. Oftentimes, patients who have failed multiple prior treatments are not taking their medication as prescribed, otherwise their symptoms likely would have been successfully treated with TCS [17]. Addressing possible problems with medication adherence is an important first step prior to escalating treatment severity [17]. As mentioned above with regard to melanocyte-specific antibodies, this may imply that JAK inhibition acting on T cell-mediated immunity may not interfere with all immune aspects in vitiligo pathogenesis, which needs to be further evaluated [4–6] Currently the safety and adverse effects of long-term JAK inhibitor use in AA and vitiligo patients are unknown. Future studies are needed to evaluate the long-term adverse effects of JAK inhibitors in patients with these conditions, with the hope that this new medication will provide symptomatic control in patients unable to tolerate other first-line therapies and ultimately improve their quality of life.

Peer review

One peer reviewer was on advisory boards for all three of the oral JAK inhibitors but had no financial stake in any of them or their parent companies. They are on the speaker’s bureau for several companies including the makers of both oral and topical JAK inhibitors, as well as dupilumab. Peer reviewers in this manuscript have no other relevant financial relationships or otherwise to disclose.

Disclosure statement

S Feldman has received research, speaking and/or consulting support from a variety of companies including Galderma, GSK/Stiefel, Almirall, Leo Pharma, Boehringer Ingelheim, Mylan, Celgene, Pfizer, Valeant, Abbvie, Samsung, Janssen, Lilly, Menlo, Merck, Novartis, Regeneron, Sanofi, Novan, Qurient, National Biological Corporation, Caremark, Advance Medical, Sun Pharma, Suncare Research, Informa, UpToDate and National Psoriasis Foundation. He is founder and majority owner of www.DrScore.com and founder and part owner of Causa Research, a company dedicated to enhancing patients’ adherence to treatment. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.