Hair Growth in a Patient with Alopecia Areata on Tocilizumab

• Tocilizumab is a recombinant humanized antihuman monoclonal antibody that targets interleukin-6 (IL-6) signaling.

• IL-6 regulates Th1/Th2 differentiation.

• IL-6 is actively expressed in the hair follicle and modulates hair growth.

• This case report demonstrates the potential ability of tocilizumab to disrupt interleukin-6 (IL-6) signaling involved in alopecia areata (AA) leading to hair loss and regrowth.

• This case report provides valuable implications for AA patients with concomitant inflammatory disease requiring IL-6-targeted therapies.

Alopecia areata (AA) is a T-cell-mediated autoimmune disease that causes nonscarring hair loss [1]. Cytokine profiling of skin and serum in patients with AA reveals upregulation of Th1- and Th2-related biomarkers [2]. Th2 skewing in particular has been found to significantly correlate with clinical disease severity [2]. This correlation between Th2 skewing and AA severity may be attributed to diminished regulatory T-cell quantity and function which plays a fundamental role in anagen hair follicle growth [3, 4].

Tocilizumab (TCZ) is a recombinant humanized antihuman monoclonal antibody [5] that is FDA-approved for use in refractory rheumatoid arthritis, giant cell arteritis, juvenile idiopathic arthritis, and cytokine release syndrome. TCZ specifically blocks the receptor of interleukin-6 (IL-6), noted for its broad functionality [5, 6]. As a powerful immunomodulator, IL-6 is known to promote development of autoimmune disease through sustained inflammation and altered immune response [7]. This is demonstrated by elevated IL-6 serum levels and integral IL-6-dependent signal transduction pathways in numerous inflammatory diseases including noninfectious uveitis (NIU) [5, 8], rheumatoid arthritis, juvenile idiopathic arthritis [5, 7], vitiligo, AA [9-11], systemic lupus erythematosus, psoriasis, Crohn’s disease, and ankylosing spondylitis [7].

IL-6 is thought to bidirectionally impact immune-mediated acute and chronic inflammatory reactions including Th1 and Th2 pathways involved in AA [7, 12]. IL-6 is also actively expressed in the hair follicle and modulates hair follicle growth [11]. IL-6 and oncostatin M, an IL-6 cytokine family member, are expressed in the hair follicle dermal papilla (DP) and root sheath, respectively [13]. While increased hair follicle oncostatin M is associated with hair growth inhibition, this negative effect is thought to be confounded by its partial pro-inflammatory role [13]. Androgens have also been found to directly interact with IL-6 pathways. In response to dihydrotestosterone, balding DP cells upregulate IL-6, precipitating hair growth inhibition, in contrast to their nonbalding DP cell counterparts [14]. This case report aims to review past reports demonstrating TCZ’s effect on hair growth as well as present a novel case of a 21-year-old woman with AA and subsequent improvement on TCZ for concomitant bilateral posterior uveitis (PU).

A 21-year-old female patient with PU presented with new patchy AA limited to the occipital scalp. PU preceded the onset of AA by 3 years with negative screening for underlying rheumatic disease, sarcoidosis, and infectious diseases including Lyme, HIV, and syphilis. AA developed following the initiation of infliximab indicated for PU (shown in Fig. 1). Subsequently, the patient discontinued infliximab and started oral methotrexate. Despite this, the patient experienced progressive worsening of scalp AA. Methotrexate was discontinued, and the patient was placed on TCZ 4 mg/kg intravenously (IV) every 4 weeks per PU treatment recommendations.

During the initial 4 months of TCZ, the patient endorsed stable vision and demonstrated no bilateral cystic changes on optical coherence tomography (OCT). However, the patient’s AA progressed further to near alopecia universalis (shown in Fig. 2), and TCZ was consequently discontinued for approximately 2 months. The patient was treated with a trial of topical minoxidil, clobetasol, and intralesional corticosteroid injections without hair regrowth. Two months following the discontinuation of TCZ, the patient also developed slightly decreased vision and increased flashes andfloaters in the left eye with new perifoveal cysts of the right eye on OCT. To improve PU disease response, TCZ was restarted and increased 7 months later to 6 mg/kg IV every 4 weeks.

At 12 months following original TCZ initiation including 1 month on increased dose of TCZ, the patient reported substantial hair regrowth which progressed to almost complete regrowth of scalp, facial, and body hair within 4 months on continued TCZ therapy (shown in Fig. 3). At this time (within 16 months from original TCZ initiation and 5 months on increased dose), the patient’s PU also appeared to improve overall on continued TCZ therapy demonstrated by no reported changes in visual acuity and only mild increases in cystic changes on OCT following a prolonged 9-week interval since her last TCZ infusion.

While the underlying mechanism of TCZ’s variable impact on the hair follicle to both induce and preclude hair regrowth remains largely unclear, TCZ is associated with hair cycle changes, supported by previous reports [9, 10]. There are conflicting reports in the literature of TCZ both causing hair loss and leading to hair regrowth in the setting of androgenic alopecia and alopecia of unspecified type (shown in Table 1) [9, 10].

In our patient, the initial AA progression at the start of TCZ may have resulted from a premature telogen phase due to an immune-mediated immediate anagen release followed by 2–3 months of telogen effluvium [15]. This would also explain the delayed AA clinical response to TCZ due to this induced shedding period [15].

While the potential role of IL-6 blockade is unclear within the current model of AA, IL-6 is associated with both Th1 and Th2 pathways, which are upregulated in AA pathogenesis [2, 6, 16]. While IL-6 indirectly promotes Th2 differentiation through nuclear factor of activated T cells and IL-4-dependent pathways, it simultaneously blocks Th1 differentiation through upregulation of suppressor of cytokine signaling [6]. IL-6-induced Th2 upregulation may contribute to the collapse of anagen hair bulb immune privilege in AA development via insufficient regulatory T-cell immunoinhibitory activity [2-4, 17].

AA has been associated with increased serum levels of IL-6 compared to healthy controls [11]. Active PU has also been associated with increased vitreous IL-6 [8]. Therefore, in the setting of AA and concomitant PU, an underlying inflammatory milieu with elevated IL-6 may clinically respond to IL-6 blockade by TCZ, as we potentially observed in our patient.

We also recognize that TCZ is not FDA-approved for NIU [5]. A randomized controlled multicenter clinical trial suggested that IL-6-targeted therapy may be safely effective for PU, NIU, and panuveitis, demonstrated by improved visual acuity and decreased vitreous haze and central macular thickness [5]. Our patient’s ophthalmologist prescribed TCZ after she failed multiple traditional therapies.

In the setting of autoimmune pathogenicity of AA and known IL-6 expression at the hair follicle, this novel case report demonstrates the potential mechanism of TCZ disruption of the IL-6 signaling involved in AA, leading to hair loss and regrowth. Our case expands on TCZ’s known impact on normal hair follicle growth by IL-6 modulation. More research is needed to further delineate the role of TCZ in regulating hair growth changes through IL-6 expression.

This case report involves important limitations to consider including the unclear nature of the patient’s chronic PU after extensive negative workup was performed. Concomitant disease pathogenesis may influence the underlying inflammatory milieu and response to TCZ. Additionally, we acknowledge that the patient may have regrown hair spontaneously independent of IL-6 modulation. Furthermore, hair regrowth was appreciated 12 months after the initiation of TCZ. However, it is unclear if a 12-month period is required for this effect, given the increase in TCZ dose 1 month prior to hair regrowth. Overall, this case report provides valuable implications for AA patients with concomitant inflammatory disorders who may require IL-6-targeted therapy.

According to the Mass General Brigham Human Research Committee policy on case studies, they do not require IRB submission for <3 individuals involved in case reports. The case subject has given her written informed consent to publish her case, including the publication of images. The identity of the subject has been protected.

The authors have no conflicts of interest to declare.

No sources of funding.

All of the authors listed have made the following contributions to this article:

1. substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work;

2. drafting the work or revising it critically for important intellectual content;

3. final approval of the version to be published; and

4. agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.