Alopecia Universalis Treated With Tofacitinib: The Role of JAK/STAT Inhibitors in Hair Regrowth

Alopecia areata (AA) is an autoimmune disease that immunopathogenetically is thought to be due to breakdown of the immune privilege of the proximal hair follicle during the anagen growth phase. Alopecia areata has been reported to have a lifetime prevalence of 1.7%.¹ Recent studies have specifically identified cytotoxic CD8⁺ NKG2D⁺ T cells as being responsible for the activation of AA.^2-4 Two interleukins—IL-2 and IL-15—have been implicated to be cytotoxic sensitizers allowing CD8⁺ T cells to secrete IFN-γ and recognize autoantigens via major histocompatibility complex class I.^5,6 Janus kinases (JAKs) are enzymes that play major roles in many different molecular processes. Specifically, JAK1/3 has been determined to arbitrate IL-15 activation of receptors on CD8⁺ T cells.⁷ These cells then interact with CD4 T cells, mast cells, and other inflammatory cells to cause destruction of the hair follicle without damage to the keratinocyte and melanocyte stem cells, allowing for reversible yet relapsing hair loss.⁸

Treatment of AA is difficult, requiring patience and strict compliance while taking into account duration of disease, age at presentation, site involvement, patient expectations, cost and insurance coverage, prior therapies, and any comorbidities. At the time of this case, no US Food and Drug Administration–approved drug regimen existed for the treatment of AA, and, to date, no treatment is preventative.⁴ We present a case of a patient with alopecia universalis of 11 years’ duration that was refractory to intralesional triamcinolone, clobetasol, minoxidil, and UVB brush therapy yet was successfully treated with tofacitinib.

Case Report

A 29-year-old otherwise-healthy woman presented to our clinic for treatment of alopecia universalis of 11 years’ duration that flared intermittently despite various treatments. Her medical history was unremarkable; however, she had a brother with alopecia universalis. She had no family history of any other autoimmune disorders. At the current presentation, the patient was known to have alopecia universalis with scant evidence of exclamation-point hairs on dermoscopy. Her treatment plan at this point consisted of intralesional triamcinolone to the active areas at 10 mg/mL every 4 weeks, plus clobetasol foam 0.05% at bedtime, minoxidil foam 5% at bedtime, and a UVB brush 3 times a week for 6 months before progressing to universalis type because of hair loss in the eyebrows and eyelashes. This treatment plan continued for 1 year with minimal improvement of the alopecia (Figure 1).

FIGURE 1. A and B, A 29-year-old woman with alopecia universalis that did not respond to 1 year of treatment with intralesional triamcinolone, clobetasol foam, minoxidil foam 5%, and a UVB brush.

The patient was dissatisfied and wanted to discontinue therapy. Because these treatment options were exhausted with minimal benefit, the patient was then considered for treatment with tofacitinib. Baseline studies were performed, including purified protein derivative, complete blood cell count with differential, comprehensive metabolic panel, lipid profile, and liver function tests, all of which were within reference range. Insurance initially denied coverage of this therapy; a prior authorization was subsequently submitted and denied. A letter of medical necessity was then proposed, and approval for tofacitinib was finally granted. The patient was started on tofacitinib 5 mg twice daily and was monitored every 2 months with a complete blood cell count, comprehensive metabolic panel, lipid panels, and liver function tests. She had a platelet count of 112,000/μL (reference range, 150,000–450,000/μL) at baseline, and continued monitoring revealed a platelet count of 83,000 after 7 months of treatment. This platelet abnormality was evaluated by a hematologist and found to be within reference range; subsequent monitoring did not reveal any abnormalities.

FIGURE 2. A and B, The patient's alopecia universalis responded to tofacitinib 5 mg twice daily with hair regrowth after 1 year.

Initial hair growth on the scalp was diffuse with thin, white to light brown hairs in areas of hair loss at months 1 and 2, with progressive hair growth over months 3 to 7. Eyebrow hair growth was noted beginning at month 6. One year later, only hair regrowth occurred without any adverse events (Figure 2). After 5 years of treatment, the patient had a full head of thick hair (Figure 3). The tofacitinib dosage was 5 mg twice daily at initiation, and after 1 year increased to 10 mg twice daily. Her medical insurance subsequently changed and the regimen was adjusted to an 11-mg tablet and 5-mg tablet daily. She remained on this regimen with success.

FIGURE 3. A and B, The patient's alopecia universalis responded to tofacitinib 5 mg twice daily with hair regrowth that was sustained after 5 years of treatment.

Comment

Use of JAK Inhibitors—Reports and studies have shed light on the use and efficacy of JAK inhibitors in AA (Table).^5-11 Tofacitinib is a selective JAK1/3 inhibitor that predominantly inhibits JAK3 but also inhibits JAK1, albeit to a lesser degree, which interferes with the JAK/STAT (signal transducer and activator of transcription) cascade responsible for the production, differentiation, and function of various B cells, T cells, and natural killer cells.² Although it was developed for the management of allograft rejection, tofacitinib has made headway in rheumatology for treatment of patients with moderate to severe rheumatoid arthritis who are unable to take or are not responding to methotrexate.² Since 2014, tofacitinib has been introduced to the therapeutic realm for AA but is not yet approved by the US Food and Drug Administration.^3,4

In 2014, Craiglow and King⁵ reported use of tofacitinib with dosages beginning at 10 mg/d and increasing to 15 mg/d in a patient with alopecia universalis and psoriasis. Total hair regrowth was noted after 8 months of therapy.⁵ Xing et al⁶ described 3 patients treated with ruxolitinib, a JAK1/2 inhibitor approved for the treatment of myelofibrosis, at an oral dose of 20 mg twice daily with near-complete hair regrowth after 5 months of treatment.⁶ Biopsies from lesions at baseline and after 3 months of therapy revealed a reduction in perifollicular T cells and in HLA class I and II expression in follicles.⁶ A patient in Italy with essential thrombocythemia and concurrent alopecia universalis was enrolled in a clinical trial with ruxolitinib and was treated with 15 mg twice daily. After 10 months of treatment, the patient had progressive hair regrowth that was sustained for more than 50 months of therapy.⁷ Baricitinib, a JAK1/2 inhibitor, was used in a 17-year-old adolescent boy to assess efficacy of the drug in chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome.⁸ The patient also had longstanding patch-type AA that was resistance to treatment and progressed to an ophiasis pattern even though he was on immunosuppressive therapies. He was on 12 mg of prednisone daily at the start of therapy with baricitinib 7 mg daily initially. The baricitinib regimen was titrated up to 7 mg in the morning and 4 mg in the evening, with tapering of prednisone to 3 mg daily after 6 months of initiation. Within 3 months of therapy, hair regrowth occurred, with only a resultant patch on the occipital scalp that further resolved after 6 more months of therapy, resulting in total persistent hair growth.⁸ A 40-year-old woman with moderate to severe alopecia universalis was treated with tofacitinib 5 mg twice daily, revealing near-complete hair regrowth after 4 months of treatment; regrowth of eyebrows and eyelashes also was seen.⁹ However, discontinuation of treatment resulted in hair loss. Microarray analyses of biopsy specimens of lesioned sites at baseline revealed elevated IFN-γ and cytotoxic T cell-level signatures that subsequently decreased—albeit not to normal control levels—after 4 weeks of treatment.⁹ Being that IFN-γ receptors mediate their effects through JAK1/2, JAK1/3, tofacitinib, ruxolitinib, and baricitinib seem to be in sync with the immunopathogenesis of AA and thus may be the therapy of choice in the near future.