Tofacitinib (Xeljanz, Pfizer) is a JAK1/3 inhibitor that has proven effective in case reports or series of cases of vitiligo. The dose of 5 mg/d led to almost complete repigmentation of the face and hands in a patient with progressive vitiligo at 5 months and with no adverse effects; however, the improvement was not sustained when treatment was suspended.49 In a patient with multifocal nonsegmental vitiligo who started tofacitinib 5 mg twice daily for 6 months for treatment of concomitant atopic dermatitis, vitiligo improved slightly (reduction in the Vitiligo Area Scoring Index [VASI] from 4.68 at baseline to 3.95 at 5 months). The patient experienced 2 episodes of upper respiratory tract infection and 1 of diarrhea that did not require treatment to be interrupted.50

Repigmentation of patients with vitiligo treated with JAK inhibitors could require photostimulation to induce migration of melanocytes to the epidermis. In a retrospective series of 10 patients receiving tofacitinib 5-10 mg once or twice daily, repigmentation only occurred when the drug was administered concomitantly with exposure to sunlight or narrowband UV-B (NB-UVB).51 A multicenter retrospective study found that repigmentation rates were higher in patients treated with NB-UVB and tofacitinib 10 mg/d than in those treated with phototherapy alone (92 vs 77%).52

The autoimmune response has been shown to be suppressed both in areas exposed to light (responders) and in those not exposed (nonresponders), thus suggesting a model where JAK inhibitors suppress the inflammatory response induced by the subtype 1 helper T-cell inflammatory response and phototherapy activates regeneration of melanocytes.51 This combination requires a lower dose of light exposure.

A pilot study analyzed 16 patients with nonsegmental vitiligo treated with tofacitinib 2% cream, of whom 13 experienced repigmentation. The mean follow-up was 153 days (range, 63-367 days). The response was more marked for facial lesions and in Fitzpatrick skin types IV-VI, whereas the mean frequency of repigmentation in nonfacial lesions was 16%.53 One of the patients had acne as an adverse effect.

Topical tofacitinib also seems to lead to greater repigmentation with exposure to light. The facial VASI score improved by 70% in a series of 11 patients with facial vitiligo treated with topical tofacitinib 2% cream twice daily, together with NB-UVB 3 times per week for 2–4 months. While these results point to a synergetic relationship, studies on extrafacial vitiligo are necessary.54

Ruxolitinib (Jakavi, Incyte/Novartis), a JAK1/2 inhibitor, was used to treat a male with alopecia areata and vitiligo at a dose of 20 mg twice-daily for 20 weeks. Facial repigmentation started at 12 weeks, reaching 51% at 20 weeks (vs 0.8% at baseline).55

Joshipura et al.56 reported higher repigmentation rates in patients treated with ruxolitinib cream 1.5% twice daily on light-exposed areas compared with nonexposed areas. A statistically significant improvement in the overall VASI score was observed in patients with vitiligo who received ruxolitinib cream 1.5% twice daily and optional NB-UVB, with a particularly marked response in the case of facial vitiligo. The response was maintained at 6 months after discontinuation of treatment.57

The efficacy and safety profile of topical ruxolitinib 1.5% in cream twice daily for treatment of vitiligo is being evaluated in ongoing clinical trials (NCT0405242558 and NCT0405757359), as is the response to different doses (NCT0309930460).

A topical JAK1/3 inhibitor (ATI-50002) for treatment of nonsegmental vitiligo is currently being evaluated in a clinical trial (NCT0346885561). Ritlecitinib (JAK3 inhibitor) and brepocitinib (JAK1 and TYK2 inhibitor) combined with phototherapy are also being evaluated in patients with active nonsegmental vitiligo (NCT0371582962).

The pathogenesis of alopecia areata is complex. Vδ1+ T cells may be involved in the early stages of the disease, since it has been observed that the Vδ1+ T-cell count is considerably higher in both affected hair follicles and those that have not yet been damaged.63 There is also evidence that cytotoxic CD8+NKG2D+ T cells could play a key role in the pathogenesis of alopecia areata in animal models; in this case, the potential objective could be follicles that lose their immune privilege during the anagen phase.64 CD8+NKG2D+ T cells produce IFN-γ, which binds to its receptor on the surface of the hair follicles and activates the JAK1/2-STAT1 pathway. This in turn leads to production of IL-15, which, on binding to its receptor on the surface of the T cells, activates JAK1/3-STAT5, thus generating production of IFN-γ and perpetuating the inflammatory response (Fig. 2).65 Analysis of skin biopsies from patients with alopecia areata has revealed overexpression of JAK3 and, albeit to a lesser extent, JAK1 and JAK2.36 Concomitantly, we can observe overregulation of various cytokines—including IL-2, IL-7, and IL-21—which signal via JAK1/JAK3 and promote activation and survival of CD8+NKG2D+ T cells.64

Given the role of JAK in the pathogenesis of alopecia areata, JAK inhibitors could prove effective for treatment. They could also exert a direct effect on follicles during the telogen phase, thus promoting re-entry into the anagen phase.64

A recent meta-analysis66 covering 289 patients with alopecia areata reported a response rate of 72.4% with JAK inhibitors, with a mean (SD) time to complete growth of 6.7 (2.2) months. The oral route was more effective than the topical route, with a probability of response that was 4-fold higher. Patients who have had the disease for longer have a diminished response to JAK inhibitors,67 and alopecia areata recurs 3 months after stopping treatment. Some areas, such as the eyelashes, eyebrows, beard, and body hair grow more quickly.68–70

The efficacy of oral tofacitinib in alopecia areata was first reported in a patient with alopecia universalis who started treatment with tofacitinib 15 mg/d for concomitant psoriasis and whose hair had completely regrown after 8 months of treatment.71 Since then, there have been reports of response in other patients with alopecia areata,72 some of whom had concomitant psoriasis,73 atopic dermatitis, or vitiligo,50,74 with simultaneous improvement of both diseases.

An open-label study of 66 patients with alopecia areata and hair loss of more than 50%, alopecia totalis, or alopecia universalis subsequently found that tofacitinib 5 mg/d twice daily for 3 months led to a change in the Severity of Alopecia Tool (SALT) score of between 5% and 50% in 32% of patients and of > 50% in 32%. However, the mean duration of the response until recurrence after discontinuation of treatment was 8.5 weeks. Infections were reported in 25.8%, mainly upper respiratory tract infection, although 2 patients had urinary tract infection, 1 developed bronchitis, and 1 had herpes zoster infection. None of the patients had to be admitted to hospital.75

Cheng et al.76 reported the cases of 11 patients with alopecia totalis/alopecia universalis treated with tofacitinib at between 5 mg/d and 11 mg/d (extended release) twice daily for a mean period of 14.4 months (range, 4.5-27 months) whose SALT score improved by a mean of 61.2% over baseline. The disease resolved completely in half of the patients, of whom some benefited from combination with intralesional triamcinolone applied to refractory areas. The adverse effects were dyslipidemia, gastrointestinal symptoms, and mild acne.

Liu et al.67 performed a retrospective study of 90 patients with alopecia areata affecting ≥ 40% of the scalp, alopecia totalis, or alopecia universalis treated with tofacitinib at ≥ 5 mg twice daily in monotherapy or combined with prednisone for a minimum of 4 months. In the 65 patients considered potential responders because they had alopecia totalis/alopecia universalis for under 10 years, the SALT score fell by >90% in 20%, by 51%-90% in 38.4%, and by 6%-50% in 18.5%. The most frequent adverse event was upper respiratory tract infection, which affected 28.9% of patients, although the authors also recorded a patient with bronchitis and 3 patients with urinary tract infection.

In a recent study of 12 patients with moderate to severe alopecia areata, alopecia totalis, or alopecia universalis, most cases required the dose of tofacitinib to be increased from 5 mg/12 h to 10 mg/12 h in order to achieve a response, with no increase in adverse effects. A response was recorded in 91.7% of patients, with a mean reduction in the SALT score of 56.8% at 32 weeks. However, when treatment was discontinued in the responders, values worsened compared with baseline in 50% after 6 months of observation.77 There have been multiple examples of patients with an initial response that was not maintained after interruption of treatment,68,78,79 with a return to levels of alopecia that were similar to or even worse than the baseline values.80 It is not clear whether this represents an increase in disease activity or whether discontinuation of treatment triggers a telogen effluvium, since JAK inhibitors promote re-entry into anagen.81

As for children and adolescents, there have been reports of cases of alopecia totalis and alopecia universalis treated satisfactorily with tofacitinib 5 mg/12 h, with no notable adverse effects.82,83

An ongoing cohort study is evaluating the safety and efficacy of tofacitinib 5 mg twice daily, together with the economic impact of the change in the quality of life of patients with extensive alopecia areata (NCT0380097984).

Topical JAK inhibitors could prove useful, especially for the treatment of localized alopecia areata. Almost complete regrowth of the hair has been observed with topical tofacitinib 2% every 12 hours for 7 months76 and of the eyelashes after a mean 7 months of treatment (range, 3-11 months),39 with no adverse effects. However, a pilot study of 10 patients treated with tofacitinib ointment 2% twice daily revealed poor results, with only 3 responders and a mean decrease in the SALT score of 34.6% at 24 weeks.37 The adverse effects observed were local irritation (40%), folliculitis (10%), and increased cholesterol (40%).

Tofacitinib ointment 1%-2% was also reported to be efficacious in a group of adolescents after 3-9 months of treatment, with no remarkable adverse effects.34 Furthermore, use of tofacitinib 2% in a liposomal base yielded a variable response in 11 pediatric patients, although the response was cosmetically acceptable in most cases. Therefore, this option could be used as adjunctive second-line treatment in these patients.38

A woman treated with oral ruxolitinib 15 mg twice daily for thrombocytopenia experienced almost complete regrowth of alopecia universalis at 10 months, and the response was maintained with treatment at 50 months.85 In another case, involving a patient with alopecia areata and vitiligo, both conditions improved with ruxolitinib 20 mg twice daily, with initiation of growth at 4 weeks and a significant improvement at 12 weeks.55

In a study of 12 patients treated with ruxolitinib 20 mg/12 h for 3-6 months, 75% achieved a response, which took the form of an improvement in the mean baseline SALT score from 65.8% to 7.3% after 6 months of treatment. Most responders had regrowth of 95%, which was noticeable at 4 weeks of treatment.86 However, the response was lost 3 weeks after suspending treatment. The most common adverse effects were upper respiratory tract infection, although the authors also reported a case of mild pneumonia. The same dose was used to treat a preadolescent male with alopecia totalis.87 At 4 months, his eyebrows and scalp hair had almost regrown; therefore, the dose was reduced to 10 mg every other day, with no loss of efficacy. Ruxolitinib 30 mg/d has also been associated with complete regrowth at 8 months in a patient with alopecia totalis. Gradual reduction of the dose was not associated with a loss of response, although the patient developed transient anemia at initiation of treatment.88

While ruxolitinib 20 mg twice daily and tofacitinib 5 mg twice daily were not associated with significant differences in terms of regrowth after 6 months of treatment or in terms of the recurrence rate, initial regrowth seems to be earlier with ruxolitinib.89

Varying responses have been reported for topical ruxolitinib 0.6%-2%.35,90 In a prospective phase 1 trial, partial regrowth was observed at 28 weeks in 5 patients with alopecia universalis in the areas treated with topical ruxolitinib 1%.91

In the case of an adolescent with universal alopecia areata who applied 0.6% cream twice daily, complete growth of the eyebrows was observed at 3 months, albeit with only 10% regrowth on the scalp. No adverse events were reported. In children, the liposomal formulation is more effective, although the nonliposomal formulation is more acceptable in cosmetic terms.34

Baricitinib (Olumiant, Eli Lilly and Company) is a JAK1/2 inhibitor. Complete regrowth was observed in a patient with ophiasis alopecia areata 9 months after starting oral baricitinib at 7 mg in the morning and 4 mg at night for treatment of concomitant CANDLE syndrome.92

A study comparing delgocitinib ointment (pan-JAK inhibitor) 30 mg/g twice daily in vehicle for treatment of alopecia areata found no statistically significant differences in the decrease in the SALT score at 12 weeks (NCT02561585).93

The efficacy of ritlecitinib and brepocitinib was evaluated in a phase 2A trial of 142 patients with moderate to severe alopecia areata (NCT0297486894). After 6 weeks of treatment with brepocitinib and ritlecitinib, the mean difference in the SALT score over baseline was 12.44% and 19.36%, respectively, compared with 1.32% in the placebo group. Complete regrowth was observed in the responders after 24 weeks of treatment.

Another JAK1 inhibitor (SHR0302) is currently being investigated in adults with moderate to severe alopecia areata (NCT04346316).95