JAK-inhibitors: an emerging treatment option for vitiligo

Therapeutic options have historically been limited. JAK inhibitors are a novel therapeutic possibility, which have shown to be remarkably effective and are currently being tested in clinical trials.

Research in vitiligo has made significant progress in the past 10 years. “Our improved understanding of its pathogenesis is leading to encouraging new treatments,” said Prof. John Harris (University of Massachusetts, USA) [1]. The most promising strategies at this time focus on targeted immunotherapy.

Vitiligo is an autoimmune disease of the skin mediated by CD8+ T cells that kill melanocytes. In addition, expression of IFN-γ is increased in the lesional skin. Neutralisation of IFN-γ prevents CD8(+) T cell accumulation and, as a result, depigmentation, suggesting a therapeutic potential for this approach [2]. In addition, the chemokine CXCL10 plays a critical role in both the progression and maintenance of vitiligo [3]. JAK inhibitors are effective in vitiligo, presumably via inhibition of IFN-γ signalling in the skin [4]. A 20-week, open-label, proof-of-concept trial of twice-daily topical treatment with the JAK inhibitor ruxolitinib cream (1.5%) provided significant repigmentation in facial vitiligo and may offer a valuable new treatment option [5]. Another vitiligo patient was successfully treated with the oral PAN-JAK inhibitor tofacitinib [6]. Three clinical trials with JAK inhibitors in vitiligo are currently ongoing.

Tissue resident memory T cells: the culprits for high relapse rates

“Unfortunately, with JAK inhibitors we have the problem we see in all vitiligo treatments: if you stop therapy, it relapses exactly in the same spots due to an autoimmune memory,” said Prof. Harris. The risk of relapse after successful repigmentation in vitiligo is estimated to be 40% within the first year. Tissue-resident memory T cells are probably responsible for the high relapse rate. “A study showed that if you block IL-15 in mice, you can block relapse [7]. This might be the cornerstone of durable treatment results. Studies in humans will follow,” said Prof. Harris.

Another active and promising area of research is to design pharmacological compounds that can specifically activate melanocyte precursors in the hair follicle in order to obtain faster, better, and more durable repigmentation, and to find agents that are able to normalise melanocyte stress. Afamelanotide, an analogue of α-melanocyte-stimulating hormone, which can induce tanning of the skin, is potentially useful in dark skinned individuals [8]. This was shown in a clinical trial where the efficacy and safety of combination therapy with this agent together with narrowband-UVB phototherapy was compared with phototherapy alone. All study participants had Fitzpatrick skin phototypes III to IV and a confirmed diagnosis of non-segmental vitiligo that involved 15% to 50% of total body surface area. Response in the combination therapy group was superior to that in the narrowband-UVB monotherapy group at day 56 (P<0.05). For the face and upper extremities, a significantly higher percentage of patients in the combination therapy group achieved repigmentation, and at earlier times. In the combination therapy group, repigmentation was 48.6% at day 168 vs 33.3% in the phototherapy group. “However, the response was more noticeable in patients with Fitzpatrick skin phototypes IV to VI and there is only a moderate improvement compared to phototherapy alone,” said Prof. Harris.

Maintenance therapy with tacrolimus

To prevent relapse in vitiligo, a maintenance therapy should be applied. “Topical steroids could be effective, but data is still lacking,” said Thierry Passeron (Hospital of Nice, France) [9]. Efficacy of topical 0.1% tacrolimus twice weekly was assessed in a randomised, double blind, placebo-controlled study in 16 patients [10]. In this trial, 48.4% of lesions in the placebo group showed depigmentation, compared with 26.8% in the tacrolimus group (P=0.059). The authors concluded that maintenance therapy with tacrolimus ointment is effective in preventing the depigmentation of vitiligo patches that have previously been successfully repigmented.

1. Harris JE. Session S002, AAD Annual Meeting, 1-5 March 2019, Washington DC, USA.
2. Harris JE. J Invest Dermatol 2012;132:1869-76.
3. Rashigi M et al. Sci Transl Med 2014:6:223ra23.
4. Liu LY et al. J Am Acad Dermatol 2017;77:675-82.
5. Rothstein B et al. J Am Acad Dermatol 2017;76:1054-60.
6. Craiglow BG, King BA. JAMA Dermatol 2015;151:1110-2.
7. Richmond J et al. Science Transl Med 2018;10:1-9.
8. Lim HW et al. JAMA Dermatol 2015:151:42-50.
9. Passeron Th. Session S002, AAD annual Meeting, 1-5 March 2019, Washington DC, USA.
10. Cavalie M et al. J Invest Dermatol 2015;135:970-4.



Posted on 19 April 201917 May 2024