Vitiligo: Oral and Topical JAKs Show Promise

Although there is still much to learn about vitiligo, from basic science to clinical manifestations to outcome measures, we continue to gain a better understanding of the pathogenesis of this complicated disease leading to better and more targeted treatments. It’s an exciting time to treat this disease for both physicians and patients. We know that vitiligo can have a very negative impact psychologically on patients, so it’s important to continue to study new treatments as well as the potential benefits of combination therapies in order to help our patients navigate their journey and improve their quality of life.

There is not a one-size-fits-all approach to treating vitiligo. In terms of stabilizing the disease, I have had treatment success with oral mini-pulse systemic steroids with dexamethasone therapy to calm the disease while initiating concomitant therapies like phototherapy and topicals. There is very limited data, but certain oral antioxidants including polypodium leucotomos extract, alpha lipoic acid, vitamin C, and others may be beneficial in trying to treat patients from a multi-modal approach, as there is not a current monotherapy available that is going to offer complete resolution. However, recent studies have suggested promising results for the Janus kinase (JAK) inhibitor family of drugs, particularly tofacitinib and ruxolitinib, offering patients a benefit from the immunologic perspective.

As our understanding of the pathogenesis of vitiligo continues to grow, we are able to target specific pathways. We know that the JAK pathway is involved in the pathogenesis of vitiligo and have seen cases of successful repigmentation in several small studies.

Data: JAKs for Vitiligo

Tofacitinib. The JAK 1/3 inhibitor tofacitinib (Xeljanz, Pfizer) was FDA approved in 2012 for the treatment of moderate to severe rheumatoid arthritis and then later also approved for psoriatic arthritis. Oral and topical formulations have demonstrated safety and efficacy for the treatment of plaque psoriasis and oral tofacitinib for treating alopecia.

Results of a 2015 case study suggested that oral tofacitinib may be effective in the treatment of vitiligo.¹ A female subject, with a one-year history of widespread and progressive vitiligo, had tried and failed treatment with triamcinolone ointment 0.1% and tacrolimus ointment 0.1%. At her time of presentation, she had undergone three narrowband UVB phototherapy treatments and expressed concern about progression of the vitiligo, particularly on her hands and face. The subject presented with white macules and patches involving the forehead, trunk, and extremities—involving approximately 10 percent of body surface area (BSA). She was initially treated with tofacitinib 5mg QOD, but after three weeks, the dosage was increased to 5mg QD, which is half the dose approved for rheumatoid arthritis (5mg BID). Partial repigmentation was noted after two months of therapy. After five months, results showed nearly complete repigmentation of the forehead and hands. The remaining involved areas demonstrated partial repigmentation. No adverse effects were reported in this case and results of laboratory monitoring revealed no abnormalities in complete blood cell count, serum creatinine, hepatic function, or lipids during the course of treatment.¹

Other studies^2,3 have suggested that treatment of vitiligo with JAK inhibitors appears to require light exposure. However, unlike treatment with phototherapy alone, repigmentation during treatment with JAK inhibitors may require only low-level light, and maintenance of repigmentation may be achieved with JAK inhibitor monotherapy. These results suggest JAK inhibitors suppress T cell mediators of vitiligo and that light exposure is needed to stimulate melanocyte regeneration.³ When the immune system attacks the melanocytes, they go into hiding, and it seems tofacitinib signals them it’s OK to come out of hiding. The UV light acts to brings them out of hibernation.

More, larger studies are needed to assess efficacy and safety, dosing, and long-term results.

Ruxolitinib. A small, open-label study published in the Journal of the American Academy of Dermatology found the JAK 1/2 inhibitor topical ruxolitinib 1.5% cream provided significant repigmentation in facial vitiligo. This 20-week, open-label, proof-of-concept trial of twice-daily topical ruxolitinib 1.5% cream included 12 patients with a minimum of one percent affected BSA of vitiligo. The primary outcome was percent improvement in vitiligo area scoring index (VASI) from baseline to week 20. Of 12 patients screened, 11 were enrolled and nine completed the study (54.5% men with a mean age of 52 years). Four patients with significant facial involvement at baseline had a 76 percent improvement in facial VASI scores at week 20. A 23 percent improvement in overall VASI scores was observed in all patients at week 20. Three of eight patients responded on body surfaces and one of eight patients responded on acral surfaces.

Adverse events were minor, including erythema, hyperpigmentation, and transient acne.

Based on these results, a randomized, double-blind, dose-ranging, vehicle-controlled, Phase 2 study evaluating ruxolitinib cream in adult patients (18 to 75 years of age) with vitiligo was initiated by Incyte. The study enrolled 157 adults diagnosed with vitiligo and with depigmented areas of at least 0.5 percent of the BSA on the face and at least three percent of the total BSA on non-facial areas. Patients were equally randomized across five treatment arms, including: ruxolitinib cream 1.5%, 0.5% or 0.15% administered QD; ruxolitinib cream 1.5% administered BID; or vehicle control for 24 weeks.

The study met its primary endpoint, demonstrating that significantly more patients treated with ruxolitinib cream for 24 weeks achieved a ≥50 percent improvement from baseline in the facial vitiligo area severity index (F-VASI50) score compared to patients treated with a vehicle control (non-medicated cream). F-VASI50 response was most notably achieved with ruxolitinib cream 1.5% administered once daily (QD) and twice daily (BID) vs. vehicle control (50 percent and 45 percent vs. 3 percent, respectively; P<0.001).

The 52-week results were released at the 28th European Academy of Dermatology and Venereology (EADV) congress in Madrid, Spain in October 2019. Updated results at week 52 show substantial improvements in total body repigmentation with ruxolitinib cream, measured by the proportion of patients achieving a ≥50 percent improvement from baseline in the total vitiligo area severity index (T-VASI50), a key secondary endpoint. In addition, after 52 weeks of treatment with ruxolitinib cream 1.5 percent administered twice daily (BID), 58 percent of patients achieved F-VASI50 and 51 percent of patients achieved a ≥75 percent improvement (F-VASI75). F-VASI75 after 24 weeks is the primary outcome measure of both the TRuE-V1 and TRuE-V2 randomized Phase 3 trials, which are underway.

Ruxolitinib cream was generally well-tolerated at all dosage strengths and no treatment-related serious adverse events were reported.

Hope for the Future of Vitiligo Treatment

There is still much to learn about the role of JAK inhibitors in treating vitiligo and other inflammatory skin diseases, but to date, the data is encouraging. However, larger efficacy and safety studies are still needed.

We will also need to advocate for better insurance coverage for vitiligo treatments. Access and cost remain issues for many patients.

1. Craiglow BG, King BA. Tofacitinib Citrate for the Treatment of Vitiligo: A Pathogenesis-Directed Therapy. JAMA Dermatol. 2015;151(10):1110–1112. doi:10.1001/jamadermatol.2015.1520

2. Kim SR, Heaton H, Liu LY, King BA. Rapid Repigmentation of Vitiligo Using Tofacitinib Plus Low-Dose, Narrowband UV-B Phototherapy. JAMA Dermatol. 2018;154(3):370–371. doi:10.1001/jamadermatol.2017.5778

3. Liu LY, Strassner JP, Refat MA, Harris JE, King BA. Repigmentation in vitiligo using the Janus kinase inhibitor tofacitinib may require concomitant light exposure. J Am Acad Dermatol. 2017 Oct;77(4):675-682.e1. doi: 10.1016/j.jaad.2017.05.043. Epub 2017 Aug 18.

4. Rothstein B, Joshipura D, Saraiya A, Abdat R, Ashkar H, Turkowski Y, et al. Treatment of vitiligo with the topical Janus kinase inhibitor ruxolitinib. J Am Acad Dermatol. 2017 Jun. 76 (6):1054-1060.e1.