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The use of Janus kinase inhibitors and narrowband ultraviolet B combination therapy in non-segmental vitiligo

By 4 May 2023October 16th, 2023No Comments

Abstract

Vitiligo is a depigmentation disorder of the skin that occurs secondary to the destruction of melanocytes by an immune-mediated process. Vitiligo clinically presents with depigmented macules and patches, most commonly on the face, acral sites, and genitalia. It can be characterized as generalized or localized based on distribution. The localized form can be further divided into segmental (linear, band-like, or Blaschkoid) and non-segmental vitiligo. The classical treatment of vitiligo includes topical steroids, pulsed oral steroids in unstable vitiligo, phototherapy, a combination of steroid therapy and phototherapy, surgical grafting, as well as intentional depigmentation therapy in severe cases. However, recent advances in understanding the immune mechanisms implicated in the pathogenesis of vitiligo have led to the use of an FDA-approved topical Janus kinase (JAK) inhibitors for vitiligo. Despite this novel therapy advancement, we recommend the addition of narrowband ultraviolet B (NB-UVB) to JAK inhibitors in patients with extensive and progressive lesions, or those not fully responsive to JAK inhibitor monotherapy.

Vitiligo is a depigmentation disorder of the skin that occurs secondary to the destruction of melanocytes by an immune-mediated process. Vitiligo can be associated with various autoimmune diseases such as hypothyroidism, pernicious anemia, alopecia areata, autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), among others.1, 2 Vitiligo clinically presents with depigmented macules and patches, most commonly on the face, acral sites, and genitalia. It can be characterized as generalized or localized based on distribution. The localized form can be further divided into segmental (linear, band-like, or Blaschkoid) and non-segmental vitiligo.1 The diagnosis of vitiligo is made clinically, and examination with Wood’s Lamp shows “milky-white fluorescence” of the depigmented patches.1 This helps differentiate vitiligo from conditions with hypopigmentation rather than depigmentation such as pityriasis alba. The classical treatment of vitiligo includes topical steroids, pulsed oral steroids in unstable vitiligo, phototherapy, a combination of steroid therapy and phototherapy, surgical grafting, as well as intentional depigmentation therapy in severe cases.1, 3–8 However, recent advances in understanding the immune mechanisms implicated in the pathogenesis of vitiligo have led to the use of an FDA-approved topical Janus kinase (JAK) inhibitors for vitiligo.9 JAK inhibitors are small molecules that disrupt the JAK–STAT (Signal Transducer and Activator of Transcription) signaling pathways, leading to inhibition of immune-mediated inflammatory pathways.4, 8–10In March of 2022, Opzelura™ (ruxolitinib), a topical JAK inhibitor was approved by the FDA for the treatment of non-segmental vitiligo in patients 12 and older.9 In the largest clinical trial for this medication, a total of 674 patients with non-segmental vitiligo were enrolled in phase 3 clinical trials of TRuE-V1 and TRuE-V2, (ClinicalTrials.gov Identifier: NCT04052425 and NCT04057573).9 Ruxolitinib therapy showed 75% improvement in Total Vitiligo Area Scoring Index (T-VASI) at 24 weeks posttreatment.9 Topical ruxolitinib addresses melanocyte dysfunction through inhibiting cytokines which lead to immune-mediated destruction of melanocytes by T cells.9 The safety profile of topical ruxolitinib has been studied in these trials and has been shown to have fewer adverse effects than the systemic route of administration.8, 9 Patients with oral JAK inhibitors are at risk of developing serious bacterial, fungal, and viral infections that may result in hospitalization or death.4Despite this novel therapy advancement, we recommend the addition of narrowband ultraviolet B (NB-UVB) to JAK inhibitors in patients with extensive and progressive lesions, or those not fully responsive to JAK inhibitor monotherapy. In Opzelura clinical trials, 25% of patients did not respond to treatment.10 Subsequently, in the study by Leu et al, treatment with topical tofacitinib led only to re-pigmentation when there was concomitant light exposure.4 Topical JAK inhibitor monotherapy might not be an appropriate choice for extensive (>5%–10% of BSA) progressive non-segmental vitiligo, therefore we recommend the addition of an optimized aggressive NB-UVB regimen to topical ruxolitinib due to its paucity of side effects.3 In NB-UVB devices, the starting safe dose (200 mJ) 2–3 times per week can be increased by a 10%–20% dose increment to achieve light pink erythema or development of skin burning, sensitivity, peeling, or thickening.5 Furthermore, the 308-nm excimer laser therapy can be considered for smaller lesions.7 There have been several studies that have investigated the use of JAK inhibitors with various adjunctive therapy, including NB-UVB and excimer laser (Table 1).8 The maximum dose depends on Fitzpatrick’s skin phototype, photosensitive, and lesion location.6 After stabilization of progression and distribution of vitiligo through NB-UVB and topical ruxolitinib combination therapy, maintenance of regimentation may be achieved with JAK inhibitor monotherapy.

TABLE 1. Vitiligo treatment modalities with JAK inhibitors and various adjunctive therapy options in different studies
Investigator Number Of subjucts JAK inhibitor dosage and frequency Study duration Adjunct therapy Outcome Adverse events
Rothstein et al (2017) 11 Ruxolitinib 1.5% cream BID 20 weeks None Face: 76% VASI improvement

Non-acral upper extremity: 3.6% VASI improvement

Lower extremity/trunk (undefined): 0% VASI improvement

 Erythema

Peripheral hyperpigmentation

Transient acne
Rothstein et al (2017) 8 Ruxolitinib 1.5% cream BID 32-week extension (52 weeks total) NB-UVB Face: 92% VASI improvement

Non-acral upper extremity: 12.6% VASI improvement

Trunk: 16.7% VASI improvement

 Erythema Transient acne
McKesey et al (2019) 11 Tofacitinib 2% cream BID 8–16 weeks NB-UVB 3 times weekly 70% VASI improvement N/A
Rosmarin et al (2020) 1 Tofacitinib 2% cream BID 24 weeks NB-UVB (3 times weekly, home unit) Face:100 repigmentation None
Ferreira et al (2021) 2 Delgocitinib cream BID 36 weeks NB-UVB (3 times weekly) Face: Significant repigmentation, Erythema Transient acne

The psychosocial and cosmetic burden from this chronic autoimmune disease can lead to patients’ isolation. The cost and access of this recent FDA-approved topical JAK inhibitor for non-segmental vitiligo can pose a burden on patients to be compliant and receive appropriate treatment. Adjuvant light exposure treatment can overcome these challenges with effective targeted treatment. Topical JAK inhibitors found their place in the treatment of vitiligo after years of investigation. Prospective clinical trials are needed to further assess adjuvant light therapy and the future formulation of topical JAK inhibitors for the treatment of non-segmental rapidly progressive vitiligo.

References

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Image source: Envato Elements

 

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