A review of JAK and IL- 23 inhibitors to treat vitiligo

Vitiligo is an autoimmune skin disorder resulting in the depigmentation of skin characterised by patches of varying sizes and shapes. A common disorder of pigmentation that affects 0.5%– 2% of the global population. Despite its well- understood autoimmune pathogenesis, the targets for effective cytokine intervention remain unclear. Current first- line treatments include oral or topical corticosteroids, calcineurin inhibitors and phototherapy. These treatments are limited, have varying efficacies, and are associated with significant adverse events or can be time-consuming. Therefore, biologics should be explored as a potential treatment for vitiligo. There are currently limited data for the use of JAK and IL- 23 inhibitors for vitiligo. A total of 25 studies were identified in the review. There is promising evidence regarding the use of JAK and IL- 23 inhibitors for the treatment of vitiligo.


INTRODUCTION
Vitiligo is one of the most frequent pigmentation disorders worldwide with a global prevalence of 0.5%-2%. [1][2][3] Vitiligo is characterised histologically by melanocyte destruction 4,5 from enzyme inhibition and presents as distinctively chronic, depigmented skin lesions that are often well-demarcated and varying in size and shape. [6][7][8] Its aetiology, pathogenesis and treatment mechanisms remain poorly understood; however, evidence of autoimmune and inflammatory mechanisms has emerged. 9 The current accepted pathogenesis theory, coined 'the convergence theory', involves a combination of genetic and environmental factors with oxidative stress and autoimmune inflammatory response. 9 Management of vitiligo focuses on three primary aspects: halting disease progression, repigmentation and maintenance of repigmentation. Current first-line treatments involve phototherapy (psoralen with ultraviolet-A (UVA), narrowband ultraviolet B (NBUVB) and Excimer Laser (EL)) with concurrent topical corticosteroids or calcineurin inhibitors. 9 Topical calcineurin inhibitors are preferred over topical corticosteroids long term due to skin barrier damage with prolonged corticosteroid use. Oral steroids and phototherapy are effective in rapidly progressing disease. Lesser supported treatments include immunosuppressants, surgical grafts, camouflage, micro-tattooing, antioxidants, ginkgo biloba, pseudocatalase cream and vitamin analogues. 9 In extensive vitiligo, monobenzone ether of hydroquinone for depigmentation is offered. Nonetheless, current options are limited, time-consuming, associated with significant side effects or have varying efficacy. [10][11][12][13][14][15][16][17][18][19][20][21][22][23] The cosmetic changes in vitiligo are caused by both immunological and inflammatory pathways and are associated with an increase in anxiety, stress, shame and depression, a loss of self-esteem; these profound impacts on social interactions and quality of life should also be considered. 24,25 With recent developments of biologics as an avenue to treat other autoimmune diseases have shown great promise, [26][27][28][29] this review will thus explore their use as a therapeutic treatment avenue for vitiligo.

Methodology
The study was performed according to PRISMA guidelines. Electronic database searches used Medline, PubMed, EMBASE, Cochrane and Google Scholar for articles published before 01 August 2021, using the search terms 'vitiligo OR depigmentation OR depigmentation OR hypopigmentation OR hypopigmentation OR depigmented or hypopigmented AND tildrakizumab OR risankizumab OR guselkumab OR tofacitinib OR baricitinib OR ruxolitinib OR Janus Kinase OR Interleukin-23'. References within searched articles were also reviewed as additional records for a more comprehensive search. Searches were limited to humans. Articles in languages other than English were reviewed by a fluent reader of the language with a medical background. The articles were first pre-screened by their title and/or abstract, and irrelevant articles were excluded. Articles without abstract or full text were requested through the UNSW interlibrary services or directly from authors.

RESULTS AND DISCUSSION
A total of 25 articles were reviewed. Nineteen involved Janus Kinase (JAK) inhibitors and six involved Interleukin (IL)-23 inhibitors. There was a total of 16 case reports (11 JAK inhibitor reports and 5 IL-23 inhibitor reports). There was a total of nine group studies (8 JAK inhibitor studies and 1 IL-23 inhibitor study). The single IL-23 inhibitor group study was a retrospective study. There was a total of 10 articles investigating oral tofacitinib, three articles investigating tofacitinib cream, one article investigating oral ruxolitinib, three articles investigating ruxolitinib cream (after excluding the extension study) and one article investigating oral baricitinib. Of the IL-23 inhibitors, there was one article investigating tildrakizumab and five articles investigating ustekinumab. No studies involving risankizumab or guselkumab were found.
Summarising the literature, the majority of studies are quite preliminary, involving single patients or small cohorts. Of the seven larger sample-sized trials, only one was randomised and blinded. 46 Amongst these seven, one study was an extension of another and did not control for adjuvant therapy (optional phototherapy allowed). 44,45 Additionally, many other studies similarly involved coadjuvant therapies, potentially altering the results of the biologic. The primary adjuvant seen was NBUVB. Outside the extension study, one other cohort study allowed optional phototherapy and another cohort study did not discuss regimens for adjuvant phototherapy. 39,41 Treatment regimens also varied, and some studies lacked clarity on the location/vitiligo type. Indeed, of the seven cohort studies, only two controlled for vitiligo type. 40,46 Treatment administration was either oral or topical in all studies. Studies also mainly involved patients outside the adolescent-young adult age where vitiligo is believed to predominantly occur 9 and some participants having a history of other autoimmune diseases. Vu et al 31 involved a patient with comorbid alopecia areata and atopic dermatitis; Joshipura et al, 32 Komnitski et al, 33 Scheinberg et al, 34 Gianfaldoni et al 35  Study durations and follow-ups varied from 2 months to 1 year. Clinical photographs were unclear or missing in some studies. Previous treatments were also not discussed in some studies. Quantitative analysis with a generalised vitiligo assessment tool was also not used or mentioned in some cases. In those that did, body surface area (BSA), Vitiligo Extent Score (VES) and Vitiligo Area Scoring Index (VASI) were most commonly used. Similarly, patient-reported outcomes were not commonly used. Furthermore, some studies did not report about adverse events.
Sunlight exposure, when used together with phototherapy, may also play a role in the efficacy of JAK inhibitors inducing repigmentation. Joshipura et al, 32 noting preferential repigmentation at 3 months on sun-exposed areas of an 45-year-old female commenced on oral tofacitinib. In the same study, topical ruxolitinib induced significant facial repigmentation at 3 months in an 49-year-old male with long-standing vitiligo. Interestingly, the forehead was not repigmented, which was hypothesised to be the result of the patient frequently covering it with a cap. Following a request to not wear the cap, repigmentation was noted on the forehead at 38 weeks. 32 Liu et al 36  that JAK inhibitor therapy is more effective when used in conjunction with sunlight exposure or phototherapy. Of 10 patients treated with oral tofacitinib in the case series, 5 experienced repigmentation, and of those 5, 3 experienced repigmentation in sunlight-exposed regions. The other 2 experienced repigmentation in areas of NBUVB use. Moreover, of the 5 without repigmentation, only 1 reported any significant sunlight exposure. 36 Conversely, Komnitski et al 33 reported a case of tofacitinib-induced repigmentation in a female with minimal sun exposure and strict sunscreen routine. Notably, following recent developments (including 2 Phase 3 trials), ruxolitinib cream, a JAK1/2 inhibitor has been approved by the Federal Drug Administration (FDA) for use in patients 12 years or older for the treatment of non-segmental vitiligo. 55 This marks the first biologic use to be approved for the treatment of vitiligo and is the first approved vitiligo pharmacotherapy with a focus on repigmentation. In Australia, ruxolitinib is not currently approved for use in vitiligo.

Interleukin-23 biologics
IL-23 is a central cytokine in autoimmunity. In the presence of TGF-β and IL-6, IL-23 will promote a differentiation of Th17 cells, inducing inflammatory response 56 involving neutrophil production and recruitment. 57 IL-23 is well-established in other autoimmune diseases including psoriasis, RA and inflammatory bowel disease. Therefore, IL-23 inhibitors that are used in these conditions may be effective in vitiligo. The IL-23 inhibitors available in Australia are tildrakizumab, risankizumab and guselkumab.
An elevation of IL-23 in vitiligo was reported by Vaccaro et al 58 One-time enzyme-linked immunosorbent assays (ELISAs) of 28 active non-segmental vitiligo (NSV) patients revealed elevated serum IL-23 levels. 58 In another study, serum levels of IL-23 were elevated in 44 patients. 59 Moreover, a study using CO 2 fractional laser therapy for vitiligo identified statistically significantly elevated IL-23 levels. Following the completion of treatment, a statistically significant drop in serum IL-23 level was identified, although this was not significant when compared with the control. 60 Considering the established documentation of IL-23 elevation in patients with vitiligo, targeted treatment should be considered as a potential novel therapy.
However, a small number of studies report no association of IL-23 levels with vitiligo. One study of 51 vitiligo patients identified no statistically significant elevation of mean serum IL-23 levels. Another study identified lower serum IL-23 levels in vitiligo patients compared to control, although this was not statistically significant. Both studies did not control for vitiligo type. 61,62 There have been several cases of successful treatment of vitiligo with IL-23 inhibitors. A total of six studies involved IL-23 inhibitors. The studies were all case reports, outside of 1 retrospective group study. Ustekinumab use induced either stabilisation or repigmentation of vitiligo. 48,50 Subjective improvement was seen from Week 16 onwards. One study reported ustekinumab-induced hair repigmentation; the authors hypothesising the inhibition of anti-melanogenic cytokine IL-6 and IL-23's involvement in melanogenesis as the factors leading to the observed repigmentation. 53 In some studies involving ustekinumab, adverse events were not reported. In those that did, ustekinumab was well-tolerated. Past treatments were described. There was only 1 study reporting on tildrakizumab use in vitiligo. 49 In this case, subjective and objective improvement was reported by Week 12. At 12 months, objective improvement was seen in VASI reduction by 55%. Patient quality of life improved, supported by DLQI decrease from 9 to 4. Clinical photographs were present, although there were no photographs from Week 12. Past treatments were described. Tildrakizumab was well-tolerated.

Reports of Vitiligo development with JAK inhibitors
Interestingly, some studies report progression or development of vitiligo when treated with biologics for other conditions. A case using tofacitinib in a 36-year-old woman with the history of rheumatoid arthritis (RA) and thyroidectomy resulted in the appearance of progressive depigmented patches over a course of 4 months, consistent with vitiligo. 63 As small sample-size studies have previously demonstrated repigmentation in vitiligo patients with tofacitinib, 64 the authors concluded that definite causation could not be confirmed owing to her significant medical history. 63 Similarly, vitiligo also developed in patients treated with anti-TNF adalimumab 65-67 although some case reports show improvement. 68

Reports of Vitiligo progression/ development with IL-23 inhibitors
Interestingly, some studies reported progression or development of vitiligo in a small subset of patients when treated with IL-23 inhibitors for other conditions. 50,69 In a French retrospective study, across 12 hospitals there were 18 reported cases of new-onset vitiligo in patients being treated with biologics for inflammatory conditions. Of these cases, three involved ustekinumab (2 cases of ustekinumab-induced vitiligo). In one case, the biologic was switched to ustekinumab from anti-TNFα infliximab, which stabilised the new-onset vitiligo. In the same study, 18 patients had pre-existing vitiligo and were commenced on biologics. Of these, 1 was placed on ustekinumab, which did not induce progression of the disease. 50 Two separate case reports also discuss worsening vitiligo from ustekinumab therapy. 51,52 In the first case, the emergence of a new vitiligo lesion on the dorsal penis shaft was noted at week 8 of ustekinumab therapy. The lesion on the penis increased in size at 6 months and was stabilised at 12 months. It should be noted the patient's pre-existing vitiligo on the subaxillary and perioral regions remained stable throughout and the patient had comorbid plaque psoriasis involving the penis, elbows and scalp. Use of co-adjuvant therapies was also not mentioned. 52 In the second case of ustekinumab-induced vitiligo (hypopigmentation on dorsum of upper extremities), it should be noted the patient had comorbid psoriatic arthritis and co-adjuvant leflunomide was used. 51

CONCLUSION
Despite the limited nature of data involving biologics in vitiligo, these results exploring the use of JAK and IL-23 inhibitors to treat vitiligo are quite promising. Therefore, further research should be encouraged to explore new avenues of vitiligo treatment. Moreover, research into safe, convenient and effective treatment options to mitigate the adverse impact on the quality of life of patients should be explored.

ACKNO WLE DGE MENTS
The principal investigators BD and DFM conceptualised and coordinated the study. HL drafted the manuscript. HL, TLC, BD and DFM accessed and verified the data contributing to the study. HL, TLC, BD and DFM edited the manuscript. All authors were involved in the organisation, coordination, conduction, critical review of the manuscript and approval of the final version. All authors had final responsibility for the decision to submit for publication. Open access publishing facilitated by University of New South Wales, as part of the Wiley -University of New South Wales agreement via the Council of Australian University Librarians.