Novel Interleukin Inhibitors and the Paradoxical Development of Vitiligo: A Systematic Review

Interleukin (IL)-12, -17, and −23 inhibitors have emerged as an effective treatment for psoriasis. ¹ However, development of vitiligo has been reported with IL inhibitors. ¹ Vitiligo results from epidermal melanocyte depletion and classically presents as depigmented macules and patches. The aim of this systematic review was to synthesize the literature characterizing development or worsening of vitiligo in patients receiving IL inhibitors.

In compliance with PRISMA 2020 guidelines (Prospero ID: CRD42022361735), we searched Ovid EMBASE and MEDLINE on September 17, 2022 by using variation of keywords “vitiligo” AND “secukinumab” OR “ixekizumab” OR “ustekinumab”. Our search strategy and PRISMA Flow Diagram may be found in Supplemental Table 1 and Figure 1. After screening, 19 studies consisting of 74 patients with a mean age of 46.4 years, and treatment with secukinumab (n = 44, 59.5%), ustekinumab (n = 24, 32.4%), ixekizumab (n = 5, 6.8%), and tildrakizumab (n = 1, 1%) were included.

In total, new onset occurred in 18.9% (n = 14/74) of patients, 1.4% (n = 1/74) experienced worsening of pre-existing vitiligo, and in 60.8% (n = 45/74) the authors did not specify previous history of vitiligo. The IL inhibitors were prescribed in 15.0% (n = 9/60) of cases for psoriasis of which 3.3% (n = 2/60) had concurrent psoriatic arthritis, and for an undisclosed autoimmune condition in 85.0% (n = 51/60). Mean latency period to new onset or worsening vitiligo following IL inhibitor initiation was 62.3 +/- 75.9 weeks. Of the patients with new onset vitiligo, 42.9% (n = 6/14) continued the drug, 14.3% (n = 2/14) switched to an alternative biologic, and 50.0% (n = 7/14) did not disclose. Thirty-five percent of new cases (n = 5/14) were started on topical tacrolimus and/or steroids, 7.1% (n = 1) started UV therapy, and 7.1% (n = 1) received no additional therapy. For new, 21.4% (n = 3/14) reported stabilization of vitiligo, 7.1% (n = 1/14) worsening, and 14.3% (n = 2/14) partial resolution, while the remaining did not disclose. The mechanism of onset is largely unclear and with limited literature. It is confounded by the fact that patients with comorbid autoimmune disorders have a higher risk of developing vitiligo, ² suggesting a coincidental development, as opposed to drug induced. ³

Conversely, resolution of vitiligo occurred in 5.4% (n = 4/74) of patients and 12.2% (n = 9/74) had persistence of disease. Eight patients with persistence were enrolled by Speeckaert et al. 2019 to assess secukinumab for vitiligo. In those with resolution, responses ranged from 55% of body surface area in Jerjen et al. 2020 to subtotal remission in Raimondo et al, 2021. Mean time to first response was 12.4 weeks +/- 8.3 weeks. The mechanism of resolution likely relates to the fact that IL levels are elevated and imbalanced within vitiligo lesions. ⁴ This imbalance exerts deleterious effects on melanocytes resulting in decreased cell size, production, and lower melanin production. ⁵

Our limitations include sample size once accounting for the several drugs included, limited follow up, and the observational nature of each study limits casual relationships. The variation in Interleukin targeted per drug reduces generalizability of findings. A mean Narajno score of 5.6 +/- 1.5 suggests only a probable relationship. Evidence for therapeutic use of IL inhibitors is greatly limited and should be trialed with caution given the low rate of disease improvement. Providers should be aware of unintended vitiligo development and educate patients with prior history of vitiligo the possible, but low risk of worsening.