Dupilumab in lichen planus, and dupilumab-induced lichenoid drug eruption: A systematic review

Dear Editor,

Lichen planus (LP) is a T-cell-mediated chronic inflammatory disorder typically presenting with violaceous polygonal papules and/or plaques.¹ Dupilumab is an interleukin (IL)-4 receptor alpha antagonist approved for treating moderate-to-severe atopic dermatitis (AD) and prurigo nodularis.² While studies suggest potential off-label efficacy of dupilumab in LP, it has also been thought to be a causative agent for lichenoid drug eruptions (LDEs).^2,3 This systematic review aimed to characterise dupilumab as an LP treatment and describe dupilumab-induced LDEs.

Following the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines, MEDLINE, Embase, and Web of Science were searched with terms “dupilumab,” “lichen planus,” and “lichenoid*” from inception to October 27, 2024. A total of 208 articles were identified and screened by two independent reviewers (BT and MU), while a third reviewer (JT) resolved disagreements. Studies in English involving patients with LP on dupilumab or who experienced dupilumab-induced LDEs were included. Ultimately, 17 studies met the inclusion criteria (14 case reports, one case series, two retrospective studies) [Figure 1,⁴ Supplementary Table S1]. Descriptive analysis was performed given the small number of studies.

Close

Figure 1:

The preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines utilised in the methodology.

Export to PPT

Ten cases of LP treated with dupilumab were identified in the literature [female: 20%; mean age: 53.6±22.3 years; one unreported, Table 1].^{S2,S5,S8,S10,S11,S13-S17} Types included cutaneous LP (n=4), LP pemphigoides (n=3), and immune checkpoint inhibitor-induced LP-like eruptions [mogamulizumab (n=1), nivolumab (n=1), and pembrolizumab (n=1)]. Both mogamulizumab- and nivolumab-induced LDEs had clinical and histological features in keeping with LP (pembrolizumab report lacked clinical description). Eight cases (80%) were histologically confirmed, with findings detailed in six [Table 1]. Initial dosing comprised a 600 mg loading injection followed by 300 mg biweekly (n=7, three unreported). Symptom improvement was observed between 3 days and 14 weeks after initiation (mean time to improvement: 39.5±32.8 days). The number of cases with complete and partial resolution was equal (n=5, each). No recurrence or adverse events were reported (mean follow-up period: 4.7±3.1 months).

There were 14 cases of dupilumab-induced LDEs.^{S1,S3, S4,S6,S7,S9,S12} Seven reported patient demographics [female: 85.7%; mean age: 38.3±21.2 years, Table 2]. Dupilumab treated AD in all reported cases (n=7). Onset of LDEs ranged between 4 to 24 months after initiation (mean time to onset: 12.8±6.6 months). Lesion duration ranged from 6 weeks to over 1 year (n=6). Mucosal involvement was noted in 28.6% of patients. Histology was reported in six patients, and biopsy timings were inconsistently documented. Dupilumab was discontinued in 5 patients (71.4%) and replaced with an immunosuppressant or corticosteroid, which resulted in complete resolution in three patients [methotrexate (n=2) and methylprednisolone (n=1)], partial resolution in one [cyclosporine (n=1)], and one was unreported. Two patients were continued on dupilumab and treated with corticosteroids [prednisone and topical methylprednisolone (n=1) and intramuscular triamcinolone (n=1)]. Both experienced complete resolution. The patient treated with triamcinolone experienced recurrence 6 months later, which self-resolved within 3 months (mean follow-up period: 10.2±7.8 months).

While LP is primarily driven by a Th1 response, studies suggest that elevated IL-6 levels in LP may enhance Th2 pathways and IL-4, IL-5, and IL-13 activity.⁵ Dupilumab inhibits IL-4 and IL-13, which could explain its effect on LP. All reported patients with refractory LP experienced symptomatic improvement with dupilumab, with no reported side effects. Nevertheless, the small sample size and case report nature preclude generalisability, and reporting bias likely favours positive outcomes.

On the other hand, LDEs represent a potential adverse effect of dupilumab. LDEs have been characterised as a Th1-mediated dermatosis.⁶ By inhibiting IL-4 and IL-13 signalling, dupilumab may induce LDEs through a Th1/Th2 imbalance that favours a Th1-dominant response.³ While 14 cases were found, dupilumab-induced LDEs may be underreported and underdiagnosed. Misclassification of LDEs remains a concern, particularly among dupilumab non-responders, as lichenoid eczema and other mimickers may present similarly. Additionally, all reported cases involved patients with AD with varied LDE onset times after treatment initiation. Monitoring for cutaneous adverse events during dupilumab therapy is thus necessary, particularly in severe AD cases. A review by Srivatsa et al. reports similar findings which this study supports with ten additional LDEs and two additional immune checkpoint inhibitor-induced LP cases.⁷

In this limited sample, dupilumab demonstrated efficacy in treating refractory (as mentioned by the authors of the reports) LP, with all patients achieving improvement without recurrence or adverse effects (mean follow-up period: 4.7±3.1 months). Meanwhile, LDEs are uncommon, largely resolve with medication discontinuation, and can be treated with oral immunosuppressants. We underscore the importance of careful clinical monitoring for LDEs, particularly in AD patients treated with dupilumab. Given the paradoxical potential of dupilumab to both treat and trigger lichenoid eruptions, further investigation is warranted. Large-scale, randomised trials with long-term follow-up are needed to characterise dupilumab in LP, as well as the true incidence of dupilumab-induced LDEs.