Introduction/Background
Dupilumab is a human monoclonal antibody of the IgG4 subclass and binds to the IL-4R alpha subunit, causing downstream inhibition of IL-4 and IL-13 signaling and thus downregulating the T-helper-2 (Th2) cytokine response.1,2,3 Approved by the Food and Drug Administration in 2017, dupilumab is FDA-approved to treat atopic dermatitis (moderate-to-severe), asthma (moderate-to-severe), chronic rhinosinusitis with nasal polyposis, and eosinophilic esophagitis.
Vitiligo is a common autoimmune depigmenting skin disorder that is prevalent in 1.38% of US adults, and 2.16% in adolescents in the US, with a range of 0.4-2% in most populations.4,5,6 It occurs when the immune system of the body attacks melanocytes, skin cells, that produce melanin, and has been linked to the Koebner phenomenon which occurs when trauma induces lesions, with events including scratching as would be noted in AD.7 AD has also been linked to Vitiligo, especially in children under the age of 12 years.8,9,10 There are many available therapies for vitiligo, topical, systemic, phototherapy, and surgical types being most commonly used.11,12,13
Objectives
To address specific features of AA/ Vitiligo/ AD overlap that would support benefit of dupilumab prescribing.
Methods
An IRB-exempt review was conducted of patient charts for individuals who received dupilumab who had alopecia areata or vitiligo associated with AD.
Results
Six patients with AD and alopecia universalis (AU), and one patient with AD, vitiligo, and alopecia areata (AA) were identified for review. The patients treated for AU included a 5 year-old Asian female, a 12 year-old white female, a 14 year-old African American male, A 15 year-old Hispanic female, a 26 year-old African American female, and a 78 year-old Hispanic female. The five year-old regrew hair for 4 months but had rapid loss when forced to discontinue due to insurance reasons. The 12 year-old female who had AU for 8 years and had no regrowth. The 15 year-old, 26 year-old, and 78 year-old had rapid regrowth of hair in addition to AD improvement, however, the 15 year-old required addition of an oral JAK inhibitor to retain hair growth. The vitiligo/AA patient is a 61 year-old female patient who had 50% BSA confetti lesion vitiligo affecting the chest, back, abdomen, arms, and legs. She had rapid disease stabilization (2 months) and at 1 year had 90% facial and 70% extremity repigmentation with dupilumab and topical 1.5% ruxolitinib. The same patient had 40% scalp hair loss which fully resolved upon repigmentation of the scalp. Response was noted rapidly but plateaued at 12 months.
Conclusions
The overlap of AD with AA and Vitiligo points to a shared pathogenesis of the conditions. One of the likely reasons for this is the Koebner phenomenon, which has been poorly characterized. We hypothesize that the Koebner phenomenon is triggered through an IL-4/ IL-13 mechanism, i.e. for specific individuals IL-4 and IL-13 hyper-reactivity can be a Koebner-based trigger. Additionally, AA overlaps with AD is poorly characterized. However, the linkage has been recognized in recent AAD guidelines addressing AD comorbidities.14
We hypothesize that IL-4/ IL-13 hyper-reactivity in the skin can act similarly in AU. There is in AA an overlap of TH1-CXCL9/10 expression and interferon gamma overexpression in addition to TH2- including IL-13 overexpression.15 Therefore, the blockade of IL-4/ IL-13 may be effective through multiple mechanisms of activity. There is already notable Phase 2a data supporting dupilumab usage in AA.16
Our experience demonstrates sustained hair growth in half of patients treated. AA/ Vitiligo overlap appears to respond well to dupilumab. This is supported by a recent case report demonstrating benefit of dupilumab in programmed cell death inhibitor-1 induced vitiligo with associated refractory pruritus.17 Liu et al have observed in vitro that rising IL-4 levels were linked to increased vitiligo risk.18
On the other hand, some reports of vitiligo after initiating dupilumab therapy do exist, with some new-onset and worsening described. These cases are limited but bear consideration. In our patient, disease stabilization was noted in a generalized confetti-vitiligo patient, but a topical JAK inhibitor was used adjunctively.19,20,21,22,23
Given the need for long-term maintenance, the safety of dupilumab is an attractive feature. Therefore, further exploration of dupilumab therapy for vitiligo/AA/AD, vitiligo/AD/Koebner+, and AU/ AD is needed. This is particularly important to address in patients under the age of 12 years who currently have no approved systemic medications for vitiligo and AU.24
When AU, vitiligo, and combinations of the two are comorbid with AD, there is an expectation of circulating IL-4/13 elevations and localized IL-4/13 elevation that support a potential role for dupilumab therapy in these conditions. Given that AD is associated with vitiligo of childhood, and severe alopecia areata is linked to AD, systemic therapy would be necessary in these individuals.
