Unmasking of a TH1-Mediated Vitiligo-like Tendency in the Setting of Dupilumab Therapy for Adult Atopic Dermatitis

The authors report a case of dupilumab-induced vitiligo in a patient with a long-standing history of atopic dermatitis. This case serves to underscore the potential adverse effects of biologics reflective of cytokine disequilibrium falling under the rubric of adverse immune reactions.

Dupilumab (Dupixent) is the first biologic targeted therapy to treat moderate to severe atopic dermatitis (AD) in adults approved by the FDA and the European Medicines Agency in 2017 and 2018, respectively. It is a subcutaneously injected monoclonal antibody that targets the IL-4 receptor alpha subunit shared by the IL-4 and IL-13 receptors. The most impressive clinical outcome achieved by blocking the T helper (T_H) cell type 2 signaling pathways is the significant improvements in inflammation, pruritus and, thereby, the overall quality of life in patients.^1-4

Dupilumab is not only used to treat AD but other diseases associated with the allergic diathesis, most notably asthma and allergic polyps. It has proven highly effective in treating AD whereby patients report a significant reduction in the overall usage of glucocorticosteroid either topically or systemically.⁵

Given the significant beneficial effects that dupilumab has on altering the T_H2 dominant cytokine milieu operational in the atopic diathesis, it is not surprising that an overzealous T_H1 response pathway could potentially become unmasked in some patients taking the drug. Specifically unexpectedly, there is paradoxical upregulation of T_H1 and interferon (IFN) γ-mediated inflammation in the setting of dupilumab therapy. The drug has profound effects on the blockade of IL-4 and IL-13 signaling of the T_H2 pathway.^6,7

However, likely attributable to this iatrogenic cytokine imbalance is the development of alopecia, psoriasis, persistent facial dermatitis, and recall dermatitis at patch test sites after the initiation of dupilumab therapy.^8-10 More recently, a rosacea-like reaction associated with dupilumab treatment has been reported.¹¹

Heibel et al¹¹ suggested that T_H2 pathway inhibition by dupilumab was conducive to the proliferation of Demodex and increased IL-17-mediated inflammation implicated in the pathophysiology of rosacea. In the same vein, perioral dermatitis can occur in the setting of dupilumab therapy and may be potentially reflective of suppression of T_H2-mediated inflammation and upregulation of T_H1 and IFNγ-mediated inflammation as a possible mechanism.

Herein, we describe a patient who developed vitiligo temporally associated with dupilumab therapy. We offer the espousal that the vitiliginous reaction reflects an immune adverse effect attributable to the altered cytokine milieu induced by the drug resulting in an unmasking of the T_H1 inflammatory cascade operational in vitiligo. 

Case Report
A 68-year-old African American man with a 2-year history of moderate to severe AD presented to clinic for evaluation and management. The patient had been using a combination of topical corticosteroids, antihistamines, and intramuscular triamcinolone without significant improvement. Due to the refractory nature of his dermatitis, the patient was started on dupilumab (one subcutaneous 600-mg injection followed by 300-mg subcutaneous injection every other week thereafter). He continued on topical corticosteroids as needed in conjunction with dupilumab.

Five weeks after drug initiation, despite significant symptomatic improvement, the patient presented with widespread hypopigmentation. On physical exam, there were new-onset bilateral and symmetrical hypopigmented patches distributed on his neck, antecubital fossae, flanks, and medial lower extremities (Figure 1). These changes were progressive with time. Given the exam findings, two punch biopsies were performed to establish a diagnosis: one from the posterior neck and one from the right anterior thigh. Dupilumab was then withdrawn for a total of 6 weeks while the patient treated his AD with topical corticosteroids and hydroxyzine (25 mg) as needed. 

Upon discontinuation of dupilumab, the patient gradually repigmented in all locations, reverting back to baseline pigment within 1 month. As the patient’s AD symptoms worsened, it was deemed that a rechallenge of dupilumab was appropriate. The prior dosing mentioned was utilized. Six weeks after the drug rechallenge, the patient presented again with hypopigmentation. This pattern varied from the initial presentation in that it was macular and haphazardly scattered on the body throughout (Figure 2). The patient discontinued dupilumab a second time, and has not undergone any repigmentation to date. 

Histopathologic examination from the markedly hypopigmented patch of the right anterior thigh exhibited a very different morphology than the largely resolved quiescent eczematous pattern captured in the neck biopsy. A Fontana-Masson preparation did not show any depigmentation, however, the Melan-A stain revealed strikingly reduced melanocyte number and stretches of epidermis devoid of melanocytes (Figure 3).  The biopsy showed a somewhat thinned appearing epidermis, with melanin pigment throughout the epidermis and within the stratum corneum. The melanocytes present had a blunted, rounded appearance.

Discussion
We have presented a patient with a long-standing history of AD treated with the novel biologic agent dupilumab. Dupilumab is a monoclonal antibody that targets the IL-4 receptor alpha subunit and blocks the intercellular signaling of IL-4 and IL-13, helping to maintain the immune response of T_H2 cells.¹²

The patient had a very good response to the dupilumab based on complete resolution of all eczematous features within the epidermis. The perceived hypopigmentation by the patient at least initially may have represented a postinflammatory leukoderma phenomenon as the neck biopsy showed a resolving eczematous process associated with many melanocytes along the dermal-epidermal junction. In addition, the Fontana-Masson preparation demonstrated substantial melanization in the epidermis and dermis. The biopsy from the thigh area defined a very different picture than the one observed in the neck area. There was no depigmentation demonstrated in the Fontana-Masson preparation, and while there was some degree of melanization throughout the epidermis, there was a remarkable reduction in melanocyte density; the melanocytes also had a blunted, rounded appearance.  In fact, the histomorphology was very reminiscent of idiopathic guttate hypomelanosis (IGH) but, of course, the patient did not have any classic features of IGH. The marked reduction in melanocyte density raises consideration regarding some type of vitiligo-like process even though one could not definitively diagnose vitiligo since there was no depigmentation.

Vitiligo can coexist with AD.^13,14 A meta-analysis of observational studies assessing the prevalence of AD with either vitiligo or alopecia areata (AA) was published in JAMA Dermatology in 2015.¹⁵ This literature review was extensive and encompassed studies published between 1946 and 2014 that examined the prevalence of AD with and without either vitiligo (n=16) or AA (n=17). Pooled analysis of studies with control patients without vitiligo (n=2) and control patients without AA (n=3) demonstrated that patients with vitiligo had significantly higher odds of AD compared with control patients without either disorder. A separate pooled analysis of three vitiligo studies found higher odds of AD in patients with early-onset vitiligo (<12 years) than with late-onset vitiligo.

The basis for the association of atopy and vitiligo is unclear, but the proinflammatory state encountered in atopy may lead to melanocyte injury exposing antigens to which the patient has not been previously exposed, hence eliciting an immune response reflective of the phenomenon of epitope spreading. One could also postulate certain common mutations that are seen in both AD and eczema.

Vitiligo is a T_H1 immune disorder while AD is reflective of a T_H2 immune dysregulatory state. Since the patient of our case report noticed the hypopigmentation following dupilumab therapy, one might offer the espousal that the cytokine axis now favoring a T_H1 profile somehow may have unmasked a vitiligo tendency. There are other considerations clinically and histologically, including IGH—which would be the favored histomorphologic diagnosis base but not a realistic consideration clinically. In particular, the blunted, rounded quality of the melanocytes is a cardinal hallmark of this condition. The lesions, however, are small and primarily in photoexposed areas. It is more reasonable to interpret the melanocyte dropout as a vitiligo-like phenomenon and reflective of the altered microenvironment conducive to a T_H1-mediated autoimmune response, triggered by dupilumab therapy. Numerous studies have shown the significance of the CXCL9/CXCL10/CXCR3 axis mediating T-cell recruitment into the skin in the setting of progressive vitiligo, emphasizing the critical importance of the T_H1 response in the development of vitiligo.¹⁶ The infiltration of vitiliginous skin by CXCR3-positive T_H1 cells could define an important targeted approach to treat the disease in the future. Paradoxically, an alteration of the cytokine milieu to one favoring a predominance of CXCR3-positive cells would clearly unmask a vitiligo tendency. One study observed a type 1 innate immune response comprising an influx of natural killer cells and innate lymphoid cell 1 producing IFNγ-positive cells in the blood and nonlesional skin of patients with vitiligo.¹⁷ Melanocytes of patients with vitiligo exhibited a significant basal level expression of the CXCR3, which is directly regulated by IFNγ. CXCR3b activation by CXCL10 at the surface of melanocytes results in melanocyte apoptosis. The remaining melanocytes activated by the IFNγ production express markers that trigger T-cell proliferation and antimelanocyte immunity. 

In another study of 30 patients with nonsegmental vitiligo vs healthy age and sex-matched controls, the vitiligo group had significantly higher percentages and absolute numbers of circulating T_H1 and T_H17 but no significant difference in T_H2 and Tregs compared with healthy controls.¹⁸ Furthermore, the vitiligo group had statistically elevated ratios of T_H1/Tregs and T_H17/Tregs as well as significantly increased IL-17A expression. 

The previously mentioned studies point toward a common T_H1-dominant cytokine microenvironment operational in vitiligo. In genetically predisposed individuals, a vitiligo tendency can be unmasked, as exemplified by our case report. n

Dr Magro is a distinguished professor of pathology and laboratory medicine in the department of pathology at Weill Cornell Medicine in New York, NY, and section editor of The Dermatopathologist in The Dermatologist. Ms Sheck is a physician assistant in private practice at Dermio Dermatology in Munster, IN. Dr Soleymani is a volunteer clinical assistant professor of dermatology at Indiana University School of Medicine in Indianapolis and is in private practice at Dermio Dermatology.

Disclosures: The authors report no relevant financial relationships.

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