Efficacy of the melanocortin analogue Nle4-D-Phe7-α-melanocyte-stimulating hormone in the treatment of patients with Hailey-Hailey disease

Abstract

Background: Hailey-Hailey disease (HHD) is a rare, chronic and recurrent blistering disorder, which is characterized clinically by erosions occurring primarily in intertriginous regions, and histologically by suprabasal acantholysis. Oxidative stress plays a specific role in the pathogenesis of HHD, by regulating the expression of factors playing an important role in keratinocyte proliferation and differentiation.

Aim: Given the significance of oxidative stress in HHD, we investigated the potential effects of the antioxidant properties of an α-MSH analogue, Nle4-D-Phe7-α-MSH (afamelanotide), in HHD lesion-derived keratinocytes.

Results: Treatment of HHD-derived keratinocytes with afamelanotide contributed to upregulation of Nrf2 [nuclear factor (erythroid-derived 2)-like 2], a redox-sensitive transcription factor that plays a pivotal role in redox homeostasis during oxidative stress. Additionally, afamelanotide treatment restored the defective proliferative capability of lesion-derived keratinocytes. Our results show that Nrf2 is an important target of the afamelanotide signalling that reduces oxidative stress. Because afamelanotide possesses antioxidant effects, we also assessed the clinical potential of this α-MSH analogue in the treatment of patients with HHD. In a phase II open-label pilot study, afamelanotide 16 mg was administered subcutaneously as a sustained-release resorbable implant formulation to two patients with HHD, who had a number of long-standing skin lesions. For both patients, their scores on the Short Form-36 improved 30 days after the first injection of afamelanotide, and both had 100% clearance of HHD lesions 60 days after the first injection, independently of the lesion location.

Conclusions: Afamelanotide is effective for the treatment of skin lesions in HHD.

Figure 1

(a–d) Experiments carried out in primary keratinocytes derived from normal-appearing (N) or lesioned (L) skin of one or more of three patients (P1, P2 and P3) with Hailey–Hailey disease (HHD). (a) Total RNA (arbitrary units). *P < 0.001 compared with control. (b) The top bands show the reduction in protein expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in lesioned skin compared with normal-appearing skin. The same blot was then stripped and reprobed with anti-tubulin antibodies. Lane 3 shows the keratinocytes that had been treated with the α-melanocyte-stimulating hormone analogue afamelanotide; the reduction in Nrf2 was lessened. (c) DNA synthesis in keratinocytes derived from healthy donors (normal human keratinocytes; NHK), and from normal-appearing and lesioned skin from patients with HHD, with or without afamelanotide treatment. Cells were pulse-labelled with 3H-thymidine for 12 h. All samples were tested in triplicate. Error bars indicate standard deviation. (d) Protein expression of the melanocortin receptor MC5R in total cell extracts (60 microgram) prepared from normal keratinocytes (NKC) derived from the normal-appearing skin biopsies of P1 and P2. The same blot was then stripped and reprobed with anti-tubulin antibodies. Lane 1 shows the control whole cell extract 10 microgram (HEK293 cells transfected with MC5R cDNA).

Figure 2

Clinical presentation of (a–c) patient 4 and (g,h) patient 5 before treatment. Clinical remission was seen after 60 days of treatment with the α-melanocyte-stimulating hormone analogue afamelanotide: (d–f) patient 4; (i,l) patient 5.