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.