26 INVESTIGATIVE REPORT
ActaDV ActaDV Advances in dermatology and venereology Acta Dermato-Venereologica
Role of Substance P and Its Receptor Neurokinin 1 in Chronic Prurigo : A Randomized , Proof-of-Concept , Controlled Trial with Topical Aprepitant
Tatevik OHANYAN 1 , Nicole SCHOEPKE 1 , Stefan EIREFELT 2 , Gert HOEY 2 , Witte KOOPMANN 2 , Tomasz HAWRO 1 , Marcus MAURER 1 and Martin METZ 1
1
Department of Dermatology and Allergy , Charité – Universitätsmedizin Berlin , Berlin , Germany , and 2 LEO Pharma A / S , Ballerup , Denmark
Substance P ( SP ) and its receptor neurokinin 1 ( NK1R ) are thought to be involved in the pathogenesis of chronic prurigo . Here , we assessed SP serum levels , cutaneous NK1R expression , and the effects of topical aprepitant , an NK1R antagonist , in patients with chronic prurigo . SP and NK1R were increased , compared with controls , in the serum and in lesional vs . non-lesional skin of the patients , respectively . Aprepitant , in a randomized , placebo-controlled , split-sided , doubleblind trial , reduced the intensity of pruritus as assessed by visual analogue scale by > 50 % from base line to day 28 (– 35.2 ), but so did placebo vehicle (– 38.1 , p = 0.76 ). Overall clinical scores improved significantly by day 28 in both treatment groups , with no significant difference between the 2 groups ( p = 0.32 ). Our findings imply that both SP and NK1R are involved in the pathogenesis of chronic prurigo . Parallel groupdesigned trials are needed to assess the efficacy of topical aprepitant treatment in this condition .
Key words : prurigo ; aprepitant ; substance P ; NK1R ; lesional skin ; pruritus intensity .
Accepted Aug 29 , 2017 ; Epub ahead of print Aug 30 , 2017 Acta Derm Venereol 2018 ; 98 : 26 – 31 .
Corr : Martin Metz , Department of Dermatology and Allergy , Charité – Universitätsmedizin Berlin , Charitéplatz 1 , DE-10117 Berlin , Germany . E-mail : martin . metz @ charite . de
Chronic prurigo ( CPG ) is a debilitating disease characterized by pruritus with chronic and persistent lesions , papules and / or hyperkeratotic nodules ( 1 ). Pruritus is so severe that patients cannot suppress the urge to scratch , creating secondary scratch lesions , often with deep excoriations . The underlying pathophysiological mechanisms of CPG are unknown . In many patients , the condition is a symptom of a specific disease , including dermatological conditions with inflamed skin ( e . g . atopic dermatitis ) ( 2 ), or diseases unrelated to the skin ( e . g . chronic kidney failure or neurological diseases ) ( 1 ). Sometimes no underlying disease can be detected and a multifactorial origin is assumed ( 3 ).
Effective treatment of CPG is difficult and , in most patients , symptom resolution is not achieved . Common treatment regimens include topical therapies with emollients and glucocorticosteroids in the case of inflamed skin , and systemic treatments . Most systemic treatments , however , do not achieve sufficient symptom control ( e . g . antihistamines ) or are associated with unacceptable sideeffects ( e . g . opioid-receptor antagonists , glucocorticosteroids , anticonvulsants or anti-depressants ), and none are licensed for the treatment of CPG ( 4 ). In addition , because CPG is often a comorbidity of another condition , patients can already be taking medications that are contraindicated with current systemic treatments . Hence , the need for a targeted and effective topical treatment is high ( 5 ).
Patients with chronic pruritus have been reported to show elevated expression of neurokinin 1 receptor ( NK1R ) on their keratinocytes ( 6 ). Substance P ( SP ), the main ligand for NK1R , has been strongly implicated in the mechanism of chronic pruritus ( 7 , 8 ). SP levels are upregulated in chronic urticaria , one of the itchiest diseases known ( 9 ) and SP stimulates dermal mast cell degranulation ( 10 ). The main source of the increased SP , i . e . from the central or peripheral nervous system , is unknown . Patients with nodular prurigo , but neither healthy controls nor patients with lichen simplex , have been shown to have an increased density of SP-positive skin nerve fibres ( 11 ), indicating that SP released from sensory nerves in the skin may be the relevant factor in CPG . Ständer et al . ( 12 ) were the first to report the therapeutic potential of aprepitant , an NK1R antagonist , in the treatment of CPG . They demonstrated that oral aprepitant significantly reduced the intensity of pruritus in patients with chronic pruritus , especially in those with CPG , by systemically inhibiting NK1R ( 12 , 13 ). Whether the observed effects were due to action on NK1R in the central nervous system ( CNS ) or in the periphery , however , is unknown . Evidence exists for a role of cutaneous SP in the pathogenesis of other dermatological conditions , such as psoriasis ( 14 ). A 1 % aprepitant topical formulation has been shown to be effective in blocking NK1R-mediated effects in gerbils ( 15 ). However , a topical preparation of aprepitant has failed to modulate allergic type I and type IV reactions in patients and healthy individuals and to ameliorate itch in patients with chronic pruritus ( 16 , 17 ). It is unclear whether the lack of efficacy in these investigations was due to insufficient epidermal penetration , or to the lack of a role for peripheral NK1R-SP interactions in pruritus .
The prospect of combining a potentially specific antipruritic treatment with a supporting topical treatment that would penetrate into the dermis prompted this study of SP and NK1R expression in patients with CPG and this cur- doi : 10.2340 / 00015555-2780 Acta Derm Venereol 2018 ; 98 : 26 – 31
This is an open access article under the CC BY-NC license . www . medicaljournals . se / acta Journal Compilation © 2018 Acta Dermato-Venereologica .