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.