Sonja Ständer

Stimulation of keratinocyte differentiation – a new role for the vanilloid receptor subtype 1 (VR1/TRPV1)?

Vanilloids and endogenous cannabinoids mediate their actions via the vanilloid receptor subtype 1 (VR1/TRPV1), a non‐selective cation channel, which is widely distributed in the central and peripheral nervous system. Only recently, VR1 has been shown to be expressed in keratinocytes in vitro and in vivo. However, a precise description of VR1 localization in epithelial cells was missing. To determine this, we investigated VR1‐immunoreactivity as well as mRNA and protein expression in a series of biopsies from normal, diseased, and capsaicin‐treated human skin. VR1 was found in epidermal keratinocytes, the inner root sheet and the infundibulum of hair follicles, differentiated sebocytes, sweat gland ducts, and the secretory portion of eccrine sweat glands upon immunohistochemistry, RT‐PCR and Western blot analysis. Interestingly, in diseased skin such as prurigo nodularis, psoriasis vulgaris, and atopic dermatitis, VR1 expression in keratinocytes correlated with the degree of epidermal differentiation. Enhanced VR1 immunoreactivity and protein content was found in prurigo nodularis in which epidermal keratinocytes are highly differentiated. Under effective capsaicin therapy of prurigo nodularis, the epidermis thinned and the distribution pattern of VR1 on epidermal keratinocytes normalized. In psoriasis vulgaris, a disease with disturbed epidermal differentiation, less intense immunostaining for VR1 was observed. This could be confirmed by western blot analysis showing less VR1 protein amount in comparison to prurigo nodularis although histologically both showed a thickened epidermis. In atopic dermatitis, which is characterized by a moderate epidermal hyperplasia only and regular differentiated keratinocytes, VR1 immunoreactivity was unchanged in comparison to normal skin. These findings suggest that VR1 may contribute to regular differentiation of keratinocytes. VR1 activation opens non‐selective cation channels with high permeability to calcium, a ion that is crucially important for the synthesis of cornification proteins such as involucrin, fillagrin and loricrin. The role of VR1 in other epithelial cells of appendage structures remains to be determined. In summary, VR1 is widely distributed in the skin suggesting a central role for this receptor not only in nociception but also maturation and function of epithelial cells.

Assessment of pruritus in atopic dermatitis: validation of the Severity of Pruritus Scale (SPS)

Introduction: Pruritus, or itch, is a central feature of atopic dermatitis (AD) and is often cited as the most bothersome symptom. The Severity of Pruritus Scale (SPS) is a 4-point rating scale adapted from the Atopic Dermatitis Severity Index to provide a measure of pruritus severity within a 24-hour recall period. The objective of this analysis was to assess the qualitative and quantitative validity of the SPS in AD. Methods: Content validity of the SPS was evaluated qualitatively in US patients with AD. Psychometric properties of the SPS were evaluated using data from 2 phase 3 trials conducted to investigate crisaborole in mild to moderate AD (study AD-301: NCT02118766; study AD-302: NCT02118792). Results: Fourteen patients were included in the qualitative analysis, considered adequate because of the single-item, single-concept nature of the SPS. Itch was the most prevalent symptom, and the SPS was easily understood and completed in US English (n=9) and US Spanish (n=5). The psychometric analysis used data from 1344 patients. Test-retest reliability analysis identified an intraclass correlation coefficient of 0.54 for a single SPS observation, and at least 0.70 when at least 2 SPS observations were averaged. SPS scores correlated with Investigator’s Static Global Assessment (ISGA) scores, measures of quality of life, and 4 of 5 signs of AD (Pearson correlations, ≥0.40 at day 29). The difference in score between the no disease group/clear (ISGA 0) and the severe disease group (ISGA 4) was 0.80. The clinically important difference was estimated to be 0.20 and the clinically important response was estimated to be at least a 0.19-point reduction from baseline. Discussion: The SPS is an appropriate tool to assess itch in patients with AD and is a valid and reliable measure of pruritus severity.

Effect of crisaborole topical ointment, 2%, on atopic dermatitis–associated pruritus: an extended analysis of 2 phase 3 clinical trials

Introduction: Pruritus is an essential feature of atopic dermatitis (AD) and is widely considered the most distressing symptom. Crisaborole ointment is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild to moderate AD. The efficacy of crisaborole for AD-associated pruritus was assessed in 2 phase 3 trials using the Severity of Pruritus Scale (SPS). Post hoc validation of the SPS identified that 1 SPS observation provided inadequate test-retest reliability. Therefore, extended analyses were conducted using at least 2 SPS observations for robust assessment of pruritus in the phase 3 crisaborole trials. Methods: Data were analyzed from 2 identically designed, vehicle-controlled, double-blind, phase 3 trials designed to investigate the efficacy and safety of crisaborole in AD patients aged 2 years and above (AD-301: NCT02118766; AD-302: NCT02118792). At least 2 SPS observations were averaged for acceptable test-retest reliability. Results: At least 2 baseline observations were available for 569 patients in AD-301 and 561 patients in AD-302. Median time to pruritus improvement (SPS score ⩽1 with at least 1-point improvement from baseline) was shorter with crisaborole than with vehicle (AD-301: 5.0 vs. 10.0u2009d, P=0.0003; AD-302: 6.0 vs. 9.0u2009d, P=0.0087). At week 4, more crisaborole-treated patients than vehicle-treated patients experienced pruritus improvement (AD-301: 37% vs. 21%, P<0.0001; AD-302: 34% vs. 21%, P=0.0006), mean pruritus scores were lower with crisaborole than with vehicle (AD-301: 0.97 vs. 1.28, P<0.0001; AD-302: 1.08 vs. 1.35, P<0.0001), and more crisaborole-treated patients than vehicle-treated patients experienced a clinically important pruritus response (AD-301: 75% vs. 57%, P<0.0001; AD-302: 72% vs. 64%, P=0.0828). Conclusions: These extended analyses show that patients treated with crisaborole experienced rapid and clinically relevant improvement in AD-associated pruritus.

Juckreiz: Neues zur Pathophysiologie und Therapie

Pruritus ist eine unangenehme, selbststandige Sinneswahrnehmung der Haut, die mit dem unstillbaren Verlangen einer mechanischen Reizbeantwortung einhergeht. Dabei handelt es sich einerseits um eine physiologische Nozizeption, die dazu dient, schadigende Noxen wie Parasiten, Pflanzenbestandteile, Chemikalien und anderes von der Haut zu entfernen, andererseits um ein Erkrankungssymptom vieler dermatologischer und systemischer Erkrankungen. Juckreiz hat auch eine wichtige diagnostische Bedeutung. Beispielsweise kann Juckreiz der Manifestation eines Morbus Hodgkin um Jahre vorausgehen. Bei Dermatosen wie der atopischen Dermatitis wird Juckreiz als ein Leitsymptom herangezogen, ohne das die Diagnose nicht zu stellen ist. Chronischer Juckreiz beeintrachtig, ahnlich wie Schmerz, das Allgemeinbefinden des Patienten erheblich und kann im Extremfall zu physischer und psychischer Erschopfung fuhren [4, 13, 14, 16, 33].