Flare Size but Not Intensity Reflects Histamine-Induced Itch

Lehmann, Sabrina; Deuring, Elyne; Weller, Karsten; Metz, Martin; Maurer, Marcus; Hawro, Tomasz

doi:10.1159/000508795

Cited by 4 publications

(9 citation statements)

References 43 publications

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“…The participant received SP if the wheal response met the acceptable saline and histamine response criteria, 20 min after each control challenge. The standardized interval of 20 min ensured that delayed responders could still participate, given that the effects of histamine are short‐lived 19,20 . The acceptable responses were defined as saline wheal less than or equal to 1 mm or histamine wheal greater than or equal to 3 mm, primarily measured using the longest diameter of the wheal by calipers, which were readily available to clinical study sites for standard use.…”

Section: Methodsmentioning

confidence: 99%

Intradermal substance P as a challenge agent in healthy individuals

ten Voorde,

Akinseye,

Abdisalaam

et al. 2023

Clinical Translational Sci

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Pharmacological challenge models are deployed to evaluate drug effects during clinical development. Intradermal injection of Substance P (SP) neuropeptide, a potential challenge agent for investigating local mediators, is associated with wheal and flare response mediated by the MRGPRX2 receptor. Although dose‐dependent data on SP effects exist, full characterization and information on potential carryover effect after repeated challenge are lacking. This open‐label, two‐part, prospective enabling study of SP intradermal challenge in healthy participants aimed to understand and distinguish between wheal and flare responses following various SP doses. Part 1 included one challenge visit to determine optimum SP dose range for evaluation in part 2, which determined variability in 20 participants and used intradermal microdialysis (IDM) for SP‐challenged skin sampling. At 5, 15, 50, and 150 pmol doses, respectively, posterior median area under the curve (AUC; AUC0–2h) was 4090.4, 5881.2, 8846.8, and 9212.8 mm2/min, for wheal response, and 12020.9, 38154.3, 65470.6, and 67404.4 mm2/min for flare response (SP‐challenge visit 2). When the challenge was repeated ~2 weeks later, no carryover effect was observed. IDM histamine levels were relatively low, resulting in low confidence in the data to define temporal characteristics for histamine release following SP challenge. No safety concerns were identified using SP. Wheal and flare responses following intradermal SP challenge were dose‐dependent and different. The results indicate that this challenge model is fit‐for‐purpose in future first‐in‐human studies and further assessment of novel drugs targeting dermal inflammatory disease responses, such as chronic spontaneous urticaria, chronic inducible urticaria, and pseudo‐allergic reactions.

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Section: Methodsmentioning

confidence: 99%

Intradermal substance P as a challenge agent in healthy individuals

ten Voorde,

Akinseye,

Abdisalaam

et al. 2023

Clinical Translational Sci

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“…The increased blood flow area was calculated after the subtraction of individual average blood flow threshold before provocation area plus 2 SDs as described previously. 18…”

Section: Assessment Of Histamine-induced Flare Reactionmentioning

confidence: 99%

“…This is a result of antidromic signal transduction and the release of inflammatory mediators and vasodilators from afferent neurons. 18 The flare reaction is particularly noticeable in histamine-induced itch, primarily due to the extensive innervation areas of histamine-sensitive mechanoinsensitive C-fibres. 19 Previously, both our team and other authors have demonstrated that the flare response in AD is dysregulated.…”

mentioning

confidence: 99%

Clinically uninvolved but not healthy—The skin of patients with atopic dermatitis is primed for itch and inflammation

Moon,

Stasikowska‐Kanicka,

Wągrowska‐Danilewicz

et al. 2023

Acad Dermatol Venereol

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BackgroundAtopic dermatitis (AD) is a highly prevalent inflammatory skin disorder characterized by episodic exacerbations and remissions. Why the clinically healthy skin of AD patients becomes rapidly inflamed and very pruritic is poorly understood.ObjectiveTo investigate cowhage‐ and histamine‐induced itch and skin expression levels of their target receptors in lesional and non‐lesional skin of AD, compared to the skin of patients with psoriasis, chronic spontaneous urticaria (CSU) and healthy subjects.MethodsPatients with AD, psoriasis and chronic spontaneous urticaria (CSU) as well as healthy control subjects (HC) (n = 20 each) were assessed for differences in itch parameters, neurogenic flare reaction and local blood flow responses to skin provocations with cowhage and histamine. Skin biopsies from 10 AD, 10 psoriasis,11 CSU and 12 HC were obtained to assess expression of protease‐activated receptors 2 and 4 (PAR‐2, PAR‐4), histamine H1 and H4 receptors (H1R, H4R), and mast cells.ResultsProvocation of non‐lesional skin of AD patients with cowhage resulted in prolonged itch (p = 0.020), which was not observed in psoriasis and CSU. Significantly prolonged and more intense cowhage‐ and histamine‐induced itch (for duration, peak and overall intensity) was also observed in lesional AD skin. Diminished neurogenic flare reaction and blood flow after histamine provocation were shown in AD and psoriasis patients. Non‐lesional AD skin along with lesional AD and psoriasis skin showed an increased expression of PAR‐2 and PAR‐4, H1R and H4R. Mast cell number was higher in lesional AD and psoriasis skin (p = 0.006 and p = 0.006, respectively).ConclusionThe non‐lesional skin of AD patients markedly differs from healthy skin in cowhage‐induced itch responses and the expression of receptors for proteases and histamine. Proactive therapeutic interventions that downregulate these receptors may prevent episodic exacerbation in AD.

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“…Spatial resolution was greatly improved by the introduction of laser Doppler imaging (LDI), although the prolonged imaging time is unsuitable for real-time perfusion monitoring [14,15]. More recently, this led to the commercialization of laser speckle contrast imaging (LSCI), combining high spatial and temporal resolution [16,17].…”

Section: Introductionmentioning

confidence: 99%

“…Beyond its value as diagnostic and pharmacodynamic biomarker, non-invasive imaging of the vasodilation induced by a histamine skin prick holds potential to assess vascular and peripheral nerve function [17], especially since these measurements lend themselves to consecutive evaluations in the context of a clinical trial or progressive disease. To date, however, a thorough characterization of the histamine-evoked vasodilation, measured objectively with LDI or LSCI, is lacking.…”

Section: Introductionmentioning

confidence: 99%

Histamine Skin Prick Tests: From Established Diagnostic Technique to Advanced Experimental Biomarker

Bamps

Berdon

Hernández

et al. 2023

Skin Pharmacol Physiol

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Introduction Skin prick tests have a long history as diagnostic and pharmacodynamic biomarker. Besides visual assessments of the wheal and flare, objective blood flow measurements using laser Doppler imaging (LDI) and laser speckle contrast imaging (LSCI) have been reported. In light of these advancements, an up-to-date characterization of the histamine-evoked response is worthwhile. Methods A single-center study was completed in healthy males. Two parameters were addressed: (1) dermal blood flow (DBF) within a 7.65 mm ring encircling the skin prick site (DBFring), and (2) surface area of the flare (AREAflare). First, the dose response was assessed using placebo (0.9% sodium chloride) or histamine (histamine dihydrochloride 1, 3 or 10 mg/mL) skin pricks on the volar surface of subjects’ (n=12) forearm. The DBFring was measured by LDI, the AREAflare by LDI and by ruler. Secondly, the inter-arm and inter-period reproducibility of the DBFring and AREAflare, as evoked by histamine (10 mg/mL) and measured by LDI and LSCI, was examined (n=14). Lastly, the effect of aprepitant (125 mg), ketotifen (1 mg) and a single (5 mg) and fourfold (20 mg) dose of desloratadine and levocetirizine on the histamine-induced (10 mg/mL) DBFring and AREAflare was evaluated with LSCI (n=13 or 12). Results All three histamine doses induced a time-dependent vasodilation. Ruler recordings did not conclusively correlate with LDI assessments of the AREAflare. The DBFring and AREAflare were reasonably reproducible when measured by using LDI or LSCI, with negligible bias between arms and study periods and poor to moderate within-subject reproducibility (0.23≤ ICC≤ 0.71). While the fourfold dose of desloratadine (p=0.0041) and the single and fourfold dose of levocetirizine (p<0.0001) managed to reduce the AREAflare, only the fourfold dose of levocetirizine (p=0.0052) reduced the DBFring. Discussion/conclusion Caution is warranted when translating years of clinical experience with histamine skin prick tests to objective recordings of the associated changes in skin perfusion. Ruler and LDI assessments of the AREAflare do not consistently correlate, and the reproducibility and histamine-dependency of the measurements is not obvious. While 10 mg/mL histamine may be a good choice for qualitative diagnostic evaluations, a lower dose may be better suited to use as a quantitative biomarker.

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Flare Size but Not Intensity Reflects Histamine-Induced Itch

Cited by 4 publications

References 43 publications

Intradermal substance P as a challenge agent in healthy individuals

Intradermal substance P as a challenge agent in healthy individuals

Clinically uninvolved but not healthy—The skin of patients with atopic dermatitis is primed for itch and inflammation

Histamine Skin Prick Tests: From Established Diagnostic Technique to Advanced Experimental Biomarker

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