INTRODUCTION

Sensitive skin (SS) is increasingly recognized as a complex syn-drome marked by heightened and often painful sensory responses to typically innocuous stimuli, such as environmental changes, physical contact, or cosmetic products. This condition affects not only physical well-being but also significantly impacts patients’ mental health and quality of life, frequently causing distress and anxiety. The multifaceted nature of SS poses challenges in both its symptoms and the lack of universally observable clinical signs1 .

    Recent advances in dermatological research underscore the role of neurogenic components in SS. Specifically, SS is now understood to involve neurogenic inflammation and may be asso-ciated with neuropathic characteristics similar to those observed in small-fiber neuropathy2 . Neurogenic inflammation in SS arises from the overactivity of sensory nerve fibers, particularly in rela-tion to C-fibers, which are responsible for transmitting sensations of pain, heat, and itch. Additionally, transient receptor poten-tial (TRP) channels, especially TRPV1, have been implicated in the exaggerated sensory responses of SS, linking this condition to an intrinsic hypersensitivity of sensory nerve endings in the skin3 . Moreover, psychological and environmental stressors play a crucial role in exacerbating SS symptoms. Psychological fac-tors, such as anxiety and stress, have been shown to lower the sensory threshold in SS patients, making them more susceptible to external triggers. Environmental factors, including pollution, ultraviolet (UV) exposure, and seasonal changes, are also well-es-tablished as aggravators of SS, contributing to the activation of sensory receptors and the initiation of neurogenic inflammatory pathways in the skin4 . This interplay of neurogenic, psychological, and environmental factors highlights the importance of a compre-hensive approach to understanding SS and underscores the need for personalized management strategies.

    Therefore, this review aims to provide an in-depth examina-tion of the definition, diagnostic challenges, and appropriate management techniques for SS. By integrating recent findings from neurobiology, psychodermatology, and environmental der-matology, this discussion will advance the understanding of SS as a distinct neurodermatological syndrome, necessitating an inter-disciplinary approach in both research and clinical practice.

DEFINITION OF SS

SS is a complex syndrome that is characterized by hypersensitivity to stimuli, and is subjective and diverse depending on the indi-vidual’s age, gender, race, etc., and is difficult to diagnose and manage due to the absence of clinical signs4 . Frosch and Klig-man introduced the concept of skin sensitivity1 . In experiments involving lactic acid sensitivity tests on various skin areas, it was confirmed that skin sensitivity varies based on gender and race, with the face being the most common site.

    Since 1987, SS has been termed ‘Cosmetic Intolerance Syndrome,’ denoting instances where discomfort arises upon cos-metic application5,6 . The definition has progressively broadened to encompass sensations induced by factors beyond cosmetics7 . It is now understood that SS can be triggered by various factors beyond cosmetics, including environmental stressors, temperature changes, hormonal fluctuations, and psychological stress8 . These triggers, which vary widely across individuals, contribute to the difficulty in establishing a universal diagnostic criterion for SS.

    In 2017, the International Forum for the Study of Itch (IFSI) redefined SS as a syndrome causing discomfort in response to typ-ically non-irritating stimuli, often linked to specific skin diseases9 . SS is acknowledged as a heterogeneous and complex syndrome lacking fully objective diagnostic criteria; while skin lesions may appear normal or present with erythema, symptoms are quantified through subjective assessment tools, such as the SS-102 .

    Meanwhile, in Fitzpatrick’s Dermatology, Dr. Bauman cate-gorizes SS into 4 types: allergic type, rosacea type, acne type, and stinging type10. This supports the argument that SS itself is asso-ciated with chronic skin conditions on the face. In other words, when defining SS, cases where a specific skin condition exists as a current symptom should be excluded from the category of SS11. This suggests that individuals with frequent abnormal skin sensa-tions may be prone to certain skin conditions, making it essential to distinguish between symptoms of chronic skin conditions and those solely due to sensitivity12.

    In summary, SS is characterized by exaggerated responses to typically non-irritating stimuli, influenced by environmental, psychological, and genetic factors, with its complex and sub-jective nature necessitating ongoing revisions and personalized approaches for accurate definition and treatment.

EPIDEMIOLOGY OF SS

SS affects a significant portion of the global population, with prevalence estimates varying widely across studies. Survey-based studies indicate that approximately 50%–60% of women and 30%–40% of men are reported to have SS13. According to a 2019 meta-analysis, self-reported prevalence of SS varies by region due to survey methods and cultural perceptions, with 71% report-ing some degree of SS and 40% reporting moderate to severe SS globally.

    Gender and age differences affect SS prevalence, with women and younger individuals (especially under 35) reporting SS more often, likely due to hormonal factors, skin thickness, cosmetic usage, and generational awareness of sensitivity8 . Environmental factors like pollution, humidity, UV exposure, and psycholog-ical stress exacerbate SS symptoms, especially in urban areas, by compromising the skin barrier and triggering inflammation, highlighting the complex factors influencing SS prevalence and severity14.

    In summary, SS is a common but diverse condition influenced by both biological and environmental factors, requiring regionally and culturally tailored approaches to diagnosis and management.

CLINICAL SYMPTOMS OF SS

SS is characterized by subjective sensory symptoms like stinging, burning, and itching in response to benign stimuli, often with-out visible signs, making diagnosis challenging, and is influenced by external triggers (e.g., temperature, pollution, cosmetics) and internal factors like psychological stress. (Table 1) 15,16. In Table 1, higher odds ratios (ORs) suggest stronger associations between specific triggers and the presence of SS. For example, cosmetics (OR, 7.12; 95% confidence interval, 3.98–12.72) represent the most significant trigger, indicating individuals exposed to cosmetics are over 7 times more likely to report SS symptoms compared to those not exposed.

Site-specific and demographic variability in symptoms

SS most commonly affects the face, especially areas with thinner skin like the cheeks and forehead, with higher intensity in East Asian populations potentially due to genetic or structural facial skin differences17.

Gender and age also influence symptom severity and frequency

Women and younger individuals report SS more frequently, likely due to factors such as thinner skin, hormonal changes, cosmetic use, environmental stressors, and greater skincare awareness8 .

Evaluating symptoms and severity

The SS-10 scale helps quantify SS severity by evaluating symptoms like stinging and burning over recent days, providing a standard-ized yet still subjective assessment of symptom intensity18,19.

PATHOPHYSIOLOGY OF SS

The pathophysiology of SS involves a multifaceted interaction among impaired barrier function, inflammatory responses, neu-rosensory dysregulation, and genetic predispositions Fig. 1. These factors collectively contribute to the heightened reactivity of SS, where otherwise benign stimuli provoke intense sensory symp-toms. Each mechanism plays a crucial role in the development and persistence of SS symptoms4,20,21.

Impaired skin barrier function

The skin barrier, particularly the stratum corneum (SC), is crucial for protecting against external irritants and preventing transepi-dermal water loss (TEWL). SS is often associated with a thinner SC and increased TEWL1,22, which allows for the penetration of irritants and allergens, exacerbating sensitivity to external stim-uli. Our previous study also demonstrated a significant difference in TEWL between the sensitive and control groups23. Studies have shown that individuals with SS have reduced levels of natural mois-turizing factors and lipids such as ceramides, leading to decreased skin hydration and compromised barrier integrity22. Additionally, conditions like atopic dermatitis (AD), where the barrier func-tion is already compromised, often overlap with SS, suggesting a synergistic effect between AD-induced barrier impairment and SS24-27. However, limited studies on the effect of barriers exist, and some investigations suggest no clear association between barrier conditions and SS24,26.

Inflammatory responses

Individuals with SS often show low-grade inflammation with-out visible signs, marked by elevated levels of pro-inflammatory cytokines like CCL17 and interferon-γ, sustaining mild skin 28 This chronic inflammation sensitizes the skin to external triggers, further lowering the threshold for irritation and increasing reactivity to stimuli such as temperature changes and certain chemicals.

Neurosensory dysregulation

SS is considered a neurogenic disorder involving skin barrier and sensory nerve dysfunction, characterized by reduced C-fiber den-sity and overstimulated TRP channels like TRPV1, which amplify sensory reactions and increase sensitivity2,29.

    Studies have shown that reduced intraepidermal nerve fiber density (IENFD) is linked to hyperesthesia in SS, resembling small fiber neuropathy30,31. Reduced IENFD in SS patients supports this pattern, with research identifying a decreased number of pepti-dergic C-fibers in SS, likely contributing to heightened reactivity in the remaining nerve endings32. The overstimulation of noci-ceptive channels on these nerve endings by neuropeptides, such

as calcitonin gene-related peptide (CGRP), may lead to neuro-genic inflammation in the skin. Activation of these receptors often results in sensations like burning, tingling, and stinging, frequently reported by SS patients33. Excessive CGRP release in SS overstimulates pain receptors via TRP channels, leading to neuropathic inflammation and sensitivity, mirroring features of small-fiber neuropathy like reduced nerve fiber density and abnor-mal heat-pain thresholds30,34-37.

    Recent studies suggest SS pathophysiology resembles neu-ropathic pruritus in small-fiber neuropathy, with a proposed condition called neurogenic rosacea exhibiting rosacea traits alongside neurological symptoms like burning and stinging, resistant to conventional therapies but partially responsive to anti-convulsants and antidepressants, supporting a neuropathic basis shared with SS38. In a recent study, some SS patients displayed typical neurogenic symptoms, as confirmed through responses to the SS-10 questionnaire15. Von Frey Filament Test assessments reveal decreased mechanical pain thresholds in SS-affected areas, like the cheeks, suggesting peripheral sensory neuropathy as a key factor in SS pathogenesis, which is also linked to neuropathic dis-orders like irritable bowel syndrome and sensitive eyes39.

    Sensations in SS are influenced by nerve fibers as well as kera-tinocytes and other epidermal cells expressing sensory proteins like TRP channels. Overexpression of channels such as TRPV1 and ASIC3 in SS leads to calcium influx and neurogenic inflammation upon activation by stimuli like acidic pH, heat, and chemicals, explaining SS’s heightened sensitivity to environmental triggers40.

    Transcriptomic studies reveal reduced PIEZO2 mRNA levels in SS patients, suggesting PIEZO2 dysfunction may contribute to SS hypersensitivity. TRPV1 channels, involved in mechanotransduction in Merkel cells, further link to this sensitivity, as genetic deletion of Merkel cells induces allokinesis, highlighting the roles of both PIEZO2 and Merkel cells in SS pathophysiology41,42. Moreover, the dedicator of cytokinesis nine gene (DOCK9), which encodes a pro-tein regulating dendrite growth, is downregulated in SS, correlating with decreased nerve fibers and increased sensitivity.

    SS pathophysiology parallels that of complex regional pain syndrome (CRPS), a disorder involving peripheral sensory neuropathy. In CRPS, repeated exposure to irritants causes sen-sory nerve damage and neurogenic inflammation, leading to peripheral neuronal sensitization with lowered sensory thresh-olds and increased excitability through the activation of protein kinases A and C, which phosphorylate sensory-specific sodium channels43. Over time, the desensitization of nociceptive neurons through phosphorylation of G-protein-coupled receptors and ion channels can gradually induce central sensitization, leading to persistent paresthesia.

    Recent transcriptomic research shows that patients with SS exhibit upregulated genes associated with inflammatory pathways, revealing a complex interplay between skin barrier dysfunction and neuropathic pruritus29. This dual neurological and dermato-logical dysfunction places SS within a spectrum of neuropathic skin disorders, similar to neuropathic pruritus.

Genetic and epigenetic contributions

Genetic factors may predispose individuals to SS, with variants in genes related to skin barrier proteins like filaggrin and neurosen-sory receptors like TRPV1, affecting skin structure and sensory perception and potentially explaining symptom variability across populations8 . Additionally, environmental influences, including pollution and lifestyle factors, may cause epigenetic modificationsthat impact the skin barrier and neurosensory pathways, further contributing to SS.

DIAGNOSIS OF SS

Diagnosing SS presents unique challenges due to the subjective nature of its symptoms and the frequent lack of visible lesions. Patients often report abnormal sensations, such as stinging and burning, triggered by common external factors like tempera-ture changes or cosmetic products. These sensations generally occur without any accompanying clinical signs, complicating the diagnostic process. Thus, a comprehensive diagnostic approach combining both subjective assessments and objective measure-ments is essential to accurately identify SS44.

Subjective diagnostic tools

The SS-10 is a self-administered questionnaire consisting of 10 items, each rated on a scale from 0 (no symptom) to 10 (extreme symptom intensity), assessing common symptoms such as sting-ing, burning, and tightness experienced over the past 3 days. The total score ranges from 0 to 100. A score ≥20 is typically indicative of SS, while scores above 50 may represent severe cases requiring intensive management. A cutoff of 12.7 has shown 72.4% sensitivity and 90.3% specificity for SS diagnosis (Fig. 2). In SS research, an SS-10 score of 20 typically defines SS, with 50 indi-cating severe cases needing intensive treatment, while a cutoff of 12.7 has demonstrated 72.4% sensitivity and 90.3% specificity in distinguishing SS cases45.

Objective diagnostic tools

Although there are often no clinical signs, diagnostic tests such as the lactate challenge test (Lactic Acid Sting Test [LAST]) and the capsaicin test are used to assess skin sensitivity44. Several methods exist to test SS, with the LAST being the most represen-tative1,11. This test entails applying a 10% lactic acid solution to the nasolabial fold and cheek area, followed by rubbing the skin after 2 minutes 30 seconds, and 5 minutes to assess sensitivity46. Patients scoring 3 or more out of 4 are classified as having SS, but due to inconsistent results in tests like the Lactic Acid Stinging Test, Sodium Lauryl Sulfate (SLS) Occlusion Test, and Capsaicin Test, SS is recognized as a heterogeneous group with limitations arising from subjective interpretation and result variability. Cur-rently, there are subjective and objective methods employed in testing patients with SS, as perceived by the subjects in terms of skin irritation. Subjective measurement methods include tests that induce sensations such as stinging test using lactic acid1 or eliciting a burning sensation with a mixture of chloroform and methanol47. Objective tests involve applying surfactants like SLS48 to measure erythema index and trans-epidermal water loss, as well as using dimethyl sulfoxide49 to induce swelling and erythema, and exposing the skin to ammonium hydroxide solution50 to measure blistering time.

    Existing research has struggled to standardize and objectify measurement methods, with studies using the Hilltop chamber to apply 0.1% lactic acid to the malar area51. This method assesses the stinging sensation over 10 minutes by comparing the onset and peak intensity, with studies showing that increasing lac-tic acid concentration up to 10% raises stinging intensity, after which it plateaus, while earlier onset and additional symptoms like erythema and itching appear51. Another study reported that the LAST is the most effective method for distinguishing sensitive from non-SS based on a survey52. Tests like LAST, SLS occlusion, and capsaicin rely on subjective assessment or show inconsis-tent results, highlighting the heterogeneity of SS and the need for objective indicators. Recent diagnostic advancements include TEWL measurements and the ANTERA 3D® system for quanti-tative evaluation of skin texture, redness, and hydration, used alongside clinical photography for long-term SS monitoring53. TEWL measurement, in particular, has proven useful in correlat-ing skin sensitivity with barrier function abnormalities, such as increased water loss and reduced hydration54.

Combining diagnostic methods

Combining SS-10 with objective measures like TEWL or LAST offers a more reliable SS diagnosis, especially for complex cases, such as those with heightened sensitivity from prolonged mask usage during the coronavirus disease 2019 (COVID-19) pandemic.

Investigation into related skin diseases

When skin sensitivity is detected, further investigation into asso-ciated skin diseases is essential. Patch testing remains crucial for diagnosing irritant and allergic contact dermatitis in SS, identi-fying triggers like allergens or irritants, especially for patients whose symptoms worsen with specific skincare products55 During COVID-19, patients reporting increased skin sensitivity from mask-wearing may have conditions like irritant or allergic contactdermatitis, folliculitis, seborrheic dermatitis, or worsened rosa- cea. Previous studies showed high sensitivity to fragrance mix 1 in SS patients through patch testing23. Coexisting skin conditions like neurogenic rosacea and AD in SS patients are assessed through facial imaging, TEWL, blood tests, patch tests, and Demodex den-sity tests, aiding in accurate treatment, identifying SS causes, and preventing recurrence.

MANAGEMENT OF SS

The treatment of SS requires a personalized approach due to the variability in symptoms and triggers across individuals (Fig. 3). Effective SS treatment plans should address underlying skin con-ditions, symptom duration, severity, and specific triggers, aiming to relieve sensations and visible issues while strengthening the skin barrier. Treatments should focus on barrier repair and neuro-sensory regulation, with gradual tapering of medication to avoid rebound symptoms, even if lesions are absent.

Identification and avoidance of triggers

Effective SS management involves identifying and minimizing triggers through patient history and using patch tests to detect allergens. Patients with AD are advised to avoid fragrances and irritants due to their compromised skin barrier56.

Emollients and barrier repair

Moisturization is key in SS treatment, but frequent changes in products can worsen sensitivity. Patients should test new prod-ucts on the forearm Repeat Open Application Test for 2 weeks, and for recurring reactions, an “as-is” patch test can confirm compatibility. TEWL is a key indicator of barrier integrity and sen-sitivity; elevated TEWL suggests barrier dysfunction. Barrier-repair products, like ceramide moisturizers, enhance resilience, while anti-inflammatory emollients (e.g., with colloidal oatmeal or nia-cinamide) help reduce discomfort and support recovery53,54.

Pharmacologic options

If symptom relief through avoidance and barrier repair is insufficient, tailored pharmacologic treatments may be used.

Antihistamines help with itching, beta-blockers reduce flushing, and serotonin-norepinephrine reuptake inhibitors and gam-ma-aminobutyric acid analogs (e.g., pregabalin, gabapentin) relieve SS symptoms by reducing sensitization and nociceptive signaling57. Topical calcineurin inhibitors, like pimecrolimus and tacrolimus, help manage SS by reducing inflammation and neurosensory sensitivity without causing skin thinning, suitable for long-term use. Intradermal botulinum toxin injections also show promise by inhibiting neurotransmitter release and reduc-ing pain.

Additional therapies: oxidative stress and neuromodulators

Oxidative stress worsens SS by weakening the skin barrier and increasing inflammation. Antioxidant treatments, such as topi-cal vitamins C and E or resveratrol, help reduce oxidative damage and aid barrier recovery, supporting SS management. Emerging SS treatments include topical neuromodulators like capsaicin, which desensitizes TRPV1 channels to reduce burning and sting ing, and cannabinoids, which may relieve inflammation and pain. Neuropathic pain management options like anticonvulsants and botulinum toxin also offer targeted relief for severe symptoms.

Comprehensive and personalized care

Managing SS requires a comprehensive, patient-centered approach that combines subjective (SS-10) and objective (TEWL, patch test-ing) assessments. Personalized plans including barrier repair, trigger avoidance, and tailored treatments improve outcomes, especially for patients affected by environmental triggers. Inte-grating new insights enhances treatment effectiveness, quality of life, and reduces symptom recurrence.

CONCLUSION

SS is a complex and multifaceted condition influenced by diverse physiological, environmental, and genetic factors. This syndrome, characterized by heightened sensory responses to otherwise non-irritating stimuli, presents unique challenges in both diag-nosis and management. Due to the subjective nature of symptoms and the absence of universal clinical signs, SS diagnosis relies on a combination of subjective assessments, such as the SS-10, and objective measures like the LAST and TEWL to confirm sensitivity and skin barrier integrity. Individualized treatment approaches are essential, focusing on mitigating skin barrier dysfunction, reducing neurosensory hypersensitivity, and avoiding known irritants. Recent studies emphasize the importance of tailored strategies to manage SS, especially in patients who experience worsening symptoms from common allergens, preservatives, and environmental stressors.

    The pathophysiology of SS underscores the importance of treating both the sensory discomfort and skin barrier impair-ment unique to each patient. By integrating recent advancements in SS assessment and management, clinicians can improve out-comes through personalized care plans that incorporate avoidance therapy, barrier repair, and pharmacologic options. As research continues to elucidate the underlying mechanisms of SS, a mul-tidisciplinary approach to both prevention and management will remain key in addressing this condition’s complexity and improv-ing patient quality of life.

ORCID iDs

Hye One Kim

https://orcid.org/0000-0001-5846-0008

Ji Young Um

https://orcid.org/0000-0003-2044-199X

Han Bi Kim

https://orcid.org/0000-0003-3190-7505

So Yeon Lee

https://orcid.org/0000-0001-9127-4290

Hyun Choi

https://orcid.org/0009-0004-1171-2051

Jihye Kim

https://orcid.org/0009-0000-3421-3942

Eunbi Ko

https://orcid.org/0000-0001-7071-711X

Bo Young Chung

https://orcid.org/0000-0002-2795-0140

Chun Wook Park

https://orcid.org/0000-0003-4512-8668

FUNDING SOURCE

This study was funded by the National Research Foundation of Korea (NRF) (grant number NRF-2022R1A2C2007739), a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number HP23C0201) and, by Hallym University Research Fund.

CONFLICTS OF INTEREST

The authors have nothing to disclose.

This article is excerpted from the 《Ann Dermatol》 by Wound World.