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MODULE 1Diagnosis and Evaluation of Sensitive Skin National Course Directors DR. RUI FERNANDEZ DR. VIDYA KHARKAR M.D. (BOM), D.V.D., D.D.V. M.D., D.V.D. (Dermatology), MBBS, D.G.C.Professor and Head of Dermatology (Retd.) Professor Seth G. S. Medical College & K.E.M. Hospital, Mumbai KEM Hospital & G.S. Medical College

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MODULE 1Diagnosis and Evaluation Of Sensitive SkinINDEXDiagnosis & Evaluation of Sensitive SkinCHAPTER 1 04Understanding sensitive skin, etiology, types 10and classification 16CHAPTER 2Importance of barrier function in case ofsensitive skin & pathophysiologyCHAPTER 3Clinical diagnosis and evaluationof sensitive skinREFERENCES 24 3

MODULE 1Diagnosis and Evaluation Of Sensitive SkinCHAPTER 1Understanding sensitive skin, etiology, types and classificationSynonymsSensitive skin has several synonyms in the scientific literature, including intolerant skin,reactive skin and hyperreactive skin. Sometimes it is also referred to as Sensitive skinsyndrome (SSS).IntroductionSensitive skin is a common term used by patients and clinicians, as well as the cosmeticindustry and represents a complex clinical challenge faced by dermatologists and otherskin care professionals.The term sensitive skin, commonly refers to a condition of subjective cutaneoushyperreactivity, an exaggerated and unpleasant sensitivity of the skin to environmentalfactors, frequent or prolonged use of everyday products such as cosmetics or toiletries.Often patients report worsening after exposure to dry and cold climate.[1] Patientswith sensitive skin often present with subjective complaints that are out of proportionto the objective clinical findings.[2],[3] Although no sign of objective irritation is commonlydetected, itching, burning, stinging and a tight sensation is constantly present. Althoughoften transient and in many cases unaccompanied by visual dermatological responses,sensitive skin affects the quality of life.[4]Maibach described the cosmetic intolerance syndrome (CIS), which covers the bulk of theclinical presentation of the sensitive skin syndrome (SSS).[5] Fisher coined the term statuscosmeticus to describe one extreme of the natural history of the CIS, in which the patientgradually becomes completely intolerant to the application of any cosmetic product.[6]DefinitionA single definition of this condition remains elusive as the condition is self-diagnosed.The term sensitive skin needs to be precisely defined. A tenuous consensus in the literatureis that sensitive skin is characterized by subjective complaints of discomfort withoutpredictable classical visible signs of irritation [7] and without an immunologic response.[7], [8]Although transient redness, dryness or tenderness may accompany adverse sensations[8]and sensitive skin may be less supple or hydrated,[9] subjects often experience sensoryeffects only.[8]Definition 1Sensitive skin (Syn: Reactive, hyperreactive, intolerant, or irritable skin) is defined[10], [11-13]as the onset of erythema and/or prickling, burning, or tingling sensations (possibly pain orpruritus), due to various factors, which may be physical (ultraviolet radiation, heat, cold andwind), chemical (cosmetics, soap, water and pollution), psychological (stress), or hormonal(menstrual cycle).4

MODULE 1Diagnosis and Evaluation Of Sensitive SkinDefinition 2Sensitive skin can also be defined in both subjective form and objective terms.[14]Subjective perceptions (stinging, burning, pruritus and tightness) of sensitive skin arenoticed immediately following cosmetic product application or delayed by minutes, hours,or days. Objective perceptions of sensitive skin are based on physician evaluation andinclude the entire repertoire of cutaneous reactions.Definition 3Sensitive skin can be defined as a complex condition that (1) is characterized by highsubjective sensitivity, (2) can be present with or without clinical symptoms, (3) can appearalone or in association with other skin conditions and (4) has a considerable impact onHRQoL (Health-related quality of life).[15]EtiologyThe etiology of sensitive skin is multifactorial, involving an underlying genetic susceptibilitycombined with exogenous and endogenous factors that can trigger or aggravate theclinical expression of the condition.[20]Endogenous factors - Are further divided into inherent factors and associated factors. • Inherent factors Sensitive skin is associated with the following inherent qualities.[18] 1. Female sex 2. Youth 3. Susceptibility to blushing and/or flushing 4. Skin pigmentation 5. Thin Stratum corneum 6. Decreased hydration of Stratum corneum 7. Disruption of Stratum corneum 8. Increased epidermal innervation 9. Increased sweat glands 10. Increased neutral lipids and decreased sphingolipids 11. High transepidermal water loss (TEWL) 12. Hormonal status 13. Cultural expectations in technologically advanced countries 14. Fair skin which is susceptible to sunburn 5

MODULE 1Diagnosis and Evaluation Of Sensitive SkinTable showing racial differences in skin properties – a comparison between the black andcaucasian races[20] Skin property Comparison results Stratum corneum thickness Equal in blacks and caucasians Number of cell layers in Stratum corneum Higher in blacks Stratum corneum resistance to stripping Higher in blacks Lipid content in Stratum corneum Higher in blacks Electrical resistance of Stratum corneum Higher in blacks Desquamation of Stratum corneum Higher in blacks Corneocyte size Equal Amount of ceramides in Stratum corneum Lower in blacks Variability of structural parameters of Stratum corneum Increased in blacks Spectral remittance Lower in blacks UV protection factor of epidermis Higher in blacks UV protection factor of Stratum corneum Higher in blacks UVB transmission through epidermis Lower in blacks (fourfold) Stratum corneum UVB transmission Lower in blacks In vitro penetration of fluocinolone acetonide Lower in blacks In vitro penetration of water No difference / differences Topical application of anaesthetic mixture Less efficacy in blacks In vivo penetration of C-labelled dipyrithione Lower in blacks (34% lower) In vivo penetration of cosmetic vehicle Lower in blacks Methylnicotinate-induced vasodilation Time to peak response equal Slower in blacks Baseline TEWL Higher in blacks Reactivity to SLS (measured by TEWL) Higher in blacks Reactivity to dichlorethylsulphide (1%) Lower in blacks Reactivity to o-chlorobenaylidene malonitrile Lower, longer time to response in blacks Reactivity to dinitrochlorobenzene Lower in blacks Stinging response Lower in blacksSLS = sodium lauryl sulphate; TEWL = transepidermal water loss; UV = ultraviolet; UVB = ultraviolet B6

MODULE 1Diagnosis and Evaluation Of Sensitive SkinAn association has also been observed between skin type and sensitivity. In an opinion pollconducted in Europe, 14.2% of respondents with sensitive skin said that they had dry skin,11.1% said that they had oily skin and 4% said that they had normal skin.[17] That studydetected a statistically significant association between cosmetic skin type and sensitive skin.Skin phototype also appears to be associated with sensitive skin and has been reported tohave a significant impact on perceived sensitivity, with phototype I being most commonlyassociated with sensitive skin.[22]Anatomical sites - Exposed skin - The nasolabial fold has been reported to be the mostsensitive region of the facial area, followed by the malar eminence, chin, forehead andupper lip.[23]Cultural factors – Hygiene practices are the most common cause of vulvar irritation.Fastidious cleansing routines (with douches, perfumes, medication, antifungal medicationsand contraceptives), which often precede irritation have some cultural component.[24]Associated factorsClassic studies have detected association between sensitive skin and seborrheic diathesis,atypical psoriasis, rosacea, perioral dermatitis and atopic dermatitis.[20]Atopic dermatitis (AD) is considered by many to be a possible predisposing condition. Apositive relationship has been demonstrated between AD and stinging[7] and the densityof cutaneous nerves has been demonstrated to be higher in atopic skin than in normalskin.[25] Also, baseline TEWL in uninvolved skin in AD patients, which is higher than that ofnormal subjects[26] was shown to predict susceptibility to irritants in other sites.[26] Atopy ingeneral has been linked by some authors to the phenomenon of sensitive skin.[26] Patientswith respiratory atopy and active rhinoconjunctivitis were demonstrated to have increasedskin susceptibility to irritants.[27] It has been conjectured that alloallergens may disruptbarrier function, thereby increasing skin susceptibility.[27]Exogenous factorsThe use of cosmetics that are unsuitable for a particular skin type is the most commonexogenous factor that can trigger sensitive skin.[20]Cosmetics and ToiletriesMany cosmetic formulations contain alcohol, propylene glycol, butylene glycol,cocamidopropyl betaine, triethanolamine, resorcine,[28] trichloroacetic acid and alphahydroxy acids, which depending on their concentration, have a greater or lesser irritant effectand can aggravate sensitive skin.[20] However in its pure form cocamidopropyl betaine hasless chances of aggravating sensitive skin. Topical corticosteroids increase skin fragilityand cause chronic localized erythema, leading to increased cosmetic intolerance andpossibly triggering symptoms of sensitive skin in the affected area.[18, 20] UV-A exposureand surgical or nonsurgical cosmetic procedures, such as phototherapy, dermabrasion,laser resurfacing and facelifts can all aggravate sensitive skin.[20] 7

MODULE 1Diagnosis and Evaluation Of Sensitive SkinEnvironmental FactorsA number of environmental factors that trigger sensitive skin reactions have beenidentified,[22, 29] including heat and cold, sun, wind, pollution and air-conditioning.[16],[18] It isknown that the decrease in temperature and humidity levels that typically occur in winterand in cold environments reduce the water content of the Stratum corneum and favor theexpression of sensitive skin symptoms. Other lifestyle-related environmental factors are:1. D iet rich in spices, alcohol, coffee etc[16], [20]2. P ersonal hygiene practices such as certain shaving techniques among men, excessive showering and overuse of body care products[18]3. Substantial work-related exposure to chemicals[18]Epidemiology - PrevalenceThe scientific literature shows a worldwide increase in the prevalence of sensitive skinin recent years. The estimated prevalence in Japan, Europe and the United States is50% among women and 30% among men, with a similar distribution across countriesand continents.[16] In European countries (France, Italy, Portugal, Germany, Switzerland,Belgium and Greece), 37.6% reported having sensitive or very sensitive skin.[17]Age: Age can have a considerable influence on susceptibility to sensitive skin and somestudies suggest that young people are more prone than older people. The medical literaturecontains no analysis of sensitive skin in children.[18] The body surface area to body massratio is very high in children, which means that they are subject to high exposure to skincare products and therefore possibly more prone to sensitive skin.Sex: With respect to sex-related differences, the general perception is that more womenclaim to have sensitive skin than men,[18, 19] but some authors have reported a significantlyhigher prevalence among men. Farage[19] reported that the perceived severity of sensitiveskin was comparable in men and women, but that men perceived less severe reactionson the face.Race: Several studies have suggested that black people have less sensitive skin thanwhite people and that white people, in turn have less sensitive skin than asians. Thereis however no statistical evidence to support these hypotheses and the differences thathave been detected between different ethnic groups are probably not race-related butrather due to psychosocial and cultural factors[16,18] (e.g. personal hygiene practices anddiet). Asians for example have stronger skin reactions to spicy food.[16]8

MODULE 1Diagnosis and Evaluation Of Sensitive SkinClassification of sensitive skinPons-Guiraud has proposed three subgroups of sensitive skin, each with different symptomintensity.[20]1. Very sensitive skin (dry or fatty) or intrinsic skin: Both types react strongly toexogenous factors (e.g.environmental insults) and endogenous factors. The symptomsare acute and permanent and tend to have psychological effects.2. Environmentally sensitive skin: This is often clear, dry, thin skin that essentiallyreacts to environmental factors such as heat and abrupt temperature changes.3. Cosmetically sensitive skin: This is mildly sensitive skin that mainly reacts tocosmetics that are generally easy to identify.Muizzuddin et al. defined three subgroups differently. His classifications include: 1. D elicate skin - characterized by easily disrupted barrier function not accompanied by a rapid or intense inflammatory response 2. Reactive skin - characterized by a strong inflammatory response without a significant increase in permeability 3. S tingers - characterized by a heightened neurosensory perception to minor cutaneous stimulation [11] 9

MODULE 1Diagnosis and Evaluation Of Sensitive Skin CHAPTER 2 Importance of barrier function in case of sensitive skin63 & pathophysiology BARRIER FUNCTIONS OF THE SKIN The skin is the outermost barrier between the human body and the environment, occupying a surface area of approximately 2 meter square in adults. It performs multiple functions, the most obvious one being protection from the environment, as a mechanical barrier preventing the penetration of microorganisms and chemicals and absorbing the sunrays. Permeability barrier The skin is a two-way permeability barrier that determines the inward and outward diffusion of substances, particularly water and electrolytes. The barrier function is mainly performed by the Stratum corneum, with protein-rich cells embedded in the lipid-rich matrix. Barrier to the penetration of microorganisms and chemicals Penetration of microorganisms is prevented by an intact Stratum corneum. Cuts or injuries to the skin, skin diseases and skin appendages can facilitate the entry of microorganisms. Lipids, glycerophospholipids and free fatty acids in the Stratum corneum have an antimicrobial effect. Barrier to UV radiation Solar radiation is composed of short and long wave UV rays (UVB and UVA) and infrared rays. Proteins in the Stratum corneum and the pigment melanin in the epidermis absorb UV radiation, minimize its effect on cellular and nuclear constituents. Mechanical barrier The skin can be compressed and is elastic due to the presence of ground substance, collagen and elastic fibers in the dermis. These mechanical properties, along with the protection provided by the epidermis and the subcutaneous fat, prevent injury due to blunt objects and pressure.10

MODULE 1Diagnosis and Evaluation Of Sensitive SkinComponents of the Stratum corneum establishing skin barrier functionEpidermal layers of the skin include the Stratum corneum, Stratum lucidum, Stratumgranulosum, Stratum spinosum and Stratum basale. In the epidermis there are multiplecomponents important to barrier function. These components include claudin, desmoglein,filaggrin, ceramide and proper control of proteases. When properly functioning, this layerprevents water loss and provides a barrier to epidermal invasion of allergens and bacteria.Functions of epidermal barrier components and its protective roleBarrier Type Function Possible Role inComponent Tight junction Preventing Atopic MarchClaudin protein Desmosome Prevention of water loss Prevention of TH2 activationDesmoglein ScaffoldingInvolucrin / Protein Prevention of water loss Blocking allergenEnvoplakin/ Chromophore penetrationPeriplakin Structural components Allowing appropriateUrocanic Acid Protein to create epidermal barrier immunoregulatory T-cell environmentFilaggrin Lipid Hygroscopic acid–base Maintaining skin barrier regulator / photoprotection functionCeramide Protein Decreased permeability of water soluble molecules / Blocking allergen penetrationSkin Protease epidermal differentiationInhibitors Blocking mast cell infiltration(SPINK) Contribution to skin /expression of TNF permeability and Blocking mast production of epidermal differentiation allergic cytokines Blocking allergen penetration Prevention of protease alteration in filaggrin and Maintaining skin barrier ceramide production function 11

MODULE 1Diagnosis and Evaluation Of Sensitive Skin Permeability layer disruption is bidirectional; allowing both epidermal water loss and allergen penetration The lipid lamellar matrix is an integral component in controlling the barrier function of the skin. The deficiency of barrier lipid free ceramides determines to be a major contributing factor in damaging the permeability barrier of the skin. Filaggrin is another key protein in protecting against water loss through the Stratum corneum (SC) and is present in the epidermis as early as 3 months of age . Degradation products of filaggrin have been found to contribute to the formation of the epidermal barrier by providing acidity. Skin pH and its relation to barrier function[64] In the last decades it has been demonstrated that skin pH largely influences barrier homeostasis, SC integrity and cohesion and antimicrobial defense mechanisms. Skin pH is normally acidic, ranging in pH values of 4–6, while the body’s internal environment maintains a near-neutral pH (7–9). This creates a steep pH gradient of 2–3 units between the SC and underlying epidermis and dermis. The physiological role of an acidic skin surface, was initially thought to be a defense mechanism against invading microorganisms. Recently, it has been demonstrated that several key enzymes involved in the synthesis and maintenance of a competent skin barrier are largely impacted by pH. Hence the importance of pH in relation to function and integrity of the skin is emerging. A number of factors including both endogenous and exogenous elements affect skin pH. Endogenous factors like age, anatomic site, genetic predisposition, ethnic differences, sebum, skin moisture, sweat and exogenous factors like detergents, cosmetics, soaps, occlusive dressings, skin irritants and topical antibacterials. Immediately after birth, skin surface pH of both fullterm and preterm neonates is elevated compared to adults and older children. The mean pH value from 6 different body sites in the first day of life in full-term neonates was 7.08, which is significantly higher than in adult controls (pH 5.7). pH decreases steeply in the first few days of the postnatal period and then more gradually in the rest of the neonatal period. pH values later in infancy are similar to that of adults. Hence the neonatal skin is very sensitive. Skin pH and barrier function - The Stratum corneum’s (SC) role as a permeability barrier hinges on its hydrophobic character, lipid distribution and organization of lipids into a series of lamellar bilayers. The formation of the SC barrier, specifically generation of its lipophilic components involves several pH-dependent enzymes. Two key lipid-processing enzymes, ß-glucocerebrosidase and acidic sphingomyelinase have pH optima of 5.6 and 4.5, respectively. Both are involved in the synthesis of ceramides, critical components of the permeability barrier. Activity of ß-glucocerebrosidase is 10 times slower in situ at pH 7.4 than at pH 5.5. Processing of lipids secreted by lamellar bodies and formation of lamellar structures require an acidic environment. Skin pH and Stratum corneum integrity - pH not only influences barrier homeostasis, but also affects SC integrity, cohesion and desquamation. Serine proteases, kallikrein 5 (SC tryptic enzyme) and kallikrein 7 (SC chymotryptic enzyme) have neutral pH optima and are intimately linked to desquamation by degrading desmoglein 1. As pH increases, these12

MODULE 1Diagnosis and Evaluation Of Sensitive Skinserine proteases are activated, while the enzymes responsible for generating ceramideswhich have an acidic optima are inactivated compromising SC structure and function. Asserine protease activity is sustained, lamellar body secretion is blocked.Skin pH and antimicrobial properties - The microflora of the skin consists of transient,temporary-resident and permanent-resident species, including coagulase-negativeStaphylococci. Normal flora growth of Staphlococcus epidermidis is optimal at acidic pHlevels, whereas pathogenic bacteria such as Staphylococus aureus thrives at neutral pHlevels. Hence maintaining an acidic pH is beneficial for normal as well as sensitive skin, sinceit not only maintains the barrier function but also maintains the Stratum corneum integrity.Pathophysiology - Potential mechanisms of sensitive skina) Sensitive skin and epidermal barrier functionSeveral studies have suggested a link between sensitive skin and a disruption of theepidermal barrier function, resulting in perception of skin discomfort (Fig. 1).[3], [30-32] Theintegrity of the epidermal barrier highly depends on lipid composition and accordingly thederangement of intercellular lipids was associated with a disrupted barrier.[33] Sensitive skinis known to cause a noticeably decreased amount of neutral lipids and upregulated levelsof sphingolipids that have been linked to reduced barrier stability.[33] A weak epidermalbarrier facilitates the penetration of irritants or allergens, fails to adequately protect nerveendings and moreover increases transepidermal water loss (TEWL).[3], [34]Figure 1 - Factors involved in development and maintenance of sensitive skin. PATHOPHYSIOLOGY Atopic predisposition Cutaneous factors Sensory nervous system Dermatosis TRPV1 Sensitive( Atopic dermatitis, rosacea) Skin (Keratinocytes, nerves) Disturbed barrier Neurogenic inflammationEnvironmental factors Life style factors Endogenous factors Cosmetics Air pollution Diet Hormones Climate Alcohol Physiological factors (e.g. Heat, wind) (e.g. Stress, emotional burden) UV irradiation CONTRIBUTING FACTORS 13

MODULE 1Diagnosis and Evaluation Of Sensitive Skin Impaired epidermal barrier integrity has also been associated with atopic dermatitis. In line with this, some studies have demonstrated that individuals with sensitive skin show an increased incidence of atopy and furthermore that the risk of developing allergies was five times higher in individuals with sensitive skin when compared to controls.[36], [39-40] A link between atopic dermatitis and sensitive skin exists, further supported by the observation that all patients diagnosed with atopic dermatitis described themselves as having sensitive skin, with 80% claiming moderate to very sensitive, whereas only 64% of the control group described their skin as being sensitive to some extent.[37] b) Role of the cutaneous nervous system in sensitive skin Due to the wide variety of sensory symptoms such as burning, tingling, stinging, pain and sometimes even itching, it is highly likely that neurosensory dysfunction in the skin might represent one of the pathomechanisms of sensitive skin.[16] Altered sensations in individuals with sensitive skin might result from an insufficient protection of cutaneous nerve endings due to impaired epidermal barrier integrity. Another mechanism through which the cutaneous nervous system could contribute to sensitive skin might be by functional hyperreactivity of cutaneous nerves. Cutaneous nerve fibres such as unmyelinated C fibres mediating pain, itch and warmth are equipped with sensory neuroreceptors such as endothelin and transient receptor potential (TRP) channels. Notably, both endothelin receptors and members of the TRP family are known to induce pain, burning and itch in sensitive skin.[16] The role of these sensory receptors in the perception of reactive skin is strengthened by their expression not only on nerve endings, but also on keratinocytes.[16],[38-40] Since sensitive skin is induced by various environmental factors, including UV light, cold, heat and air pollution, the activation of cutaneous endothelin receptors and TRP channels might represent a mechanism by which external stimuli are transferred to individuals with sensitive skin. TRPV1, initially named capsaicin or vanilloid 1 receptor, was identified on nociceptive sensory nerve endings and is known to mediate sensations of pain, itch, warmth and afferent functions to chemical stimuli. It has been conclusively proven that besides in neuronal cells, TRPV1 is also expressed in cutaneous non-neuronal cells such as keratinocytes, mast cells or Langerhans cells.[41] In keratinocytes, for instance, activation of TRPV1 results in an increased Ca2+ influx and finally induces cell apoptosis.[41] Consequently, in a disrupted epidermal barrier, as present in sensitive skin, TRPV1 stimulation delays barrier recovery, whereas the administration of a TRPV1 antagonist improves barrier repair.[42],[43] The assumption that TRPV1 might play a central role in sensitive skin is further strengthened by the suggestion that the TRPV1 antagonist trans-4-tert-butylcyclohexanol could be a promising therapeutic option for the treatment of sensitive skin.[44]14

MODULE 1Diagnosis and Evaluation Of Sensitive Skinc) Immune cells implicated in sensitive skinThe activation of TRPV1 results in the local cutaneous release of neuropeptides suchas substance P (SP), which subsequently activates different cell types in the skin. e.g.keratinocytes, mast cells, antigen-presenting cells and T-cells located in close vicinityto the sensory nerve endings. SP by binding to its receptor, induces the release ofproinflammatory cytokines and chemokines, resulting in the recruitment of further immunecell subsets to the skin.[45]d) StressStress is commonly reported as a trigger for sensitive skin and mast cell degranulation issupported by the finding that sensitive skin sufferers had higher density of mast cells andsize of lymphatic microvasculature.[46]Sensitive skin has been classified into three different types based on their physiologicalparameters. Type I has been defined as the low barrier function group. Type II has beendefined as the inflammation group with normal barrier function and inflammatory changes.Type III has been specified as the pseudo-healthy group in terms of normal barrier functionand no inflammatory changes. In all types, a high content of nerve growth factor hasbeen observed in the Stratum corneum, relative to that of non-sensitive skin. Both in typeII and III, the sensitivity to electrical stimuli was high,[47] as this data suggests that thehypersensitive reaction of sensitive skin is closely related to nerve fibres innervating theepidermis.Skin sensitivity is a complex process in which a range of pathophysiological phenomenahave been observed. Roussaki-Schulze et al.[32] for example, in a study comparing sensitiveskin and nonsensitive skin, described the following objective biophysical findings in thegroup of individuals with sensitive skin:1. V ery dry skin with low oilyness, which leads to a disturbance of the protective skin barrier function2. Hyperreaction of the skin blood vessels3. Increased transcutaneous penetration of water-soluble chemicals4. Enhanced immune responsiveness5. Significant decrease of alkali resistance6. Heightened neurosensory stimulationStructural contributors to sensitive skinThe structural contributors to sensitive skin includes a thin Stratum corneum (SC),decreased hydration and disruption of SC, increased sweat glands influence permeability,increased epidermal innervation, increased neutral lipids and decreased sphingolipids andhigh baseline TEWL associated with increased susceptibility to irritants. 15

MODULE 1Diagnosis and Evaluation Of Sensitive SkinCHAPTER 3Clinical diagnosis and evaluation of sensitive skin Clinical features of sensitive skin Patients with sensitive skin usually present without visible skin lesions. Their discomfort is mainly based on the presence of subjective symptoms such as itching, stinging, burning or pain, which has a high impact on quality of life.[16], [48-50] The neurosensory symptoms are known to resemble neuropathic pain symptoms. Sensitive skin symptoms may occur spontaneously and can also be induced by cosmetic ingredients, certain environmental conditions (e.g. ultraviolet light, temperature, wind) and psychological (e.g. stress) or hormonal (e.g. menstrual cycle) factors.[16], [48-50] In most patients, symptoms occur within 1hr following exposure to the trigger factors and may persist for minutes or even hours. Symptoms occur in the face, but may uncommonly also involve trunk or genital areas.[3], [51] In some patients, an extensive erythema follows induction of the symptoms occurring along with or independently of an atopic predisposition.[48-50] Some may present with patchy erythema, dry skin or scaling. It is necessary to distinguish between patients with these symptoms and those with inflammatory dermatoses, which might also cause sensitivity of the face. Examples of inflammatory dermatoses include atopic dermatitis, rosacea, perioral dermatitis, seborrheic dermatitis and psoriasis. Sensitive skin is associated with the characteristics described below: 1. High Subjective Sensitivity Individuals with high subjective skin sensitivity experience an almost continuous sensation of tingling, burning, stinging and tightness of the skin.[52] While the face is the most common site for sensitive skin,[16] a study by Saint-Martory et al.[3] found that other parts of the body are also affected, namely hands (58%), scalp (36%), feet (34%), neck (27%), torso (23%) and back (21%). A. Face - The facial area is probably affected most by sensitive skin because of the high number of cosmetic products used on the face and the fact that it has a weaker skin barrier than other parts of the body as well as a large number of nerve endings.[4] The nasolabial fold is considered to be the most sensitive part of the face due to the permeability of its Stratum corneum, its high density of sweat glands and hair follicles and its rich innervations.[18] The next most sensitive areas are the malar eminence, the chin, the forehead and the upper lip.[17] B. Scalp- Misery et al.[54] assessed scalp sensitivity in a sample of 1011 individuals; of these, 44.2% claimed that they had a sensitive scalp and within this group, 11.5% had a scalp disease. There was a significant association between hair loss and scalp sensitivity. Prickling, itching and pain were more common in the sensitive skin group and the main triggers were pollution, heat, emotions and shampoo. Based on their findings,16

MODULE 1Diagnosis and Evaluation Of Sensitive Skin Misery et al. concluded that scalp sensitivity was a genuine, common condition. A subsequent study reported that the most common symptoms associated with sensitive scalp were itching and tingling and also stated that dandruff could not be considered a symptom of sensitive skin.[55] C. Vulvar region - In a group of patients with chronic vulvar irritation, 29% were found to have contact hypersensitivity, while 94% reported secondary sensitization to topical medication.[56] As concluded by Farage and Maibach,[4] vulvar sensitivity is often related to contact hypersensitivity, which in turn, is related to the use of topical medication and hygiene products.2. Presence or absence of objective signsSensitive skin is associated with a wide range of non-specific clinical signs, includingerythema, telangiectasis and scaling.3. Presence or absence of associated conditionsIndividuals with sensitive skin can also present clinical signs typically associated withconcomitant conditions such asacne, contact dermatitis, psoriasis, rosacea, atopicdermatitis, seborrheic dermatitis and vitiligo.4. Impact on quality of lifeSensitive skin has considerable psychological effects and has been seen to adverselyaffect quality of life, with greater impairment seen in individuals with more sensitive skin.[22]Zafiriou et al.[57] observed an association between skin hypersensitivity and somatization,anxiety, phobic anxiety, hostility and interpersonal sensitivity.Clinical DiagnosisMisery et al.[17] recommend that dermatologists regularly ask their patients whether theyhave sensitive skin. The syndrome is generally self-diagnosed and is characterizedby a wide range of symptoms of greatly varying intensity. Kligman et al.[2 ] described differentdefinitions of sensitive skin which, in their opinion, facilitate diagnosis.These areas follows:1. Subjective irritation: irritant response without visible clinical signs2. Neurosensory irritation: neurally mediated responses such as itching, stinging, burning, tightness3. Chemosensory irritation: sensory responses induced by chemicals in contrast to physical, mechanical and environmental factors4. P sychophysical irritation: irritation with a psychological componentHowever, to facilitate diagnosis, patients must complete questionnaires and undergophysical tests that will provide information on these aspects of sensitive skin. 17

MODULE 1Diagnosis and Evaluation Of Sensitive SkinQuestionnaires One of the questionnaires used to evaluate sensitive skin was designed by Querleux et al.[58] The questions are related to the typical characteristics of very sensitive skin and contemplate reactions due to the topical application of personal hygiene products and environmental factors questionnaire to identify individuals with sensitive skin.[58] The answers to the questions will be either yes or no. 1 Do you regard yourself as having sensitive facial skin? 2 Do you consider that your facial skin is prone to irritation? 3 D o you consider yourself to have ‘‘reactive’’ (Stinging, burning and/or itching sensation with or without redness) facial skin? 4 D o you avoid certain cosmetics you feel may cause your facial skin to react? (Stinging, burning and/or itching sensation with or without redness). 5 Do you consider that your facial skin reacts (Stinging, burning and/or itching sensation with or without redness) readily to cosmetics or toiletries? 6Do some cosmetics or toiletry products make your facial skin itch, sting, or burn? 7 Have you ever experienced an adverse reaction on your face to a cosmetic or toiletry product? 8 D oes the expression ‘‘does not tolerate cold weather or a cold environment’’ apply to your facial skin? 9 D oes the expression ‘‘does not tolerate hot weather or a hot environment’’ apply to your facial skin? 10 D oes the expression ‘‘does not tolerate fast changes in temperature’’ (e.g. Going into a warm shop from a cold street) apply to your facial skin? 11 Does going out in the wind cause your facial skin to itch, burn or sting? 12 Does going out in the sun cause your facial skin to itch, burn or sting? 13 D oes your facial skin react (Stinging, burning and/or itching sensation with or without redness) to pollution?18

MODULE 1Diagnosis and Evaluation Of Sensitive SkinPhysical TestsMany attempts have been made to find a test capable of providing an objective diagnosisof sensitive skin, but none of the tests analyzed have proven to be sufficiently effective,highlighting the subjective nature of sensitive skin.[20], [59]Farage et al.[18] reviewed the available tests for the assessment of sensitive skin andclassified them into 3 major groups:(1) Those that assessed neuro-sensory responses (sensory reactivity tests);(2) Those that assessed visible signs of skin irritation (irritant reactivity tests); and(3) T hose that measured structural and physiological parameters of the skin as indicators of the irritant effect (dermal function tests)[18]The stinging test designed by Frosch and Kligman[60] is considered to be the most effective.It involves the application of 0.5 ml of 10% lactic acid to one nasolabial fold and distilledwater at room temperature to the other. The symptoms, assessed subjectively, are scoredon a scale of 1 to 4 according to the intensity.[16],[20] Other substances used in this test arecapsaicin, ethanol, menthol, sorbic acid and benzoic acid.[18],[20]The stinging test is considered to be the best way to diagnose sensitive skin.[18],[20] Furthermore, it is fast, cheap and simple,[18] although it lacks predictive value. Marriot et al.[23]indicated that a positive stinging test result in the nasolabial fold does not necessarilypredict subjective responses to products applied to other parts of the face.The plastic occlusion stress test combined with the measurement of TEWL-desorptioncurves provides a more objective assessment of sensitive skin.[61] It is a new, dynamicapproach, which unlike baseline TEWL measurements, provides unequivocal evidenceof skin barrier impairment.[61] Accordingly, it would seem that this test could be used todiagnose or predict sensitive skin.[61]Pons-Guiraud[20] recommends including cosmetics andpersonal care products used by patients in allergy tests to detect subclinical manifestationsof contact allergy. Should any signs of sensitive skin be detected, the author recommendswithdrawing all cosmetics and reintroducing them, one by one, at 2-week intervals andnotes that it is important to limit the type of cosmetics used and the frequency with whichthese are applied in the final stage of the program.[20]Evaluation of sensitive skin[62]Testing methods for the investigation of sensitive skin are as follows[30] and they aretabulated with the details in respective tables:• Tests for the development of sensitive skin panels [Table 1]• Bio-engineering tests to measure skin response [Table 2]• In vivo testing on sensitive skin population [Table 3]• In vitro tests to demonstrate irritancy [Table 3] 19

MODULE 1Diagnosis and Evaluation Of Sensitive SkinTests for the development of sensitive skin panels [Table 1] Test Method Test site Interpretation Nasolabial fold/ Sting experience rated by patient Lactic acid Application of 10% cheek at 2.5 & 5 minutes after application facial sting test aqueous solution of of 4-points scale. 3 or >3 points – lactic acid at room Malar eminence patient classified as ‘stinger’ with Christensen temperature sensitive skin and Kligman Malar eminence test Application of 10% Time to initial stinging and peak racemic D-L lactic stinging noted and divide stingers Chloroform: acid in 1.7-cm into mild, moderate and severe Menthol Hilltop chamber for (20:80) test 10 mins To elicit burning Application of 20:80 solution DMSO test 2ml application Forearm/cheek Strong burning reaction in sensitive of 90% or 100% skin with erythema and urticaria DMSO at RTP for 5 mins SLS occlusion Various Forearm Erythema due to vasodilatation as test concentrations of “sensitive skin” SLS applied Nicotine test Methyl nicotinate Upper third of Erythema due to vasodilatation as (1.4-13.7%) applied ventral forearm “sensitive skin” for 15 secs Histamine test Intradermal Forearm Indicate intensity of itch sensation injection of using a predetermined scale and histamine (100 µg duration of itch recorded in 1 ml of normal saline) Washing test Subjects asked to Face Individual sensation of tightness, wash their face with burning, itching and stinging a specific soap or evaluated by predetermined point detergent scale. It identifies a subpopulation with “sensitive skin” DMSO: Dimethyl sulfoxide, SLS: Sodium lauryl sulfate, RTP: Room temperature20

MODULE 1Diagnosis and Evaluation Of Sensitive SkinBio-engineering tests to measure skin response [Table 2]Test Parameter Technique monitoredEvaporimetry To access barrier Closed chamber method, ventilated chamber(TEWL dysfunction, water method and open chamber methodmeasurement) evaporation from the skinComeometry Method for \"Capacitance\" measuring device operating at measuring SC low frequency. It estimates water content in water content (skin the epidermis to an approximate depth ranging hydration) between 60 and 100 µm.Profilmetry Analyse changes in It involves obtaining a silicone rubber cast of the the surface texture skin surface, transforming the cast into a plastic (SC cohesion) positive and obtaining a computerized contour tracing of the surface. It can be inaccurate because the silicone can flatten and disturb the desquamating skin scale.Squametry Analyse changes in Inaccuracy of silicone rubber cast can be overcome the surface texture by squametry, where the loosely adherent skin (SC cohesion) is harvested by pressing a sticky tape against the skin. Tape is analysed through computerized image processing. Blood flow andLDV erythema. LDV extracts the frequency-shifted signal and Most important derives an output proportional to the flux of parameters to erythrocytes in the blood flow. predict early signs of skin irritation.Colorimetry Redness quantifies Colorimeter allows for quantitative comparison of surface color erythema in individuals and between individuals changes in the skin comparable with visual assessment.Corneosurfametry Index of redness Reflectance colorimetry as parameter of the irritation caused by surfactantA-scan ultrasound Alteration in skin Ultrasound thicknessTEWL: Trans-epidermal water loss, LDV: Laser Doppler velocimetry, SC: Straum corneum 21

MODULE 1Diagnosis and Evaluation Of Sensitive SkinIn vivo testing on sensitive skin population [Table 3]In vitro tests to demonstrate irritancy [Table 3]. In vivo and Tests Procedure/interpretation In vitro tests In vivo tests on Patch tesing Performed with singly or finished products; sensitive skin Repeat insult patch test 10 patches are applied to the same site at 48-72 population hrs intervals for 3-4 week periods. After 2 weeks rest and test site re-challenged and graded. Cumulative irritancy test Patch test applied to the same site for 10-21 days and evaluated for irritant reaction. Chamber scarification test Volar surface of the forearm is scratched to the level of the papillary dermis and the test product applied under a Finn chamber repeatedly for 3 days and evaluated up to 1 week after patch removal. In vitro tests to Collagen swelling test Uses a 1 cm2 collagen sheet, incubated for demonstrate 24hrs at 50oC with a solution of the finished irritancy cleanser product at 1% of the dry extract at its own pH. Collagen is weighed before and after pH rise test exposure to determine the amount of swelling. More swelling indicates increased product irritation. Incubate equal volumes of a 2% solution of bovine serum albumin at a pH of 5.6 with 2% solution of the finished product at room temperature (RT). Greater the pH rise indicates increased product irritation. Zein test Done with protein that is insoluble in aqueous solution until denatured by irrtating surfactant products. The more protein that is solubilized, the more irritating the product.Kligman was the pioneering dermatologist showing great interest in the development of non-invasive skin assessment allowing presumably more accurate evaluation of physiologicalchanges indicative of sensitive skin. It is presumed that physiological changes indicativeof sensitive skin can be detected at low levels before clinical disease presentation.[30]Following are the tests done and the parameters monitored in the test.[30], [52]22

MODULE 1Diagnosis and Evaluation Of Sensitive Skin• TEWL: Water evaporation from the skin• Corneometry: Skin hydration• Colorimetry: Redness/erythema• Squametry and Corneosurfametry: SC cohesion• Laser Doppler velocimetry: Blood flow alterations/erythema• A-scan ultrasound: Alteration in skin thickness.Most popular non-invasive test is TEWL measurement. It is based on the estimation ofwater pressure gradient above the skin surface. It is done by two different techniques:Open chamber method and ventilated chamber method. Detailed account of methodscan be found in article by Primavera and Berardesca.[52]In vivo testing on sensitive skin population includes patch testing, repeat insult patchtesting, cumulative irritancy testing, the chamber scarification test, the modified soapchamber test and the forearm controlled application technique. The details are tabulatedin Table 3. Three common in vitro tests to evaluate the irritant potential of soaps arecollagen swelling test, pH rise test and Zein test. 23

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