The SCINEXA a novel, validated score to simultaneously assess and differentiate between intrinsic and extrinsic skin ageing

doi 10 1016j jdermsci 2008 10 001 The SCINEXA A novel, validated score to simultaneously assess and differentiate between intrinsic and extrinsic skin ageing Andrea Vierkötter, Ulrich Ranft, Ursula.ádsadaSAD

The SCINEXA: A novel, validated score to simultaneously assess and

differentiate between intrinsic and extrinsic skin ageing

Institut fu¨r Umweltmedizinische Forschung (IUF), Du¨sseldorf, Germany

1 Introduction

Increasing life expectancy and the resulting demographic

consequences have made skin ageing a health topic that is of

growing concern to the general population This is best illustrated

by recent sale rates for cosmetic products which have been

developed to prevent, slow down or even reverse the clinical signs

of skin ageing Accordingly, in 2008 the skin care business has been

a 15 billion US$ anti-ageing and rejuvenation industry with growth

rates of more than 10% for cosmeceuticals[1] Many of these

anti-ageing products contain molecules with defined biological

activities and are claimed to modulate molecular processes

involved in the pathogenesis of skin ageing Efficacy testing of

such products is of outmost importance for consumers,

dermatol-ogists, cosmetic industry and regulatory institutions Although for

the demonstration of molecular mechanisms, invasive test

methods are clearly the gold standard, it has to be realized that

for obvious ethical reasons efficacy testing of the already large and still growing number of anti-ageing skin products has to be based

on non-invasive methods

In this regard, several skin ageing score have been developed which are mainly descriptive in nature, which may involve photographic grading scales and which can be used as global indicators of skin ageing[2], for the assessment of photoageing[3– 5] or of single clinical skin ageing signs [6,7] Skin ageing is, however, the consequence of intrinsic and extrinsic factors Intrinsic or chronological skin ageing and extrinsic skin ageing, which is primarily due to chronic exposure to ultraviolet (UV) radiation[8–10]and therefore is also called photoageing, can be distinguished histologically and clinically, involve distinct patho-genetic causes and mechanisms and their prevention is based on different principles[11–15] It is therefore surprising to see that no validated skin ageing scores exists that differentiates between these two different forms of skin ageing[2]

Here we report on the development of an easy to use skin ageing score, the ‘SCINEXA’, which is based on the assessment of 18 skin symptoms which are highly characteristic of extrinsic skin ageing and 5 skin symptoms which are indicative of intrinsic skin ageing

A R T I C L E I N F O

Article history:

Received 7 July 2008

Received in revised form 29 September 2008

Accepted 6 October 2008

Keywords:

SCINEXA

Intrinsic and extrinsic skin ageing

Sunbed use

A B S T R A C T

Background: Studies on the pathogenesis of skin ageing as well as efficacy testing of cosmetic and aesthetic measures to prevent or reverse skin ageing require – as an easy to use method – a validated non-invasive clinical score, which allows to simultaneously assess and differentiate between intrinsic (=chronological) and extrinsic (=photo-) skin ageing Such an ideal score, however, does currently not exist

Objectives: We developed a novel skin ageing score ‘SCINEXA’ comprising 5 items indicative of intrinsic and 18 items highly characteristic of extrinsic skin ageing These items were used to define an index (indexdiscr) that allowed differentiating between intrinsic versus extrinsic skin ageing In order to validate the ‘SCINEXA’, we asked whether it can be used to discriminate regular sunbed users, which have been chronically exposed to ultraviolet radiation and thus are prone to photoageing, from non-sunbed users, which were considered paradigmatic for intrinsic skin ageing

Methods: For this purpose, 58 non-sunbed users and 16 regularly sunbed users were assessed In addition

to the clinical examination of the 23 score items potential confounders were considered by questionnaire Results: By employing the indexdiscr, we were able to classify 92% of all study subjects correctly as sunbed

or non-sunbed users Specifically, an index above 2 was associated with sunbed use and thus extrinsic skin ageing, whereas an index below 2 indicated intrinsic skin ageing

Conclusion: The novel ‘SCINEXA’ is suitable for the simultaneous assessment of intrinsic and extrinsic skin ageing

ß2008 Japanese Society for Investigative Dermatology Published by Elsevier Ireland Ltd All rights reserved

* Corresponding author.

E-mail address: Krutmann@rz.uni-duesseldorf.de (J Krutmann).

Contents lists available atScienceDirect Journal of Dermatological Science

j o u r n a l h o m e p a g e : w w w i n t l e l s e v i e r h e a l t h c o m / j o u r n a l s / j o d s

0923-1811/$30.00 ß 2008 Japanese Society for Investigative Dermatology Published by Elsevier Ireland Ltd All rights reserved.

We have used this score to asses skin ageing in two groups of human

volunteers: (i) regular sunbed users as a group that is paradigmatic

for long-term, chronic exposure to UV radiation, and (ii) non (or rare)

sunbed users, and we have found that by means of this new skin

ageing score it is possible to discriminate these two groups

2 Materials and methods

2.1 Study subjects

We studied 74 volunteers from North Rhine Westphalia (NRW)

in Germany in the age between 19 and 72 years One group (n = 58)

had never used a sunbed before or had used it rarely (i.e no sunbed

use for at least 18 months) This group will be referred to as

non-sunbed users The second group (n = 16) consisted of volunteers,

who used sunbeds once a week for at least 10 years This makes a

sunbed user percentage of 21% in our study, which represents the

sunbed user percentage of the German population of about 20%

2.2 ‘SCINEXA’: Score for Intrinsic and Extrinsic skin Ageing

Skin ageing symptoms of study subjects were evaluated by a

dermatologist using a newly developed skin ageing score called

‘SCINEXA’ This score contained 5 items characteristic for intrinsic

skin ageing and 18 items characteristic for extrinsic skin ageing

(for details seeTable 1) The complete skin was examined and the

clinical signs of skin ageing were graded using ordinal scales as

follows: 0 (none), 1 (mild), 2 (moderate) and 3 (severe) In addition,

the items: sunburn freckles, lentigines solaris, cutis rhomboidalis

nuchae, dryness, comedones and teleangiectasis were assessed on

defined locations For the items: uneven pigmentation, cutis

rhomboidalis nuchae, Favre racouchot, actinic precancerosis and

the skin cancer types a binary scale ‘‘Yes’’ (present = 3) or ‘‘No’’

(absent = 0) was used The dermatologist evaluated the skin of the

study subjects without knowing if they used sunbeds or not

2.3 Collection of individual data

In order to discover possible confounders, the following individual data known to have an effect on skin ageing were collected by questionnaire: gender, chronological age, body mass index (BMI) [16], reactivity of the skin to sun exposure using Fitzpatrick’s 4 level phototype classification (always burn and never tan, usually burn and tan with difficulty, sometimes mild burn and tan about the average, or rarely burn and tan with ease [17]), and smoking status[18] There was no difference in exposure

to daily sunlight and job history in the both study groups 2.4 Statistical analysis

Statistical analysis was done by using statistical software SAS 9.1

The relations between single items of the score with potential influencing factors were evaluated in two steps In a first step we used correlation analysis to assess the association of the potentially confounding factors: gender, age, BMI, sunbed use, skin phototype and smoking with single items of the score In a second step, the relationship between every single score item as dependent variable with relevant influencing factors (significant with p < 0.1 in the first step) as independent variables was analysed by applying logistic regression The independent vari-ables were adjusted for each other and their relation with the score items was expressed as odds ratios (OR) with its confidence intervals (CI) and p-values

Additionally two sub-scores were built: the extrinsic score defined as the sum of the 18 extrinsic score items (Se) and the intrinsic score defined as the sum of the 5 intrinsic score items (Si) The associations between Seand Siand the relevant influencing factors were analysed by multiple linear regression and the results are presented as mutually adjusted standardised mean differences (MD ¼ ðbxDxunitÞ= ¯x) with their confidence intervals (CI)

Table 1

Skin ageing symptoms included in the skin ageing score ‘SCINEXA’ and number of study subjects (n, %) showing the respective skin ageing symptoms to different degrees other than 0.

Skin ageing score: SCINEXA n (%) with symptom Skin ageing symptoms Location Evaluation

1 Part: intrinsic skin ageing items Uneven pigmentation 0/3 69 (93.2)

Reduced fat tissue 0/1/2/3 26 (35.1) Benign skin tumors 0/1/2/3 6 (8.1) Maximal achievable intrinsic score 15

2 Part: extrinsic skin ageing items Sunburn freckles Shoulders 0/1/2/3 38 (51.4)

Lentigines solaris Back of forearm 0/1/2/3 38 (51.4)

Change of skin phototype 0/1/2/3 19 (25.7)

Cutis rhomboidalis nuchae Neck 0/3 3 (4.1)

Dryness Face, back of forearms 0/1/2/3 57 (77.0) Comedones Periorbital 0/1/2/3 4 (5.4) Teleangiectasis Cheeks/nose 0/1/2/3 44 (59.5) Permanent erythema 0/1/2/3 15 (20.3)

Squamous cell carcinoma 0/3 1 (1.4)

Maximal achievable extrinsic score 54

Finally we defined an index (indexdiscr) consisting of intrinsic

and extrinsic elements to discriminate between sunbed users and

non-sunbed users as follows:

indexdiscr¼Seþ 1

Siþ 1

3 Results

In Table 1details of the newly developed skin ageing score

‘SCINEXA’ are presented (upper part: 5 items characteristic for intrinsic skin ageing and lower part 18 items of extrinsic skin ageing) These items were chosen because they are thought to be specific for either intrinsic or extrinsic skin ageing and because the main parts are known to occur frequently In this table also the frequencies of study subjects with the skin ageing symptoms are given Nearly all study subjects had an ‘uneven pigmentation’ (93.2%) and the majority showed ‘fine wrinkles’ (75.6%) and

‘dryness’ (77.0%) None of the subjects had ‘Favre racouchot’ and for each skin cancer type there was in each case only one volunteer, who showed the respective skin cancer

The distribution of gender, chronological age, BMI, sunbed use, skin phototype and smoking habits for both study groups are summarized inTable 2 In order to analyse the impact of these potential confounders on the newly developed skin ageing score correlation analysis was conducted A significant effect was only determined for age and, most importantly, for sunbed use Accordingly, inTable 3the odds ratios for the association of each single skin ageing symptom with age and sunbed use are summarized The associations of age and sunbed use were additionally adjusted for each other In case there were significant interactions between age and sunbed use the odds ratios for age effects were listed separately for both groups and the odds ratios for sunbed effects were given separately for <45 years and 45 years For age, the prevalence of almost all skin ageing symptoms significantly increased Regular sunbed use was associated with an even higher prevalence of the vast majority of extrinsic skin ageing

Table 2

Distribution of individual data: gender, chronological age, skin phototype (SPT),

body mass index (BMI) and smoking status separated for the both study groups

sunbed and non-sunbed users.

Individual data Group of

non-sunbed users: (n = 58)

Group of sunbed users:

(n = 16) Gender 38 men; 20 women 9 men, 7 women

Mean age 41.5  15.9 45.9  16.5

Skin phototype (%):

Body mass index (%):

18.5 < BMI < 25 27 9

25 BMI < 30 24 6

Smoking status (%):

Current smokers 12 5

Table 3

Odds ratios (OR) with confidence intervals (CI) for the associations of skin ageing symptoms ((A) intrinsic items and (B) extrinsic items) with age (per age decade) and sunbed use adjusted for each other.

A

Skin ageing symptoms OR (CI) for age OR (CI) for sunbed use

1 Intrinsic skin ageing items Uneven pigmentation 1.25 (0.68–2.31) 0.34 (0.1–2.34)

Fine wrinkles Rarely sunbed use: 7.26 (3.58–14.69) *** <45 years: 1.36 (0.21–8.62)

Regularly sunbed use: 2.72 (1.14–6.48) *

45 years: 0.11 (0.02–0.71) *

Lax appearance 3.15 (2.01–4.92) ***

0.04 (0.01–0.28) ***

Reduced fat tissue 4.23 (2.35–7.61) ***

0.05 (0.01–0.37) **

benign skin tumors 1.59 (0.87–2.92) n.e.

B

Skin ageing symptoms OR (CI) for age OR (CI) for sunbed use

2 Extrinsic skin ageing items Sunburn freckles Rarely sunbed use: 1.93 (1.34–2.78) ***

<45 years: 5.53 (1.04–29.40) *

Regularly sunbed use: 1.07 (0.62–1.88) 45 years: 1.19 (0.3–5.01) Lentigines solaris 3.21 (2.10–4.89) ***

9.38 (2.74–32.15) ***

Pigment change 3.28 (1.93–5.55) ***

25.39 (5.68–113.53) ***

Skin type change 2.26 (1.39–3.66) ***

40.37 (8.93–182.46) ***

Yellowness 4.18 (1.88–9.30) *** 657.54 (20.06–999) ***

Coarse wrinkles 2.17 (1.36–3.46) ** 40.89 (9.04–185.04) ***

Elastosis 2.34 (1.66–3.30) ***

20.87 (5.72–76.22) ***

Dryness 2.24 (1.59–3.16) ***

8.60 (2.53–29.28) ***

Comedones 5.72 (0.98–33.50) (*)

n.e.

Teleangiectasis 2.10 (1.53–2.89) ***

1.62 (0.56–4.62) Pseudo scars 3.04 (1.9–4.86) ***

12.32 (3.26–46.50) ***

Permanent erythema 1.73 (1.14–2.62) ** 3.44 (0.97–12.21) (*)

Cutis rhomboidales nuchae 5.73 (0.87–37.73) 0.83 (0.05–15.09) Actinic precancerosis 1.09 (0.56–2.13) 12.69 (1.20–133.90) *

Basal cell carcinoma 0.73 (0.17–3.04) n.e.

Squamous cell carcinoma 0.73 (0.17–3.04) n.e.

Malignant melanoma 1.09 (0.31–3.85) n.e.

OR: odds ratio; CI: confidence interval; n.e.: not evaluable.

(*)

p  0.1.

*

p  0.05.

**

p  0.01.

***

symptoms (Table 3B), but with a decrease in most of the intrinsic

skin ageing items (Table 3A) The associations between the sum of

intrinsic skin ageing score items (Si) and the sum of extrinsic skin

ageing score items (Se) with age and sunbed use are summarized in

Fig 1 The association of the intrinsic and extrinsic score with age

are similar (intrinsic score: MD = 0.22 (CI: 0.18–0.27) and extrinsic

score: MD = 0.34 (CI: 0.25–0.43)) It should be noted that for

sunbed users there is a very strong positive association with the

extrinsic score (MD = 1.33 (CI: 0.98–1.69)) and a negative

association with the intrinsic score (MD = 0.36 (CI: 0.54 to

0.18)

InFig 2the indexdiscrfor sunbed versus non-sunbed users is

given separately for subjects <45 years of age and 45 years It

appears that the indexdiscrstill increases with age for non-sunbed

users, but not for sunbed users Furthermore there is a clear

differentiation between the two study groups at an indexdiscrof 2

Almost all non-sunbed users have an index <2, whereas sunbed

users have an index 2 InTable 4the precise classification of each

study subject as sunbed user or non-sunbed user is presented

using an indexdiscrlevel of 2 as the cutting point Only 2 out of 16

sunbed users and 4 out of 58 non-sunbed users were misclassified Hence, by means of the SCINEXA, 91.9% of the study subjects could

be classified correctly as sunbed or non-sunbed users

4 Discussion

We have developed and validated a novel skin ageing score which allows to discriminate between intrinsic versus extrinsic skin ageing This score that we have termed ‘SCINEXA’ represents

an easy to use, non-invasive and sensitive tool for the simultaneous assessment of intrinsic and extrinsic skin ageing We expect that the ‘SCINEXA’ will greatly facilitate the efficacy testing of most types of cosmetic, cosmeceuticals and aesthetic measures which are directed at the prevention or reversal of intrinsic and/or extrinsic skin ageing In addition, this score may prove useful in studies on the different pathogenetic background of intrinsic versus extrinsic skin ageing Accordingly, by means of this score we have recently obtained evidence that – in addition to chronic UV irradiation – exposure to ambient particle pollution from traffic related sources significantly contributes to extrinsic skin ageing [19]

The ‘SCINEXA’ was validated by assessing intrinsic versus extrinsic skin ageing in a collective of 74 subjects which comprised regular sunbed users and non-sunbed users In accordance with the existing literature we have assumed that regular sunbed use for more than 10 years will cause extrinsic skin ageing[20,21], whereas non-sunbed users will show more signs of intrinsic skin ageing By means of the ‘SCINEXA’ we were indeed able to classify 92% of these subjects correctly according to their sunbed use

Fig 1 Relation of the intrinsic (S i ) and extrinsic skin ageing score (S e ) with age and sunbed use adjusted for each other.

Fig 2 Index (=index discr ) for sunbed and non-sunbed users for <45 years and 45

Table 4 Classification of the study subjects of the sunbed user groups according to their index discr Number of individuals correctly classified are bold.

index discr Sunbed user groups Total

Non-sunbed users Sunbed users

<45 years 45 years All <45 years 45 years All

Total 28 30 58 8 8 16 74

habits This clear differentiation was made possible by means of

the indexdiscrwhich was defined as the ratio of the extrinsic skin

ageing score and the intrinsic skin ageing score A misclassification

occurred only for 2 out of 16 regular sunbed users younger than 45

years and 4 out of 58 of older (45 years) non-sunbed users We

believe that in the first case the misclassification may be due to the

fact that the sunbed-induced skin damage in young regular sunbed

users is perhaps less advanced, so that they have indexdiscrvalues

at the borderline of 2 In the latter case other confounding factors,

which are not related to sunbed use, may have caused extrinsic

skin ageing Overall these results further support the notion that

regular sunbed use causes extrinsic skin ageing

In this study we observed that intrinsic (=chronological) skin

ageing as well as extrinsic skin ageing increase with age This result

is expected and reflects the age-dependent cumulative effect of

environmental factors on human skin It also emphasizes that

intrinsic and extrinsic skin ageing are not completely independent

from each other

Besides age sunbed use was the only other factor with a positive

associationwiththeextrinsicskinageingscore In particular,the odds

ratios for the association between extrinsic skin ageing items and

sunbed use were much higher than those for a 10 year increase in age

The only exceptions werecomedones and teleangiectasis.Chronic UV

exposure is a triggering factor for the formation of comedones and

teleangiectasis but the pathogenetic basis includes intrinsic factors

such as genetic, endocrine and infectious determinants

Interestingly, chronic sunbed users showed a decrease in the

intrinsic skin ageing score This decrease is most likely due to the

superposition of extrinsic skin ageing factors, e.g coarse wrinkles

superpose fine wrinkles, and therefore the intrinsic skin ageing

symptoms seem to decrease This observation also points to a

limitation of the ‘SCINEXA’, because it can not be used to measure

intrinsic skin ageing in severely photoaged skin

In the present study, no confounding effects were observed for

BMI, skin phototype or smoking habits, all of which are known to

significantly affect either extrinsic or intrinsic skin ageing In this

regard it is important to note that the collective used in this study

was small and only chosen according to their sunbed user habits As

previously mentioned, chronic UV exposure and thus regular sunbed

use is a very strong influencing factor on extrinsic skin ageing, which

has therefore been termed photoageing, and smaller effects by other

factors might not be detectable in such a small and preselected study

group Clearly, the ‘SCINEXA’ needs to be further validated in larger

collectives with a more balanced graduation of environmental

factors other than UV exposure Indeed, in an independent study the

‘SCINEXA’ has proven to be useful for identifying exposure to

ambient particle pollution from traffic related sources as a

UV-independent factor causing extrinsic skin ageing[19]

Acknowledgements This study has been supported by the Deutsche Forschungsge-meinschaft (DFG), Collaborative Research Center (SFB) 728, TP C1

We would like to thank Dr M Matsui (Estee Lauder Inc.) for critically reading the manuscript

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