Wrinkles

Abstract

Introduction

Skin disorders associated with photodamage from ultraviolet light include wrinkles, hyperpigmentation, tactile roughness, and telangiectasia, and are more common in people with white skin compared with other skin types. Wrinkles are also associated with ageing, hormonal status, smoking, and intercurrent disease.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for skin wrinkles? We searched: Medline, Embase, The Cochrane Library, and other important databases up to February 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 33 studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: botulinum toxin injection (e.g., botulinum toxin type A and type B), carbon dioxide laser, chemical peel (including alpha and beta hydroxyl acids), dermabrasion, isotretinoin, tazarotene, tretinoin, and variable pulse erbium:YAG laser.

Key Points

Skin disorders associated with damage by ultraviolet light include wrinkles, hyperpigmentation, tactile roughness, and telangiectasia, and are more common in people with white skin compared with those with other skin types.

• Wrinkles are also associated with ageing, hormonal status, smoking, and intercurrent disease.

Exposure to ultraviolet light may be associated with photodamage to the skin. Guidelines suggest that avoiding direct sunlight, either by staying indoors or in the shade, or by wearing protective clothing, is the most effective measure for reducing exposure to ultraviolet light.

Botulinum toxin injection (given in a single session) seems to be more effective than placebo at improving wrinkles at up to 120 days.

• We found no RCTs comparing repeated injections of botulinum toxin versus placebo over a long period of time.

Topical tretinoin may improve fine wrinkles when applied daily, compared with vehicle cream, in people with mild to severe photodamage, but its effect on coarse wrinkles is unclear.

• Topical tretinoin may cause itching, burning, erythema, and skin peeling.

• Isotretinoin cream applied daily may improve fine and coarse wrinkles compared with vehicle cream in people with mild to severe photodamage, but may cause severe irritation of the face.

Tazarotene applied daily may improve the appearance of fine wrinkles compared with placebo/vehicle cream. However, it can cause burning of the skin.

• We don't know whether tazarotene is more effective than tretinoin at improving fine and coarse wrinkles in people with moderate photodamage, as studies have given inconclusive results.

We don't know whether chemical peel (including alpha and beta hydroxyl acids) is beneficial.

We don't know whether dermabrasion is more effective at improving wrinkles compared with carbon dioxide laser treatment, as studies have given inconclusive results, but adverse effects are common with both treatments, especially erythema.

• We don't know whether variable pulse erbium:YAG laser treatment improves wrinkles, as few studies were found.

About this condition

Definition

Wrinkles are visible creases or folds in the skin. Wrinkles less than 1 mm in width and depth are defined as fine wrinkles. Wrinkles that are 1 mm or more in width and depth are defined as coarse wrinkles. Most RCTs have studied wrinkles on the face, forearms, and hands.

Incidence/ Prevalence

We found no information on the incidence of wrinkles alone, only on the incidence of skin photodamage, which includes a spectrum of features such as wrinkles, hyperpigmentation, tactile roughness, and telangiectasia. The incidence of skin disorders associated with ultraviolet light increases with age and develops over several decades. One Australian study (1539 people, aged 20–55 years, living in Queensland) found moderate to severe photodamage in 72% of men and 47% of women under 30 years of age. Severity of photodamage was significantly greater with increasing age, and was independently associated with solar keratoses and skin cancer. Wrinkling was more common in people with white skin (especially skin phototypes I and II). We found few reports of photodamage in black skin (phototypes V and VI). One study reported that the incidence of photodamage in European and North American populations with Fitzpatrick skin types I, II, and III is about 80% to 90%. As Asian skin is more pigmented (Fitzpatrick skin types III–V), wrinkling is not readily apparent until approximately the age of 50 years, with wrinkles being less severe than in white skin of similar age. A prospective study (85 white women living in North America and 70 Japanese women living in Tokyo, aged 20–69 years) comparing age-related changes in wrinkles in eight areas of the facial skin (forehead, glabella, upper eyelid, corner of the eye, lower eyelid, nasolabial groove, cheek, and corner of the mouth) and sagging in the subzygomatic area found more wrinkle formation in all areas of the face in younger age groups of white women than in Japanese women (aged 20–29 years). Another prospective study (160 Chinese women and 160 French women, aged 20–60 years) found that wrinkle onset was delayed by about 10 years in Chinese women compared with French women.

Aetiology/ Risk factors

Wrinkles may be caused by intrinsic factors (e.g., ageing, hormonal status, and intercurrent diseases) and by extrinsic factors (e.g., exposure to ultraviolet radiation and cigarette smoke). These factors contribute to epidermal thinning, loss of elasticity, skin fragility, and creases and lines in the skin. The severity of photodamage varies with skin type, which includes skin colour and the capacity to tan. It is becoming increasingly clear that brief incidental sun exposures, which occur during the activities of daily living, add significantly to the average individual's daily exposure to ultraviolet light. One review of five observational studies found that facial wrinkles in men and women were more common in smokers than in non-smokers. It also found that the risk of moderate to severe wrinkles in lifelong smokers was more than twice that in current smokers who had been smoking for a shorter period (RR 2.57, 95% CI 1.83 to 3.06). A twin study (67 pairs of Japanese monozygotic twins) found that facial texture or wrinkle scores were significantly higher in twins who smoked or did not use skin protection compared with twins not exposed to cigarettes or using skin protection (P = 0.04 and P = 0.03, respectively). Another study (400 German women, aged 70–80 years) found a significant correlation between exposure to air pollutants and signs of extrinsic skin ageing, including wrinkles. The effects of pregnancy and menopause on facial wrinkling have also been investigated by some researchers. In postmenopausal women, oestrogen deficiency is thought to be an important contributory factor for development of wrinkles. One observational study (186 Korean women, aged 20–89 years) found that facial wrinkling increased significantly with an increase in the number of full-term pregnancies (OR 1.84, 95% CI 1.02 to 3.31) and the number of years since menopause (OR 3.91, 95% CI 1.07 to 14.28). However, postmenopausal women who had HRT had significantly less facial wrinkling compared with postmenopausal women who had no history of HRT (OR 0.22, 95% CI 0.05 to 0.95). The effects of sleep positioning and facial wrinkles have also been studied. One cross-sectional study (100 US women, aged 23–71 years) found no significant correlation between sleep side preference and the appearance of wrinkles.

Prognosis

Wrinkles cannot be considered a medical illness requiring intervention, but concerns about changes in physical appearance brought on by ageing can have a detrimental effect on quality of life. In some cases, concerns about physical appearance can affect personal interactions, occupational functioning, and self-esteem. Geographical differences, culture, and personal values potentially influence a person's anxieties about ageing. In societies in which the maintenance of a youthful appearance is valued, the demand for interventions that ameliorate visible signs of ageing grows as ageing populations expand.

Aims of intervention

To improve fine and coarse wrinkling in adults, and to improve quality of life, with minimal adverse effects.

Outcomes

Wrinkle improvement includes physician and participant evaluation of improvement in skin texture that reduces the visibility of wrinkles; quality of life; adverse effects. We excluded RCTs based solely on non-clinical outcomes, such as histological assessment, photography, or optical profilometry.

Methods

Clinical Evidence search and appraisal February 2014. The following databases were used to identify studies for this systematic review: Medline 1966 to February 2014, Embase 1980 to February 2014, and The Cochrane Database of Systematic Reviews, issue 1 (1966 to date of issue). Additional searches were carried out in the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment (HTA) database. We also searched for retractions of studies included in the review. Titles and abstracts identified by the initial search, run by an information specialist, were first assessed against predefined criteria by an evidence scanner. Full texts for potentially relevant studies were then assessed against predefined criteria by an evidence analyst. Studies selected for inclusion were discussed with an expert contributor. All data relevant to the review were then extracted by an evidence analyst. Study design criteria for inclusion in this review were: published RCTs and systematic reviews of RCTs in the English language, at least single-blinded, and containing 20 or more people (10 in each arm), of whom more than 80% were followed up. There was no minimum length of follow-up. We excluded all studies described as 'open', 'open label', or not blinded unless blinding was impossible. We included RCTs and systematic reviews of RCTs where harms of an included intervention were assessed, applying the same study design criteria for inclusion as we did for benefits. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. Most RCTs in the review recruited people with moderate to severe photodamage and wrinkles, rather than people with wrinkles alone. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as RRs and ORs. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table.

GRADE Evaluation of interventions for Wrinkles.

Important outcomes	Adverse effects, Quality of life, Wrinkle improvement
Studies (Participants)	Outcome	Comparison	Type of evidence	Quality	Consistency	Directness	Effect size	GRADE	Comment
What are the effects of treatments for skin wrinkles?
2 (912)	Wrinkle improvement	Tazarotene versus placebo/vehicle cream	4	–1	–1	0	0	Low	Quality point deducted for incomplete reporting of results; consistency point deducted for inconsistent effect with different doses
2 (291)	Wrinkle improvement	Tazarotene versus tretinoin	4	–2	–1	0	0	Very low	Quality points deducted for uncertainty about randomisation and allocation concealment, and inconsistent assessment of results; consistency point deducted for conflicting results
13 (1480)	Wrinkle improvement	Tretinoin versus vehicle cream	4	–3	0	0	0	Very low	Quality points deducted for uncertainty about randomisation and allocation concealment, inconsistent assessment of results, and short-term follow-up in some RCTs; consistency point deducted for conflicting results, but added for dose response
2 (1099)	Wrinkle improvement	Isotretinoin versus vehicle cream	4	–3	0	0	0	Very low	Quality points deducted for poor follow-up, no intention-to-treat analysis, and incomplete reporting of results
2 (149)	Wrinkle improvement	Glycolic acid versus vehicle cream	4	–2	0	–1	0	Very low	Quality points deducted for sparse data, and incomplete reporting of results; directness point deducted for uncertainty about clinical significance of the outcome; consistency point deducted for conflicting results, but added for possible dose response
1 (74)	Wrinkle improvement	Lactic acid versus vehicle cream	4	–2	0	–1	0	Very low	Quality points deducted for sparse data and incomplete reporting of results; directness point deducted for uncertainty about clinical significance of the outcome
3 (55)	Wrinkle improvement	Carbon dioxide laser versus dermabrasion	4	–2	0	0	0	Low	Quality points deducted for sparse data and incomplete reporting of results
2 (44)	Wrinkle improvement	Carbon dioxide laser versus chemical peel (including alpha and beta hydroxyl acids)	4	–3	–1	0	0	Very low	Quality points deducted for sparse data, inadequate blinding, and incomplete reporting of results; consistency point deducted for contradictory results
4 (83)	Wrinkle improvement	Carbon dioxide laser versus erbium:YAG laser	4	–3	–1	–1	0	Very low	Quality points deducted for sparse data, incomplete blinding, and incomplete reporting of results; consistency point deducted for conflicting results; directness point deducted for different outcomes assessed
1 (20)	Wrinkle improvement	Carbon dioxide laser versus carbon dioxide laser plus variable pulse erbium:YAG laser	4	–3	0	0	0	Very low	Quality point deducted for sparse data, incomplete blinding, and incomplete reporting of results
19 (3195)	Wrinkle improvement	Botulinum toxin injection versus placebo	4	–1	0	0	0	Moderate	Quality point deducted for weak methods (possible bias, and pharmaceutical involvement in publications)

We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.

Glossary

Botulinum toxin

A neurotoxin produced by the bacterium Clostridium botulinum. There are eight antigenically distinguishable subtypes (A, B, C1, C2, D, E, F and G). Type A is the most potent toxin, followed by types B and F. Botulinum toxin works by blocking the release of acetylcholine – the principal neurotransmitter at the neuromuscular junction, thus interfering with neural transmission. Subtypes A and B are the only commercially available form of botulinum toxin for clinical use.

Erbium:YAG laser

An yttrium aluminium garnet laser. Laser delivered in short pulse durations with relatively long intervening time periods between each pulse is referred to as ‘variable pulsed’. Laser delivered via a laser beam divided into thousands of microscopic treatment zones that target a fraction of the skin is referred to as ‘fractional’.

Fitzpatrick skin phototype classification

I = always burns easily, never tans; II = always burns easily, tans minimally; III = burns moderately, tans gradually (light brown); IV = burns minimally, always tans well (brown); V = rarely burns, tans profusely (dark brown); VI = never burns, deeply pigmented (black).

Low-quality evidence

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Mild/moderate/severe photodamage

A spectrum of features including wrinkles, hyperpigmentation, tactile roughness, and telangiectasia. Usually measured on a scale from 0–9 (0 = none, 1–3 = mild, 4–6 = moderate, and 7–9 = severe).

Moderate-quality evidence

Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Very low-quality evidence

Any estimate of effect is very uncertain.

Visual Analogue Scale (VAS)

A commonly used scale in pain assessment. It is a 10-cm horizontal or vertical line with word anchors at each end, such as 'no pain' and 'pain as bad as it could be'. The person is asked to make a mark on the line to represent pain intensity. This mark is converted to distance in either centimetres or millimetres from the 'no pain' anchor to give a pain score that can range from 0–10 cm or 0–100 mm.

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