Topical treatments and skin‐resurfacing techniques for skin ageing

Objectives

This is a protocol for a Cochrane Review (intervention). The objectives are as follows:

To assess the efficacy and safety of topical treatments and skin‐resurfacing techniques for skin ageing that is sufficient for people to seek treatment, and to identify optimum treatment concentrations, frequencies of application and therapy durations.

Background

Description of the condition

Skin ageing is defined as the alteration in the structure, function and appearance of the skin due to intrinsic factors from chronological ageing, and extrinsic factors, primarily due to photodamage from prolonged or repeated ultraviolet (UV) exposure. The term photodamage is used synonymously with photoageing.

Intrinsic skin ageing is mediated by genetic factors and physiological changes over time (Farage 2008). Factors influencing intrinsic skin ageing include the amount and type of skin pigmentation, anatomical site variations within a single individual and hormonal changes (Farage 2008; Humbert 2012; Zouboulis 2012). Extrinsic skin ageing is related to cumulative exposure to environmental factors, mainly from UV radiation, but also airborne pollution and cigarette smoking (Krutmann 2016). Sun exposure is a highly significant factor in skin ageing (Kohl 2011).

In this review, we will study topical treatments and skin‐resurfacing techniques to target changes related to skin ageing, which are most frequently mediated by UV radiation, the main cause of extrinsic skin ageing. For consistency, we will use the term 'skin ageing' throughout the review.

Prevalence

Skin ageing that is of sufficient concern for people to seek treatment is increasing annually. According to the American Society of Plastics Surgeons, about 16 million people underwent minimally invasive cosmetic procedures in the US in 2019, an increase of 2% from 2018, and an exponential increase of 3181% since 1992 (ASPS 2019). This increased demand for treatment to address skin ageing is reflected in society's emphasis on youth and beauty.

Psychosocial implications

Advancements in medical science and improvement in socioeconomic status have resulted in an increase in life expectancy. This means that individuals are now exposed to environmental factors over a longer time, allowing cumulative damage to occur. Some consider the visible changes of skin ageing as cosmetically unappealing, leading to increased demand for topical treatments and procedures that have rejuvenating effects on the skin. Furthermore, there are psychological implications associated with skin ageing due to societal emphasis on a youthful appearance. Increasing numbers of individuals are becoming concerned about skin ageing, and in some cases, this can lower one's self‐esteem and confidence, leading to issues with interpersonal relations (Gupta 1996).

Causes and risk factors 

There are multiple factors leading to skin ageing (Farage 2008; Dupont 2013). The prevalence of skin ageing is dependent on intrinsic factors, such as increased age, gender, amount and type of skin pigmentation, as well as extrinsic factors such as smoking status and exposure to UV radiation (Tsukahara 2004; Oldenburg 2013). In general, the less pigmented the skin, the greater the risk for skin ageing and other sun‐induced conditions including skin cancer (Richmond‐Sinclair 2010). Skin ageing is observed more often in individuals with a lower amount of pigmentation (Table 1; Dobos 2015). Unlike intrinsic ageing, extrinsic ageing may be ameliorated by avoidance of modifiable factors. Excessive exposure to UV radiation is the most significant factor, which leads to sunburn and suppression of cellular immunity in the short‐term, and skin ageing and skin cancer in the long‐term (Dupont 2013; Marmon 2014). Smoking status is linked with facial wrinkling in both genders (Chung 2001; Manríquez 2014). Cigarette smoking is postulated to decrease capillary and arteriolar blood flow in the skin, damaging connective tissue components that are important to maintain skin elasticity (Grady 1992; Oldenburg 2013). In postmenopausal women, oestrogen deficiency is an important contributory factor for wrinkles (Thornton 2013), while in men, skin ageing is associated with outdoor occupations and outdoor activities due to prolonged and repeated UV radiation.

1. Fitzpatrick Skin Phototype: classification and description.

Type	Description
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)

Clinical manifestations

Intrinsic and extrinsic skin ageing are associated with different characteristic clinical features. The overall appearance is related to the relative contribution of environmental factors imposed on the natural changes related to intrinsic ageing (Benedetto 1998). Clinical features of intrinsically aged skin include smooth texture, skin atrophy, loss of elasticity and fine wrinkles (Gilchrest 1996). Clinical features of extrinsically aged skin include rough texture, loss of elasticity, telangiectasia, elastosis, irregular pigmentation and coarse wrinkles (Yaar 2002). Facial areas most susceptible to skin ageing include the eyelids, forehead, corner of the mouth, cheek, glabella and the nasolabial groove (Nouveau‐Richard 2005). The rate of UV radiation‐induced skin ageing depends on the balance between the frequency, intensity and duration of exposure and the natural protection by skin pigmentation (Kammeyer 2015).

Pathophysiology

At the cellular level, skin ageing from sun damage results in irregular thickening of the stratum corneum, epidermal thinning, collapsed fibroblasts, reduced basal cell division and reduced levels of glycosaminoglycans (GAGs), resulting in decreased moisture retention in the epidermis and dermis, reduced and fragmented collagen and elastin resulting in skin fragility, loss of elasticity, and lines and creases in the skin (Thibault 1998; Katz 2015). Microscopic changes include atypical epidermal cells, skin thinning and atrophy, elastosis, increased melanogenesis, excessive deposition of GAGs and decreased collagen. At the molecular level, regardless of whether the cause is extrinsic or intrinsic, skin ageing involves DNA damage, decrease in antioxidant levels, and an increase in matrix metalloproteinases (MMPs), which degrade collagen and elastin in the dermis (Gonzaga 2009; Kammeyer 2015; Lephart 2016).

Classification system 

There are several scales to describe skin ageing caused by photodamage. The main classification systems include:

1. Glogau Classification of Photoaging (Glogau 1996); and

2. Rubin's System (Rubin 1995).

The Glogau Classification of Photoaging is a validated descriptive scale, which evaluates the severity of wrinkles from a scale of I to IV in relation to age, as well as the presence of keratosis, which can develop into actinic keratosis or precursors to cancerous skin lesions (Table 2). Rubin's system classifies ageing signs according to three levels (Table 3). According to this classification, changes in pigment are related to damage caused by the sun. This includes freckles in younger people and senile lentinges in older people. Also, it recognises that the skin changes in texture with age. Here, texture is defined via descriptive terms such as dull, leathery and rough. Unlike the Glogau system, age is not a consideration for the Rubin's system.

2. Glogau Classification of Photoaging.

Group	Classification	Typical age (years)	Description	Skin characteristics
1	Mild	28–35	No wrinkles	Early photoageing: mild pigment changes, no keratosis, minimal wrinkles, minimal or no make‐up
2	Moderate	35–50	Wrinkles in motion	Early to moderate photoageing: early brown spots visible, keratosis palpable but not visible, parallel smile lines begin to appear, wears some foundation
3	Advanced	50–65	Wrinkles at rest	Advanced photoageing: obvious discolorations, visible capillaries (telangiectasias), visible keratosis, wears heavier foundation always
4	Severe	60–75	Only wrinkles	Severe photoageing: yellow‐grey skin colour, prior skin malignancies, wrinkles throughout. No normal skin, cannot wear makeup because it cakes and cracks

3. The Rubin Aging Analysis Classification System.

Group	Description
Level 1	Individuals may or may not have wrinkles. In terms of pigmentation, there may be some freckles and lentinges. The stratum corneum may be showing signs that it is becoming thicker. Wrinkles at this level are very minimal with some fine static lines, if any.
Level 2	This level is marked by more severe signs of sun damage. Individuals may have pigmentation issues like freckles and lentinges. Overall, there will be a higher degree of irregularity in the skin colour. The stratum corneum has become much thicker. Smile lines are prominent as well as wrinkles in other areas, particularly around the eyes. The skin at this stage can be described as 'crinkled.'
Level 3	This is the most severe form of skin damage. It is marked by wrinkles in the form of deep lines which are apparent when the person is resting. Skin is also characterised by discolorations and comedones. And it can be described as being thick and leathery in texture.

Medical terms are defined in the glossary table (Table 4).

4. Glossary table.

Term	Definition
Acneiform	A description of skin conditions resembling small, raised and acne‐like bumps to form.
Actinic keratosis	A scaly skin spot caused by excessive sun exposure.
Antimetabolite	Drug(s) that interfere with the synthesis of DNA.
Antioxidant	A substance that protects cells from damage caused by free radicals, which are unstable molecules produced by the process of oxidation during normal metabolism.
Arrhythmia	A condition which describes an abnormality with the rate or rhythm of the heartbeat.
Arteriolar	A small artery that leads to a capillary at its distal end.
Atrophy	A decrease in the size of a normally developed organ or tissue.
Basal cell	A cell in the deepest layer of the cellular covering of internal and external surfaces of the body.
Cardiotoxicity	A condition where there is damage to the cardiac tissue.
Ceramide	A family of fatty acids in the skin that help to maintain the skin barrier by retaining moisture.
Collagen	A family of protein found in connective tissue, giving it strength and flexibility.
Contraindicate	A reason to avoid a certain medical treatment due to the harm it would cause the patient.
Cytotoxic	A chemical or process that leads to cell damage or cell death.
Dendritic cells	A special type of immune cell that is found in tissues, such as the skin, and boosts immune responses by showing antigens on its surface to other cells of the immune system.
Dermal	An adjective referring to the dermis, the inner layer of the skin beneath the epidermis.
Desquamation	It refers to the shedding of the outermost layer of the skin.
Dyspigmentation	An abnormality in the formation or distribution of pigment in the skin.
Ectasia	A term referring to dilation of ducts due to loss of elastic tissue.
Elastin	A protein that makes up elastic fibres in elastic structures such as tendons and ligaments.
Elastin fibres	Highly extensible fibres made of the protein elastin.
Elastin gene	A genetic code that controls the synthesis of the protein elastin.
Elastosis	A term referring to degenerative changes in elastic tissue.
Extracellular matrix	A scaffold of molecules outside the cells of a tissue that provides support to those cells.
Fibrillin	A specific protein found in connective tissue.
Fibrillin‐1	A specific type of fibrillin found in connective tissue to provide structural support to tissues.
Fibrillin‐rich microfibrillar network	A network of fibrillin found in an extracellular matrix, which endows connective tissue with mechanical stability and elastic properties.
Fibroblastic	Relating to fibroblasts.
Fibroblasts	Cells found in connective tissue, which produce proteins such as collagen and elastin.
First‐generation	Of, relating to or being the first form of a class of medication.
Glabella	The area between the eyebrows just above the nose.
Glycosaminoglycans	Complex molecular structures involved in essential biological cell processes.
Histological	An adjective pertaining to the study of biological tissue under the microscope.
Hypertrophic	An adjective pertaining to excessive growth.
Immune response modifier	An agent that targets the body’s immune system to combat disease.
Keloid scarring	A process where a thick scar results from excessive growth of fibrous tissue.
Keratin	A family of proteins produced by cells called keratinocytes; these proteins form the bulk of the outer lining of hair and nails.
Keratosis	A term for a descriptive word for any scaly lesion. The plural term is keratoses.
Lentigines	A plural term for patches of dark spots on the skin, resulting from excessive sun exposure.
Macrophage	A specialised immune cell involved in the detection and destruction of foreign organisms.
Matrix metalloproteinases	Enzymes that degrade proteins, such as collagen, normally found in the spaces between cells in a tissue.
Melanin	A family of biological pigment derived from an amino acid, and produced by cells called melanocytes.
Melanisation	The process of producing pigments resulting in skin darkening.
Melanocytes	Specialised cells that produce the pigment melanin.
Melanogenesis	An increase in skin pigment production by melanocytes.
Melanosomes	Cells that synthesise, store and transport melanin.
Messenger ribonucleic acid (mRNA)	A type of genetic material that provides the template for protein synthesis.
Metabolite	Metabolites are intermediate and end products of cellular regulatory processes.
Microfibrillar	Basic building blocks of the elastic fibres of connective tissues.
Mid‐reticular dermis	The bottom layer of the dermis.
Milia	Small 1‐2 millimeter skin bumps due to accumulated skin cells.
Monocyte	An immune cell that is a precursor to a macrophage.
Nasolabial groove	The furrow on either side of the face that runs from the nostril down to the outer edge of the upper lip.
Papillary dermal fibroplasia	A term describing scarring of the uppermost layer of the dermis.
Papillary dermis	The uppermost layer of the dermis.
Photosensitivity	A term to describe sensitivity to ultraviolet radiation from the sun and other light sources.
Post‐inflammatory hyperpigmentation	A term to describe temporary darkening following injury to the skin.
Pruritus	An unpleasant sensation of the skin that leads to the urge to scratch.
Pyrimidine	An organic compound that is essential for protein synthesis.
Retinoid	Retinoids are a class of compounds related to Vitamin A and its derivatives.
Rete ridges	A plural term referring to epithelial extensions that project into the underlying connective tissue in skin.
Rosacea	A common skin condition that causes redness and visible blood vessels on the face.
Sebaceous	A term to describe glands that open into a hair follicle to secrete an oily matter called sebum.
Solar elastosis	A term describing the degeneration of elastic tissue in the dermis due to excessive sun exposure.
Stratum corneum	The outermost layer of the skin, consisting of dead skin cells.
Telangiectasia	A descriptive term for widened blood vessels causing thread‐like red lines on the skin.
Teratogenic	An agent that can disturb the development of an embryo or fetus.
Third generation	Of, relating to, or being the third form of a class of medication.
Toll‐like receptor	A class of proteins that are involved in early responses to foreign organisms.
Tropoelastin	Basic building blocks of elastic fibres.

Description of the intervention

Topical treatments are used to promote cell turnover. They are easy to administer, readily available and affordable compared to invasive, surgical treatment. Treatment options currently available for skin ageing include creams and lotions containing retinoids, 5‐fluorouracil (5‐FU), imiquimod, α‐hydroxyl acids and skin‐resurfacing techniques.

Other cosmetic interventions, which are not within the scope of this review, include face‐lifts, and botulinum toxin and collagen injections. These treatments produce visible improvement in ageing skin but have potential harms and contain no element of prevention (Holmkvist 2000; Ross 2001).

This review will focus on the efficacy and safety of topical treatments such as creams and lotions, and skin‐resurfacing techniques, both of which are commonly used.

Topical retinoids

Topical retinoids are natural derivatives of vitamin A. First‐generation retinoids include topical tretinoin and isotretinoin, while tazarotene and adapalene are in the third generation of topical retinoids. Retinoid‐containing derivatives are established treatments based on clinical trials, demonstrating efficacy in improving skin changes associated with photodamage (Kang 2001; Babcock 2015).

Regimen: topical retinoids are applied via a thin layer once daily to clean, dry skin. It is applied to skin away from eyes, mouth, nasal creases and mucous membranes.

Adverse effects: common adverse effects include erythema, scaling, dryness, burning, stinging and irritation. Irritation to the skin is exacerbated by sun exposure. Therefore, it should be applied once daily at bedtime. To assess irritation, a test dose may be applied and washed off one hour later. To minimise irritation, topical retinoids should be started at a low concentration, and titrated upward as needed (Yoham 2020).

Interactions: interactions from topical retinoid application include increased photosensitivity, and sunscreen application is needed. Due to the known teratogenic effects of oral vitamin A products, topical retinoids are listed as pregnancy Category C drugs.

5‐Fluorouracil

The antimetabolite 5‐FU is formulated as a solution and cream. Topical 5% 5‐FU, which is approved for use in superficial basal cell carcinoma and actinic keratosis, has been suggested for use in reversing skin ageing (Korgavkar 2017). Multiple studies have reported improvement in skin texture and wrinkling with systemic 5‐FU use (Guimarães 2014). Similarly, there is accumulating evidence that topical 5‐FU can lead to improvement in photodamaged skin (Sachs 2009).

Regimen: topical 5‐FU creams are applied once daily to clean, dry skin, using enough to cover the entire area with a thin film. Skin near the eyes, nostrils or mouth should be avoided. A standard course is up to four weeks as tolerated and used in clinical studies (Korgavkar 2017). It has minimal systemic adverse effects due to limited skin absorption.

Adverse effects: common adverse effects arising from topical application include skin irritation, pain, pruritus, erythema and eczematous skin reactions (Prince 2018). Similar to retinoids, people using topical 5‐FU are advised to avoid prolonged exposure to sunlight or other forms of UV radiation during treatment due to increased photosensitivity.

Interactions: contraindications to treatment with 5‐FU include people with a documented deficiency of dihydropyrimidine dehydrogenase, an enzyme which degrades over 80% of 5‐FU into biologically inactive metabolites, which can otherwise lead to life‐threatening toxicity if these metabolites accumulate. It is also contraindicated in women who are or may become pregnant.

Imiquimod

Imiquimod is a synthetic compound that works as a topical immune‐response modifier, and is approved for use in several dermatological conditions, such as actinic keratoses, superficial basal cell carcinoma and genital warts. The use of imiquimod cream for ageing skin is described in the literature, which documents clinical and histological improvement in aged skin (Kligman 2006; Metcalf 2007). However, the exact mechanism of action remains unclear, and there is limited evidence for the efficacy and safety of topical imiquimod for skin ageing (Smith 2007).

Regimen: imiquimod is applied to clean, dry skin via a thin film, covering a 1‐cm margin around affected skin. It is prescribed as a daily application for three months, unless rest periods are necessary due to intolerability to adverse effects. Based on existing studies, histological effects are more pronounced with sustained use, with a noticeable dermal effect after three months of use. Shorter use of imiquimod limits the effects within the epidermis (Metcalf 2007).

Adverse effects: common adverse effects include severe erythema, scabbing and skin ulceration, with clinicians strongly advised to prescribe strategies including a pause in treatment, use of emollients and, in some instances, topical steroids. It has been reported that topical imiquimod application can result in pemphigus‐like lesions both at and distant from the application site, which resolved after treatment cessation (Bauza 2009).

Interactions: there are no known interactions of topical imiquimod with other drugs so far. 

Skin‐resurfacing techniques

Current skin‐resurfacing techniques are chemical peeling, classic dermabrasion, microdermabrasion (MDA), ablative and non‐ablative lasers, and photodynamic therapy (PDT) (Clark 2008).

Chemical peeling

Chemical peeling, also known as chemoexfoliation or derma‐peeling, is the process of applying chemicals to the skin to ablate the epidermis with or without part of the dermis to promote skin remodelling, resulting in improved appearance.

Chemical peels are classified into three categories according to the depth of skin injury they induce (Soleymani 2018).

1. Superficial‐depth agents induce epidermal injury via intra‐epidermal disruption. Common agents include alpha hydroxy acids (AHAs) such as glycolic acid (30% to 50%), lactic acid (10% to 30%) or mandelic acid (40%); beta hydroxy acids (BHAs) such as salicylic acid (30%); and alpha keto acids (AKAs) such as pyruvic acid. Common adverse effects include erythema, pruritus, superficial desquamation and post‐inflammatory hyperpigmentation (PIH).

2. Medium‐depth agents cause full‐thickness epidermal injury, extending into the papillary dermis. Common agents are acids in higher concentrations compared with superficial‐depth agents, such as 70% glycolic acid. A pre‐treatment primer, such as Jessner's solution, may be used; a common treatment is salicylic acid greater than 30% in a multi‐layer application and trichloroacetic acid (TCA) 30% to 50%, applied in a single layer, with or without pretreatment using Jessner's solution. Jessner's solution is a combination of salicylic acid, 14 g; resorcinol 14 g; lactic acid (85%) 14 g; and ethanol to 100 mL, used as a primer to optimise medium‐depth peels by disrupting cornified skin. Common adverse effects include those for superficial‐depth peels, and superficial bacterial or fungal infection, herpes simplex virus reactivation, scarring, milia, acneiform eruption and greater thickness desquamation.

3. Deep peels involve agents that induce full‐thickness epidermal injury, extending into the papillary dermis and the mid‐reticular dermis. Two main agents are used, and they are TCA (greater than 50% in a monolayer application, with pretreatment using Jessner's solution), or Baker‐Gordon phenol peel, which uses detergent, croton oil, to remove the epidermal layer, with phenol and water for dilution to 50% to 55% phenol. Adverse effects overlap with those seen with superficial and medium‐depth peels, but also include cardiotoxicity or arrhythmia (due to systemic absorption of phenol) (or both) and hepatotoxicity or nephrotoxicity (or both). Specific to deep peels, hypopigmentation can occur.

Regimen: Treatment every four to six weeks is required to achieve desired results, with the entire procedure taking approximately 30 to 60 minutes. Superficial features of skin ageing, such as superficial wrinkles, can be treated with superficial peels, while deeper features of skin ageing require a medium‐ or deep‐depth peel (Soleymani 2018). Where appropriate, a combination of different peels is often used to enhance or complement the cosmetic benefits of individual agents (Clark 2008; Salam 2013).

Adverse effects: common adverse effects expected of chemical peeling are elaborated above. Time needed for healing, healing rate and potential for adverse effects are directly proportional to the depth of the peel. Of note, people with Fitzpatrick skin types IV to VI with a history of scar formation have increased risk of dyspigmentation, and hypertrophic and keloid scarring. People who are pregnant, those using oestrogens or having excessive sun exposure are prone to PIH. For Fitzpatrick skin types IV to VI, expert consensus recommends tretinoin cessation one week before the peel to prevent excessive penetration of chemical agents (Garg 2008). Patient education on adverse effects remains important, and strict adherence to pre‐peel and post‐peel instructions, especially sun avoidance, is important to optimise results.

Interactions: current literature recommends people discontinue oral isotretinoin at least six months prior to the use of chemical peels (Monheit 2001).

Dermabrasion

Dermabrasion is a minimally invasive technique that surgically abrades or planes the epidermis and papillary dermis using a rapidly rotating wire brush or diamond fraise, creating a newly contoured open wound to heal by secondary intention (Harmon 2016). MDA, or particle‐resurfacing technique, is a similar outpatient skin‐resurfacing technique that deploys abrasive microcrystals, such as aluminium oxide or sodium chloride, against the skin under the control of a handheld vacuum system (Alkhawam 2009). Both techniques result in mechanical abrasion to the skin, removing the stratum corneum, the outermost layer of the skin. Ultimately, these two techniques aim to promote collagen remodelling and re‐epithelialisation (Harmon 2016).

Regimen: people undergoing dermabrasion or MDA may require treatment every four to six weeks to achieve the desired effects. The interval between treatments can be increased if adverse effects are persistent. Unlike dermabrasion, which penetrates the dermis, MDA only ablates the uppermost skin layer. Thus, the superficial nature of MDA may not result in lasting changes to the skin (Shah 2020). MDA is also not recommended for pigmentary disorders given its lack of efficacy in treating skin pigmentation associated with photodamage (Karimipour 2010).

Adverse effects: common complications include tenderness to treated skin, swelling, erythema and petechiae. As there is removal of stratum corneum, increased photosensitivity is expected. In addition, there is a risk of reactivation of latent herpes virus in an orofacial distribution in people undergoing dermabrasion (Karimipour 2010). Other important adverse effects include the risk of bleeding in people who are prone, and people who have herpetic episodes during the time of treatment, or people who indicate a strong history of multiple herpetic episodes per year, may benefit from prophylactic antiviral medications, such as aciclovir (Clark 2008).

Interactions: the current or recent use of isotretinoin is an absolute contraindication to dermabrasion and MDA, due to the elevated risk of hypertrophic scarring. Isotretinoin should be discontinued for a minimum of six months prior to dermabrasion and other skin‐resurfacing techniques. People with rosacea and telangiectasia may experience an exacerbation of their condition when undergoing dermabrasion and MDA.

Laser techniques

Laser techniques involved in the treatment of ageing skin employ a selective ablation of the dermis without affecting the epidermis, denaturing dermis proteins such as collagen, to stimulate collagen synthesis and the wound healing process (Heidari Beigvand 2020). Non‐fractionated lasers act on the whole projected surface area of the treated skin, while fractionated lasers target therapy to specific fractions of treated skin surface area. Ablative lasers are considered more aggressive as they vaporise tissue, versus non‐ablative lasers, which leave the treated skin intact. There are four main categories.

1. Ablative, non‐fractionated lasers. The most common ablative lasers for skin‐resurfacing are carbon dioxide and erbium‐doped yttrium aluminium garnet (Er:YAG) lasers, or a combination of the two.

2. Ablative, fractional lasers are the most recent generation of ablative lasers using carbon dioxide, with a safer adverse‐effect profile compared to ablative, non‐fractionated lasers.

3. Non‐ablative, non‐fractionated lasers. Common non‐ablative lasers include intense pulsed light (IPL), pulsed dye laser (PDL), pulsed potassium titanyl phosphate (PPTD) and neodymium‐doped yttrium aluminium garnet (Nd YAG) diode lasers.

4. Radiofrequency systems. This modality is presented here as it is often used in combination with other laser techniques to achieve better clinical effects in ageing skin (Doshi 2005). Current radiofrequency systems are non‐ablative, and work like thermal heating systems.

Regimen: while clinical improvement is contingent on several factors, including the type of device, skin type and proportion of affected skin, multiple treatments are recommended to establish significant improvement. Ablative treatments may result in more marked response due to more significant tissue damage, but it should be noted that these benefits are offset by a longer time required for healing (Chapas 2008).

Adverse effects: common adverse effects observed for laser resurfacing techniques include post‐procedure erythema and swelling, delayed skin healing, pigmentary changes in the skin and skin irritation, and, in some people, acne flares, milia formation and dermatitis (Nanni 1998).

Interactions: topical retinoids should be ceased one week before commencement of laser resurfacing as they can blunt the heat shock response, which is integral in facilitating rapid re‐epithelisation following tissue injury (Shah 2012).

Photodynamic therapy 

PDT is the use of a light source in combination with a photosensitising agent to induce tissue damage via the generation of singlet oxygen, and studies have suggested this is effective in treating the visible signs of skin ageing (Friedmann 2016; Sanclemente 2018). Photosensitising agents include aminolevulinic acid (ALA) and methyl aminolevulinate, the methylated derivative of ALA.

Regimen: PDT is used as an off‐label indication for skin ageing, and therefore, the regimen for the use in skin ageing has not been established. Multiple treatments spaced at least one month apart are typically needed to establish visible clinical effects.

Adverse effects: adverse effects are mainly local, and include erythema, swelling, pain, pruritis, contact dermatitis and pigment changes.

Interactions: people with photosensitising dermatoses, such as porphyria and systemic lupus erythematous, are advised to avoid using PDT. As the photosensitising agents are under pregnancy Category C, PDT is contraindicated in pregnant women.

How the intervention might work

Although skin ageing is thought to be irreversible, accumulating clinical evidence since the early 2000s has shown that topical treatments and skin‐resurfacing techniques can result in sustained and improved clinical features of skin ageing (Kang 2001; Katz 2015).

Topical retinoids

Topical retinoids improve features of skin ageing via several mechanisms. Studies have shown that many of their tissue effects are mediated by their interaction with specific cellular and nuclear receptors of the nuclear retinoic acid receptor family, which activate transcription of target genes. At an epidermal level, retinoids influence keratin synthesis and sebaceous secretion and decrease epidermal melanin content, which is increased in photodamaged skin causing dyspigmentation. At a dermal level, they modulate the composition of the extracellular matrix through regulation of fibroblastic proliferation and collagen metabolism. Retinoids also stimulate production of collagen I and VII (anchoring fibrils) and production and arrangement of elastic fibres, restoring the fibrillin‐rich microfibrillar network in the papillary dermis. This is likely to be due to induced elastin gene expression and elastin fibre formation via increased messenger ribonucleic acid (mRNA) and protein levels of tropoelastin and fibrillin‐1. The beneficial effects of retinoids in photodamage are also mediated by inhibition of MMP expression, responsible for collagen degradation, facilitating the formation of new collagen in the dermis (Griffiths 1993; Griffiths 1994; Lowe 1994; Griffiths 1995; Maddin 2000; Sorg 2005; Yaar 2007).

5‐Fluorouracil

5‐FU causes injury to the epidermis, which promotes wound healing and remodeling of the deeper layers of the skin. It follows a wound healing pattern similar to laser treatment of photoaging, and results in an increase in levels of procollagen Type I and III, resulting in improved appearance (Sachs 2009).

Imiquimod

Imiquimod acts as an immune response modifier and has potent antiviral and antitumour activity. It is licensed to treat genital warts, actinic keratosis and superficial basal cell carcinoma. It works by binding to toll‐like receptor 7 on the surface of dendritic cells, macrophages and monocytes, thereby inducing the synthesis and release of proinflammatory agents which enhance acquired immunity via a type 1 helper T‐cell immune response (Bilu 2003). Topical imiquimod appears to induce reparative changes to the epidermis and the dermal collagen in chronically sun‐damaged skin. This includes a significant increase in papillary dermal fibroplasia and reduction in solar elastosis together with improvement in epidermal thickness and melanisation, thereby leading to a reduction in skin ageing (Metcalf 2007).

Skin‐resurfacing techniques

Chemical peels work by inducing damage and inflammation of the outer skin layers via controlled chemical ablation. This stimulates epidermal regeneration and postinflammatory collagen synthesis with remodelling of collagen and elastic fibres and deposition of GAGs in the dermis, and the regeneration of new keratinocytes (Piacquadio 1996; Clark 2008). Overall, this results in the rejuvenation of the epidermis and concomitant rise in dermal volume.

Dermabrasion physically removes the skin layer by layer until the desired effect is obtained. By completely removing the epidermis and penetrating into the dermis, there is controlled damage of the skin surface, and this process remodels the skin's structural proteins into a more organised manner during the healing process, which may results in clinically significant improvements in skin structure and appearance (Smith 2014).

MDA exfoliates the skin by removing the most superficial skin layer. It decreases skin sebum, increases epidermal concentration of ceramide, decreases epidermal water loss and enhances skin texture (Smith 2014). MDA also affects deeper layers of the epidermis and dermis, by causing a rearrangement of melanosomes in the basal layer of the epidermis, flattening of rete ridges and increased collagen deposition at the dermal–epidermal junction, and vascular ectasia in the reticular dermis (Tan 2001).

Both ablative and non‐ablative lasers, as well as radiofrequency techniques, coagulate proteins such as collagen within the dermis, stimulating the wound healing process. Fractionated lasers heat deep dermis columns to stimulate the same process. As a result, collagen synthesis occurs on the substrate of the skin and extracellular matrix (Heidari Beigvand 2020).

PDT, in combination with a topical photosensitiser, produces cytotoxic oxygen species, which leads to the elimination of damaged collagen. There is also an upregulation of factors that increases the synthesis of Type I/III procollagen, and downregulate MMPs, thus resulting in sustained collagen synthesis (Park 2010).

Why it is important to do this review

The visible changes that accompany skin ageing are considered by many people as undesirable for cosmetic reasons, leading to an increased demand for effective interventions to reduce the signs of skin ageing. With many prescription medications and cosmetic treatments available to consumers, many are using these products without clear knowledge about their effectiveness and safety (Barrett 2005). Therefore, it is important to establish the efficacy and safety profiles of both commercial and prescription treatments for skin ageing.

In the 2020 Cochrane Skin prioritisation exercise, the editorial board ranked 'efficacy of dermocosmetics' highly. This review will be a partial update of a Cochrane Review 'Interventions for photodamaged skin,' first published in 2015 (Samuel 2015).

Objectives

To assess the efficacy and safety of topical treatments and skin‐resurfacing techniques for skin ageing that is sufficient for people to seek treatment, and to identify optimum treatment concentrations, frequencies of application and therapy durations.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs), including cross‐over trials, within‐person trials (e.g. split‐face studies or facial subunits analysis studies) and cluster randomised trials.

Should there be concerns about the potential for a 'carry over effect' in within‐person trials, whereby the intervention applied to one part of the face or in an area of the eye can affect the other part of the face or eye systematically, we will exclude these studies. For cross‐over trials, we will only include the first phase if there are concerns of a 'carry over effect.' We will exclude quasi‐RCTs and observational studies. Quasi‐RCTs are defined as trials with an allocation procedure such as alternation, date of birth, identification number or case record number.

Types of participants

People of any age with a clinical diagnosis of skin ageing, based primarily on the clinical manifestations, or the use of a validated classification scale (Table 1; Table 2; Table 3), on any part of the body will be included in this review. For studies that include a subset of eligible participants, we will only include if these data can be obtained separately for these participants.

Types of interventions

1. Topical interventions including use of topical retinoids, 5‐FU and imiquimod.

2. Skin‐resurfacing interventions including chemical peels, dermabrasion, MDA, ablative laser resurfacing, non‐ablative laser resurfacing, radiofrequency therapy and PDT.

3. Comparator including placebo, another active treatment or no treatment.

We will include trials comparing different doses and durations of the same treatment.

Types of outcome measures

For this review, all clinically relevant outcomes will be dichotomised into two categories of 'improved' or 'not improved.' The data on moderately improved and improved will be grouped as 'improved,' while the data on slight or no improvement will be grouped as 'not improved.'

There will be no restrictions on time points of interest for data points, but preference will be given to those reported at six months, or one year or more. We will separate the study effects into short‐term (i.e. six months or less) or long‐term (i.e. greater than six months).

Primary outcomes

1. Physician‐rated outcomes at six months or less, which analyse the physician's overall evaluation in improvement in features of skin ageing on any part of the body. If studies use a classification system, such as Glogau Classification or Rubin System (or both), we will analyse to determine if they fit into either of the two categories, grouping an improvement in the grading as 'improved.'

2. Participant‐rated outcomes at six months or less, which analyse the patient's overall evaluation in improvement in features of skin ageing on any part of the body. They will include subjective evaluation of the improvement in features of skin ageing. If studies use a Likert scale or a similar questionnaire, we will analyse them to determine if they fit into either category.

3. Presence of adverse effects, defined as effects directly attributable to the treatment or study withdrawal due to adverse events attributable to the treatment. We will dichotomise the outcomes into two categories of 'reported adverse effects' and 'no adverse effects.'

Secondary outcomes

1. Physician‐rated long‐term outcomes in improvement in features of skin ageing on any part of the body at more than six months. If studies use a classification system, such as Glogau Classification or Rubin System (or both), we will analyse them to determine if they fit into either of the two categories, grouping an improvement in the grading as 'improved.'

2. Participant‐rated long‐term outcome in the patient's overall evaluation in improvement in features of skin ageing on any part of the body at more than six months. If studies use a Likert scale or a similar questionnaire, we will analyse them to determine if they fit into either category.

3. Improvement of fine wrinkling on any part of the body studied. Wrinkle evaluation commonly relies on clinical evaluation with the aid of adjunctive tools such as the use of photographs, and we will analyse them to determine if they fit into either of the two categories.

4. Improvement of coarse wrinkling on any part of the body studied. We will apply the same consideration for analysing improvement in fine wrinkling here.

5. Improvement in quality of life measured using tools such as the Likert scale or the Dermatology Life Quality Index, a simple practical questionnaire for routine clinical use (Finlay 1994).

Search methods for identification of studies

We will identify all relevant RCTs regardless of language or publication status (published, unpublished, in press or in progress).

Electronic searches

The Cochrane Skin Information Specialist will search the following databases for relevant trials with no restriction by date:

1. the Cochrane Skin Specialised Register;

2. the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library;

3. MEDLINE via Ovid (from 1946 onwards); and

4. Embase via Ovid (from 1974 onwards).

She has devised a draft search strategy for RCTs for MEDLINE (Ovid), which is displayed in Appendix 1. This will be used as the basis for search strategies for the other databases listed.

Trial registers

Two review authors (CWQ and WMSL) will search the following trial registers using the search terms: photodamage, photoageing, skin ageing.

1. ClinicalTrials.gov (www.clinicaltrials.gov).

2. World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (apps.who.int/trialsearch/).

Searching other resources

Searching reference lists

We will manually check the bibliographies of included studies and any relevant systematic reviews identified for further references to relevant trials.

Correspondence with trialists/experts/organisations

We will contact original authors for clarification and further trial data if reports are unclear.

We will contact experts/organisations in the field to obtain additional information on relevant trials.

Adverse effects

We will not perform a separate search for adverse effects of interventions used for the treatment of skin ageing. We will consider adverse effects described in included studies only.

Errata and retractions 

The Cochrane Skin Information Specialist will run a specific search to identify errata or retractions related to our included studies, and we will examine any relevant retraction statements and errata that are retrieved.

Data collection and analysis

We will summarise data following the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021). We will perform the analyses using Review Manager 5 (Review Manager 2014) and RevMan Web (RevMan Web 2020).

Selection of studies

1. Level 1 screening (screening of titles and abstracts): two review authors (CWQ and WMSL) will independently and in parallel review titles and abstracts of the studies identified through the electronic databases. They will determine the study eligibility according to the inclusion and exclusion criteria, described in ‎the Criteria for considering studies for this review section. If there is disagreement about study relevance, they will reach consensus with a third review author (HJ).

2. Level 2 screening (screening of full texts): two review authors (CWQ and WMSL) will independently and in parallel obtain and review the full‐text publications selected at level 1. They will determine the study eligibility according to the inclusion and exclusion criteria described ‎in the Criteria for considering studies for this review section. If there is disagreement about study relevance, they will reach consensus with a third review author (HJ).

We will use Covidence to manage the study selection (Covidence). The review authors will include an adapted PRISMA flow diagram of study selection for the review (Moher 2009).

Where studies have multiple publications, we will collate the reports of the same study so that each study, rather than each report, is the unit of interest for the review, and such studies have a single identifier with multiple references.

Data extraction and management

For studies that fulfil the inclusion criteria, two review authors (CWQ, WMSL) will independently extract data using a piloted standard form (Excel Spreadsheet). We will resolve disagreements by discussion with team members prior to entering the data into RevMan web (RevMan Web 2020). We will extract the following data and enter them into the 'Characteristics of included studies' table.

Study characteristics, including:

1. study design;

2. inclusion/exclusion criteria for participation in the study;

3. number of participants in the study;

4. risk of bias items (e.g. randomisation methods, concealment of allocation, blinding, methods, dropouts or missing data; selective reporting);

5. baseline population characteristics (e.g. demographics, age at diagnosis, ethnicity, disease classification, severity, prior treatments received);

6. treatment duration, dose and frequency; prior treatments received;

7. baseline scores for outcomes of interest;

8. funding sources;

9. declarations of interest.

Outcome measures, including:

1. instruments used to assess improvement;

2. time point(s) at which outcome data were collected;

3. number (percentage) of participants who improved, or mean scores at final endpoint;

4. number (percentage) of participants who had adverse events;

5. follow‐up and outcome measures.

We will not be blinded to the names of trial authors or journals. We acknowledge that conference abstracts, posters and grey literature are often incomplete reports. Therefore, where necessary, we will contact the corresponding authors to obtain any unreported data, such as number of participants randomised to groups, information on subgroups eligible to be included, group means and standard deviations (SD), details of dropouts and details of intervention received by the control group.

Assessment of risk of bias in included studies

Two review authors (CWQ and WMSL) will independently assess the risk of bias using the ROB 2 tool (version 6 dated 25 June 2019; Sterne 2019). We will resolve any differences in opinion through discussion, and, in the case of unsettled disagreements, a third review author (HJ) will adjudicate. This will be performed using the RoB 2 Excel tool (RoB 2 Development Group 2019). We will assess risk of bias for all primary and secondary outcome measures. We will assess the effect of assignment to intervention (the 'intention to treat' effect).

We will assess risk of bias using the following five domains.

1. Risk of bias in the randomisation process.

2. Bias due to deviations from intended interventions.

3. Bias due to missing outcome data.

4. Bias in measurement of the outcome.

5. Bias in the selection of the reported result.

Each domain has a number of signalling questions. The response options for the signalling questions will be: Y = Yes; PY = Probably Yes; PN = Probably No; N = No; NA = Not Applicable; NI = No Information. We will use the algorithms that map responses to signalling questions; these will result in proposed risk of bias judgements for each domain. The judgments are 'low risk of bias,' 'unclear risk of bias' (some concerns) or 'high risk of bias.' The overall risk of bias will also be determined using the tool algorithms. Review authors may override these proposed judgements if they consider it is appropriate to do so.

We will assess cluster randomised trials and cross‐over RCTs using the RoB 2 sections on considerations for cluster‐randomised trials and variants on randomised trials, respectively (Higgins 2021). For cluster randomised, parallel group trials, we will assess bias due to timing of identification and recruitment of individual participants in relation to the timing of randomisation. For individually randomised, cross‐over trials, we will assess bias due to period effects, time for carry‐over effects to disappear and appropriate statistical testing.

We will present the RoB 2 data in brief in the main tables, and in full in supplementary files.

Measures of treatment effect

Dichotomous outcomes

If outcomes are reported as dichotomous data, we will calculate the risk ratios (RR) with 95% confidence intervals (CI).

Ordinal data from trials will be dichotomised to 'improved' or 'not improved.' We will group the data on moderately improved and improved as 'improved.'

Continuous outcomes

Where outcomes are measured as continuous data, we will compute the mean differences (MD) of the change scores, depending on the data available. When all included studies use the same scale, we will calculate the MDs and their 95% CI, as it preserves the original units and is, therefore, easier to interpret. Where the included studies use different scales for the same outcome, we will calculate standardised mean differences (SMDs) to allow pooling. If some studies are based on change data and others on post‐test data, we will include all studies in the same meta‐analysis, with change data and endpoint data as subgroups. If SDs or standard errors are not reported, we will attempt to compute them using the P values, t values or CIs (Higgins 2021).

Unit of analysis issues

For each included study, we will determine whether the unit of analysis is appropriate for the unit of randomisation and the design of each study (i.e. whether the number of observations matches the number of 'units' that were randomised) (Deeks 2011).

Cluster randomised trials

Authors of cluster randomised trials may fail to account for the intraclass correlation coefficient (ICC), leading to a 'unit of analysis’ error, whereby CIs are unduly narrow and statistical significance overestimated (Divine 1992). If clustering is not accounted for in primary studies, we will seek to contact the corresponding author to obtain the ICC of their clustered data and adjust for this by using methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Chapter 23 in Higgins 2021). If we are unable to obtain ICC data from the authors, we will try to incorporate external estimates of ICC obtained from similar studies or use an estimate based on known patterns in ICCs for particular types of cluster or outcome as the methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Chapter 23 in Higgins 2021).

If cluster studies are appropriately analysed taking into account the ICC, and the report documents relevant data, synthesis with other studies will be possible using the generic inverse variance technique. In this case, we will present data adjusted for the clustering effect as if from a parallel‐group randomised study, but we will perform sensitivity analyses in which we exclude such studies.

Cross‐over trials

For cross‐over trials, if carry‐over effect is thought to be a problem, we will confine analysis to the first period alone before participants cross over. However, if the carry‐over effect is not considered a problem, we will incorporate the results from a paired sample t‐test to evaluate the difference between the measurement on the experimental intervention and measurement on control intervention for each participant. The mean of the difference and its standard error will be pooled with the MDs and their standard errors from other studies in the meta‐analysis using the generic variance approach in Review Manager 5 (Review Manager 2014). Details of the methods can be found in Section 23.2 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021).

Studies with multiple treatment groups

Studies may also compare several interventions with one comparison group. In this case, we will analyse the effects of each intervention group versus the comparison separately, but divide the total number of participants in the comparison group to avoid including the same participants multiple times in the analysis. We will combine studies that use different drugs within the drug class, but subsequently conduct subgroup analyses to examine if the effects would vary for the different drugs. Similarly, we will apply subgroup analyses to different doses and treatment duration. In the case of continuous outcomes, we will divide the total number of participants in the comparison group, but leave the means and SDs unchanged (see Chapter 23 in Higgins 2021).

We will list all treatment groups in the 'Characteristics of included studies' table, even if they are not used in the review.

Within‐person comparisons

We will include studies including within‐person comparisons in the meta‐analysis if they analyse the data using a paired sample t‐test and present the mean of the difference and its standard error. Then, we will pool the result with other studies presenting the MDs and standard errors using the generic variance approach in Review Manager 5 (Review Manager 2014).

Dealing with missing data

We will conduct the outcome analyses, as far as possible, on an intention‐to‐treat basis, meaning that we will attempt to include all participants randomised to each group in the analyses, regardless of whether they received the allocated intervention or not. We will assess missing data and dropouts/attrition in our risk of bias assessments and discuss the extent to which the missing data could alter the results/conclusions of the review. Where necessary, we will contact the corresponding authors to obtain any unreported data, such as group means and SDs, details of dropouts and details of intervention received by the control group.

Where SDs are missing, we will attempt to obtain them by contacting trial authors. Where SDs are not available from trial authors, we will calculate them from t values, CIs or standard errors, where reported in articles. If these additional figures are not available or obtainable, we will not include the study data in the comparison of interest.

We will investigate, through sensitivity analyses, the effects of any imputed data on pooled effect estimates, using the strategy recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021).

We will report all attempts made to contact authors, the specific reason for the approach and the responses received in detail (if any).

Assessment of heterogeneity

If we judge that the included trials are too clinically heterogeneous to warrant a formal meta‐analysis, we will present the results of the included trials in a narrative format. We will assess clinical heterogeneity by comparing the distribution of important participant factors between trials (e.g. age; skin damage severity at baseline; the classification system used, e.g. Glogau Classification or Rubin System, or both; treatment dose; frequency of treatment). We will assess statistical heterogeneity in each meta‐analysis using the I² statistic recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021). We will assess heterogeneity using the following categories: 

0% to 40%: might not be important; 
30% to 60%: may represent moderate heterogeneity; 
50% to 90%: may represent substantial heterogeneity; and 
75% or greater: considerable heterogeneity. 

The importance of the observed value of I² depends on magnitude and direction of effects, and strength of evidence for heterogeneity (e.g. P value from the Chi² test, or a confidence interval for I²: uncertainty in the value of I² is substantial when the number of studies is small) (Higgins 2021). We will present the Chi² statistic and its P value, and consider the direction and magnitude of the treatment effects through forest plot inspection.

Assessment of reporting biases

To minimise the risk of publication bias, we will attempt to obtain the results of any unpublished trials in order to compare findings extracted from published reports with results from other sources (including drug regulatory agencies and correspondence). If there are more than 10 trials grouped in a comparison, we will assess whether reporting biases are present using funnel plots to investigate any relationship between effect estimates and study size/precision, as recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021).

Data synthesis

We will perform statistical analyses according to the statistical guidelines in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021). Where results are estimated for individual studies with low numbers of events (fewer than 10 in total) or where the total sample size is fewer than 30 participants and uses an RR, we will report the proportion of events in each group together with a P value from a Fisher's Exact test. The main analyses will include all studies regardless of the risk of bias judgements. We will use Review Manager 5 for meta‐analyses (Review Manager 2014). We will estimate the treatment effect across studies using a random‐effects model for the meta‐analysis. If there is clinical heterogeneity sufficient to expect that the underlying treatment effects differ between trials, or if we detect substantial statistical heterogeneity based on the I² value (see Assessment of heterogeneity), we will attempt to explain the heterogeneity based on differences in clinical, quality or other characteristics between studies.

Subgroup analysis and investigation of heterogeneity

We will perform subgroup analyses for studies with dose variations (e.g. tretinoin 0.001%, 0.01%, 0.02%, 0.05%), treatment period (e.g. 24 weeks, 52 weeks), frequency of treatment administration (e.g. once or twice daily) and skin types regardless of the I² test values. We will present the Chi² statistic and its P value and consider the direction and magnitude of the treatment effects. Usually, a P value for this test of less than 0.1 indicates a statistically significant subgroup effect.

Sensitivity analysis

We will conduct sensitivity analyses to establish whether findings are sensitive to restricting the analyses to studies judged at low risk of bias for the primary outcomes of interest in this review.

To explore the influence of imputation of missing data on the intervention effect size, we will conduct the sensitivity analyses as described under Dealing with missing data.

Summary of findings and assessment of the certainty of the evidence

To rate the certainty of the evidence we will use the GRADE approach and we will create Summary of findings tables including five clinically important outcomes using GRADEpro (GRADEpro GDT; Schünemann 2013).

Primary outcomes

1. Physician‐rated outcomes at six months or less, which analyse the physician's overall evaluation in improvement in features of skin ageing on any part of the body.

2. Patient‐rated outcomes at six months or less, which analyse the patient's overall evaluation in improvement in features of skin ageing on any part of the body.

3. Presence of adverse effects, defined as effects directly attributable to the treatment or study withdrawal due to adverse events attributable to the treatment.

Secondary outcomes

1. Participant‐rated long‐term outcome in the patient's overall evaluation in improvement in features of skin ageing on any part of the body at more than six months.

2. Physician‐rated long‐term outcomes in improvement in features of skin ageing on any part of the body at more than six months.

We will prepare a 'Summary of findings' table for the following comparisons.

1. Topical retinoids versus placebo or no treatment.

2. Chemical peels versus placebo or no treatment.

3. Dermabrasion versus placebo or no treatment.

4. Topical retinoids versus chemical peels.

5. Dermabrasion versus chemical peels.

6. Topical retinoids versus dermabrasion.

Two review authors (CWQ and WMSL) will assess five factors referring to limitations in the study design and implementation of included studies that suggest the certainty of the evidence: overall risk of bias; indirectness of evidence (population, intervention, control, outcomes); unexplained heterogeneity or inconsistency of results (including problems with subgroup analyses); imprecision of results (wide CIs as evaluated); and a high probability of publication bias. We will define the levels of evidence as 'high,' 'moderate,' 'low' or 'very low.' If there is disagreement, we will reach a consensus with a third review author (HJ). We will give reasons for downgrading or upgrading the ratings in the footnotes of the summary of findings tables. These grades are defined as follows.

1. High certainty: this research provides a very good indication of the likely effect; the likelihood that the effect will be substantially different is low.

2. Moderate certainty: this research provides a good indication of the likely effect; the likelihood that the effect will be substantially different is moderate.

3. Low certainty: this research provides some indication of the likely effect; however, the likelihood that it will be substantially different is high.

4. Very low certainty: this research does not provide a reliable indication of the likely effect; the likelihood that the effect will be substantially different is very high.

We will conduct the review according to this published protocol and report any deviations from it in the 'Differences between protocol and review' section of the systematic review.

Appendices

Appendix 1. Draft search strategy for MEDLINE (Ovid)

1. Skin Aging/               

2. skin aging.ti,ab.

3. skin ageing.ti,ab.             

4. photo ag$.ti,ab.

5. photoag$.ti,ab.

6. dermatoheliosis.ti,ab.      

7. sun damage$.ti,ab.          

8. farmer$ skin.ti,ab.           

9. sailor$ skin.ti,ab.              

10. Skin/re [Radiation Effects]           

11. rubin.ti,ab.      

12. glogau.ti,ab.   

13. or/1‐12           

14. Sunlight/        

15. Ultraviolet Rays/            

16. 14 or 15          

17. (wrinkle$ or wrinkly or wrinkling).ti,ab.     

18. freckle$.ti,ab. 

19. (lentigine$ or lentine$).ti,ab.       

20. exp Keratosis/

21. keratos$.ti,ab.

22. texture$.ti,ab.

23. Skin/

24. or/17‐23        

25. 16 and 24       

26. 13 or 25          

27. randomized controlled trial.pt.   

28. controlled clinical trial.pt.            

29. randomized.ab.              

30. placebo.ab.    

31. clinical trials as topic.sh.              

32. randomly.ab.  

33. trial.ti.              

34. 27 or 28 or 29 or 30 or 31 or 32 or 33       

35. exp animals/ not humans.sh.      

36. 34 not 35        

37. 26 and 36

[Lines 27‐36: Cochrane Highly Sensitive Search Strategy for identifying randomized trials in MEDLINE: sensitivity‐ and precision‐maximizing version (2008 revision); Ovid format, from Section 3.6.1 of Lefebvre C, Glanville J, Briscoe S, Littlewood A, Marshall C, Metzendorf M‐I, et al. 4.S1 Technical Supplement to Chapter 4: Searching for and selecting studies. In: Higgins JP, Thomas J, Chandler J, Cumpston MS, Li T, Page MJ, et al, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 6. Cochrane, 2019. training.cochrane.org/handbook/archive/v6.1].

Contributions of authors

CWQ was the contact person with the editorial base.
CWQ, MS and LWMS co‐ordinated the contributions from the co‐authors and wrote the final draft of the protocol.
CWQ and MS worked on the methods sections.
CWQ, MS, KN, HJ, CYH, REW, PDM, WWST, CPC and LWMS drafted the clinical sections of the background and responded to the clinical comments of the referees.
MS, WWST and LWMS responded to the methodology and statistics comments of the referees.
CWQ, MS, REW and LWMS contributed to writing the protocol.
KIW was the consumer co‐authors and checked the protocol for readability and clarity. She also ensured that the outcomes were relevant to consumers.
CWQ is the guarantor of the final review.

Disclaimer

This project was supported by the National Institute for Health Research (NIHR), via Cochrane Infrastructure funding to the Cochrane Skin Group. The views and opinions expressed herein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, National Health Service or the Department of Health.

Sources of support

Internal sources

• NUS Yong Loo Lin School of Medicine, Singapore

  Provided biostatistical and research support.

• National University Health Systems, Singapore

  Provided research support.

• Department of Dermatology, Royal Victoria Infirmary, Newcastle Upon Tyne, UK

  Provided research support.

External sources

• The National Institute for Health Research (NIHR), UK

  The NIHR, UK, is the largest single funder of the Cochrane Skin Group.

Declarations of interest

Wei Qiang Chng: declared that they have no conflict of interest.
Miny Samuel: declared that they have no conflict of interest.
Khimara Naidoo: declared that they have no conflict of interest.
Wai Mun Sean Leong: declared that they are currently in full‐time employment as an Associate Consultant in Dermatology at the National Skin Centre in Singapore, but have no conflicts of interest.
Huma Jaffar: declared that they have no conflict of interest.
Ing Wei Khor: declared that they have no conflict of interest.
Chan Yiong Huak: declared that they have no conflict of interest.
Rachel EB Watson: reports a research grant for a Fundamental research programme from Walgreens Boots Alliance, and a Studentship (PhD) for fundmental research from Unilever T&D; money to institution. REBW is a Board member of the European Society for Dermatological Research. REBW was involved in conducting a study that is eligible for inclusion in the review: Manchester Patch Test Assay, commercially‐funded applied research: Degussa AG, Walgreens Boots Alliance (formerly The Boots Company and Alliance Boots), L'Oreal R&I.
Paola De Mozzi: declared that they have no conflict of interest.
Wilson Wai San Tam: declared that they have no conflict of interest.
Cristina Pires Camargo: declared that they have no conflict of interest.

The clinical referee Torunn E Sivesind declares that they receive fellowship funding from the Pfizer Global Medical Grant (PI: RP Dellavalle): Dermatology Fellowship 58858477.

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