Interventions for acne scars

Rania Abdel Hay; Khalid Shalaby; Hesham Zaher; Vanessa Hafez; Ching‐Chi Chi; Sandra Dimitri; Ashraf F Nabhan; Alison M Layton

doi:10.1002/14651858.CD011946.pub2

. 2016 Apr 3;2016(4):CD011946. doi: 10.1002/14651858.CD011946.pub2

Interventions for acne scars

Rania Abdel Hay ^1,^✉, Khalid Shalaby ², Hesham Zaher ¹, Vanessa Hafez ³, Ching‐Chi Chi ^4,⁵, Sandra Dimitri ⁶, Ashraf F Nabhan ⁶, Alison M Layton ⁷

Editor: Cochrane Skin Group

PMCID: PMC7069546 PMID: 27038134

Abstract

Background

Acne scarring is a frequent complication of acne and resulting scars may negatively impact on an affected person's psychosocial and physical well‐being. Although a wide range of interventions have been proposed, there is a lack of high‐quality evidence on treatments for acne scars to better inform patients and their healthcare providers about the most effective and safe methods of managing this condition. This review aimed to examine treatments for atrophic and hypertrophic acne scars, but we have concentrated on facial atrophic scarring.

Objectives

To assess the effects of interventions for treating acne scars.

Search methods

We searched the following databases up to November 2015: the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (2015, Issue 10), MEDLINE (from 1946), EMBASE (from 1974), and LILACS (from 1982). We also searched five trials registers, and checked the reference lists of included studies and relevant reviews for further references to randomised controlled trials.

Selection criteria

We include randomised controlled trials (RCTs) which allocated participants (whether split‐face or parallel arms) to any active intervention (or a combination) for treating acne scars. We excluded studies dealing only or mostly with keloid scars.

Data collection and analysis

Three review authors independently extracted data from each of the studies included in this review and evaluated the risks of bias. We resolved disagreements by discussion and arbitration supported by a method expert as required. Our primary outcomes were participant‐reported scar improvement and any adverse effects serious enough to cause participants to withdraw from the study.

Main results

We included 24 trials with 789 adult participants aged 18 years or older. Twenty trials enrolled men and women, three trials enrolled only women and one trial enrolled only men. We judged eight studies to be at low risk of bias for both sequence generation and allocation concealment. With regard to blinding we judged 17 studies to be at high risk of performance bias, because the participants and dermatologists were not blinded to the treatments administered or received; however, we judged all 24 trials to be at a low risk of detection bias for outcome assessment. We evaluated 14 comparisons of seven interventions and four combinations of interventions. Nine studies provided no usable data on our outcomes and did not contribute further to this review's results.

For our outcome 'Participant‐reported scar improvement' in one study fractional laser was more effective in producing scar improvement than non‐fractional non‐ablative laser at week 24 (risk ratio (RR) 4.00, 95% confidence interval (CI) 1.25 to 12.84; n = 64; very low‐quality evidence); fractional laser showed comparable scar improvement to fractional radiofrequency in one study at week eight (RR 0.78, 95% CI 0.36 to 1.68; n = 40; very low‐quality evidence) and was comparable to combined chemical peeling with skin needling in a different study at week 48 (RR 1.00, 95% CI 0.60 to 1.67; n = 26; very low‐quality evidence). In a further study chemical peeling showed comparable scar improvement to combined chemical peeling with skin needling at week 32 (RR 1.24, 95% CI 0.87 to 1.75; n = 20; very low‐quality evidence). Chemical peeling in one study showed comparable scar improvement to skin needling at week four (RR 1.13, 95% CI 0.69 to 1.83; n = 27; very low‐quality evidence). In another study, injectable fillers provided better scar improvement compared to placebo at week 24 (RR 1.84, 95% CI 1.31 to 2.59; n = 147 moderate‐quality evidence).

For our outcome ‘Serious adverse effects’ in one study chemical peeling was not tolerable in 7/43 (16%) participants (RR 5.45, 95% CI 0.33 to 90.14; n = 58; very low‐quality evidence).

For our secondary outcome ‘Participant‐reported short‐term adverse events’, all participants reported pain in the following studies: in one study comparing fractional laser to non‐fractional non‐ablative laser (RR 1.00, 95% CI 0.94 to 1.06; n = 64; very low‐quality evidence); in another study comparing fractional laser to combined peeling plus needling (RR 1.00, 95% CI 0.86 to 1.16; n = 25; very low‐quality evidence); in a study comparing chemical peeling plus needling to chemical peeling (RR 1.00, 95% CI 0.83 to 1.20; n = 20; very low‐quality evidence); in a study comparing chemical peeling to skin needling (RR 1.00, 95% CI 0.87 to 1.15; n = 27; very low‐quality evidence); and also in a study comparing injectable filler and placebo (RR 1.03, 95% CI 0.10 to 11.10; n = 147; low‐quality evidence).

For our outcome ‘Investigator‐assessed short‐term adverse events’, fractional laser (6/32) was associated with a reduced risk of hyperpigmentation than non‐fractional non‐ablative laser (10/32) in one study (RR 0.60, 95% CI 0.25 to 1.45; n = 64; very low‐quality evidence); chemical peeling was associated with increased risk of hyperpigmentation (6/12) compared to skin needling (0/15) in one study (RR 16.00, 95% CI 0.99 to 258.36; n = 27; low‐quality evidence). There was no difference in the reported adverse events with injectable filler (17/97) compared to placebo (13/50) (RR 0.67, 95% CI 0.36 to 1.27; n = 147; low‐quality evidence).

Authors' conclusions

There is a lack of high‐quality evidence about the effects of different interventions for treating acne scars because of poor methodology, underpowered studies, lack of standardised improvement assessments, and different baseline variables.

There is moderate‐quality evidence that injectable filler might be effective for treating atrophic acne scars; however, no studies have assessed long‐term effects, the longest follow‐up being 48 weeks in one study only. Other studies included active comparators, but in the absence of studies that establish efficacy compared to placebo or sham interventions, it is possible that finding no evidence of difference between two active treatments could mean that neither approach works. The results of this review do not provide support for the first‐line use of any intervention in the treatment of acne scars.

Although our aim was to identify important gaps for further primary research, it might be that placebo and or sham trials are needed to establish whether any of the active treatments produce meaningful patient benefits over the long term.

Plain language summary

Treatment for acne scars

Review question

Which treatments are effective for acne scars?

Background

Acne scars may have a damaging effect on a person's physical, mental, and social well‐being. Although a wide range of treatments are used, there is a lack of high‐quality evidence on which are the most effective for acne scars.

This review aimed to better inform patients and healthcare providers about the most effective and safe methods to manage this problem. We have examined treatments for atrophic scars (depressions in the skin surface) and hypertrophic scars (lumpy scars that stick out from the skin surface) in acne but have concentrated on facial atrophic scarring. Our main outcomes of interest were participant‐reported scar improvement and any adverse effects serious enough to cause participants to withdraw from the study.

Study characteristics

We include 24 randomised controlled trials (RCTs) with 789 people with acne scars (from searches up to November 2015). Twenty‐one RCTs (706 people) enrolled both men and women, three RCTs (75 people) enrolled only women and one RCT (eight people) enrolled only men. Most of the studies we included (21 RCTs with 744 people) enrolled people with atrophic acne scars. One RCT enrolled 20 individuals with mixed atrophic and hypertrophic acne scars.

Key results

There is insufficient evidence from trials to support fractional laser for treatment of acne. However, this management approach is adopted by some in clinical practice for the treatment of acne scarring.

For our outcome 'Participant‐reported scar improvement' fractional laser was more effective in producing scar improvement change than non‐fractional non‐ablative laser. Fractional radiofrequency showed similar scar improvement to fractional laser. Chemical peeling showed similar scar improvement to both fractional laser and skin needling. Combined chemical peeling with skin needling showed similar scar improvement to fractional laser and to deep chemical peeling. Injectable fillers provided better scar improvement compared to placebo.

Our outcome ‘Serious adverse effects’ was reported in one study, showing that chemical peeling was not tolerable in 16% of those taking part. Other outcomes, ‘Participant‐reported' and 'Investigator‐assessed' adverse events in the short term (less than 24 weeks), were more or less acceptable by those taking part and by investigators and did not reveal a big difference between the studied interventions.

Four out of six of our comparisons were completely inconclusive and they were of very low‐quality evidence. There is a lack of studies that establish efficacy of treatments compared to placebo or sham interventions, and it is possible that finding no evidence of difference between two active treatments could mean that neither is very useful.

We did not identify any trials that examined treatment for acne scars on the back.

The results of this review do not support the first‐line use of any intervention in the treatment of acne scars, and no studies provided evidence to confirm that any short‐term benefit will translate to long‐term effects.

Quality of the evidence

We rated the quality of the evidence for several outcomes as very low to moderate. The lower quality evidence for treatments was mostly because there were few people in the studies, making the results less precise, and there was a lack of blinding (people knew the treatment they were receiving).

Future studies should consider adopting patient‐reported outcomes as a primary measure. There should be a set of core outcome measures reported in all RCTs for treating acne scars, and outcomes should be evaluated several months after the treatment has been done. Lack of reporting of serious side effects was one of the research gaps found in this review.

Summary of findings

Background

A description of key medical terms can be found in Appendix 1.

Description of the condition

Acne and its prevalence

Acne vulgaris is a chronic inflammatory condition of the pilosebaceous unit (Fabbrocini 2010; Williams 2012). It is notable for open or closed comedones or both and for inflammatory lesions including papules, pustules, or nodules (Strauss 2007). Acne vulgaris is among the top 10 most prevalent conditions worldwide (Hay 2014), and it is one of the most common skin conditions. Some degree of acne affects almost all adolescents between 15 and 17 years of age (Collier 2007; Williams 2012). Up to 80% of adolescents and up to 5% of adults experience acne (Jacob 2001).

The impact of acne on the quality of life can be profound (Dalgard 2009). Compared to people without acne, individuals with acne are at a higher risk of experiencing depression and anxiety, especially in those whose quality of life has been affected (Duman 2015). They are more likely to have lower self esteem and lower body satisfaction and may be at an increased risk of suicide attempts (Purvis 2006). Optimal treatments may significantly improve the appearance, quality of life, and self esteem of affected people (Purvis 2006).

It is important for dermatologists to be aware of a condition known as dysmorphophobia or body dysmorphic disorder, which can affect people with acne and acne scars. It is characterised by a distressing and excessive preoccupation with a slight or imagined defect of a physical feature and may significantly damage psychosocial functioning and decrease the quality of life of those affected (Conrado 2010; Gupta 2013).

Acne scars: aetiology, pathology, and prevalence

Scarring, as a physical disfigurement, is a frequent complication of acne. The psychological impact of scarring can be profound; scars can occur as a result of damage to the skin during the healing of active acne (Patel 2010). Although active acne can persist for a decade or more, acne scars may persist for a lifetime (Jordan 2000). One publication (Layton 1994) on the prevalence of acne scarring suggests that the type and extent of scarring correlates with the site and severity of previous acne and duration of acne before effective treatment. Facial scarring affects both sexes equally and occurs in up to 95% of cases (Layton 1994).

Several classifications and scales have been proposed for facial acne scarring (Dreno 2007; Goodman 2006a; Goodman 2006b).

Often, scarring is the consequence of severe inflammatory nodulocystic acne, but it may also be the product of superficial inflamed lesions or the squeezing or picking of lesions with the fingernails (Patel 2010). There are three general types of acne scars, depending on hyperproliferation or loss of collagen: hypertrophic scars, keloid scars or atrophic scars. A person might have one or more types occurring in the same skin area (Basta‐Juzbasic 2010; Maibach 2011).

Atrophic scars are seen in almost 80% to 90% of patients (Patel 2010). These scars present clinically as indentations in the skin due to loss of collagen and destructive inflammation in the deep dermis with subsequent contraction (Jacob 2001). Atrophic scars may be further classified into ice pick scars (V‐shaped epithelial tracts with a sharp margin that can extend deeper in the skin), boxcar scars (a round to oval scar with sharp vertical sides that can extend deeper in the skin), or rolling scars (irregular scars with a rolling or undulating shape that may reach up to 5 mm in diameter) occurring in 60% to 70%, 20% to 30%, and 15% to 25% of patients respectively (Jacob 2001). These three scar types are usually seen in the same person, making it difficult to differentiate between them (Lee 2009; Levy 2012).

Limited morphological classification of scarring has been described and to date there is poor consensus; clinical assessment of scars demonstrates significant variation between assessors (Finlay 2013). The lack of a universally accepted standardised objective quantification or qualitative scoring to estimate the global severity and burden of disease makes comparisons of treatments for scarring challenging. There is some evidence for differences in innate immune responses in those that scar and do not scar (Holland 2004); this makes it difficult to interpret results between participants.

Hypertrophic and keloidal scars show excessive deposition of collagen with reduced collagenase activity (Alster 2003). Individuals with Type IV/V Fitzpatrick skin types are more liable to develop hypertrophic or keloid scars, and both scars predominantly occur on the trunk (Brown 2009). Typically, hypertrophic scars are raised firm pink lesions that remain within the borders of the original site of injury (Gauglitz 2011). In contrast, keloids appear reddish‐purple and take the form of papules and nodules usually extending beyond the borders of the original wound (Gauglitz 2011). Keloids do not tend to regress spontaneously and are frequently resistant to treatment and have a high recurrence rate (Brown 2009; Fabbrocini 2010; Lee 2009).

The destructive treatments that we consider in this review can worsen keloids (Mutalik 2005). We therefore exclude management of keloidal scars from this review, so this will need to be addressed in a separate review.

Description of the intervention

The management of acne scarring includes various types of resurfacing (chemical peels, lasers, dermabrasion); use of injectable fillers; and also surgical methods, such as needling, subcision, punch excision, or punch elevation (Basta‐Juzbasic 2010; Cao 2015; Fabbrocini 2010). Different factors, e.g. colour, texture, and morphology, can affect the treatment choice for each individual scar (Basta‐Juzbasic 2010). Combining interventions may produce more benefit compared with a single method alone. Complete resolution of acne scars can not be achieved by the currently available treatment modalities (Basta‐Juzbasic 2010). Early effective treatment of acne is probably the best strategy to prevent or limit post‐acne scarring (Goodman 2014; Williams 2012).

Different interventions for the treatment of acne scars sometimes entail a significant cost (Jordan 2000). The costs for the same intervention sometimes vary considerably between different countries or regions.

How the intervention might work

Traditional ablative laser resurfacing removes the epidermis and part of the dermis of the scars, allowing collagen remodeling and re‐epithelialisation (Jordan 2000). Patients typically do not need more than one treatment, but the treatment has adverse effects including persistent erythema, hypopigmentation, hyperpigmentation, infections, and scarring. It also has a recovery period (up to two weeks) (Goodman 2014). Proper training is required for performing ablative laser resurfacing (Goodman 2014).

Non‐ablative laser resurfacing produces dermal thermal injury while preserving the epidermis; this dermal thermal injury promotes collagen remodeling through the formation of new collagen, which leads to an improvement in the scarring (Hedelund 2010).

Fractional laser resurfacing acts, as the name indicates, "on regularly‐spaced arrays over a fraction of the skin surface to induce thermal ablation of microscopic columns of epidermal and dermal tissue" (Goel 2011). This approach is more effective than non‐ablative resurfacing while providing a faster recovery when compared with ablative resurfacing (Alexiades‐Armenakas 2008). Fractional and non‐ablative laser resurfacing have become more popular in practice than ablative laser resurfacing, despite a non‐comparable efficacy, probably because of a lower rate of adverse events (Alexiades‐Armenakas 2008).

Chemical peels (employing glycolic acid, phenol, salicylic‐mandelic acid, or trichloroacetic acid) are used in treating small depressed scars but not ice pick or deep boxcar scars (Garg 2008; Garg 2014). A combination of chemical peeling, subcision, and microneedling may result in a better outcome (Fabbrocini 2010). However, excessive systemic absorption of phenolic chemical peels might increase the risk of cardiac toxicity (Landau 2007).

Dermabrasion involves the use of tools (e.g. high‐speed brush, diamond cylinder, fraise, or silicon carbide sandpaper) to remove the epidermis or epidermis and part of the dermis. An advantage of the procedure is that it allows the clinician to etch scar edges precisely without thermal injury. It may be effective for some acne scars, but is usually not used for ice pick or deep boxcar scars (Goodman 2014). Adverse effects include significant pain and a considerable recovery time. Scarring, pigment alterations, and milia formation can also occur with dermabrasion (Goodman 2014).

Skin‐needling procedures may diminish the appearance of acne scars. A needling device is rolled over the surface of the skin to form numerous perforations in the epidermis and dermis, with a goal of stimulating new collagen (Alam 2014). Needling therapy has been associated with improvement of dermatologist‐rated acne scarring (Alam 2014). The advantages of skin needling include low cost, a relatively short recovery period (two to three days), and a very low risk for postinflammatory hyperpigmentation (Fabbrocini 2009). Skin needling treatment is well tolerated by most people and the pain is minimal (Alam 2014).

Punch excision may be an effective treatment for ice pick scars and small (< 3 mm) boxcar scars. A punch biopsy instrument of equal to or slightly greater diameter than the scar is used to incise the tissue to the subcutaneous fat layer and excise the scar (Grevelink 1998). It has been associated with good results, but secondary widening of the scar may occur (Goodman 2014).

Punch elevation is best suited for boxcar scars (Goodman 2007). The scar border is excised, leaving the deepest part of the scar that is adherent to the fat layer. The scar is raised higher than the surrounding skin; it then retracts during healing to become level with the surface (Goodman 2014).

Subcision is used for the management of rolling or depressed scars; a blade inserted parallel to the skin surface is used to cut fibrotic strands tethering the scar to the underlying tissue (Jacob 2001). Reported adverse effects include bruising and swelling, bleeding, and infection (Alam 2005).

Injectable filler injections used for atrophic scars have been proposed to improve the appearance of acne scars; collagen, autologous fat transfer, and artificial injectable fillers are most commonly used (Karnik 2014). Their effect lasts from three to 18 months, depending on the type of filler used (Karnik 2014).

Hypertrophic scars are classically treated with intralesional corticosteroid injections (Arno 2014). Using multiple treatment methods gives the maximum potential for success, including earlier use of 5‐fluorouracil (Mutalik 2005). Clinical research increasingly supports the use of newer agents (e.g. bleomycin, onion extract, imiquimod, mitomycin C) and laser therapy (pulsed‐dye, fractional) for this type of scar management (Gold 2014).

Why it is important to do this review

Acne scars may cause important detrimental effects on a person's physical, mental, and social well‐being (Purvis 2006). Although a wide range of interventions have been proposed in this field, there is a lack of high‐quality synthesised evidence on interventions for acne scars to better inform caregivers and consumers about the most effective and safe methods to manage this problem.

Treatment of acne scars is among the top 10 research priorities for the treatment of acne identified by the Acne Priority Setting Partnership. The Acne Priority Setting Partnership was set up to identify and rank treatment uncertainties by bringing together consumers and professionals who provide care within and beyond the National Health Service (NHS) (Layton 2015). The National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme and its initiative to support the current review will use knowledge gaps identified by the review to inform areas of future research.

We have built on and expanded the work previously published in a Cochrane review that assessed laser resurfacing for facial acne scars (Jordan 2000). We have taken into account the uncertainties identified by that review.

Given the physical disfigurement associated with acne vulgaris, along with the potentially profound psychological impact of this skin disorder, we think it is necessary to assess the evidence on the benefits and harms of available treatments for acne scars. We are interested in acne scars on both face and back, but we have concentrated in this review on facial scars.

The plans for this review were published in the protocol 'Interventions for acne scars' (Abdel Hay 2015)

Objectives

To assess the effects of interventions for treating acne scars.

Methods

Criteria for considering studies for this review

Types of studies

We include randomised controlled trials (RCTs) allocating participants (whether by split‐face or parallel study designs) to any active intervention (or a combination) for treating acne scars. In multi‐arm trials, we have included all eligible arms.

We exclude cluster trials, cross‐over trials, and quasi‐RCTs.

Types of participants

People of either gender, all ages, and all ethnic groups who had been diagnosed by a dermatologist or an experienced investigator as having atrophic or hypertrophic acne scars. We include all grades of scar severity.

We exclude studies dealing with only or mostly keloid scars, because the destructive treatments that we consider in this review may worsen keloids.

Types of interventions

We include all interventions versus an active intervention, placebo, or no treatment. We consider all active interventions, including chemical peeling, dermabrasion and microdermabrasion, laser therapy, radiofrequency, punch techniques and dermal grafting, tissue‐augmenting agents, needling, subcision, intralesional steroid injection, silicone gel, cryotherapy, pulsed dye laser, imiquimod, 5‐fluorouracil, interferon, bleomycin, surgery, or combined therapy.

Types of outcome measures

Primary outcomes

Participant‐reported scar improvement: measured by a scar improvement, grading, or severity scale.
Participants with adverse effects serious or severe enough to have caused their withdrawal from the study. We define 'serious' adverse effects' as events that pose a threat to a participant's life or functioning whereas 'severe' adverse effects are defined by their intensity.

Secondary outcomes

Investigator‐assessed scar improvement: measured by a scar improvement, grading, or severity scale.
Participant satisfaction: measured by a participant satisfaction questionnaire.
Quality of life: measured by a quality‐of‐life scale, whether global or specific.
Participant‐reported adverse events, e.g. pain, erythema, oedema, infection, oozing, crusting, hyperpigmentation, or scarring.
Investigator‐assessed adverse events, e.g. erythema, oedema, infection, oozing, crusting, hyperpigmentation, or scarring.
Duration, in days, of post‐procedure down time. We defined the down time as the number of days following the procedure during which the participant had oedema and erythema and felt unable or unwilling to go out in public.

Timing of outcomes

We assessed our primary outcome of scar improvement over a time frame of up to 24 weeks (short‐term) and more than 24 weeks (long‐term).

We assessed our adverse events outcomes in the short term up to four weeks after the procedure and in the long term more than four weeks after the procedure.

Search methods for identification of studies

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

Electronic searches

We searched the following databases up to 18 November 2015:

the Cochrane Skin Group Specialised Register using the following terms: acne and (cicatri* or scar*);
the Cochrane Central Register of Controlled Trials (CENTRAL) 2015, Issue 10, in the Cochrane Library using the search strategy in Appendix 2;
MEDLINE via Ovid (from 1946) using the strategy in Appendix 3;
EMBASE via Ovid (from 1974) using the strategy in Appendix 4;
LILACS (Latin American and Caribbean Health Science Information database, from 1982) using the strategy in Appendix 5.

Trials registers

We searched the following trials registers on 24 December 2015, using the following terms: "acne" and (cicatri* or scar*).

The ISRCTN registry (www.isrctn.com/).
The US National Institutes of Health Ongoing Trials Register (www.clinicaltrials.gov).
The Australian New Zealand Clinical Trials Registry (www.anzctr.org.au).
The World Health Organization International Clinical Trials Registry platform (apps.who.int/trialsearch).
The EU Clinical Trials Register (www.clinicaltrialsregister.eu).

Searching other resources

We checked the bibliographies of included trials and review articles for further references to relevant trials.

We searched manufacturers' websites for relevant trial information.

We contacted trial authors for missing data and information about ongoing trials.

Adverse effects

We did not perform a separate search for adverse effects of interventions used for treating acne scars. We considered adverse effects described in the included studies only.

Data collection and analysis

Some of the data collection and analysis section of this review is based on a standard template used by the Cochrane Pregnancy and Childbirth Review Group.

Selection of studies

We downloaded all potentially relevant studies identified from the searches into reference management software and removed duplicates. Two review authors independently screened titles and abstracts of studies from literature searches for inclusion in the review and coded them as "retrieve" (eligible, potentially eligible, or unclear) or "do not retrieve". We obtained the full texts of those coded "retrieve", and two review authors independently screened the full texts to identify studies for inclusion. We did not include studies reported as abstracts only, as we could not extract enough information for 'Risk of bias' assessment and completion of the Characteristics of included studies tables. We resolved disagreements by discussion, and if we did not reach consensus a third author made the judgement.

We recorded reasons for the exclusion of any ineligible studies in the 'Characteristics of excluded studies' tables.

We carried out the selection process in sufficient detail to complete a study flow diagram.

Data extraction and management

We used the data extraction form available from the Cochrane Skin Group's website and developed a computer database tool to be used for data extraction. We piloted the data extraction form within the review team using a sample of the studies to be reviewed. For eligible studies, two review authors independently extracted the data using the agreed form and then entered the data into Review Manager 5 software (RevMan 2014). We cross‐checked the data for accuracy. We resolved discrepancies through discussion or if required we consulted a third author. When information regarding any of the above was unclear, we contacted the authors of the original reports to elicit further details.

Assessment of risk of bias in included studies

Two review authors independently assessed the risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We resolved any disagreement by discussion or with the involvement of a third author.

(1) Sequence generation (checking for possible selection bias)

We describe for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.

We assessed the risk as one of the following:

low (any truly random process, e.g. random number table, computer random number generator);
high (non‐random approach, e.g. sequence generated by odd or even date of birth, sequence generated by some rule based on date of admission); or
unclear.

(2) Allocation concealment (checking for possible selection bias)

We describe for each included study the method used to conceal the allocation sequence in sufficient detail to determine whether allocation of the intervention could have been foreseen in advance of or during recruitment, or changed after assignment.

We assessed the risk as one of the following:

low (e.g. telephone or central randomisation, consecutively‐numbered sealed opaque envelopes);
high (open random allocation, unsealed or non‐opaque envelopes); or
unclear.

(3) Blinding (checking for possible performance and detection bias)

We describe for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant would receive. We assessed blinding separately for performance and detection bias and for different outcomes or classes of outcomes.

We assessed the risk as one of the following:

low, high, or unclear for participants;
low, high, or unclear for personnel; and
low, high, or unclear for outcome assessors.

(4) Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)

We describe for each included study and for each outcome or class of outcomes the completeness of data, including attrition and exclusions from the analysis. We considered both the overall attrition rate (the proportion of participants randomly assigned to the study groups for whom outcome data are not available) and the differential attrition rate (the difference in attrition rates between groups). We considered an overall attrition rate above 20% or a differential attrition rate above 5% as representing a high risk of attrition bias.

We state whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups. Where sufficient information was reported or could be supplied by the trial authors, we re‐included missing data in the analyses that we undertook. We assessed risk as one of the following:

low;
high; or
unclear.

(5) Selective reporting bias

We describe for each included study how we investigated the possibility of selective outcome reporting bias and what we found, on the basis of what was present in the trial registry documents. We wrote to authors to ask for protocols if these were not published.

We assessed the risk as follows:

low, where it was clear that all of the study's prespecified outcomes and all expected outcomes of interest to the review were reported;
high, where not all of the study's prespecified outcomes were reported, one or more reported primary outcomes were not prespecified, outcomes of interest were reported incompletely and so could not be used, or the study failed to include results of a key outcome that could be expected to be reported; or
unclear.

(6) Other sources of bias

We describe for each included study any important concerns that we have about other possible sources of bias, e.g. baseline imbalance and blocked randomisation in unblinded trials.

We assessed the risk as one of the following:

low;
high; or
unclear.

(7) Overall risk of bias

We made explicit judgements about whether studies were at high risk of bias according to the criteria given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). With reference to (one) to (six) above, we assessed the likely magnitude and direction of the bias and whether we considered that it was likely to impact on the treatment effects. We explore the impact of the level of bias through undertaking sensitivity analyses.

Measures of treatment effect

Dichotomous data

For dichotomous data, we present results as summary risk ratios (RRs) with 95% confidence intervals (CIs).

Continuous data

For continuous data, we use the mean difference (MD) if outcomes were measured in the same way across trials. We use the standardised mean difference (SMD) to combine trials that measured the same outcome using different scales. We present change data and endpoint data separately in cases where we used the SMD.

Unit of analysis issues

We anticipated that the trials included in this review might randomise either participants or split‐face. We followed the guidance in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We intended to incorporate trials using a split‐face design to approximate a paired analysis using the generic inverse variance method, and to undertake a sensitivity analysis where we had used imputations and to perform meta‐analyses of these trials separately from parallel trials. However paired data were unavailable and we were not able to adjust for the within‐individual variability. We report those studies separately as a RR without a P value or 95% CI. We include two multi‐arm trials in the review, using the two arms that compared different interventions for acne scars. We include these studies as pair‐wise comparisons.

Dealing with missing data

For all outcomes, we attempted to conduct analyses on an intention‐to‐treat basis. When there were missing data, we contacted the authors of the study to obtain the relevant missing data (See Table 8). We carefully evaluated important numerical data. If we could not obtain missing data for dichotomous outcomes, we considered participants with missing outcome data as treatment failures. We used sensitivity analysis to assess how sensitive results were to reasonable changes in the assumptions that we made. We addressed the potential impact of missing data on the findings of the review in the Discussion section.

1. Contacted authors.

Study	Contact author	Contact email	Reply/did not reply
Ahmed 2014	Mohammed G	dr_ghada77@hotmail.com	Did not reply
Asilian 2011	Salimi E	s_salimi@resedent.mui.ac.ir	Did not reply
Bernstein 2001	Bernstein EF	dermguy@hotmail.com	Did not reply
Chae 2015	Choi YS	uuhderma@hanmail.net	Responded
Cho 2010	Kim DH	terios92@hanmail.net	Did not reply
Gadkari 2014	Gadkari R	drreshmagadkari@gmail.com	Did not reply
Hedelund 2010	Hedelund L	lene.hedelund@hotmail.com	Did not reply
Hedelund 2012	Hedelund L	lenhed@rm.dk	Did not reply
Karnik 2014	Smith SR	ssmith@stacyrsmithmd.com	Did not reply
Kim 2009	Lee JH	juhee@yuhs.ac	Did not reply
Kim 2009a	Kim S	i4ks@yahoo.com	Did not reply
Lee 2009	Suh DH	daehun@snu.ac.kr	Did not reply
Lee 2011	Kim BJ	beomjoon@unitel.co.kr	Did not reply
Linkner 2014	Linkner RV	Rita.Linkner@mountsinai.org	Did not reply
Manuskiatti 2013	Manuskiatti W	woraphong.man@mahidol.ac.th	Did not reply
Min 2009	Suh DH	daehun@snu.ac.kr	Did not reply
Mohammed 2013	Mohammed G	dr_ghada77@hotmail.com	Did not reply
Munavalli 2013	Munavalli GS	gmunavalli@carolinaskin.com	Did not reply
Nofal 2014	Nofal E	ahmadnofal5@hotmail.com	Did not reply
Rongsaard 2014	Rongsaard N	nopnarueporn@gmail.com	Responded
Sage 2011	Kouba DJ	dkouba1@hfhs.org	Did not reply
Tanzi 2004	Alster TS	talster@skinlaser.com	Did not reply
Zhang 2013	Chen J	xdchen@medmail.com.cn	Did not reply

Gap No.	Reason(s) for Gap*	POPULATION (P)	INTERVENTION (I)	COMPARISON (C)	OUTCOMES (O)	SETTING (S)	Free Text Gap
1	A1	People with acne scars	Fractional Laser	No treatment	Participant‐reported scar improvement (long‐term)	Hospital‐based/outpatient	Lack of a validated standardised improvement scale
2	A1 D4	People with acne scars	Fractional Laser	Non‐fractional non‐ablative laser	Participant‐reported scar improvement (long‐term)	Hospital‐based/outpatient	Lack of a validated standardised improvement scale
3	A2 A3 A4 B2 C1	People with acne scars	Fractional Laser	Non‐fractional non‐ablative laser	Participant‐reported scar improvement (short‐term)	Hospital‐based/outpatient	Lack of a validated standardised improvement scale
4	A1 D4	People with acne scars	Fractional Laser	Radiofrequency	Participant‐reported scar improvement (long‐term)	Hospital‐based/outpatient	Lack of a validated standardised improvement scale
5	A2 A3 B2 C1	People with acne scars	Fractional Laser	Radiofrequency	Participant‐reported scar improvement (short‐term)	Hospital‐based/outpatient	Lack of a validated standardised improvement scale
6	A1	People with acne scars	Fractional Laser	Chemical peeling	Participant‐reported scar improvement (short‐ and long‐term)	Hospital‐based/outpatient	Lack of a validated standardised improvement scale
7	A2 A3 B2 C1	People with acne scars	Fractional Laser	Combined chemical peeling plus needling	Participant‐reported scar improvement (long‐term)	Hospital‐based/outpatient	Lack of a validated standardised improvement scale
8	A1	People with acne scars	Fractional Laser	Combined chemical peeling plus needling	Participant‐reported scar improvement (short‐term)	Hospital‐based/outpatient	Lack of a validated standardised improvement scale
9	A1	People with acne scars	Fractional Laser	Microdermabrasion	Participant‐reported scar improvement (short‐ and long‐term)	Hospital‐based/outpatient	Lack of a validated standardised improvement scale
10	A1	People with acne scars	Fractional Laser	Needling	Participant‐reported scar improvement (short‐ and long‐term)	Hospital‐based/outpatient	Lack of a validated standardised improvement scale
11	A1	People with acne scars	Fractional Laser	Injectible fillers	Participant‐reported scar improvement (short‐ and long‐term)	Hospital‐based/outpatient	Lack of a validated standardised improvement scale
12	A1 D4	People with acne scars	Chemical peeling	Placebo/no treatment	Participant‐reported scar improvement (long‐term and short‐term)	Hospital‐based/outpatient	Lack of a validated standardised improvement scale
13	A2 A3 B2 C1	People with acne scars	Chemical peeling	Combined chemical peeling with any active intervention	Participant‐reported scar improvement (long‐term)	Hospital‐based/outpatient	Lack of a validated standardised improvement scale
14	A1	People with acne scars	Chemical peeling	Combined chemical peeling with any active intervention	Participant‐reported scar improvement (short‐term)	Hospital‐based/outpatient	Lack of a validated standardised improvement scale
15	A1 D4	People with acne scars	Chemical peeling	Needling	Participant‐reported scar improvement (long‐term)	Hospital‐based/outpatient	Lack of a validated standardised improvement scale
16	A2 A3 B2 C1	People with acne scars	Chemical peeling	Needling	Participant‐reported scar improvement (short‐term)	Hospital‐based/outpatient	Lack of a validated standardised improvement scale
17	A1 D4	People with acne scars	Injectable fillers	Placebo/no treatment	Participant‐reported scar improvement (long‐term)	Outpatient	Lack of a validated standardised improvement scale
18	A2 C1	People with acne scars	Injectable fillers	Placebo/no treatment	Participant‐reported scar improvement (short‐term)	Outpatient	lack of a validated standardised improvement scale
19	A1	People with acne scars	Injectable fillers	Autologous bone marrow stem‐cell transplant	Participant‐reported scar improvement (short‐ and long‐term)	Hospital‐based	Lack of a validated standardised improvement scale
20	A1	People with acne scars	Microdermabrasion	No treatment	Participant‐reported scar improvement (short‐ and long‐term)	Outpatient	Lack of a validated standardised improvement scale
21	A1	People with acne scars	Microdermabrasion	Needling	Participant‐reported scar improvement (short‐ and long‐term)	Outpatient	Lack of a validated standardised improvement scale
22	A1	People with acne scars	Microdermabrasion	Subcision	Participant‐reported scar improvement (short‐ and long‐term)	Outpatient	Lack of a validated standardised improvement scale
23	A1	People with acne scars	Needling	No treatment	Participant‐reported scar improvement (short‐ and long‐term)	Outpatient	Lack of a validated standardised improvement scale
24	A1	People with acne scars	Needling	Subcision	Participant‐reported scar improvement (short‐ and long‐term)	Outpatient	Lack of a validated standardised improvement scale

Fractional laser versus non‐fractional non‐ablative laser for acne scars
Patient or population: people with acne scars  Settings: hospital‐based  Intervention: fractional laser versus non‐fractional non‐ablative laser
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of Participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Fractional laser versus non‐fractional non‐ablative laser
Participant‐reported scar improvement (long‐term)	See comment	See comment	Not estimable	‐	See comment	This outcome was not measured
Participant‐reported scar improvement (short‐term)   N of participants with > 50% improvement in acne scars  Follow‐up: mean 6 months	94 per 1000	375 per 1000   (117 to 1000)	RR 4   (1.25 to 12.84)	64  (1 study)	⊕⊝⊝⊝  very low^1,2	‐
Investigator‐assessed adverse events (short‐term) Hyperpigmentation   N of participants with adverse events  Follow‐up: mean 4 weeks	312 per 1000	188 per 1000   (78 to 453)	RR 0.6   (0.25 to 1.45)	64  (1 study)	⊕⊝⊝⊝  very low^1,3	‐
Participant‐assessed adverse events (short‐term) Burning   N of participants with adverse events  Follow‐up: mean 4 weeks	1000 per 1000	1000 per 1000   (940 to 1000)	RR 1   (0.94 to 1.06)	64  (1 study)	⊕⊝⊝⊝  very low^1,4	‐
Participant satisfaction	See comment	See comment	Not estimable	‐	See comment	This outcome was not measured
Quality of life	See comment	See comment	Not estimable	‐	See comment	This outcome was not measured
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: 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.  Very low quality: We are very uncertain about the estimate.

Fractional laser versus radiofrequency for acne scars
Patient or population: people with acne scars  Settings: hospital‐based  Intervention: fractional laser versus radiofrequency
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of Participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Fractional laser versus radiofrequency
Participant‐reported scar improvement (long‐term)	See comment	See comment	Not estimable	‐	See comment	This outcome was not measured
Participant‐reported scar improvement (short‐term)   N of participants with > 50% improvement in acne scars  Follow‐up: mean 8 weeks	450 per 1000	351 per 1000   (162 to 756)	RR 0.78   (0.36 to 1.68)	40  (1 study)	⊕⊝⊝⊝  very low^1,2	Rongsaard 2014 reported a mean improvement of 2.89 for the fractional laser and 2.74 for the radiofrequency
Investigator‐assessed adverse events (short‐term)	See comment	See comment	Not estimable	‐	See comment	Unclear whether the reported higher events (erythema, oedema, PIH) with the laser are participant‐ or investigator‐assessed
Participant‐assessed adverse events (short‐term)	See comment	See comment	Not estimable	‐	See comment	More pain with fractional laser was noticed, Rongsaard 2014 and Zhang 2013 reported higher incidence of positive adverse events with fractional laser
Participant satisfaction	See comment	See comment	Not estimable	‐	See comment	Zhang 2013 reported that 30/33 and 31/33 of participants were satisfied with laser and radiofrequency respectively with no significant difference
Quality of life	See comment	See comment	Not estimable	‐	See comment	This outcome was not measured
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: 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.  Very low quality: We are very uncertain about the estimate.

Fractional laser versus combined chemical peeling plus needling for acne scars
Patient or population: people with acne scars  Settings: hospital‐based  Intervention: fractional laser versus combined chemical peeling plus needling
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of Participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Fractional laser versus combined chemical peeling plus needling
Participant‐reported scar improvement (long‐term)   N of participants with > 50% improvement in acne scars  Follow‐up: mean 12 months	692 per 1000	692 per 1000   (415 to 1000)	RR 1   (0.6 to 1.67)	26  (1 study)	⊕⊝⊝⊝  very low^1,2	‐
Participant‐reported scar improvement (short‐term)	See comment	See comment	Not estimable	‐	See comment	This outcome was not measured
Investigator‐assessed adverse events (short‐term)	See comment	See comment	Not estimable	‐	See comment	This outcome was not measured
Participant‐assessed adverse events (short‐term)   N of participants with adverse events  Follow‐up: mean 4 weeks	1000 per 1000	1000 per 1000   (860 to 1000)	RR 1   (0.86 to 1.16)	25  (1 study)	⊕⊝⊝⊝  very low^1,3	‐
Participant satisfaction	See comment	See comment	Not estimable	‐	See comment	This outcome was not measured
Quality of life	See comment	See comment	Not estimable	‐	See comment	This outcome was not measured
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: 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.  Very low quality: We are very uncertain about the estimate.

Chemical peeling versus placebo or no treatment for acne scars
Patient or population: people with acne scars  Settings: out‐patient  Intervention: chemical peeling versus placebo or no treatment
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of Participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Chemical peeling versus placebo or no treatment
Participant‐reported scar improvement (long‐term)	See comment	See comment	Not estimable	‐	See comment	This outcome was not measured
Participant‐reported scar improvement (short‐term)	See comment	See comment	Not estimable	‐	See comment	This outcome was not measured
Investigator‐assessed adverse events (short‐term)	See comment	See comment	Not estimable	‐	See comment	This outcome was not measured
Participant‐assessed adverse events (short‐term)	See comment	See comment	Not estimable	‐	See comment	Burning sensation and deep erythema were reported following frosting in some cases from the chemical peeling
Participant satisfaction	See comment	See comment	Not estimable	‐	See comment	This outcome was not measured
Quality of life	See comment	See comment	Not estimable	‐	See comment	This outcome was not measured
Serious or severe adverse events   N of participants with positive severe adverse events  Follow‐up: mean 6 months	0 per 1000	0 per 1000   (0 to 0)	RR 5.45   (0.33 to 90.14)	58  (1 study)	⊕⊝⊝⊝  very low^1,2	7/43 participants experienced serious adverse events with chemical peel but 0/15 in the placebo group
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: 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.  Very low quality: We are very uncertain about the estimate.

Chemical peeling versus combined chemical peeling plus any active intervention for acne scars
Patient or population: people with acne scars  Settings: hospital‐based  Intervention: chemical peeling versus combined chemical peeling plus any active intervention
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of Participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Chemical peeling versus combined chemical peeling plus any active intervention
Participant‐reported scar improvement (long‐term)   N of participants with > 50% improvement in acne scars  Follow‐up: mean 8 months	800 per 1000	992 per 1000   (696 to 1000)	RR 1.24   (0.87 to 1.75)	20  (1 study)	⊕⊝⊝⊝  very low^1,2	‐
Participant‐reported scar improvement (short‐term)	See comment	See comment	Not estimable	‐	See comment	This outcome was not measured
Investigator‐assessed adverse events (short‐term)	See comment	See comment	Not estimable	‐	See comment	This outcome was not measured
Participant‐assessed adverse events (short‐term)   N of participants with adverse events  Follow‐up: mean 4 weeks	1000 per 1000	1000 per 1000   (830 to 1000)	RR 1   (0.83 to 1.2)	20  (1 study)	⊕⊝⊝⊝  very low^1,3	‐
Participant satisfaction	See comment	See comment	Not estimable	‐	See comment	This outcome was not measured
Quality of life	See comment	See comment	Not estimable	‐	See comment	This outcome was not measured
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: 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.  Very low quality: We are very uncertain about the estimate.

Chemical peeling versus needling for acne scars
Patient or population: people with acne scars  Settings: hospital‐based  Intervention: chemical peeling versus needling
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of Participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Chemical peeling versus needling
Participant‐reported scar improvement (long‐term)	See comment	See comment	Not estimable	‐	See comment	This outcome was not measured
Participant‐reported scar improvement (short‐term)   N of participants with > 50% improvement in acne scars  Follow‐up: mean 1 months	667 per 1000	747 per 1000   (460 to 1000)	RR 1.13   (0.69 to 1.83)	27  (1 study)	⊕⊝⊝⊝  very low^1,2	‐
Investigator‐assessed adverse events (short‐term)   N of participants with adverse events  Follow‐up: mean 4 weeks	Study population		RR 16   (0.99 to 258.36)	27  (1 study)	⊕⊕⊝⊝  low³	6/12 participants experienced adverse events with chemical peel but 0/15 with needling
	0 per 1000	0 per 1000   (0 to 0)
	Moderate
	0 per 1000	0 per 1000   (0 to 0)
Participant‐assessed adverse events (short‐term)   N of participants with positive adverse events  Follow‐up: mean 4 weeks	1000 per 1000	1000 per 1000   (870 to 1000)	RR 1   (0.87 to 1.15)	27  (1 study)	⊕⊝⊝⊝  very low^1,4	‐
Patient satisfaction   N of satisfied participants  Follow‐up: mean 4 weeks	667 per 1000	747 per 1000   (460 to 1000)	RR 1.13   (0.69 to 1.83)	27  (1 study)	⊕⊝⊝⊝  very low^1,2	‐
Quality of life	See comment	See comment	Not estimable	‐	See comment	This outcome was not measured
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: 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.  Very low quality: We are very uncertain about the estimate.

Injectable fillers versus placebo or no treatment for acne scars
Patient or population: people with acne scars  Settings: outpatient  Intervention: injectable fillers versus placebo or no treatment
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of Participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Injectable fillers versus placebo or no treatment
Participant‐assessed scar improvement (long‐term)	See comment	See comment	Not estimable	‐	See comment	This outcome was not measured
Participant‐reported scar improvement (short‐term)   N of participants with > 50% improvement in acne scars  Follow‐up: mean 6 months	420 per 1000	773 per 1000   (550 to 1000)	RR 1.84   (1.31 to 2.59)	147  (1 study)	⊕⊕⊕⊝  moderate¹	Munavalli 2013 reported 43% vs 18% improvement with the dermal filler and placebo respectively
Participant satisfaction   N of satisfied participants  Follow‐up: mean 6 months	520 per 1000	848 per 1000   (640 to 1000)	RR 1.63   (1.23 to 2.15)	147  (1 study)	⊕⊕⊕⊝  moderate¹	‐
Participant‐reported adverse events (short‐term)   N of participants with positive adverse events  Follow‐up: mean 4 weeks	20 per 1000	21 per 1000   (2 to 222)	RR 1.03   (0.1 to 11.1)	147  (1 study)	⊕⊕⊝⊝  low²	‐
Investigator‐assessed adverse events (short‐term)   N of participants with positive adverse events  Follow‐up: mean 4 weeks	260 per 1000	174 per 1000   (94 to 330)	RR 0.67   (0.36 to 1.27)	147  (1 study)	⊕⊕⊝⊝  low³	Munavalli 2013 reported comparable incidence of events with dermal filler and placebo
Quality of life	See comment	See comment	Not estimable	‐	See comment	This outcome was not measured
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: 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.  Very low quality: We are very uncertain about the estimate.

Within‐individual studies
Study	Interventions	Summary Outcomes	Comment
Bernstein 2001	One side: Non‐fractional non‐ablative laser (Nd:YAG) Other side: untreated control	Participant‐reported scar improvement (short‐term): In the treatment arm: average 53.6% (range 10% ‐ 90%) Participant‐reported adverse events (short‐term): No side effects were noted.	Bernstein 2001 did not assess the primary outcome ‘Serious adverse effects’ and the secondary outcomes ‘Investigator‐assessed scar improvement’, ‘Participant satisfaction’, ‘Quality of life’, ‘Investigator‐assessed adverse events’ and ‘Post‐procedure down time’

Medical term	Explanation
Ablative laser	A laser that removes thin layers of the skin
Acellular	Tissue that is not made of cells
Atrophic	Loss of tissue
Blackhead comedones	Comedones (primary lesion for acne) that are open at the surface of the skin and filled with excess oil and dead skin cells
Chronic	Persisting for a long time or constantly recurring
Collagen	Extracellular fibres arranged in bundles representing the major component of the deeper layer of the skin
Comedone	Primary lesion diagnostic for acne disorder whether blackhead or whitehead
Dermis/dermal	Deep layer of the skin
Epidermis/epidermal	Superficial layer of the skin
Erythema	Redness
Fraise	A diamond wheel with rough edges used to remove the upper layers of the skin
Hyalinised	Transformation of a substance to a glasslike or transparent state
Hyperpigmentation	Increased pigmentation
Hyperproliferation	Abnormally high rate of proliferation
Hypertrophic	Abnormal enlargement of a part or organ
Intralesional	Injection inside the lesion itself
Keloids	Hard growths as scar tissue grows excessively
Microneedling	The use of small needles to cause punctures in the skin for therapeutic purposes
Milia	A small white or yellowish nodule produced in the skin by the retention of sebaceous secretion
Morphology	Shape
Nodules	Solid elevation in the skin measuring 0.5 cm or more in diameter
Nodulocystic	Having both nodules and cystic lesions
Oedema	An accumulation of an excessive amount of watery fluid in tissues
Papules	Solid elevation in the skin measuring less than < 0.5 cm in diameter
Pilosebaceous unit	Epidermal structure containing both hair follicle and sebaceous gland
Pustules	Small elevation of the skin containing pus
Re‐epithelialize	Restoration of structure of injured tissue
Subcision	A process through which you separate the skin tissue from the deeper scar tissue
Whitehead comedones	Comedones (primary lesion for acne) that stay closed at the surface of the skin when oil and skin cells prevent a clogged hair follicle from opening.

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 Participant‐reported scar improvement (short‐term)	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Investigator‐assessed scar improvement (short‐term)	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3 Participant‐reported adverse events (short‐term)	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3.1 Burning	1	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Investigator‐assessed adverse events (short‐term)	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4.1 Hyperpigmentation	1	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 Participant‐reported scar improvement (short‐term)	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Investigator‐assessed scar improvement (short‐term)	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3 Within‐individual studies		Other data	No numeric data

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 Participant‐reported scar improvement (12 months)	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Investigator‐assessed scar improvement (12 months)	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3 Participant‐reported adverse events (< 4 weeks)	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 Participant‐reported scar improvement (8 months)	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Investigator‐assessed scar improvement (8 months)	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3 Participant‐reported adverse events (< 4 weeks)	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4 Investigator‐assessed adverse events (8 months)	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Methods	This pilot study was a single‐centre (at an urban academic institution), rater‐blinded, split‐face, placebo‐controlled, randomised clinical trial (from 30‐November‐2009 through 27‐July‐2010).
Participants	20 healthy adults (both genders) were enrolled (5 individuals dropped out, 15 completed the treatment and are analysed) Inclusion: "Age of 18 to 70 years, good general health, Global Acne Scarring Classification grades 2 through 4, and at least 2 5 × 5‐cm areas of acne scarring on the face (with at least 3 definable acne scars in each area)". Exclusion: "History of keloids or hypertrophic scars, skin infection or active skin disease other than mild acne in or around the study areas, active systemic or local skin disease likely to alter wound healing, treatment within the last 6 months or pending treatment within the subsequent 6 months with injectable fillers or ablative or non‐ablative laser resurfacing to the study areas, medication with isotretinoin or other oral retinoids within the past 12 months, current treatment with anticoagulants or antithrombotics, or allergy to topical anaesthetics".
Interventions	Intervention: 3 treatment visits were performed at 2‐week intervals (i.e. weeks 1, 3, and 5). At each of these visits, needling was performed on the study treatment area. Comparator: 3 treatment visits were performed at 2‐week intervals (i.e. weeks 1, 3, and 5). At each of these visits, topical anaesthetic was only massaged into the control area.
Outcomes	Improvement of acne scars (6 months), using the quantitative global scarring grading system, developed by Goodman 2006b then a scale of 1 to 4 (1 = < 25% improvement; 2 = 26% ‐ 50%; 3 = 51% ‐ 75%; 4 = > 75%) Participant satisfaction (6 months), using a word scale (very satisfied, satisfied, slightly satisfied, and unsatisfied) Any adverse event (6 months) Timing: at baseline, at 3 months and 6 months
Funding source	Departmental Research Funds, Department of Dermatology, Northwestern University, Chicago, Illinois
Declaration of interest	Dr Alam is employed at Northwestern University. Northwestern University has a clinical trials unit that receives grants from corporate and governmental entities to perform clinical research. Dr Alam has been a consultant for Amway and Leo Pharma, both unrelated to this research. Dr Alam has been principal investigator on studies funded in part by Allergan, Medicis, Bioform, and Ulthera. In all cases, grants and gifts in kind have been provided to Northwestern University and not Dr Alam directly, and Dr Alam has not received any salary support from these grants. Dr Alam receives royalties of less than USD 5000 per year from Elsevier for technical books he has edited.
Notes	USA Approved by the Northwestern University Institutional Review Board The trial was registered as ClinicalTrials.gov Identifier: NCT00974870 Written informed consent was obtained
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Randomly generated 1’s and 2’s were used to assign the leftmost labelled acne scar area on a given participant to the treatment arm (1) or the control arm (2), with the contralateral side then receiving the remaining assignment." Comment: Insufficient data
Allocation concealment (selection bias)	Low risk	Quote: "Randomly generated 1’s and 2’s were sealed separately in opaque envelopes." Comment: Probably done.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Quote: "Given that the control arm was easily distinguished from the treatment arm during treatment, participants and the treating dermatologist were not blinded." Comment: Probably not done.
Blinding of outcome assessment (detection bias)   Investigator‐ assessed	Low risk	Quote: "The two dermatologist raters of photographs did not participate in randomisation or treatment and therefore were able to be blinded". Comment: Probably done.
Blinding of outcome assessment (detection bias)   Participant‐reported	High risk	Quote: "Given that the control arm was easily distinguished from the treatment arm during treatment, participants and the treating dermatologist were not blinded." Comment: No blinding of participants and the outcome assessment is likely to be influenced by lack of blinding.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	20 individuals consented, and 5 dropped out before the first treatment. The remaining 15 completed all treatments and are analysed.
Selective reporting (reporting bias)	Low risk	The study protocol is available and all of the study’s prespecified outcomes that are of interest in the review have been reported in the prespecified way
Other bias	Low risk	The study appears to be free of other sources of bias

Methods	A randomised blinded clinical trial (from 01‐March‐2009 through 01‐October‐2010)
Participants	64 participants (skin type II IV, aged 19 43 years) presenting with moderate to severe atrophic facial acne scars Inclusion: "Any type of moderate to severe facial atrophic acne scar (rolling, boxcar, ice pick)" Exclusion: "Pregnancy, lactation, history of keloid formation, immunosuppressant or isotretinoin use, and filler substance injections or skin resurfacing by dermabrasion or lasers within the preceding 6 months"
Interventions	Intervention: 32 participants received QSwitched 1064nm Nd: YAG (Venus 3, Input Voltage 22v/50Hz, April 2003, Korea) for the entire face by a single operator with an average fluence of 2.5 J/cm, spot size: 7 mm for a total of 4 treatments at 4week intervals Comparator: 32 participants received fractional CO₂ laser (Pixel Alma 10600nm) for the entire face by a single operator using pulse width of 110 msec (ontime), 600 msec (offtime) and pulse duration of 350 μs for a total of 4 treatments at 4week intervals
Outcomes	Improvement of acne scars (6 months), using a quartile grading scale: mild = < 25%; moderate = 25% ‐ 50%; good = 51% ‐ 75%; excellent = 76% to 100% Participant satisfaction (6 months), using satisfaction survey: mild = < 25%; moderate = 25% ‐ 50%; good = 51% ‐ 75%; excellent = 76% to 100% Any adverse event (3 weeks) Timing: 3 and 6 months after the 4th session of treatment
Funding source	No available data
Declaration of interest	Authors have no conflict of interests
Notes	Iran The study was approved by the ethical committee of Isfahan University of Medical Science Written informed consent was obtained from all participants before enrolment
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The patients were divided into two different treatment groups, using a table of random numbers." Comment: Probably done
Allocation concealment (selection bias)	Unclear risk	Insufficient information about the allocation concealment process to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Blinding of outcome assessment (detection bias)   Investigator‐ assessed	Low risk	Quote: "Assessments of the treatment areas using comparative photographs were performed by two blinded dermatologists" Comment: Probably done
Blinding of outcome assessment (detection bias)   Participant‐reported	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Low risk	64 participants completed 4 treatment sessions and all of them were followed up for 6 months after the last session
Selective reporting (reporting bias)	Low risk	The study protocol is not available but it is clear that the published reports include all expected outcomes that are of interest in the review
Other bias	Low risk	The study appears to be free of other sources of bias

Methods	A pilot split‐face study to explore the side‐effect profile and subjective improvement of acne scarring afforded by non‐ablative resurfacing. The treatment side was randomised from participant to participant
Participants	11 women (between the ages of 43 and 64 years and with Fitzpatrick skin types I through III) with acne scarring. Inclusion: women with mild‐to‐moderate acne scarring Exclusion: deep ice‐pick scars or previously treated with laser resurfacing
Interventions	Intervention: A frequency‐doubled Nd:YAG laser was used on 1 cheek at a wavelength of 532nm, a spot diameter of 3 mm, and a pulse duration of 2 ms (VersaPulse‐C, Coherent Medical Lasers, Santa Clara, CA, USA). The laser was used for 2 ‐ 4 sessions with time interval between treatment sessions ranging from 3 to 6 weeks Comparator: The contra‐lateral side was kept as an untreated control.
Outcomes	improvement of acne scars (by observer) (6 months) improvement of acne scars (by participant) (3 months), using a percentage improvement over their pretreatment condition Side effects (1 week) Timing: 1 week, 3 months, and 6 months
Funding source	No available data
Declaration of interest	No available data
Notes	USA
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Subjects were randomised to receive treatment on one cheek, while the contra‐lateral side was kept as an untreated control." Comment: Insufficient data
Allocation concealment (selection bias)	Unclear risk	Insufficient information about the sequence generation process to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Quote: "Subjects with acne scarring were randomized to receive treatment on one cheek, while the contra‐lateral side was kept as an untreated control." Comment: Given that the control arm was kept untreated, participants and the treating dermatologist were not blinded
Blinding of outcome assessment (detection bias)   Investigator‐ assessed	Low risk	Quote: "An observer blinded as to which side received treatment attempted to identify the treated side 6 weeks following the final treatment." Comment: Probably done
Blinding of outcome assessment (detection bias)   Participant‐reported	High risk	Quote: "Subjects with acne scarring were randomized to receive treatment on one cheek, while the contra‐lateral side was kept as an untreated control." Comment: No blinding of participants and the outcome assessment is likely to be influenced by lack of blinding
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All participants completed the study and were analysed
Selective reporting (reporting bias)	Low risk	The study protocol is not available but it is clear that the published reports include all expected outcomes that are of interest in the review
Other bias	Low risk	The study appears to be free of other sources of bias

Methods	A randomised, controlled, single‐blinded study (from 01‐September‐2012 through 01‐March‐2013)
Participants	40 participants with atrophic acne scars Inclusion: Healthy, with no dermatologic or any other disorder, except for acne scars Exclusion: Patients who had received acne scar treatment during the prior 6 months, pregnant or lactating
Interventions	Intervention: Group A (n = 20) received the 1550 nm Er:Glass fractional laser (FXL) with a Sellas apparatus (Dinona, Daejeon, Korea) at 4‐week intervals. FXL was performed on the basis of 500 MTZ/cm2 and 15–20 mJ/MTZ energy level Comparator; Group B (n = 20) received the fractional radiofrequency microneedle (FRM) utilising the Inskin device (Einsmed, Seongnam, Korea) at an intensity of 40 – 60 W (maximum power 80 W, 2‐mm‐depth needle with 36 microneedle electrode tip) and 0.1 ms radiofrequency conduction time in the continuous wave mode.
Outcomes	Improvement of acne scars (8 weeks), using a 5‐point scale (1 = no change, 0%; 2 = slight, 0% – 25%; 3 = average, 26% – 50%; 4 = good, 51% – 75%; 5 = excellent, 76% – 100%) Participant satisfaction (8 weeks), using 5‐point scale of self‐assessed participant satisfaction (1 = no change, 0%; 2 = slight, 0% – 25%; 3 = average, 26% – 50%; 4 = good, 51% – 75%; 5 = excellent, 76% – 100%) Side effects (8 weeks) Timing: week 4, week 8, week 12, and week 20
Funding source	No available data
Declaration of interest	No available data
Notes	Korea Approved by the Institutional Review Board, before enrolment. All participants provided written informed consent.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "The patients were randomly and equally distributed into either group A (FXL) or group B (FRM)." Comment: Insufficient data
Allocation concealment (selection bias)	Unclear risk	Insufficient information about the sequence generation process to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Quote: "single‐blinded study" Comment: Probably not done
Blinding of outcome assessment (detection bias)   Investigator‐ assessed	Low risk	Quote: "Two independent dermatologists not involved in the study examined the serial photos and rated the overall improvements compared to baseline." Comment: Probably done
Blinding of outcome assessment (detection bias)   Participant‐reported	High risk	Quote: "single‐blinded study" Comment: No blinding of participants and the outcome assessment is likely to be influenced by lack of blinding
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All 40 participants completed the study and were analysed
Selective reporting (reporting bias)	Low risk	The study protocol is not available but it is clear that the published reports include all expected outcomes that are of interest in the review
Other bias	Low risk	The study appears to be free of other sources of bias

Methods	A randomised, split‐face, evaluator‐blinded study
Participants	8 men (mean age 21.3 years, range 20 – 23; Fitzpatrick skin type IV), with mild‐to‐severe atrophic acne scars Exclusion: "Patients who had undergone concomitant treatments including skin resurfacing procedures, chemical reconstruction of skin scars (CROSS) using trichloroacetic acid, collagen induction therapy using a micro‐needle therapy system, non‐ablative fractional photothermolysis system and CO₂ fractional laser treatments within the previous 6 months. Patients with keloids, pregnancy, immunosuppression and history of isotretinoin."
Interventions	Intervention: 1 side of each participant’s face was treated with a single session of non‐ablative 1550‐nm erbium‐doped fractional photothermolysis systems (FPS) using the Fraxel SR1500 (Reliant Technologies, Mountain View, CA, USA) Comparator: The other side of the face was treated with a single session of CO₂ fractional laser systems (CO₂ FS) using the 10600‐nm Ultrapulse Encore laser (Lumenis Inc., Santa Clara, CA, USA)
Outcomes	Improvement of acne scars (3 months), using quartile grading scale for evaluations: grade 1 = < 25%, minimal to no improvement; grade 2 = 26% ‐ 50%, moderate improvement; grade 3 = 51% ‐ 75%, marked improvement; grade 4 = > 75%, near‐total improvement Participant satisfaction (3 months), using the following scale: very satisfied, satisfied, slightly satisfied and unsatisfied Side effects (3 months) Timing: at baseline and 3 months after the treatment
Funding source	No available data
Declaration of interest	Nothing to be declared
Notes	Korea Approved by the institutional review board of Bundang CHA General Hospital, Pochon CHA University, College of Medicine, Seongnam
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "A randomised, split‐face, evaluator‐blinded study" Comment: Insufficient data
Allocation concealment (selection bias)	Unclear risk	Insufficient information about the sequence generation process to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Blinding of outcome assessment (detection bias)   Investigator‐ assessed	Low risk	Quote: "Objective clinical assessments were accomplished separately for each side of the face by two blinded dermatologists in non‐chronological order" Comment: Probably done
Blinding of outcome assessment (detection bias)   Participant‐reported	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All participants completed treatment sessions and all were analysed
Selective reporting (reporting bias)	Low risk	The study protocol is not available but it is clear that the published reports include all expected outcomes that are of interest in the review
Other bias	Low risk	The study appears to be free of other sources of bias

Methods	A single, blind, placebo‐controlled, randomised comparative clinical study.
Participants	58 women, ranging in age from 18 ‐ 41 years, with atrophic acne scars Exclusion: "Hypertrophic, depressed‐fibrotic, and ice‐pick scars or keloids and those with severe active inflammatory acne lesions, pregnancy, lactation, a history of isotretinoin ingestion in the preceding 6 months, concomitant use of an oral contraceptive or any hormone preparation, the presence of active herpes infection, concomitant serious systemic or skin disease, depression and antidepressive therapy, and a history of hypertrophic scar or keloid".
Interventions	23 participants received biweekly serial glycolic acid (GA) peels in a gradually increasing manner in time (2 ‐ 5 mins) and concentration (20%, 35%, 50%, 70% GA) 20 participants were instructed to use 15% GA home‐care product twice daily for a period of 24 weeks 15 participants received a base cream for 24 weeks
Outcomes	Improvement of acne scars (6 months), using a 10‐point scale as follows: 0 = No scar; 1 = very mild; 2 ‐ 3 = mild; 4 ‐ 7 = moderate; 8 ‐ 9 = severe; 10 = very severe Side effects (6 months) Timing: at baseline, at 4‐week intervals, and at 6 months
Funding source	No available data
Declaration of interest	No available data
Notes	Turkey Participants gave informed consent before enrolment
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Patients were randomly divided into three groups." Comment: Insufficient data
Allocation concealment (selection bias)	Unclear risk	Insufficient information about the sequence generation process to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Quote: " A single, blind, ...." Comment: No blinding of study participants and personnel
Blinding of outcome assessment (detection bias)   Investigator‐ assessed	Low risk	Quote: "Clinical assessments were conducted by an independent blind investigator" Comment: Probably done
Blinding of outcome assessment (detection bias)   Participant‐reported	High risk	Quote: " A single, blind, ...." Comment: No blinding of participants and the outcome assessment is likely to be influenced by lack of blinding
Incomplete outcome data (attrition bias)   All outcomes	High risk	48/58 participants (16 in group A, 18 in group B, 14 in group C) completed the study. 7 women from group A withdrew because they were unable to tolerate concentrations > 20% or 35% and contact times > 2 mins. 3 women (2 from group B and 1 from group C) were lost to follow‐up
Selective reporting (reporting bias)	Low risk	The study protocol is not available but it is clear that the published reports include all expected outcomes that are of interest in the review
Other bias	Low risk	The study appears to be free of other sources of bias

Methods	A randomised splitface clinical trial
Participants	42 Iranian patients aged 18 – 55 years Inclusion: "Fitzpatrick skin types III to IV and moderate to severe atrophic acne scars on both cheeks" Exclusion: "Pregnancy, lactation, active inflammatory acne, Immunocompetence, history of deep chemical peeling or filler injection in the previous 6 months, history of hypertrophic scars and keloids, use of isotretinoin in the previous 6 months, allergy to anaesthesia, active infection in the treatment area, pre‐malignant or malignant lesions in the treatment area, bleeding tendencies, and history of herpes simplex or herpes zoster infection on the face".
Interventions	Intervention: 1 side of the participant's face was treated using the 10600nm fractional CO₂ laser alone (M×7000/Stamp Type, Daeshin, South Korea) Comparator: The other side of the face was treated with the same fractional CO₂ laser plus punch elevation (2.5 – 3 mm biopsy disposable punches)
Outcomes	Improvement of acne scars (4 months), using a grading scale as follows: 1 = < 25% (minimal) improvement; 2 = 25% – 50% (moderate) improvement; 3 = 51% – 75% (good) improvement; 4 = > 75% (excellent) improvement Participant satisfaction (4 months), using a VAS; (rating of 0 was no satisfaction, and a rating of 10 was the best possible satisfaction) Side effects (4 months) Timing: 1 and 4 months after the second treatment session
Funding source	Skin Diseases and Leishmaniasis Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
Declaration of interest	Nothing to be declared
Notes	Iran The Isfahan University of Medical Sciences Ethical Committee, Isfahan, Iran, approved the study protocol. The trial was registered in the Iranian Registry of Clinical Trials: IRCT2014080218647N1. Note: trial was registered after the start of the trial Participants signed an informed consent form for participation in the study.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Using random allocation software" Comment: Probably done
Allocation concealment (selection bias)	Low risk	Quote: "The assignment sequence was concealed in opaque envelopes." Comment: Probably done
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Quote: "One side received fractional CO laser treatment and the other received one session of punch elevation combined with two sessions of laser fractional CO laser treatment" Comment: Probably not done. Given that the control arm was easily distinguished from the treatment arm during treatment, participants and the treating dermatologist were not blinded
Blinding of outcome assessment (detection bias)   Investigator‐ assessed	Low risk	Quote: "Two dermatologists blinded to treatment side evaluated clinical improvement of acne scars." Comment: Probably done
Blinding of outcome assessment (detection bias)   Participant‐reported	High risk	Quote: "One side received fractional CO laser treatment and the other received one session of punch elevation combined with two sessions of laser fractional CO laser treatment" Comment: No blinding of participants and the outcome assessment is likely to be influenced by lack of blinding
Incomplete outcome data (attrition bias)   All outcomes	Low risk	42 participants (100%) completed the 2 treatment sessions, and all were followed up for 4 months after the last treatment session
Selective reporting (reporting bias)	Low risk	The study protocol is available and all of the study's prespecified outcomes that are of interest in the review have been reported in the prespecified way
Other bias	Low risk	The study appears to be free of other sources of bias

Methods	A split‐face randomised clinical trial with blinded on‐site response evaluations in a hospital setting Duration of the trial is 5 months (treatment duration: 2 months and follow‐up duration: 3 months) (from 01‐November‐2007 through 01‐Jun‐2008)
Participants	10 participants were enrolled Inclusion: "age 18 – 60 years, white, with skin type I – IV, duration of atrophic acne scars 1 year or more, scarring manifested such that 2 areas of similar size and appearance were available in contralateral anatomical regions (cheeks, temporal regions, forehead, back), and willingness and ability to comply with the requirements of the protocol". Exclusion: "a tendency to produce hypertrophic scars or keloids, previous treatment of the study areas with dermabrasion, chemical peeling, filler, laser treatment or intense pulsed light, photosensitivity, pregnancy or lactation, current treatment with anticoagulative medication, treatment with oral retinoid drugs within the past 6 months, pigmentation after recent exposure to the sun or use of a solarium, and potential inability to follow the treatment protocol".
Interventions	Intervention: An area on the site (A) received 3 active erbium:glass rod laser treatment sessions at 4‐week intervals using a StarLux‐300 with a Lux 1,540‐nm fractional handpiece (Palomar Medical Technologies, Burlington, MA). The same physician performed all treatments (K.M.) Comparator: The area on the contralateral site (B) received no treatment
Outcomes	Improvement in scar texture (12 weeks), using a numerical scale ranging from 0 to 10 (0 even skin texture without scarring, 5 moderate scarring, and 10 worst possible scarring)  Side effects (12 weeks)  Participant satisfaction (12 weeks), as follows: 0 no satisfaction, 10 best imaginable satisfaction  Overall acne scar appearance (12 weeks), using a 5‐point scale (worse, not improved, slightly improved, moderately improved, significantly improved) Timing: at week 4 and week 12 after the final treatment
Funding source	MediTech, Scandinavia, Denmark provided on loan a StarLux 1540 nm fractionated handpiece, had no role in the design or conduct of the study, in the collection, analysis and interpretation of the data, or in the preparation, review and approval of the manuscript
Declaration of interest	Dr. Haedersdal received a research grant and a StarLux 1540 nm fractionated handpiece on loan from MediTech, Scandinavia, Denmark, to support this study. The authors have no relevant personal financial interest in this article
Notes	Denmark Written informed consent was obtained from all study participants The study was approved by the Committee on Biomedical Research Ethics of Copenhagen and Frederiksberg
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Before treatment two contralateral areas of similar size and appearance were outlined and marked “A” and “B”. The areas were randomised to treatment or no treatment. Randomization and allocation was carried out by the patient selecting one of two opaque sealed envelopes containing a card with the treatment code (“laser treatment” of site A and “no treatment” of site B)." Comment: Probably done
Allocation concealment (selection bias)	Low risk	Quote: "By the patient selecting one of two opaque sealed envelopes containing a card with the treatment code (“laser treatment” of site A and “no treatment” of site B)." Comment: Probably done
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Quote: "The areas were randomized to treatment or no treatment." Comment: Probably not done. Given that the control arm was easily distinguished from the treatment arm during treatment, participants and the treating dermatologist were not blinded
Blinding of outcome assessment (detection bias)   Investigator‐ assessed	Low risk	Quote: "...with blinded on‐site response evaluations" "This treating investigator was not included in the assessment of patients before and after treatment. Moreover, patients were instructed not to inform the evaluating physician of which area had been treated and which not treated." Comment: Probably done
Blinding of outcome assessment (detection bias)   Participant‐reported	High risk	Quote: "The areas were randomized to treatment or no treatment." Comment: No blinding of participants and the outcome assessment is likely to be influenced by lack of blinding
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All participants completed the allocated treatments and were included in the analyses
Selective reporting (reporting bias)	Low risk	The study protocol is not available but it is clear that the published reports include all expected outcomes that are of interest in the review
Other bias	Low risk	The study appears to be free of other sources of bias

Methods	A split‐face randomised clinical trial Duration of study: 8 months (treatment duration: 8 ‐ 10 weeks and follow‐up duration: 6 months) (from 01‐December‐2909 through 01‐November‐2010)
Participants	13 healthy volunteers (6 men and 7 women). They had moderate to severe atrophic acne scars (Icepick, rolling and boxcar types). Inclusion: age of 18 – 60 years, white, with skin types I – III, duration of atrophic acne scars 1 year or more, willingness and ability to comply with the requirements of the protocol. Exclusion: History of hypertrophic scars or keloids, "previous treatment with ablative lasers of study areas, photosensitivity, pregnancy or lactation, current anticoagulative medication, oral retinoid drugs within the past 6 months, pigmentation after recent exposure to sun or solarium, and patients not considered to be able to follow the treatment protocol"
Interventions	Intervention: An area ((9 – 30 cm²) on site A received 3 laser treatments at 4‐ to 5‐week intervals. The laser system was a CO₂ laser (MedArt 610) equipped with a scanner (MedArt 458) developed specifically for fractional treatments (MedArt, Hvidovre, Denmark) Comparator: A similar area on site B received no treatment
Outcomes	Improvement of scars texture and depth using a numerical scale ranging from 0 (even skin texture without scarring/atrophy) to 10 (worst possible scarring/atrophy). Time frame: 1, 3, and 6 months after the final treatment Participant satisfaction and participant self assessments of scar texture improvement using a numerical scale from 0 (unsatisfied/even skin texture without scarring) to 10 (maximal satisfaction/worst possible scarring). Time frame: 1, 3, and 6 months after the final treatment Pain assessed using a numerical scale ranging from 0 (no pain) to 10 (worst imaginable pain). Time frame: immediately after treatment Adverse effects using a numerical scale ranging from 0 to 3 (0 = absent; 1 = mild; 2 = moderate; 3 = severe). Time frame: at 2 or 3 days after first treatment and 1, 3, and 6 months after the final treatment
Funding source	A grant by MedArt A/S, Hvidovre, Denmark
Declaration of interest	Nothing to be declared
Notes	Denmark The study was approved by The Ethical Committee of Copenhagen and Frederiksberg Written informed consent was obtained from all study participants
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Two facial areas of similar size and appearance were outlined, marked ‘‘A’’ and ‘‘B’’ and randomised to treatment versus no treatment. Randomisation by patients drawing lots between opaque sealed envelopes, containing cards with treatment code (‘‘laser treatment’’ of site A and ‘‘no treatment’’ of site B or vice versa)." Comment: Probably done
Allocation concealment (selection bias)	Low risk	Quote: "Patients drawing lots between opaque sealed envelopes, containing cards with treatment code" Comment: Probably done
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Quote: "Two facial areas ...... were outlined, marked ‘‘A’’ and ‘‘B’’ and randomized to treatment  versus no treatment" Comment: Probably not done. Given that the control arm was easily distinguished from the treatment arm during treatment, participants and the treating dermatologist were not blinded
Blinding of outcome assessment (detection bias)   Investigator‐ assessed	Low risk	Quote: "Treatment response and adverse effects were evaluated by clinical on‐site evaluations by three blinded physicians. The treating investigator was not included in preoperative or post‐treatment assessments of patients. Moreover, patients were instructed not to inform the evaluating physicians of which area was treated or untreated." Comment: Probably done
Blinding of outcome assessment (detection bias)   Participant‐reported	High risk	Quote: "Two facial areas ...... were outlined, marked ‘‘A’’ and ‘‘B’’ and randomized to treatment  versus no treatment" Comment: No blinding of participants and the outcome assessment is likely to be influenced by lack of blinding
Incomplete outcome data (attrition bias)   All outcomes	Low risk	13 participants were included in the study and received the allocated treatments. 12 completed the study (1 participant withdrew before the final evaluation and was not included in the analysis 6 months postoperatively)
Selective reporting (reporting bias)	Low risk	The study protocol is not available but it is clear that the published reports include all expected outcomes that are of interest in the review
Other bias	Low risk	The study appears to be free of other sources of bias

Methods	A double‐blind, randomised controlled trial conducted at 10 investigative centres across the USA
Participants	Potential 147 participants with acne scars (average age 44 years, 39% male) Inclusion: 18 years of age or older, at least 4 moderate to severe, atrophic, distensible acne scars of the cheek, willingness to withdraw any confounder therapies Exclusion: "Pregnancy or breastfeeding, prohibited therapies within a time frame which could obscure the results of the study, inflammatory skin diseases including acne (> 3 inflammatory lesions per cheek), history of granulomatous or connective tissue disease, hypertrophic scarring, predominance of acne scars other than rolling scars, allergy to beef, beef products or any components of the study materials"
Interventions	Intervention: 97 participants received injection with PMMA suspended in bovine collagen (ArteFill, Suneva Medical Inc, Santa Barbara, CA) in a 2:1 fashion Comparator: 50 participants received saline injections in a 2:1 fashion. Control injections were performed with preservative‐free saline in a similar manner
Outcomes	Improvement of acne scars (6 months) using Physician and Subject Global Aesthetic Improvement Scales Participant satisfaction (6 months) using a scale as follows: 6 = very satisfied; 5 = satisfied; 4 = somewhat satisfied; 3 = somewhat dissatisfied; 2 = dissatisfied; 1 = very dissatisfied Side effects (6 months)
Funding source	Suneva Medical Inc
Declaration of interest	Nothing to be declared
Notes	USA The trial was registered as ClinicalTrials.gov Identifier: NCT01559922 Before screening, participants underwent an informed consent process and signed an Institutional Review Board approved informed consent form
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Subjects were randomised to receive either PMMA‐collagen or saline injections in a 2:1 fashion respectively, using a randomisation system that controlled for gender and Fitzpatrick skin type. Treatment centres had no access to randomisation data." Comment: Probably done
Allocation concealment (selection bias)	Unclear risk	Insufficient information about the allocation concealment process to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "A double‐blind trial. Control injections were performed with preservative‐free saline in a similar manner." Comment: Probably done
Blinding of outcome assessment (detection bias)   Investigator‐ assessed	Low risk	Quote: "A blinded investigator who performed subject evaluations only without knowledge of the treatment assignment." Comment: Probably done
Blinding of outcome assessment (detection bias)   Participant‐reported	Low risk	Qoute: "A double‐blind trial. Control injections were performed with preservative‐free saline in a similar manner." Comment: Probably done
Incomplete outcome data (attrition bias)   All outcomes	Low risk	199 participants were screened, 175 were randomised, and 147 received at least 1 injection and were included in the primary analysis
Selective reporting (reporting bias)	Low risk	The study protocol is available and all of the study’s prespecified outcomes that are of interest in the review have been reported in the prespecified way
Other bias	Low risk	The study appears to be free of other sources of bias

PERMALINK

Interventions for acne scars

Rania Abdel Hay

Khalid Shalaby

Hesham Zaher

Vanessa Hafez

Ching‐Chi Chi

Sandra Dimitri

Ashraf F Nabhan

Alison M Layton

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Acne and its prevalence

Acne scars: aetiology, pathology, and prevalence

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Timing of outcomes

Search methods for identification of studies

Electronic searches

Trials registers

Searching other resources

Adverse effects

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

(1) Sequence generation (checking for possible selection bias)

(2) Allocation concealment (checking for possible selection bias)

(3) Blinding (checking for possible performance and detection bias)

(4) Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)

(5) Selective reporting bias

(6) Other sources of bias

(7) Overall risk of bias

Measures of treatment effect

Dichotomous data

Continuous data

Unit of analysis issues

Dealing with missing data

1. Contacted authors.

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

'Summary of findings' tables

Summary of research gaps

2. Summary of research gaps.

Results

Description of studies

Results of the search

1.

Included studies

Design

Sample sizes

Setting

Participants

Interventions

Outcomes

Funding source

Studies awaiting classification

Methods	A split‐face trial conducted in patients with acne scars. Facial halves were randomly assigned to receive either treatment
Participants	20 participants (6 women and 14 men) aged 22 – 37 years with mild to moderate acne scars and Fitzpatrick Skin Types IV and V. The participants were grouped as rolling type group and icepick type group according to the predominant scar type Exclusion: "Pregnancy or lactation, history of hypertrophic scarring or keloid formation, history of active or recurrent herpes simplex, presence of infected skin lesions, refusal to give signed informed consent, and use of isotretinoin within 6 months before treatment"
Interventions	Intervention: 1 facial half received treatment with 1550 nm Er:Glass fractional laser (Mosaic1, Lutronic Corporation, Gyeonggi, Korea). The 1550 nm Er:Glass fractional laser applied pulse energy of 30 – 32 mJ and density of 300 – 350 spots/cm2 using a 6 mm handpiece tip 3 times during a 6‐week interval Comparator: The contralateral half received CROSS method using 100% TCA. The CROSS method repeated 2 times every 12 weeks
Outcomes	Improvement of acne scars (12 weeks), using a quartile scale (0 = no improvement; 1 = 1% – 25% improvement; 2 = 26% – 50% improvement; 3 = 51% – 75% improvement; 4 = > 75% improvement) Participant satisfaction (12 weeks) using the same quartile scale Side effects (12 weeks), including severity of the pain on a 10‐point scale (0 – 9), erythema lasting days, and overall down time Timing: at baseline, at week 6, week 12, week 18, week 24,and 12 weeks after the final treatment
Funding source	Yonsei University Research Fund of 2007
Declaration of interest	No available data
Notes	Korea Informed consent was obtained from all participants Study approved by the hospital’s medical ethnic committee
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Facial halves were randomly assigned" Comment: Insufficient data
Allocation concealment (selection bias)	Unclear risk	Insufficient information about the allocation concealment process to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Quote: "One side was treated with the 1,550nm Er:Glass fractional laser .....And the other side was treated with CROSS method " Comment: Probably not done. Given that the control arm was easily distinguished from the treatment arm during treatment, participants and the treating dermatologist were not blinded
Blinding of outcome assessment (detection bias)   Investigator‐ assessed	Low risk	Quote: "Patient photographs were reviewed by 2 independent physicians who were blinded to the study." Comment: Probably done
Blinding of outcome assessment (detection bias)   Participant‐reported	High risk	Quote: "One side was treated with the 1,550nm Er:Glass fractional laser .....And the other side was treated with CROSS method " Comment: No blinding of participants and the outcome assessment is likely to be influenced by lack of blinding
Incomplete outcome data (attrition bias)   All outcomes	Low risk	18/20 participants completed the trial and were included in the data. 1 participant dropped out because of slight discomfort of the treatment such as pain and erythema, and the other dropped out because of scheduling conflicts
Selective reporting (reporting bias)	Low risk	The study protocol is not available but it is clear that the published reports include all expected outcomes that are of interest in the review
Other bias	Low risk	The study appears to be free of other sources of bias

Methods	A 14‐week, single‐blinded, randomised, comparative split‐face study of a 585‐nm PDL and a 1064‐nm long‐pulsed Nd:YAG laser for the treatment of atrophic facial acne scars
Participants	18 participants (10 men, 8 women) Inclusion: "Age of at least 18 years and a diagnosis of mild to moderate atrophic acne scarring" Exclusion: "Known photosensitivity, pregnancy or lactation, a history of hypertrophic or keloidal scarring, the use of isotretinoin, a history of facial laser treatment or surgical procedure within 6 months of study enrolment, and patients with a medical condition that might have influenced the wound healing process"
Interventions	Intervention: 1 side of the face was treated with non‐overlapping pulses of 585‐nm PDL (Cynergy, Cynosure Inc, Westford, MA) at a sub‐purpuric fluence of 10 to 11 J/cm2 and a 40‐ms pulse duration using a 7‐mm hand piece. All participants received 4 treatment sessions at 2‐week intervals Comparator: At the same session, the contralateral side was treated with a 1064‐nm long‐pulsed Nd:YAG laser (Cynergy) at a fluence of 50 to 70 J/cm² and a 50‐ to 100‐ms pulse duration using a 7‐mm spot size All participants received 4 treatment sessions at 2‐week intervals
Outcomes	Improvement of acne scars (14 weeks), using percentage improvements (0% ‐ 100%) versus baseline Patient satisfaction (14 weeks), using a scale of 0 (neutral) to 10 (highly satisfied) Side effects (14 weeks) Timing: at week 2, week 4, week 6, week 10, week 14
Funding source	No available data
Declaration of interest	No available data
Notes	Korea Study approved by the Institutional Review Board of Seoul National University Hospital Written informed consent was obtained from all participants before enrolment
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "At treatment sessions, according to baseline randomization, affected areas on one side of the face were treated with one type of laser. Similarly, at these sessions, contralateral sides were treated with the other laser type." Comment: Insufficient data
Allocation concealment (selection bias)	Unclear risk	Insufficient information about the allocation concealment process to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Quote: "single blinded" Comment: Probably not done
Blinding of outcome assessment (detection bias)   Investigator‐ assessed	Low risk	Quote: "Acne scar improvements were quantified by assessing the degrees of improvement by two masked dermatologists." Comment: Probably done
Blinding of outcome assessment (detection bias)   Participant‐reported	High risk	Quote: "single blinded" Comment: No blinding of participants and the outcome assessment is likely to be influenced by lack of blinding
Incomplete outcome data (attrition bias)   All outcomes	Low risk	18 participants enrolled in this study and completed the 14‐week study
Selective reporting (reporting bias)	Low risk	The study protocol is not available but it is clear that the published reports include all expected outcomes that are of interest in the review
Other bias	Low risk	The study appears to be free of other sources of bias

Methods	A split‐face randomised trial. Each participant’s entire face was then treated with an ablative CO₂ fractional laser (Q‐ray, Diosis Inc., Seoul, Korea) using a pulse energy of 25 mJ per fixed 150‐mm‐diameter microbeam and a density of 400MTZ/cm²
Participants	14 Korean participants (Fitzpatrick skin types III – V) with moderate to severe acne scars. The mean participant age was 28.1 (range 21 – 38), and the sample included 4 women and 10 men Exclusion: "History of keloid scar formation, any active inflammation, oral isotretinoin use within the preceding 6 months, diabetes, collagen vascular disease, or ablative or non‐ablative laser skin resurfacing within the preceding 12 months, pregnant or lactating women. Formation, any active inflammation, oral isotretinoin general vascular disease, or ablative or non‐ablative laser skin resurfacing within the preceding 12 months"
Interventions	Intervention: After ablative CO₂ laser resurfacing, 1 facial half received intradermal treatment with 0.3 mL autologous PRP at 20 individual sites. Sites were spaced at 1.5 to 2 cm intervals. 1 month after the initial treatment, all participants underwent 1 additional treatment session with the same therapeutic protocol. Comparator: After ablative CO₂ laser resurfacing, the other facial half received intradermal injection with 0.3 ml normal saline at 20 individual sites spaced at 1.5 to 2 cm intervals. 1 month after the initial treatment, all participants underwent 1 additional treatment session with the same therapeutic protocol
Outcomes	Improvement of acne scars using a quartile grading scale (0 = no improvement; 1 = < 25% improvement; 2 = 25% – 50% improvement; 3 = 51% – 75% improvement; 4 = > 75% improvement). Timing: baseline and 4 months after the last treatment Side effects: Erythema and oedema were graded on a 5‐point scale (0 = none; 1 = trace; 2 = mild; 3 = moderate; 4 = severe).Timing: days 0, 2, 4, 6, 8, 15, and 30
Funding source	Chung‐Ang University
Declaration of interest	The authors have indicated no significant interest with commercial supporters
Notes	South Korea
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Facial halves were randomly assigned" Comment: Insufficient data
Allocation concealment (selection bias)	Unclear risk	Insufficient information about the allocation concealment process to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Blinding of outcome assessment (detection bias)   Investigator‐ assessed	Low risk	Quote: "Two different blinded dermatologists evaluated overall clinical improvement, comparing digital photographs taken before treatment (baseline) and 4 months after the last treatment" Comment: Probably done
Blinding of outcome assessment (detection bias)   Participant‐reported	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All 14 participants completed the study
Selective reporting (reporting bias)	Low risk	The study protocol is not available but it is clear that the published reports include all expected outcomes that are of interest in the review
Other bias	Low risk	The study appears to be free of other sources of bias

Methods	A prospective, parallel, randomised controlled, hospital‐based study. Duration of the study from start until the end of follow‐up was 10 months (from October‐2008 through August‐2009)
Participants	30 participants (16 men, 14 women) with different types of atrophic acne scars were enrolled. The mean duration of acne scars was 4.8 years (range 2 – 10 years) Exclusion: "Systemic retinoids or immunosuppressive drug intake during the previous 6 months, coagulation defects or blood diseases, evidence or history of keloid scars, pregnancy or lactation, and unrealistic expectations"
Interventions	Intervention (n = 15): Percutaneous collagen induction, plus Dermaroller Comparator (n = 15): full‐concentration (100%) TCA, CROSS technique
Outcomes	Improvement in acne scars (investigator and participant): (week 4 post‐treatment) using a quartile grading scale (0 = slight improvement, < 25%; 1 = moderate improvement, 25% – 49%; 2 = significant improvement, 50% – 74%; 3 = marked improvement, > 75%) Side effects (week 4 post‐treatment) Timing: baseline, week 4, week 8, week 12, week 16
Funding source	No funding source
Declaration of interest	Nothing to be declared
Notes	Egypt The Dermatology Research Ethical Committee, Faculty of Medicine, Cairo University approved the study All participants provided written informed consent
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Computer‐generated random sequence prepared by a statistician" Comment: Probably done
Allocation concealment (selection bias)	Low risk	Quote: "Sequentially numbered, sealed, opaque envelopes, and kept by a nurse not involved in the study" Comment: Probably done
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Quote: "group 1 underwent four sessions ......of PCI, and group 2 underwent four sessions ......of 100% TCA CROSS" Comment: Probably not done. Given that the control arm was easily distinguished from the treatment arm during treatment, participants and the treating dermatologist were not blinded
Blinding of outcome assessment (detection bias)   Investigator‐ assessed	Low risk	Quote: "The assessor was blinded to the intervention used." Comment: Probably done
Blinding of outcome assessment (detection bias)   Participant‐reported	High risk	Quote: "group 1 underwent four sessions ......of PCI, and group 2 underwent four sessions ......of 100% TCA CROSS" Comment: No blinding of participants and the outcome assessment is likely to be influenced by lack of blinding
Incomplete outcome data (attrition bias)   All outcomes	High risk	Of the thirty participants enrolled, twenty‐seven of completed the course of treatment. Three participants in the TCA‐100% CROSS technique group received only 1 session. Only twelve participants were included in the analysis.
Selective reporting (reporting bias)	Low risk	The study protocol was obtained by contacting the investigators. The published reports include all expected outcomes that are of interest in the review
Other bias	Low risk	The study appears to be free of other sources of bias

Methods	A parallel, randomised, controlled, single‐blinded, hospital‐based study. Duration of the study from start until the end of follow‐up 13 months (from May‐2009 through June‐2010)
Participants	24 enrolled participants and 20 completed the study (12 women, 8 men, aged from 22 ‐ 40 years) with post‐acne atrophic scars Exclusion: "pregnancy or lactation, history of hypertrophic scarring or keloid formation, history of active or recurrent herpes simplex, presence of infected skin lesions, diabetes, neuromuscular disease, bleeding disorder, collagen vascular disease, acute or chronic corticosteroid or anticoagulant treatment, presence of skin cancers, warts, solar keratoses, refusal to give signed informed consent, and use of isotretinoin within 6 months before treatment"
Interventions	Intervention (n = 12): 1 session of deep peeling using a non‐hydro‐alcoholic solution of oil phenol in 60% concentration formula with few drops of croton oil/litre (lip and eyelid formula, Skintech Inc., Spain) Comparator (n = 12): 4 sessions (6 weeks apart) of percutaneous collagen induction, using the Dermaroller (model MF8; Horst Liebl CEO, Fresenheim, France), combined with TCA 20% in the same session
Outcomes	Improvement in acne scars (investigator and participant) (8 months), using a quartile grading scale (0 = minimal improvement < 25%; 1 = mild improvement 25% – 50%; 2 = moderate improvement 51% – 75%; 3 = significant improvement > 75% improvement) Side effects (investigator) (8 months) Timing: at baseline, week 6, week 12, week 18, week 32
Funding source	No funding source
Declaration of interest	Nothing to be declared
Notes	Egypt Study approved by the Dermatology Research Ethical Committee, Faculty of Medicine, Alexandria University Written and signed informed consent was obtained from all participants
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Computer‐generated random sequence prepared by a statistician" Comment: Probably done
Allocation concealment (selection bias)	Low risk	Quote: "Sequentially numbered, sealed, opaque envelopes, and kept by a nurse not involved in the study" Comment: Probably done
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Quote: "group 1 was subjected to one session of deep peeling using phenol, and group 2 was subjected to four sessions of PCI combined with TCA 20%." Comment: Probably not done. Given that the control arm was easily distinguished from the treatment arm during treatment, participants and the treating dermatologist were not blinded
Blinding of outcome assessment (detection bias)   Investigator‐ assessed	Low risk	Quote: "The assessor was blinded to the intervention used." Comment: Probably done
Blinding of outcome assessment (detection bias)   Participant‐reported	High risk	Quote: "group 1 was subjected to one session of deep peeling using phenol, and group 2 was subjected to four sessions of PCI combined with TCA 20%." Comment: No blinding of participants and the outcome assessment is likely to be influenced by lack of blinding
Incomplete outcome data (attrition bias)   All outcomes	Low risk	24 participants were enrolled. 4 (2 in each group) did not receive the intended treatment. Only 20 participants were analysed
Selective reporting (reporting bias)	Low risk	The study protocol was obtained by contacting the investigators. The published reports include all expected outcomes that are of interest in the review
Other bias	Low risk	The study appears to be free of other sources of bias

Methods	A randomised multiple‐arm single‐blinded, hospital‐based study. Duration of the study from start until the end of follow‐up 17 months (from July‐2009 through December‐2010)
Participants	39 participants with Skin Phototype III and IV with atrophic acne scars were enrolled Exclusion: "pregnancy, lactation, diabetes, history of keloids or hypertrophic scars, active infection, cancers, receiving treatment for more than 6 months"
Interventions	Trial arm 1 (n = 13): 6 sessions (4 weeks apart) of percutaneous collagen induction with 20% TCA Trial arm 2 (n = 13): 6 sessions (4 weeks apart) of 1540 nm fractional photothermolysis laser system Trial arm 3 (n = 13): 6 alternating sessions (4 weeks apart) of PCI with 20% TCA (3 sessions) and fractional photothermolysis (3 sessions)
Outcomes	Improvement of acne scar (investigator and participant) (12 months), using a quartile grading scale (0 = minimal improvement < 25%; 1 = mild improvement 25% – 50%; 2 = moderate improvement 51% – 75%; 3 = significant improvement > 75% improvement) Side effects (12 months) Timing: at baseline, and at week 48
Funding source	No funding source
Declaration of interest	Nothing to be declared
Notes	Egypt
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Computer‐generated random sequence prepared by a statistician" Comment: Probably done
Allocation concealment (selection bias)	Low risk	Quote: "Sequentially numbered, sealed, opaque envelopes, and kept by a nurse not involved in the study" Comment: Probably done
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Quote: "Patients were randomly divided into three equal groups; group 1: received six sessions …. of PCI …Group 2: received six sessions of 1540 nm fractional photothermolysis ….laser …. Group 3: received combined alternating sessions of the previously mentioned two modalities …" Comment: Probably not done. Given that the control arm was easily distinguished from the treatment arm during treatment, participants and the treating dermatologist were not blinded
Blinding of outcome assessment (detection bias)   Investigator‐ assessed	Low risk	Quote: "The assessor was blinded to the intervention used." Comment: Probably done
Blinding of outcome assessment (detection bias)   Participant‐reported	High risk	Quote: "Patients were randomly divided into three equal groups; group 1: received six sessions …. of PCI …Group 2: received six sessions of 1540 nm fractional photothermolysis ….laser …. Group 3: received combined alternating sessions of the previously mentioned two modalities …" Comment: No blinding of participants and the outcome assessment is likely to be influenced by lack of blinding
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Number of participants enrolled: 39. Number of participants with missing data or lost during follow‐up: 1
Selective reporting (reporting bias)	Low risk	The study protocol was obtained by contacting the investigators. The published reports include all expected outcomes that are of interest in the review
Other bias	Low risk	The study appears to be free of other sources of bias

Methods	A split‐face, single‐centre, randomised double‐blinded study
Participants	5 healthy adult women (age range 36 ‐ 46 years) with either ice pick, rolling, or boxcar atrophic moderate‐to‐severe acne scars on the face Exclusion: "Females who were pregnant, breastfeeding, or attempting to conceive were excluded as well as those with a history of known or suspected intolerance to any of the excipients of ALA or any of its vehicle components. Subjects with a history of cutaneous photosensitization (including porphyria or systemic lupus erythematosus), active skin malignancy or infection, and those taking any photo sensitizing medications. All medications, topical and oral, known to alter the course of acne scarring or acne vulgaris taken within two weeks of initiation or during the study period were prohibited."
Interventions	Intervention: "A solution of 20% δ‐aminolevulinic acid (commercially available as Levulan Kerastick, Dusa: ALA‐PDT) was applied topically to either the right or left sides of the face for a 60‐minute incubation period after microdermabrasion. After incubation, lesions were illuminated with 417nm blue light (Blu‐U Blue Light Photodynamic Therapy Illuminator) with irradiance of 10mW/cm2 for 1,000 seconds, with a total light dose of 10J/cm2. A therapeutic course of five consecutive treatments four weeks apart was used." Comparator: "A vehicle solution alone (vehicle‐PDT, supplied by Dusa) was applied topically to the other side of the face for a 60‐minute incubation period after microdermabrasion. After incubation, lesions were illuminated with 417nm blue light (Blu‐U Blue Light Photodynamic Therapy Illuminator) with irradiance of 10mW/cm2 for 1,000 seconds, with a total light dose of 10J/cm2. A therapeutic course of five consecutive treatments four weeks apart was used."
Outcomes	Improvement of acne scars (4 months), using the Physician’s Global Assessment of Acne Scarring scale. Timing: at baseline, week 4, week 8, week 12, week 16  Participant satisfaction (4 months) using patient questionnaire  Side effects (5 months) using a 10‐point scale (0 = none; 1 – 3 = mild; 4 – 6 = moderate; 7 – 9 = severe). Timing: during and immediately after each treatment
Funding source	No funding source
Declaration of interest	Nothing to be declared
Notes	USA
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Subjects with moderate‐to‐severe acne scarring who were randomly assigned" Comment: Insufficient data
Allocation concealment (selection bias)	Unclear risk	Insufficient information about the allocation concealment process to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "A double‐blinded study" Comment: Probably done
Blinding of outcome assessment (detection bias)   Investigator‐ assessed	Low risk	Quote: "Two blinded assessors reviewed pretreatment and end‐of‐study split‐ and full‐face photographs taken at each visit and evaluated acne scar severity" Comment: Probably done
Blinding of outcome assessment (detection bias)   Participant‐reported	Low risk	Quote: "A double‐blinded study" Comment: Probably done
Incomplete outcome data (attrition bias)   All outcomes	Low risk	6 participants were enrolled with 5 completing the study
Selective reporting (reporting bias)	Low risk	The study protocol is not available but it is clear that the published reports include all expected outcomes that are of interest in the review
Other bias	Low risk	The study appears to be free of other sources of bias

Methods	A split‐face prospective, randomised, comparative interventional trial
Participants	24 Thai adults aged 22 – 51 (mean 29.5, both genders) with skin phototype IV. "All participants had shallow or deep boxcar scars or both on their faces for least 6 months before entering the study. 20 participants completed the study" Exclusion: "People who were pregnant or lactating, had concomitant treatment to involved skin areas, had a propensity for keloid scarring, had received isotretinoin, or had undergone filler injections or ablative or non‐ablative laser skin resurfacing procedures within the preceding 12 months"
Interventions	Intervention: 1 side of the face treated with 1 pass of ablative fractional Er:YAG laser with a pulse duration of 350 ls and an energy of 14 mJ with average of 5% skin surface coverage. Participants received 2 treatment sessions with a 2‐month interval. Comparator: The other side of the face treated with 1 pass of ablative fractional CO₂ laser with a pulse duration of 950 ls and a mean energy of 13.75 (12.5 – 15) mJ with average of 5% skin surface coverage. Participants received 2 treatment sessions with a 2‐month interval
Outcomes	Improvement of acne scars by physician: 6 months using a quartile grading scale (0 = < 25%; 1 = 25% – 50%; 2 = 51% – 75%; 3 = > 75% improvement)  Improvement of acne scars by participants: 6 months as follows: slightly better (< 25%), fair (25% – 50%), good  (51% – 75%), and excellent (≥ 76%)  Side effects (6 months), using a 10‐point pain scale (0 = no pain to 10 = severe pain)  Objective assessment of scar volume (6 months) using an ultraviolet A (UVA) light video camera (Visioscan VC 98; Courage‐Khazaka, Köln, Germany) with analysis software. Timing: at baseline and 3 and 6 months after the final treatment Timing: at baseline, at week 8, and 1, 3, and 6 months after the final treatment session
Funding source	No funding source
Declaration of interest	Nothing to be declared
Notes	Thailand Informed consent was obtained from all study subjects Institutional Review Board approved the study
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Using a random digit table" Comment: Probably done
Allocation concealment (selection bias)	Unclear risk	Insufficient information about the allocation concealment process to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Blinding of outcome assessment (detection bias)   Investigator‐ assessed	Low risk	Quote: "Two blinded medical assessors independently assessed clinical improvement in the appearance of acne scars." Comment: Probably done
Blinding of outcome assessment (detection bias)   Participant‐reported	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Low risk	20/24 participants enrolled completed the treatment protocol and were followed through the end of the study. 4 participants were withdrawn from the study because 3 had scheduling conflicts and the other was unable to be contacted during follow‐up
Selective reporting (reporting bias)	Low risk	The study protocol is not available but it is clear that the published reports include all expected outcomes that are of interest in the review
Other bias	Low risk	The study appears to be free of other sources of bias

Methods	A single‐blinded randomised comparative split‐face study
Participants	19 participants (7 men and 12 women) with atrophic acne scarring. Ages ranged from 21 to 30 (average 23), and Fitzpatrick skin types were IV or V. Exclusion: "known photosensitivity, pregnancy or lactation, a previous history of hypertrophic or keloidal scarring, the use of isotretinoin, and a previous history of facial laser treatment or of a surgical procedure within 6 months of study enrolment. Patients with a medical condition that might have influenced the wound healing process"
Interventions	Intervention: 1 facial side was treated using non‐overlapping pulses of a long‐pulse Nd:YAG laser at a fluence of 50 to 70 J/cm² and a 50‐ to 100‐ms pulse duration using a 7‐mm spot size. 2 passes of laser treatment were delivered at each session. All participants received 4 treatment sessions at 2‐week intervals. Comparator: at the same session, contralateral side was treated using a combined 585/1064‐nm laser (Cynergy, Cynosure Inc., Westford, MA). 2 passes of laser treatment were delivered at each session. All participants received 4 treatment sessions at 2‐week intervals
Outcomes	Improvement of acne scars (14 weeks), as % improvements (0% – 100%) from baseline using ECCA scores  Participant satisfaction (14 weeks), using a numerical scale ranging from 0 (neutral) to 10 (highly satisfied)  Side effects (14 weeks)  Histological analyses: 8 weeks before treatment began and again at 8 weeks after final treatment Timing: at baseline, week 2, week 4, week 6, week 10, week 14
Funding source	No funding source
Declaration of interest	Nothing to be declared
Notes	Korea Study approved by the Institutional Review Board of Seoul National University Hospital Written informed consent was obtained from all participants before enrolment
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Randomly selected facial sides" Comment: Insufficient data
Allocation concealment (selection bias)	Unclear risk	Insufficient information about the allocation concealment process to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Quote: "A single‐blinded" Comment: Probably not done
Blinding of outcome assessment (detection bias)   Investigator‐ assessed	Low risk	Quote: "Two blinded dermatologists assessed acne scar improvements" Comment: Probably done
Blinding of outcome assessment (detection bias)   Participant‐reported	High risk	Quote: "A single‐blinded" Comment: No blinding of participants and the outcome assessment is likely to be influenced by lack of blinding
Incomplete outcome data (attrition bias)   All outcomes	Low risk	The 19 participants completed the 14‐week study
Selective reporting (reporting bias)	Low risk	The study protocol is not available but it is clear that the published reports include all expected outcomes that are of interest in the review
Other bias	Low risk	The study appears to be free of other sources of bias

Methods	A split‐face randomised multicentre, double‐blind, placebo‐controlled trial
Participants	Healthy adults (62 women and 47 men, aged 19 ‐ 65 years) with moderate or severe facial acne scarring on both cheeks Exclusion: "Hypertrophic acne scarring or numerous icepick acne scars in the treatment area, aesthetic procedures (e.g. fractional or traditional ablative/non‐ablative laser resurfacing, subcision, microdermabrasion, chemical peels) to the treated area within the past 12 months, or ever previously received injectable fillers in the treated area. History of heavy smoking, alcohol or drug abuse, or steroid treatment"
Interventions	Intervention: 1 cheek of each participant received autologous fibroblasts (LaViv, azficel‐T, Fibrocell Sciences, Inc, Exton, PA) (10 – 20 million cells/mL) injected into the high papillary dermis at a maximum dose of 2 mL per treatment for 3 treatments about 14 days apart Comparator: The other cheek received vehicle control (dye‐free, protein‐free cell culture medium) injected into the high papillary dermis at a maximum dose of 2 mL per treatment for 3 treatments about 14 days apart
Outcomes	Improvement of acne scars (participant and evaluator): 4 months using a 5‐point scale (–2 = much worse; –1 = worse; 0 = no change; +1 = improved; +2 = much improved) by evaluators and a 5‐point evaluator live acne scar assessment scale (0 = clear; 1 = very mild; 2 = mild; 3 = moderate; 4 = severe) by participants  Side effects (4 months) Timing: 1, 2, 3, and 4 months after the third treatment
Funding source	This study was funded by Fibrocell Science, Inc
Declaration of interest	Drs. Munavalli, Smith, and Weiss are consultants and serve on the advisory board for Fibrocell Science, Inc. Mr. Maslowski is an employee of Fibrocell Sciences, Inc
Notes	USA A centralised Institutional Review Board, Chesapeake Research Review, Inc., reviewed and approved the protocol Informed consent forms and written informed consent was obtained from all participants at 7 USA sites before study participation
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "The cheeks of each subject were randomised" Comment: Insufficient data
Allocation concealment (selection bias)	Unclear risk	Insufficient information about the allocation concealment process to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "A double‐blind, placebo‐controlled trial." Comment: Probably done
Blinding of outcome assessment (detection bias)   Investigator‐ assessed	Low risk	Quote: "Evaluators were blinded to the treatment each cheek had received." Comment: Probably done
Blinding of outcome assessment (detection bias)   Participant‐reported	Low risk	Quote: "A double‐blind, placebo‐controlled trial." Comment: Probably done
Incomplete outcome data (attrition bias)   All outcomes	Low risk	96/99 participants completed the series of 3 treatments. Of the 99 treated, there were 7 early study exclusions. 1 participant withdrew consent for reasons unrelated to adverse events, and 6 were lost to follow‐up
Selective reporting (reporting bias)	Low risk	The study protocol is not available but it is clear that the published reports include all expected outcomes that are of interest in the review.
Other bias	Low risk	The study appears to be free of other sources of bias