Advances in Understanding Atrophic Acne Scarring and the Role of Adapalene/Benzoyl Peroxide

Jerry Tan MD FRCPC

Faculty of Medicine, Western University, London, ON, Canada

Introduction

Interventions to reduce atrophic acne scarring can be conceived in 3 dimensions: prevention of acne, early/aggressive treatment of acne, and correction of existing acne scars. Newly developed atrophic acne scars from primary acne lesions are not always permanent. Up to ⅓ can spontaneously resolve within 6 months. The evolution to persistence or resolution is due to a balance between matrix degradation and repair mechanisms. A recent study with a fixed dose combination adapalene 0.3%/BPO 2.5% (Tactupump ForteTM; Galderma) provides evidence for efficacy in both acne as well as mitigation of ongoing scar formation and enhancement of scar resolution. The mechanism of the latter effect may be due to enhanced collagen deposition due to the topical retinoid component, adapalene. The added benefit of this option in preparation for scar repair procedures is worthy of future research.

Acne and Acne Scarring

• Acne scarring is a direct consequence of acne and can lead to adverse physical, social and psychological impact. These include embarrassment, negative self-perception, anxiety and depression.¹
• Acne scarring can also lead to stigmatization as those with scars are perceived to be shyer and more stressed; less healthy, physically skilled; and more likely to make others feel uncomfortable.²
• Acne scars are changes in skin texture and volume resulting from primary acne lesions. Initiating lesions are primarily inflammatory papules/pustules and nodules. Scars do not refer to changes solely in skin color such as redness or brown discoloration in the absence of volume changes.
• Acne scarring is observed across the spectrum of severity, even in those with milder grades of acne. Those at higher risk of developing atrophic acne scars include severe and very severe acne presentations, with a prolonged duration of acne, family history of scarring and history of squeezing and manipulation of acne lesions.³

Natural Evolution

• Atrophic acne scars develop directly from inflammatory papules or from a transitional state of macular discoloration from inflammatory papules.
• In a non-interventional observational study, of scars developing within a 6-month observation period, ⅓ spontaneously resolved.⁴
• Those at higher risk of acne scarring have a more intense early innate immune response and a prolonged adaptive response leading to greater inflammatory intensity and duration.^5,6
• Acne scar resolution or persistence is likely due to relative contributions by matrix degradation (matrix metalloprotease activation versus tissue inhibitors of matrix metalloproteases) and repair (platelet derived growth factor, transforming growth factor beta) mechanisms.

Types

• Acne scars can be due to volume loss or gain:
  • Volume loss can occur at the epidermis (sometimes termed macular atrophy) or dermis (atrophic scars);
  • Volume gain can be within the perimeter of the initiating injury (hypertrophic scar) or beyond (keloidal).
• Most acne scars are atrophic (Figure 1).⁷

Severity Grading

• Scales in frequent use include global grading measures for severity determination and for guidance in scar repair options.
• A morphological scale for acne scars with relevance to repair methods is based on presumed cross-sectional features of atrophic acne scars. These are categorized as ice-pick, boxcar and rolling.⁸
• A global assessment measure based on involved extent of atrophic acne scars termed SCAR-S, can be applied to each of the face, chest and back.

  • Grades and descriptive text range from clear (no visible scars), almost clear (hardly visible scars from 2.5 m), mild (easily recognizable with less than half the affected area involved), moderate (more than half the affected area involved), severe (entire area involved) and very severe (entire area with prominent atrophic or hypertrophic scars).⁹

Prevalence

• In acne patients, readily discernible acne scars are observed on the face, back and chest in 55%, 24% and 14% respectively.⁹
• Atrophic acne scars are observed across the spectrum of acne severity at time of presentation. Scar prevalence increased with acne severity whereby scarring was observed in 28% with minimal/mild acne, 51% in moderate and 77% in severe acne.¹⁰
• The prevalence and severity of scarring increases with duration of acne such that acne scar severity scores peak at approximately 3 years.^11,12

Management

Atrophic acne scar management can be divided into prevention, mitigation and correction.

1. Prevention of acne will negate acne scar development

   • Genetic and environmental factors are important in acne development.
     • Ongoing topics of debate include avoidance of high glycemic index diets and dairy products.

• • However, there are no studies evaluating prevention of acne.

1. Timely and effective therapy of acne can mitigate increased acne scarring risk

   • Acne clinical practice guidelines can provide guidance on appropriate therapy based on severity.
   • Topical retinoids and BPO are important options in all acne severities except for those with nodulocystic presentations.
   • The fixed dose combination of adapalene and benzoyl peroxide is a rational combination for treatment of mild – moderate acne (adapalene 0.1%/BPO 2.5%,

     TactuPump) and moderate-severe acne (adapalene 0.3%/BPO 2.5%, TactuPump FORTE).

     • Adapalene is a retinoid with anti-inflammatory, anti-comedogenic, and comedolytic activity.
     • BPO is an antimicrobial with anti-inflammatory and comedolytic properties but no risk of inducing antibiotic resistance.
   • In a 12 week RCT of moderate and severe acne, adapalene 0.3%/BPO 2.5% was threefold more effective than vehicle in acne lesion reduction and achieving overall grade of clear/almost clear (34% vs 11%).¹³
     • Tolerability profile of adapalene 0.3%/BPO 2.5% was comparable to adapalene 0.1%/BPO 2.5% with mean scores of less than mild at all study visits and with reports of skin irritation in 4%.
   • In a 24 week split face RCT of moderate acne, adapalene 0.3%/BPO 2.5% (TactuPump FORTE) was more effective than vehicle in reducing acne (threefold greater proportions achieving clear/almost clear on a 5 category global grading scale of clear, almost clear, mild, moderate and severe) and in reducing risk of acne scars with approximately 30% difference in numbers of scars (from baseline, percentage of scars increased with vehicle by 14% but decreased with adapalene 0.3%/BPO 2.5% by 15%).¹⁴
   • In a 24 week open label study of adapalene 0.3% twice daily in moderate to severe facial atrophic acne scars improvement in acne scars was observed in at least 50% of patients. Immunohistochemistry studies of treated skin demonstrated increased procollagen-1 and collagen-3 levels.¹⁵

1. With extant acne scars, corrective procedures are available

• Scar correction procedures depend on the type and extent of acne scars. Ice-pick scars are primarily addressed by TCA cross technique, punch excision/elevation; boxcars scars by resurfacing with mechanical, chemical, laser (including fractionated ablative and non-ablative) means, microneedling techniques with or without radiofrequency; and rolling scars by filler elevation and possible subcision.
• As most patients present with multiple atrophic acne scar types, combination therapy is typically required.
• These procedures are often costly, discomforting and incompletely effective.  Furthermore, there is little high-quality evidence to help direct patients and providers to best corrective options. More evidence-based research is an unmet need in this context.

For keloidal and hypertrophic acne scars

• Consider conservative monitoring or silicone gel applications as some will resolve with time.
• Alternate options include intralesional steroid injections, topical imiquimod, pulse dye laser, and cryotherapy.¹⁶

Conclusion

There have been important advances in our understanding of acne scarring. Specifically, acne scars affect a large proportion of people with acne. Acne scars can resolve, and their evolution is determined by a balance between matrix repair and degradation. Timely, effective management of acne can minimize risk of subsequent acne scarring. The use of a combined topical retinoid and BPO product has been shown to be efficacious in mild – moderate acne (adapalene 0.1%/BPO 2.5%, TactuPump) and moderate-severe acne (adapalene 0.3%/BPO 2.5%, TactuPump FORTE). The latter has also been shown to mitigate further development of acne scars and may enhance scar repair. This is likely due to the effect of adapalene enhancing dermal deposition of collagen. Further advances in understanding the mechanisms underlying acne scarring will lead to further therapeutic options for this prevalent and consequential sequela of acne.