Acne Vulgaris Scarring – Pathogenesis and Factors Influencing Scar Formation
A scar is defined as “fibrous tissue that replaces normal tissue destroyed by injury or disease” (1). In acne vulgaris, scarring is the end result of abnormal wound healing from damage to the pilosebaceous unit and surrounding tissue. Clinically, it may present as increased (hypertrophic or keloidal) or more commonly as loss (atrophy) of tissue.
Few studies have examined the incidence of acne scarring, with Goulden et al. reporting an 11% frequency of acne scars in men and 14% in women (2), while Layton et al. observed some degree of facial scarring in up to 95% of both men and women, but a higher incidence of scarring on the trunk was seen in men, as were hypertrophic and keloidal scars in these sites (3). Not surprisingly, there was a significant correlation between the severity of acne and degree of scarring in both sexes at all sites. Scars are often cosmetically unacceptable to patients, and they add to the significant psychosocial distress that is observed in patients with acne vulgaris (4). Concern for scar formation is one of the main motivating factors in patients seeking treatment for acne.
As in all wounded tissues, acne scars are the end result of various phases of healing that includes inflammation, formation of granulation and fibrous tissues, neovascularization, wound contracture, and tissue remodeling (5). However, the exact mechanism that initiates and leads to scarring in acne is not fully under-stood and is likely multifactorial in nature.
Several key factors are involved in acne pathogenesis including follicular hyperkeratinization, obstruction of sebaceous follicles, stimulation of sebaceous gland secretion by androgens, and colonization by the gram-positive bacteria Propionibacterium acnes (6). How inflammatory lesions develop is unclear, but the resulting inflammation is believed to play a key role in subsequent scarring. Similar to wound healing, acne scarring is a consequence of the complex interplay between the type of inflammatory response, dermal matrix remodeling, repetitive injury, and resulting imperfect repair (7).
A Study of Acne Scars
Although it is generally accepted that acne scars result from inflammatory lesions, few studies have vigorously examined their evolution. A recent photo-graphic tracking study of facial acne scars over a 12-week period demonstrated that the most common type of scar in patients with mild to moderate acne is ice pick (69%), followed by boxcar (29%) and rolling scars (2%) (8). At week 12, a total of 104 scars were identified in 22 subjects. When all the atrophic scars were tracked to week 0, 53 were clinically normal skin, 30 were established scars, and 21 were acne lesions (7 papules, 6 erythematous macules, 4 pustules, and 4 closed comedones). No open comedones at baseline corresponded to atrophic scars. Papules, closed comedones, and erythematous macules at baseline were mostly associated with ice pick, followed by boxcar, and then rolling scars. Interestingly, all pustular lesions present at week 0 corresponded with only boxcar scars at week 12. These results confirm that inflammatory acne lesions often lead to atrophic scarring. Furthermore, it suggests that 12 weeks is long enough to develop and establish atrophic scars.
Interestingly, this study also suggests that some scarring may arise from initially noninflammatory lesions. Jeremy et al. demonstrated that inflammatory events are involved in acne lesion initiation (9). Biopsy specimens of clinically normal pilosebaceous follicles from acne patients showed vascular endothelial cell activation, an increased number of macrophages, and upregulation of the proinflammatory cytokine interleukin (IL)-1. Furthermore, biopsies of clinically noninflamed facial comedones showed significant upregulation of inflammatory mediators including human R-defensin 2, IL-8, matrix metalloproteinase (MMP)-1, MMP-9, and MMP-13 (10). Taken together, aggressive treatment of inflammatory and noninflammatory acne is likely warranted to minimize acne scarring.
Stages of Wound Healing
Although normal wound healing is not an exact mirror to acne scar formation, it provides an important framework to better understand the mechanism of scar-ring. The three phases that define wound healing are inflammatory, proliferative, and remodeling (11).
The inflammatory phase is composed of cellular and vascular responses. Inflammatory cells such as neutrophils and monocytes are induced to migrate to the wound by chemotactic factors and inflammatory mediators, which also serve to upregulate adhesion molecules that mediate cell-cell binding. Other mediators such as histamine, complements, and growth factors contribute to the inflammatory phase resulting in vasodilation, fibroblast proliferation, and mast cell activation. The increased fluid leakage into the extravascular space and blockade of lymphatic drainage give rise to the signs of inflammation rubor (redness), tumor (swelling), and calor (heat). However, macrophages are considered the most important regulatory cell in the inflammatory reaction and allow for induction of angiogenesis and formation of granulation tissue. The acute inflammatory reaction usually lasts 24 to 48 hours but can persist up to two weeks or longer in some patients.
- The proliferative phase is characterized by cellular responses that involve angiogenesis and fibroplasia three to five days after wounding. Angiogenesis refers to new vessel formation (revascularization) that provides oxygen and nutrients to the wound. Hypoxia in wounds can stimulate the profibrotic cytokine transforming growth factor (TGF)-R and collagen synthesis and therefore promote increased fibrosis (12). Fibroplasia is the reinforcement of injured tissue with new granulation tissue, consisting of new vessels and fibroblasts that produce matrix materials including elastin, proteoglycans, and collagen (predominantly type III), during early wounding.
- The remodeling phase is a dynamic process of deposition and changes in the extracellular matrix. Importantly, it heralds the change from type III col-lagen that is made in the early phase of healing to type I collagen that normally makes up 80% of the collagen found in preinjured dermis. Enzymatic activities of collagenases facilitate this transition, and the stim-ulus for this conversion between collagen types may be the mechanical strain on the wound (13). Therefore, more scar tissue is necessary in areas of the body that are on mobile extremities, which may also explain why hypertrophic and keloidal scars in acne have a greater predilection for the shoulders than, for example, the face.
Inflammatory Cascade in Acne Scarring
In addition to the changes described above, an inflammatory cascade involving activated protein (AP)-1, nuclear factor (NF)-xB signaling, and MMPs have been shown to have a crucial role in acne scarring (7). MMPs are a family of zinc-dependent endopeptidases that are capable of degrading extracellular matrix proteins including collagen. In inflammatory acne lesions, there is increased gene transcription of AP-1 regulated MMPs (7).
- NF-xB is a transcription factor important in the upregulation of many proinflammatory cytokine genes, including tumor necrosis factor (TNF)-oc and IL-10 that propagate the inflammatory response by acting on endothelial cells to increase the expression of adhesion molecules and thus facilitate recruitment of inflammatory cells into the skin. TNF-oc and IL-10 also stimulate the production of secondary cytokines such as IL-8 by keratinocytes, which increases the influx of inflammatory cells such as neutrophils. Although TNF-oc and IL-10 primarily signal through the NF-xB signaling pathway, they also activate the AP-1 pathway through mitogen-activated protein (MAP) kinases.
- AP-1 is a critical regulator of several MMPs including MMP-1 (collagenase-I), MMP-3 (stromelysin-I), and MMP-9 (92-kD gelatinase or collagenase-4), all of which are overexpressed in inflammatory acne lesions (7). MMP-1 is critical in the degradation of mature type 1 collagen, which is the pre-dominant collagen in the dermis. Upon initial cleavage of collagen by collagenases (MMP-1, MMP-8, MMP-13), resulting gelatin is further degraded by other MMPs such as gelatinase and stromeolysin.
Matrix Synthesis and Repair in Acne Scarring
As part of wound healing, matrix degradation is followed by matrix synthesis and repair, with increased expression of procollagens I and III, which are increased in inflammatory acne lesions. Concomitant increase in TGF-01 level suggests participation of this profibrotic cytokine (7). These sequences of events would leave imperfections in the organization, composition, or both of the extracellular matrix that may not be clinically detectable. That may explain why some and not all inflammatory lesions progress to scarring. However, with significant magnitude in their changes (matrix degradation and procollagen synthesis), clinically visible acne scars are expected to result. When acne lesions are physically manipulated by patients, this process is aggravated. Therefore, an aberration in the dynamic interactions between the various components of wound healing that govern the direction of repair can lead to clinical expression of acne scars (excessive hypertrophic scars at one end and loss of substance in atrophic scars at the other end of the spectrum) (14).
FACTORS INFLUENCING SCAR FORMATION
Genetics are important in determining individual susceptibility to acne. In a study of 204 patients over the age of 25 with facial acne that persisted from adolescence, the risk of adult acne occurring in a relative was significantly higher than that for the relative of an unaffected individual (15). Although similar studies examining the familial risk of scarring are lacking, genetics are likely to play a role as not all patients with inflammatory acne will scar and patients often report that their parents also have severe scarring from acne in their youths.
Data suggest that the likelihood of scarring is associated with the type of inflammatory response. Holland et al. observed that in inflammatory lesions from patients who have less scarring, there is a brisk inflammatory cellular infiltrate composed of T-helper lymphocytes, macrophages, and Langerhans cells, with accompanying angiogenesis that quickly resolves compared with patients who are prone to scarring, where the inflammation and angiogenesis start slowly but is maintained over a longer period. It is speculated that the prolonged inflammatory response in patients prone to scarring is a delayed-type hypersensitivity reaction to persistent antigenic stimulus that they were initially unable to eliminate (16). As there is no tool to predict who will develop this delayed-type reaction, treating early inflammation is the best approach in pre-venting acne scarring.
CLASSIFICATION OF ACNE SCARS
Acne scars are broadly divided into either increased tissue formation (hyper-trophic or keloidal) or, more commonly, loss of tissue (atrophic). They can have associated color changes including erythema with or without associated telan-giectasias and hyper and/or hypopigmentation. Hypertrophic/keloidal scars can be symptomatic with pruritus or pain (6).
Hypertrophic and keloidal scars are associated with excess collagen formation and decreased collagenase activity. Hypertrophic scars are usually pink, raised, and firm lesions that remain within the borders of the original site of injury. In contrast, keloids form as reddish-purple papules and nodules that proliferate beyond the borders of the original wound. Histologically, hypertrophic scars and keloids both exhibit excess collagen in whorled masses with varying numbers of fibroblastic cells. In addition, keloids demonstrate characteristic hyalinized hypocellular zones of fibrous tissue in contrast to more cellular nodules in hypertrophic scars (17). Acne-associated hypertrophic and keloidal scars are often found on the upper trunk, more commonly seen in men and in people with darker-pigmented skin (18).
Different types of atrophic scars have been defined according to the degree and depth of scarring, a reflection of the extent of inflammation, which is usually below the epidermis, at the infrainfundibular region of the pilosebaceous unit. The widely used atrophic scar categories as proposed by Jacob et al. are “ice pick,” “rolling,” and “boxcar” (19). Ice pick scars are narrow (<2 mm), sharply delineated, and tapered at the base in the dermis or subcutaneous tissue forming a “V” shape. It is usually too deep for treatment with conventional skin resur-facing. Rolling scars occur from subdermal tethering, creating a shallow broad scar that is usually 4 to 5 mm wide, and successful treatment depends on cor-recting the subdermal component. Boxcar scars are broad and can be shallow or deep with sharp vertical edges that do not taper at the base like ice pick scars. However, although the precise categorization helps facilitate choosing the type of therapy, acne scars are sometimes mixed and not easily classifiable. To help standardize grading of acne scar severity, a few systems have been proposed including the ECCA scale (e´chelle d’e´valuation Clinique des cicatrices d’acne´) designed for clinical use. The authors reported good interob-server reliability for the scale, which is based on qualitative assessment of six scar types (using their own classification of atrophic scars) and a quantitative score for each scar type identified (determined semiquantitatively by a four-point scale from no scar to many scars >20) multiplied by a weighting factor (keloid scars have the highest weight) to produce the final score of severity (20). Goodman and Baron also developed a quantitative global scarring grading system, which assigns points based on the type and number of scars, with fewer points given for macular and mild atrophic scars (21). These grading systems help standardize discussions on acne scars in clinical practice and research.
Treatment of acne scars depends on several factors including the individual patient, types of scars present, and costs involved. There are numerous available options with varying efficacy including medical (e.g., corticosteroids, silicone, retinoids), surgical (e.g., primary elliptical excision, punch excision, punch elevation, subcision, skin grafting, debulking), procedural (cryotherapy, chemi-cal peels, microdermabrasion), and emerging new technologies including lasers (e.g., ablative, nonablative, and light) and tissue augmentation (e.g., dermal fillers) (22). The optimal therapy depends on the scar type. For example, intralesional corticosteroids is usually the first line of treatment for hypertrophic and keloid scars. Punch excision is best for ice pick scars with deep bases and narrow (<3 mm) deep boxcar scars. Wide (>3 mm), deep boxcar scars can be treated with either punch excision or punch elevation, while shallow boxcar scars are best treated with laser resurfacing. Dermal fillers can be used for rolling scars; however, the benefit is temporary, and therefore, subcision may be pre-ferred (19).
However, prevention is always preferred. Retinoids have been shown to reduce inflammation in acne through inhibition of migration of leukocytes in the skin (23). In addition, isotretinoin reduces the expression of MMP-9 and MMP-13 in the sebum of acne patients (24). Therefore, these agents may reduce the risk of subsequent scar formation by shifting the balance of MMPs and tissue inhibitors toward normal (6).
Scarring is an untoward result in patients with mild to severe acne vulgaris. It is a consequence of the complex interplay between inflammation, repetitive injury, and wound healing, which can be compounded by host and environmental factors. Further elucidation into the complexity of acne scar development is needed to help prevent this outcome as effective scar therapies remain limited.
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