Abstract
The pathogenesis of acne is complex, with strong evidence supporting the involvement of sebaceous hyperplasia, follicular hyperkeratinisation, bacterial hypercolonisation, as well as immune reactions and inflammation. High sebum concentrations and follicular hyperkeratinisation lead to a change of the follicular milieu with consecutive proliferation of bacteria, chiefly Propionibacterium acnes. This leads to further increased production of the pro-inflammatory cytokines interleukin-1α and tumour necrosis factor α by T cells and keratinocytes, leading to proliferation of both cell types. Follicular keratinocytes fail to differentiate by apoptosis and produce hypergranulosis similar to the impermeable skin outer layer, resulting in the formation of microcomedones. Further inflammatory responses lead to the development of increasing degrees of severity in inflammatory forms of acne.
Retinoids aid the differentiation and reduce the hyperproliferation of keratinocytes, and can inhibit the migration of leucocytes. Combination therapy using retinoids plus benzoyl peroxide or antibacterials can treat existing acne lesions faster than the individual agents alone and can also prevent the development of new lesions. The new retinoids (e.g. adapalene) have not only the typical potent comedolytic activity but also anti-inflammatory effects. When added to antibacterial therapy, topical retinoids demonstrate faster and significantly greater reduction of inflammatory acne lesions and comedones than antibacterials alone.
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Acne represents a significant challenge to dermatologists because of its prevalence, complexity and range of clinical expression. Acne vulgaris is the single most common skin disease, affecting an estimated 85% of teenage boys and 80% of teenage girls. Furthermore, acne can continue throughout adulthood or present at any age, and affects 8% of adults aged 25–34 years and 3% of those aged 35–44 years.[1] In the US alone, between 40–50 million people are estimated to be affected by some form of acne, with approximately 17 million having clinical acne. A third of these patients require specialist treatment and represent the largest patient group seen by dermatologists.[2]
Although superficial and not life threatening, acne is a disease that, if left untreated, can have serious physical and psychological consequences.[3,4] Severe acne can result in permanent physical scarring, an outcome that has been implicated as a risk factor for suicide, particularly in men.[5] Even patients with mild to moderate acne have a higher prevalence of suicidal ideation, comparable to that among patients with far more chronic and disfiguring dermatological problems.[6] Other psychological scars include lowered self-esteem and professional expectations, social inhibition, depression and anxiety.[7] Furthermore, severe acne has been associated with decreased employability in adulthood.[8] Therefore, it should be recognised as a serious disorder.
Acne presents in a wide variety of clinical forms depending on the type, number and severity of the predominant lesion. Indeed there are almost as many classifications of acne as there are manifestations of the disease.[9] In most patients, acne is a spectrum of disease. At one end lies the invisible microcomedone — the development of which is the first essential step in acne lesion formation — and at the other end is the deep scarring inflammatory nodule.[10] An understanding of the interplay between the various aetiological factors, and the clinical and histopathological stages of acne pathogenesis is central to the development of new treatments and the optimal use of existing anti-acne therapy. This article aims to provide a comprehensive review of the current understanding of acne pathogenesis and outlines treatment strategies targeted at acne pathogenic factors.
1. Acne Pathogenesis
The pilosebaceous unit (PSU) is the site of acne and in normal skin is composed of large, multilobulated sebaceous glands, a rudimentary hair and a wide follicular canal lined with stratified squamous epithelium. During the regular turnover process of the skin, desquamated cells from the follicular epithelium are carried up the follicular canal, towards the infundibulum (the funnel-shaped opening at the top of the follicle), by sebum secreted from the sebaceous glands. Normal development, growth and differentiation of the PSU requires the interaction of androgens with numerous other biological factors, including growth factors and thyroid hormone.[11] If the infundibulum of the PSU becomes more and more occluded, the trapped sebum and shed cells promote bacterial proliferation, immune reactions and inflammation, resulting in the development of acne vulgaris.
1.1 Processes Involved in the Development of Acne
1.1.1 Sebum Production and Cell Differentiation
Increased sebum production and follicular epithelial cell development and abnormal desquamation play key roles in acne pathogenesis.[10,12–14] Sebum is a complex and variable mixture of lipids produced by the sebaceous glands under the control of androgens, mainly testosterone. Testosterone is converted to the more active 5α-dihydrotestosterone (5α-DHT) by the enzyme type I 5α-reductase. This more active androgen then stimulates increased sebum production. In addition, 17β-hydroxysteroid dehydrogenase (HSD) also plays an important role in androgen metabolism at the local site.[15] Excessive sebum production (seborrhoea) is closely implicated in acne pathogenesis,[16] by providing an anaerobic, lipid-rich environment in which Propionibacterium acnes can grow. In individuals with seborrhoea and in patients with acne the number of lobules per gland is higher when compared with healthy controls.[14]
The epidermis is a stratified squamous epithelium that is under a constant state of proliferation, commitment to develop along the epidermal cell lineage, differentiation, elimination and desquamation so that the functional integrity of the tissue is maintained.[17] The process of elimination and desquamation is a complex biological event that is not clearly understood. It involves a well regulated transition of strongly cohesive epithelial cells to a loosely attached surface layer of cells among which most of the intercellular cohesion has been lost.[18] Basic concepts include the importance of degradation of proteins responsible for cell cohesion and the modification of cell-junction desmosomes as a prerequisite for normal desquamation. Abnormal epithelial development or desquamation, either due to increased proliferation of ductal keratinocytes or inadequate separation of ductal corneocytes (or a combination of the two), are implicated in acne pathogenesis.[19,20]
1.1.2 Comedogenesis and the Development of Inflammatory Lesions
The processes whereby sebum production and epithelial desquamation are altered, leading to the formation of microcomedones and acne vulgaris are complex and multifactorial. The earliest morphological change in the PSU in acne is aberrant follicular epithelial differentiation resulting in the microcomedone, which, although not clinically visible, is the precursor of all acne lesions (figure 1). Blockage of sebum flow and progressive enlargement of microcomedones gives rise to clinically visible comedones (non-inflammatory lesions) and inflammatory acne lesions. Open comedones (blackheads) are filled with desquamated keratinous cells and serum, and have a dilated orifice. They manifest as flat or slightly raised lesions ranging from 1–5mm in diameter, and their black colour is due to the refraction of light (detritus, melanin) as when expressed, they are white in colour. The contents of the open comedone are able to escape to the skin surface. Open comedones can resolve spontaneously or develop into inflammatory acne lesions.[10,12–14]
As sebum accumulates following follicular blockage, a closed comedone (whitehead) appears (figure 2). Closed comedones are firm, pale, 1–2mm in diameter and slightly elevated, lying just beneath the skin surface. Closed macrocomedones (microcysts) are up to 5mm in size. With continued sebum accumulation, the closed comedone becomes distended, the follicular sac can rupture into the adjacent tissue, leading to the production of inflammatory lesions. If the process is superficial a pustule forms — these are raised white lesions filled with pus. Because of their superficial location, pustules generally resolve within days with no scarring (unless traumatised). Papules (≤5mm) represent a deeper dermal inflammatory reaction and appear as erythematous, raised solid lesions. As a consequence, they take longer to resolve and often do so with scarring. Small nodules (5–10mm), nodules (>10mm) or pseudocysts represent the most severe form of acne, and are large, deep-seated abscesses that may be fluctuant when palpated. In the clinically acute acne subtype, acne conglobata, nodules and pseudocysts predominate. These coalesce and dissect under the skin to produce highly inflamed sinus tracts and leave severe scarring on resolution.[10,12–14]
Hair follicles and the pilosebaceous duct have well-regulated life cycles.[19,22] Normal follicular and comedonal cycles may be linked, and environmental stimuli may result in follicles either being pushed into the comedonal cycle with resultant acne lesion formation or comedones being pushed into the normal follicle cycle with resultant comedonal resolution. Comedonal cycling may explain why many non-inflammatory acne lesions resolve without treatment.[19]
1.1.3 Ductal Hyperproliferation
There is immunohistochemical evidence that ductal hyperproliferation processes are, in part, responsible for the accumulation of corneocytes in the pilosebaceous duct. Using an antibody that reacts with a nuclear antigen (Ki-67) expressed by actively cycling cells, it was shown that follicles from skin affected by acne showed stronger staining than follicles from the skin of individuals without acne.[23] Furthermore, there was also evidence of ductal hyperproliferation in normal follicles from patients with acne, indicating that skin from these patients, although clinically normal, may in fact be acne-prone.[23] Using skin samples from patients with acne, some clinically normal follicles were shown to have microcomedonal features when examined histologically.[24] Increased expression of some keratins in the comedone wall has also been reported and this was suggested to be a secondary effect of increased cell turnover in the skin of patients with acne.[25]
1.1.4 Aberrant Desquamation
Evidence is limited for the role of aberrant desquamation in comedogenesis. Desmosomes contribute towards adhesion between adjacent keratinocytes. However, comparison of expression of various desmosomal antigens in individuals with and without acne has not identified any changes that might explain the increased adhesion between follicular keratinocytes during comedogenesis.[26] On the other hand, increased expression of tenascin, an extracellular matrix glycoprotein that can interact with cells and alter their capacity to adhere, migrate and proliferate, has been associated with the development of acne lesions.[27]
1.1.5 Androgens
Androgens regulate sebum production and may also play a role in the follicular hyperkeratinisation seen in acne. The activity of the enzyme type I 5α-reductase varies within regions of the PSU. Compared with interfollicular epidermal cells, infrainfundibular keratinocytes have been shown to have an increased capacity for metabolising androgens, suggesting that androgen activity and follicular hyperkeratinisation are related.[28] This association may in part be supported by the successful use of oral contraceptives in the treatment of acne.[29,30] While it has been shown that reduced hyperkeratinisation is part of this treatment success,[30] how much is due to reduced sebum production, which is also under androgenic control, remains to be seen.
Although it is well established that microcomedones are the precursor of all acne lesions, and the general mechanisms have been identified, the trigger for acne is not fully understood. Only one out of ten follicles is involved in the actual acne process. It is possible that acne is triggered by a combination of androgen-mediated seborrhoea, follicular keratinocyte growth, bacterial proliferation, pre-clinical inflammatory processes and abnormal epithelial differentiation (table I). Secondary or late stage inflammatory processes lead to the formation of inflammatory lesions. The remainder of this article focuses on the role of each pathogenic factor in the development of acne. An overall theory for acne pathogenesis is then presented, followed by discussion of pathogenesis-targeted treatment strategies.
1.2 The Role of Sebum and Seborrhoea
Enlargement of the sebaceous glands and increased production of sebum is stimulated by the increasing production of androgens at puberty. Of these, the most important androgen is testosterone, which is converted to the more active 5α-DHT by type I 5α-reductase. The correlation between increased sebum production and acne is well established, and explains why the first signs of acne commonly coincide with the onset of puberty.[10,12–14] Furthermore, studies demonstrate that seborrhoea is more intense in individuals who are acne-prone than in those who are free of acne.[14,31] Increased sebum production seen in patients with acne is primarily as a result of individual increased sebaceous gland sensitivity to androgen (end-organ hyper-response hypothesis),[32,33] to increased circulating levels of androgen[10,12–14,34] or increased type I 5α-reductase activity.[33,35] Type I 5α-reductase is most abundantly expressed in facial sebocytes,[36] which may account for the prevalence of facial acne in all age groups. Currently, the role of 17β- or 3α-HSD activity in the PSU and also recirculation of 3α-metabolites are not fully understood. However, retinol dehydrogenase-4 has enzymatic activities resembling 3α-HSD, and is thought to play a role in the regulation of 5α-DHT levels in keratinocytes and sebocytes.[37] Thus, the mechanism of action of isotretinoin might involve not only an interaction with endogenous retinoid metabolism but also with androgen metabolism in the sebaceous glands.[37]
It has been suggested that sebum production and flow from individual follicles is more important than overall sebum excretion rate in acne pathogenesis.[38] Piérard and colleagues studied the relationship between seborrhoea and acne in 50 males with mild to moderate acne and 50 individuals without acne. They observed that the activity of the sebaceous follicles differs between the two groups of patients. In those free of acne, seborrhoea appears to be linked to a large number of moderately active sebaceous follicles, whereas in those prone to acne, seborrhoea is related to the presence of a small number of sebaceous follicles with an unusually high rate of sebum output.[31] These data are somewhat contradictory to those reporting a higher number of lobules per gland as ‘anlage’.[14] In addition, body areas prone to acne have a different response to androgens than non-acne sites.[39]
Acne cannot develop without the sebocyte differentiation and proliferation that occurs under androgen stimulation. This may be mediated by interaction of androgens with peroxisome proliferator-activated receptors (PPARs), molecules that regulate lipogenesis during adipocyte differentiation. PPAR activation and over-expression are thought to be necessary for the lipogenesis that characterises the late stages of sebocyte differentiation.[40–42] In addition, linoleic acid is able to stimulate maturation of sebocytes in culture, suggesting a distinct role for long chain fatty acids in sebocyte differentiation.[41]
Preliminary observations on cultured sebocytes indicate that these cells may be able to initiate the development of inflammatory acne lesions by an intrinsic mechanism leading to expression of the inflammatory cytokine interleukin (IL)-1α.[16] Furthermore, previous concepts that the free fatty acids found abundantly in acne lesions are a product of bacterial triglyceride metabolism alone have been challenged by indications that they can be synthesised by sebocytes themselves in the absence of bacterial colonisation.[43] These free fatty acids may be an irritant to the follicular wall and the surrounding dermis, and exacerbate the inflammatory process. However, intracutaneous injections of physiological amounts adapted to the volume given in the sebaceous follicle did not produce relevant inflammation.[10,19] Sebocyte production of IL-1α and free fatty acids may contribute as additional intrinsic co-factors in the evolution of inflammatory acne lesions.
1.3 The Role of Microorganisms
The microbiology of the PSU involves three co-existing groups of microorganisms: aerobic staphylococci and micrococci; semi-anaerobic P. acnes and P. granulosum; and lipophilic yeasts. The anaerobic conditions found in PSUs are unsuited to aerobic bacteria and therefore staphylococci and micrococci settle in the acroinfundibulum and should play a negligible role in typical acne. However, recent research again tries to implicate staphylococci in acne pathogenesis.[44] The yeast have not been found in acne lesions and again appear to have no significant role in acne pathogenesis.[45] In contrast, there has been substantial evidence for several years for P. acnes playing a significant role in the pathogenesis of acne.[10,12–14]
1.3.1 Propionibacterium acnes
Normal skin shows age- and body-related differences in P. acnes colonisation. The density of P. acnes is higher in infancy than in early childhood. At puberty, the amount of this bacteria increases, with significantly higher levels seen in late adolescence. Maximum counts are attained in early adulthood and remain constant until old age, when a trend toward lower numbers occurs. These changes seem to correlate with the production of sebum[46] and thus with onset of acne. They further suggest that sebum represents a growth substrate for P. acnes proliferation. P. acnes levels are highest in regions of the body rich in sebaceous glands, such as the face and scalp. In contrast, intermediate levels are found on the trunk and upper arms, with low levels on the lower extremities.[47] P. acnes is overwhelmingly the predominant microorganism in acne, appears to be the target for antibacterials used to successfully treat acne, and secretes several products that may cause or exacerbate inflammation.
1.3.2 The Role of P. acnes in Comedogenesis
It has generally been assumed that the bacterial flora of the infundibulum does not have a major role to play in comedone development. However, since antibacterial treatment leads to a reduction in the number of comedones, it is conceivable that bacteria are indeed of significance later in comedone formation.[48] Sebaceous follicles containing large amounts of sebum provide an anaerobic, lipid-rich environment in which P. acnes flourishes. P. acnes produces an extracellular lipase that hydrolyses sebum triglycerides to glycerol, used by the organism as a growth substrate, and free fatty acids, which have pro-inflammatory and comedogenic properties.[49,50] In addition, the lipid squalene has been implicated in the pathogenesis of acne, with squalene oxidation acting as a link between comedogenesis and P. acnes colonisation.[51]
There is also an association between P. acnes and biologically active IL-1α, a pro-inflammatory cytokine, in comedones with high levels of bacteria.[52] This association may be as a result of an indirect effect of cutaneous microflora in vivo such as the stimulation of a third factor that interacts with migrating immune cells to release IL-1α. Histamine, tryptamine and short-chain fatty acids have also been identified in culture supernatants from P. acnes and may, if produced in vivo, contribute directly to the release of IL-1α.[53] Expression of IL-1α is closely implicated in comedogenesis (see next sections).
1.3.3 P. acnes and Inflammatory Factors
The generation of an inflammatory response initially involves a co-ordinated expression of cell adhesion molecules and post-capillary venules, which results in the trapping of peripheral blood cells such as lymphocytes and neutrophils. There is strong evidence that T cells first occur at sites of the follicular wall within the development of inflammatory processes.[54] Recently, Ingham suggested that P. acnes antigens were taken up by Langerhans cells (Ingham E, personal communication). Accumulation of clusters of polymorphonuclear leucocytes along the periphery of the walls of predominantly closed comedones has been described as the first change marking the transition of quiescent non-inflamed acne lesions to inflamed ones,[55] but is now believed to be the second change. Marked overgrowth of P. acnes is reported in comedogenic follicles, and this proliferation can be accompanied by the generation of pro-inflammatory molecules and subsequent inflammation.[56] Several mechanisms have been proposed as to how this bacterial overgrowth may produce inflammation. These include chemotactic-, antibody- and complement-mediated, and cell-mediated inflammatory and immune processes.
Supernatants of P. acnes cultures contain cell wall peptidoglycan-polysaccharide fragments, which are small enough to diffuse through the follicular epithelium. These compounds can stimulate macrophage production of the cytokines IL-8 and tumour necrosis factor (TNF)-α, both of which up-regulate adhesion molecules.[57] P. acnes also produces serum-independent neutrophil and lymphocyte chemo-attractant factors, which, coupled with the adhesion molecules, may cause the recruitment of neutrophils and lymphocytes into the epithelial walls of sebaceous follicles.[58]
The complement system today is seen to play a minor role in inducing the inflammation seen in acne lesions. P. acnes cells in comedonal material have been shown to be responsible for complement activation, possibly in conjunction with corneocytes. Soluble factors are produced that generate chemotactic factors after diffusion through the follicular wall.[59–62]
It has been postulated that inflammatory acne represents hypersensitivity to P. acnes,[63] accounting for the individual variation in disease severity. Circulating immune complexes are reported to be elevated in some patients with acne and the degree of elevation has been correlated with the severity of acne inflammation.[45] This elevated antibody response appears to be specific to P. acnes.[64]
There is also evidence that cell-mediated immunity to P. acnes contributes to the development of inflammation in acne. Patients with varying degrees of acne, acne-free adult controls and samples of cord blood were investigated for cell-mediated immunity to P. acnes using a leucocyte migration inhibition test. Only patients with severe acne exhibited cell-mediated immunity, suggesting that it contributes to inflammation, rather than initiating it.[65] Furthermore, delayed skin test reactivity to P. acnes has been shown to correlate with severity of inflammation in acne.[66,67] The presence of T cells in early acne lesions within hours or days of clinical appearance suggest that lymphocytic infiltration may represent a cell-mediated immune response to antigen within the follicular duct.[54]
In conclusion, P. acnes may contribute to inflammatory acne through the generation or stimulation of chemotactic agents and cell-mediated immune responses, and, in addition, activation of the complement system and humoral responses.
1.4 Inflammation
The successful isolation and maintenance of the infundibulum in vitro has allowed histological modelling of the major infundibular changes seen in acne and elucidation of the cellular inflammatory factors that contribute to acne pathogenesis.[68–70] Introduction of IL-1α to the isolated follicular infundibulum in vitro caused a hypercornification and scaling, which was similar to that seen in comedones and other inflammatory skin disorders. Other research supports these data. IL-1α exists in high concentrations in open comedones,[71] IL-1α immunoreactivity is present in sections of human sebaceous glands and infundibula,[72] and concentrations of IL-1α are up to 1000 times higher in intrafollicular keratinocytes than in most tissues.[73]
IL-1α may cause hypercornification by a direct effect on infundibular keratinocytes involving signal transduction through the IL-1 receptor or by the stimulation of release of other growth factors, e.g. vascular endothelial growth factor. IL-1α may also be the mediating factor between the rate of sebum production and the severity of acne. Alterations in composition of sebum or the rate of its excretion[74] may precipitate the release of IL-1α from infundibular keratinocytes, so stimulating comedogenesis. IL-1α also causes up-regulation of cytoplasmic retinoic-acid-binding protein (CRABP) II and small, proline rich protein 1 in keratinocyte cultures, which correlates with keratinocyte differentiation,[75] suggesting that IL-1α is a signal for keratinocyte terminal differentiation.
Progression of acne to inflammatory lesions also seems to involve the action of cellular inflammatory factors. Bioactive IL-1α-like material present in the majority of open comedones may be involved in the initiation of inflammation following rupture of the pilosebaceous follicle wall.[71] Also, in the isolated in vitro infundibulum, exposure to epidermal growth factor (EGF) or transforming growth factor-α promoted the rupture of the infundibulum.[70] This mechanism may lead to the disorganisation of keratinocytes and movement of the highly inflammatory sebum into the dermis to form pustular acne lesions.[76,77] Furthermore, there is increasing evidence that the skin is an immunocompetent organ whose cells are capable of modulating both inflammatory and immune responses. The pro-inflammatory cytokine TNFα is also expressed in the PSU.[78] The existence of a cascade of events leading to stimulation of pro-inflammatory agents may be pivotal to the transition from non-inflammatory to inflammatory acne.
IL-1α and EGF may also be involved in the resolution of acne lesions. Comedone development is associated with atrophy of the sebaceous gland and a reduced excretion of sebum.[79] This may remove the stimulus to release IL-1α, thereby preventing further hypercornification and inflammation. Levels of the EGF receptor reduce with increasing age.[80] This may lead to reduction in the sensitivity of infundibular keratinocytes to EGF, and the prevention of infundibular disorganisation and inflammation. This model provides the basis for the spontaneous resolution of acne as patients grow older.
These data are very persuasive towards suggesting key roles for cellular inflammatory factors in acne pathogenesis. However, more research is required to further elucidate the full role of IL-1α and other cytokines in comedogenesis and the evolution of inflammatory lesions.
1.5 Other Pathogenic Factors Affecting Cell Proliferation and Differentiation
A range of factors has been implicated in cell proliferation and differentiation, and it is likely that some if not all of them contribute to comedogenesis (table I). These factors include lipoxygenases, linoleic acid and retinoids.
1.5.1 Lipoxygenases
A role for lipoxygenases in the pathogenesis of acne has recently been shown in a study demonstrating a specific lipoxygenase inhibitor to be clinically effective in the treatment of patients with inflammatory acne.[81] The efficacy of the drug was found to correlate with its ability to reduce total lipid levels, especially pro-inflammatory lipids, in sebum. These preliminary results suggest that future anti-acne compounds should be targeted at reducing pro-inflammatory lipids in sebum and thereby down-regulating acne-related inflammatory signals.[81]
1.5.2 Linoleic Acid
Linoleic acid has been implicated in acne pathogenesis because of its effect on sebocyte differentiation[41] and its role in the disturbed keratinisation of the follicular infundibulum.[82,83]
The low levels of skin surface linoleic acid found in patients with acne[19] may play a role in triggering hyperkeratinisation and subsequent comedogenesis. It has been postulated that the low linoleic acid concentration in sebum imposes a state of fatty acid deficiency on the cells of the follicular epithelium, resulting in abnormal differentiation with subsequent hyperkeratosis.[82] Dietary deficiency of linoleic acid, which is the major polyunsaturated fatty acid in normal skin, results in a characteristic scaly skin disorder.[83] Furthermore, topically applied linoleic acid is comedolytic and can reduce the size of microcomedones.[84] However, evidence is scarce for abnormalities in sebaceous lipids other than linoleic acid being involved in comedogenesis.[19]
Sebum composition changes with age. Prepubertal children have higher concentrations of sebum linoleic acid than do young adults and it has been suggested that this may account for the low prevalence of acne in young children.[85] The metabolism of polyunsaturated fatty acids is highly active in the epidermis. Polyunsaturated fatty acids are metabolised mainly into monohydroxy fatty acids, which have demonstrated anti-inflammatory properties in vitro.[84] Linoleic acid deficiency would therefore be expected to lead to reduced production of these anti-inflammatory metabolites and exacerbate the inflammatory processes in acne. Linoleic acid was found to decrease inflammation due to phagocytosis and generation of reactive oxygen species (ROS).[86] It is possible that the decreased levels of linoleic acid in acne comedones may contribute to, or exacerbate, inflammatory acne through elevated neutrophil-mediated phagocytosis and ROS generation. However, since hyperseborrhoea persists despite resolution of acne and production of comedones, the relative deficiency of linoleic acid in sebum can only partly contribute to acne pathogenesis.
1.5.3 Retinoids
Retinol (vitamin A) and its biologically active retinoid metabolites are essential for the maintenance of epithelial differentiation. Retinoids influence cell proliferation and differentiation, modify immune reactions, exert anti-inflammatory actions, regulate DNA synthesis with subsequent differential expression of specific proteins, and suppress the production of sebum from the sebaceous glands. The mechanism of action of retinoids is dependent upon the target tissue. In epidermal keratinocytes, retinoid activity is mediated by binding to nuclear receptors that are part of the steroid/thyroid receptor family. Retinol is converted to retinoic acid, which binds to CRABP. This protein transports retinoic acid to the nucleus where it interacts with retinoic acid receptors (RARs). The RAR complex dimerises with a second RAR complex comprised of 9-cis-retinoic acid and a receptor designated as RXR (since initially the identity of the ligand was unknown). This dimer then acts as a transcription factor and alters the expression of selected genes and subsequent epithelial activity.[87,88] CRABP, which is differentially expressed during squamous differentiation of human epidermal keratinocytes, may control the concentration of retinoic acid in the cell and, therefore, indirectly regulate gene expression.[89]
Retinoids can affect the proliferation of human epidermal keratinocytes and sebocytes either positively or negatively, and influence the multi-step programme of differentiation in epidermal keratinocytes at specific stages.[90,91] In an immortalised human sebaceous gland cell line, the addition of retinoids to the culture medium significantly inhibited the proliferation of selected cell clones.[91] Similarly, retinoic acid was found to induce ultrastructural changes and to inhibit proliferation in cultured human keratinocytes.[92] Isotretinoin has been shown to markedly increase retinol levels in sebaceous glands, while decreasing levels of dehydroretinol (vitamin A2).[93] Since dehydroretinol is known to accumulate in hyperproliferative, keratinising skin lesions, its reduction with isotretinoin treatment may relate to a reduction in cell proliferation or to dedifferentiation. Retinoids and their associated receptors may, therefore, play a role in hyperkeratinisation and comedogenesis. This is supported by the fact that both topical and oral retinoids benefit the majority of acne patients. It is now believed that the action of retinoids via RARs and their anti-inflammatory actions account for their therapeutic effect in acne.[94] An additional mechanism of action of the retinoids has recently been suggested, following the realisation that isotretinoin interacts not only with endogenous retinoid metabolism but also with androgen metabolism in the sebaceous glands.[37]
2. An Overall Theory for Acne Pathogenesis
Acne is essentially a sub-clinical and clinical inflammatory disease of the PSU, involving abnormalities in sebum production, follicular keratinisation, bacterial proliferation, inflammation and delayed-type immune response. Despite much research, the aetiology and pathogenesis of acne are not completely understood. However, emerging evidence points to key factors in the formation of the microcomedone and its progression to the inflammatory lesions of severe acne. Figure 3 shows a proposed overall scheme for acne pathogenesis.
The earliest morphological change in the PSU is abnormal follicular keratinisation with subsequent microcomedone formation. The onset of acne often corresponds with increased androgen production at puberty, leading to increased sebum production. Although seborrhoea is more intense in individuals who are acne prone than in those who are free of acne, only some hyperandrogenic patients present with acne despite showing much virilisation.[38,62] This suggests that increased sebum production may stimulate or exacerbate an underlying abnormality, but that seborrhoea alone is not sufficient to initiate microcomedone formation. Familial nevus-like sebaceous hyperplasia is characterised by hyperplastic sebaceous glands and hyperseborrhoea, but no inflammatory lesions.[95,96] Patients with atopy syndrome or manifest atopic dermatitis show less severe acne,[97] which may be in part due to a different composition or lower volume of sebum production. Seborrhoea, in patients with acne, may lead to a proliferation of bacteria (particularly P. acnes) by providing an ideal anaerobic medium for their growth. The chemotactic factors produced by P. acnes and sebum may then cause lymphocyte attraction and expression of the inflammatory cytokine IL-1α by CD4+ cells. IL-1α causes the hypercornification and scaling characteristic of minor comedones. A range of other factors, including linoleic acid deficiency and abnormalities in retinoids and/or their associated receptors may also play a role in hyperkeratinisation and comedogenesis.
Secondary or late-stage inflammatory processes underlie the progression from microcomedones to mature comedonal and/or inflammatory acne. A cascade of events leading to the stimulation of pro-inflammatory agents may be pivotal to the development of inflammatory lesions. Sebocytes and P. acnes both cause expression of IL-1α and other cellular inflammatory proteins that may lead to accumulation of polymorphonuclear leucocytes and rupture of the pilosebaceous follicle wall. Linoleic acid deficiency may lead to enhanced neutrophil-mediated phagocytosis and ROS generation, with subsequent exacerbation of inflammation. P. acnes may further contribute to inflammation via the activation of cell-mediated immune processes. Movement of sebum into the dermis is also highly inflammatory. Differences in sensitivity to P. acnes might explain variations in the severity of inflammatory acne amongst individuals. Genetic factors may also play a role in determining individual susceptibility and severity.
While there is an increasing amount of information on acne pathogenesis, some key questions remain unanswered. Further research is needed on the underlying molecular and non-inflammatory mechanisms that cause comedogenesis, and the secondary inflammatory mechanisms that lead to the development of visible inflammatory acne lesions.
3. Pathogenesis-Related Treatment Approaches
There is currently a range of effective treatments for acne vulgaris but no recommended management outlines; however, some do exist on the national level in some countries. Early and effective intervention is extremely important. The scarring associated with severe inflammatory acne is primarily responsible for the long-term physical and psychosocial problems of acne vulgaris.[3,5–8] Unfortunately, facial scarring may affect up to 95% of patients with acne. The degree and type of scarring are related to the severity and duration of acne before the commencement of effective therapy. A time delay of up to 3 years between acne onset and adequate treatment has been related to the ultimate degree of scarring.[98] The primary goals of acne treatment are, therefore, to alleviate clinical symptoms and prevent scarring.
Successful acne therapy should be based on the treatment of both the pathogenic causes and the clinical symptoms. Therapeutic goals are to:
-
reduce sebum production
-
reverse hyperproliferation and normalise keratinisation
-
clear existing microcomedones and comedones
-
reduce P. acnes colonisation and inflammation
-
prevent development of new microcomedones, and subsequent comedones and inflammatory lesions and
-
clear existing inflammatory acne lesions.
Table II lists the commonly used treatments for acne and their associated pathogenic activities. Topical treatments are generally used for mild to moderate acne, whereas systemic treatments are generally used in more moderate acne. The systemic agents are associated with more significant and diverse adverse effects than the topical agents.[99] In brief, retinoids have strong comedolytic and anti-comedogenic effects, moderate anti-inflammatory effects, and some direct and more indirect weak antibacterial effects. Conversely, antibacterials (including azelaic acid and benzoyl peroxide) are more or less strongly antibacterial with some comedolytic and anti-inflammatory effects.
3.1 Topical Treatments
Current topical therapies address three of the four main factors identified in acne pathogenesis, although no single topical therapy is effective against all three. Only systemic isotretinoin and oral contraceptives possess sebosuppressive activity.[3,94,100]
3.1.1 Topical Retinoids
Retinoids are molecular agents that act via RARs to affect proliferation, differentiation and inflammation. In the past, topical retinoids were generally limited to treating comedonal acne because of perceived tolerability limitations and under-recognition of their anti-inflammatory effects; however, they are equally effective in the treatment of inflammatory and non-inflammatory lesions.
The first-generation retinoids, tretinoin and isotretinoin, have no or weak anti-inflammatory effects when used topically. While they effectively treat acne lesions, their use is limited by the occurrence of initial pustular flaring and irritation shortly after initiation of therapy.[101] Molecular modification has resulted in the development of second-generation mono-aromatic compounds, etretinate and acitretin, which are synthetic analogues of the first-generation molecules. Recently, further modification has produced the polyaromatic third-generation retinoids known as arotinoids, adapalene and tazarotene.[102]
Adapalene, a novel naphthoic acid derivative, is the first of the third-generation retinoids to be approved for the treatment of acne vulgaris since the introduction of tretinoin. It addresses many of the problems that have limited the effectiveness of long-term topical retinoid therapy: local skin irritation and photo-instability are reduced, while comedolytic, keratolytic and anti-inflammatory activity are present.[101] Analysis of follicular casts from cyanoacrylate strips revealed a significant increase in ceramide levels following treatment with adapalene or tretinoin, confirming that these drugs influence follicular keratinisation and stabilise barrier functions.[103] Adapalene has also demonstrated moderate to potent anti-inflammatory activity in several in vivo and in vitro models.[104] Recently, a novel anti-inflammatory mechanism of adapalene has been proposed at the cellular level, involving the toll-like receptors (TLR). Adapalene and tretinoin have been shown to inhibit the expression of TLR2 on monocytes and macrophages, inhibiting the release of cytokines by these cells and thereby suppressing an inflammatory response.[105] Several studies have demonstrated that adapalene 0.1% gel is at least as effective as 0.025% tretinoin gel in reducing the number of acne lesions, while being significantly less irritating.[106–109] In addition, adapalene demonstrates a faster onset of action than tretinoin,[108,110] leading to improvements in quality of life[110] and possibly enhanced patient compliance.
Tazarotene is a synthetic acetylenic retinoid approved for the treatment of mild to moderate acne. Topical gel application provides direct delivery of tazarotene into the skin, where it is rapidly hydrolysed to its active metabolite, tazarotenic acid. Tazarotenic acid binds to nuclear RARs, affecting keratinocyte differentiation, cell proliferation and inflammation.[111] The superior efficacy and comparable safety profile of tazarotene 0.1% gel to tretinoin has been reported in two multicentre, double-blind, randomised studies in patients with mild to moderate facial acne vulgaris.[112,113] Dryness, peeling, erythema, pruritus, burning and itching with both tazarotene and tretinoin never exceeded trace levels in either of these studies.
Overall the third-generation retinoids are equally effective as the first-generation, with a slightly faster onset of action and an improved tolerability profile.
3.1.2 Topical Antibacterials
Azelaic acid is a dicarboxylic acid derivative that demonstrates moderate antibacterial and keratolytic activity, as well as weak anti-inflammatory effects. Clinical studies have shown it to be as effective as benzoyl peroxide or tretinoin in the treatment of mild to moderate acne, but better tolerated with mild transient erythema and cutaneous irritation the most frequently reported adverse events.[99]
Benzoyl peroxide is the gold standard in the treatment of mild to moderate inflammatory acne. It has potent antibacterial and weak comedolytic activity; however, local adverse effects such as drying and irritation are common.[94]
Topical antibacterial agents such as tetracycline, clindamycin and erythromycin are good alternatives to benzoyl peroxide, as they not only reduce the population of P. acnes in sebaceous follicles, but also demonstrate indirect comedolytic and weak anti-inflammatory activity. All of the topical antibiotics can cause local irritation,[99] which may be influenced by the vehicle used.
3.2 Systemic Treatments
Systemic isotretinoin and oral contraceptives are the only agents to effectively combat each of the four pathogenic factors of acne.
3.2.1 Oral Antibacterials
The oral antibacterials, erythromycin, clindamycin, co-trimoxazole, trimethoprim and the tetracyclines (tetracycline, minocycline, doxycycline and lymecycline) are widely used for the treatment of moderate to severe inflammatory acne.[99,114] These agents suppress the growth of P. acnes and also inhibit bacterial lipases, reducing the concentration of free fatty acids.[21] Tetracyclines are prescribed most frequently as they are both effective and inexpensive. However, the adverse effects of tetracyclines are well known and include gastrointestinal tract disturbances, vaginal yeast infections and photosensitivity reactions.[99,114] Erythromycin, clindamycin and minocycline are useful in patients with tetracycline-resistant acne. The development of bacterial resistance is an important consideration with the use of all systemic antibacterial agents but there are fewer reports of P. acnes resistance with minocycline than with tetracycline or doxycycline.[99]
3.2.2 Systemic Retinoids
Systemic retinoids, in particular isotretinoin, are the most effective therapy for moderate to severe inflammatory acne and for patients unresponsive to conventional therapy.[21,94] Systemic isotretinoin is also the drug of choice in severe seborrhoea, as it reduces sebum excretion rates by a much greater extent than any other known agent.[115] The major disadvantage of isotretinoin is its teratogenicity and significant adverse effect profile. Common adverse effects include profound dryness of the mucous membranes, stiffness, fatigue, headaches, inflammatory bowel disease, conjunctivitis, peeling of the skin from the palms and soles, transient abnormalities in liver function tests and elevations in serum cholesterol and/or triglyceride levels.[21,116]
3.2.3 Hormonal Therapy
The adverse effects of hormonal therapy are usually more moderate than those of systemic retinoids.[117] Anti-androgen therapy plus ethinylestradiol combination is the most effective treatment for adolescent females with moderate to severe acne plus seborrhoea and/or any signs of hirsutism and/or androgenic alopecia, and in those with late onset acne. The general mechanism of the anti-androgens such as cyproterone (cyproterone acetate), chlormadinone (chlormadinone acetate) or drospirenone is the suppression of sebocyte activity,[118] and probably follicular keratinocyte activity that can be measured by sebum excretion rates or comedo counts. The oestrogens suppress ovarian androgen production[118] and increase peripheral sex hormone binding globulin levels. Glucocorticosteroids are rarely used; however, late onset adrenogenital syndrome patients benefit from such treatment.[119] Other contraceptive pills containing progestogens such as dienogest, desogestrel or norgestimate are less effective when compared with the combinations mentioned above; however, they are more effective than the combination of ethinylestradiol plus levonorgestrel.
3.2.4 Combination Therapies
Because of the multifactorial nature of the pathogenesis of acne, many dermatologists consider it insufficient to treat the disease with a single therapy. No single therapy is able to counter both growth of P. acnes and comedogenesis as effectively as the combination of antibacterials and retinoids.[102,120,121] Combination therapies have been developed to target two or more of the causative elements of the disease, for example a retinoid that combats comedogenesis and inflammation in combination with an antibacterial to arrest the proliferation of P. acnes. Clinical trial results support the use of combinations of topical retinoids plus topical or oral antibacterials,[122,123] and topical retinoids plus topical benzoyl peroxide[124,125] as the most effective therapies for acne vulgaris. Using a combination of agents opens up avenues to treat more of the factors involved in the disease pathogenesis and, in clinical practice, the combination of topical retinoids with topical antibacterials has proven one of the most effective therapeutic options.[102,120,121] When topical retinoids are added to antibacterials, the addition of both agents produces faster and significantly greater reductions in acne lesions than when using antibacterials alone. The antibacterials treat current lesions rapidly by acting quickly to reduce bacterial colonisation and, to a certain extent, inflammation. Topical retinoids act more slowly to treat the underlying cause and help prevent the formation of new lesions as a result of their immunomodulatory effects on inflammation and comedogenesis. The rapid and lasting effects of the antibacterial plus retinoid combination therapy are likely to have a positive effect on both patient compliance, and on their self-esteem and psychological well-being.
The major benefits of combination therapy are only realised when both treatments are initiated from the start of therapy, even for inflammatory acne. There is no need to delay the use of a retinoid until after a course of antibacterial therapy. This is particularly applicable to the use of the third-generation retinoids because of their significantly reduced potential to cause flaring and irritation. A reduced irritancy profile and greater ease of use is likely to lead to improved patient compliance in the long-term, which is important for both acute and maintenance treatment of acne. Stopping the antibacterial after 3–4 months of the combination regimen and continuing the retinoid for long-term maintenance therapy seems to be a prudent and highly effective strategy, given the concerns of bacterial resistance as a result of long-term antibacterial use.[126]
4. Conclusion
In conclusion, seborrhoea, P. acnes colonisation and proliferation, and inflammatory and immune responses all contribute to microcomedone formation and the progression to comedones and inflammatory acne lesions. A greater understanding of the triggers for initiation of microcomedone formation and transformation of non-inflammatory to inflammatory lesions is essential if current and new treatments are to be used optimally. Acne is a highly treatable and preventable disease, and combination therapy targeted at the multiple pathogenic mechanisms underlying the disease is the state of the art in present day management.
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Acknowledgements
Professor Gollnick has conducted clinical studies for Galderma, Schering Berlin (AG), Yamanouchi, Hoffmann-la Roche and Hermal Company. Preparation of this manuscript was supported by Galderma International.
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Gollnick, H. Current Concepts of the Pathogenesis of Acne. Drugs 63, 1579–1596 (2003). https://doi.org/10.2165/00003495-200363150-00005
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DOI: https://doi.org/10.2165/00003495-200363150-00005