Acne. Current pathophysiologic considerations

Seborrhea, follicular hyperkeratosis, propionibacteria, and inflammatory reactions are the most important factors leading to acne. The combination of increased sebum producation and follicular hyperkeratosis facilitates an increased growth of Propionibacterium acnes. Its metabolic products lead to follicular inflammation and, in extreme cases, even to perifollicular abscesses. Sebum production is influenced by androgens, so that abnormalities in androgen levels can produce seborrhea and acne. Follicular hyperkeratosis may be triggered by a relative deficiency in linoleic acid, peroxides from sebum components, and especially by inflammatory mediators such as interleukin-1. Bacterial metabolic products such as lipases, proteases, or chemotactic factors lead to the perifollicular inflammation. This inflammation is not only a response to other pathogenetic factors, but also a cause of acne. An initial mild perifollicular inflammation can induce comedogenesis via a variety of mediators. The influence of dietary factors on the initiation and course of acne has recently received increased recognition. A connection has been postulated between acne and a high nutrients with glycemic index, as well as with milk products.     

Akne

Seborrhea, follicular hyperkeratosis, propionibacteria, and inflammatory reactions are the most important factors leading to acne. The combination of increased sebum producation and follicular hyperkeratosis facilitates an increased growth of Propionibacterium acnes. Its metabolic products lead to follicular inflammation and, in extreme cases, even to perifollicular abscesses. Sebum production is influenced by androgens, so that abnormalities in androgen levels can produce seborrhea and acne. Follicular hyperkeratosis may be triggered by a relative deficiency in linoleic acid, peroxides from sebum components, and especially by inflammatory mediators such as interleukin-1. Bacterial metabolic products such as lipases, proteases, or chemotactic factors lead to the perifollicular inflammation. This inflammation is not only a response to other pathogenetic factors, but also a cause of acne. An initial mild perifollicular infammation can induce comedogenesis via a variety of mediators. The influence of dietary factors on the initiation and course of acne has recently received increased recognition. A connection has been postulated between acne and a high nutrients with glycemic index, as well as with milk products.     

The pathophysiology of acne vulgaris in children and adolescents, part 2: Tailoring treatment

Various pathophysiologic factors are involved in the development of acne lesions, microcomedones, comedones, and inflammatory lesions. These factors include follicular hyperkeratosis, increased colonization of follicles by Propionibacterium acnes, increased sebum production, and inflammatory mediators. Optimal treatment of acne involves the use of agents that address these various underlying pathogenetic factors.     

New developments in our understanding of acne pathogenesis and treatment

Abstract:  Interest in sebaceous gland physiology and its diseases is rapidly increasing. We provide a summarized update of the current knowledge of the pathobiology of acne vulgaris and new treatment concepts that have emerged in the last 3 years (2005–2008). We have tried to answer questions arising from the exploration of sebaceous gland biology, hormonal factors, hyperkeratinization, role of bacteria, sebum, nutrition, cytokines and toll-like receptors (TLRs). Sebaceous glands play an important role as active participants in the innate immunity of the skin. They produce neuropeptides, excrete antimicrobial peptides and exhibit characteristics of stem cells. Androgens affect sebocytes and infundibular keratinocytes in a complex manner influencing cellular differentiation, proliferation, lipogenesis and comedogenesis. Retention hyperkeratosis in closed comedones and inflammatory papules is attributable to a disorder of terminal keratinocyte differentiation. Propionibacterium acnes, by acting on TLR-2, may stimulate the secretion of cytokines, such as interleukin (IL)-6 and IL-8 by follicular keratinocytes and IL-8 and -12 in macrophages, giving rise to inflammation. Certain P. acnes species may induce an immunological reaction by stimulating the production of sebocyte and keratinocyte antimicrobial peptides, which play an important role in the innate immunity of the follicle. Qualitative changes of sebum lipids induce alteration of keratinocyte differentiation and induce IL-1 secretion, contributing to the development of follicular hyperkeratosis. High glycemic load food and milk may induce increased tissue levels of 5α-dihydrotestosterone. These new aspects of acne pathogenesis lead to the considerations of possible customized therapeutic regimens. Current research is expected to lead to innovative treatments in the near future.     

Hormonal therapy for acne using oral contraceptive pills

The etiology of acne vulgaris is multifactorial and complex. The four key factors involved in the development of acne include follicular plugging, inflammation, the presence and activity of Propionibacterium acnes, and sebum. Androgen hormones stimulate the sebaceous gland and promote sebum excretion. Therefore, therapies that have an overall antiandrogen effect, like combination oral contraceptive pills, may be useful in the management of acne vulgaris. Numerous combination oral contraceptive pills have been evaluated in the treatment of acne vulgaris and have been found to be effective. With a thorough understanding of their proper use and potential associated risks, these hormonal treatments may be prescribed safely and effectively to women with acne.     

The pathophysiology of acne vulgaris in children and adolescents, Part 1

Microcomedones, the earliest lesions of acne, appear at adrenarche, which typically occurs at about 8 years of age when androgens of adrenal origin begin to stimulate follicular hyperkeratosis and sebaceous hyperplasia in pilosebaceous units on the face. Comedones appear about 2 years later, when androgens of gonadal origin are produced and colonization of follicles by Propionibacterium acnes increases. Inflammatory lesions, such as pustules, papules, and nodules, are the result of the host's immune responses to P acnes; the proinflammatory cytokines are released by immunocompetent leukocytes that are recruited in response to this bacterium and its metabolic by-products. Androgens also affect the barrier function of the skin, and disturbances of barrier function may stimulate epidermal DNA synthesis. This leads to epidermal hyperplasia, which may also contribute to follicular hyperkeratosis in acne. Optimal treatment for this disorder will address these various pathophysiologic factors.     

(7) Genetic control of sebum excretion and acne—a twin study

Twin studies have shown the almost 100% occurrence of acne in identical twins, but the authors did not compare the severity of acne nor sebum excretion rate. We have investigated 20 sets of identical and 20 sets of non-identical twins. The acne was graded by the Burke and Cunliffe technique¹ and sebum excretion measured by the gravimetric technique.²
The non-identical twins had dissimilar levels of sebum excretion ( P < 0·01) and acne ( P < 0·01). However, although identical twins had virtually identical rates of sebum excretion, they displayed a significantly different degree of acne severity ( P < 0·01).
These results were contrary to our hypothesis that identical twins would probably have a similar degree of acne severity. We concluded that sebum excretion is under genetic control but the development of lesions is modified by environmental factors, the most likely factors being variation in the growth rate of Propionibacterium acnes and its production of biological mediators of inflammation.     

Acne

Acne is a chronic disease with a high prevalence among adolescents. Key pathogenetic factors (and their clinical correlates) are increased sebum production (seborrhea), follicular hyperkeratosis (comedones), and perifollicular inflammation (papules and pustules). The disease is modulated by a variety of endogenous (androgens, IGF‐1, neuroendocrine factors) and exogenous (Propionibacterium acnes, diet, friction, ingredients of medical or cosmetic topical products) triggers. Acne is associated with high morbidity, and even mild manifestations may potentially cause considerable impairment in quality of life. Effective topical and systemic treatments are available. Optimal therapeutic results require continuous patient management over the course of the entire treatment period as well as adjustment of treatment modalities based on symptoms and disease severity.     

Expanding the microcomedone theory and acne therapeutics: Propionibacterium acnes biofilm produces biological glue that holds corneocytes together to form plug

The Propionibacterium acnes biofilm has previously been shown to exist via genomic studies and to make a biological glue which allows for adherence to follicular walls. This gylcocalyx polymer secreted by P acnes also finds its way into sebum composition where it causes the adhesiveness of keratinocytes leading to comedones. An appreciation of P acnes biofilms and secretions has implications in immunogenicity of the organism, clinical course of acne, and therapy for comedonal and inflammatory acne.     

Newer approaches in topical combination therapy for acne

Acne vulgaris is a common chronic inflammatory cutaneous disease involving the pilosebaceous unit. Its pathophysiology is multifactorial and complex, including obstruction of the pilosebaceous unit due to increased sebum production, abnormal keratinization, proliferation of Propionibacterium acnes (P. acnes), and inflammation. Topical agents are the most commonly used therapy for acne. First generation topicals mainly consist of single agent retinoids, benzoyl peroxide (BPO) and antibacterials that target comedones, P. acnes, and inflammation. Novel topical therapies include combination products with advanced vehicle formulations that target multiple acne pathophysiologies and offer simplified treatment regimes. For example, the combination of clindamycin and tretinoin in a unique vehicle formulation allows for progressive follicle penetration and decreased irritation, resulting in increased efficacy. Furthermore, adapalene or clindamycin with BPO combinations target comedones, inflammation, and P. acnes synergistically. These newer combination products have the potential to increase both efficacy and patient adherence when compared with single agent treatment.     

Involvement of adenosine triphosphate‐binding cassette subfamily B member 1 in the augmentation of triacylglycerol excretion by Propionibacterium acnes in differentiated hamster sebocytes

An onset of acne, a common inflammatory skin disease, is associated with excess sebum production and secretion in sebaceous glands. Because Propionibacterium acnes has been reported to augment intracellular sebum accumulation in sebaceous glands in hamsters, it remains unclear whether P. acnes influences sebum secretion from differentiated sebocytes. Both P. acnes culture media (Acnes73‐CM ) and formalin‐killed P. acnes (F‐Acnes73) dose‐dependently increased the extracellular levels of triacylglycerol (TG ), a major sebum component, and Rhodamine 123, a substrate of adenosine triphosphate‐binding cassette (ABC ) transporter, from differentiated hamster sebocytes (DHS ). In addition, the gene expression of the ABC subfamily B member 1 (ABCB 1) was dose‐dependently augmented by adding Acnes73‐CM and F‐Acnes73 into DHS . Furthermore, the F‐Acnes73‐induced increase of TG excretion was suppressed by PSC 833, a selective ABCB 1 inhibitor. On the other hand, peptidoglycan (PGN ), which is a Toll‐like receptor 2 (TLR 2) ligand in P. acnes , increased extracellular TG levels, transporter activity and ABCB 1 mRNA expression in DHS . The PGN ‐augmented TG excretion was suppressed by PSC 833. Thus, these results provide novel evidence that P. acnes facilitates sebum secretion due to the activation of ABCB 1 concomitantly with the increased ABCB 1 expression, which may result from the activation of the TLR 2 pathway in DHS . Therefore, the ABCB 1 inhibitor is likely to become a candidate as a possible therapeutic for the treatment of acne.     

Systemic antibiotic therapy for acne: a review

Acne is a multifactorial disease of the pilosebaceous unit in the skin. Four contributing pathogenic factors need to be elucidated and include excess sebum production, follicular hyperkeratinization, colonization of the pilosebaceous unit by Propionibacterium acnes, which is a gram positive anaerobic diphtheroid, and the release of inflammatory mediators into the follicle and dermis. One or more of these factors are targeted by each of the systemic therapies for this disease and its variant, including systemic antibiotic therapies, which will be reviewed here.     

A microbial etiology of acne?

The view is advanced that sebum as originally produced must contain materials, other than lipids, which may serve as a selective substrate for growth of bacteria and yeasts. Growth of large numbers of P. acnes and P. granulosum in some follicles is considered to place those follicles at risk of undergoing pathological changes. Deleterious products of bacterial growth could be not only lipase and free fatty acids, but also other enzymes as well as bacterial antigens and unspecified toxins or irritants. The possibility is suggested that follicles heavily infested with P. acnes and P. granulosum may be identified by their reddish fluorescence under ultraviolet light, thus permitting identification and study of those which are at risk. Antibiotics may be helpful in reducing the formation of harmful bacterial products during continued growth of the organisms. The eventually self-limiting nature of the disease may be due to the immune response to bacterial products, or to an accommodation of the follicular epithelium to the long-continued presence of irritant materials within the follicle.     

Pathological mechanisms of acne with special emphasis on Propionibacterium acnes and related therapy

Acne is a common disease that in cases of extreme disfiguration can have severe consequences for the personality development of young people and is associated with a relatively high prevalence of depression and suicide. Spontaneous regression is common, but acne can extend into the fourth and fifth decades of life. The pathogenesis is still not fully understood. Factors promoting the development of acne are: increased sebum production, ductal cornification, bacterial colonization of the pilosebaceus ducts and inflammation. However, there is evidence that inflammation is not a factor but rather a consequence of the interaction of the other three factors. Propionibacterium acnes releases pro-inflammatory cytokines as well as antigens and mitogen(s), with cellular and non-cellular responses to these products triggering inflammation. Treatment is often frustran. Therapeutical strategies are needed based on new understandings of the pathomechanisms involved in acne. The aim of this review is to summarize the data on aetiopathological factors in acne and their contribution to acne pathology and therapy.     

Antibodies elicited by inactivated propionibacterium acnes-based vaccines exert protective immunity and attenuate the IL-8 production in human sebocytes: relevance to therapy for acne vulgaris

Propionibacterium acnes is a key pathogen involved in the progression of inflammation in acne vulgaris. We examined whether vaccination against P. acnes suppressed P. acnes-induced skin inflammation. Inactivation of P. acnes with heat was employed to create a P. acnes-based vaccine. Intranasal immunization in mice with this inactivated vaccine provoked specific antibodies against P. acnes. Most notably, immunization with inactivated vaccines generated in vivo protective immunity against P. acnes challenge and facilitated the resolution of ear inflammation in mice. In addition, antibodies elicited by inactivated vaccines effectively neutralized the cytotoxicity of P. acnes and attenuated the production of proinflammatory cytokine IL-8 in human sebocyte SZ95 cells. Intranasal immunization using heat-inactivated P. acnes-based vaccines provided a simple modality to develop acne vaccines. These observations highlight the concept that development of vaccines targeting microbial products may represent an alternative strategy to conventional antibiotic therapy.     

Acne-like chronic inflammatory activity of Propionibacterium acnes preparations in an animal model: correlation with ability to stimulate the reticuloendothelial system

The ability of strains and fractions of killed propionibacteria suspensions to produce chronic rat ear inflammation after intradermal injection of 70-micrograms aliquots was highly correlated with production of splenomegaly in the mouse after i.p. injection of 1.4 mg Propionibacterium acnes strains CN 6134, VPI 0009, ATCC 11828, and UCLA SC and N1 produced a 2- to 3-fold increase in rat ear thickness and a 5- to 7-fold increase in mouse spleen weight 15 days post injection. In contrast P. granulosum CN 5888, P. acnes UCLA 6S and periodated, acetylated, or 12-h cultures of VPI 0009 were inactive or weakly active as stimulators of chronic ear inflammation and splenomegaly. Active strains produced in the rat ear a transepidermal elimination response characterized by follicular encapsulation and the formation of secondary comedones. These effects correlated with persistence of phagocytized bacteria within macrophages. Furthermore, when rats were first immunized and then challenged with active strains of P. acnes, an increased sensitivity to low doses of P. acnes and a chronic exacerbation of inflammation was observed.     

Acne: topical treatment

Acne vulgaris is a common skin disease, affecting about 70-80% of adolescents and young adults. It is a multifactorial disease of the pilosebaceous unit.(1) The influence of androgens at the onset of adolescence leads to an enlargement of the sebaceous gland and a rise in sebum production. Additional increased proliferation and altered differentiation of the follicular epithelium eventually blocks the pilosebaceous duct, leading to development of the microcomedo as the primary acne lesion. Concomitantly and subsequently, colonization with Propionibacterium acnes increases, followed by induction of inflammatory reactions from bacteria, ductal corneocytes, and sebaceous proinflammatory agents (Fig 1).(2-5)     

The facial red fluorescence of ultraviolet photography: is this color due to Propionibacterium acnes or the unknown content of secreted sebum?

Background/purpose: Red fluorescence of the face induced by ultraviolet light is thought to be due to Propionibacterium acnes . However, recently there are reports correlating this red fluorescence with the amount of facial sebum secretion. This study was performed to investigate the relationship between the areas of facial red fluorescence with culture results of P. acnes and the amount of sebum secretion.
Methods: Nineteen patients with acne were included. P. acnes cultures were done on specimens obtained from areas with red fluorescence. In addition, the amount of facial sebum secretion and the skin surface pH (SSPH) were measured. Correlation analysis of these parameters and the culture results were performed with the image analysis data from the red fluorescence of the face.
Results: P. acnes was cultured in 36.5% of cases. The correlation of the culture rate with the red fluorescence areas was not significant. After classifying the patients into high-sebum and low-sebum groups, there was a significant difference in the red fluorescence areas. In addition, the red fluorescence area correlated with the SSPH.
Conclusions: The red fluorescence area showed a stronger correlation with sebum secretion than with the presence of P. acnes . This finding suggests that the red fluorescence is affected by sebum not just P. acnes .     

Medikamentöse Therapie der Akne

Acne is treated according to the clinical picture and the pathophysiologically relevant mechanisms, such as seborrhea, follicular hyperkeratosis, P. acnes colonisation,and inflammation. In mild forms of acne, topical therapy is most appropriate. Comedonal acne can be treated with topical retinoids; papulopustular acne with a combination of retinoids and topical antimicrobial substances (benzoyl peroxide, antibiotics, or azelaic acid). Moderate forms or those with extrafacial involvement can be treated with oral antibiotics combined with topical retinoids or benzoyl peroxide. Acne conglobata and other severe manifestations are treated with oral isotretinoin. Women are also treated with oral contraceptives containing anti-androgenic progestins. If inflammation is prominent, initial short term treatment with oral glucocorticoids is helpful. Second-line agents include oral zinc or dapsone. Following successful treatment, topical retinoids are suitable for maintenance therapy.