Clinics in Dermatology (2014) 32, 389–396
Acne as a chronic systemic disease Christos C. Zouboulis, MD, PhD ⁎ Departments of Dermatology, Venereology, Allergology, and Immunology, Dessau Medical Center, Auenweg 38, 06847 Dessau, Germany
Abstract Acne is the most common skin disorder. In the majority of cases, acne is a disease that changes its skin distribution and severity over time; moreover, it can be a physically (scar development) and psychologically damaging condition that lasts for years. According to its clinical characteristics, it can be defined as a chronic disease according to the World Health Organization criteria. Acne is also a cardinal component of many systemic diseases or syndromes, such as congenital adrenal hyperplasia, seborrhea-acne-hirsutism-androgenetic alopecia syndrome, polycystic ovarian syndrome, hyperandrogenism-insulin resistance-acanthosis nigricans syndrome, Apert syndrome, synovitis-acne-pustulosishyperostosis-osteitis syndrome, and pyogenic arthritis-pyoderma gangrenosum-acne syndrome. Recent studies on the Ache hunter gatherers of Paraguay detected the lack of acne in association with markedly lower rates of obesity, diabetes mellitus, hyperlipidemia, and cardiovascular diseases, a finding that indicates either a nutritional or a genetic background of this impressive concomitance. © 2014 Elsevier Inc. All rights reserved.
Introduction Acne is the most common skin disease and also the lead diagnosis in medicine1; however, it is widely considered to be a simple, self-limited disorder of adolescents. The majority of lay people, as well as many physicians, believe that treatment of acne is only required in extreme cases. Unfortunately, not only successful acne treatment can become difficult but acne, itself, can be a devastating disease for the patient, both because it manifests on visible body parts of children and adolescents, who are vulnerable both socially and psychologically, but also because it can heal with considerable scar sequelae.1 The pathogenesis of acne is dominated by up-regulation of inflammatory signaling in skin epithelial cells, leading to excessive sebum production and hyperproliferation/hyperkeratosis of the infrainfundibulum of the sebaceous follicles.2–5 Hypercolonization of the sebaceous follicles with ⁎ Corresponding author. Tel.: + 49 340 5014000; fax: + 49 340 5014025. E-mail address: [email protected]. 0738-081X/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clindermatol.2013.11.005
Propionibacterium acnes, a commensal bacterium, has been considered as an additional pathogenetic factor.6 Several cellular or animal models are used for acne research6–15; nevertheless, there is no single cellular or animal model that encompasses all the pathogenic factors and their interactions in acne formation, which is a genuine human disease.
Acne is a chronic disease In most cases, acne is not an acute disease but rather a condition that continuously changes in its distribution and severity.1 Treatment of acne is usually necessary for months to, sometimes, years, and mostly, acne may cause scarring and associated negative psychological effects despite treatment. It is important for dermatologists to educate other clinicians and patients that acne is a chronic disease1,16 and not just a self-limited disorder of teenagers. For many patients, acne has characteristics that the World Health Organization (WHO) has used to define chronicity of diseases: A prolonged course, a pattern of recurrence or
390
C.C. Zouboulis
Fig. 1 WHO criteria for classifying acne as a chronic disease (after Gollnick et al.).1 Comparison of acne and atopic dermatitis, a widely accepted chronic disease, reveals striking similarities.
relapse, manifestation as acute outbreaks or slow onset, and a psychological and social impact that affects the individual’s quality of life16,17 (Figure 1). There is wide evidence that acne can be a physically (scar development) and psychologically damaging condition that lasts for years,18–24 even, if there is not always correlation with the clinician’s assessment of severity at one point in time.1,25 In addition, there is evidence that acne can persist into adult years in as many as 50% of individuals.19,26–29
Acne as a manifestation of systemic diseases Acne is an essential component of many systemic diseases or syndromes, 30 among them (1) congenital adrenal hyperplasia (CAH), (2) seborrhea-acne-hirsutismandrogenetic alopecia (SAHA) syndrome, (3) polycystic
ovarian syndrome (PCOS), (4) hyperandrogenism-insulin resistance-acanthosis nigricans (HAIR-AN) syndrome, (5) synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome, (6) pyogenic arthritis-pyoderma gangrenosumacne (PAPA) syndrome, and (7) Apert syndrome.
CAH CAH (OMIM 201910) represents a heterogeneous group of autosomal inherited enzymatic defects in the biosynthetic pathway of cortisol and/or aldosterone.31 21-hydroxylase (21-OH) deficiency due to mutations in the 21-hydroxylase gene (CYP21, 6p21.3) is the most common defect (95%).32 Cortisol deficiency results in oversecretion of adrenocorticotropic hormone (ACTH), and overstimulation and hyperplasia of the adrenals, via the impaired cortisol-mediated
Fig. 2 A female patient with acne due to nonclassical CAH before (A) and after treatment with prednisolone 5 mg/d orally over 6 months (B) (after Zouboulis and Piquro-Martin).38
Acne as a systemic disease negative feedback control of ACTH secretion from the anterior pituitary. Androgen excess affects the pilosebaceous units, resulting in androgenic alopecia, hirsutism, and acne. Classic CAH (complete loss of enzyme function), presenting in the neonatal period, occurs in 1/15,000 births, while late onset nonclassic CAH is more frequent, affecting 1% of the general population.33 Acne and hirsutism are the major skin manifestations of CAH and usually develop during adolescence. Classic CAH clinical manifestations, such as virilization, impaired fertility, short stature, early appearance of facial/axillary/pubic hair, and acne, are more severe. 31,34 Nonclassic CAH is also associated with hyperandrogenic manifestations, such as severe acne refractory to treatment, hirsutism, androgenic alopecia or seborrhea, but also with irregular menses and polycystic ovaries.35–37 The determination of 17-hydroxyprogesterone, the immediate substrate for 21-OH, is used for biochemical diagnosis.35 For mild nonclassical CAH with normal basal adrenal steroids, the ACTH stimulation test is recommended. Oral glucocorticoids and/or fludrocortisone reduce increased androgen production in CAH.33 The treatment of nonclassical CAH is symptom-associated. Low-dose prednisolone (2.5-5 mg/day; Figure 2) or low-dose dexamethasone (0.250.75 mg) can be administered orally at bedtime.31,38
SAHA syndrome The association of seborrhea and acne with hirsutism and/ or androgenetic alopecia in women was defined in 1982 as SAHA syndrome.39 It includes the dermatologic manifestations of androgen excess in women, either on the basis of high circulating androgen levels (hyperandrogenemia) or due to the capacity of the pilosebaceous apparatus to respond with increased sensitivity to normal circulating androgen levels (hyperandrogenism).40,41 The SAHA syndrome is classified into idiopathic, ovarian, adrenal, and hyperprolactinemic types,40 and can be associated with polycystic ovaries, cystic mastitis,
Fig. 3
391 obesity, insulin resistance (IR), and infertility.42 All four major signs of SAHA syndrome are present in approximately 20% of the patients; seborrhea is always present, acne occurs in 10% of the patients, androgenetic alopecia in 21%, and hirsutism in 6% of the patients (Figure 3).40,42,43 Androgen excess in women is one of the most frequent endocrine disorders considered to affect 5% to 10% of them in reproductive age. It can be caused by elevated androgen synthesis in adrenals and ovaries, disturbed peripheral metabolism of androgens or induction of metabolism and activation of androgens in the skin.41 The sebaceous gland is an important organ of active androgen formation, expressing all the necessary enzymes for the de novo biosynthesis of testosterone.2,44 Local androgen excess induces shortening of the follicular anagen phase and progressive conversion of terminal hair to intermediate ones, leading to androgenic alopecia45; moreover, up to 50% of the total circulating testosterone in women is produced in the skin and in other peripheral organs. The diagnosis of SAHA syndrome requires a complete history, physical examination with emphasis on evidence of androgen excess and—in the presence of hyperandrogenemiaassociated signs—laboratory investigations, including dehydroepiandrosterone sulphate, testosterone, prolactin, and 17-OH-progesterone to exclude hyperandrogenemia.3,40 Treatments for the dermatologic conditions of hyperandrogenism include lifestyle modification, oral contraceptives, hormonal antiandrogens, and insulin-sensitizing medications.46
PCOS The PCOS (OMIM 184700) is a complex endocrine disorder affecting 5% to 20% of women depending on their ethnical background. It is characterized by clinical and/or biochemical evidence of hyperandrogenism with oligo- and/ or anovulation and polycystic ovaries.47 Hyperandrogenemia and altered gonadotropin secretion, as well as IR, are involved in its pathogenesis. There is accumulating evidence for a strong genetic background of PCOS.48,49 A clear
SAHA syndrome with acne and hirsutism, signs of hyperandrogenism, without hyperandrogenemia.
392
C.C. Zouboulis
relationship with obesity-associated genes has recently been shown.50 Women with PCOS frequently suffer from infertility, acne, hirsutism, and alopecia.42 Acne is detected in about 23% to 35% of patients with PCOS, while the prevalence of PCOS in the acne group was estimated to be 27% or even higher. Women with severe acne, late onset acne, persistent acne, and acne resistant to conventional therapies are likely to have PCOS. Clinical examination hormonal examinations are mandatory for making the diagnosis.47 Gynecological examination routinely includes ovarian ultrasound, ovulation tests, and the validation of a menses calendar. Lifestyle intervention, insulin sensitizers (metformin), and oral contraceptives are the most common therapeutic approaches for the management of PCOS. In case that family planning is not an issue for the patients, oral contraceptives with an established antiandrogen efficacy can help to control both androgen levels and skin symptoms and hirsutism.46,47
The primary abnormality in patients with this syndrome is supposed to be IR with a compensatory elevation in insulin levels, which may have a direct short-term effect on the regulation of steroidogenesis in ovaries, leading to a subsequent overproduction of androgens.52 Hyperinsulinemia and hyperandrogenemia together stimulate epithelial proliferation and melanin accumulation and result in the cutaneous manifestation of AN. The binding of insulin to insulin receptors and insulinlike growth factor (IGF)-receptors on keratinocytes and fibroblasts leads to epidermal thickness, which probably induces formation of the AN lesions.53 The enhanced lipogenesis of the sebaceous gland caused by IGF-1 may indirectly lead to oily skin and acne formation in patients with HAIR-AN syndrome. A mutation in the fibroblast growth factor receptor 3 was recently reported to be associated with AN, hyperinsulinemia, and skeletal dysplasia.54 Current management of HAIR-AN syndrome resembles that of SAHA and PCOS.51,52
HAIR-AN syndrome
SAPHO syndrome
HAIR-AN is the acronym for hyperandrogenism, IR, and acanthosis nigricans (AN). HAIR-AN syndrome can be considered as a unique subtype of PCOS in women.51 Patients with the disorder usually present with clinical signs of hypandrogenemia, such as seborrhea, acne, hirsutism, menstrual irregularities, androgenic alopecia, deepening of voice, clitoromegaly, and changes in muscle mass, plus IR with diabetic symptoms, as well as AN (Figure 4). Five percent of women with hyperandrogenemia, are considered to have this condition.52 Generally, these patients have markedly elevated insulin levels, elevated or high-normal levels of testosterone and androstenedione, but normal levels of luteinizing hormone and prolactin. Adrenal function is normal.
The acronym SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) defines a syndrome, which was first described in 1987.55 It is a rare, probably underrecognized, disease with an estimated prevalence probably no greater than 1/10,000.30 It primarily affects children and young adults. 56 Three diagnostic criteria for this syndrome have been proposed: (1) chronic recurrent multifocal osteomyelitis with or without skin manifestations; (2) acute or chronic sterile arthritis associated with either pustular psoriasis or palmoplantar pustulosis or severe acne; and (3) sterile osteitis in the presence of one of the skin manifestations. Any of these three presentations is sufficient for diagnosis of this syndrome.57
Fig. 4
HAIR-AN syndrome presenting with papulopustular acne and hirsutism on the face, indicating a manifesting hyperandrogenemia.
Acne as a systemic disease SAPHO syndrome is characterized by a rheumatoid factor-negative osteoarthropathy and various dermatologic manifestations, such as acne/hidradenitis suppurativa/dissecting folliculitis of the scalp, psoriasis/pustular psoriasis/ palmoplantar pustulosis, Sweet’s syndrome, SneddonWilkinson disease, and pyoderma gangrenosum. The clinical presentation of acne varies greatly, from mild to severe type, such as acne conglobata or acne fulminans. These dermatologic conditions may occur concomitantly but may also precede or follow bone involvement.58 A long-term followup study of 120 confirmed cases showed 55% of patients with palmoplantar pustulosis, 31% with psoriasis vulgaris, and 25% with severe acne, whereas 16% patients did not exhibit skin manifestations.58 Association with inflammatory bowel diseases, such as Crohn’s disease and ulcerative colitis, has been reported. The pathogenesis of SAPHO syndrome remains poorly understood. Current results support the view that SAPHO syndrome may be triggered by an infectious state, leading to strong humoral and cellular inflammatory responses.59 Treatment experience of SAPHO syndrome is limited, mainly based on limited experiences in treating small groups of patients.60
PAPA syndrome The clinical triad of pyogenic sterile arthritis, pyoderma gangrenosum (PG), and acne conglobata was noted in several families and described with the acronym PAPA syndrome (OMIM 604416) in 1997.61 In 2002, the gene of CD2-binding protein 1 (CD2BP1; also called proline/ serine/threonine phosphatase-interacting protein 1, PSTPIP1) on chromosome 15q24–25.1 was identified as the responsible gene.62 PAPA syndrome belongs to the autoinflammatory diseases group, the CD2BP1 protein binds pyrin, which is an inhibitor of the inflammatory process. Because pyrin is expressed on neutrophils, but not on T or B cells, the decreased amount of unbound pyrin results in neutrophilic infiltration in arthritis, acne, PG, and other neutrophilic dermatoses.63 The manifestation of PAPA syndrome with its clinical triad varies in the affected family members. Arthritis is the most consistent sign, followed by acne and PG. Arthritis is the earliest sign occurring between ages 1 and 16 years.63 Being aseptic and seronegative, the pauci-articular, nonaxial arthritis of variable severity commonly affects knees, elbows, and ankles. At puberty, severe nodulocystic acne develops. PG occurs in adolescence or adulthood, usually after the appearance of acne. The transition of PAPA syndrome from inflammatory arthritis to cutaneous manifestations with acne and PG at puberty is notable. Of the triad, PG and acne may be present for decades. PAPA is responsive to systemic or locally administered glucocorticoids. Antimicrobial therapy is not effective. Dapsone can be helpful. Recombinant human interleukin
393 (IL)-1 receptor antagonists have shown efficacy in PAPA syndrome and other autoinflammatory diseases.64
Apert syndrome Apert syndrome (OMIM 101200), also known as acrocephalosyndactyly, was first described in 1906.65 Its prevalence is estimated to be 15/1,000,000, based on a recent population-based study, making up approximately 4% of all cases of craniosynostosis.66 Apert syndrome is inherited in an autosomal dominant manner and is characterized by synostoses of the extremities, vertebrae, and skull, with syndactyly of fingers and toes. Several Apert syndrome patients with acne have been described, having an unusual distribution with lesions extending to the surface areas of the forearms.67 Seborrhea and moderate to severe acne are the dermatologic hallmark of Apert syndrome, which often begins in early puberty.67 Histologic examination exhibits dilated follicular infundibula extending to mid-dermis, follicular abscesses in the upper and mid portions of the corium, and numerous larger sebaceous lobules. Plasma androgen levels and androgen receptor staining of sebaceous glands are normal.68 Two specific heterozygous missense germ-line mutations of the fibroblast growth factor receptor 2 gene (FGFR2) have been identified in patients with Apert syndrome.69 The two detected FGFR2 isoforms and their specific ligands are involved in mesenchymal-epithelial signaling, leading to downstream effects of activated FGFR2-signaling on follicular keratinocyte proliferation, sebaceous lipogenesis, and inflammatory cytokine response.70 In acne of Apert syndrome, FGFR2-mediated up-regulation of phosphoinositol-3 kinase (PI3K)/Akt may result in a nuclear deficiency of the transcription factor FoxO1, recently suggested to be a key transcription factor in the pathogenesis of acne vulgaris.71 The early onset of severe and persistent acne during puberty can be well explained by androgen-dependent up-regulation of fibroblast growth factor synthesis, which activates the mutated FGFR2 receptors; thus, overstimulating FGFR2-mediated downstream signal transduction, leading to a nuclear deficiency of FoxO1. Accumulating evidence supports the view that isotretinoin treatment restores decreased nuclear levels of FoxO1,72 which is in accordance with the excellent response of acne in Apert syndrome to oral isotretinoin treatment.
Dietary lipids and inflammatory process in acne Topically applied linoleic acid was shown to induce an almost 25% reduction in the overall size of microcomedones over a 1-month treatment period.73 Arachidonic acid, an essential, long-chain, proinflammatory ω-6 fatty acid, stimulates IL-8 and IL-6 synthesis in cultured human sebocytes74 and enhances synthesis of sebaceous lipids.75 Leukotriene B4 inhibition in vivo reduces concomitantly proinflammatory
394 sebaceous fatty acids and inflammatory acne lesions.76 The role of nutrition in acne still remains controversial. Inuit Eskimos, the inhabitants of the Okinawa Island, and the Chinese have been observed to develop acne with the changing of their nutrition habits.77 Westernized nutrition includes low amounts of ω-3-fatty acids and antioxidant vitamins and higher amounts of the proinflammatory ω-6 and trans-fatty acids.78 A current study reported that the Kitavan islanders of Papua New Guinea and the Ache hunter-gatherers of Paraguay do not have acne,79 but also present markedly lower rates of obesity, diabetes mellitus, hyperlipidemia, and cardiovascular diseases; however, other authors have suggested that these population studies may have detected a genetic background rather than a nutritional effect.80
Conclusions The manifestation and involvement of acne in different diseases/syndromes highlight the multifaceted nature of acne. In CAH, as well as SAHA, PCOS, and HAIR-AN syndromes, excessive hormones (in circulation or in situ) and/or exaggerated hormone response via aberrant hormone receptor expression/postbinding response induce the accelerated growth and differentiation of pilosebaceous units. The presence of acne in all syndromes reported above indicates the interplay of androgenic hormones in the pathogenesis.68 In daily medical practice, nonclassical CAH, PCOS, and SAHA syndrome should be excluded in patients with severe acne, acne tarda, acne associated with other signs (alopecia, hirsutism, or obesity), or acne recalcitrant to various therapies, especially in women. Acne accompanied by joint/bone involvement and/or other neutrophilic dermatoses, may be an early sign for SAPHO or PAPA syndrome, especially in a familial occurrence. The manifestation of acne in PAPA and SAPHO syndromes provides further evidence to the argument that acne is a genuine inflammatory disorder.2–5 The specific involvement of sebaceous gland in PAPA syndrome is unique among the so-called autoinflammatory diseases and raises the question of the targeted treatment against IL-1 may also benefit patients with acne.81
Acknowledgment The author thanks Dr. Razvigor Darlenski, Sofia, Bulgaria for his support in the arrangement of the manuscript.
References 1. Gollnick HP, Finlay AY, Shear N. Can we define acne as a chronic disease? If so, how and when? Am J Clin Dermatol. 2008;9:279-284.
C.C. Zouboulis 2. Zouboulis CC. Is acne vulgaris a genuine inflammatory disease? Dermatology. 2001;203:277-279. 3. Zouboulis CC. Acne and sebaceous gland function. Clin Dermatol. 2004;22:360-366. 4. Zouboulis CC, Eady A, Philpott M, et al. What is the pathogenesis of acne? Exp Dermatol. 2005;14:143-152. 5. Kurokawa I, Danby FW, Ju Q, et al. New developments in our understanding of acne pathogenesis and treatment. Exp Dermatol. 2009;18:821-832. 6. Zouboulis CC. Propionibacterium acnes and sebaceous lipogenesis: a love-hate relationship? J Invest Dermatol. 2009;129:2093-2096. 7. Frost P, Gomez EC. Inhibitors of sex hormones: development of experimental models. Adv Biol Skin. 1972;12:403-420. 8. Guy R, Ridden C, Barth J, et al. Isolation and maintenance of the human pilosebaceous duct: 13-cis retinoic acid acts directly on the duct in vitro. Br J Dermatol. 1993;128:242-248. 9. Guy R, Ridden C, Kealey T. The improved organ maintenance of the human sebaceous gland: modeling in vitro the effects of epidermal growth factor, androgens, estrogens, 13-cis retinoic acid, and phenol red. J Invest Dermatol. 1996;106:454-460. 10. Zouboulis CC, Xia L, Akamatsu H, et al. The human sebocyte culture model provides new insights into development and management of seborrhea and acne. Dermatology. 1998;196:21-31. 11. Mirshahpanah P, Maibach HI. Models in acnegenesis. Cutan Ocul Toxicol. 2007;26:195-202. 12. Nakatsuji T, Liu YT, Huang CP, et al. 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. J Invest Dermatol. 2008;128:2451-2457. 13. Xia LQ, Zouboulis C, Detmar M, et al. Isolation of human sebaceous glands and cultivation of sebaceous gland-derived cells as an in vitro model. J Invest Dermatol. 1989;93:315-321. 14. Zouboulis CC, Schagen S, Alestas T. The sebocyte culture: A model to study the pathophysiology of the sebaceous gland in sebostasis, seborrhea and acne. Arch Dermatol Res. 2008;300:397-413. 15. Zouboulis CC, Seltmann H, Neitzel H, et al. Establishment and characterization of an immortalized human sebaceous gland cell line (SZ95). J Invest Dermatol. 1999;113:1011-1020. 16. Centers for Disease Control. “Classifications of diseases and functioning and disability”. In: Classifications of Diseases and Functioning and Disability. Definition of Disability Reference. National Center for Health Statistics; 2001. 17. O'Halloran J, Miller GC, Britt H. Defining chronic conditions for primary care with ICPC-2. Fam Pract. 2004;21:381-386. 18. Cunliffe WJ. Acne and unemployment. Br J Dermatol. 1986;115:386. 19. Goulden V, McGeown CH, Cunliffe WJ. The familial risk of adult acne: a comparison between first-degree relatives of affected and unaffected individuals. Br J Dermatol. 1999;141:297-300. 20. James WD. Clinical practice. Acne. N Engl J Med. 2005;352: 1463-1472. 21. Kellett SC, Gawkrodger DJ. The psychological and emotional impact of acne and the effect of treatment with isotretinoin. Br J Dermatol. 1999;140:273-282. 22. Niemeier V, Kupfer J, Demmelbauer-Ebner M, et al. Coping with acne vulgaris. Evaluation of the chronic skin disorder questionnaire in patients with acne. Dermatology. 1998;196:108-115. 23. Tan J. The Canadian acne epidemiologic survey: baseline demographics and interim analysis. J Am Acad Dermatol. 2004;50:15. 24. Thiboutot DM, Lookingbill DP. Acne: acute or chronic disease? J Am Acad Dermatol. 1995;32(Suppl):S2-S5. 25. Thiboutot D, Gollnick H, Bettoli V, et al. New insights into the management of acne: an update from the Global Alliance to Improve Outcomes in Acne group. J Am Acad Dermatol. 2009;60:S1-S50. 26. Collier CN, Harper JC, Cafardi JA, et al. The prevalence of acne in adults 20 years and older. J Am Acad Dermatol. 2008;58:56-59. 27. Dreno B, Layton A, Zouboulis CC, et al. Adult female acne: a new paradigm. J Eur Acad Dermatol Venereol. 2013;27:1063-1070.
Acne as a systemic disease 28. Goulden V, Stables GI, Cunliffe WJ. Prevalence of facial acne in adults. J Am Acad Dermatol. 1999;41:577-580. 29. Poli F, Dreno B, Verschoore M. An epidemiologic study of acne in female adults: results of a survey conducted in France. J Eur Acad Dermatol Venereol. 2001;15:541-545. 30. Chen W, Obermayer-Pietsch B, Hong J-B, et al. Acne-associated syndromes: models for better understanding of acne pathogenesis. J Eur Acad Dermatol Venereol. 2011;25:637-646. 31. Dessinioti C, Katsambas A. Congenital adrenal hyperplasia. Dermatoendocrinol. 2009;1:87-91. 32. Trakakis E, Basios G, Trompoukis P, et al. An update to 21hydroxylase deficient congenital adrenal hyperplasia. Gynecol Endocrinol. 2010;26:63-71. 33. New MI. An update of congenital adrenal hyperplasia. Ann N Y Acad Sci. 2004;1038:14-43. 34. Speiser PW, White PC. Congenital adrenal hyperplasia. N Engl J Med. 2003;349:776-788. 35. Witchel SF. Nonclassic congenital adrenal hyperplasia. Steroids. 2013;78:747-750. 36. Caputo V, Fiorella S, Curiale S, et al. Refractory acne and 21hydroxylase deficiency in a selected group of female patients. Dermatology. 2010;220:121-127. 37. Trakakis E, Rizos D, Loghis C, et al. The prevalence of non-classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency in Greek women with hirsutism and polycystic ovary syndrome. Endocr J. 2008;55:33-39. 38. Zouboulis CC, Piquero-Martin J. Update and future of systemic acne treatment. Dermatology. 2003;206:37-53. 39. Orfanos CE. Antiandrógenos en dermatología. Arch Arg Derm. 1982;32(Suppl 1):51-55. 40. Orfanos CE, Adler YD, Zouboulis CC. The SAHA syndrome. Horm Res. 2000;54:251-258. 41. Zouboulis CC, Chen WC, Thornton MJ, et al. Sexual hormones in human skin. Horm Metab Res. 2007;39:85-95. 42. Lowenstein EJ. Diagnosis and management of the dermatologic manifestations of the polycystic ovary syndrome. Dermatol Ther. 2006;19:210-223. 43. Carmina E. Mild androgen phenotypes. Best Pract Res Clin Endocrinol Metab. 2006;20:207-220. 44. Chen WC, Zouboulis CC. Hormones and the pilosebaceous unit. Dermatoendocrinol. 2009;1:81-86. 45. Carmina E, Rosato F, Janni A, et al. Extensive clinical experience: relative prevalence of different androgen excess disorders in 950 women referred because of clinical hyperandrogenism. J Clin Endocrinol Metab. 2006;91:2-6. 46. Zouboulis CC, Rabe T. Hormonal antiandrogens in acne treatment. J Dtsch Dermatol. Ges. 2010;8(Suppl 1):S60-S74. 47. Witchel SF, Recabarren SE, Gonzalez F, et al. Emerging concepts about prenatal genesis, aberrant metabolism and treatment paradigms in polycystic ovary syndrome. Endocrine. 2012;42:526-534. 48. Ewens KG, Stewart DR, Ankener W, et al. Family-based analysis of candidate genes for polycystic ovary syndrome. J Clin Endocrinol Metab. 2010;95:2306-2315. 49. Deligeoroglou E, Kouskouti C, Christopoulos P. The role of genes in the polycystic ovary syndrome: predisposition and mechanisms. Gynecol Endocrinol. 2009;25:603-609. 50. Wehr E, Schweighofer N, Moller R, et al. Association of FTO gene with hyperandrogenemia and metabolic parameters in women with polycystic ovary syndrome. Metabolism. 2010;59:575-580. 51. Adler YD, Zouboulis CC, Geilen CC, et al. Eine seltene Variante des SAHA Syndroms. Z Hautkr. 2000;76:327-328. 52. Rager KM, Omar HA. Androgen excess disorders in women: the severe insulin-resistant hyperandrogenic syndrome, HAIR-AN. Sci World J. 2006;6:116-121. 53. Makrantonaki E, Vogel K, Fimmel S, et al. Interplay of IGF-I and 17beta-estradiol at age-specific levels in human sebocytes and fibroblasts in vitro. Exp Gerontol. 2008;43:939-946.
395 54. Blomberg M, Jeppesen EM, Skovby F, et al. FGFR3 mutations and the skin: report of a patient with a FGFR3 gene mutation, acanthosis nigricans, hypochondroplasia and hyperinsulinemia and review of the literature. Dermatology. 2010;220:297-305. 55. Chamot AM, Vion B, Gerster JC. Acute pseudoseptic arthritis and palmoplantar pustulosis. Clin Rheumatol. 1986;5:118-123. 56. Hayem G, Bouchaud-Chabot A, Benali K, et al. SAPHO syndrome: a long-term follow-up study of 120 cases. Semin Arthritis Rheum. 1999;29:159-171. 57. Kahn MF, Khan MA. The SAPHO syndrome. Baillieres Clin Rheumatol. 1994;8:333-362. 58. Kahn MF, Bouvier M, Palazzo E, et al. Sternoclavicular pustulotic osteitis (SAPHO). 20-year interval between skin and bone lesions. J Rheumatol. 1991;18:1104-1108. 59. Hurtado-Nedelec M, Chollet-Martin S, Nicaise-Roland P, et al. Characterization of the immune response in the synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome. Rheumatology (Oxford). 2008;47:1160-1167. 60. Olivieri I, Padula A, Palazzi C. Pharmacological management of SAPHO syndrome. Expert Opin Investig Drugs. 2006;15:1229-1233. 61. Lindor NM, Arsenault TM, Solomon H, et al. A new autosomal dominant disorder of pyogenic sterile arthritis, pyoderma gangrenosum, and acne: PAPA syndrome. Mayo Clin Proc. 1997;72: 611-615. 62. Wise CA, Gillum JD, Seidman CE, et al. Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder. Hum Molec Genet. 2002;11:961-969. 63. Kanazawa N, Furukawa F. Autoinflammatory syndromes with a dermatological perspective. J Dermatol. 2007;34:601-618. 64. Dierselhuis MP, Frenkel J, Wulffraat NM, et al. Anakinra for flares of pyogenic arthritis in PAPA syndrome. Rheumatology (Oxford). 2005;44:406-408. 65. Apert E. De l`a acrocéphalosyndactylie. Bull Soc Med Hop (Paris). 1906;23:1310-1330. 66. Boulet SL, Rasmussen SA, Honein MA. A population-based study of craniosynostosis in metropolitan Atlanta, 1989–2003. Am J Med Genet A. 2008;146A:984-991. 67. Solomon LM, Fretzin D, Pruzansky S. Pilosebaceous abnormalities in Apert's syndrome. Arch Dermatol. 1970;102:381-385. 68. Melnik BC, Schmitz G. Role of insulin, insulin-like growth factor-1, hyperglycaemic food and milk consumption in the pathogenesis of acne vulgaris. Exp Dermatol. 2009;18:833-841. 69. Wilkie AO, Slaney SF, Oldridge M, et al. Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome. Nat Genet. 1995;9:165-172. 70. Melnik BC. Role of FGFR2-signaling in the pathogenesis of acne. Dermatoendocrinol. 2009;1:141-156. 71. Melnik BC. FoxO1-the key for the pathogenesis and therapy of acne? J Dtsch Dermatol Ges. 2010;8:105-114. 72. Melnik BC. Is nuclear deficiency of FoxO1 due to increased growth factor/PI3K/Akt-signalling in acne vulgaris reversed by isotretinoin treatment? Br J Dermatol. 2010;162:1398-1400. 73. Letawe C, Boone M, Pierard GE. Digital image analysis of the effect of topically applied linoleic acid on acne microcomedones. Clin Exp Dermatol. 1998;23:56-58. 74. Alestas T, Ganceviciene R, Fimmel S, et al. Enzymes involved in the biosynthesis of leukotriene B4 and prostaglandin E2 are active in sebaceous glands. J Mol Med (Berl). 2006;84:75-87. 75. Wrobel A, Seltmann H, Fimmel S, et al. Differentiation and apoptosis in human immortalized sebocytes. J Invest Dermatol. 2003;120:175-181. 76. Zouboulis CC, Nestoris S, Adler YD, et al. A new concept for acne therapy: a pilot study with zileuton, an oral 5-lipoxygenase inhibitor. Arch Dermatol. 2003;139:668-670. 77. Steiner PE. Necropsies on Okinawans; anatomic and pathologic observations. Arch Pathol (Chic). 1946;42:359-380. 78. Simopoulos AP. Evolutionary aspects of diet and essential fatty acids. World Rev Nutr Diet. 2001;88:18-27.
396 79. Cordain L, Lindeberg S, Hurtado M, et al. Acne vulgaris: a disease of Western civilization. Arch Dermatol. 2002;138:1584-1590. 80. Thiboutot DM, Strauss JS. Diet and acne revisited. Arch Dermatol. 2002;138:1591-1592.
C.C. Zouboulis 81. Thielitz A, Reinhold D, Vetter R, et al. Inhibitors of dipeptidyl peptidase IV and aminopeptidase N target major pathogenetic steps in acne initiation. J Invest Dermatol. 2007;127: 1042-1051.
Acne as a chronic systemic disease Christos C. Zouboulis, MD, PhD ⁎ Departments of Dermatology, Venereology, Allergology, and Immunology, Dessau Medical Center, Auenweg 38, 06847 Dessau, Germany
Abstract Acne is the most common skin disorder. In the majority of cases, acne is a disease that changes its skin distribution and severity over time; moreover, it can be a physically (scar development) and psychologically damaging condition that lasts for years. According to its clinical characteristics, it can be defined as a chronic disease according to the World Health Organization criteria. Acne is also a cardinal component of many systemic diseases or syndromes, such as congenital adrenal hyperplasia, seborrhea-acne-hirsutism-androgenetic alopecia syndrome, polycystic ovarian syndrome, hyperandrogenism-insulin resistance-acanthosis nigricans syndrome, Apert syndrome, synovitis-acne-pustulosishyperostosis-osteitis syndrome, and pyogenic arthritis-pyoderma gangrenosum-acne syndrome. Recent studies on the Ache hunter gatherers of Paraguay detected the lack of acne in association with markedly lower rates of obesity, diabetes mellitus, hyperlipidemia, and cardiovascular diseases, a finding that indicates either a nutritional or a genetic background of this impressive concomitance. © 2014 Elsevier Inc. All rights reserved.
Introduction Acne is the most common skin disease and also the lead diagnosis in medicine1; however, it is widely considered to be a simple, self-limited disorder of adolescents. The majority of lay people, as well as many physicians, believe that treatment of acne is only required in extreme cases. Unfortunately, not only successful acne treatment can become difficult but acne, itself, can be a devastating disease for the patient, both because it manifests on visible body parts of children and adolescents, who are vulnerable both socially and psychologically, but also because it can heal with considerable scar sequelae.1 The pathogenesis of acne is dominated by up-regulation of inflammatory signaling in skin epithelial cells, leading to excessive sebum production and hyperproliferation/hyperkeratosis of the infrainfundibulum of the sebaceous follicles.2–5 Hypercolonization of the sebaceous follicles with ⁎ Corresponding author. Tel.: + 49 340 5014000; fax: + 49 340 5014025. E-mail address: [email protected]. 0738-081X/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clindermatol.2013.11.005
Propionibacterium acnes, a commensal bacterium, has been considered as an additional pathogenetic factor.6 Several cellular or animal models are used for acne research6–15; nevertheless, there is no single cellular or animal model that encompasses all the pathogenic factors and their interactions in acne formation, which is a genuine human disease.
Acne is a chronic disease In most cases, acne is not an acute disease but rather a condition that continuously changes in its distribution and severity.1 Treatment of acne is usually necessary for months to, sometimes, years, and mostly, acne may cause scarring and associated negative psychological effects despite treatment. It is important for dermatologists to educate other clinicians and patients that acne is a chronic disease1,16 and not just a self-limited disorder of teenagers. For many patients, acne has characteristics that the World Health Organization (WHO) has used to define chronicity of diseases: A prolonged course, a pattern of recurrence or
390
C.C. Zouboulis
Fig. 1 WHO criteria for classifying acne as a chronic disease (after Gollnick et al.).1 Comparison of acne and atopic dermatitis, a widely accepted chronic disease, reveals striking similarities.
relapse, manifestation as acute outbreaks or slow onset, and a psychological and social impact that affects the individual’s quality of life16,17 (Figure 1). There is wide evidence that acne can be a physically (scar development) and psychologically damaging condition that lasts for years,18–24 even, if there is not always correlation with the clinician’s assessment of severity at one point in time.1,25 In addition, there is evidence that acne can persist into adult years in as many as 50% of individuals.19,26–29
Acne as a manifestation of systemic diseases Acne is an essential component of many systemic diseases or syndromes, 30 among them (1) congenital adrenal hyperplasia (CAH), (2) seborrhea-acne-hirsutismandrogenetic alopecia (SAHA) syndrome, (3) polycystic
ovarian syndrome (PCOS), (4) hyperandrogenism-insulin resistance-acanthosis nigricans (HAIR-AN) syndrome, (5) synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome, (6) pyogenic arthritis-pyoderma gangrenosumacne (PAPA) syndrome, and (7) Apert syndrome.
CAH CAH (OMIM 201910) represents a heterogeneous group of autosomal inherited enzymatic defects in the biosynthetic pathway of cortisol and/or aldosterone.31 21-hydroxylase (21-OH) deficiency due to mutations in the 21-hydroxylase gene (CYP21, 6p21.3) is the most common defect (95%).32 Cortisol deficiency results in oversecretion of adrenocorticotropic hormone (ACTH), and overstimulation and hyperplasia of the adrenals, via the impaired cortisol-mediated
Fig. 2 A female patient with acne due to nonclassical CAH before (A) and after treatment with prednisolone 5 mg/d orally over 6 months (B) (after Zouboulis and Piquro-Martin).38
Acne as a systemic disease negative feedback control of ACTH secretion from the anterior pituitary. Androgen excess affects the pilosebaceous units, resulting in androgenic alopecia, hirsutism, and acne. Classic CAH (complete loss of enzyme function), presenting in the neonatal period, occurs in 1/15,000 births, while late onset nonclassic CAH is more frequent, affecting 1% of the general population.33 Acne and hirsutism are the major skin manifestations of CAH and usually develop during adolescence. Classic CAH clinical manifestations, such as virilization, impaired fertility, short stature, early appearance of facial/axillary/pubic hair, and acne, are more severe. 31,34 Nonclassic CAH is also associated with hyperandrogenic manifestations, such as severe acne refractory to treatment, hirsutism, androgenic alopecia or seborrhea, but also with irregular menses and polycystic ovaries.35–37 The determination of 17-hydroxyprogesterone, the immediate substrate for 21-OH, is used for biochemical diagnosis.35 For mild nonclassical CAH with normal basal adrenal steroids, the ACTH stimulation test is recommended. Oral glucocorticoids and/or fludrocortisone reduce increased androgen production in CAH.33 The treatment of nonclassical CAH is symptom-associated. Low-dose prednisolone (2.5-5 mg/day; Figure 2) or low-dose dexamethasone (0.250.75 mg) can be administered orally at bedtime.31,38
SAHA syndrome The association of seborrhea and acne with hirsutism and/ or androgenetic alopecia in women was defined in 1982 as SAHA syndrome.39 It includes the dermatologic manifestations of androgen excess in women, either on the basis of high circulating androgen levels (hyperandrogenemia) or due to the capacity of the pilosebaceous apparatus to respond with increased sensitivity to normal circulating androgen levels (hyperandrogenism).40,41 The SAHA syndrome is classified into idiopathic, ovarian, adrenal, and hyperprolactinemic types,40 and can be associated with polycystic ovaries, cystic mastitis,
Fig. 3
391 obesity, insulin resistance (IR), and infertility.42 All four major signs of SAHA syndrome are present in approximately 20% of the patients; seborrhea is always present, acne occurs in 10% of the patients, androgenetic alopecia in 21%, and hirsutism in 6% of the patients (Figure 3).40,42,43 Androgen excess in women is one of the most frequent endocrine disorders considered to affect 5% to 10% of them in reproductive age. It can be caused by elevated androgen synthesis in adrenals and ovaries, disturbed peripheral metabolism of androgens or induction of metabolism and activation of androgens in the skin.41 The sebaceous gland is an important organ of active androgen formation, expressing all the necessary enzymes for the de novo biosynthesis of testosterone.2,44 Local androgen excess induces shortening of the follicular anagen phase and progressive conversion of terminal hair to intermediate ones, leading to androgenic alopecia45; moreover, up to 50% of the total circulating testosterone in women is produced in the skin and in other peripheral organs. The diagnosis of SAHA syndrome requires a complete history, physical examination with emphasis on evidence of androgen excess and—in the presence of hyperandrogenemiaassociated signs—laboratory investigations, including dehydroepiandrosterone sulphate, testosterone, prolactin, and 17-OH-progesterone to exclude hyperandrogenemia.3,40 Treatments for the dermatologic conditions of hyperandrogenism include lifestyle modification, oral contraceptives, hormonal antiandrogens, and insulin-sensitizing medications.46
PCOS The PCOS (OMIM 184700) is a complex endocrine disorder affecting 5% to 20% of women depending on their ethnical background. It is characterized by clinical and/or biochemical evidence of hyperandrogenism with oligo- and/ or anovulation and polycystic ovaries.47 Hyperandrogenemia and altered gonadotropin secretion, as well as IR, are involved in its pathogenesis. There is accumulating evidence for a strong genetic background of PCOS.48,49 A clear
SAHA syndrome with acne and hirsutism, signs of hyperandrogenism, without hyperandrogenemia.
392
C.C. Zouboulis
relationship with obesity-associated genes has recently been shown.50 Women with PCOS frequently suffer from infertility, acne, hirsutism, and alopecia.42 Acne is detected in about 23% to 35% of patients with PCOS, while the prevalence of PCOS in the acne group was estimated to be 27% or even higher. Women with severe acne, late onset acne, persistent acne, and acne resistant to conventional therapies are likely to have PCOS. Clinical examination hormonal examinations are mandatory for making the diagnosis.47 Gynecological examination routinely includes ovarian ultrasound, ovulation tests, and the validation of a menses calendar. Lifestyle intervention, insulin sensitizers (metformin), and oral contraceptives are the most common therapeutic approaches for the management of PCOS. In case that family planning is not an issue for the patients, oral contraceptives with an established antiandrogen efficacy can help to control both androgen levels and skin symptoms and hirsutism.46,47
The primary abnormality in patients with this syndrome is supposed to be IR with a compensatory elevation in insulin levels, which may have a direct short-term effect on the regulation of steroidogenesis in ovaries, leading to a subsequent overproduction of androgens.52 Hyperinsulinemia and hyperandrogenemia together stimulate epithelial proliferation and melanin accumulation and result in the cutaneous manifestation of AN. The binding of insulin to insulin receptors and insulinlike growth factor (IGF)-receptors on keratinocytes and fibroblasts leads to epidermal thickness, which probably induces formation of the AN lesions.53 The enhanced lipogenesis of the sebaceous gland caused by IGF-1 may indirectly lead to oily skin and acne formation in patients with HAIR-AN syndrome. A mutation in the fibroblast growth factor receptor 3 was recently reported to be associated with AN, hyperinsulinemia, and skeletal dysplasia.54 Current management of HAIR-AN syndrome resembles that of SAHA and PCOS.51,52
HAIR-AN syndrome
SAPHO syndrome
HAIR-AN is the acronym for hyperandrogenism, IR, and acanthosis nigricans (AN). HAIR-AN syndrome can be considered as a unique subtype of PCOS in women.51 Patients with the disorder usually present with clinical signs of hypandrogenemia, such as seborrhea, acne, hirsutism, menstrual irregularities, androgenic alopecia, deepening of voice, clitoromegaly, and changes in muscle mass, plus IR with diabetic symptoms, as well as AN (Figure 4). Five percent of women with hyperandrogenemia, are considered to have this condition.52 Generally, these patients have markedly elevated insulin levels, elevated or high-normal levels of testosterone and androstenedione, but normal levels of luteinizing hormone and prolactin. Adrenal function is normal.
The acronym SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) defines a syndrome, which was first described in 1987.55 It is a rare, probably underrecognized, disease with an estimated prevalence probably no greater than 1/10,000.30 It primarily affects children and young adults. 56 Three diagnostic criteria for this syndrome have been proposed: (1) chronic recurrent multifocal osteomyelitis with or without skin manifestations; (2) acute or chronic sterile arthritis associated with either pustular psoriasis or palmoplantar pustulosis or severe acne; and (3) sterile osteitis in the presence of one of the skin manifestations. Any of these three presentations is sufficient for diagnosis of this syndrome.57
Fig. 4
HAIR-AN syndrome presenting with papulopustular acne and hirsutism on the face, indicating a manifesting hyperandrogenemia.
Acne as a systemic disease SAPHO syndrome is characterized by a rheumatoid factor-negative osteoarthropathy and various dermatologic manifestations, such as acne/hidradenitis suppurativa/dissecting folliculitis of the scalp, psoriasis/pustular psoriasis/ palmoplantar pustulosis, Sweet’s syndrome, SneddonWilkinson disease, and pyoderma gangrenosum. The clinical presentation of acne varies greatly, from mild to severe type, such as acne conglobata or acne fulminans. These dermatologic conditions may occur concomitantly but may also precede or follow bone involvement.58 A long-term followup study of 120 confirmed cases showed 55% of patients with palmoplantar pustulosis, 31% with psoriasis vulgaris, and 25% with severe acne, whereas 16% patients did not exhibit skin manifestations.58 Association with inflammatory bowel diseases, such as Crohn’s disease and ulcerative colitis, has been reported. The pathogenesis of SAPHO syndrome remains poorly understood. Current results support the view that SAPHO syndrome may be triggered by an infectious state, leading to strong humoral and cellular inflammatory responses.59 Treatment experience of SAPHO syndrome is limited, mainly based on limited experiences in treating small groups of patients.60
PAPA syndrome The clinical triad of pyogenic sterile arthritis, pyoderma gangrenosum (PG), and acne conglobata was noted in several families and described with the acronym PAPA syndrome (OMIM 604416) in 1997.61 In 2002, the gene of CD2-binding protein 1 (CD2BP1; also called proline/ serine/threonine phosphatase-interacting protein 1, PSTPIP1) on chromosome 15q24–25.1 was identified as the responsible gene.62 PAPA syndrome belongs to the autoinflammatory diseases group, the CD2BP1 protein binds pyrin, which is an inhibitor of the inflammatory process. Because pyrin is expressed on neutrophils, but not on T or B cells, the decreased amount of unbound pyrin results in neutrophilic infiltration in arthritis, acne, PG, and other neutrophilic dermatoses.63 The manifestation of PAPA syndrome with its clinical triad varies in the affected family members. Arthritis is the most consistent sign, followed by acne and PG. Arthritis is the earliest sign occurring between ages 1 and 16 years.63 Being aseptic and seronegative, the pauci-articular, nonaxial arthritis of variable severity commonly affects knees, elbows, and ankles. At puberty, severe nodulocystic acne develops. PG occurs in adolescence or adulthood, usually after the appearance of acne. The transition of PAPA syndrome from inflammatory arthritis to cutaneous manifestations with acne and PG at puberty is notable. Of the triad, PG and acne may be present for decades. PAPA is responsive to systemic or locally administered glucocorticoids. Antimicrobial therapy is not effective. Dapsone can be helpful. Recombinant human interleukin
393 (IL)-1 receptor antagonists have shown efficacy in PAPA syndrome and other autoinflammatory diseases.64
Apert syndrome Apert syndrome (OMIM 101200), also known as acrocephalosyndactyly, was first described in 1906.65 Its prevalence is estimated to be 15/1,000,000, based on a recent population-based study, making up approximately 4% of all cases of craniosynostosis.66 Apert syndrome is inherited in an autosomal dominant manner and is characterized by synostoses of the extremities, vertebrae, and skull, with syndactyly of fingers and toes. Several Apert syndrome patients with acne have been described, having an unusual distribution with lesions extending to the surface areas of the forearms.67 Seborrhea and moderate to severe acne are the dermatologic hallmark of Apert syndrome, which often begins in early puberty.67 Histologic examination exhibits dilated follicular infundibula extending to mid-dermis, follicular abscesses in the upper and mid portions of the corium, and numerous larger sebaceous lobules. Plasma androgen levels and androgen receptor staining of sebaceous glands are normal.68 Two specific heterozygous missense germ-line mutations of the fibroblast growth factor receptor 2 gene (FGFR2) have been identified in patients with Apert syndrome.69 The two detected FGFR2 isoforms and their specific ligands are involved in mesenchymal-epithelial signaling, leading to downstream effects of activated FGFR2-signaling on follicular keratinocyte proliferation, sebaceous lipogenesis, and inflammatory cytokine response.70 In acne of Apert syndrome, FGFR2-mediated up-regulation of phosphoinositol-3 kinase (PI3K)/Akt may result in a nuclear deficiency of the transcription factor FoxO1, recently suggested to be a key transcription factor in the pathogenesis of acne vulgaris.71 The early onset of severe and persistent acne during puberty can be well explained by androgen-dependent up-regulation of fibroblast growth factor synthesis, which activates the mutated FGFR2 receptors; thus, overstimulating FGFR2-mediated downstream signal transduction, leading to a nuclear deficiency of FoxO1. Accumulating evidence supports the view that isotretinoin treatment restores decreased nuclear levels of FoxO1,72 which is in accordance with the excellent response of acne in Apert syndrome to oral isotretinoin treatment.
Dietary lipids and inflammatory process in acne Topically applied linoleic acid was shown to induce an almost 25% reduction in the overall size of microcomedones over a 1-month treatment period.73 Arachidonic acid, an essential, long-chain, proinflammatory ω-6 fatty acid, stimulates IL-8 and IL-6 synthesis in cultured human sebocytes74 and enhances synthesis of sebaceous lipids.75 Leukotriene B4 inhibition in vivo reduces concomitantly proinflammatory
394 sebaceous fatty acids and inflammatory acne lesions.76 The role of nutrition in acne still remains controversial. Inuit Eskimos, the inhabitants of the Okinawa Island, and the Chinese have been observed to develop acne with the changing of their nutrition habits.77 Westernized nutrition includes low amounts of ω-3-fatty acids and antioxidant vitamins and higher amounts of the proinflammatory ω-6 and trans-fatty acids.78 A current study reported that the Kitavan islanders of Papua New Guinea and the Ache hunter-gatherers of Paraguay do not have acne,79 but also present markedly lower rates of obesity, diabetes mellitus, hyperlipidemia, and cardiovascular diseases; however, other authors have suggested that these population studies may have detected a genetic background rather than a nutritional effect.80
Conclusions The manifestation and involvement of acne in different diseases/syndromes highlight the multifaceted nature of acne. In CAH, as well as SAHA, PCOS, and HAIR-AN syndromes, excessive hormones (in circulation or in situ) and/or exaggerated hormone response via aberrant hormone receptor expression/postbinding response induce the accelerated growth and differentiation of pilosebaceous units. The presence of acne in all syndromes reported above indicates the interplay of androgenic hormones in the pathogenesis.68 In daily medical practice, nonclassical CAH, PCOS, and SAHA syndrome should be excluded in patients with severe acne, acne tarda, acne associated with other signs (alopecia, hirsutism, or obesity), or acne recalcitrant to various therapies, especially in women. Acne accompanied by joint/bone involvement and/or other neutrophilic dermatoses, may be an early sign for SAPHO or PAPA syndrome, especially in a familial occurrence. The manifestation of acne in PAPA and SAPHO syndromes provides further evidence to the argument that acne is a genuine inflammatory disorder.2–5 The specific involvement of sebaceous gland in PAPA syndrome is unique among the so-called autoinflammatory diseases and raises the question of the targeted treatment against IL-1 may also benefit patients with acne.81
Acknowledgment The author thanks Dr. Razvigor Darlenski, Sofia, Bulgaria for his support in the arrangement of the manuscript.
References 1. Gollnick HP, Finlay AY, Shear N. Can we define acne as a chronic disease? If so, how and when? Am J Clin Dermatol. 2008;9:279-284.
C.C. Zouboulis 2. Zouboulis CC. Is acne vulgaris a genuine inflammatory disease? Dermatology. 2001;203:277-279. 3. Zouboulis CC. Acne and sebaceous gland function. Clin Dermatol. 2004;22:360-366. 4. Zouboulis CC, Eady A, Philpott M, et al. What is the pathogenesis of acne? Exp Dermatol. 2005;14:143-152. 5. Kurokawa I, Danby FW, Ju Q, et al. New developments in our understanding of acne pathogenesis and treatment. Exp Dermatol. 2009;18:821-832. 6. Zouboulis CC. Propionibacterium acnes and sebaceous lipogenesis: a love-hate relationship? J Invest Dermatol. 2009;129:2093-2096. 7. Frost P, Gomez EC. Inhibitors of sex hormones: development of experimental models. Adv Biol Skin. 1972;12:403-420. 8. Guy R, Ridden C, Barth J, et al. Isolation and maintenance of the human pilosebaceous duct: 13-cis retinoic acid acts directly on the duct in vitro. Br J Dermatol. 1993;128:242-248. 9. Guy R, Ridden C, Kealey T. The improved organ maintenance of the human sebaceous gland: modeling in vitro the effects of epidermal growth factor, androgens, estrogens, 13-cis retinoic acid, and phenol red. J Invest Dermatol. 1996;106:454-460. 10. Zouboulis CC, Xia L, Akamatsu H, et al. The human sebocyte culture model provides new insights into development and management of seborrhea and acne. Dermatology. 1998;196:21-31. 11. Mirshahpanah P, Maibach HI. Models in acnegenesis. Cutan Ocul Toxicol. 2007;26:195-202. 12. Nakatsuji T, Liu YT, Huang CP, et al. 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. J Invest Dermatol. 2008;128:2451-2457. 13. Xia LQ, Zouboulis C, Detmar M, et al. Isolation of human sebaceous glands and cultivation of sebaceous gland-derived cells as an in vitro model. J Invest Dermatol. 1989;93:315-321. 14. Zouboulis CC, Schagen S, Alestas T. The sebocyte culture: A model to study the pathophysiology of the sebaceous gland in sebostasis, seborrhea and acne. Arch Dermatol Res. 2008;300:397-413. 15. Zouboulis CC, Seltmann H, Neitzel H, et al. Establishment and characterization of an immortalized human sebaceous gland cell line (SZ95). J Invest Dermatol. 1999;113:1011-1020. 16. Centers for Disease Control. “Classifications of diseases and functioning and disability”. In: Classifications of Diseases and Functioning and Disability. Definition of Disability Reference. National Center for Health Statistics; 2001. 17. O'Halloran J, Miller GC, Britt H. Defining chronic conditions for primary care with ICPC-2. Fam Pract. 2004;21:381-386. 18. Cunliffe WJ. Acne and unemployment. Br J Dermatol. 1986;115:386. 19. Goulden V, McGeown CH, Cunliffe WJ. The familial risk of adult acne: a comparison between first-degree relatives of affected and unaffected individuals. Br J Dermatol. 1999;141:297-300. 20. James WD. Clinical practice. Acne. N Engl J Med. 2005;352: 1463-1472. 21. Kellett SC, Gawkrodger DJ. The psychological and emotional impact of acne and the effect of treatment with isotretinoin. Br J Dermatol. 1999;140:273-282. 22. Niemeier V, Kupfer J, Demmelbauer-Ebner M, et al. Coping with acne vulgaris. Evaluation of the chronic skin disorder questionnaire in patients with acne. Dermatology. 1998;196:108-115. 23. Tan J. The Canadian acne epidemiologic survey: baseline demographics and interim analysis. J Am Acad Dermatol. 2004;50:15. 24. Thiboutot DM, Lookingbill DP. Acne: acute or chronic disease? J Am Acad Dermatol. 1995;32(Suppl):S2-S5. 25. Thiboutot D, Gollnick H, Bettoli V, et al. New insights into the management of acne: an update from the Global Alliance to Improve Outcomes in Acne group. J Am Acad Dermatol. 2009;60:S1-S50. 26. Collier CN, Harper JC, Cafardi JA, et al. The prevalence of acne in adults 20 years and older. J Am Acad Dermatol. 2008;58:56-59. 27. Dreno B, Layton A, Zouboulis CC, et al. Adult female acne: a new paradigm. J Eur Acad Dermatol Venereol. 2013;27:1063-1070.
Acne as a systemic disease 28. Goulden V, Stables GI, Cunliffe WJ. Prevalence of facial acne in adults. J Am Acad Dermatol. 1999;41:577-580. 29. Poli F, Dreno B, Verschoore M. An epidemiologic study of acne in female adults: results of a survey conducted in France. J Eur Acad Dermatol Venereol. 2001;15:541-545. 30. Chen W, Obermayer-Pietsch B, Hong J-B, et al. Acne-associated syndromes: models for better understanding of acne pathogenesis. J Eur Acad Dermatol Venereol. 2011;25:637-646. 31. Dessinioti C, Katsambas A. Congenital adrenal hyperplasia. Dermatoendocrinol. 2009;1:87-91. 32. Trakakis E, Basios G, Trompoukis P, et al. An update to 21hydroxylase deficient congenital adrenal hyperplasia. Gynecol Endocrinol. 2010;26:63-71. 33. New MI. An update of congenital adrenal hyperplasia. Ann N Y Acad Sci. 2004;1038:14-43. 34. Speiser PW, White PC. Congenital adrenal hyperplasia. N Engl J Med. 2003;349:776-788. 35. Witchel SF. Nonclassic congenital adrenal hyperplasia. Steroids. 2013;78:747-750. 36. Caputo V, Fiorella S, Curiale S, et al. Refractory acne and 21hydroxylase deficiency in a selected group of female patients. Dermatology. 2010;220:121-127. 37. Trakakis E, Rizos D, Loghis C, et al. The prevalence of non-classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency in Greek women with hirsutism and polycystic ovary syndrome. Endocr J. 2008;55:33-39. 38. Zouboulis CC, Piquero-Martin J. Update and future of systemic acne treatment. Dermatology. 2003;206:37-53. 39. Orfanos CE. Antiandrógenos en dermatología. Arch Arg Derm. 1982;32(Suppl 1):51-55. 40. Orfanos CE, Adler YD, Zouboulis CC. The SAHA syndrome. Horm Res. 2000;54:251-258. 41. Zouboulis CC, Chen WC, Thornton MJ, et al. Sexual hormones in human skin. Horm Metab Res. 2007;39:85-95. 42. Lowenstein EJ. Diagnosis and management of the dermatologic manifestations of the polycystic ovary syndrome. Dermatol Ther. 2006;19:210-223. 43. Carmina E. Mild androgen phenotypes. Best Pract Res Clin Endocrinol Metab. 2006;20:207-220. 44. Chen WC, Zouboulis CC. Hormones and the pilosebaceous unit. Dermatoendocrinol. 2009;1:81-86. 45. Carmina E, Rosato F, Janni A, et al. Extensive clinical experience: relative prevalence of different androgen excess disorders in 950 women referred because of clinical hyperandrogenism. J Clin Endocrinol Metab. 2006;91:2-6. 46. Zouboulis CC, Rabe T. Hormonal antiandrogens in acne treatment. J Dtsch Dermatol. Ges. 2010;8(Suppl 1):S60-S74. 47. Witchel SF, Recabarren SE, Gonzalez F, et al. Emerging concepts about prenatal genesis, aberrant metabolism and treatment paradigms in polycystic ovary syndrome. Endocrine. 2012;42:526-534. 48. Ewens KG, Stewart DR, Ankener W, et al. Family-based analysis of candidate genes for polycystic ovary syndrome. J Clin Endocrinol Metab. 2010;95:2306-2315. 49. Deligeoroglou E, Kouskouti C, Christopoulos P. The role of genes in the polycystic ovary syndrome: predisposition and mechanisms. Gynecol Endocrinol. 2009;25:603-609. 50. Wehr E, Schweighofer N, Moller R, et al. Association of FTO gene with hyperandrogenemia and metabolic parameters in women with polycystic ovary syndrome. Metabolism. 2010;59:575-580. 51. Adler YD, Zouboulis CC, Geilen CC, et al. Eine seltene Variante des SAHA Syndroms. Z Hautkr. 2000;76:327-328. 52. Rager KM, Omar HA. Androgen excess disorders in women: the severe insulin-resistant hyperandrogenic syndrome, HAIR-AN. Sci World J. 2006;6:116-121. 53. Makrantonaki E, Vogel K, Fimmel S, et al. Interplay of IGF-I and 17beta-estradiol at age-specific levels in human sebocytes and fibroblasts in vitro. Exp Gerontol. 2008;43:939-946.
395 54. Blomberg M, Jeppesen EM, Skovby F, et al. FGFR3 mutations and the skin: report of a patient with a FGFR3 gene mutation, acanthosis nigricans, hypochondroplasia and hyperinsulinemia and review of the literature. Dermatology. 2010;220:297-305. 55. Chamot AM, Vion B, Gerster JC. Acute pseudoseptic arthritis and palmoplantar pustulosis. Clin Rheumatol. 1986;5:118-123. 56. Hayem G, Bouchaud-Chabot A, Benali K, et al. SAPHO syndrome: a long-term follow-up study of 120 cases. Semin Arthritis Rheum. 1999;29:159-171. 57. Kahn MF, Khan MA. The SAPHO syndrome. Baillieres Clin Rheumatol. 1994;8:333-362. 58. Kahn MF, Bouvier M, Palazzo E, et al. Sternoclavicular pustulotic osteitis (SAPHO). 20-year interval between skin and bone lesions. J Rheumatol. 1991;18:1104-1108. 59. Hurtado-Nedelec M, Chollet-Martin S, Nicaise-Roland P, et al. Characterization of the immune response in the synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome. Rheumatology (Oxford). 2008;47:1160-1167. 60. Olivieri I, Padula A, Palazzi C. Pharmacological management of SAPHO syndrome. Expert Opin Investig Drugs. 2006;15:1229-1233. 61. Lindor NM, Arsenault TM, Solomon H, et al. A new autosomal dominant disorder of pyogenic sterile arthritis, pyoderma gangrenosum, and acne: PAPA syndrome. Mayo Clin Proc. 1997;72: 611-615. 62. Wise CA, Gillum JD, Seidman CE, et al. Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder. Hum Molec Genet. 2002;11:961-969. 63. Kanazawa N, Furukawa F. Autoinflammatory syndromes with a dermatological perspective. J Dermatol. 2007;34:601-618. 64. Dierselhuis MP, Frenkel J, Wulffraat NM, et al. Anakinra for flares of pyogenic arthritis in PAPA syndrome. Rheumatology (Oxford). 2005;44:406-408. 65. Apert E. De l`a acrocéphalosyndactylie. Bull Soc Med Hop (Paris). 1906;23:1310-1330. 66. Boulet SL, Rasmussen SA, Honein MA. A population-based study of craniosynostosis in metropolitan Atlanta, 1989–2003. Am J Med Genet A. 2008;146A:984-991. 67. Solomon LM, Fretzin D, Pruzansky S. Pilosebaceous abnormalities in Apert's syndrome. Arch Dermatol. 1970;102:381-385. 68. Melnik BC, Schmitz G. Role of insulin, insulin-like growth factor-1, hyperglycaemic food and milk consumption in the pathogenesis of acne vulgaris. Exp Dermatol. 2009;18:833-841. 69. Wilkie AO, Slaney SF, Oldridge M, et al. Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome. Nat Genet. 1995;9:165-172. 70. Melnik BC. Role of FGFR2-signaling in the pathogenesis of acne. Dermatoendocrinol. 2009;1:141-156. 71. Melnik BC. FoxO1-the key for the pathogenesis and therapy of acne? J Dtsch Dermatol Ges. 2010;8:105-114. 72. Melnik BC. Is nuclear deficiency of FoxO1 due to increased growth factor/PI3K/Akt-signalling in acne vulgaris reversed by isotretinoin treatment? Br J Dermatol. 2010;162:1398-1400. 73. Letawe C, Boone M, Pierard GE. Digital image analysis of the effect of topically applied linoleic acid on acne microcomedones. Clin Exp Dermatol. 1998;23:56-58. 74. Alestas T, Ganceviciene R, Fimmel S, et al. Enzymes involved in the biosynthesis of leukotriene B4 and prostaglandin E2 are active in sebaceous glands. J Mol Med (Berl). 2006;84:75-87. 75. Wrobel A, Seltmann H, Fimmel S, et al. Differentiation and apoptosis in human immortalized sebocytes. J Invest Dermatol. 2003;120:175-181. 76. Zouboulis CC, Nestoris S, Adler YD, et al. A new concept for acne therapy: a pilot study with zileuton, an oral 5-lipoxygenase inhibitor. Arch Dermatol. 2003;139:668-670. 77. Steiner PE. Necropsies on Okinawans; anatomic and pathologic observations. Arch Pathol (Chic). 1946;42:359-380. 78. Simopoulos AP. Evolutionary aspects of diet and essential fatty acids. World Rev Nutr Diet. 2001;88:18-27.
396 79. Cordain L, Lindeberg S, Hurtado M, et al. Acne vulgaris: a disease of Western civilization. Arch Dermatol. 2002;138:1584-1590. 80. Thiboutot DM, Strauss JS. Diet and acne revisited. Arch Dermatol. 2002;138:1591-1592.
C.C. Zouboulis 81. Thielitz A, Reinhold D, Vetter R, et al. Inhibitors of dipeptidyl peptidase IV and aminopeptidase N target major pathogenetic steps in acne initiation. J Invest Dermatol. 2007;127: 1042-1051.
