VOLUME 70, AUGUST 2002 101

Continuing Medical Education

Acne vulgaris is a chronic inflammatory diseaseof the pilosebaceous units. It is a pleomorphicdisorder with multifactorial pathogenesis. Themany expressions of acne rarely present a diag-nostic challenge, but correct classification ofacne is crucial in choosing the appropriate ther-apies. Although previous research has provideda better understanding of the pathogenic fac-tors, there is sti l l a great deal to be learned.

PerspectiveAcne vulgaris, the most common skin disorder, affectsvirtually all individuals at least once. Incidence peaksin 18-year-olds, but substantial numbers of 20- to 40-year-olds also develop the disease. The effects ofacne should not be underestimated. It can persist foryears; produce disfigurement and permanent scarring;and have significant psychosocial consequences,including diminished self-esteem, embarrassment,social withdrawal, depression, and unemployment.1The extent and severity of these effects underline theimportance of providing adequate therapy, whichproduces satisfactory results in most cases.

PathogenesisAcne is a complex disease with multifactorial patho-genesis and considerable variation in severity. Thus,

Acne Vulgaris, I: Pathogenesis and DiagnosisSteve S. Oberemok, MD; Alan R. Shalita, MD

From the Department of Dermatology, State University of New York Downstate Medical Center, Brooklyn. Dr. Oberemok is aClinical Assistant Instructor. Dr. Shalita is a Distinguished Teaching Professor and Chairman.Reprints: Alan R. Shalita, MD, Department of Dermatology, SUNYDownstate Medical Center, 450 Clarkson Ave, Brooklyn, NY 11203(e-mail: ashalita@downstate.edu).

GOAL

To describe the pathogenic mechanisms associated with acne and

the variable clinical presentation

OBJECTIVES

Upon completion of this activity, dermatologists and general practitioners should be able to:

1. Discuss the morphologic changes that give rise to acne lesions.

2. Outline the role of sebum and Propionibacterium acnes in the production of acne.

3. Describe the clinical presentation, range of lesion severity, and differential diagnosis for acne.

CME Test on page 97.

This article has been peer reviewed andapproved by Michael Fisher, MD, Professor ofMedicine, Albert Einstein College of Medicine.Review date: July 2002.

This activity has been planned and implementedin accordance with the Essential Areas and Policiesof the Accreditation Council for Continuing MedicalEducation through the joint sponsorship of AlbertEinstein College of Medicine and QuadrantHealthCom, Inc. The Albert Einstein College of

Medicine is accredited by the ACCME to providecontinuing medical education for physicians.

Albert Einstein College of Medicine designatesthis educational activity for a maximum of 1.0 hourin category 1 credit toward the AMA Physician’sRecognition Award. Each physician should claimonly those hours of credit that he/she actually spentin the educational activity.

This activity has been planned and produced inaccordance with ACCME Essentials.

Acne Vulgaris, I: Pathogenesis and Diagnosis

102 CUTIS®

therapy can be directed at multiple factors and mod-ified for individual patients.

Acne is a disorder of the sebaceous follicles,which are special pilosebaceous units located on theface, neck, chest, upper back, and upper arms. Theseunits consist of relatively large sebaceous glandsassociated with small hair follicles. Acne arises fromthe interaction of 4 factors:

1. Comedogenesis—sebaceous follicle obstruc-tion arising from increased cohesiveness offollicular epithelial cells, hyperproliferationof ductal keratinocytes, or both.2

2. Excessive sebum production caused by andro-genic stimulation of sebaceous glands at oraround adrenarche or later.

3. Proliferation of Propionibacterium acnes, ananaerobic diphtheroid that populates seba-ceous follicles and is a normal constituent ofcutaneous flora. P acnes produces chemotac-tic factors and proinflammatory mediatorsthat may lead to inflammation.3

4. Inflammation is a direct or indirect result of P acnes proliferation. Follicular rupture andextension of inflammation into the dermisresult in formation of the inflammatorylesions of acne vulgaris—papules, pustules,and nodules (Figure).

The earliest morphologic change or primarypathologic event is sebaceous follicle obstructiongiving rise to microcomedones, precursors of all acnelesions. The mechanism of microcomedo formationis unclear, but reasonable evidence supports hyper-proliferation of ductal keratinocytes.4 This mecha-nism was identified immunohistochemically using amonoclonal antibody to Ki-67, a nuclear markerexpressed by actively cycling cells. In subjects withacne but not in normal control subjects, Ki-67showed increased labeling by basal keratinocytes ofthe follicular epithelium of both comedones andmicrocomedones. In addition, suprabasal expressionof keratin K16, a marker of hyperproliferation andabnormal differentiation, occurs in ductal keratino-cytes of acne lesions.

Some “normal follicles” of acne-prone skin alsomay show overexpression of Ki-67 and K165—which underscores the need for topical treatment ofall acne-prone skin that shows early clear evidenceof microcomedo formation. Increased keratinocytecohesion as a primary event has been questioned asa factor in comedogenesis, as there is no clear evidence of abnormality of ductal desmosomes.

Some evidence, however, shows that the com-position of sebaceous lipids becomes altered andthat such alteration may cause follicular cells toadhere to one another more. Increases in free fatty

Abnormal follicular epithelial desquamation

Microcomedo formation

Excessive sebum production

Mixture of cells and sebum provides environment

for Propionibacterium acnes

Noninflammatory

Open and closed comedones

(blackheads and

whiteheads)

Chemotaxis

Cytokines

Inflammatory lesions—

papules, pustules, nodules

Propionibacteriumacnes

Pathogenesis of acne.

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VOLUME 70, AUGUST 2002 103

acids,6 squalene, and squalene oxide7 and adecrease in sebaceous linoleic acid could all triggerabnormal cohesion of cells in sebaceous follicles.According to another hypothesis, hyperkeratosis insebaceous follicles is the result of a local deficiencyof vitamin A.8 Androgens may have an importantrole in controlling ductal hyperproliferation eitherdirectly or indirectly through stimulation of seba-ceous glands. More recently, cytokines proved tohave an important controlling effect.9 In the in vitromodel used in the study, comedones were producedunder the influence of interleukin-1� (IL-1�), andthis process can be inhibited by adding IL-1�receptor antagonist to the system.

Sebum, the lipid-rich secretion of sebaceousglands, has a central role in the pathogenesis ofacne and provides a growth medium for P acnes.Enlargement of sebaceous glands and increasedproduction of sebum are stimulated by increasedproduction of adrenal and gonadal androgens—achange preceding clinical onset of puberty. Inter-estingly, sebum production rates are inversely pro-portional to the concentration of linoleic acid inskin-surface lipids; subjects with acne and normalcontrol subjects are marked by a difference insebum composition. According to a current expla-nation of acne pathogenesis, follicular epitheliumdifferentiation may be influenced by a lower con-centration of linoleate in sebum. The relationbetween acne and sebum overproduction has longbeen acknowledged, as has been the correlationbetween acne severity and sebum production rates.

Androgenic hormones control sebaceous glandsecretions. Testosterone is the main circulatingandrogen. In women, however, the adrenal glandand its main androgens dehydroepiandrosterone(DHEA) and sulfate salt of DHEA (DHEAS) haveimportant roles in androgen control of sebaceousglands. Testosterone is assumed to convert to dihydrotestosterone, which then binds to a high-affinity specific cytoplasmic receptor protein that istransported to the cell nucleus where the DNA-driven events occur.

Even though free testosterone levels may be ele-vated in women with acne compared with womenwithout acne, actual values fall within the normalrange.10 Given the efficacy of antiandrogen treat-ments, however, the sebaceous glands of patientswith acne are likely to be hypersensitive to andro-gens. In men, the association of acne and highandrogen concentrations is less consistent.11 To besure, there are no reports of conclusive repro-ducible studies supporting a consistent mechanisminvolved in sebum overproduction as it relates toandrogen production.

P acnes is the predominant organism in seba-ceous follicles, where it grows in a relatively anaer-obic lipid-rich environment of microcomedones. P acnes counts on the skin of teenage subjects withacne and P acnes counts on the skin of age-matchedcontrol subjects differ significantly. P acnes, how-ever, is not essential for comedogenesis, as was con-firmed by research involving children with earlyacne. P acnes produces an extracellular lipase thathydrolyzes sebum triglycerides to glycerol, used bythe bacteria as a growth substrate, and to free fattyacids, which may possess comedogenic and/orproinflammatory qualities.12 Inhibition of bacteriallipase alone, however, failed to improve inflamma-tory acne.13 The initial event in acne inflammationmay be the disruption of follicular epithelium,which allows microcomedones to come into con-tact with inflammatory systems. Early, apparentlyintact comedones contain neutrophils, which sug-gests that soluble inflammatory factors may diffusefrom comedones. Lee et al14 found that P acnes alsoproduced high-molecular-weight chemotactic fac-tors, one of which was the lipase itself. In subse-quent studies, P acnes may have simultaneouslyproduced both high- and low-molecular-weightchemoattractants, and the majority of neutrophilchemotactic activity in P acnes culture supernatantwas less than 2 kd.15 In another study, the role ofcellular immunity in initiation of acne lesions wasexplored.16 Not surprisingly, CD4+ lymphocyteswere prominent in early acne lesions. This finding,which is consistent with elevation of anti–P acnescellular immunity in patients with severe acne, issignificant, as antibody titers to P acnes parallelacne severity.17 These antibodies are required toactivate the classic pathway of complement. Onthe other hand, the alternative pathway is acti-vated by P acnes wall carbohydrate.

The comedo also may contain other inflammatoryfactors. Allaker and Greenman18 showed that P acnesproduces compounds that engage in histaminelikeactivity. Ingham et al19 found significant levels of IL-1–like activity and tumor necrosis factor–likemolecules in a majority of open comedones. The ori-gins and actual structures of these factors have yet tobe defined.

When neutrophils arrive at the comedo, P acnes,already opsonized by C3b or immunoglobulins, isingested. This interaction releases intracellularhydrolytic enzymes but does not kill P acnes. Theselysosomal enzymes degrade the follicular epithelium,which leads to rupture of the follicular wall andextrusion of follicular epithelium, sebaceous lipids, P acnes, and hair into the dermis, which in turncauses inflammation. Several P acnes–produced

Acne Vulgaris, I: Pathogenesis and Diagnosis

104 CUTIS®

extracellular enzymes (eg, hyaluronidase, protease)also may be important in inflammation.20

Clearly, the immune response in acne is not pro-tective. Inappropriately activated immunity seemslikely to lead to propagation of inflammatory lesionsand subsequent scarring.

DiagnosisAcne is generally limited to areas where sebaceousglands are largest and most abundant—the face,neck, chest, upper back, and upper arms. Individuallesions are centered about sebaceous follicles.

Correct classification of lesion type (Table) isessential for choosing the most effective therapy. At the 1990 Consensus Conference on Acne Classification,21 a global evaluation of lesions andtheir complications (eg, drainage, hemorrhage,pain) was proposed. Psychosocial impact, failureto respond to previous therapies, and occupa-tional disability are 3 additional factors used ingrading acne.

Noninflammatory acne lesions are either closedor open comedones. Acne that manifests as non-inflammatory lesions is not classified severe unlessthe number, size, and extent of such lesions are sooverwhelming as to warrant the designation.

Inflammatory acne lesions are papules, pustules,and nodules. These lesions are classified as papulo-pustular, nodular, or both. The severity gradesassigned (mild, moderate, severe) are based onlesion count approximations (Table).

The term cystic acne should probably be aban-doned, as there are no true cysts in acne (on rareoccasion, these cysts develop as a residual effect ofacne lesion healing). The term severe acne may beapplied if ongoing scarring or persistent lesion-drainage is involved or if sinus tracts are present. Inaddition, the most destructive forms of acne—acneconglobata, acne fulminans, follicular occlusiontriad—are classified as very severe.

Differential DiagnosisAlthough most acne diagnoses present no difficul-ties, certain conditions or overlapping conditionsmay be confusing. Differential diagnosis may bestimulated by this noninclusive list: rosacea, ulery-thema ophryogenes, gram-negative folliculitis,steatocystoma multiplex, steroid acne, drug erup-tions, perioral dermatitis, iododermas, verruca vul-garis, verruca plana, bromodermas, syringomas,sarcoidosis, trichoepitheliomas, follicular muci-nosis, angiofibromas, infectious folliculitis, andkeratosis pilaris.

REFERENCES1. Koo J. The psychological impact of acne: patient’s percep-

tions. J Am Acad Dermatol. 1995;32:S26-S30.2. Plewig G, Fulton JE, Kligman AM. Cellular dynamics of

comedo formation in acne vulgaris. Arch Dermatol Forsch.1971;242:12-29.

3. Vowels BR, Yang S, Leyden JJ. Induction of proinflam-matory cytokines by a soluble factor of P acnes: implica-tions for chronic inflammatory acne. Infect Immun.1995;63:3158-3165.

4. Knaggs HE, Holland DB, Morris C, et al. Quantifica-tion of cellular proliferation in acne using the mono-clonal antibody Ki-67. J Soc Invest Dermatol.1994;102:89-92.

5. Cunliffe WJ, Holland DB, Clark SM, et al. Comedogenesis:some new aetiological, clinical and therapeutic strategies.Br J Dermatol. 2000;142:1084-1091.

6. Kligman AM, Katz AC. Pathogenesis of acne vulgaris. ArchDermatol. 1968;98:53-57.

7. Motoyoshi K. Enhanced comedo formation in rabbit earskin by squalene and oleic acid peroxides. Br J Dermatol.1983;109:191-198.

8. Kealey T. Hypovitaminosis A of follicular duct as a cause ofacne vulgaris [letter]. Lancet. 1988;2:449.

9. Guy R, Greem MR, Kealey T. Modeling acne in vitro. JInvest Dermatol. 1996;106:176-182.

Acne Classification by Severity of Inflammatory Lesions

Severity Papules/Pustules Nodules

Mild Few to several None

Moderate Several to many Few to several

Severe Numerous to extensive Many

10. Thiboutot D, Gilliland K, Light J, et al. Androgenmetabolism in sebaceous glands from subjects with andwithout acne. Arch Dermatol. 1999;135:1041-1045.

11. Pochi PE, Strauss JS, Rao RS, et al. Plasma testosteroneexcretion and sebum production in males with acne vulgaris. J Clin Endocrinol Metab. 1965;51:287-291.

12. Shalita AR, Lee WL. Inflammatory acne. DermatolClin. 1983;1:361-364.

13. Weeks JG, McCarty L, Black T, et al. The inability of abacterial lipase inhibitor to control acne vulgaris. JInvest Dermatol. 1977;69:236-243.

14. Lee WL, Shalita AR, Suntharalingam K, et al. Neu-trophil chemotaxis by Propionibacterium acnes lipaseand its inhibition. Infect Immun. 1982;35:71-78.

15. Webster GF, Leyden JJ. Characterization of serum-independent polymorphonuclear leukocyte chemotacticfactors produced by Propionibacterium acnes. Inflammation.1980;4:261-269.

16. Norris JFB, Cunliffe WJ. A histological and immunocy-tochemical study of early acne lesions. Br J Dermatol.1988;118:651-659.

17. Puhvel SM, Barfatani M, Warnick M. Study of anti-body levels to Corynebacterium acnes. Arch Dermatol.1964;90:421-427.

18. Allaker RP, Greenman S. The production of inflamma-tory compounds by Propionibacterium acnes and otherskin organisms. Br J Dermatol. 1987;117:175-183.

19. Ingham E, Eady EA, Goodwin CE, et al. Proinflamma-tory levels of IL-1-like bioactivity are present in themajority of open comedones in acne vulgaris. J InvestDermatol. 1992;98:895-901.

20. Puhvel SM, Hoffman LK. The production ofhyaluronidase by Corynebacterium acnes. J Invest Dermatol. 1972;58:66-70.

21. Report of the Consensus Conference on Acne Classification.J Am Acad Dermatol. 1991;24:495-500.

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DISCLAIMERThe opinions expressed herein are those of the authors and do not necessarily represent the views of the sponsor or its publisher. Please review complete prescribinginformation of specific drugs or combination of drugs, including indications, contraindications, warnings, and adverse effects before administering pharmacologictherapy to patients.

FACULTY DISCLOSUREThe Faculty Disclosure Policy of the College of Medicine requires that faculty participating in a CME activity disclose to the audience any relationship with a pharma-ceutical or equipment company that might pose a potential, apparent, or real conflict of interest with regard to their contribution to the program. It is required by theAccreditation Council for Continuing Medical Education that each author of a CME article disclose to the participants any discussion of an unlabeled use of a commer-cial product or device or an investigational use not yet approved by the Food and Drug Administration.Dr. Oberemok reports no conflict of interest. Dr. Shalita is a consultant for Allergan, Inc; Dermik Laboratories; Medicis Pharmaceutical Corporation; and StiefelLaboratories, Inc. He also has received research grants from and served on speakers bureaus for Allergan, Inc; Collagenx Pharmaceuticals, Inc; Connetics Corporation; Dermik Laboratories; Galderma Laboratories, LP; Medicis Pharmaceutical Corporation; and Stiefel Laboratories, Inc. Dr. Fisher reports no conflict of interest.