New insights into the management of acne:
`An update from the Global Alliance to Improve
`Outcomes in Acne Group
`
`Authors and Guest Editors: Diane Thiboutot, MD,a and Harald Gollnick, MDb
`Co-Authors and Steering Committee: Vincenzo Bettoli, MD,c Brigitte Dre´no, MD, PhD,d Sewon Kang, MD,e
`James J. Leyden, MD,f Alan R. Shalita, MD,g and Vicente Torres Lozada, MDh
`Co-Authors and Global Alliance Members: Diane Berson, MD,i Andrew Finlay, MBBS, FRCP,j
`Chee Leok Goh, MD, MRCP, FRCP, FAMS,k Marı´a Isabel Herane, MD,l Ana Kaminsky, MD, PhD,m
`Raj Kubba, MD,n Alison Layton, MB, ChB, FRCP,o Yoshiki Miyachi, MD, PhD,p Montserrat Perez, MD,q
`Jaime Piquero Martin, MD,r Marcia Ramos-e-Silva, MD, PhD,s Jo Ann See, MBBS, FACD,t Neil Shear, MD,
`FRCPC,u and John Wolf, Jr, MD,v on behalf of the Global Alliance to Improve Outcomes in Acne
`Hershey and Philadelphia, Pennsylvania; Magdeburg, Germany; Ferrara, Italy; Nantes, France;
`Baltimore, Maryland; Brooklyn and New York, New York; Mexico City, Mexico;
`Cardiff and Harrogate, United Kingdom; Singapore; Santiago, Chile; Buenos Aires, Argentina;
`New Delhi, India; Kyoto, Japan; Barcelona, Spain; Caracas, Venezuela; Rio de Janeiro, Brazil;
`Sydney, Australia; Toronto, Ontario, Canada; and Houston, Texas
`
`The Global Alliance to Improve Outcomes in Acne published recommendations for the management of
`acne as a supplement to the Journal of the American Academy of Dermatology in 2003. The recommen
`dations incorporated evidence based strategies when possible and the collective clinical experience of the
`group when evidence was lacking. This update reviews new information about acne pathophysiology and
`treatment such as lasers and light therapy and relevant topics where published data were sparse in 2003
`but are now available including combination therapy, revision of acne scarring, and maintenance therapy.
`The update also includes a new way of looking at acne as a chronic disease, a discussion of the changing
`role of antibiotics in acne management as a result of concerns about microbial resistance, and factors that
`affect adherence to acne treatments. Summary statements and recommendations are provided throughout
`the update along with an indication of the level of evidence that currently supports each finding. As in the
`original supplement,
`the authors have based recommendations on published evidence as much as
`possible. ( J Am Acad Dermatol 2009;60:S1 50.)
`
`Key words: acne; acne scarring; adherence; antibiotic resistance; lasers; maintenance; pathophysiology;
`retinoids.
`
`From the Department of Dermatology, Pennsylvania State Univer
`sity College of Medicine, Hersheya; the Department of Derma
`tology and Venereology, Medical Faculty, Otto von Guericke
`University, Magdeburgb; Clinical Dermatologica at Arcispedale S.
`Anna, University of Ferrarac; Hotel Dieu, Nantesd; Department of
`Dermatology, Johns Hopkins Medicine, Baltimoree; University of
`Pennsylvania School of Medicine, Philadelphiaf; Department of
`Dermatology State University of New York Downstate Medical
`Center, Brooklyng; and Juarez Hospital, Mexico Cityh; the De
`partment of Dermatology, Weill Medical College, New Yorki;
`Department of Dermatology, Cardiff University School of Med
`icinej; National Skin Center, Singaporek; Department of Derma
`tology, University of Chilel; Department of Dermatology, School
`of Medicine, University of Buenos Airesm; Delhi Dermatology
`Group, New Delhin; Department of Dermatology, Harrogate
`District Hospitalo; Department of Dermatology, Kyoto University
`Graduate School of Medicinep; Hospital de San Pablo, Barcelo
`naq; Service of Dermatology, Institute of Biomedicine, Hospital
`Vargas, Caracasr; Universidade Federal do Rio de Janeiros; Central
`Sydney Dermatologyt; Department of Dermatology, Sunnybrook
`and Women’s College Health Sciences Center, Torontou; Depart
`ment of Dermatology, Baylor College of Medicine, Houston.v
`
`Supported by an educational grant from Galderma International.
`Disclosure: Dr Berson has
`served on advisory boards
`for
`Galderma, Kao, Stiefel, Dusa, Johnson & Johnson, and Ortho
`Neutrogena and received honoraria. Dr Bettoli has served as
`an investigator for Galderma, Intendis, Astellas, and La Roche
`Posay and a speaker for Galderma, Intendis, Astellas, Stiefel,
`and La Roche Posay and received grants in compensation. Dr
`Dre´no has served on advisory boards for Galderma, La Roche
`Posay, and Expansicone and has been a speaker for Pierre
`Fabre and an investigator for Biollevis and received honoraria.
`Dr Finlay has served on advisory boards and as speaker for
`Galderma and Pierre Fabre and on advisory boards for York
`Pharma and has received grants or honoraria. Dr Goh has
`served as a consultant to Galderma and received travel grants.
`Dr Gollnick has served as an investigator and speaker for
`Schering, Stiefel, and Galderma, and on advisory boards for
`Galderma; in addition, he has been a consultant to Basilea and
`IMTM and has received honoraria for these duties. Dr Herane
`has served as an investigator for Bioderma, Vichy, and Isden
`and a speaker for Galderma and Stiefel and has received
`honoraria and other financial benefits for this work. Dr Kang
`has served as an investigator and consultant for Galderma and an
`
`1 of 50
`
`Almirall EXHIBIT 2036
`
`Amneal v. Almirall
`IPR2019-00207
`
`

`

`S2 Thiboutot et al
`
`J AM ACAD DERMATOL
`MAY 2009
`
`INTRODUCTION
`In 2003, a group of physicians and researchers in
`the field of acne, known as the Global Alliance to
`Improve Outcomes in Acne, published recommen
`dations for the management of acne.1 The goal was
`to make recommendations that were evidence based
`when possible and that included input from numer
`ous countries. Since the initial meeting of the Global
`Alliance in 2001, the group has continued to meet
`regularly to discuss various aspects of acne manage
`ment and create educational initiatives for dermatol
`ogists around the world. Regional groups in Europe,
`Asia, and Latin America have been established.
`Global Alliance members have actively worked
`with national dermatology societies to formulate
`guidelines for management of acne that take into
`account the individual characteristics of the country
`while harmonizing with the international recom
`mendations. In addition, the Global Alliance pre
`sented a written consensus opinion to the US Food
`and Drug Administration (FDA) Guidance for
`
`Abbreviations used:
`
`ECOB:
`
`ALA:
`AP 1:
`BPO:
`CO2:
`ECCA:
`
`aminolevulinic acid
`activator protein
`benzoyl peroxide
`carbon dioxide
`e´chelle d’e´valuation Clinique des
`cicatrices d’acne´
`Elaboration d’un outil d’evaluation de
`l’observance des traitements
`medicamenteux
`Er:YAG: erbium doped yttrium aluminum garnet
`FDA:
`Food and Drug Administration
`HLA DR: Human leukocyte antigen DR
`ICAM:
`intercellular adhesion molecule
`ICG:
`indocyanine green
`IL:
`interleukin
`IPL:
`intense pulsed light
`MAL:
`methyl aminolevulinate
`MMP:
`matrix metalloproteinase
`PDL:
`pulsed dye laser
`PDT:
`photodynamic therapy
`RF:
`radiofrequency
`TCA:
`trichloroacetic acid
`TLR:
`toll like receptor
`VCAM:
`vascular cell adhesion molecule
`
`investigator for Stiefel and has received honoraria or grant
`support. Dr Kubba has served as a consultant to Galderma and
`Schering Plough and in another capacity for Ranbaxy and
`Janssen Cilag and has received grants and honoraria. Dr Layton
`has served as an advisor, speaker, and investigator
`for
`Galderma and received grants and travel grants and has also
`been an investigator for Roche, receiving grants. Dr Leyden has
`served as a consultant and on advisory boards for Allergan,
`Galderma, Obagi, SkinMedica, Medicis, and Stiefel and received
`grants and honoraria. Dr Miyachi has served on advisory boards
`for Galderma, Otsuka, and Sanofi Aventis and has received
`grants and honoraria. Dr Piquero Martin has served as a speaker
`for Galderma and received benefits. Dr Ramos e Silva has
`served on advisory boards for Galderma, Johnson, Stiefel,
`Novartis, La Roche Posay, and Roche; she has been an inves
`tigator for Galderma, Johnson, Stiefel, Novartis, La Roche Posay,
`Biolab, Aventis, and Pfizer, and has been a speaker
`for
`Galderma, Johnson, Stiefel, Novartis, LaRoche Posay, Vichy,
`and Roche and has received honoraria or grant support. Dr See
`has received honoraria as a speaker for Galderma and L’Oreal.
`Dr Shalita has served as a consultant to Galderma, Stiefel,
`Allergan (including consultancies to companies acquired by
`these companies), Baxbier, Quinoa, and Ortho and has been an
`investigator
`for Galderma, Stiefel, and Allergan and has
`received grants and honoraria; he has stock options in Medicis.
`Dr Shear has served on advisory boards for Galderma, and as a
`consultant and other for Galderma and has received honoraria
`and residency or fellowship program funding; Dr Shear has
`also served as a consultant and other for Dermik and received
`honoraria and residency or
`fellowship program funding.
`Dr Thiboutot has been an investigator, consultant, or advisory
`board member
`for Allergan,
`Inc, Arcutis,
`Inc, Dusa,
`Inc,
`Galderma, Inc, Stiefel, Inc, QLT, Inc, and Medicis, Inc and has
`received honoraria or grant
`support. Dr Torres Lozada
`has been a consultant and investigator for Galderma and has
`received honoraria. Dr Wolf has been an investigator for
`Galderma and Medicis, an advisory board member, consultant,
`
`and speaker for Galderma and Medicis, an advisory board
`member and consultant for QLT, and a speaker for Stiefel and
`Dermik; he has received grants and honoraria and has stock in
`Medicis. Drs Kaminsky and Perez have no conflicts of interest
`to declare.
`Preparation of the manuscript was a joint effort as follows. The
`manuscript outline, content development and selection of
`references, review of the data, and generation of the first draft
`were done in sections, with responsibilities as follows.
`‘‘Rec
`ognizing the chronicity of acne’’ section: Drs Shear, Finlay, and
`Gollnick, and Ms Sanders.
`‘‘Update: Pathogenesis of acne’’
`section: Drs Thiboutot, Kang, and Gollnick, and Ms Sanders.
`‘‘Update: Treatment of acne’’ was further subdivided into the
`following sections. ‘‘The changing role of antibiotics in manag
`ing acne’’ section: Drs Layton, Bettoli, Miyachi, Dre´no, Perez, and
`Leyden, and Ms Sanders. ‘‘Retinoid based combination therapy
`for acne’’ section: Drs Thiboutot, Kaminsky, Gollnick, Miyachi,
`Wolf, Herane, and Piquero Martin, and Ms Sanders.
`‘‘Does
`enough evidence now exist for using lasers and lights to treat
`inflammatory acne?’’ section: Drs Leyden, Berson, Kang, See,
`Shalita, Torres Lozada, and Gollnick, and Ms Sanders. ‘‘The role of
`topical retinoids in acne maintenance therapy’’ section: Drs
`Gollnick, Bettoli, Thiboutot, and Leyden, and Ms Sanders. ‘‘Man
`agement of acne scarring’’ section: Drs Dre´no, Goh, Kubba,
`Ramos e Silva, and Bettoli, and Ms Sanders. ‘‘Optimizing adher
`ence with acne therapy’’ section: Drs Thiboutot, Dre´no, Layton,
`Herane, and Dr Perez, and Ms Sanders. Ms Valerie Sanders is a
`medical writing consultant to Galderma International. Changes
`to the first draft and subsequent drafts were generated by each
`of the authors. All authors reviewed the complete final draft
`including all sections.
`Reprint requests: Diane Thiboutot, MD, Department of Dermatol
`ogy, The Pennsylvania State University College of Medicine,
`Hershey, PA. E mail: dthiboutot@psu.edu.
`0190 9622/$36.00
`ª 2009 by the American Academy of Dermatology, Inc.
`doi:10.1016/j.jaad.2009.01.019
`
`2 of 50
`
`

`

`J AM ACAD DERMATOL
`VOLUME 60, NUMBER 5
`
`Thiboutot et al S3
`
`Industry on Acne Vulgaris (Docket No. 2005D 0340)
`regarding development of drugs for acne and design
`of clinical
`trials in this arena. A subgroup of
`European members of the alliance formulated a
`response to recent changes in the European Union
`regulations for use of oral isotretinoin. As new issues
`come up, the alliance will continue to advocate for
`clinicians who treat patients with acne and the
`patients’ rights to optimal treatment. Finally, the
`Global Alliance has established a World Wide Web
`site (www.acneglobalalliance.org), which provides
`information about
`the management of acne and
`recent developments in the field.
`The first publication in 2003 encompassed current
`information about
`acne pathophysiology and
`comprehensive treatment recommendations. This
`edition includes updates on pathophysiology and
`treatment,
`including our research into treatments
`that have recently emerged such as lasers and light
`therapy and areas where published data were
`sparse in 2003 but are now available,
`including
`combination therapy, revision of acne scarring, and
`maintenance therapy. In addition to an updated
`discussion of acne pathophysiology and treatment,
`we share in this supplement a new way of looking at
`acne as a chronic disease, a discussion of
`the
`changing role of antibiotics in acne management,
`and factors that affect adherence to acne treatments.
`As in the original supplement, we have tried to base
`recommendations on published evidence as much as
`possible. However, it should be noted that some
`recommendations are based primarily on our expert
`opinion (level V evidence) because of a lack of
`studies and different designs and methodologies of
`existing studies. We have strived to clearly acknowl
`edge in text which recommendations are based
`primarily on opinion, citing them as supported by
`Level V evidence.
`In addition, a number of the clinical trials included
`in our evaluations of data were performed as regis
`tration trials for regulatory approval. We acknowl
`edge that a particular type of patient is selected for
`study and results may not be generalizable to all
`patients; regulatory bodies typically address this in
`the package insert. In acne, the registration trial study
`inclusion and exclusion criteria often exclude pa
`tients with cystic acne ([2 nodules or cysts), truncal
`acne is often not evaluated, and minimum and
`maximum numbers of inflammatory and noninflam
`matory lesions at baseline are specified to give an
`objective measure of acne severity. To our knowl
`edge, there are no data suggesting that acne in
`various population subgroups adolescent, adult,
`male, female is different in terms of pathophysiol
`ogy with the exception of a greater effect of
`
`hormones in female patients. Assessment of popu
`lation differences would be an interesting topic for
`future studies.
`In the case of acne, monotherapy is used relatively
`rarely despite that regulatory bodies require mono
`therapy studies for drug approval. Because acne is a
`multifactorial disease, multiple classes of drugs are
`typically used in the clinical setting. Indeed, combi
`nation therapy is now recommended as the first line
`approach for acne.1 In this publication, the Global
`Alliance group considered the type and severity of
`acne in making recommendations. The Global
`Alliance plans to publish additional articles on the
`topics of hormonal/antiandrogenic therapy and the
`current use of oral isotretinoin.
`The following definitions were used to evaluate
`the strength of the evidence for recommendations in
`the supplement:
`
`Strong evidence from systematic review of mul
`d I
`tiple well designed, randomized, controlled trials;
`d II
`Strong evidence from at least one properly
`designed, randomized, controlled study of appro
`priate size;
`d III Evidence from well designed trials without
`randomization, single group pre/post, cohort,
`time series, or matched case controlled studies;
`d IV Evidence from well designed nonexperimen
`tal studies from more than one center or research
`group;
`d V Opinions of respected authorities, based on
`clinical evidence, descriptive studies, or reports of
`expert committees.
`
`RECOGNIZING THE CHRONICITY OF
`ACNE
`Editor’s note: This section summarizes ideas that
`were presented in full
`in a recent article in the
`American Journal of Clinical Dermatology.2
`It is important for dermatologists to take the lead
`in educating other clinicians that acne is often a
`chronic disease and not just a self limiting disorder of
`teenagers. For many patients, acne has the following
`characteristics that have been used to define chro
`nicity3,4: a prolonged course, a pattern of recurrence
`or relapse, manifestation as acute outbreaks or slow
`onset, and a psychologic and social
`impact that
`affects the individual’s quality of life. In considering
`whether acne is a chronic disease, it is interesting to
`compare it with atopic dermatitis (Table I). The
`similarities between the conditions are striking and
`range from underlying pathology (inflammation) to
`characteristic manifestation (frequently relapsing
`and recurrent diseases).
`
`3 of 50
`
`

`

`S4 Thiboutot et al
`
`J AM ACAD DERMATOL
`MAY 2009
`
`CONSENSUS: Acne Should Be Approached
`as a Chronic Disease
`
`Level of Evidence: V
`Characteristics of acne that define chronic diseases:
`
`d Pattern of recurrence or relapse
`d Prolonged course
`d Manifestation as acute outbreaks or slow onset
`d Psychological and social impact
`
`Acne warrants early and aggressive treatment
`Maintenance therapy is often needed for optimal
`outcomes
`
`Why is this important? Because many of our
`medical colleagues and a significant proportion of
`the lay public dismiss acne as a natural part of
`growing up that has few real consequences. Yet
`considerable evidence shows that acne can be a
`psychologically damaging condition that
`lasts
`years.5-11 The members of the Global Alliance believe
`that acne one of the most common skin diseases
`treated in routine dermatologic care should be rec
`ognized and investigated as a chronic disease with
`psychologic sequelae that do not always correlate
`with the clinician’s assessment of severity at one point
`in time.5
`There are no definitive longitudinal studies of the
`natural history of acne; however,
`in the group’s
`experience approximately 60% of acne cases are
`self limiting and can be managed with acute treat
`ment followed by topical maintenance therapy. In
`other cases, acne is a disease that requires treatment
`for a prolonged period. Oral isotretinoin the most
`effective acne treatment developed to date is ad
`ministered during a 20 week period and sometimes
`must be given in repeated courses.5 Further, as
`reviewed later in this supplement, recent well con
`trolled studies have shown that maintenance therapy
`is an effective strategy to minimize the risk of
`relapse.12-14 In addition, the members of the Global
`Alliance believe that limiting the duration of active
`acne by effective treatment may, in turn, reduce the
`likelihood of physical and emotional scarring. For
`these reasons, we encourage early and aggressive
`treatment of acne.
`How often do negative outcomes occur after acne?
`That question is difficult
`to answer definitively.
`However, there is good evidence that acne can persist
`into adult years in as many as 50% of individuals.7,15-18
`Negative psychologic outcomes,
`including anxiety,
`depression, and social withdrawal, have all been
`reported among individuals with acne and acne
`
`Table I. Comparison of chronicity in acne and
`atopic dermatitis
`
`Basic character
`Duration
`
`Genetic
`influence
`
`Age at onset, y
`Self-limiting?
`
`Counseling?
`Medication
`
`Social impact
`Psychologic
`impact
`Postdisease
`sequelae
`Physical scarring
`Psychologic
`
`Acne
`
`Atopic dermatitis
`
`Inflammatory
`[3 mos /
`5-30 years
`Yes, particularly in
`long-term
`courses;
`thought
`to be polygenic
`;10
`In ;80% of cases
`by third decade
`of life
`Intervals/years
`Continuously/
`intervals
`Yes
`Yes
`
`Inflammatory
`[3 mo / 5-40
`years
`Yes, thought to
`be polygenic
`
`;1
`In ;80% of cases
`by second
`decade of life
`Intervals/years
`Continuously/
`intervals
`Yes
`Yes
`
`Yes
`
`Yes
`
`Yes
`Yes
`
`Reprinted from Gollnick et al2 with permission from Wolters
`Kluwer Health.
`
`scars.7,9,10 Physical scars, persistent hyperpigmentation,
`or both are not uncommon sequelae of acne and are
`usually expensive and difficult to treat effectively. The
`effects of acne can persist for many years, even among
`individuals who had self limited adolescent acne.
`Unfortunately,
`the reason why acne becomes
`chronic in some patients is not well understood
`and it
`is currently difficult
`to determine which
`patients will have a chronic course of the disease.
`Factors that have been linked to a chronic course
`include stress related production of adrenal andro
`gens,19 Propionibacterium acnes colonization,20 fa
`milial background,7 and specific subtypes of acne
`(conglobata, keloidal,
`inversa, androgenic, scalp
`folliculitis, and chloracne).21,22 The members of the
`Global Alliance advocate further study to determine
`the link between these and other characteristics and
`the development of chronic acne.
`In summary, dermatologists are aware that acne is
`a chronic disease with important ramifications. We
`are charged in our role as skin experts with the
`mission of helping other health care professionals
`and patients to achieve a better understanding of
`acne and improve awareness of the highly effective
`treatments that are available. We must also be
`vigilant in ensuring that insurers and government
`regulatory bodies are aware of
`the impact and
`import of acne. Because the physical and emotional
`
`4 of 50
`
`

`

`J AM ACAD DERMATOL
`VOLUME 60, NUMBER 5
`
`Thiboutot et al S5
`
`sequelae associated with acne can last for many
`years, insurers need to be encouraged to provide
`reimbursement
`for acute and maintenance acne
`treatments that have been proven effective in clin
`ical trials.
`
`UPDATE: PATHOGENESIS OF ACNE
`More detailed information regarding the molecu
`lar events contributing to the pathogenesis of acne
`has emerged since 2003. There are 4 primary path
`ogenic factors, which interact in complex manner to
`produce acne lesions: (1) sebum production by the
`sebaceous gland; (2) P acnes follicular colonization;
`(3) alteration in the keratinization process; and (4)
`release of inflammatory mediators into the skin.
`Now, cellular culture studies have provided more
`information about the role of sebaceous lipids and
`inflammatory mediators including MMPs.
`Jeremy et al23 investigated the initiating events for
`acne lesions, and found that immune changes and
`inflammatory responses occur before hyperprolifer
`ation of keratinocytes, with a pattern similar to a
`type IV delayed hypersensitivity response. The
`1
`lymphocytes and
`immune response is led by CD4
`macrophages.23 These researchers hypothesize that
`the subsequent production of cytokines activates
`local endothelial cells, up regulating inflammatory
`vascular markers (E selectin, vascular cell adhesion
`molecule 1
`[VCAM 1],
`intercellular
`adhesion
`molecule 1 [ICAM 1], and human leukocyte anti
`gen DR [HLA DR]) in the vasculature around the
`pilosebaceous follicle.23 They further have postu
`lated that the entire process is initiated by interleukin
`(IL) 1a up regulation in response to a relative linoleic
`acid deficiency caused by excess sebum and pertur
`bation of barrier function within the follicle.23
`More than a decade ago, an in vitro study by
`Vowels et al24 demonstrated the presence of a
`soluble factor of P acnes that induced proinflamma
`tory cytokine production in human monocytic cell
`lines. Although distinct from lipopolysaccharide, this
`soluble factor had similar characteristics, in that its
`activity was dependent on the presence of CD14, a
`so called pattern recognition receptor for lipopoly
`saccharide and other lipid containing ligands. This P
`acnes product induced the synthesis of tumor ne
`crosis factor a and IL 1b in the cell
`lines. Later
`research showed that the cytokine induction by P
`acnes was occurring through TLR 2.25 TLR, a mam
`malian homologue of a drosophila protein known as
`toll, has emerged as a key regulator of host responses
`to infection.26 This transmembrane protein has a
`cytoplasmic portion that is homologous to the IL
`1 receptor and thus could trigger a signaling cascade
`that activates nuclear factor kB. A recent in vivo
`
`study by Jugeau et al27 demonstrated that these
`events occur in inflammatory lesions of patients
`with facial acne and confirmed the earlier observa
`tions of Kim et al25 in acne lesions. This provided
`additional evidence that
`inflammatory cytokines,
`working via autocrine and paracrine mechanisms
`through their respective receptors, amplify the sig
`naling pathways that activate the activator protein
`(AP) 1 transcription factor.28 Activation of AP 1 in
`duces MMP genes, whose products degrade and alter
`the dermal matrix.28 Retinoids are known to inhibit
`AP 1.29 Very recent studies indicate that retinoids can
`1
`macro
`induce monocytes to develop into CD209
`phages that phagocytose P acnes bacteria.30 These
`data further substantiate how such currently avail
`able treatments as topical retinoids can have anti
`inflammatory activity against acne. In addition, they
`may help to explain why acne can flare after initia
`tion of therapy; for example, disruption of sebocytes
`may result in release of proinflammatory molecules,
`leading to the clinical result of increased inflamma
`tion in some patients.
`More has been learned about the role of sebor
`rhea in acne as well. Sebaceous lipids are at least
`partly regulated by peroxisome proliferator acti
`vated receptors and sterol response element binding
`proteins.31,32 Peroxisome proliferator activated re
`ceptor nuclear receptors act in concert with retinoid
`X receptors to regulate epidermal growth and differ
`entiation and lipid metabolism.31 Sterol response
`element binding proteins mediate the increase in
`sebaceous lipid formation induced by insulin like
`growth factor 1.32
`In parallel, research into the functions of the
`sebaceous gland has yielded exciting information
`about the central role these glands play in regulation
`of skin functions.33 The sebaceous gland regulates
`independent endocrine functions of the skin and has
`a significant role in hormonally induced aging of
`skin.34,35 In addition, the sebaceous gland has both
`direct and indirect antibacterial activities. Sapienic
`acid, a lipid in sebum, has innate antimicrobial
`activity and is up regulated by activation of TLR 2
`by skin bacteria.36,37 Further, the sebaceous gland
`has ubiquitous expression of antibacterial peptides
`and proinflammatory cytokines/chemokines; these
`substances are induced in sebocytes by the pres
`ence of bacteria.38 The sebaceous gland acts as an
`independent endocrine organ in response to
`changes in androgens and hormones, and is the
`control center for a complex regulatory neuropep
`tide program that acts like the hypothalamus pitu
`itary adrenal axis.33 This aspect of sebaceous gland
`function is primarily influenced by corticotrophin
`releasing hormone,
`its binding protein,
`and
`
`5 of 50
`
`

`

`S6 Thiboutot et al
`
`J AM ACAD DERMATOL
`MAY 2009
`
`What Is New in Acne Pathophysiology
`
`d Inflammatory events have been found to precede hyperkeratinization
`d P acnes contributes to inflammation via activation of toll-like receptor (TLR) on the membranes of inflammatory cells
`d Peroxisome proliferator-activated receptors partly regulate sebum production
`d The sebaceous gland is a neuroendocrine-inflammatory organ that likely coordinates and executes a local response
`to stress and normal functions
`d Androgens have influence on follicular corneocytes
`d Oxidized lipids in sebum can stimulate production of inflammatory mediators
`d Matrix metalloproteinases (MMPs) occur in sebum and diminish with treatment-related resolution of acne lesions
`
`corticotrophin receptors.39-41 corticotrophin releas
`ing hormone levels change in response to stress,
`and its role in regulating sebaceous gland function
`is likely a link in the brain skin connection that is
`thought to explain the relationship between stress
`and skin disorders with an inflammatory component
`such as acne. Similarly, substance P,42 a melanocyte
`hormone,43,44
`and
`corticotrophin
`stimulating
`releasing hormone receptor 145 are involved in
`regulating sebocyte activity. In addition, an active
`role of receptors for highly conserved ectopeptidases
`such as dipeptidylpeptidase IV and aminopeptidase
`N in regulation of sebocytes has been reported.46
`The response of skin to stress is a subject of active
`investigation and may soon suggest new targets for
`therapeutic interventions.
`An additional area of interest that has recently
`emerged is the action of vitamin D in the skin.
`Sebocytes are capable of metabolizing and synthe
`sizing the primary vitamin D metabolite 1,25 dihy
`droxyvitamin D3.47 Several lines of evidence suggest
`that the vitamin D endocrine system is involved in
`regulating sebocyte function and physiology, includ
`ing production of sebum. Further, vitamin D ana
`logues may potentially be useful
`in normalizing
`sebaceous gland physiology in patients with acne.33
`Using a human keratinocyte cell line, Ottaviani
`et al48 showed that peroxidation of sebum lipids can
`activate inflammatory mediators, including IL 6 and
`lipoxygenases. Oxidized squalene can also stimulate
`hyperproliferative behavior of keratinocytes, suggest
`ing that
`this lipid may be partly responsible for
`comedo formation.48 Zouboulis et al49,50 have hypoth
`esized that lipoperoxides exert a proinflammatory
`effect on the pilosebaceous duct. Lipoperoxides pro
`duce leukotriene B4, which is a powerful chemo
`attractant
`that can recruit both neutrophils and
`macrophages, and stimulate production of proinflam
`matory cytokines.23,49,51
`Papakonstantinou et al52 investigated the role of
`MMPs in acne. These enzymes, which include colla
`genases, gelatinases, stromelysins, and matrilysins,
`
`have a prominent role in both inflammatory matrix
`remodeling and proliferative skin disorders. Sebum
`includes several MMPs, which are thought to origi
`nate in keratinocytes and sebocytes. In addition, oral
`isotretinoin can reduce concentrations of MMPs in
`sebum in parallel with clinical improvement.51
`The improved understanding of acne develop
`ment on a molecular level suggests that acne is a
`disease that involves the innate and adaptive im
`mune system and inflammatory events. Treatment
`that
`targets both immune system activation and
`inflammatory pathways is, therefore, desirable. A
`full discussion of how antiacne agents work at the
`molecular level is beyond the scope of this text;
`however, research indicates that many of the agents
`currently used to treat acne have effects on cellular
`receptors, inflammatory mediators, and other mo
`lecular targets. As more becomes known, new targets
`for treatment may also be identified.
`
`UPDATE: TREATMENT OF ACNE
`Several aspects of acne management have been
`evolving since the 2003 Global Alliance recommen
`dations.1 These include the role of antibiotics in
`treatment, use of lasers and light based therapies,
`issues regarding maintenance therapy, and treat
`ment of acne scars. There is increased evidence
`supporting the recommendation of a combination
`of a topical retinoid plus an antimicrobial agent as
`first line therapy for most patients with acne as a
`means of targeting multiple pathogenic features and
`both inflammatory and noninflammatory acne le
`sions. Studies published since 2003 support
`the
`recommendations outlined in the original algorithm,
`which has undergone minor modification to reflect
`the addition of new combination products for acne
`(Fig 1).
`
`The changing role of antibiotics in
`managing acne
`Antibiotic resistance is a significant public health
`concern in virtually all parts of the world,58 and the
`
`6 of 50
`
`

`

`J AM ACAD DERMATOL
`VOLUME 60, NUMBER 5
`
`Thiboutot et al S7
`
`CONSENSUS: Strategies to Limit Antibiotic Resistance Are Important in Acne Management
`
`Level of Evidence: V
`d Treatment regimens that limit, or even reduce, the incidence of bacterial antibiotic resistance are recommended
`o Selection pressure can affect other, more pathogenic bacteria in addition to P acnes53,54
`o High rates of resistance have been correlated with high outpatient use of antibiotics55
`
`d Use of oral antibiotics can lead to resistance in commensal flora at all body sites; topical antibiotics lead to
`resistance largely confined to skin of treated site56
`o Oral antibiotics are recommended for moderate to moderately severe acne1
`o Topical antibiotics may be used in mild to moderate acne as long as they are combined with benzoyl peroxide
`(BPO) and a topical retinoid1
`o Limit the duration of antibiotic use1,57 and assess response to antibiotics and continuing need at 6 to 12 weeks
`o Some countries have regulatory guidance limiting the duration of use of topical antibiotics (alone and in fixed-
`dose combination products) to 11 to 12 weeks
`
`d Use BPO concomitantly as a leave-on or as a wash
`o BPO for 5 to 7 days between antibiotic courses may reduce resistant organisms on the skin; however, BPO does
`not fully eradicate potential for resistant organisms
`
`d Avoid using antibiotics (either oral or topical) as monotherapy either for acute treatment or maintenance therapy
`d Avoid the simultaneous use of oral and topical antibiotics without BPO, particularly if chemically different
`
`Fig 1. Acne treatment algorithm. BPO, benzoyl peroxide. Reprinted from Gollnick et al1 with
`permission from