Physiopathology of acne vulgaris: recent data, new understanding of the treatments

ARTICLE

Auteur(s) : Henry PAWIN¹_, Claire BEYLOT², Martine CHIVOT³, Michel FAURE⁴, Florence POLI⁵, Jean REVUZ⁵, Brigitte DRÉNO⁶

¹ 11, Chaussée de la Muette, 75016 Paris, France
² Service de Dermatologie, Hôpital du Haut Lévêque, 33600 Pessac, France
³ 28, rue Viala 75015 Paris, France
⁴ Service de Dermatologie, Hôpital Edouard Herriot, 5 place d'Arsonval, 69003 Lyon, France
⁵ Service de Dermatologie, Hôpital Henri Mondor, 51 avenue Maréchal de Lattre de Tassigny 94000 Créteil, France
⁶ Service de Dermatologie, Hôtel-Dieu, Place Alexis Ricordeau 44035 Nantes Cédex 01, France

Article accepted on 04/11/2003

Acne is the most common reason for consulting a dermatologist. But on the other hand the intimate mechanisms underlying this skin condition are poorly understood. Research in the last few years has improved our knowledge of the condition. The mechanisms of formation of acne lesions and the role of Propionibacterium acnes (P. acnes) are now better understood. Innate immunity is also thought to play a part. The aim of the present review is to provide an update on the most recent data and to consider their value in the perspective of the treatment of patients suffering form acne. To better identify recent data throughout this article we have systematically distinguished the notion "classical" and "recent". Most recent studies have been performed as in vitro tests and it is difficult to transpose these data in vivo. However, they may provide us a more accurate idea of the intimate mechanisms involved in the development of acne lesions.

Methodology

This paper was prepared from a literature search “Medline – Ovid” performed between 1988 and 2003. We reviewed all articles that referred to the physiopathology of acne and mechanisms of action of acne treatment during this period and selected those that provided new information in one of the 2 domains since 1998. The study was performed by 7 French dermatologists interested in the field of acne with a hospital and/or private practice.

Mechanisms of formation of acne lesions

Acne is a chronic disease of the pilosebaceous follicle [1] under hormonal dependence, involving three well defined steps:
– First step: Stimulation of sebaceous gland production, inducing hyperseborrhea that generally starts at puberty (Fig. 1).
– Second step: Formation of micro-comedos considered as the first elementary lesion of acne which is due to anomalies of keratinocyte proliferation, adhesion and differentiation in the infrainfundibulum of the pilosebaceous follicle (Fig. 2).
– Third step: Formation of inflammatory lesions in which p. acnes, an anaerobic bacterium, plays an essential part (Fig. 3).
Only the first two steps are mandatory and lead to formation of retention lesions (open comedos and closed comedos also known as microcysts), considered to be the elementary lesions of acne. The inflammatory step that leads to transformation of the retention lesions into papules, pustules and nodules is not mandatory. This means that the clinical presentation of acne can take several forms: pure retention, mixed with retention predominant or inflammation predominant, pure inflammation (at least in the clinical appearance).

First step: sebaceous hypersecretion

Classical concepts

Sebaceous secretion is stimulated by androgens [1]. Testosterone is transformed in the sebocyte by 5α reductase [2, 3] into dihydrotestosterone which is the locally active form of androgen.

Recent data

Sebaceous gland and hormones
Sebocytes all possess the necessary enzyme systems to synthesize androgens de novo from cholesterol or transform weak androgens into more powerful derivatives – steroid sulfatase (identified in acne lesions and in normal acneic skin), 3 beta-hydroxy-steroid dehydrogenase (type 1 essentially), 17 beta-hydroxysteroid dehydrogenase (type 2 predominant with maximum activity in the face), 5 alpha reductase, 3 alpha-hydroxysteroid dehydrogenase and aromatase. The activity of these enzymes is increased in the sebaceous glands of patients with acne [4]. Development of specific antagonists to these iso-enzymes of the sebaceous gland represents a new therapeutic approach to acne and is being explored [4].
It has been shown in vitro that sebocyte response (proliferation) to stimulation by testosterone and dihydrotestosterone differs depending on their origin [5] – sebocytes from the face multiply faster than sebocytes taken from another part of the body. Proliferation is dose dependent. This means that the sensitivity of sebaceous glands to hormones depends on their location. These data highlight the central role of androgen sensitivity in acne.

Distribution of 5α reductase
The activity of 5α reductase varies depending on the cutaneous region [2]. It is very active in the face and scalp, less so in parts of the body not affected by acne. There are two types of 5α reductase, type I and type II whose distribution in the organism differs. Type I predominates in the sebaceous glands of the face and scalp, type II is found in the sebaceous glands of zones not affected by acne [2]. These results can explain the predominance of facial acne.

PPAR receptors
PPAR receptors α, β, γ have been identified in sebocytes, with the γ form being the most important. Free fatty acids, linoleic acid and androgens activate these receptors which bind to RXR retinoid receptors (formation of hetero dimers) inducing modifications of sebocyte proliferation and differentiation and synthesis of free fatty acids. They are therefore involved in maturation of the sebaceous gland and initiation of the inflammatory reaction in acne. The PPAR present in the sebaceous gland could provide a new target for acne treatments [6, 7].

Role of neuro mediators in hyperseborrhea
Besides the androgen receptors, the sebaceous gland possesses receptors for substance P which is a neuromediator. In vitro, substance P stimulates sebaceous secretion [8]. It is produced by peri-sebaceous nerve endings that are more numerous in substance P in patients with acne than in healthy subjects [9]. Substance P stimulates the production of a neutral endopeptidase in the sebocyte and of E-selectine around the sebaceous gland [10]. Hyperseborrhea induced by stress, a phenomenon well known to patients, could be due to production of substance P.

Composition of the sebum
Sebocytes in the sebaceous gland produce free fatty acids without intervention by P. acnes [11]. In hyperseborrhea, the composition of the sebum is modified, in particular the linoleic acid concentration is decreased by dilution [1]. Furthermore, the percentage of squalene increases in the pilosebaceous follicle with a meal rich in fat, particularly unsaturated fat. This could be the beginnings of a possible link between diet and acne [12].

Second step: formation of the micro-comedo

Classical concepts

Obstruction of the pilosebaceous follicle canal occurs in the infrainfundibulum [1, 13]. This is due to anomalies of proliferation, adhesion and differentiation of keratinocytes which do not separate from each other and so obstruct the canal lumen, leading to the formation of a micro-comedo. This initial acneiform lesion, generally invisible clinically, is present in 28% of biopsies of apparently normal skin in patients with acne [14].

The sebaceous gland continues to produce sebum which cannot be evacuated, leading to dilation of the pilosebaceous follicle and hence to a clinically visible lesion, the "comedo" [1, 13].

Recent data

Role of hormones
Keratinocytes in the infrainfundibulum, as well as sebocytes, are also targets for androgens. Keratinocytes in the pilosebaceous canal possess androgen receptors and the enzyme system required to metabolize androgens [4].
– 5α reductase type I predominates in keratinocytes in the infrainfundibulum of the pilosebaceous canal [3] whereas 5α reductase type II is predominant in normal epidermis.
– In vitro, it has been shown that the combined activity of 5α reductase type I and 17β hydroxysteroid dehydrogenase is two to seven times greater in keratinocytes in the infrainfundibulum than in those in other parts of the epidermis [15].
This suggests that anomalies in androgen metabolism in keratinocytes in the infrainfundibulum could lead to anomalies in proliferation and differentiation of these cells. Local hormonal phenomena would also contribute to formation of the micro-comedo.
These data reinforce the notion that acne is related to sensitivity to “peripheral” androgens. More recently, it has been shown that both keratinocytes and sebocytes have the enzymes necessary for the transformatation of cholesterol into dehydroepiandrosterone. Thus skin may be considered as a steroidogenesis organ [16].

Role of cytokines
In vitro, addition of interleukin-1α to culture medium containing a human pilosebaceous canal [17, 18] led to the formation of micro-comedos. This effect may be inhibited by antagonists of interleukin-1α which block the receptor, confirming the specificity of the phenomenon. Interleukin-1α is secreted by keratinocytes in the epidermis and infrainfundibulum, notably in reaction to local irritation.
This could explain the frequency of open and closed comedos of the chin (area rubbed with the fingers) and around the scalp (rubbed by hair, irritation from hair gels). Likewise, the irritation induced by some hygiene or cosmetic products could help in the formation of new micro-comedos and be a factor in maintaining acne.

Hyperproliferation of keratinocytes
Ex vivo, keratinocytes of the pilosebaceous canal have a higher proliferation index (marking with Ki 67), in subjects with acne compared to healthy control subjects. This increased proliferation index is found in the affected area and apparently healthy acne skin [19]. These results justify treatment of the entire surface of the acneiform zone whether or not there are visible lesions.

Role of adhesive molecules
Integrins are adhesive molecules that ensure cohesion between keratinocytes. They notably act on regulation of the proliferation and migration of keratinocytes [20, 21]. Recent studies have shown modifications in expression of integrins α2, α3, α5 in keratinocytes in the infrainfundibulum of acne follicles [22]. Changes in expression of integrins could also play a role in the formation of the micro-comedo.

Role of sebum composition
Hyperseborrhea decreases the concentration of linoleic acid in sebum by dilution (see above). This low linoleic acid content could induce an anomaly of keratinocyte differentiation in the infrainfundibulum affecting formation of the micro-comedo [1]. A recent double-blind study [23] against placebo compared the effects of a topical treatment containing linoleic acid on acne lesions. After one month, the size of the comedos had significantly decreased in zones receiving linoleic acid. Free fatty acids, which have been shown to be produced in the sebaceous gland, could also affect keratinocyte differentiation [11].
Thus, formation of micro-comedo, the initial acne lesion, could be the result of several anomalies of the infrainfundibular keratinocyte and its environment: production of interleukin-1, abnormal expression of keratinocyte integrins, anomalies of intra keratinocyte metabolism of androgens and anomalies in the composition of sebum.

Third step: Formation of inflammatory lesions

Classical concepts

Histology studies have shown that right at the start of the formation of a comedo, T lymphocytes are present around the pilosebaceous follicle [24, 25]. Subsequently, P. Acnes plays a central role in the inflammatory phenomena associated with acne [1]. This Gram positive anaerobe proliferates in the comedo. It contains lipases that split sebum triglycerides into glycerol and free fatty acids. Free fatty acids and other fragments of P. acnes diffuse across the comedo wall, leading to an afflux of polynuclear neutrophils by chemotaxis [26]. Polynuclear neutrophils produce enzymes in the perifollicular tissue, notably metalloproteases, which cause rupture of the pilosebaceous follicle wall [27] with diffusion of inflammation in the deep layers. The inflammatory reaction is amplified by reaction to foreign bodies (many macrophages and giant cells) [1, 26, 27].

The classical actors in inflammation become involved-prostaglandins, leucotrienes, macrophages, complement. Today, this is leading to the development of a therapeutic approach via 5 lipoxygenase inhibitors [28].

Recent data

From the immunological viewpoint, a distinction is made between non-specific immunity and specific immunity comprising humoral immunity (production of antibodies) and T cell immunity. The most recent studies draw attention to the major role of non-specific immunity in the development of the inflammatory lesions of acne.

Specific immunity
Cellular immunity
The peri-lesional cell infiltrate, in the first 4 hours of inflammation of an acne lesion, is essentially composed of T CD 4 lymphocytes [24, 25]. In vitro, P. acnes stimulates proliferation of T lymphocytes by two mechanisms: specific antigenic stimulation and production of non-specific mitogens [29].
Humoral immunity
The role of humoral immunity in the development of the inflammatory reaction in acne is discussed. The presence of circulating anti-P antibodies is mentioned several times in the literature but the correlation with the severity of acne has been the subject of contradictory results [1, 30, 31].
P. acnes super antigen
A superantigen activates cells directly, independently of the action of an antigen-presenting cell, which produces rapid and extensive activation of effector cells.
Recent studies indicate that some membrane fractions of P. acnes could sometimes act as a superantigen [29] causing amplification of the inflammatory reaction by activation notably of keratinocytes and release of inflammatory cytokines in situ. This phenomenon could perhaps play a role in the development of acne fulminans and acute inflammatory reactions under isotretinoin where large quantities of P. acnes antigens may be released during the first weeks of treatment.

Non-specific immunity
Many immunological studies in recent years have investigated immune defenses that do not involve B or T lymphocytes. The importance of non-specific immunity is stressed by two findings amongst others [32]:
Some animal species, in particular drosophila, do not have a specific immune system but nevertheless their resistance to bacterial and fungal infections is excellent. There is therefore a defense system which does not depend on lymphocytes.
In toxic-infectious shock due to Gram-negative bacilli, the organism's response time to infectious toxins is extremely fast and suggests that non-specific immune mechanisms are involved. Non-specific defense mechanisms involve polynuclear neutrophils, cytokines, Toll receptors, defensins, metalloproteases, and free radicals.
Polynuclear neutrophil chemotaxis does not depend only on free fatty acids. The free fatty acid theory has long been deemed inadequate to explain the attraction of polynuclear cells to the pilosebaceous follicle. P. acnes produces many substances that diffuse into the pilosebaceous follicle. 15% of these have a molecular weight under 3 000 daltons and could easily cross the comedo wall [33]. They have the chemotactic potential to attract polynuclear neutrophils around the comedo. Free fatty acids produced by sebocytes also play a chemotactic role [11].
Role of cytokines.
Many cytokines are involved in the acne inflammatory process [1, 34-36]. However, four play an essential part in the control of its formation and also, paradoxically, in the spontaneous regression of the acne lesion: Interleukin-1α, interferon-γ, TGF-α and interleukin-4. Interleukin-1α plays a central role [1, 34-36]. Secreted by activated keratinocytes, it [1, 17, 18] induces formation of the comedo and stimulates non-specific immunity [37]. TNF-α, interleukin-6 and interleukin-8 [1, 34-36] also secreted by keratinocytes, amplify the inflammatory reaction in the pilosebaceous follicle and polynuclear neutrophil chemotaxis.
P. acnes itself also amplifies the inflammatory reaction in situ by secreting interleukin-1α like, interleukin-8 like and TNF-α like [26] factors.
Recent in vitro studies, targeting the infrainfundibulum, show the essential role that cytokines could play in the acne lesion cycle. In a first phase, interleukin-1α encourages formation of the comedo, TGF the rupture of the comedo and interferon gamma and TNF-α, the diffusion of the inflammatory reaction. In a second phase, these cytokines inhibit sebum production by epithelial differentiation of sebocytes explaining the spontaneous regression of the acne lesion [38].
Role of toll receptors
A new family of membrane receptors was recently discovered [32] – the Toll receptors – which play a role in immediate immunity. They exist in mammals and non-mammals. They are bound to another membrane receptor involved in toxi-infectious shock, the CD 14 or LPS receptor. In man, to date, two TOLL receptors have been implicated in acne [39]:
Toll-R2 or TLR2 are principally stimulated by Gram+ bacteria and yeast. These are mainly found in monocyte and polynuclear neutrophil membranes [39] but were recently described in keratinocytes [40].
Toll-R4 or TLR4 are stimulated by Gram-bacteria and are found in monocyte and keratinocyte membranes [37, 40].
Stimulation of polynuclear neutrophil and monocyte Toll receptors produces secretion of many cytokines, in particular interleukin-1α, interleukin-8α, TNF and a metalloprotease, MMP 9 [37, 40]. The Toll receptors act via nuclear complexes AP1 and NF-κb.
In acne, P acnes, a gram positive bacillus, is thought to bind to the TLR 4 receptors present in keratinocytes in the infundibulum and in monocytes, causing a rapid and intense inflammatory reaction. One hypothesis could be that important release of P acnes antigens under isotretinoin could induce “hyperactivity” of these receptors leading to exaggerated stimulation and intense inflammatory lesions.
The defensins
The defensins are antibiotic peptides [41]. They act by making the target membrane permeable [41]. In the skin, defensins 1β and 2β are present in the epidermis, they are produced by keratinocytes [42]. Their role in inflammation during acne has been raised, since they are found in perilesional keratinocytes [43]. Their production would be stimulated by interleukin-8α 1α [43].
The metalloproteases
Metalloproteases, MMP 9 in particular, are produced by keratinocytes and polynuclear neutrophils. They are collagenases that participate in rupture of the pilosebaceous follicle wall and diffusion of inflammation to deeper layers. Furthermore, they could play a part in the genesis of scars.
Role of free radicals
In patients with acne, polynuclear neutrophils produce more free radicals than in healthy subjects. This is accompanied by an increase in anti-radical enzyme activity (glutathion peroxidase and dismutase superoxide) [44]. Linoleic acid, whose concentration is decreased in the sebum of patients with acne, inhibits the production of free radicals [45]. PPAR receptors
These receptors induce production of interleukin-1 and TNF-α by the sebaceous gland. They are therefore involved in initiation of the inflammatory reaction in acne [6, 7].
Melanocortin receptors
Melanocortin 1 receptors have also been identified recently in the sebaceous gland in vitro and in vivo. Activation of these receptors by alpha MSH (a neuromediator) could decrease production of interleukin-8 cytokine chemo attractant [46].

The genetic factor

Classical concepts

Acne often appears as a family setting - severe forms are also frequently found within the same family [1].

Recent data

Structural modifications of the androgen receptors of genetic origin are probably at the origin of modifications in the peripheral response to androgens [47, 48].

Predominance of an allele of the gene cytochrome p 450 has been shown in patients with acne. This mutation could be responsible for accelerated degradation of natural retinoids that might lead to disorders of keratinocyte differentiation and hyperkeratinization of the pilosebaceous follicle canal, responsible for obstruction [49].

The importance of family history and discordance in the therapeutic effect from one patient to another might be due to the reasons suggested in these studies.

Application to the mechanisms of action of treatment

Recent advances in the physiopathology of acne may increase our understanding of the targets for therapeutic action and improve our treatment strategy (table 1).

Local retinoids

Classical concepts

Retinoids play a central part in the treatment of acne due to their keratolytic activity and modulation of proliferation and differentiation leading to elimination of the comedo [1, 14].

Recent data

Mode of action variable depending on the retinoid studied
The retinoids act by binding to specific nuclear receptors. There are two types: the RAR (retinoic acid receptors) and the RXR (retinoic X receptors) which each have three sub-types α, β, γ [50, 51]. New generation retinoids (adapalene) show more selective binding to nuclear receptors. Tretinoin binds to the three sub-types of RAR and not to RXR [50, 51] while adapalene binding to RAR α and RXR is low and the molecule has greater affinity for RAR β and γ [52], this last being particularly expressed in the epidermis [50, 53].

Action on adhesive molecules
Cohesion of the plug is aggravated by anomalies in adhesive molecules, in particular integrins which modulate proliferation and differentiation of keratinocytes. Integrin α3, which modulates proliferation of keratinocytes, is decreased in the infrainfundibulum of the pilosebaceous follicle [22]. Retinoic acid applied for 15 days and compared to vehicle alone leads to restoration of the expression of integrin α3 in the epidermis [54].

Anti-inflammatory action
Local retinoids are mainly used for their anti-retention action [1], however recent work has demonstrated that they also have variable anti-inflammatory activity depending on the type of retinoid.
In vitro, tretinoin inhibits secretion of interleukin-6 and interferon-γ and production of free radicals [48].
Adapalene acts on non-specific immunity. It inhibits chemotaxis of polynuclear neutrophils and production of free radicals. Furthermore, recently it has been shown that, in vitro, adapalene shows dose-dependent inhibition of the expression of Toll R2 receptors expressed by monocytes in the perifollicular space, whereas no inhibition was obtained in parallel with a corticoid (dexamethasone). This inhibition could involve inhibition of the AP-1 complex or RAR receptors. Finally, it inhibits production of leucotrienes by the lipoxygenase route. This action has been demonstrated in vitro and in vivo: adapalene is a more potent inhibitor of this route than indomethacin and 17 betamethasone valerate [55].

Local antibiotics

Classical concepts

Local antibiotics inhibit in-vitro proliferation of P. acnes and chemotaxis of polynuclear neutrophils [26].

Recent data

Local antibiotics increase the number of resistant strains of P. acnes. This phenomenon may be related to insufficient concentrations of the antibiotic in the pilosebaceous follicle, however the concentration remains difficult to determine [1]. Similarly, topical antibiotics also show anti-inflammatory action by inhibiting lipase production and chemotaxis of polynuclear neutrophils.

Benzoyl peroxide

Classical concepts

Benzoyl peroxide is a potent antibacterial that is active against P. acnes [1].

Recent data

There is no bacterial resistance [1]. Benzoyl peroxide inhibits in-vitro production of free radicals by a direct toxic effect on polynuclear neutrophils [56].

Cyclins

Classical concepts

Cyclins have two modes of action:
– An anti-infectious action on P. acnes [1].
– Anti-inflammatory action, classically by inhibition of lipases [1].
The respective roles of these two actions are poorly understood. Increased knowledge may improve our assessment of the risks of inefficacy of antibiotic treatment when resistant bacterial strains are present in the skin of the patient with acne.

Recent data

The anti-inflammatory properties of the cyclins are getting better understood and appear to be multiple:
– Direct inhibitory action on production or secretion of free radicals [44].
– Modulation of interleukin-8α 1α [1, 26], inhibition of lipases and proteases [1, 26].
– Decrease in protein synthesis by P. acnes, hence a decrease in production and secretion of chemotactic substances.
– Inhibition of collagenases (metalloproteases) [26].
– Decrease in production of free radicals secreted by polynuclear neutrophils [44].
– Decrease in formation of inflammatory granuloma.
– Modulation of cytokine expression (alpha MSH, IL-6).
– Inhibition of NO synthetase and caspase 1 and 3 production.
A randomized clinical study using low doses of doxycyline (50 mg/day) continuously, so as not to modify the cutaneous flora targeting the anti-inflammatory activity of cyclins, provides evidence in favor of the anti-inflammatory activity of cyclins in acne. In addition, after 6 months of treatment, there was a decrease in comedos and inflammatory lesions compared to the placebo group. However this study, with a limited number of patients, requires confirmation [57].

Hormones

Classical concepts

– Hormonal treatment of acne is to be considered as anti-androgenic treatment [58].
– True anti-androgens (cyproterone acetate at a dose of 50 mg daily and spironolactone) act by binding to androgen receptors. Other mechanisms may exist but are of lesser importance – anti-gonadotrophic effect of cyproterone acetate, inhibition of the synthesis of dihydrotestosterone and other progestatives. They still need to be fully described [58].
– Estroprogestatives have an indirect anti-androgenic effect via anti-gonadotropic activity and increased plasma SHBG. (They could also reduce the quantities of free circulating testosterone) [58]. However, an estroprogestative association could induce acne lesions by increasing or revealing cutaneous hyperandrogenism, notably if the progestative has an androgenic effect (for example due to affinity for SHBG or even the androgenic receptor). This is the case in particular of associations containing a progestative of the first or second generation [58].

Recent data

The anti-acne effect or, on the contrary, the androgenic effect of an estroprogestative depends on individual susceptibility, which seems to be related to genetic polymorphism of the receptor [58]. The anti-acne effect of an estroprogestative association also depends on the dose of progestative. Hence the same progestative may, used alone, induce or aggravate acne (levonorgestrel for example) whereas in an estroprogestative association it may improve it [59, 60]. Some associations have a so-called anti-androgen progestative, acting by binding to androgen receptors (this is the case of associations containing cyproterone acetate, dienogest or drospirenone) [58].

Isotretinoin

Classical concepts

Isotretinoin acts by inhibiting sebaceous secretion by atrophy of the sebaceous gland [61, 62].

Recent data

Isotretinoin does not bind to nuclear retinoid receptors (RARs and RXRs) [63]. Part of the isotretinoin is probably transformed to all-trans-retinoic acid and another part to 9-cis-retinoic acid [64]. It has a differentiating action on the sebocyte (elimination of sebaceous secretion) and keratinocyte.

The mechanism of the inflammatory effect is complex. It has an anti-inflammatory action by inhibition of inflammatory cytokines [65], and a pro-inflammatory action probably related to release of P acnes antigen and/or antigens of the pilosebaceous follicle. These antigens could induce intense inflammation notably by a mechanism involving super antigens and/or Toll Like receptors. It may also have a modulating effect on many inflammation factors [66].

Zinc

Classical concept

Zinc acts by inhibition of polynuclear neutrophil chemotaxis.

Recent ideas

Zinc inhibits 5α reductase, TNF-α and stimulates anti-radical enzyme systems [67-73]. Furthermore, it modulates the expression of integrins.

Conclusion

Recent data reveal the importance of immunological phenomena in the development of an acne lesion from the pilosebaceous follicle. This information enhances our understanding of the mode of action of treatments allowing optimization of use. If P. acnes plays an important role, this appears to be related to production of pro-inflammatory substances rather than to infectious action, which raises the question of the clinical significance of "bacteriological" resistance. Likewise, detection of anti-inflammatory activity of retinoids suggests a broader spectrum of activity than retention lesions and hence earlier prescription in the treatment of acne at the inflammatory lesion stage. The potential role of immediate immunity in the development of inflammatory reactions under isotretinoin explains the clinical interest of use of low doses, at least at the start of treatment. n

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