Dermatology 2014;229:1–46
Accepted: May 23, 2014
DOI: 10.1159/000364860
Acne Pathogenesis: History of Concepts
Gérard Tilles
Bibliothèque Henri-Feulard, Hôpital Saint-Louis, Paris, France
Key Words
Acne · History of dermatology · Pathogenesis · Therapy
Abstract
From the first reliable descriptions of acne in the early 19th
century, dermatologists recognized it as a disease of the pi-
losebaceous follicle. Until the middle of the 20th century,
they hypothesized that seborrhoea, follicular keratosis and
microorganisms could be individually responsible for the
acne lesions. Inflammation was only regarded as the final
and inescapable step of the acne process. Although the
importance of these factors has been reevaluated, recent
works still regarded them as mandatory. In the 1970s, the
onset of isotretinoin dramatically improved acne manage-
ment. It also provided great opportunities for a better un-
derstanding of the pathogenic factors of acne. This study
analyzes their genesis and development from the seminal
contributions until recent advances. © 2014 S. Karger AG, Basel
© 2014 S. Karger AG, Basel
1018–8665/14/2291–0001$39.50/0
E-Mail karger@karger.com
www.karger.com/drm
Received: March 5, 2014
Published online: September 13, 2014
Introduction
Reviewing the Hellenistic medical literature, Hebra
(1816–1880, Vienna), European leader of mid 19th cen-
tury dermatology, pointed out the absence of any descrip-
tion of acne in the Hippocratic writings. Considering its
frequency, Hebra [1] inferred that the Greek physicians
ignored acne as a disease. Celsus, followed by Galen, is
actually considered as the first to give a description of a
cutaneous disease consisting of lesions located on the face
of young people that may look like acne for a modern
reader. He named it ‘varus’ or ‘varius’ to underline the
variety of the lesions [2].
The word ‘acne’ was probably employed for the first
time in the 6th century by Aetius Amidenus, physician in
Constantinople who named ‘ionthos’ (ίονθωξ,) or ‘acnae’
the lesions occurring on the face at the ‘acme’ of life, i.e.
puberty [3]. Used as a lay term, ‘acme’ had actually no of-
ficial spelling and the similarity of ‘m’ and ‘n’ until the
12th century supports the hypothesis that a misprint of
αχμη (akme) is at the origin of αχνη (acne) in the treatise
of Aetius [4–6]. Another explanation recalled by Grant
[7] suggests that acne was so called due to the absence of
pruritus. In this hypothesis, acne would derive from the
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Gérard Tilles, MD, PhD
Bibliothèque Henri-Feulard, Hôpital Saint-Louis
Kainan University
1, avenue Claude-Vellefaux
Downloaded by:
FR–75475 Paris Cedex 10 (France)
E-Mail Gerard.Tilles @ sfr.fr

Fig. 1. Acne punctata and simplex. From Bateman [15], plate LXII.
Coll. bibliothèque Henri-Feulard, Hôpital Saint-Louis, Paris.
Greek letter α as a prefix to a contraction of a κνησισ
meaning ‘scratching’. A third hypothesis Grant regarded
as less tenable suggests that αχνη, ‘acne’, means ‘anything
that comes off the surface’.
Boissier de Sauvages (1706–1767, Montpellier) [8],
French physician and botanist, brought a minor evolu-
tion in the nomenclature of the disease he named ‘psydra-
cia achne’ characterized by small, red and hard tubercles
that cause neither pain nor pruritus, altering the appear-
ance of the face, occurring in childhood sometimes until
adolescence. In 1776, Josef Plenck (1735–1807, Vienna)
[9], also physician and botanist, published a 128-page
book that broke with the previous approaches of the di-
agnosis in dermatology. He proposed a classification of
the cutaneous diseases according to their initial lesions
later named elementary lesions [9]. Plenck [10] gave short
descriptions of skin diseases the diagnosis of which be-
came possible with a reasonable degree of approximation.
2 Dermatology 2014;229:1–46
DOI: 10.1159/000364860
He still used the word ‘vari’ to name hard and small tu-
bercles, classed in the papulae group, located on the face
of pubertal youngsters. A year after Plenck, Lorry (1726–
1783, Paris) [11] authored a treatise on ‘morbis cutaneis’.
He also used ‘varus’ to mention a skin disease affecting
the face made of red tubercles [11]. Finally to recognize
acne in these descriptions remained hazardous.
In 1808, Robert Willan (1757–1812, London) pub-
lished a treatise ‘universally acknowledged as the corner-
stone of modern dermatology’ [12]. Whereas Plenck
mainly classified the skin diseases, Willan behaved as a
true dermatologist authoring proper descriptions of der-
matoses. He restricted the Austrian classification into 8
morphological orders according to the same nosological
system, i.e. papulae, squamae, exanthemata, bullae, pus-
tulae, vesiculae, tuberculae and maculae [13]. Willan ac-
tually described only the first 4 classes. The remaining
were completed by his pupil Thomas Bateman (1778–
1821) who enriched the knowledge of acne with the first
illustrations and descriptions a 21st century dermatolo-
gist can accept [14].
According to Bateman, acne – the elementary lesion of
which is a tubercle – is made of 4 varieties: punctata, sim-
plex, indurata and rosacea. He considered however that
the two first ‘species of acne so constantly occur together
as in the case here engraving from a drawing of Dr. Wil-
lan’s that it was not deemed necessary to figure them sep-
arately’ [15] (fig.  1). Acne simplex is characterized by
small tubercles becoming moderately inflamed and ‘leav-
ing a transient purplish red mark behind’. Acne punctata
‘consists of a number of black points surrounded by a very
slight raised border’. In fact wrote Bateman, when the
‘puncta are removed the disease becomes acne simplex’.
In acne indurata, ‘the tubercles are larger, as well as more
indurated and permanent than in acne simplex. They rise
often in considerable numbers, of a conical or oblong co-
noidal form and are occasionally somewhat acuminated.
(…) Sometimes two or three coalesce, forming a large ir-
regular tubercle, which occasionally suppurates. (…) the
tubercles (…) are always sore and tender to the touch.
(…) In its most severe form this eruption nearly covers
the face, breast, shoulders and top of the back but does
not descend lower than an ordinary tippet in dress. (…)
By the successive rise and progress of the tumours, the
whole surface, within the limits just mentioned, was spot-
ted with the red and livid tubercles, intermixed with the
purple discolorations and depressions, left by those which
had subsided and variegated with yellow suppurating
points and small crusts so that very little natural skin ap-
peared.’ In summary, wrote Bateman, the lesions of acne
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Kainan University
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are ‘generally seen at the same time in the various stages
of growth and decline; and, in the more violent cases (…),
intermixed likewise with the marks or vestiges of those
which have subsided’ [16] (fig. 2).
Following Bateman, the 19th century dermatologists
published similar descriptions also illustrated by educa-
tive and artistic engravings, wax moulages and photos
(fig. 3–15). Alibert (1768–1837), founder of the French
School of dermatology at the Hôpital Saint-Louis (Paris),
recognized varus comedo or sebaceus – he also named it
‘dartre pustuleuse – due to the black aspect that gives the
face an unpleasant and almost hideous appearance’ and
‘varus miliaris characterized by whitish grains occurring
on the forehead before puberty’ (transl. G. Tilles) [17].
Wilson (1809–1884, London) [18] gathered the various
forms of acne under the name ‘acne vulgaris’, a term
coined by Fuchs (1803–1855, Göttingen) [19].
As far as pathogenesis is concerned, early dermatolo-
gists recognized acne as a disease of the pilosebaceous fol-
licle and postulated the essential role of sebum leading to
the obstruction of the follicular duct. Then, histochemical
stainings and optical improvements, both of German or-
igin, allowed dermatologists to explore the skin diseases
at an infraclinical level [20]. A follicular hyperkeratosis
was noted and regarded as possible initiator of the acne
sequence. From the 1880s, microbiological investigations
generated great expectations. Dermatologists searched
the cause of acne through the lenses of microscopes. They Fig. 2. Acne indurata. From Bateman [15], plate LXIII. Coll. bib-
found bacilli and cocci and regarded them as cause of liothèque Henri-Feulard, Hôpital Saint-Louis, Paris.
comedones, of seborrhea and finally of acne. Unna and
Sabouraud suspected that the intervention of 2 factors
(follicular keratosis and microorganisms or sebum and
microorganisms) was mandatory. However, further in- tion of the factors, each of them being ‘an absolute pre-
vestigations led to question the responsibility of microor- requisite without which the process sinks below clinical
ganisms and to disregard acne as an infectious disease. visibility’ [23], whereas Cunliffe [24] had pointed out the
From the 1950s, the efficiency of tetracyclines reinforced acceptance of the 4 factors with ‘various degrees of proof
the microbiological approach although the exact role of and myth’. An updated overview on the subject has vali-
microorganisms remained debated. In fact, evidence dated this approach underlining a relative permanence of
obliged investigators to admit that the infectious agents the conceptual approach [25].
could act only indirectly. As inflammatory lesions they In the 1970s, the use of 13-cis-retinoic acid (isotreti-
were only considered as the final and inescapable step of noin) opened a new era in the history of acne. For the first
the acne sequence, preceding scars. time, patients could obtain a definite cure of their disease
Finally in the mid 20th century none of the hypothe- with a treatment affecting the 4 pathogenic factors direct-
sized factors could entirely explain the processes that ly or indirectly, albeit not to the same degree. A great
cause the various acne lesions. Acneologists therefore number of investigations contributed to improve the mo-
suggested that a ‘chain of factors’ [21] and a ‘web of etio- dalities of the prescription of isotretinoin, to manage the
logic agencies’ [22] contribute to the formation of the le- side effects and to understand its mechanisms of action
sions, namely keratinization at the opening of the follicle, that remain unclear. Moreover, the understanding of the
bacterial invasion, sebum alteration and inflammation. spectacular efficacy of isotretinoin provided a great op-
This dynamic concept was strengthened by the interac- portunity for a reappraisal of the role of the actors in-
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Fig. 3. Varus miliaris. From Alibert [400]. Coll. bibliothèque Hen-
ri-Feulard, Hôpital Saint-Louis, Paris.
volved in the acne sequence, to enrich the pathogenic
model of acne and notably to stress the pivotal role of se-
bum.
Since its first clinical description, acne has been the
subject of a great number of publications, actually about
10,000 in PubMed using ‘acne vulgaris’ as a key word.
Only very few of them dealt with the history of the disease
focusing on semantic considerations (see above) or quot-
ing the main authors and their works [26]. Parish and
Witkowski [27] and more recently Plewig and Kligman
[28] gave illustrated accounts of the history of acne, sum-
marizing milestones in chronological order. To the best
of our knowledge, the genesis and development of the 4
factors that constitute the pathogenic framework of acne
have not been studied from a historical point of view. The
aim of this work is therefore to analyze these aspects, to
show the areas of overlapping and the therapeutic impli-
cations of the pathogenic trends. This approach will also
4 Dermatology 2014;229:1–46
DOI: 10.1159/000364860
Fig. 4. Acné du dos. From Rayer [30]. Coll. bibliothèque Henri-
Feulard, Hôpital Saint-Louis, Paris.
highlight the thoughts of the master acneologists, their
passionate, sometimes provocative debates and contro-
versies and finally will give an overall account of the his-
tory of acne pathogenesis.
Seborrhea and Acne: Inseparable Players of the
Pathogenic Process
Observing acne patients Alibert noticed seborrhea that
‘takes place on the surface of the nose and forehead (…)
filtered by the skin ducts and blackened which gives the
face an unpleasant and almost hideous appearance’
(transl. G. Tilles). He quoted his pupils Dauvergne and
Eichhorn (Göttingen) as the first to establish an anatom-
ical link between seborrhea and sebaceous glands [29].
Rayer (1793–1867, Paris) [30] also emphasized the role of
the sebaceous follicles in seborrhea pointing out the ab-
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Kainan University
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Fig. 5. Acne vulgaris. From Wilson [401]. Coll. bibliothèque Hen-
ri-Feulard, Hôpital Saint-Louis, Paris.
sence of acne on the palms and soles deprived of these
glands and the concomitant existence of a greasy skin in
the acne areas. Bazin (1807–1878, Paris) [31] and Duhring
(1845–1913, Philadelphia) [32] asserted that as far as the
anatomical nature of acne is concerned, ‘the process orig-
inates and has its seat in the sebaceous gland and follicles
of the skin’. In summary, from the first clinical descrip-
tion of acne, seborrhea was regarded as a key actor.
Further works provided evidence of the role played by
sebum excretion and its components.
Increased Sebum Excretion Rate in Acne: A ‘High
Dogma’
Using the method of Strauss and Pochi [33] modified
by Cunliffe and Shuster [34], Shuster measured the se-
bum excretion rate in acne patients, in patients who had
Acne Pathogenesis: History of Concepts
Fig. 6. Acne disseminata. From Hebra [402]. Coll. bibliothèque
Henri-Feulard, Hôpital Saint-Louis, Paris.
had acne and in patients who had never had acne. The
patients with acne had seborrhea, and the severity of the
disease was related to the rate of the sebum excretion. The
authors concluded that acne is due to the interaction be-
tween an increased rate of sebum secretion and a second
factor that might be a greater resistance to sebum flow or
an increased viscosity [35]. Cotterill et al. [36] confirmed
the relationship between the severity of acne and sebum
excretion rate in 40 males and 85 females aged between
11 and 25 years. Studying male acne patients and compar-
ing them with men of the same age without acne, Pochi
and Strauss [37] obtained similar conclusions: a greater
sebum secretion was observed in the patients afflicted
with the severest forms of acne. They suggested that the
increased sebaceous activity might be due to excessive
hormonal stimulation or to a genetically enhanced re-
sponsiveness. Few years later, Plewig [38] showed that the
increased sebum excretion is actually the result of 2 fac-
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Fig. 7. Acne vulgaris. From Morrow [403]. Coll. bibliothèque Hen-
ri-Feulard, Hôpital Saint-Louis, Paris.
Fig. 8. Acne vulgaris (back). From Crocker [404]. Coll. biblio-
thèque Henri-Feulard, Hôpital Saint-Louis, Paris.
6 Dermatology 2014;229:1–46
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tors: increase in lipid cell production and increase in se-
baceous gland size.
Contrasting with these findings, other authors denied
the correlation between sebum excretion rate and acne
severity. Fry and Ramsay [39] set a double-blind cross-
over trial of tetracycline and placebo on patients with
acne vulgaris. Both tetracycline and placebo produced
significant improvement of the acne. However, they failed
to show any correlation between sebum output and sever-
ity of acne [39]. Powell and Beveridge [40] could not find
any relation between the sebum excretion rate and the
presence of acne in 30 patients either.
The discrepancy of these results incited Burton and
Shuster [41] to investigate the possible relationship be-
tween sebum excretion rate and acne. They showed that
the sebum excretion rate is related to acne severity in male
and female patients [41]. Finally, although the responsi-
bility for sebum was not sufficient to explain all cases of
acne – ‘sebum may fuel the process but not everyone
catches fire’ insisted Kligman and Katz [42] – the in-
creased sebum excretion rate became a ‘high dogma’ [43].
Few dermatologists only consider sebum as ‘a measurable
quantity whose status as a trapped commodity within the
duct is exaggerated and overrated’ [44].
Due to the role played by sebum in the pathogenesis of
acne, the reduction of its secretion was considered as a
main therapeutic objective. The results obtained with
benzoyl peroxide – first used in 1965 by Pace [45] – failed
to convince all acneologists. Cunliffe et al. [46] were even
surprised to show that the sebum excretion rate increased
following treatment with benzoyl peroxide. They how-
ever did not consider that benzoyl peroxide increases se-
bum production and suggested that it might influence se-
bum excretion. As benzoyl peroxide reduces noninflamed
lesions, the outflow resistance to sebum would be re-
duced. It could also reduce the volume of sebum accumu-
lated in the intercorneocyte crevices. These elements
might explain the elevation of sebum excretion that would
reduce the colonization of bacteria in the pilosebaceous
unit, therefore preventing the onset of inflamed lesions
[46]. Contrasting with Cunliffe’s results, Schmidt et al.
[47] suggested that benzoyl peroxide may affect the se-
bum excretion rate in some patients only whereas Burk-
hart et al. [48] asserted that benzoyl peroxide does not
have sebosuppressive capabilities. So far, isotretinoin and
hormonal therapies are the only drugs that can reduce
sebum production (see further).
Besides the responsibility of the quantitative alteration
of sebum, the composition of sebum was also a matter of
questions.
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Kainan University
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 Sebum Comedogenicity

The Rabbit Ear Model

According to Kligman (1916–2010), Adams et al. [49]
and Kligman and Kwong [50] were the first to show that
chemicals that had caused occupational acne, would
evoke follicular hyperkeratosis when applied to the ex-
ternal ear canal of rabbits. Considering that chloracne-
genic chemicals applied to the inner surface of the rabbit
ear could induce hyperkeratosis in its pilosebaceous fol-
licle, Lorincz et al. [51] suggested a possible link between
fractions of the skin lipids and comedo formation. They
investigated the result of the application of human skin
lipids and free fatty acid fractions. Judging the results
from the stereomicroscopic appearance, they concluded
that free fatty acids promote a follicular hyperkeratosis
[51].
The rabbit ear model was highlighted by Kligman and
Katz [42]. After application of scalp sebum onto the ex-
ternal ear of rabbits daily for 2 consecutive weeks, they
demonstrated that the epidermis begins to thicken within
24 h. The hyperkeratosis appeared within 48 h, a dermal
mononuclear infiltrate appeared mainly around the fol-
licles and migrated into them without damaging the fol-
licular epithelial lining. However, the comedones induced
differed in several aspects from those of acne vulgaris:
they were smaller and immature, no bacteria could be
found by Gram staining, they did not rupture and inflam- Fig. 9. Acne vulgaris. From Fox [405]. Coll. bibliothèque Henri-
matory lesions never developed. The authors had there- Feulard, Hôpital Saint-Louis, Paris.
fore to admit that the rabbit model could reproduce only
comedones, i.e. the initial step of acne the definition of
which includes the clinical polymorphism of the lesions.
For that reason the authors preferred to use the term
‘comedogenic’ instead of ‘acneigenic’ to describe the ef-
fects produced by the sebum in the rabbit ear [42]. Few
years later, Mills and Kligman [52] showed that substanc-
es moderately to strongly comedogenic in rabbit ears
were capable of inducing comedones in a human model.
They inferred that the rabbit model is ‘isomorphic with
the human’.
Contrasting with this statement, Kanaar [53] stressed
the differences between the induced follicular keratosis in
the rabbit’s ear and that observed in the early stages of
comedones formation in acne: the epithelial hyperplasia
observed on the rabbit ear was absent in the early stages
of comedones; the dedifferentiation of sebaceous glands
during the development of comedones was absent in the
rabbit’s ear. For these reasons, Kanaar [53] proposed to Fig. 10. Comedone acne (back). Male patient, aged 21, 1890, mou-
use the term ‘follicular keratosis’ instead of ‘comedo for- lage No. 1537. Coll. Musée des moulages de l’hôpital Saint-Louis,
mation’. Paris.
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Fig. 11. Comedone acne (chest). Male patient, aged 21, 1890, mou-
lage No. 1536. Coll. Musée des moulages de l’hôpital Saint-Louis,
Paris.
The rabbit ear model was actually far from consensus.
Shuster [54], opponent to the comedo as the initial and
mandatory step of the acne process (see further), consid-
ered the ‘comedogenic response of the rabbit ear occurs
even to a smile, especially Philadelphic, and it’s just non-
specific’. For Cunliffe et al. [55] the relevance of the rabbit
model to the human skin was also controversial.
The Controversial Role of the Free Fatty Acids
The role of free fatty acids resulting from the hydro-
lyzed triglycerides contained in the skin surface lipids was
one of the main acne-pathogenic concepts of the 1960s
and 1970s [56, 57].
Sulzberger (1895–1993) – quoted by Sutton (1878–
1952) [58] – was probably the first to hypothesize that ab-
normal constituents of sebum might be responsible for an
‘irritation’ that could provoke the hyperkeratosis at the
mouth of the follicle. In 1957 Nicolaides and Wells [59]
8 Dermatology 2014;229:1–46
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Fig. 12. Polymorphous acne (chest). Male patient, 20 years old,
barman, 1888, moulage No. 1415. Coll. Musée des moulages de
l’hôpital Saint-Louis, Paris.
showed that radioactive tripalmitin applied to the skin
was hydrolyzed with the formation of free fatty acids.
They concluded that a lipase probably located in the seba-
ceous ducts was responsible for the free fatty acid fraction
found on the skin surface. Since activity was suppressed
by prior treatment with antibiotics, they hypothesized that
the resident bacteria might be the source of lipolytic en-
zymes [59]. Strauss and Mescon [60] came to a similar
conclusion. They demonstrated a liberation of acid sub-
stances when comedones are incubated with olive oil. As
lipase could not be produced by dead keratinized squamae
or by sebaceous glands usually absent in comedo-bearing
follicles, they regarded it as highly probable that Propioni-
bacterium acnes in great numbers inside the comedones
generated the lipases [60]. P. acnes was in fact demonstrat-
ed to play an important role by causing a breakdown of
the lipids [61]. In vitro experiments indicated that Staphy-
lococcus albus and P. ovale possess the enzymatic material
indispensable to hydrolyze triglycerides [62, 63]. Howev-
er, elimination of aerobic cocci resident in the follicles had
no effect on the amount of free fatty acids [64].
The suppression of lipolytic activity after sterilization
of the skin surface reinforced the participation of the sur-
face bacteria in the formation of free fatty acids. However,
the fact that the lipolytic activity was not completely sup-
pressed by sterilization suggested that the production of
lipases might also be of cellular origin [65].
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Fig. 13. Polymorphous acne (chest). Male patient, aged 26, 1887,
moulage No. 1300. Coll. Musée des moulages de l’hôpital Saint-
Louis, Paris.
Demonstrating that the injection of sebum causes se-
vere inflammation, Strauss and Kligman [66] suggested
that the major inflammatory agents were the short-chain
fatty acids which produced severe damage when injected
alone. Moreover, the removal of free fatty acids from se-
bum before its intradermal injection greatly reduced the
inflammatory response [66, 67].
The free fatty acids from C8 to C14 produced actually
more irritation than those with a shorter or longer chain
[68]. Kligman [69] stressed the necessity to distinguish
between the irritancy and the comedogenicity of free fat-
ty acids: those fatty acids which play a role in comedo
formation being probably different from those which
may participate in inciting the later events of inflamma-
tion. Freinkel [70] pointed out the fact that the inflamma-
tory reaction triggered by the free fatty acids when they
reach the dermis does not necessarily implicate them in
the initial damage to the follicular epithelium.
Contrasting with these arguments that supported the
role of free fatty acids, some investigators considered it
unwise to extend the in vitro results to the much more
complex in vivo situations. Savin [71] pointed out how
tempting it was to give free fatty acids a role in acne patho-
genesis due to the fact that P. acnes and aerobic cocci have
lipases which can liberate fatty acids from the triglycer-
ides in sebum. Cunliffe [72] recalled that most authors
found no difference in the surface lipid composition of
Acne Pathogenesis: History of Concepts
Fig. 14. Polymorphous acne (shoulder). Male patient, aged 26,
1887, moulage No. 1301. Coll. Musée des moulages de l’hôpital
Saint-Louis, Paris.
subjects with and without acne, whereas Krakow et al.
[73] confirmed the indication of a difference in sebum
composition between normal and acne patients. Com-
paring free fatty acids of human surface triglycerides on
men with and without acne, Kellum and Strangfeld [74]
observed only 1 free fatty acid (with carbon number
17.52) present in significantly greater amounts in acne
patients. Cunliffe and Cotterill [75] suggested that since
the comedo formation is associated with sebaceous gland
atrophy (see above) one might argue against the role of
free fatty acids in producing pilosebaceous obstruction.
Anderson et al. [76] could not find a significant decrease
in free fatty acid contents after oral treatment with tetra-
cycline. They concluded that acne severity can be reduced
without concomitant quantitative change in surface lip-
ids [76]. Puhvel and Sakamoto [77] found that intracuta-
neous injections of physiological amounts of free fatty ac-
ids do not produce more than a very mild inflammatory
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Fig. 15. Polymorphous acne of the face (acne conglobata according
to today’s nomenclature). Male patient, aged 17, 1922, moulage
No. 320. Coll. Musée des moulages de l’hôpital Saint-Louis, Paris.
reaction. They concluded that free fatty acids might not
be the prime inflammatory agents in acne [77]. Weeks et
al. [78] treated acne patients by a topical inhibitor of li-
pases for 5 weeks. Although the free fatty acids were de-
creased in all patients, the bacterial and lesion counts re-
mained unchanged. The authors proposed to reevaluate
the role of free fatty acids in the pathogenesis of acne [78].
Voss [79] underlined the difficulty to say that changes
caused by external application of great amounts of free
fatty acids can be reproduced by the smaller amounts of
free fatty acids liberated within the follicle.
Finally the role of free fatty acids in the pathogenesis
of acne was summarized in two contrasted opinions.
Kligman [22] asserted that ‘sebum contains comedogenic
substances. The most important of these are free fatty ac-
ids. (…) squalene is also quite comedogenic. When these
substances or whole sebum are placed in the external ear
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canal of the rabbit they elicit comedones. It is inferred that
they can do the same in the human. (…) Sebum also pro-
vides a substrate for the growth of Corynebacterium acnes:
it is the lipases of the latter which release from triglycer-
ides the glycerol which this organism utilizes as a carbon
source. Without C. acnes, the disease cannot attain clini-
cal significance.’ Shuster [80] replied that ‘the work on
lipid composition of sebum reaching the skin surface has
been the biggest single red herring in acne research and
much time and money has been wasted on it’.
In the context of the questioned role of lipases to gen-
erate free fatty acids, interest in other substances pro-
duced by P. acnes increased. Hyaluronate lyase was sus-
pected as capable to break down intracellular substances
within the pilosebaceous duct wall and therefore to in-
crease the permeability of the follicular epithelium [81].
The proteases, possibly keratolytic, were also considered
as interesting substances associated with P. acnes [82]. Fi-
nally P. acnes was shown to produce toxic substances and
enzymes which attack the follicular epithelium and lead
to extrusion of comedonal contents – proteases, lecithin-
ase, lipase, hyaluronate lyase, neuraminidase – ‘quite a
cocktail of active material’ [83].
The Linoleic Acid Deficiency, a ‘Fascinating’ and
Debated Concept
Other investigators focused their attention on sebum
linoleic acid. According to Downing and his group [84–
86], the deficiency of linoleate would suppress its incor-
poration into epithelium acylceramides so that the fol-
licular epithelium would become hyperkeratotic and
more permeable to sebaceous fatty acids. Finally, exces-
sive permeability of the epithelium might allow excessive
growth of follicular microorganisms and allow chemotac-
tic substances produced in the follicular duct to promote
inflammation.
Melnik et al. [87] formulated the concept of follicular
deficiency of epidermal lipids. In this concept the in-
creased sebum production (triglycerides, free fatty acids,
squalenes, wax esters) leads to the dilution of epidermal
lipids of the follicular epithelium, to a decrease in cho-
lesterol and a decrease in ceramides and linoleoyl ce-
ramides. The decrease in cholesterol would cause a dis-
turbance of the follicular cholesterol/cholesterol sulfate
equilibrium, thus an increase in follicular keratinocyte
adhesion, a follicular hyperkeratosis and finally a come-
do. Moreover, the decrease in ceramides would be re-
sponsible for a disturbance of the follicular permeability
barrier increasing the follicular hydratation that pro-
motes the growth of P. acnes and facilitates the diffusion
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of the chemotactic factors produced by P. acnes and fi-
nally causes a pustule.
Holland et al. [88] proposed an innovative and specu-
lative pathogenic sequence that also enhanced the role of
linoleic acid deficiency. In this sequence, the 4 classical
factors were replaced by ‘initiation, damage, response, re-
gression’. According to these authors, in a follicle with a
high sebum excretion rate the system may become lin-
oleic acid deficient. The deficiency would affect the bar-
rier function of the follicle wall. The authors had then to
suppose that there will be an increased flux of water from
the dermis into the lumen of the follicle which would en-
hance the colonization and increase the microbial con-
tent. The consequences would depend on the location of
the microorganisms: the nearer to the skin surface colo-
nization occurs, the fewer problems will appear because
the follicle wall is thicker. If colonization occurs on the
wall where the number of keratinized layers is low, pro-
inflammatory cytokines might be released from the kera-
tinocytes, diffuse in the dermis and initiate inflammation.
Holland et al. [88] hypothesized the production of por-
phyrin by P. acnes in the presence of increasing oxygen
tensions because of changes in the follicle wall. In this as-
sumption, molecular oxygen would interact with porphy-
rin and produce free radicals that would damage kerati-
nocytes. The second assumption is that P. acnes has a
‘quorum-sensing mechanism’ and upregulates extracel-
lular enzyme production – hyaluronidase lyases, prote-
ases, neuraminidases – that may affect keratinocyte integ-
rity and the wall follicle barrier [88]. Few years later, in a
double-blind placebo-controlled randomized study, Le-
tawe et al. [89] showed that linoleic acid topically applied
onto patients with mild acne could reduce by 25% the size
of microcomedones after 1 month of treatment.
Although they found the concept ‘fascinating’, Plewig
and Kligman [90] considered it overestimated the role of
linoleic acid.
The Dietary Influence on Sebum: An Evolving
Question
The influence of diet is one of the main controversies
of the history of acne pathogenesis. Bateman [91] who
published the first reliable description of acne advised
against ‘the copious use of raw vegetables in diet (…) as
well as the free use of vegetable acids’. His countryman
Green [92] advised ‘the individual affected (to) give up
the use of wine, strong beer, spirits, coffee and stimulants
of every description and heavy meals of animal foods’. A
Acne Pathogenesis: History of Concepts
century later as far as diet might influence acne, Wise and
Sulzberger [93] were certain that there was ‘not an iota of
scientific evidence that there is any disturbance of carbo-
hydrate metabolism in acne’. Few years later, Sulzberger
and Baer [94] admitted however that, in some cases, ‘one
or more foods must be eliminated to keep the patient free
from new lesions’. Chocolate, milk and shellfish were
mainly incriminated [94]. Baer and Witten [95] main-
tained a similar statement as they wrote that ‘the number
of foods which play a specific role in aggravating acne is
relatively small’. As for the effects of high amounts of
chocolate on 65 patients, Fulton et al. [96] failed to find
any significant change in the course of acne or the output
or composition of sebum. In the 1970s dermatologists
were still reluctant about the elimination of foods [97],
and in 1976 Leyden and Kligman [98] asserted that diet
has ‘no role’ in acne pathogenesis.
Since the beginning of the 2000s authors have consid-
ered that significant data support the role of diet in acne
notably on sebum composition. Whether fatty acids can
pass from the blood to the sebaceous glands has been
questioned. Pappas et al. [99] were probably the first to
follow the fate of exogenously supplied labeled fatty acids
in human sebaceous glands and to consider that seba-
ceous glands can use fatty acids from the bloodstream for
the synthesis of sebum. Although they considered this
study as insufficient to prove that diet could affect the
composition and the secretion rate of sebum, Wolf et al.
[100] refuted the theory that such an event is impossible.
However, for the majority of authors the sebaceous glands
synthesize their secreted lipids by themselves.
Beside this question, the influence of hyperinsulinemia
caused by highly glycemic meals has been studied. Hyper-
insulinemia might promote acne by its androgenic effect
on sebum production. It can also provoke a growth factor
response via insulin-like growth factor (IGF)-1 that can
augment sebogenesis independently of its potentiation of
androgen production [101] whereas low-fat diets tend to
decrease the concentrations of IGF-1 and androgens. The
circulating concentration of IGF-1 also regulates kerati-
nocyte proliferation and induces lipid synthesis in cul-
tures of sebocytes. These data would suggest that the en-
docrine cascade induced by diet-induced hyperinsu-
linemia enhances sebum synthesis. Moreover vitamin D
would regulate sebum production.
As far as inflammatory lesions are concerned, Cordain
[102] pointed out the fact that the western diet promotes
a proinflammatory cytokine that underlies the develop-
ment of inflammatory disorders. In this respect, increased
consumption of dietary ω–3 polyunsaturated fatty acids
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may be of therapeutic value because of their ability to
suppress inflammatory cytokine production [102]. The
ratio of ω–6 to ω–3 fatty acids in western diets – at least
10:1 – has been implicated. High levels of ω–3 fatty acids
may decrease IGF-1 and prevent hyperkeratinization of
sebaceous follicles. In contrast ω–6 fatty acids have been
associated with the development of inflammatory acne
[103].
From the papers published in 2009–2010 on acne,
Smith et al. [104] considered that a possible role of dietary
factors could not be dismissed. However, Davidovici and
Wolf [105] pointed out the few studies on humans that
have yielded inconsistent results. They concluded that
despite the numerous studies mostly of unsatisfactory
quality there is a paucity of reliable information on the
influence of dietary measures on acne [105]. Bowe et al.
[106] however considered there is reasonably compelling
evidence that a highly glycemic diet may exacerbate acne,
the role of ω–3 fatty acids, antioxidants, zinc and vitamin
A being unclear. Finally, in a recent overview Bhate and
Williams [107] insisted on the weakness of the evidence
that suggests a possible link between dairy products and
acne.
Hormones and Sebum, a Definite Dependence
Updating acne vulgaris in 1949, Sulzberger and Baer
[108] insisted on the hormonal influence on acne: ‘If one
were obliged to name one factor without which acne vul-
garis could not occur one would surely select the endo-
crine (sic) factor.’ More than a century before, Bateman
had already pointed out that acne occurs ‘in the early part
of the life from the age of puberty to thirty or thirty-five’
and Cunliffe and Cotterill [109] quoted Riolan (1638)
[110] as the first to note an association between acne and
disordered menstruation.
Two landmark reports actually attested to the rela-
tionship between acne, androgens and sebum. Hamilton
[111] showed that castrated males who had no acne could
develop the disease after administration of testosterone.
Two years later, Rony and Zakon [112] demonstrated
that prepubertal boys treated with testosterone experi-
enced enlargement of their sebaceous glands.
Strauss et al. [113] confirmed the hormonal depen-
dence of the sebaceous glands on mainly androgenic ste-
roids. Androgens in less than physiological doses caused
enlargement of the sebaceous glands of the prepubertal
males and females in few weeks. Topical use of testoster-
one propionate stimulated the prepubertal gland at the
12 Dermatology 2014;229:1–46
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treated site as compared to the untreated one. They
stressed the ‘insignificant’ appearance of sebaceous glands
before puberty and in contrast, their postpubertal aspect
in that ‘the usual size relationships are inverted, the glands
having acquired an extraordinary size and the hairs hav-
ing been reduced to a mere vestige’ [113]. Pochi [114]
hypothesized that androgens influence acne not only by
their effect on sebaceous glands, but also by their action
on the follicular epithelium as suggested by the enhance-
ment of the comedo formation in the rabbit ear pretreat-
ed with androgen.
However, Levell et al. [115] could not find a correla-
tion between plasma androgen and acne severity or the
sebum excretion rate. Gollnick et al. [116] pointed out the
fact that the ‘average’ acne patient is not characterized by
increased levels of circulating hormones with androgenic
potency. Thiboutot et al. [117] showed nevertheless that
plasma androgen levels in women with acne were in-
creased compared with those women without acne.
Other clinical evidence supported an essential role for
androgens in stimulating sebum production: androgen-
insensitive patients lacking androgen receptors do not
produce sebum and do not develop acne; carcinomas that
produce androgens in excess are often associated with
acne; serum dehydroepiandrosterone sulfate is signifi-
cantly associated with the initiation of acne in young girls;
acne severity is correlated with circulating dehydroepi-
androsterone sulfate; a significant correlation exists be-
tween inflammatory lesion number and free testosterone
level; systemic administration of testosterone or dehy-
droepiandrosterone increases the size and secretion of se-
baceous glands [118].
The observations that the skin of acne patients con-
tains more 5α-reductase (responsible for the conversion
of testosterone to dihydrotestosterone, a more potent an-
drogen) suggested an abnormal local endocrine event
even in the absence of systemic androgen abnormalities
[119]. The potential role of androgens in follicular kera-
tinocytes was therefore explored. Testosterone and dihy-
drotestosterone were identified as the major androgens
interacting with the receptors located to the basal layer of
the sebaceous glands and the outer keratinocytes of the
hair follicles [120, 121]. The activity of type 1 isozyme of
5α-reductase is more active in glands from areas that are
prone to acne such as the face [122]. It was also found
greater in infrainfundibular keratinocytes than in kerati-
nocytes cultured from the interfollicular epidermis. In-
vestigators suggested that infrainfundibular keratino-
cytes have an increased capacity to produce androgens
compared with the epidermis [123].
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 Like many factors, the role of 5α-reductase was also
questioned. Leyden et al. [124] used a selective inhibitor
of type I 5α-reductase alone and in combination with sys-
temic minocycline in a multicentric, placebo-controlled
trial. Inhibition of type I 5α-reductase was not correlated
with acne improvement when used alone and did not en-
hance the clinical benefit of systemic minocycline. The
authors concluded with the necessity to better under-
stand the action of androgens on the sebaceous glands
[124].
As far as the action of estrogens is concerned, Pochi
and Strauss [125] showed that they do not antagonize the
action of androgens at the sebaceous gland. They hypoth-
esized that the suppressive effect of high doses of estro-
gens may be due to the reduction in the endogenous syn-
thesis of androgens. The role of estrogens in the develop-
ment of acne lesions is actually not fully understood.
Estrogens suppress sebaceous secretion only when higher
than physiological doses are used.
Growth hormone has also been supposed to play a role
in acne pathogenesis due to its high serum levels in ado-
lescence. Moreover, the presence of acne and seborrhea
in acromegaly where growth hormone is in excess sup-
ports its role in acne.
The androgen dependency of acne has incited re-
searchers to propose hormonal therapy in women not re-
sponding to conventional treatment, either by androgen
receptor blockers or by inhibitors of androgen produc-
tion by the ovary or adrenal gland such as estrogens in the
form of oral contraceptive drugs that reduce the seba-
ceous gland secretion [126, 127].
Androgen receptor blockers admitted as options to
treat acne in women [128] include cyproterone acetate,
spironolactone and flutamide [129, 130]. Oral contracep-
tives that reduce the production of androgen and sebum
have been demonstrated to be effective in the treatment
of acne reducing 40–70% of the lesion count. Cyproter-
one acetate inhibits the binding of dihydrotestosterone at
its receptor and reduces the activity of 5α-reductase. It
may also increase sebaceous linoleate concentration, thus
indirectly reducing comedones. Combined with ethinyl
estradiol, it is widely used in Europe in the form of an oral
contraceptive and has been shown to significantly im-
prove acne. Spironolactone acts as an androgen receptor
blocker competing with testosterone and dihydrotestos-
terone and decreases androgen-stimulated sebocyte pro-
liferation. It also inhibits androgen synthesis, inhibits
5α-reductase and would increase steroid hormone-bind-
ing protein. Muhlemann et al. [131] treated 21 women
with oral spironolactone in a placebo-controlled, double-
Acne Pathogenesis: History of Concepts
blind crossover study. They could observe an objective
improvement in 75% of patients. They suggested that spi-
ronolactone should be considered for women whose acne
has not responded to tetracyclines and for those who have
severe hirsutism [132]. Saint-Jean et al. [133] used spi-
ronolactone in an open study on 14 females whose acne
failed to improve with a previous systemic therapy. Spi-
ronolactone was combined with a topical treatment. Six
patients could obtain a reduction of the total number of
lesions by 50% in the face and a significant reduction of
the lesions of the back. The authors insisted on the value
of spironolactone for the patients who failed to respond
to isotretinoin [133].
Flutamide is approved by the Food and Drug Admin-
istration in the treatment of prostate cancer. It is also
effective to treat hirsutism and acne. The use of fluta-
mide – converted into a potent metabolite that blocks the
androgen receptors – is limited by its hepatic toxicity.
Despite the role of hormones in sebum production
and the therapeutic value of hormonal therapy that sub-
stantiate the hormonal control of acne, the acne patient
cannot be considered to be an ‘androgen mismatch’ [132].
Epilogue
Acne outcome is definitely regarded as highly depen-
dent on sebum reduction. Therefore the common answer
to the question ’Can sebum reduction predict acne out-
come?’ is ‘Yes’ [134]. Beside the hyperproduction of se-
bum, other functions of the sebaceous glands may be in-
volved in the acne process: oxidant/antioxidant ratio of
the skin surface lipids, regulation of local androgen syn-
thesis, production of antimicrobial peptides, neuropep-
tides and synthesis of specific lipids with antimicrobial
activity such as sapienic acid [135, 136]. Moreover, fol-
licular keratinocytes and sebocytes may act as immune
active cells. Alteration of saturated and unsaturated fatty
acid composition in sebum previously considered as ini-
tiator of follicular inflammation may regulate the innate
immunity response [137]. Williams et al. [25] proposed
that each sebaceous gland functions like an independent
endocrine organ influenced by corticotropin-releasing
hormone which may mediate the link between stress and
acne exacerbations. Sebaceous follicles that contain a mi-
crocomedo offer an anaerobic and lipid-rich environ-
ment in which P. acnes can flourish. Matrix metallopro-
teinases in sebum may have an important role in inflam-
mation, cell proliferation and degradation of the dermal
matrix [25].
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 Comedogenesis: From the Horny Plug to the Biofilm
Theory

According to Plewig and Kligman [28], the word ‘com-

edo’ appeared in writings of Velschius (1764) [138]. In
Plenck’s Doctrina [10], closed comedones are recogniz-
able under the name ‘grutum sine milium’. Open come-
dones named ‘crinones’ are described in class XII, ‘insec-
ta class’. Plenck considered them as simulating maggots
or grubs with black heads (‘simulacra vermiculum cum
capite nigro exhibent’). Like Plenck, Alibert [139] report-
ed that lay people regarded comedones as worms respon-
sible for weight loss of children. Their extraction was
therefore supposed to restore a healthy condition [139].

Seminal Observations

Using gaze as the only tool for diagnosis and patho-

genic speculations, Bateman [140] regarded comedones
as made of ‘concreted mucus or sebaceous matter mould-
ed in the ducts of sebaceous glands and responsible for
the distension of the ducts’. Consequently, the sebaceous
glands sometimes inflame and form tubercles with little
black points on their surface. Few years later, Samuel
Plumbe (1795–1837, London) [141] confirmed this view
and hypothesized the alteration of sebum ‘too hard to
pass readily to the surface’ responsible for the obstruction
of the sebaceous duct. Then, ‘the follicle is destroyed by
this process, the matter is discharged, a little redness re-
mains for a day or two and the part returns to the healthy
state’. Finally, wrote Plumbe [141], in its most simple
form acne consisted ‘merely of obstruction of the seba-
ceous follicle’ which leads to its destruction.
For Hebra (Vienna) [142] not every comedo evolves
into inflammatory lesions. Most of them in fact remain
unchanged. In some cases, the sebum that constitutes a
comedones is expelled from the sebaceous duct, and no
other comedo will appear. According to Hebra, ordinary
comedones and comedones responsible for inflamma-
tion around them have to be separated. Only the latter
cause the inflammatory lesions of acne which aspect re-
flects the location of the sebaceous retention: acne punc-
tata in case of a superficial occlusion of the pilosebaceous
duct whereas acne indurata results from a deeper ductal
occlusion. As a therapeutic consequence, Hebra [142]
suggested that the removal of the superficial layers of the
epidermis connected to the cutaneous glands would open
the sebaceous ducts and let the sebum flow freely.
Fig. 16. Pathological aspects of acne pilaris. 1 = Pilosebaceous fol-
licle (microcomedo or early open comedo according to today’s no-
menclature); 2 = pustule; 3, 4 = pustule and indurated lesion. From
Cornil [143], Coll. bibliothèque Henri-Feulard, Hôpital Saint-
Louis, Paris.
To the best of our knowledge, Cornil (1837–1908)
[143], professor of pathology at the Paris Faculty of Med-
icine, was the first to describe the pathological aspects of
the follicular epidermis in acne and to publish histopatho-
logical images. He reported that ‘the cavity of the follicle
contains several lanugo hairs. This enlarged cavity is filled
with epidermal cells between which one sees few lymphat-
ic cells. (…) In the most superficial area of the piloseba-
ceous follicle there is a considerable amount of corneous
cells mixed with globules of pus. The layer is very thick at
the top of the follicle and becomes thinner and thinner at
its inferior extremity’ [143] (transl. G. Tilles) (fig. 16).
Few years later, Leloir (1855–1896), professor of der-
matology at the Lille Faculty of Medicine, and Vidal
(1825–1893), head at the Hôpital Saint-Louis, Paris – who
preferred ‘acne pilaris’ instead of ‘acne vulgaris’ – de-
scribed ‘a cork of sebaceous matter surrounded by corni-
fied epidermal cells’, responsible for the obstruction and
distension of the sebaceous duct. They explained the
plugging either by an ‘atonia’ of the follicle unable to
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evacuate the sebum or by the inability of the hair con-
nected to the sebaceous gland to prevent the sebum from
being eliminated on the skin surface. This theory will be
enhanced by several investigators (see further). Like
Plumbe, they actually favored the thickening of sebum
that cannot flow out of the follicle causing a plug sur-
rounded by epidermal cells and containing one or several
lanugo hairs. In some cases, wrote the French authors,
‘the sebaceous duct closes, the sebaceous gland enlarges,
then comes the milium. When the sebaceous matter in-
creases, the walls of the follicle thicken, and a true seba-
ceous cyst may appear’ [144] (transl. G. Tilles). Leloir and
Vidal [145] published histopathological images that em-
phasized the dilatation of the follicle filled with globular
corneous cells, pus and sometimes cocci (fig. 17). A mod-
erate epidermal hyperplasia is mentioned; the sebaceous
glands are seen as healthy. They confirmed Cornil’s pre-
vious observations on the internal wall of the follicle that
remains initially intact. Leloir and Vidal mentioned the
presence of Demodex folliculorum inside comedones that
actually plays no role in acne pathogenesis.
Unna’s and Sabouraud’s Concepts, Complementary
Models
Unna’s Model: Follicular Hyperkeratosis and Infection
Just detected by Cornil, Leloir and Vidal, the follicular
hyperkeratosis became in Unna’s work the pathological
hallmark of the comedogenesis. Unna (1850–1929), the
German master who dominated cutaneous histopathol-
ogy at the turn of the 19th century [146], regarded acne
as characterized ‘in its first stage by a superficial hyper-
keratosis of the epidermis which, extending to the follicle
mouth leads to the formation of comedones’. In this re-
spect, the comedones ‘are in no way the result of an ab-
normal secretion of sebum’, wrote Unna. The sebum
stopped by the hyperkeratosis is transformed into a cylin-
drical plug or barrel-shaped horny cyst that ‘separates it-
self from its horny surroundings’ and becomes a ‘firm
bullet-like body’ – the comedo – of which Unna pub-
lished a minute and dynamic description: ‘Filled with a
quantity of sebum and a number of lanugo hairs, bent,
twisted or rolled into bundles (the comedo) is usually di-
vided by horny septa and contains onion-scale-like horny
flakes and sebaceous cells along with a few hairs. (…)
From severe and persistent pressure the comedo changes
its format at its upper end, the part lying under the surface
of the skin becoming globularly swollen and the head (…)
is still more compressed, thinned and horizontally placed.
Acne Pathogenesis: History of Concepts
Fig. 17. Dilated follicle filled with pus, corneocytes and hair sur-
rounded by a perifollicular inflammation. The sebaceous glands
are not altered. From Leloir and Vidal [145], plate I. Coll. biblio-
thèque Henri-Feulard, Hôpital Saint-Louis, Paris, France.
(…) The comedo is then covered at its upper end by a
tangentially running horny layer which, however, is al-
ways distinguished by its thickness and darker color’
(fig. 18). As the comedo increases, the epithelial surface
undergoes atrophy. Then the destruction of the hair fol-
licles occurs and the sebaceous gland may vanish.
Darier (Paris) confirmed Unna’s views. For Darier, a
comedo ‘looking like a barrel made of corneous lamellae’
is the result of the hyperkeratosis of the upper part of the
follicle that prevents the sebum outflow. He mentioned
that atrophy of the sebaceous gland may occur [147, 148]
(fig. 19).
According to Unna the blackening of the comedo did
not depend on external factors (dirt, dust) as previously
suggested by Bateman, Wilson, Leloir and Vidal: ‘The
blackness is not in the horny layer, not in the upper lamel-
lae of the head of the comedo and thus not in the parts in
communication with the atmosphere.’ Unna hypothe-
sized that the blackness came from keratin itself. Blair and
Lewis [149] showed the color is due to melanin pigment
produced by melanocytes in the upper layers of the seba-
ceous follicle epithelium.
Besides the histopathological findings, Unna [150] ob-
served in the head and mantle of the comedones an oat-
shaped ‘bottle bacillus’ – first mentioned in 1875 by Ma-
lassez – and the diplococcus he previously described in
seborrheic eczema. He pointed out the fact that in acne,
‘almost every comedo contains a swarm of microorgan-
isms’, harbored in a ‘protected and temperate chamber,
often in pure culture, than that, up to now, we should
have had no suspicion of their existence’. The bacilli,
about 1/3 to 1/2 μm broad and 1.25–1.5 μm long, were
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Fig. 18. Comedo. H = Hair; U = unblackened horny layer; S = se-
baceous gland. The regression of the sebaceous lobules is typical of
this stage of a comedo. From Unna [150]. Coll. bibliothèque Hen-
ri-Feulard, Hôpital Saint-Louis, Paris.
Fig. 19. Histopathology of the comedo (Darier). a = Comedo made
of intricate corneocytes in a dilated follicle surrounded by a fol-
licular hyperkeratosis; b, c = pilosebaceous follicles; d = pus cells
infiltrate the follicle wall leading to a perifollicular abscess; e = leu-
kocytes surrounding vessels around pustule. From Thibierge
[147]. Coll. bibliothèque Henri-Feulard, Hôpital Saint-Louis, Par-
is.
16 Dermatology 2014;229:1–46
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arranged in threads, looking like ‘bundles of spelicans’
that extended to the ostium of the sebaceous gland. De-
spite the fact that he could not obtain a pure culture of it,
he regarded the microbacillus not as an ‘accompaniment
but as the actual cause of the comedo formation’ and of
the suppurated lesions. For Unna, the microbacillus was
the only agent of acne [150].
Few years later Hodara (Constantinople) [151], Unna’s
pupil, following his master’s advice investigated the mi-
crobiology of comedones from 20 patients and observed 3
kinds of microorganisms: a coccus specific to the comedo-
nes, large bacilli similar to the bottle bacilli (‘Flaschenba-
cillen’) and small bacilli. The cocci were present in the
head and external lamellae of the comedones, never in the
center or in the bottom of the comedones. The bottle ba-
cilli were always located in the head of the comedones,
often in external or internal lamellae, never in the bottom
or in the central cavities. The third type, found always in
the deeper part of the comedones and in the central cavi-
ties, was ‘never absent in the comedones’. Despite many
attempts on various media, Hodara [151] failed to obtain
indefinite cultures of the bacilli.
Sabouraud’s Model: Hyperseborrhea and Infection
Whereas Unna emphasized hyperkeratosis of the epi-
dermis and a microbacillus as causes of the comedones,
Sabouraud (1864–1938), both dermatologist and microbi-
ologist, favored the combined role of seborrhea microor-
ganisms. Two years after Unna, he published his work on
the subject in the leading French paper on microbiology
[152]. In Sabouraud’s physiopathological concept, the
acne process does not start from the epidermis but from
seborrhea that has 2 symptoms in glabrous areas: enlarge-
ment of the pilosebaceous ostiums and overproduction of
sebum. In pilaris areas, a third symptom of seborrhea could
occur: alopecia. For Sabouraud the elementary lesion of
seborrhea is the fat cylinder – Plewig and Kligman called it
precomedo (see below) – extracted from the pilosebaceous
ostium: ‘In every clinical form of acne, the seborrheic fila-
ment is the first lesion because there is no acne without
preliminary seborrhea’ (transl. G. Tilles) [153] (fig. 20, 21).
In Sabouraud’s model, the comedo is therefore not the
elementary lesion of acne in the willanist meaning of the
word: it is the beginning of secondary lesions and the end
of preexisting lesions, namely seborrhea [154]. Not every
seborrheic filament, wrote Sabouraud, evolves into a com-
edo. The majority of them will never be transformed. ‘Ini-
tially, the seborrheic filament is only a cylinder made of
pure fat.’ Then, some filaments close at their upper and
lower parts and evolve into ‘cocoon’s (…) monstrous
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 a b
Fig. 20. The seborrheic filament. a First stage of its formation: the
cavity of the follicle is filled with microbacilli. The seborrheic fila-
ment is surrounded by exfoliated epidermal layers that will consti-
tute its envelopes. b Second stage of its formation. The epidermal
layers that surround the filament become more and more crinkled
due to the sebum outflow. From Sabouraud [153]. Coll. biblio-
thèque Henri-Feulard, Hôpital Saint-Louis, Paris.
form’ of the seborrheic filament the center of which ‘is a
pure colony of billions of microbacilli’. The microbacillus
colony will keep on growing, the seborrheic cylinder will
enlarge and finally completely obstruct the pilosebaceous
duct. The comedo is completed. ‘The core of the comedo
is a pure colony of microbacilli made of billions of ag-
glomerated specimens. The colony is cut in masses of var-
ious sizes and forms, enclosed in a cavity surrounded by a
thick corneous envelope around which are numerous oth-
er envelopes that constitute the mantle of the comedo. Be-
tween the envelopes are bacilli and fragments of atrophic
hairs. The lower extremity of the comedo is a round dead
end. The top of the comedo looks like a chimney whose
deeper part is filled with bacilli. The superior orifice of the
comedo being plugged, it has the appearance of a round
bottle. Consequently ‘the older the seborrheic infection,
the less intense the sebum outflow due to the thickening
of the comedo that looks like a round bottle the neck of
which would be closed’ (transl. G. Tilles). Pigmented frag-
ments inside the epidermal layers and microorganisms re-
sponsible for secondary infections are always present at
the top of the comedo’ (transl. G. Tilles) (fig. 22).
On microscopic examination of the seborrheic fila-
ment, Sabouraud identified myriads of thin Gram-posi-
Acne Pathogenesis: History of Concepts
a b
Fig. 21. The seborrheic filament. a Third stage of its formation.
The epidermal layers form cavities. b Fourth stage of its formation.
The formation of the cavities containing microbacilli is completed.
The top and the bottom of the cocoon are closed. From Sabouraud
[153]. Coll. bibliothèque Henri-Feulard, Hôpital Saint-Louis, Par-
is.
tive bacilli in the upper part of the follicle between the
skin surface and the ostium of the sebaceous gland. ‘To
the best of my knowledge no cutaneous infection is as
pure and as abundant as seborrhea’, wrote Sabouraud. He
succeeded in cultivating the microbacillus on a glycerin
acid agar but could not reproduce the disease by inocula-
tion (fig. 23–29). Like Vidal and Leloir before him, Sa-
bouraud noticed in the seborrheic filament (fat cylinder)
several samples of D. folliculorum that he regarded as car-
riers of bacilli.
While dermatohistopathologists and microbiologists
considered sebum, follicular keratosis and microorgan-
isms as seminal actors of the acne process, other derma-
tologists hypothesized various pathogenic sequences,
some of them emphasizing a link between hairs and com-
edo formation.
Alternative Hypotheses on Comedogenesis
Rindfleisch [155] hypothesized that in healthy situa-
tions, the hair scoured out the pilosebaceous follicle as it
grew. In case of oversecretion of sebum as it occurs in
puberty, the hair can no more remove sebum properly;
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Dermatology 2014;229:1–46 17
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a b
Fig. 22. a, b Comedo. mb = Microbacilli; is = cocci responsible for
secondary infections; p = fragments of hairs between the epidermal
layers; mc = mantle of the comedo; dp = pigmentary fragments.
From Sabouraud [153]. Coll. bibliothèque Henri-Feulard, Hôpital
Saint-Louis, Paris.
Fig. 23. Morphology of the seborrheic microbacillus. From Sa-
bouraud [153]. Coll. bibliothèque Henri-Feulard Hôpital Saint-
Louis, Paris.
then a comedo will appear [155]. Milton [156] proposed
a similar explanation. Jamieson [157] regarded the change
from downy to coarser hair as the first local cause of acne.
McKenzie [158] pointed out that acne occurred in parts
where the sebaceous glands ‘were large and numerous
and associated with relatively imperfectly developed
hairs; it did not occur on the scalp or on the parts of
the face where the hairs grew strong’. Commenting the
18 Dermatology 2014;229:1–46
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McKenzie lecture, Payne stressed that acne resides in ru-
dimentary hairs, ‘their glands being also imperfect pro-
duced imperfect sebum which was too thick to be diffused
along the hairs but clogged up the follicles’ [158].
Like McKenzie, Bregman [159] pointed out the ab-
sence of acne lesions on the scalp despite the great num-
ber of sebaceous glands. According to him the reason was
probably an efficient drainage of the sebaceous glands
due to the more vigorous expulsion of their content by
strong arrectores pilorum on the scalp. By contrast, wrote
Bregman, the sebaceous glands located in the areas where
acne occurs are connected with lanugo hairs that lack vig-
orous arrectores pilorum. ‘The drainage of sebum be-
came then insufficient and a stagnation takes place’ [159].
In 1940 Lynch [160], using newer histological tech-
niques, proposed a reinterpretation of ‘the older descrip-
tions by Unna’. He indicated that several follicles, thought
clinically to contain comedones, actually showed similar
changes as the normal follicles. Moreover, in case of clin-
ical comedo, Lynch could see only ‘little more than these
changes though characteristically the plug is larger’. In
1 case he even observed an epithelial atrophy within the
follicular mouth instead of the follicular hyperkeratosis
described by Unna. Finally, concluded Lynch, the exami-
nation of early acne lesions could ‘afford no clue as to the
cause of the comedo’.
A different pathological approach of the ductal ob-
struction was proposed by O’Brien [161]. According to
this author, the follicular opening, like the sweat pore, is
surrounded by a ‘follicular keratin ring’ made of concen-
tric lamellated keratin. In this view the obstruction is not
inside the duct but is caused by the ring that surrounds it.
Moreover, considering similarities between staphylococ-
cal folliculitis and acne lesions that showed keratosis, in-
fection and obstruction, he suggested that the initial le-
sion of acne, ‘obstructive in nature’, located at the follicu-
lar ‘keratin ring’ is caused by primary or secondary
infection [161].
Cohen [162] suggested to envision the pilosebaceous
follicle as a physiological entity – the more sebum pro-
duced, the smaller amount of keratin (hair) formed: ‘The
comedones form in the pilosebaceous follicle in which the
hair is rudimentary. (…) Follicles with lanugo hairs usu-
ally have small pilomotor muscles. Thus excess sebum is
formed and meets a narrowed hyperkeratotic follicular
ostium. The small hair cannot act as drain for the sebum.
At the same time the pilomotor muscles are too small and
weak to help propel the sebum to the surface. The sebum
may be abnormal physically or chemically. If it be too vis-
cid, obstruction will be assisted. A change of chemical
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 24

25

Fig. 24. Pure culture of the seborrheic mi-

crobacillus. From Sabouraud [153]. Coll.
bibliothèque Henri-Feulard Hôpital Saint-
Louis, Paris.
Fig. 25. Sebaceous gland and infection. The
colony of microbacilli (mb) is located in the
upper part of the follicle. The sebaceous
gland (dg) is enlarged. dé = epidermal frag-
ments above the follicle infected with mi-
crobacilli; ef = exfoliation of epidermal fol-
licle surrounding the microbial colonies;
of = ostium of a pilosebaceous follicle;
mb = microbacilli in the upper part of the
follicle; og = ostium of the sebaceous gland
in the pilous follicle; d = dermis; dg = digi-
tations of the sebaceous gland. From Sa-
bouraud [153]. Coll. bibliothèque Henri-
Feulard, Hôpital Saint-Louis, Paris.

composition might stimulate the overgrowth of horn at
the ostium.’ Cohen however refused to give priority to the
theories that linked hair and acne over those that empha-
sized the role of hyperkeratosis and microbes (see fur-
ther). He suggested that both concepts could be pertinent,
the ‘mechanisms being not necessarily the same in all the
conditions in which comedones occur’ [162].
In a similar way, Grant [163] proposed to measure a
‘hair index’, i.e. the number of hair-bearing follicles in
which both mature hairs and succeeding hair are visible.
Grant suggested the existence of a ‘dynamic polarity’ be-
tween the production of sebum and hair so that a follicle
which produced more sebum would produce less hair.
According to him, the relationship between hair and
comedones was supported by measurement of the index
which increased or decreased in parallel with the clinical
severity of acne [163].
In 1956, Van Scott and McCardle [164] examined bi-
opsy specimens of early acne lesions from 10 white pa-
tients. They observed a keratinous plug continuing into
the mouth of the sebaceous gland the dilated orifice of
which was filled with the keratinous substance. They stat-
ed that the plug derived from the epithelial lining of the
excretory duct of the sebaceous gland. They hypothesized
this alteration was the primary focus of the acne lesion.
Vasarinsh [164] failed to observe the obstruction of the
sebaceous duct in any of the 94 biopsy specimens he ex-
amined. Moreover Van Scott and McCardle [165] ob-
served that a large percentage of hairs involved in the ear-
ly acne lesions of the back are in the telogen phase which
might also suggest that a growing hair prevents the for-
mation of a keratinous plug. They also saw that in the
bearded area there are 2 separate channels through the
follicular neck of the pilosebaceous unit: one being tra-
versed by the hair shaft, the other one connected to the
excretory duct of the sebaceous gland. Since the latter is
isolated from that which the hair traverses, the authors
concluded that as far as the acne lesions of the face are
concerned, the state of growth of the hair should have no
physical influence on keeping the sebaceous channel clear
of sebum and cells [165].
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Fig. 26. Seborrheic cocoon filled with microbacilli in a follicle of
the glabrous area. From Sabouraud [153]. Coll. bibliothèque Hen-
ri-Feulard, Hôpital Saint-Louis, Paris.
Fig. 27. Acne pustulosa inferior. C = Comedo (only a sebaceous
filament); A = abscess; S = unaltered sebaceous cells; R = rupture
and abscess into surrounding tissues. From Unna [150]. Coll. bib-
liothèque Henri-Feulard, Hôpital Saint-Louis, Paris.
20 Dermatology 2014;229:1–46
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Kligman’s Model: Landmark in the History of
Comedogenesis
In 1958 Strauss and Kligman [166] proposed an ap-
proach of the comedo formation that gave the sebaceous
gland an essential part. Examining the pathological
changes of sebaceous glands on more than 50 biopsy
specimens of acne patients, they suggested that as the
comedo forms, a variable degree of undifferentiation de-
velops. Observing that the changes are similar to those
after plucking hairs, they concluded that the gland is in-
fluenced by any follicular disturbance, especially horny
distension of the follicle. In this respect, the failure of se-
baceous maturation and replacement by undifferentiated
epithelial cells are a response to various stresses, chemi-
cal, physical or comedonic. Strauss and Kligman viewed
this response as a stereotyped defense of the gland that
temporarily ceases to synthesize specialized cell products.
Then after the appearance of undifferentiated cells the
sebaceous gland would have the potential to undergo ke-
ratinous metaplasia with the production of keratinized
squamae rather than sebaceous cells. In fact, a gradual
atrophy of the gland appears secondary to the comedo
formation. Redifferentiation into specialized cells occurs
when the inhibiting forces are removed [166]. However,
wrote Kligman later, despite the role attributed to the se-
baceous cells in this concept, ‘the custom of classifying
acne under diseases of sebaceous glands is incorrect’ [43].
In 1960, the same authors published spectacular histo-
pathological images of comedones. Whereas open com-
edones looked innocent and peaceful due to their large
mouths that allow the outflow of their content, the closed
comedones connected to the skin surface through a min-
ute channel were regarded as ‘truly baleful clinical mani-
festations of acne’ or ‘sine qua non of acne’ [98], ‘time
bombs’ in which ‘explosion sets off the inflammatory pro-
cess’ [66]. In the same period Villanova [167] also pub-
lished similar histopathological images of comedones.
Kligman described 2 forms of comedones: primary ones
evolving into microcomedones seen only at the histopath-
ological level that transform into closed comedones, then
into open comedones; secondary comedones resulting
from the rupture and reencapsulation of the primary ones.
Besides the closed and open comedones, Plewig and Klig-
man [23] added the precomedones, sebaceous filaments –
similar to Sabouraud’s description a century before (see
further) – that are the origin of the comedones. More re-
cently Cunliffe et al. [168] completed the catalogue of com-
edones, either visible or not, that reinforced their role in
the acne process: ordinary comedones, missed comedones
better seen when stretching the skin, very small, almost
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confluent closed comedones he named sandpaper come-
dones, and submarine comedones.
Using autoradiography after intradermal injection of
tritiated thymidine, Plewig et al. [169] showed that com-
edones formation results from increased formation of
horny cells and increased coherence among these cells.
Plewig [170] added a point to the patterns of keratiniza-
tion experimentally induced: after their removal open
comedones reappeared clinically after 20–40 days where-
as closed comedones appeared after 30–50 days. More-
over, after removal of the entire epithelium, new comedo-
nes did not appear.
Then, Kligman [43] claimed that the acroinfundibu-
lum plays no part in the comedo formation: ‘A comedo
begins in the infrainfundibulum where the entire epithe-
lial lining undergoes a change in the pattern of keratiniza-
tion.’ The horny cells in the infrainfundibulum become
‘more distinct and sturdy and begin to stick together. (…)
Instead of sloughing into a loose disorganizing mass, the
horny cells begin to pack together. (…) they form an im-
Fig. 28. Acne pustule. as = Superior abscess in the dilated follicle
paction which distends the lumen; the follicle then be-
orifice; ai = inferior abscess; cf = follicular duct filled with leuko-
comes microcomedones. (…) As the expansion en- cytes. From Sabouraud [153]. Coll. bibliothèque Henri-Feulard,
croaches on the acroinfundibulum, it becomes shallower Hôpital Saint-Louis, Paris.
and the horny mass forces the pore to dilate. The horny
core then protrudes through the orifice and the comedo
becomes open’ [43]. Kligman [22] rejected ‘the idea of a
plug or obstruction at the opening of the follicle (that) has
dominated all thinking about how the comedo starts. (…)
The fact is the cork conception is wrong.’ In fact, human
sebum, always a viscous and fluid substance, never blocks
the follicle.
Plewig [171] observed in closed comedones a continu-
ous sloughing of labeled cells, then ‘a glacier-like move-
ment’ of horny cells through the pore. By contrast, due to
the small size of its pore, the matter contained in the
closed comedo could not be discharged. Plewig regarded
them as ‘sealed time bombs’ and called this initial period
the ‘embryonic stage of acne’.
Stressing the fact that the fine structure of the early fol- Fig. 29. Follicular abscess. a = Microbacillary cocoon; a’ = dissem-
inated colonies of microbacilli; b = leucocytes in the colonies of
licular changes leading to the comedogenesis had not yet microbacilli; c = deep abscess linked to the superficial abscess
been reported, Knutson [172] published a great amount through a narrow neck. No coccus of secondary infection can be
of information on the ultrastructure of acne lesions, pilo- found on this pathological image. From Sabouraud [153]. Coll.
sebaceous units and the possible mechanisms of the com- bibliothèque Henri-Feulard, Hôpital Saint-Louis, Paris.
edo formation. Analyzing 70 biopsy specimens from acne
patients with the electron microscope, he showed that the
normal keratinization of the upper follicle is not the same tact. The granular cells that form this layer in the comedo
as that of the epidermis but varies along a gradient from have fewer tonofilaments and larger keratohyalin than
the follicular ostium to the sebaceous gland. As far as normal cells.
comedones are concerned, the keratinized layer of the in- Beside these aspects, Knutson pointed out the most
frainfundibulum does not disintegrate but remains in- striking difference between comedones and normal fol-
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licles: the multiple intracellular lipid inclusions within ke-
ratinized and granular cells. He proposed that the process
of abnormal keratinization could result from 3 different
mechanisms: a production of an abnormal lipid, a lack of
an enzyme for the degradation of normal lipid or a pro-
duction of an abnormal keratin which cannot complex
normally with lipid. Knutson hypothesized that abnor-
mal keratinization could be the primary event coinciding
with puberty or may arise as a secondary cellular response
to comedogenic substances within susceptible follicles.
He admitted however that the events leading to the al-
tered follicular keratinization in comedones remained
unknown [172].
Synthesizing these elements, Plewig and Kligman
[173] – authors of a so far unrivaled textbook on acne –
proposed a pathophysiological approach to comedogen-
esis. Contrary to what happens when a comedogenic
agent is applied, only the infrainfundibulum is involved
in the comedo formation: ‘Hence the follicle swells below
and the orifice does not dilate. Instead of a cork at the
outlet, the whole follicular canal becomes filled with com-
pact corneocytes’ [173]. A 2-compartment model – bricks
and mortar – inspired from abnormalities in retention
hyperkeratosis was used to explain the comedo forma-
tion. The bricks from the comedonal kernel – corneo-
cytes – would be of other quality than their epidermal
counterparts, often nuclei or nuclear remnants and much
larger than those from the epidermis. The intercellular
cement had to change in some way, notably the intercel-
lular lipids, particularly the ceramides. Plewig and Klig-
man hypothesized that lytic enzymes are no longer se-
creted into the intercellular spaces to weaken the cement.
Membrane-coating granules were supposed to play a ma-
jor role in this process. Whereas they are numerous in the
normal infrainfundibulum, they had been reported to de-
crease when comedones form. In acne patients, infrain-
fundibulum cells contain a lot of tonofilaments and des-
mosomes and fewer granules. The desmosomes – corneo-
somes – that failed to disintegrate as keratinocytes reach
the horny layer would prevent desquamation. Therefore,
the failure of corneocytes to slough normally produces a
hyperkeratosis. Large intracellular probable lipids are vis-
ible. The decreased number of lamellar granules indicates
a critical defect that explains the cohesiveness of desqua-
mated follicular corneocytes [174].
In this context that emphasized the role of comedos,
some authors regarded their removal as a valuable ad-
junct to topical or systemic therapy as it can improve the
patient’s appearance which may positively impact com-
pliance with the treatment program [175, 176]. More-
22 Dermatology 2014;229:1–46
DOI: 10.1159/000364860
over, as Taub [177] wrote, the removal of the comedones
provides immediate improvement and patient satisfac-
tion. Steventon [178] postulated that controlling the tim-
ing of comedo extraction at ovulation is a key step in the
reduction of premenstrual acne. Plewig and Kligman
[179] have provided histopathological images of the ben-
efits and detriments, sequelae and complications of com-
edo extraction.
Debates and Controversies
Cunliffe and Shuster [35] expressed some doubts on
the role of the follicular keratosis as the initial factor of
the acne process. Publishing a study on the role of sebum
in acne, they concluded that acne is not only due to an
obstacle in the follicular duct, but also to ‘the interaction
between an increased sebum secretion and a second fac-
tor (increased resistance to sebum flow from organic ob-
struction or increased sebum viscosity)’ [35]. Later Cun-
liffe [180] favored the sebum production as the most im-
portant factor and regretted that dermatologists ‘obsessed
in looking at initiating factors’ had devoted only a very
limited number of publications to the resolution of acne
‘which could provide us with very useful information’
[181]. Strauss [182], although describing the excessive ke-
ratinization within the follicular duct as the initial event
in the comedo formation, regarded its role ‘in the patho-
genesis of acne’ as ‘uncertain’. Although he defended the
follicular hyperkeratosis as the key initial factor, Plewig
[171] admitted that the retention of epidermal cells might
be minimal and that in some acne types (aestivalis, steroid
acne) the inflammatory lesions were initial and the pro-
duction of horny cells secondary. Vasarinsh [183] point-
ed out the fact that the onset of inflammatory papules
after ingestion of chocolate in susceptible patients sug-
gests that the major role in the acne process is played by
sebaceous gland activity rather than by chronic hyperke-
ratinization: ‘Sudden increase in sebum production could
well trigger the time-bomb inherent in the partially ob-
structed comedo.’
Among the authors who questioned the role attributed
to the follicular keratosis in the comedogenesis, Shuster
[184] occupied an original position presenting his views
in a humoristic, rather polemic, sometimes aggressive
and finally unique manner.
Shuster strongly defended what he called ‘a reduction-
ist theory which explains adolescent acne by an increase
in sebum excretion’, the other factors being for him ‘sec-
ondary events’, notably the duct blockage, ‘mistress of the
Acne Barons (Kligman, Strauss, Plewig and Cunliffe)’.
For Shuster, there was ‘no good evidence of functional
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blockage of the duct in adolescent acne’ [184]. To focus
the debate with the ‘Barons’, Shuster summarized their
views: ‘Acne is strictly a follicular dermatosis; the comedo
is the initial primary lesion of acne; the primary event is
duct obstruction; the prime defect is abnormal keratini-
zation; acne can be thus defined as a disease of the infun-
dibular canal of the sebaceous follicles.’ Shuster qualified
the ‘idea of invisible duct blockage’ as ‘an amazing piece
of charlatanism’. However, he did not deny the existence
of excessive follicular keratosis, the main question being
for him ‘whether the keratinization is a primary or sec-
ondary event’. For Shuster, ‘the evidence, apart from ex-
istence of keratin in the duct as to whether this is of
primary importance is nil’. In summary, ‘(a) there is no
good evidence that the keratinaceous and other materials
to be seen in the ducts actually (functionally) block them;
(b) there is no evidence that comedones are the primary
lesions of acne; (c) the evidence, such as it is, is that the
ductal changes are secondary’ [185]. As a therapeutic
consequence, ‘traditional topical therapies and the newer
ones such as retinoic acid are merely placebos’.
In fact, wrote Shuster, the debate should not exist, the
sebum production as the primary factor of acne being an
‘indisputable evidence. (…) Remove sebum and you re-
move acne’ [186]. ‘If the fat glands of the acneic patient
could be got small and empty, he would no longer have
acne’ [187]. Shuster quoted the evidence provided by Po-
chi and Strauss [37] that sebum ‘correlates better with
severity of acne than any other characteristic’. Regretta-
bly, wrote Shuster, they did not realize the importance of
their finding and ‘took up the curious North American
obsession with sebum composition and duct blockage’.
He also recalled Cunliffe’s work who showed that the fol-
licular plugs decrease in size after treatment of acne with
tetracycline. In this respect, questioned Shuster, tetracy-
cline should lead to an increase in the sebum excretion
rate. For Cunliffe and Cotterill [188], this assessment was
an ‘apparent paradox. (…) easily explained. As an indi-
vidual has thousands of sebaceous follicles producing se-
bum, (…) the small number of blocked ducts will not sig-
nificantly reduce the seborrhoea.’
In this circumstance, ‘what has the debate been about?
Why despite the evidence for seborrhea do dermatologi-
cal journals still carry advertisements for agents alleged to
act by relief of duct blockage.’ For Shuster [189] the an-
swer has to be searched in the writings of the ‘Four Knights
of the Blackheads and their magic mottos: acne is strictly
a follicular dermatosis’. He denounced the ‘kligmania’
that ‘led on to the central role of the comedo when the
only evidence of its centrality was its position in the duct’.
Acne Pathogenesis: History of Concepts
He also attempted to minimize the power of the images
in Plewig and Kligman’s book and finally named the par-
tisans of the follicular keratosis ‘plumbing school of acne’.
Shuster stressed the fact that for those who empha-
sized the duct blockage there are only 2 consequences:
‘Either the seborrhoea is secondarily provoked by the
blockage or the seborrhoea is an unrelated finding even
though its quantitative relationship to acne is proved. If
you believed the first you will believe anything; if you be-
lieved the second you are willing to disbelieve anything.’
Shuster finally concluded that ‘on purely theoretical
grounds duct obstruction can be dismissed as ignorable
or untenable’. In fact, Shuster wrote: ‘The belief in duct
blockage has all the perverse characteristics of a myth: it
persists in spite of reality. (…) The notion that a blocked
duct could increase sebum production is nonsense.’
Moreover, Shuster denied the consequences of the
horny plug emphasized by their defenders: ‘The idea that
it precipitates a sequence of duct blockage onward to rup-
ture of a follicular time bomb, can only be taken as a liter-
ary artifact, an aesthetic appreciation of one aspect of the
histology of acne.’ According to him, this can be rejected
by every dermatologist ‘even with half an eye’. In fact, the
two pathological events – comedones and inflammatory
lesions – are distinct: ‘The dissociation between the in-
flammatory concomitants of acne and the comedo is so
gross and obvious that I teach the students that the com-
edo is acne-protective.’ Finally he summarized his views
on acne pathogenesis as follows: ‘My reductionist theory
is that the prime defect in acne vulgaris is (something as
yet undissociable from) an increase in sebum excretion
which in turn leads to bacterial colonization and infec-
tion, and which in turn causes the histopathological (and
clinical) lesions of acne – a minor component of which is
the ductal changes with which our myth has been con-
cerned’ [189].
Initially regarded as insects the removal of which could
restore a healthy condition, the comedones became con-
sidered from the end of the 19th century as initial and
mandatory actors of the acne pathogenesis. After Unna’s
views of a horny cork at the opening of the follicle, the
speculations on the relationship between hairs and com-
edones, the hypothesis on the keratin follicular ring, the
model conceptualized by Kligman and his disciples be-
came a definite truth for a vast majority of dermatology
investigators. The intellectual coherence of the mechanist
model, the vocabulary employed by Kligman and his co-
workers to name the effects of comedones (time bombs,
explosion), the efficiency of tretinoin he discovered, his
‘pontifical role’ emphasizing his own works – ‘I have tak-
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Dermatology 2014;229:1–46 23
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en over 600 facial biopsies from every kind of lesion and
variety of the disease, I have studied and treated thou-
sands of afflicted youngsters’ – have certainly accounted
for the success of his model on comedogenesis [22]. De-
spite his eloquence, Shuster’s arguments could not pre-
vent Kligman’s concepts to prevail. In fact, the hyperke-
ratinization in the follicular infundibulum is still regard-
ed as ‘crucial event’ [190].
Epilogue
Recent works have emphasized the role of androgens,
of P. acnes and of the immune response in comedo forma-
tion.
The onset of acne that coincides with a rise of dehy-
droepiandrosterone leads to consider the role of the an-
drogens in follicular keratosis [191, 192]. The activity of
17β-hydroxysteroid dehydrogenase and 5α-reductase
that converts testosterone to dihydrotestosterone was
found to be greater in follicular infrainfundibulum kera-
tinocytes than in epidermal keratinocytes. Androgen re-
ceptors were shown in the outer root sheath of the follicles
and in sebaceous glands. Increased dihydrotestosterone
was supposed to act on infundibular keratinocytes lead-
ing to abnormal keratinization. Conversely the reduction
in the number of comedones in patients treated by anti-
androgens provided another argument in favor of the role
of androgens in comedo formation [193]. The piloseba-
ceous unit is now regarded not only to be influenced by
androgens, but also as a contributor to cutaneous andro-
gen production. This new role could account for the ef-
ficiency of the antiandrogen therapy [194].
The biofilm theory has emphasized the interaction be-
tween comedogenesis, P. acnes and sebum. Defined as ‘a
complex aggregation of microorganisms that encase
themselves within an extracellular polysaccharide lining
which the organism secretes after adherence to a surface’,
the biofilm would act like a ‘glue’ that leads to the binding
of keratinocytes inside the infundibulum. The proponents
of the theory speculated that the microcomedo may be the
reflection of the action of P. acnes secreting substances
into the sebum to set up a biofilm that leads to the binding
of keratinocytes in the infundibulum resulting in a com-
edo. Burkhart and Burkhart [195] admitted however that
the existence of a P. acnes biofilm and its adherence to the
follicular wall need to hypothesize that the biological glue
would find its way into sebum composition.
Recent investigations have suggested that immune-
mediated inflammation might play an active role in com-
24 Dermatology 2014;229:1–46
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edogenesis: interleukin (IL)-1α-like material has been
found in open comedones in acne patients; the sebaceous
glands express several cytokines; the addition of IL-1α in
the follicular infundibulum in vitro results in hyperkera-
tosis similar to that seen in comedones, the effect inhib-
ited by an antibody blocking IL-1 receptors [25, 196].
Other studies have shown the aggravating role of P. acnes
in comedogenesis through IL-1 production (see further
on P. acnes). Eady et al. [197] compared the cytokine pro-
files and bacterial flora of open comedones from patients
before and after treatment with tetracycline or minocy-
cline. They could see a significant effect of antibiotics on
cytokine levels. They suggested that increased levels of
IL-1 in comedones may enhance resolution and promote
repair of the damaged follicular epithelium [197]. Besides
these pieces of evidence and speculations, abnormal ke-
ratinization has been associated with a disorder in the ter-
minal differentiation of infundibular keratinocytes relat-
ed to increased filaggrin.
Despite the advances, many of them speculative, the
mechanisms of the comedogenesis remain ‘ambiguous’
[190].
From Acne Microbacillus to P. acnes: Facts,
Controversies and Speculations
From the 1870s the discovery of bacteria opened a new
era in medicine. The causes of diseases previously regard-
ed as mysterious were suddenly revealed through the
lenses of the microscope. Physicians came even to hy-
pothesize that microbiology would explain all the diseas-
es. Those who did not live these times, recalled Darier,
cannot imagine the intellectual movements and expecta-
tions they aroused [198]. In this context, lecturing at the
first international congress of dermatology, Paris, in
1889, Barthélémy [199] did not hesitate to assert that acne
is a transmitted disease and the consequence of an infec-
tion by a microorganism yet unidentified.
Acne Microbacillus or Bacillus acnes, Actual Cause of
Acne?
As seen above, Unna’s and Sabouraud’s works gave the
microorganisms an essential role in comedogenesis. In
May 1899, Gilchrist (1862–1927) lectured at a meeting of
the American Dermatological Society on a bacillus simi-
lar to Unna’s he had found in the pustules of acne pa-
tients. He could obtain pure cultures of it and inferred
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that pustules and nodules of acne were not due to an or-
dinary staphylococcus but to the microorganism he
named B. acnes. The serum of the patients agglutinated
the bacillus in vitro and when inoculated into animals, the
bacillus produced an abscess from which it had been re-
covered in pure cultures. Gilchrist could therefore write:
‘It seems to be now definitely proved that the B. acnes is
the primary cause of acne’ [200].
Withfield (1868–1947) [201] confirmed the role of the
microbacillus ‘responsible for the comedo, not for the
seborrhea’. He rejected the infectious specificity of acne
(‘It is a retrograde step to look upon acne as a specific in-
fective disease caused by this ubiquitous organism’) and
asserted that the secondary suppuration ‘was due to ordi-
nary pyogenic staphylococci’. He suggested that the epi-
thelium of the follicle would deal with the microbacillus
in the way in which the epidermis always deals with for-
eign bodies, namely by encysting it with horny cells ex-
plaining the comedo formation.
Alexander Fleming (1881–1955, London) [202], later
worldwide celebrated as the discoverer of penicillin, rede-
scribed the bacillus as a ‘small Gram staining bacillus
varying in length from under 1 micron to 3–4 microns
and about 1/2 micron wide’. He could not reproduce the
serum reactions described by Gilchrist but gave what he
thought to be a complementary evidence of the infectious
role of B. acnes in producing acne by inoculation. He
‘rubbed vigorously into the skin of the forearm of a per-
son suffering from acne a culture of acne bacillus freshly
isolated from him. (…) After five days definite pustules
form (…) Films of these pustules were examined and no
organism other than the acne bacillus could be discov-
ered.’ The same cultures were inoculated into the forearm
of a person who had never suffered from acne; the result
was negative. Fleming concluded that the bacillus is re-
sponsible for the comedo and capable of producing a pus-
tular folliculitis in a susceptible person. Then he came to
the treatment of acne by vaccination of patients with a
mixed culture of B. acnes and staphylococcus. He con-
cluded that a large number of cases had been improved
and in some of them acne had even disappeared [202].
Commenting on Fleming’s article, The Lancet declared
B. acnes was ‘the essential causative factor’ in acne vul-
garis [203] while Molesworth [204] reinforced the rela-
tionship between acne and microorganisms.
In Paris, Hallé and Civatte (1877–1956, Paris) [205]
confirmed the existence in the comedo of a Gram-posi-
tive anaerobic bacillus similar to the one described by
Unna while Ramel (1895–1941, Lausanne) [206] favored
a tuberculosis concept of acne.
Acne Pathogenesis: History of Concepts
The Microorganisms in Question
Contrasting with the enthusiastic comments on the
microbial etiology of acne, Lovejoy and Hastings [207]
invalidated the direct role of B. acnes. They actually found
it in early lesions of acne (comedones and superficial pus-
tules) and also in healthy skin around the alar folds of the
nose from which they could cultivate the bacilli ‘as read-
ily as those obtained from pathological lesions’. The
pathogenic role of the bacillus in the acne lesions became
therefore seriously questioned – ‘what bearing the pres-
ence of the bacillus in the healthy skin has upon the
pathogenicity of the organism remains to be worked
out’ [207] – and the infectious concept of acne based on
‘very inadequate grounds’ [208]. Additional evidence
supported the questioning on the responsibility of B.
acnes.
When cultivating material from healthy skin and skin
from acne patients, Lynch [209] observed ‘the fairly con-
stant presence of two organisms apparently identical with
those observed in the sections of tissue’. Sutton [210] re-
called that ‘no one ever caught acne and pus from the le-
sions is innocuous’. Pochi and Strauss [211] showed that
sulfonamides are ineffective in vitro on C. acnes and not
particularly effective in vivo. Analyzing the article, the
editors of the Year Book of Dermatology stressed that sul-
fonamides are sufficiently efficient in some cases to make
it extremely unlikely that C. acnes plays any role in the
production of the disease [212].
Moreover, no investigator could validate Koch’s pos-
tulates, a series of steps that should be followed in order
to prove that a specific microorganism is the causal agent
of a specific infectious disease: the organism must be con-
stantly present in the diseased tissue, it must be grown in
pure culture, the pure culture must induce the disease
when injected into an animal.
Finally, a ‘considerable doubt’ attenuated the patho-
genic role of B. acnes, and the cocci were therefore re-
garded ‘as secondary invaders or perhaps saprophytes or
(less probably) the etiologic organisms of acne’ [213]. In
these circumstances, naming the so-called B. acnes was
criticized due to its questionable specificity. Eberson
[214] proposed to name it in a more generic way C. acnes.
After it had been classified within the Propionibacteriae
by Werkman and Brown [215], in 1946 Douglas and
Gunther [216] renamed it P. acnes because the bacteria
fermented glucose to produce propionic acid and acetic
acid. Many authors however kept on naming it C. acnes
for several years.
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 The infectious concept of acne agreed since Unna’s
seminal work was then more and more questioned. The
antibiotics’ – notably tetracyclines – efficacy on acne le-
sions reemphasized the role of microorganisms [217].
The Antibiotics Efficacy, Reawakening of the
Infectious Concept
Reporting that Terramycin was highly beneficial in
pustular acne, Andrews and Domonkos [218] asserted
that it would become an ‘increasingly valuable remedy in
severe pustular types of acne’. Robinson [219] showed
that oxytetracycline, chlortetracycline and erythromycin
were the drugs of choice to treat acne vulgaris and acne
conglobata. He did no recommend the use of topical an-
tibiotics [219]. In the following years, additional works
reinforced the credit of antibiotics and therefore empha-
sized the role of microorganisms even though their exact
roles remained unknown. Cronck et al. [220], using tet-
racycline in over 70 patients, observed a reduction of the
pustules in more than 60 patients within 2 months. King
and Forbes [221] obtained similar results. Goltz and
Kjartansson [222] showed that whatever the density of
the bacterial flora prior to the treatment, tetracycline
caused a marked drop in the number of both aerobic and
nonaerobic Gram-positive microorganisms. Finally tet-
racycline became the first choice, erythromycin the sec-
ond [223]. In this context, the antibiotics efficiency in-
cited ‘the major portion of investigators’ to consider that
the ‘microbacillus of Unna and Sabouraud found in the
comedo plugs is (…) the direct cause of the disorder’
[224].
However, some investigators expressed doubts on the
efficiency of tetracyclines arguing that ‘good trials of an-
tibiotics in acne are rare’ [225]. Crounse [226] failed to
obtain better results with tetracycline than with placebo
in a crossover study in acne nurses. Cornbleet [227]
brought evidence of the beneficial effects of tetracycline
even in doses much lower than those usually used against
infectious diseases. Baer and Witten [228] observed that
many nonpustular forms of acne responded to antibacte-
rial treatment. Furthermore, as Cornbleet [227], they
pointed out the fact that in some patients acne could be
suppressed with doses which might be regarded as insuf-
ficient for bacteriostatic or bactericidal action. They pro-
posed that antibiotics may act not on the microorganisms
in the acne lesions but on those in the intestinal tract and
that modes of action other than antibacterial had to be
considered [228].
26 Dermatology 2014;229:1–46
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Cove et al. [229] were also dubious about the precise
role of P. acnes. They concluded from their studies that
greater numbers of bacteria are not associated with in-
creasing severity of acne and that the effectiveness of oral
tetracycline could not be explained by a reduction in the
number of bacteria. The fall in free fatty acid levels on skin
during tetracycline, erythromycin or clindamycin thera-
py provided a complementary explanation of their mech-
anisms of action on P. acnes. In acne patients treated by
tetracycline, a great reduction of C. acnes was observed
correlated with a decline of free fatty acids [230–232].
Kligman et al. [233] finally suggested that sebum would
be less comedogenic if triglyceride hydrolysis could be
inhibited either by inactivation of lipases or by suppres-
sion of the bacteria that produced them. Tetracycline had
the potential to do both.
P. acnes, Dominant Actor of Acne Microflora
The studies on acne microflora also generated contrast-
ing results. Whereas some authors reported only staphylo-
cocci similar to those found on the skin from seborrheic
areas of normal subjects [234], others found Corynebacte-
rium and staphylococci, while others described the acne
microflora made of 4 genera of microorganisms: P. acnes,
Staphylococcus, Micrococcus, and Pityrosporon [235]. Few
authors even considered acne lesions sterile [236].
Contrasting with these puzzled observations, Sheha-
deh and Kligman [237] claimed that ‘the bacteriology of
acne is simple’. They did not even hesitate to incite the
students who wished ‘to learn about the kinds of organ-
isms in acne lesions (…) not to consult the literature. (…)
It is a bramble thicket which will scratch rather than sup-
ply the mind. (…) In sheer wealth of error it is a classic
in dermatomythology.’ Studying the microorganisms
occurring in acne lesions of over 100 boys and girls, they
showed that the bacteriology of acne is ‘the very anti-
thesis of the bacterial potpourri cooked up in the litera-
ture. Practically speaking, only 2 microbes, Staphylococ-
cus albus and P. acnes, inhabit the diverse lesions that
acne presents in the various forms of its development.’
Moreover, they pointed out that the occurrence of both
microorganisms is foretold by their resident status in the
normal follicle of the face: ‘These organisms have posses-
sion by squatters rights, so to speak, of the normal follicle
before it becomes the site of comedones.’ They added,
like Sabouraud, that these species are always found to-
gether in every case of comedo that constitutes a ‘succu-
lent cocoon in which bacteria proliferate prodigiously’.
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In the inflammatory lesions, the authors could not find
both microbes constantly; P. acnes might be found sin-
gly. They interpreted this finding as an increased hardi-
ness of P. acnes, S. albus being eliminated by the mopping
up defenses of the host. As the severity of the lesions in-
creases, P. acnes tends therefore to be preponderant.
Moreover, since all acne lesions regress, Shehadeh and
Kligman [237] postulated ‘a dynamic sequence of a
changing host-parasite balance in which the bacteria will
gain a variable numerical strength in the beginning and
will eventually succumb as the healing forces become as-
cendant’.
Whereas yeasts and cocci were considered as bystand-
ers only, the pathogenic role of P. acnes was reinforced
by numerous works. Izumi et al. [238] confirmed the
presence of P. acnes in comedones either open or closed.
The density of P. acnes was higher in closed ones prob-
ably because of a greater hydratation and lower oxygen
tension. They observed a decrease in P. acnes in pustules
and hypothesized its rapid phagocytation after the com-
edo bursts [238]. Kirschbaum and Kligman [239] exam-
ined whether P. acnes could proliferate in certain cysts
and provoke their rupture. The cysts of 3 patients inject-
ed with P. acnes remained quiescent for a week before
they became tender, swollen and reddened. Regarding
comedo as a cyst-like lesion which contents are similar,
the authors speculated that its transformation into a pus-
tule or nodule might be the consequence of a ‘sustained
bacterial multiplication’ of P. acnes [239]. This did not
happen when cocci were injected and comedones in-
duced in humans by topical application of coal tar that
harbor very few P. acnes did not undergo inflammatory
breakdown.
Considering that the ‘heavy fall of papers has even
seemed to obscure the outlines of the subject’, microbi-
ologists enumerated bacteriological certainties: crowds of
P. acnes accumulate in the follicle at the onset of comedo
formation; patients with severe acne have higher than av-
erage counts of both groups of organisms on the forehead
skin; all comedones contain both C. acnes and aerobic
cocci; there are more diphtheroids than cocci in both
open and closed comedones; closed comedones have sig-
nificantly more P. acnes than open ones; the colonization
of comedones by P. acnes is responsible for rupture and
incitation of inflammatory lesions; aerobic cocci and P.
acnes are present in equal numbers in pustules; the excess
of P. acnes in a closed comedo fails to maintain itself dur-
ing the change to a pustule; antibiotics that suppressed P.
acnes or reduced the free fatty acids also moderate acne
[240]; a high correlation exists between P. acnes and se-
Acne Pathogenesis: History of Concepts
bum production which suggests that the increased sebum
would provide a better environment for the development
of P. acnes [241]; P. acnes is rare in children from 1 to 8
years of age, a time when sebum production is low; on the
scalp and face characterized by the presence of large se-
baceous glands and high levels of sebum, there is virtu-
ally 100% colonization of the follicles by P. acnes [242].
Finally P. acnes was regarded as ‘the only serious candi-
date for a leading role in acne’ [43], although its exact role
remained controversial [243–245]. As far as D. folliculo-
rum was concerned, there was not enough evidence to
support the idea that it controls the C. acnes population
[245, 246].
Although there could be little doubt on the pathogen-
ic role of P. acnes, its mode of action that was not ex-
plained only by its presence and number in the acne le-
sions remained highly controversial. Leeming et al. [247]
could not find the microorganisms associated with acne
in more than 10% of closed comedones and more than 7%
of open ones. They concluded that the presence of micro-
organisms is not a prerequisite for comedo formation
[247]. Holland et al. [82] suggested that microorganisms
may cause inflammation in acne by changing their pro-
duction levels of inflammatory agents as an adaptive re-
sponse to survive. An overproduction and reduced
sloughing of keratin to form a microcomedo would be the
initial environmental change activated by intrinsic fac-
tors of the host. The microcomedo may become inflamed
and another environmental shift produced. A microenvi-
ronmental change in a follicle could affect the microbial
ecology such as proportions of propionibacteria, staphy-
lococci and P. ovale [82].
In this context of uncertainties about the role of P.
acnes, its impact was regarded not dependent on its inva-
siveness but on its products [248]. Kligman [43] stressed
the fact that P. acnes produces comedogenic substances
whereas Puhvel et al. [249] viewed P. acnes as an allergen.
Holland et al. [250] showed that oxygen tension and pH
have an effect on the physiology of P. acnes in producing
more or less or no exoenzymes (lipase, hyaluronidase,
proteases) and soluble antigens. Finally they concluded
that in any follicle the environment is not constant there-
fore a continually shifting in the physiology of bacteria
may be predicted. Moreover, as the changes of one follicle
may be different from another, the differences may ex-
plain why some follicles develop acne whereas others do
not [250].
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 Epilogue
Regarded in the 1890s as the actual cause of acne, seri-
ously questioned from the 1910s due to its presence in
healthy skin, then reawakened in the 1950s in the context
of the antibiotics efficacy, again subject of a great matter
of attention from the 1970s, P. acnes and its role on the
acne pathogenesis seemed to evolve in a ‘love-hate rela-
tionship’ [251].
Since the 2000s the community of acneologists has
adopted a common position with regard to the role of
P. acnes: acne is not a bacterial disease, P. acnes is not the
cause of acne, bacteria only played one part in the multi-
faceted process of acne [252]. In this context, some der-
matologists pointed out the contrast between the ‘current
scientific opinion generally (that) views the cutaneous
microflora as of secondary importance (and) the pharma-
ceutical industry (that) continues to develop acne thera-
pies with antimicrobial activities’ [253].
The activities of different strains of P. acnes, its inter-
vention in the innate cutaneous immunity, the knowl-
edge of its genome and the biofilm theory have provided
innovative pathogenic views. It was shown that the
dominant P. acnes type I observed in the severest acne
cases produces higher quantities of butyric and propi-
onic acids than other biotypes of P. acnes suggesting that
different stains may have different proinflammatory
profiles and be therefore responsible for the develop-
ment of various forms of mild, severe or even no acne
[254]. The publication by Fitz-Gibbon et al. [255] that
different P. acnes strain populations exist in acne in
comparison with healthy skin was accepted as an excit-
ing possibility and stimulated controversies that en-
riched the history of the relationship between P. acnes
and acne [255–257].
The elucidation of the complete genome of P. acnes
strain KPA171202 has allowed to validate many of the
previous speculations [258, 259]. It has confirmed the
existence of P. acnes lipases and various enzymes by
which P. acnes may damage the follicular wall. According
to its genomic composition P. acnes is also capable of
elaborating stress proteins created by the rapid prolifera-
tion of the microbe during puberty. The P. acnes genome
contains genes encoding for various features of porphy-
rin synthesis that may accelerate squalene oxidation and
therefore lower the oxygen tension in the sebaceous fol-
licle, thus favoring colonization of P. acnes. The genome
deciphering supports the existence of a biofilm the aim
of which it would be to form a protective exoskeletal bar-
rier that preserves proper oxygen tension, promotes quo-
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DOI: 10.1159/000364860
rum sensing and limits the effective antimicrobial con-
centration within the biofilm [260]. The latter fact could
explain why prolonged antibiotic therapies are required
to clear acne. The biofilm would also account for the ob-
servation that the association of benzoyl peroxide and
antibiotic is usually more efficient than antibiotic alone.
Moreover genomic loci have been identified from a num-
ber of potential antigens, then justifying the use of anti-
biotics in an ultralow dose which have activity of block-
ing the immune system [261]. However, despite the evi-
dence brought by the genome deciphering, the fine
degree of resolution ‘only begins to satisfy Koch’s postu-
lates’ [262].
The interaction of P. acnes and antimicrobial pep-
tides has been emphasized although their exact role, ei-
ther beneficial or detrimental, remains unclear [263].
P. acnes extracts seem able to modulate the differentia-
tion of keratinocytes by inducing integrin and filaggrin
expression on keratinocytes [264]. The production by
P. acnes of tumor necrosis factor-α, IL-1α and IL-8, the
inflammation triggered through Toll-like receptor-2 is
considered to play an important role in acne pathogen-
esis [265]. Recently IL-17 has been demonstrated to be
induced by P. acnes and expressed in acne lesions sug-
gesting that Th17 cells present near the pilosebaceous
follicles may also have a role in acne pathogenesis. The
use of vitamins A and D that inhibit the induction of IL-
17 by P. acnes cells was suggested as a treatment of acne
[266].
Besides its proinflammatory characteristics, P. acnes
increases in vitro epidermal proliferation that can be
mediated through the IGF-1. P. acnes also stimulates the
production of sebum via the corticotropin-releasing
hormone [267]. Interactions with other markers of in-
nate immunity have been recently underlined, such as
protease-activated receptors or matrix metalloprotein-
ase, that may play a role in the chronic evolution of acne
lesions.
Qin et al. [268] provided evidence of the role of P.
acnes in the inflammatory phase of the acne sequence by
triggering the activation of the NLRP3 inflammasome – a
cytoplasmic molecular complex that initiates inflamma-
tion upon sensing pathogen – and finally enhancing IL-
1β secretion, therefore leading to new expectations in
acne treatment [269]. However, despite these new ways
of understanding, ‘how and if P. acnes influences the de-
velopment and perpetuation of acne lesions remains un-
clear at this stage’ [270].
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 Inflammation: Evolving Actor in Acne Pathogenesis
From the early descriptions, the polymorphism of mix-
ing noninflammatory and inflammatory lesions was con-
sidered as essential to the clinical diagnosis of acne. For
Cazenave (1795–1877) [271] and the French willanists
until the end of the 20th century, acne was defined by its
elementary lesion, a pustule, even though the comedo was
essential to the diagnosis. Rayer (1793–1867, Paris) [272],
author of a masterpiece treatise that emphasized an anato-
mophysiological approach to skin diseases, also consid-
ered acne as a ‘chronic inflammation of the sebaceous fol-
licles (…) characterized by isolated pustules, located on
the back and chest, more seldom on the face, followed by
violin spots, or whitish indurated tubercles mixed with
sebaceous cysts and follicular papules’ (transl. G. Tilles).
As for the mechanisms that cause inflammation, infec-
tion, sebum retention, foreign-body reaction and micro-
bial hypersensitivity were hypothesized.
Infection of the Pilosebaceous Follicle, Cause of
Inflammation
According to Unna the ‘bacilli’ were the unique cause
responsible for the inflammatory process: ‘In case of
closed comedo the suppuration does not proceed from
the bacilli in the comedo but from those in the supracom-
edonal horny layers. A bacillogenic impetigo is created
and secondary on it a slight pericomedonal suppuration
appears which extends more or less deeply. (…) If the
comedo is open, the suppuration assumes much greater
dimensions. One can distinguish two cases, folliculitis
pustulosa superior and inferior, according to whether the
suppuration begins with an impetigo or is induced by a
collection of bacilli underneath the comedo in the hair
follicle or sebaceous gland. In all cases the abscesses are
always limited to the follicle and do not extend like the
staphylogenic suppurations due to the differences in the
behavior between the microorganisms. (…) In the slight-
est cases only the comedo is thrown off and every reason
for further suppuration being removed the skin returns
to normal and comedo may again be formed in the same
follicle. If all follicular epithelium is destroyed, we have a
simple granulation and a deep-sunken scar in the place of
the follicle. If several suppurated follicles run together,
they form a single larger cavity which retracts in the scar
formation’ [273].
Whereas Unna considered that inflammatory lesions
are the consequence of the infection by a single micro-
Acne Pathogenesis: History of Concepts
organism, in Sabouraud’s model the acne inflammatory
lesions are not provoked by the microbacillus but by a
staphylococcal infection. ‘The top of the comedo that
looks like a chimney is always secondarily infected with
microbial colonies that have no relationship with the pri-
mary one made of microbacilli. The staphylococcal colo-
nies are the starting point of the infections that constitute
the polymorphous acne. They are located around the fol-
licular ostium that never invades the comedo. Initially the
staphylococcal infection will create a mild inflammation
on the top of the comedo that leads to a papule. Then due
to the leukocyte inflow, the papules will evolve into pus-
tules. When the staphylococcal colonies extend inside the
comedo and under its lower extremity, the infection
causes abscesses’ [274] (transl. G. Tilles). In summary,
once formed, the comedones can be the target of second-
ary infections that constitute the polymorphous acne:
papules centered by the ostium, pustules constituted
around the bacterial colonies as foreign-body reactions,
abscesses when staphylococci penetrated inside the com-
edo or between the comedo and the follicular wall and
nodules depending on the deepness of the infection [275].
However, wrote Sabouraud, when seborrhea is intense no
secondary infection will occur; the microbacillus pre-
vents secondary infections. In some pustules no microor-
ganism other than microbacilli can be shown joining Un-
na’s statement on the responsibility of microbacillus as
the unique microorganism found in comedones.
The severity of the inflammatory disfiguring lesions
incited early 20th century dermatologists to treat them
with the X-rays supposed to act by destroying hairs in-
volved in the acne process and to cause atrophy of the
sebaceous glands. The procedure was even regarded by
some authors as the best treatment notably for the sever-
est cases of acne vulgaris [276]. After X-rays applied to
inflammatory lesions of acne, Hahn (Hamburg) [277] ob-
served ‘the pustules dried and the skin remains smooth
and beautiful’ (transl. G. Tilles). Pusey (1865–1940, Chi-
cago) [278] after treating 11 patients afflicted with intrac-
table acne concluded enthusiastically that ‘the results are
so direct and so constant in all of the cases that I think
there is little room for doubt that they must be attributed
to effects of the rays. (…) The method is an advance over
any other way of treating acne with which I am acquaint-
ed.’ The same year Campbell [279] declared that ‘the uni-
formity of the results obtained is conclusively shown to
be due to the effect of X-ray light’. The X-ray therapy of
acne was used until the 1970s when the physicians real-
ized that the hazards associated with this therapy includ-
ing thyroid cancers far outweigh the gains [280, 281].
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 Inflammation: A Foreign-Body Reaction
According to Biett (Paris) [282], Willan’s French dis-
ciple, the sebaceous duct filled with sebum provokes an
inflammation clinically visible as a pustule on the top of
the follicle. Cazenave and Schédel [283], Biett’s pupils,
confirmed their master’s view and described a ‘small oval
body made of sebaceous concrete matter’ (comedo) that
could be seen inside few pustules. However, they denied
the fact that comedones evolved constantly into pustules.
Like Rayer [284] they actually considered this occurrence
only as a complication. Virchow (1863) quoted by Hebra
considered acne as an inflammatory disease consequence
of the sebaceous retention in the sebaceous duct, the va-
riety of the lesions depending on the effects of the inflam-
mation on the surrounding tissues. Kaposi (1837–1902)
[285], Hebra’s successor in Vienna, also regarded the ir-
ritation caused by the sebum remaining in the sebaceous
gland or duct as the actual cause of acne. Duhring (Phila-
delphia) [286] also asserted that ‘the first stage of the acne
pustule consists in retention of the secretion’.
Contrasting with his contemporaries who considered
the inflammatory lesions as consequences of the comedo-
nes, Alibert [287] described comedones, either open (var-
us comedo vel sebaceus) or closed (varus miliaris vel fron-
talis), not as the cause of inflammatory lesions but as ‘the
result of the chronic inflammation inside the sebaceous
ducts’.
The pioneer in the histopathology of acne Cornil [288]
described the inflammation limited to the follicle ob-
structed by a plug made of epidermal cells. Then, suc-
ceeding the occlusion, the ‘lining that formed the inner
wall of the follicle has in some places disappeared. In the
dermis around the follicles are dilated blood vessels and
a great quantity of lymphoid cells’ (transl. G. Tilles).
Cornil, like Bazin (1807–1878, Paris) [289] before him,
considered that sebaceous glands had no part in the initial
pathogenic sequence.
Three mechanisms were hypothesized to explain the
transformation of noninflammatory to inflammatory le-
sions: the horny plug like a foreign body is responsible for
an ‘irritation’ in the dermis; external microorganisms or
toxic substances entering the follicle cause a pustular
perifolliculitis; drugs or microbes circulating in the blood
may be eliminated through the sebaceous glands. Leloir
and Vidal [290] actually favored the chemical alterations
of sebum that might enhance the irritation caused by the
comedo as a foreign body. Consequently the surrounding
dermis would enflame, a perifollicular inflammation ap-
pear and the comedo become a pustule that can evolve
30 Dermatology 2014;229:1–46
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into nodules in case of intense inflammation. They con-
firmed Cornil’s observations on the pus inside the follicle
coming from the surrounding dermis through a breach of
the internal wall of the follicle. Finally, concluded the
French authors, the follicles are entirely surrounded by
suppuration that causes the destruction of the follicle and
the sebaceous gland. Therefore when pressing a pustule
some sebaceous matter may appear followed by few drops
of pus [290].
Besnier and Doyon (Paris) [291] shared the hypothe-
ses of Leloir and Vidal [290] on the cause of the inflam-
mation that could come from outside (tars) or from in-
side (unknown substances or toxic substances, bromines,
iodine) eliminated by the epidermis but not by the seba-
ceous glands. They regarded the role of the sebaceous
gland as secondary or even invalid.
In the mid 20th century the origin of the inflammatory
lesions still involved the same actors: microorganisms, ob-
struction of the follicle, rupture of the follicular wall and
finally destruction of the follicle. Lynch [292] was proba-
bly one of the first to suggest that ‘the inflammatory phase
of the acne papule can arise without apparent rupture of
the follicle and without demonstrable bacterial invasion of
the follicle wall, the glands or the connective tissues’.
Commenting the statement of Lynch, Sulzberger (cited in
Lynch [292]) suggested that several mechanisms might be
involved in the genesis of inflammatory lesions: the con-
tent of the follicle passes through the epithelium to the
dermis, the lipids and substances derived from microor-
ganisms infiltrate the dermis, the inflammatory reaction
is therefore a response to this infiltrating material; the de-
struction of the follicle wall due to the pressure of the plug
leads to the creation of other products which act as foreign
bodies; plugging and atrophy of the follicle may prevent
normal excretion of material, ‘damming up material
which normally passes into the follicular orifice from the
cutis’; this material may be gathered around the follicle
producing an inflammatory reaction.
Strauss and Kligman [66] made the pathogenesis of the
inflammatory lesions more clear. According to them small
breaks occur constantly in the sebaceous follicle through
which the leakage of sebum causes the liberation of lipoids
and horny material into the surrounding dermis provok-
ing a foreign-body reaction that leads to inflammatory le-
sions, papules or pustules. In fact, for Kligman’s school,
‘acne (…) begins with the comedo; all the other lesions are
subsequent to the breakdown of the comedo. (…) Acne
becomes an inflammatory process when the comedo rup-
tures. (…) The severity of the inflammatory lesion is di-
rectly correlable with the extensiveness of the rupture.’
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However, Kligman [22] wrote: ‘Rupture is not a conse-
quence of simple pressure. (…) What seems to happen is
that a pocket of neutrophils collects along the border usu-
ally in a quite circumscribed focus. The epithelium is leaky
at that point and chemotactic substances escape. Neutro-
phils invade the epithelium inducing spongiotic changes
which eventuate in cellular degeneration. Granulocytes
pour through the gap and spread out on the inner surface
of the comedo. If this tide is stemmed, the breach will re-
main localized and will soon be patched. Whether the rup-
ture is large or small, the inevitable result is a variable in-
tra- and extrafollicular abscess. (…) Partial ruptures take
the clinical form of pustules. (…) In case of massive rup-
ture of the comedo, its content literally becomes extruded
into the tissue, a foreign mass in the dermis. A violent in-
flammatory reaction ensues provoking a tender, intensely
red papule or even a nodule.’ A several-month study by
serial photography of the progression of comedones in a
male adolescent with untreated acne showed the transfor-
mation of open and closed comedones into inflammatory
lesions, papules and pustules [293].
Finally Plewig and Kligman [294] proposed a complete
sequence from comedo to inflammatory lesions: ‘The col-
lapse of the comedo gives rise to the deep-seated, long
lasting papule. (…) The comedo core is not often dis-
charged to the surface and remains within the tissue as a
foreign body. (…) A foreign-body granuloma is provoked
within a week or so and then makes many weeks and
months to resolve.’ Pustule ‘represents a partial break-
down of the comedo. (…) Usually the roof of the pustule
bursts, allowing pus to escape. (…) What happens to the
comedonal core? Fortunately, it is usually not extruded
into the dermis. (…) if extruded however, granulocytes
partially liquefy and disperse the horny matrix. Hydro-
lytic enzymes of the granulocytes attack corneocytes and
break them down. (…) Two outcomes have been ob-
served excluding serious scarring: the epithelium may re-
sume the production of coherent corneocytes; the com-
edo then continues its growth after a brief inflammatory
interlude. Thus the secondary comedo is born. Re-encap-
sulation inevitably results in the variable enlargement of
the lesions. The sebaceous follicle may be reconstituted
usually after with some distortion in architecture. (…)
The comedo’s life is terminated. This is probably the
more usual outcome.’ Nodule ‘represents the total disin-
tegration of the comedo with far-flung consequences.
Two or more adjacent comedones often break down and
fuse to create these monstrous lesions. (…) The nodule is
a volcanic eruption which destroys a large surrounding
territory’ [294].
Acne Pathogenesis: History of Concepts
Inflammation: An Immune Response to P. acnes
Although Kligman insisted on the role of neutrophils as
primary cells around the follicular wall, which cells arrived
first to the follicular rupture was a controversial matter.
Lynch [292] and Vasarinsh [295] considered the lympho-
cytes as the initial cells in the inflamed site. Intradermal
injection of P. acnes provokes an inflammatory reaction
suggestive of cell-mediated delayed allergy [250]. A de-
layed type hypersensitivity was also suggested by Kersey et
al. [296] who performed skin testing by using heat-killed
P. acnes in acne patients. The intensity of the response was
correlated with the severity of acne [296]. For Norris and
Cunliffe [297] the infiltrates were mainly lymphoid in the
6- and 24-hour biopsies of inflammatory lesions. Poly-
morphonuclear leukocytes were predominant only at 72 h
and associated with the follicular rupture. They hypothe-
sized that the patient with acne develops a ‘contact sensi-
tivity’ to an antigen (P. acnes or keratin breakdown prod-
ucts) within his own sebaceous duct [297]. However, the
histological changes in inflammatory lesions were not
consistent with a delayed type hypersensitivity [298].
Anti-P. acnes antibodies in acne patients were sup-
posed to contribute to the intensification of the inflam-
matory response after the release of P. acnes antigens into
the dermis following the rupture of comedones [299].
Observing large numbers of P. acnes contained in the fol-
licular ducts, Cunliffe [180] suggested that optimal envi-
ronmental conditions would produce low-molecular-
weight substances that diffuse into the dermis and provoke
inflammation by stimulating chemotaxis and activation
of the alternative complement pathway.
Epilogue
Contrasting with the approach that considered in-
flammation as the end of the acne sequence, since the
2000s immune-mediated inflammatory processes have
been regarded as the initial step of acne pathogenesis, re-
sponsible for the initiation of the acne lesions and for
their resolution [300]. In this respect acne is even viewed
as a ‘genuine inflammatory disease’ that deserves to be
treated by anti-inflammatory therapy [132].
Inflammation is now supposed to be essentially pro-
duced by an immunological reaction to P. acnes. Investi-
gators actually insist on the involvement of P. acnes in the
adaptive response. An interaction of P. acnes and Lan-
gerhans cells at the lower infrainfundibulum is suggested
[301]. Numbers of CD4+ T cells and macrophages that
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might stimulate the pilosebaceous vasculature were found
elevated in the perifollicular and papillary dermis. Neu-
trophils were not observed in the infiltrate [302].
Moreover Toll-like receptor-2 expression was dem-
onstrated within acne lesions particularly in perifollicu-
lar regions and the quantity of Toll-like receptor-2-pos-
itive cells detected increased with the age of the acne le-
sions [190, 303]. P. acnes has been shown to stimulate
IL-1α production from keratinocytes. Cytokines secret-
ed by follicular keratinocytes and sebocytes would dif-
fuse through the follicular wall even before the rupture
of the canal. Then after the rupture, keratin, hair and
lipids from the sebum initiate inflammation and a for-
eign-body reaction. In this sequence the release of IL-1α
from ductal keratinocytes seems to be an early event of
the acne pathogenesis suggesting that P. acnes may pro-
mote hyperkeratinization [181]. This hypothesis is sup-
ported by the finding of IL-1α-like material in open com-
edones. Moreover, the addition of IL-1α in the follicular
infundibulum in vitro results in hyperkeratosis similar to
that seen in comedones. The effect can be inhibited by
antibody-blocking IL-1 receptors [304]. P. acnes would
also trigger production and release of antimicrobial pep-
tides from keratinocytes, monocytes, neutrophils and T
cells in the perifollicular region where P. acnes resides.
These products provoke the inflammation of the sur-
rounding dermis resulting in tissue and microbe de-
struction [305].
Although they considered inflammation as the leading
stage of the acne sequence, Williams et al. [25] pointed
out the fact that what triggers acne remains unclear.
Twenty-seven years previously, Kligman [22], major ac-
tor in the history of acne, had anticipated the question
and proposed an answer: ‘Many aspects of the disease
have been looked into by highly trained specialists each
searching to uncover the etiologic forces which underlie
the disease. Bacteriologists have pursued bacteria, endo-
crinologists have measured hormone levels, biochemists
have studied sebaceous lipids and various aspects of cu-
taneous metabolism, psychiatrists have looked into emo-
tional derangements, histochemists have examined en-
zymes and microscopists have offered mechanistic expla-
nations. Much has been learned but the secret of acne has
not been revealed. This may be very well because there is
no answer to the question that has generally been asked.
So far nothing has been found that really distinguishes the
acne patient. The search for ‘‘the’’ cause of acne is in fact
a futile and misguided enterprise. No organism, no enzy-
matic or metabolic deficiency, no abnormality in blood
or tissue lipids, in fact nothing is likely to be discovered
32 Dermatology 2014;229:1–46
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that is unique to acne in the sense that individuals who
are not invaded by the tubercle bacillus absolutely cannot
develop tuberculosis.’
From Vitamin A to Isotretinoin: Innovative Views on
Acne Pathogenesis and Treatment
The history of the biology of vitamin A started in 1909
with the isolation from egg yolk of a fat-soluble extract
essential for life. Later named vitamin A, its first synthesis
was reported in 1937 [306]. The use of vitamin A (retinol)
in acne started in the 1940s when Straumfjord [307]
claimed that the daily administration of 100,000 USP
units of vitamin A for periods from 9 to 18 months re-
sulted in the disappearance of the lesions in almost every
treated patient. Impressed by the results, Obermayer and
Frost [308] tried to repeat Straumfjord’s experiment.
They could only state that vitamin A is beneficial in some
forms of acne while others did no respond. They consid-
ered the positive results plausible because ‘the pathologi-
cal feature (of acne) is identical with the hyperkeratosis of
the pilosebaceous follicle seen in avitaminosis A’ [308].
Lynch and Cook [309] were less convinced by the value
of vitamin A in acne. Whereas some patients had satisfac-
tory results others became worse after the treatment had
been stopped. They wondered whether the results were
the effects of psychotherapy [309]. Three years later, Sa-
vitt and Obermayer [310] conducted a placebo-controlled
study on patients with mild to moderate forms of acne.
Due to the small number of control subjects, the authors
could not demonstrate a therapeutic efficacy of vitamin
A [310].
In the 1960s tretinoin (all-trans-retinoic acid) became
available. In 1959, Stüttgen had recognized the pharma-
cological activity of tretinoin. In 1962, he published its
effect on patients with ichthyosis, pityriasis rubra pilaris
and on 2 acne patients topically treated. He reported the
keratolytic action and irritation occurring after few days
[311]. The same year, Beer [312] published a study in
which systemic and topical treatment were given to 53
patients, 20 of them suffering from acne. The acne pa-
tients did not respond [312]. ‘In 1963, at a staff conference
at the University of Pennsylvania, Kligman observed that
the skin of a patient treated for ichthyosis had turned red
and was peeling. Thus, he extrapolated that tretinoin
would make a useful acne medicament. He was the scien-
tist who truly discovered the benefits of tretinoin in acne’
[28]. In 1971, Schumacher and Stüttgen [313] reported
the effects of oral and topical vitamin A acid in keratin-
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izing dermatoses and acne. They observed a clearing of
comedones and pustules. On electron microscopy, Plewig
and Braun-Falco [314] showed that hyperkeratosis de-
creases as a result of epidermal cell proliferation.
In Kligman’s model on comedogenesis, treating the
hyperproliferation and hypercohesiveness of keratino-
cytes was regarded as the ideal solution. Kligman et al.
[315] proposed to deliver tretinoin (vitamin A acid) top-
ically to the acne lesions. They observed that the drug
had not the antikeratinizing action originally suspected.
It inhibited the synthesis of tonofilaments, promoted the
detachment of desmosomes and therefore decreased cell
cohesion, made the follicular microclimate more aero-
bic and less hospitable to P. acnes and accelerated the
turnover of keratinocytes leading thus to thinning of the
horny layer [316, 317]. Finally they claimed that ‘no oth-
er drug matches the comedolytic action of tretinoin’, re-
garded as a first-line treatment for acne vulgaris [318].
Woo-Sam [319] confirmed the loss of cohesion and des-
quamation produced by topical tretinoin in experimen-
tally induced comedones in the rabbit ear. More recent-
ly Kligman [320] was surprised to observe that twice dai-
ly applications of 0.05% tretinoin cream for 8 weeks
reduced sebum production by about 25%. He also
showed that spot applications lead to rapid resorption of
inflammatory lesions [320]. Contrasting with Kligman’s
view on topical tretinoin, other authors were less enthu-
siastic. Peachey and Connor [321] using 0.1% retinoic
acid lotion pointed out the unacceptable level of erythe-
ma and peeling probably because the concentration of
retinoic acid was too high. In fact dermatologists in favor
of topical tretinoin underlined the necessity of the pa-
tient’s co-operation in order to manage the irritant reac-
tions of the drug. Finally, topical vitamin A acid therapy
became the mainstay of acne therapy influencing des-
quamation of abnormal epithelium, altering the micro-
climate of microcomedones, resolving mature comedo-
nes, preventing new lesions and enhancing penetration
of other drugs [322].
Adapalen followed tretinoin and reflected ‘the princi-
ples of a logical transition of scientific skills from the lab-
oratory to the clinic’. Cunliffe [323] underlined its reti-
noid function with respect to its antiproliferative effect on
corneocytes and its anti-inflammatory action reflected by
its lack of a primary irritant dermatitis.
In 1975 Stüttgen et al. [324] and Stüttgen [325] ob-
tained good results on acne patients treated with doses of
oral tretinoin associated with side effects which limited
the administration of the drug.
Acne Pathogenesis: History of Concepts
Systemic treatment with 13-cis-retinoic acid (isotreti-
noin) – its synthesis was achieved in 1955 – for the treat-
ment of skin diseases (psoriasis) was first published in
Europe in 1973 [326]. Hartmann and Bollag [327] have
related the circumstances that led to its use in acne.
The 1970s: Turning Point in the History of Acne
Management
‘Although vitamin A and vitamin A acid had shown
good effects in mild to moderate acne and disorders of
keratinization, their clinical oral use was restricted, main-
ly because of side effects, particularly the severe headache
associated with vitamin A acid. Therefore in 1968 a chem-
ical synthesis program was started in our laboratories
with the aim of finding compounds structurally related to
vitamin A or all-trans-retinoic acid with a better disso-
ciation between side effects and therapeutic efficacy. In
1969, Werner Bollag discovered that 13-cis-retinoic acid
was such a compound. (…) clinical studies in acne pa-
tients were initiated soon thereafter in Europe. These ear-
ly studies were carried out by H. Eichenberger in Zürich
(17 cases), E. Meyer-Latzke in Berlin (23 cases) and W.
Vollrath in Bonn-Bad Godesberg (50 cases). The results
of these trials were very encouraging. Daily doses between
5 and 20 mg given for 12 weeks resulted in good to excel-
lent responses in about 80% of all cases including the se-
vere cystic forms of acne’ [327].
The first US study in acne patients published in 1978
constituted a definite turning point in the dermatological
practice and in the acne patient’s daily life. Isotretinoin
was given orally to patients suffering from Darier’s dis-
ease, lamellar ichthyosis, pityriasis rubra pilaris, basal cell
carcinoma and to 14 patients with cystic or conglobate
acne who completed a 4-month course of treatment. Ten
of them had complete resolution and maintained a pro-
longed remission 8 months after discontinuation of ther-
apy. As far as the mechanisms by which the drug acts are
concerned, the investigators suggested that it might be
related to the ability of vitamin A to affect glycoprotein
synthesis and epithelial differentiation [328].
A year later Peck et al. [329] reported the results of
isotretinoin given to patients with treatment-resistant
cystic and conglobate acne. The title of the article under-
lined the 2 main features of isotretinoin: its efficacy and
the prolonged remissions after the treatment had been
stopped. Out of 14 patients treated with 2 mg/kg, 13
experienced complete clearing of the disease. The other
had 75% improvement. Remissions lasting as long as 20
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months after the treatment had been discontinued were
observed in all patients. The authors hypothesized that
the drug might be stored in the sebaceous glands. Three
biopsies during treatment revealed a reduction in seba-
ceous gland size and an inhibition of sebaceous differen-
tiation. Sebum production in a few patients was decreased
by as much as 90%. They suggested that the inhibition of
sebum might be one of the mechanisms responsible for
the prolonged remissions. However, these changes re-
turned to normal after discontinuation of the treatment.
The skin surface lipid composition observed during treat-
ment was similar to that expected before puberty. The
authors underlined the fact that no other drug than 13-cis-
retinoic acid had inhibited sebum production to the ex-
tent necessary for an alteration of the skin surface com-
position [329].
Jones et al. [330] confirmed these spectacular results
and summarized the evidence: reduction of sebaceous
gland size on histological examination, replacement of pi-
losebaceous units by an epidermal cord in some cases,
excessive scaling in all patients, reduction of the nonin-
flamed lesions. The same year Farrell et al. [331] treated
patients suffering from severe, treatment-resistant, nod-
ulocystic acne with 13-cis-retinoic acid either 0.1, 0.5 or
1.0 mg/kg daily for 12 weeks, in a double-blind study. A
clinical improvement was noted in all treated groups
which persisted into the posttreatment period. No statis-
tical difference between the groups was observed [331].
Peck [332] concluded that the results of isotretinoin
orally given to acne patients are ‘striking in several re-
gards’: patients experienced complete clearing; patients
who had not shown complete clearing at the end of the
4-month treatment continued to heal after discontinua-
tion of the drug; prolonged remissions lasting an average
of 30 months had been observed; the isotretinoin effect
was not a placebo response; side effects resulting from
drying skin and mucous membranes were currently ob-
served; teratogenicity shared by all retinoids contraindi-
cate isotretinoin prescription in women of childbearing
age without contraception.
In the 1980s a series of clinical investigations set both
in Europe and the USA confirmed the promising results of
isotretinoin in acne. In May 1981 a workshop on oral reti-
noids in dermatology was held in Iowa City. Several com-
munications were devoted to the dramatic effects of oral
synthetic retinoids on sebaceous glands and acne [333]. A
year later a special issue of the Journal of the American
Academy of Dermatology reported that the impact of reti-
noids in dermatology was to be regarded similar to that of
topical corticosteroids [334]. Isotretinoin orally adminis-
34 Dermatology 2014;229:1–46
DOI: 10.1159/000364860
tered was approved by the Food and Drug Administration
in 1982 for the treatment of severe cystic acne and 1 year
later in Europe. An international symposium held in Ge-
neva in 1984 expressed the same enthusiasm about the
therapeutic possibilities promised by these drugs [335].
The dramatic efficacy of isotretinoin was confirmed by
all investigators, the range of healing varying from 70 to
100% of the patients [336–338]. In a multicenter study on
150 patients with treatment-resistant nodulocystic acne,
Strauss et al. [339] obtained the same clinical improve-
ment for all groups studied whatever the dosage em-
ployed (0.1, 0.5, 1 mg/kg). The differences between side
effects and laboratory abnormalities were minor [339].
Investigators recommended that patients with severe
acne should be given a dose of 1.0 mg/kg/day for 4 months
[340]. It was suggested that a daily dose superior to 1 mg/
kg did not enhance the efficacy whereas it provoked more
side effects [341].
Cunliffe and Norris [342] investigated the factors that
predeterminate the outcome to treatment with isotreti-
noin: younger patients responded less well than older
ones, subjects with more truncal acne fare less well than
those with facial acne, a return of the reduced sebum ex-
cretion rate to within 10% of the pretreatment level was a
poor prognostic factor.
The monograph published by Harms [343] in 1989 re-
flects the knowledge and her own experience on isotreti-
noin 10 years after its first use in acne. The isotretinoin-
treated patients experienced the first side effects (cheili-
tis) and the decrease in seborrhea a week after the onset
of the treatment. The inflammatory lesions decreased af-
ter 4 weeks, the comedones after 6–8 weeks. Patients were
cured after 3–8 months. A paradoxical flare-up the patho-
genesis of which was unknown might appear in the first
month. The side effects were numerous but in the major-
ity of cases well tolerated and rarely led to withdrawal
from the treatment. Most of the side effects, clinical and
biological, disappeared after the treatment had been
stopped. Affective disorders had been reported only once.
As far as the frequency of relapses is concerned, Harms
et al. [344] followed 89 patients for many months (mean
14 months) after the treatment had been stopped. They
first failed to find a significant relationship between the
frequency of the relapses and the total amount of isotreti-
noin administered. They suggested a possible link to sex,
the relapses occurring more frequently in males [344].
Few years later, they analyzed the relapse rate related to
the daily dose and to the cumulative dose in more than 200
patients [345]. There was no difference in the relapse rate
between patients treated with 0.5 or 1.0 mg/kg/day. They
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considered that the cumulative dose is a better indicator
to estimate the lowest relapse rate and suggested that a cu-
mulative dose of approximately 100 mg/kg might be a
threshold for a long-term efficacy [345]. The long-term
study published by Cunliffe et al. [346] 10 years after its
first use confirmed these results and the correlation be-
tween cumulative doses and relapses. Isotretinoin was
definitely regarded ‘as a supremely effective drug for acne’
[346] and deserved ‘its sobriquet as a miracle drug’ [347].
The Pathogenic Factors Targeted by Isotretinoin
One of the most spectacular features of isotretinoin,
noticed by all investigators, was its action on the 4 acne
pathogenic factors, sebaceous secretion and P. acnes hav-
ing more impact.
Sebum, Sebaceous Glands and Isotretinoin
Prior to isotretinoin, the therapy of acne was mainly
directed toward the follicular hyperkeratosis or P. acnes.
The action of isotretinoin was supported by numerous
publications that led to hypothesize that some pharmaco-
kinetic properties result in the specific targeting of seba-
ceous glands in reducing its size and sebum production
[348, 349]. Isotretinoin is actually considered as the most
potent inhibitor of sebum production.
Using male hamsters as experimental model, Gomez
[350] showed that the subcutaneous injection of isotreti-
noin provoked an involution of the sebaceous glands of
the flank without inhibiting the growth of other andro-
gen-dependent structures of the flank organ. The author
suggested that isotretinoin might act at an extrahormon-
al site rather that by an antiandrogen effect. By compari-
son, etretinate in comparable dosage did not produce the
inhibitor effect on sebaceous gland activity [350]. The at-
rophy of the sebaceous gland observed in the animal was
confirmed by Landthaler et al. [351]. The size of the seba-
ceous glands was drastically reduced after 12 weeks of
treatment. The sebaceous follicle was reduced to a ‘wick’-
like structure. Moreover, the reduction was correlated
with the total amount of isotretinoin administered which
enforced a likely relationship between the dose and the
efficacy of the drug [351]. Goldstein et al. [352] came to
similar results in a multicenter double-blind study in pa-
tients with severe nodulocystic acne. Although they ad-
mitted that the reason of the superiority of isotretinoin
over etretinate was unknown, they considered it reason-
able to suppose that the superior sebostatic action of
isotretinoin was essential [352]. Electron microscopic ob-
Acne Pathogenesis: History of Concepts
servations confirmed the alterations of the sebaceous fol-
licle entirely reduced in size. The length and width of the
follicular duct were decreased. The sebaceous acini were
dramatically affected by isotretinoin. The sebocytes bore
no sign of sebum production and no sign of keratiniza-
tion. However, Plewig et al. [353] underlined the inter-
and intraindividual variations of these alterations.
Peck et al. [354] tested the efficacy of isotretinoin versus
placebo in a double-blind protocol. The marked sebum re-
duction observed in previous reports was confirmed. Biop-
sies of lesion-free skin from 3 patients during treatment
showed a reduction in sebaceous gland size [354].
Strauss and Stranieri [355] investigated sebum pro-
duction in 20 patients in whom isotretinoin therapy had
been discontinued. They confirmed the correlation be-
tween acne improvement and sebum production. Two
patients however did not respond to isotretinoin despite
a marked inhibition of the sebaceous gland activity.
Moreover, among the patients who had clinical improve-
ment, only one half had prolonged inhibition of sebum
production. The authors therefore inferred that sebum
could not be accepted as the only cause of isotretinoin ef-
ficacy. Among the therapeutic mechanisms responsible
for clinical improvement, they hypothesized the reversal
of an abnormal pattern of keratinization in the follicular
duct, a reduction in the number of P. acnes, inhibition of
microbial enzyme activity and a direct anti-inflammatory
activity. The authors concluded that the mechanism of
action of isotretinoin remained ‘far from certain’ [355].
Due to the role of androgens in the production of lipids
by sebaceous gland cells, the action of isotretinoin on an-
drogen metabolism was explored. Isotretinoin was shown
to induce a significant decrease in dihydrotestosterone
formation in skin biopsies and a decrease in serum dihy-
drotestosterone [356].
Studying the histopathology of acne lesions after
isotretinoin orally given to 15 patients, Dalziel et al. [357]
showed a reduction of sebaceous gland tissue occurring
within the first month of treatment. Then, as a conse-
quence of its sebostatic action, isotretinoin would reduce
the rise of pressure within closed comedones that may al-
low time for dilatation of the pore so that the comedo be-
comes an open one which does usually not evolve into an
inflammatory lesion [357]. A complementary study [358]
confirmed the reduction of the sebaceous gland volume
and the decrease in the activity during isotretinoin treat-
ment. By contrast they could not demonstrate any change
in epidermal differentiation within the follicular duct
[358]. It was therefore postulated that the sebosuppressive
effect explained the isotretinoin efficiency to such an ex-
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tent that sebum measurement was considered to be the
best method to predict the potential usefulness of isotret-
inoin [359].
As far as the ultrastructure of sebaceous glands under
treatment with isotretinoin (0.5 mg/kg) is concerned,
electron microscopic examination revealed them to be
smaller than prior to treatment, a marked reduction in
the number of immature cells and no mitotic figures.
Most of the cells were mature and full of lipid droplets.
Two months after the treatment had been discontinued,
the tissues showed mostly a normal-appearing ultrastruc-
ture [360].
Not only the quantity of sebum was targeted by isotret-
inoin, but also its composition. Of 8 treated patients
Strauss et al. [361] noted an increase in the percentage of
cholesterol plus cholesterol esters and a decrease in the
percentage of squalene and wax esters. They concluded
that administration of oral isotretinoin induces changes in
skin surface lipid composition that resembled those noted
in the prepubertal age [361]. Few years later they con-
firmed these results on 16 patients with severe cystic acne
treated with oral isotretinoin 0.1, 0.5 or 1 mg/kg for 12
weeks. They noticed a marked decrease in sebum produc-
tion accompanied by a decrease in the concentration of
wax esters, a slight decrease in the concentration of squa-
lene and an increase in the cholesterol concentration.
They concluded that although nonspecific, these changes
represent the change in the contribution of the sebaceous
glands to the surface film, wax esters and squalene being
considered to be unique to sebaceous lipids [362].
The same year, Farrell et al. [363] observed that the sig-
nificant reduction in sebum secretion in the first 2-week
period was maximum by the third or fourth week of treat-
ment and was maintained throughout the treatment. Af-
ter the therapy had been discontinued, there was a rapid
increase in sebum production inversely related to the dos-
age of isotretinoin used during the treatment. The initial
improvement might be related to the reduction of sebum
secretion, the protracted remissions would not necessar-
ily be mediated through sebaceous gland inhibition. The
authors observed a significant correlation between the re-
duction of sebaceous gland activity and the decrease in the
number of cysts and their greatest diameters [363].
In conclusion investigations showed a dramatic action
of isotretinoin on sebaceous glands: reduction of sebum
excretion by up to 90% in few weeks, the effect being
maintained several months after the treatment has been
stopped; decreased proliferation of basal sebocytes and
inhibition of sebocyte differentiation [364, 365]; dramat-
ic change of the skin surface lipid composition occurring
36 Dermatology 2014;229:1–46
DOI: 10.1159/000364860
during the treatment and remaining for several months
after the discontinuation of the drug. By comparison cy-
proterone acetate-ethinylestradiol produces 65% sup-
pression; ethinylestradiol-prednisolone 55%; spironolac-
tone 45% and ethinylestradiol 35% [366]. It was finally
admitted that the antiacne effect of isotretinoin is mainly
related to its potential to inhibit the production of sebum.
Among oral retinoids, only 13-cis-retinoic acid exerts
such an effect on sebum production. The reason of this
specificity remained ‘intriguing’ [367].
The prolonged remission after the treatment had been
stopped was one of the most spectacular characteristics
of isotretinoin efficacy. In fact, a strong relationship be-
tween re-increase in seborrhea after treatment and re-
lapses was noted. However, a few patients whose sebum
excretion rate was restored to the pretreatment levels did
not experience relapses. This intriguing observation in-
cited Harms [368] to propose a new concept: the ‘hetero-
geneity of sebaceous follicles’. Few years before, Piérard
[369] had shown intraindividual and interindividual
variations on the number of active sebaceous follicles. In
fact, wrote Piérard, many of the sebaceous glands are
‘quiescent or barely active’. He had also noted that open
comedones are functionally ‘closed’ and do not partici-
pate in the excess of sebum in acne patients, supporting
the earlier observation that large open and closed com-
edones, through the regression of other sebaceous lob-
ules, contribute barely to the lipid (sebum) film of the
skin surface. For a given amount of sebum, the excretion
varied from gland to gland suggesting the existence of
‘acne-prone’ follicles. Little evidence explains however
why only 1–3% of sebaceous follicles show acne in acne-
prone people [369, 370].
Harms confirmed Piérard’s observations and suggest-
ed that after isotretinoin some initially active acne-prone
sebaceous follicles experienced irreversible atrophy, al-
though there was never proof of evidence of this hypoth-
esis. In this concept, once these follicles are destroyed by
the inflammation, acne would vanish. Harms stressed the
fact that this concept implied that only a part of the seba-
ceous follicles are acne prone and specifically sensitive to
isotretinoin.
Comedo Formation and Isotretinoin
Isotretinoin was supposed to be comedolytic through
its effect on the lipids of the intercellular cement, re-
sulting in a reduction of comedo formation or in an in-
creased separation of comedones [371]. Electromicroscopy
showed disintegration of desmosomes between the cor-
neocytes, the tight junctions lost so that the cells appeared
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separated from one another, their arrangement disrupted
by the presence of an amorphous material in the intercel-
lular spaces as observed after application of topical treti-
noin resulting in a lack of cohesion between cornified
cells [372, 373].
Melnik et al. [374] showed that oral low-dose isotreti-
noin treatment over 6 weeks reduced the amount of com-
edonal triglycerides, diglycerides, free fatty acids and
squalene, major lipids of sebaceous origin. In contrast the
relative levels of free sterol and ceramides, primarily of
epidermal origin, increased within comedones causing a
significant elevation of the ratio of free sterols and cho-
lesterol sulfate that favored corneocyte desquamation.
The authors hypothesized that the restoration of epider-
mal lipid homeostasis of the follicular epithelium due to
inhibition of increased sebaceous lipogenesis was of crit-
ical importance for the antikeratinizing activity of isotret-
inoin. They suggested that the increase in ceramides and
free sterols may improve the follicular permeability bar-
rier leading to follicular hydratation, bacterial growth and
diffusion of chemotactic factors of P. acnes [374].
From a clinical point of view, changes in the size of
microcomedones were noted during the first week of
treatment. There was an apparent increase due to a loos-
ening of the microcomedones. Finally, under isotretinoin
treatment, ‘the comedones are loosened and unrooted,
literally popping out of the follicle’ [375]. However, as
Harms [376] pointed out, the comedolytic effect of reti-
noid is not sufficient to cure acne.
P. acnes and Isotretinoin
In 48 patients treated with isotretinoin for 16 weeks,
King et al. [377] observed a significant decrease in the
aerobic and anaerobic microbial population whatever the
daily doses, although the reduction in the numbers of aer-
obic bacteria was less marked than that in the anaerobes
and yeasts. They suggested that the reduction in microor-
ganisms might be secondary to the decrease in sebum ex-
cretion and hypothesized that isotretinoin may also act
directly on microbial cells [377].
In 40 acne patients treated with isotretinoin 1.0–1.5
mg/kg daily, Leyden and McGinley [378] demonstrated a
significant reduction in levels of P. acnes within 1 month
of treatment. Like King et al. [377], the authors hypothe-
sized that the reduction of P. acnes was the consequence
of the sebosuppression that probably deprived P. acnes of
important nutrients. They observed however the persis-
tence of P. acnes reduction 6 months after the treatment
had been discontinued despite the return of sebum excre-
tion levels to a nonsignificant difference from pretreat-
Acne Pathogenesis: History of Concepts
ment levels. They could not explain this ‘surprising’ ob-
servation. They suggested that the prolonged reduction in
P. acnes may play an important role in the prolonged re-
missions seen with isotretinoin therapy. They also noticed
a steady recovery of Staphylococcus aureus from the ante-
rior nares and face. According to the authors, their results
indicated an alteration of the ecosystem of the cutaneous
bacterial flora provoked by isotretinoin [378]. Moreover,
Coates et al. [379] demonstrated a significant reduction of
erythromycin-resistant strains of P. acnes on 40 patients
receiving oral isotretinoin 1.0 mg/kg for 8 weeks.
Inflammation and Isotretinoin
Plewig and Wagner [380] using a 40% potassium io-
dide patch test in patients with severe acne treated by
isotretinoin for 12 weeks showed that all patients had a
significant clinical improvement of their disease and a re-
duction of the inflammatory reaction in the patch tests.
Lavker et al. [381] after treating patients suffering from
severe cystic acne with isotretinoin 1.0 mg/kg/day ob-
served a dramatic reduction of the cellular infiltrate with-
in 1 month of therapy. The effect occurred before the de-
crease in sebum production. They inferred that the effect
of isotretinoin might primarily reflect an anti-inflamma-
tory action. The authors however admitted that how the
inflammation is suppressed was unknown [381].
Epilogue
Initially isotretinoin was only given to subjects suffer-
ing from severe acne as the only drug offering long remis-
sions and sometimes definite cures [382]. Due to its tre-
mendous efficacy, dermatologists came to use it in less
complex situations: patients whose acne had relapsed
rapidly after discontinuation of conventional oral treat-
ment, patients whose acne had not significantly im-
proved despite many changes of therapy. In fact a con-
sensus meeting held in Brussels in 1995 considered that
oral isotretinoin should be prescribed to patients whose
acne was severe or poorly responsive (less than 50%) af-
ter 6 months with combined oral and topical antibiotics
[383].
Due to the increased number of treated patients, the
severest risks, namely suicide and teratogenicity, became
more emphasized leading to unreasonable fears notably
in the lay press and to strong constraints to the prescrip-
tion of isotretinoin.
In a short review of the publications issued during the
35 years on the relationship between isotretinoin and af-
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fective disorders, Thiboutot and Zaenglein [384] recalled
that in 1987 Rubinow et al. [385] had shown that isotreti-
noin given to acne patients might have beneficial effects
in reducing their anxiety and depression. Then a retro-
spective study on patients treated from 1980 to 1990
showed that the increased risk of suicide attempts 6
months into treatment could not be attributed solely to
isotretinoin [386]. It was suggested that patients should be
monitored for up to 1 year after treatment has ended
[387]. After reviewing all papers related to isotretinoin de-
pression and suicide, Bremner et al. [388] concluded that
the literature is consistent with an association between
isotretinoin, depression and suicide in some susceptible
individuals. In contrast, Nevoralova and Dvorakova [389]
treating 100 patients in a no-blind, no-controlled prospec-
tive study failed to find any depressive symptoms or sui-
cide risk caused by isotretinoin. They even found a sig-
nificant improvement of the Beck’s Depression Inventory
score [389]. Marron et al. [390] published similar results.
After 30 weeks of treatment of 346 patients, they could
observe a significant reduction of the negative impact on
quality of life as did the depression scale scores for anxiety
and depression [390]. Following the study of Bremner et
al. [388], Rowe et al. [391] published recommendations
prior to the initiation of isotretinoin, throughout treat-
ment and for a period following the cessation of treat-
ment: establishing the degree of the impact the patients’
acne has on their quality of life; identifying mental health
for each patient concurrently with the prescription of
isotretinoin; reducing the initial dose of isotretinoin in or-
der to alleviate the patient’s concerns about using the
medication; performing routine baseline investigations
prior to the prescription of isotretinoin; monitoring the
mental state of patients from 4 weeks after the beginning
of isotretinoin; referring to a mental health practitioner if
mental symptoms are identified [391]. Finally, the Psy-
chodermatology Group of the French Dermatology Soci-
ety considered that prescription of isotretinoin is not con-
traindicated in subjects presenting depression [392].
As a retinoid, the teratogenicity of isotretinoin was
known from the very beginning of its use. By August 15,
1983 – i.e. 4 years after Pleck’s seminal publication – 15
cases of adverse pregnancy outcome associated with
isotretinoin exposure had been submitted to the Food
and Drug Administration: 5 birth defects and 7 spontane-
ous abortions were reported [393].
Four programs have been developed in the USA to
prevent fetal exposure. In the first, Roche Inc., the manu-
facturer of the drug, provided leaflets to patients describ-
ing the teratogenic effects of isotretinoin. The second
38 Dermatology 2014;229:1–46
DOI: 10.1159/000364860
(Pregnancy Prevention Program) was also set by Roche
Inc. in 1998. It was followed in 2002 by the SMART (Sys-
tem to Manage Accutane-Related Teratogenicity) pro-
gram that mandated registration of the patients. Fetal ex-
posures continued to occur however at a lower level. The
iPLEDGE program was created in 2006 [394]. Patients –
even males – and prescribers have to register. Due to the
increased work related to these constraints, some pre-
scribers have chosen not to prescribe isotretinoin. How-
ever, fetal exposure has not decreased with the iPLEDGE
program (122 pregnancies in the first year data for
iPLEDGE vs. 120 in the first year for SMART). Leyden et
al. [395] reported that if one considers the annual number
of reported pregnancies relative to the number of females
of childbearing potential, isotretinoin-exposed pregnan-
cies were reported 0.00083% in year 3 of the iPLEDGE
program and 0.00064% in year 5. In this respect, the only
way to reduce the fetal exposure to zero would require
removing the drug from the market. Such an attitude
would leave ‘the millions of people who use this drug
without an option for effective treatment’ [396].
Less rigid than the iPLEDGE program are the European
directives set in 2006. Dermatologists have however un-
derlined the practical, clinical and financial difficulties they
produce either for patients or for physicians. They fear that
the main consequence of this program may be a reduction
of isotretinoin prescriptions that would disadvantage pa-
tients, notably those who suffer from the severest form of
acne that threatens their quality of life [397]. Finally, the
side effects of isotretinoin on pregnancy and the contro-
versies on affective disorders that have restricted its legal
prescription and possibly increased illegal purchase over
the Internet [398] may transform a revolutionary actor of
the acne management into a ‘downtrodden hero’ [399].
Acknowledgments
I thank Prof. Jacques Poirier (Paris), Prof. Jean-Hilaire Saurat
(Geneva) and Dr. Daniel Wallach (Paris).
Disclosure Statement
The author declares no conflict of interest.
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