DOI: 10.1111/j.1610-0387.2010.07513.x
`
`Review Article
`
`21
`
`The potential role of microorganisms in the
`development of rosacea
`Elizabeth Lazaridou, Christina Giannopoulou, Christina Fotiadou, Eustratios Vakirlis, Anastasia Trigoni,
`Demetris Ioannides
`First Department of Dermatology-Venereology, Aristotle University Medical School, Thessaloniki, Greece
`
`JDDG; 2011 (cid:129) 9:21–25
`
`Submitted: 26.5.2010 | Accepted: 7.7.2010
`
`Keywords
`(cid:129) pathogenesis
`(cid:129) microbes
`(cid:129) etiology
`(cid:129) Helicobacter pylori
`(cid:129) Demodex folliculorum
`
`Summary
`Rosacea is a chronic cutaneous disorder characterized by centrofacial persist-
`ing erythema, telangiectases, papules, pustules, edema, phymas and ocular
`involvement. Despite being one of the most common skin disorders, its patho-
`genesis remains unclear and controversial. Although the disease triggering
` factors are well recognized, the underlying causes of rosacea have not yet been
`identified. Several different postulates about its pathogenesis can be found in
`the medical literature. Abnormalities of the pilosebaceous unit, as well as
`genetic, vascular, inflammatory, environmental and microbial factors have been
`described. The microorganisms that have been associated include Helicobacter
`pylori, Demodex folliculorum, Staphylococcus epidermidis, and Chlamydia
` pneumonia; all the studies have been inconclusive. We review currently avail-
`able scientific data on the potential pathogenetic role of microorganisms in the
`development of rosacea.
`
`Introduction and Epidemiology
`Rosacea is one of the most common
` dermatoses, accounting for almost 1 %
`of all the skin disorders diagnosed by
`dermatologists [1]. It affects primarily
`adults of 30–60 years of age, with
`women being more often affected, espe-
`cially in the earlier disease stages [2].
`Rosacea is diagnosed on clinical manifes-
`tations and specific morphologic charac-
`teristics; there is no laboratory test to
`confirm the diagnosis.
`
`Clinical features and classification
`Either a single or a clustering of signs
`such as flushing, persistent erythema,
`telangiectasia, papules, pustules and phy-
`mas with a centrofacial distribution is
`present. Additionally, eye involvement
`with blepharitis, iritis and conjunctivitis
`occurs in a considerable percentage [3].
`
`Four subtypes of the disease have been
`recognized:
`erythematotelangiectatic
`(ETR), papulopustular (PPR), phyma-
`tous and ocular [1, 3, 4]. Erythema has
`been proposed as the main morphologi-
`cal feature [5] with all the other manifes-
`tations having a supportive role towards
`the diagnosis and designation of disease
`subtype [5]. Disease classification is of
`great importance due to the fact that the
`pathogenetic mechanisms described in
`the literature relate to specific forms of
`the disease and the therapeutic interven-
`tions are different amongst the described
`subtypes.
`
`Etiology and Pathogenesis
`There are several different factors impli-
`cated in the pathophysiology of rosacea.
`Inherent abnormalities in the cutaneous
`vascular and lymphatic system and inap-
`
`propriate responses to hyperthermia are
`mechanisms described as responsible for
`flushing [4, 5]. Solar radiation is also
` implicated through the destruction of
`cutaneous blood vessels and dermal
` connective tissue [4–7]. The presence of
`elastotic granulomas is a common histo-
`logical finding in rosacea patients and
`rosacea appears mostly in sun exposed
`areas. These facts indicate that there is a
`link between chronic sun exposure, solar
`degenerative elastosis and disease devel-
`opment [7]. There is also the dermal ma-
`trix degeneration theory suggesting that
`the disease manifestations are due to the
`poor connective tissue support for the
` facial vessels [5]. Dietary agents and
`drugs have also been implicated as trig-
`gering factors inducing disease flares,
`however the pathophysiological associa-
`tion is not clear [5]. Abnormalities of the
`
`© The Authors (cid:129) Journal compilation © Blackwell Verlag GmbH, Berlin (cid:129) JDDG (cid:129) 1610-0379/2011/0901
`
`JDDG | 1˙2011 (Band 9)
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`Galderma Laboratories, Inc. Ex 2011
`Dr. Reddy's Labs v. Galderma Labs., Inc.
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`22
`
`Review Article
`
`The role of microorganisms in rosacea
`
`pilosebaceous units have also been
` described in a considerable percentage of
`patients [8].
`The role of microorganisms in the devel-
`opment of rosacea has been addressed in
`a variety of studies, but clear evidence for
`their pathogenic role in rosacea has not
`been demonstrated.
`
`Helicobacter pylori
`Helicobacter pylori has been presented as
`one of the potential causative factors, but
`the studies performed to date remain
`controversial. The pathogenetic mecha-
`nism through which H. pylori could be
`involved in rosacea has not been identi-
`fied. It is proposed that the bacterium,
`through the production of specific cyto-
`toxins and the release of vascular media-
`tors such as histamine, prostaglandins,
`leukotrienes and cytokines might be the
`triggering factor for the development of
`rosacea, but robust evidence is lacking
`[5, 9]. There are no specific histological
`features identified in the patients in
`whom H. pylori is found [7].
`The prevalence of H. pylori in rosacea pa-
`tients is presented as being higher than in
`the healthy population in many studies
`[10–14], while other studies suggest that
`there
`is no
`substantial difference
`[15–17]. Powell et al. in 1992 found
`higher anti-Hp antibody levels in rosacea
`patients [10]. Szlachcic et al. examined
`the prevalence of gastric H. pylori infec-
`tion in rosacea patients [11]. In this
`study, 67 % of the rosacea patients had
`strains of H. pylori which were positive
`for a known virulence factor cytotoxin-
`associated gene A (CagA), while only
`32 % of patients with non-ulcer dyspepsia
`(NUD) had CagA positive strains [11].
`Such correlation has been demonstrated
`also in the study of Argenziano et al.
`where the anti CagA antibodies were
`present in 75 % of patients with both
`rosacea and gastric symptomatology
`[12]. In this study serum IgG and anti
`IgA anti-Hp antibodies were evaluated
`and it was shown that IgG antibodies
`were detected in 81 % of the patients
`with rosacea and dyspepsia [12]. Both
`studies concluded that rosacea is associ-
`ated with various gastrointestinal symp-
`toms and is related to gastritis with H.
`pylori expressing CagA and elevated
`plasma levels of TNF␣ and IL-8. They
`suggest that rosacea could be an extragas-
`tric manifestation of H. pylori infection
`mediated by bacterial cytotoxins and
`
` cytokines [11, 12]. In 2002 Szlachcic
`demonstrated that there was a statisti-
`cally significant greater prevalence of
`H. pylori in patients with rosacea [13]. In
`2004 Baz et al. showed that in the
`rosacea population studied the seroposi-
`tivity was higher for IgM and lower for
`IgG antibodies against H. pylori com-
`pared to controls, concurring with the
`previous findings that the H. pylori
`infection rate is higher in rosacea popula-
`tion [14]. The same study detected in-
`creased level of malondialdehyde (MDA)
`and decreased antioxidant potential
`(AOP) in the rosacea group, demonstrat-
`ing that these patients have increased
` reactive oxygen species (ROS) activity.
`These findings did not correlate to the
`seropositivity to H. pylori and the au-
`thors conclude that rosacea is an oxida-
`tive stress condition related to deficient
`function of the antioxidant system,
` regardless of H. pylori infection [14].
`This statement though needs to be sup-
`ported by further studies.
`Schneider et al. (1992) found no statisti-
`cal difference in H. pylori
`infection
`prevalence in rosacea patients [15]. This
`was also the case in the study performed
`by Son et al. in Korean patients [16] and
`in the more recent study performed by
`Herr et al. the difference in anti-Hp
` antibodies was again not significant
`between the two groups [17]. Bonamingo
`et al. suggested that no differences ap-
`pear in the frequency of H. pylori expo-
`sure in rosacea patients. However, they
`speculated that the previous systemic use
`of antibiotics could lead to incorrect
`conclusions regarding the differences in
`disease prevalence [18]. Our study also
`demonstrated no significant differences
`in the prevalence of anti-Hp antibodies,
`but, after stratification according to the
`prior use of antibiotics, the results were
`modified suggesting a strong association
`between H. pylori and rosacea in the
`population not previously treated with
`antibiotics [6, 19]. Gurer et al. found
`that although in the population they
`studied the seropositivity of anti-Hp
` antibodies was higher in the rosacea
`group, nitric oxide serum levels were
`normal [20].
`Despite exhaustive studies the seropreva-
`lence of anti-H. pylori antibodies remains
`a point of controversy. Helicobacter
` pylori infection is one of the most com-
`mon infections in humans [21] and thus
`it is our belief that all the variables that
`
`have been proven to control its preva-
`lence would need to be taken into
` consideration in order to identify the
` association with rosacea. The same con-
`troversy also lies with the association of
`the eradication of H. pylori and rosacea’s
`clinical improvement [19, 22–24]. There
`are studies supporting the therapeutic ef-
`fect in rosacea after H. pylori eradication
`[23–25] and other studies that demon-
`strate no relation of the eradication of
`H. pylori with the clinical improvement
`of skin lesions [22, 26]. A factor that
`needs to be taken into consideration is
`the efficacy of metronidazole in rosacea
`as well as in H. pylori eradication.
`In conclusion we believe that based on
`all the studies to date, due to the high
`prevalence of anti-Hp antibodies in hu-
`mans in conjunction with the fact that
`the antibiotics are effective for both dis-
`ease entities, it would be very difficult to
`stratify the population studied against all
`factors that influence both rosacea and
`H. pylori infection. Thus, these studies
`remain inconclusive and do not help
` towards the development of the best
`therapeutic approach for these patients.
`
`Demodex folliculorum
`Demodex folliculorum is also implicated
`in the disease pathogenesis by several
`publications. Demodex is found in a very
`large number of the general population;
`with recent sensitive techniques the
`prevalence approaches almost 100 % [5].
`Therefore only the identification of the
`mite in rosacea patients adds no value
` towards the proof of its pathogenetic
`role. Demodex-specific antibodies were
`detected only in 22 % of 31 rosacea pa-
`tients in a study performed by Grosshans
`et al. [27]. Several studies suggest that
`the mean density of mites in the pilose-
`baceous units as well as their extrafollicu-
`lar deposition are correlated with the
`pathogenesis of rosacea [1, 5, 6, 28, 29].
`In our study, performed in the northern
`Greek population, we identified signifi-
`cantly higher density of Demodex in the
`rosacea patients, in comparison not only
`to healthy controls but also to patients
`with discoid lupus erythematosus and
`acne group [6]. Other studies also have
`demonstrated that the density of the
`mites in the rosacea population is higher
`than in the age-matched healthy individ-
`uals, although this observation is not
`valid for the telangiectatic disease, but
`only for the papulopustular form [5]. A
`
`JDDG | 1˙2011 (Band 9)
`
`© The Authors (cid:129) Journal compilation © Blackwell Verlag GmbH, Berlin (cid:129) JDDG (cid:129) 1610-0379/2011/0901
`
`Galderma Laboratories, Inc. Ex 2011
`Dr. Reddy's Labs v. Galderma Labs., Inc.
`IPR2015-01777
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`

`
`The role of microorganisms in rosacea
`
`Review Article
`
`23
`
`density of more than 5 mites per follicle
`or 5 mites per cm2 has been considered to
`be pathogenic [28]. Perifollicular lympho-
`histiocytic inflammation
`linked with
`Demodex was observed by Forton in 69
`rosacea specimens [30]. In another study
`Forton et al. suggest that in patients with
`papulopustular rosacea the density of De-
`modex is very rarely normal and this den-
`sity is higher as visible immune reaction is
`lower [29]. Aroni et al. detected increased
`numbers of Demodex density in 35 % of
`rosacea patients, even though 54 % of
`these had neither perifollicular inflamma-
`tion nor penetration into the dermis [7].
`The pathogenic mechanisms involved
`include stimulation of the immune
` response, hair follicle blockage and for-
`eign body granulomatous reaction to the
`mites and their products [28]. Based on
`all these studies, we can therefore
` speculate that Demodex represents a con-
`tributing cofactor to the inflammatory
`reaction seen in rosacea.
`
`Mite-related Bacteria
`Another theory suggests that Demodex
`mites can act as vectors for other patho-
`genetic microorganisms [28, 31]. Bacter-
`ial endosymbionts could indeed play an
`important role and this can explain the
`therapeutic effects of antibiotics in these
`patients [1]. The study performed by
`Borgo et al. to assess the occurrence of
`Wolbachia in Demodex mites, failed to
`demonstrate any association of this en-
`dosymbiont with the human mites [31].
`Bacillus olenorium, another bacterium
`found in Demodex, has been linked with
`the
`initiation of the
`inflammatory
` response in rosacea patients through the
`production of antigenic proteins [32].
`The inflammatory process about the cen-
`trofacial pilosebaceous units seen in
`papulopustular rosacea can be explained
`by the fact that the density of Demodex
`mites and thus of the associated bacterial
`agents such as B. olenorium is higher in
`these areas [1, 28, 29, 31]. It is hypothe-
`sized that the accumulation of the mites
`in the follicles causes their distension and
`damage allowing diffusion of bacterial
`agents through the follicular wall, thus
`resulting in the immune response around
`the pilosebaceous units [32]. Further
`research is required towards this direction.
`
`Staphylococcus epidermidis
`Staphylococcus epidermidis has also been
`described as a potential causative mi-
`
`croorganism in a study performed by
`Dahl et al. in 2004 [33]. Still, cultures
`performed from rosacea pustules failed
`to isolate bacteria and S. epidermidis can
`be considered a contaminant since it is a
`normal inhabitant of human skin.
`
`Bacterial Toxins
`Bacteria grow at different rates in differ-
`ent temperatures producing different
`toxins [34]. As Dahl et al. described, the
`temperature in rosacea patients is higher
`than the healthy population [33]. Differ-
`ence in the bacterial behavior in higher
`temperatures could lead to the produc-
`tion of the papules and pustules seen in
`rosacea. S. epidermidis strains isolated
`from rosacea patients were consistently
`␤-hemolytic in contrast with the control
`group; the proteins produced by this
`strain are different at 37° C. Lipase levels
`have been higher in rosacea patients and
`it is postulated that not only the nature
`but also the amount of these proteins
`play a role in the disease development.
`As suggested by the authors, other strains
`of the facial skin microflora, such as De-
`modex and symbionts or yeasts such as
`Malassezia ovalis might be involved in
`the inflammatory process through this
`mechanism. However, this study only
`lays the grounds for further research into
`this direction.
`
`Chlamydia pneumoniae
`Chlamydia pneumoniae have been sug-
`gested as potential causative agents of
`rosacea by a study performed by Fernan-
`dez-Obregon and Patton [35]. C. pneu-
`moniae-antigen was detected in 4 out
`of 10 and serum antibodies against
`C. pneumoniae were detected in 8 out of 10
`rosacea patients. Patients were treated
`successfully with azithromycin. This is
`only a preliminary study and the possible
`involvement of C. pneumoniae in rosacea
`needs to be investigated more.
`
`Intestinal bacteria
`Small intestinal bacterial overgrowth
`(SIBO) was demonstrated to have
`greater prevalence in rosacea patients and
`its eradication led to skin lesion improve-
`ment [36, 37]. Additionally, in rosacea
`patients who were SIBO negative the an-
`tibiotic therapy had no effect on the skin
`lesions [36]. The clinical effectiveness of
`SIBO eradication in rosacea suggests
`that these bacteria might play a role in
`the pathogenesis of rosacea lesions as
`
`well, but not enough evidence has been
`provided yet.
`Intestinal bacteria that are involved in
`the pathogenesis of inflammatory bowel
`disease (IBD) are also hypothesized to
`play a role in rosacea through the devel-
`opment of neurogenic inflammation
`[38]. Kendall has described a case of a
`patient without digestive tract disease
`who experienced complete remission of
`his rosacea after treatment for reduction
`of the gut transit time below 30 hours
`[39]. Intestinal bacteria can activate
`plasma kallikrein-kinin system (PKKS)
`and it is of interest that rosacea patients
`consistently demonstrate an activation of
`PKKS [38]. The possible involvement of
`intestinal bacteria in the pathogenesis of
`rosacea would also explain why metron-
`idazole is efficacious in both rosacea and
`IBD, but the data available are currently
`inadequate to prove this hypothesis.
`
`Antimicrobial peptides
`Changes of the proteolytic balance of the
`skin lead to a reduced epidermal barrier
`function [40]. Proteases, their inhibitors
`and target proteins may contribute to the
`inflammatory responses seen in rosacea.
`Increased serine protease activity and
`cathelicidin promote skin inflammation
`in these patients [39]. The proteolytic
`imbalance can be caused by exogenous
`proteases, such as dust mite or microbial
`proteases, leading to the hypothesis that
`these proteins could play a role in rosacea
`pathogenesis [40]. Antimicrobial pep-
`tides (AMPs) constitute a primary sys-
`tem for protection against microbial in-
`vasion [41]. Cathelicidins belong to this
`group and their dysfunction could be
`one of the factors leading to the rosacea
`inflammatory response [41]. One of the
`cathelicidin peptides (LL-37) induces
`the production of cytokines in ker-
`atinocytes, chemotaxis, and angiogenesis
`[41]. Rosacea patients have abnormally
`high levels of cathelicidin (LL-37) and
`thus the increased AMP production
`along with their dysfunction is thought
`to lead to disease genesis [41]. Therefore
`agents that would be blocking catheli-
`cidin could be beneficial in rosacea but
`this statement needs to be proved.
`
`Discussion
`The causes of rosacea remain unknown.
`Based on the controversial studies and
`opinions expressed in the literature it seems
`that we are rather far from identifying
`
`© The Authors (cid:129) Journal compilation © Blackwell Verlag GmbH, Berlin (cid:129) JDDG (cid:129) 1610-0379/2011/0901
`
`JDDG | 1˙2011 (Band 9)
`
`Galderma Laboratories, Inc. Ex 2011
`Dr. Reddy's Labs v. Galderma Labs., Inc.
`IPR2015-01777
`
`

`
`24
`
`Review Article
`
`The role of microorganisms in rosacea
`
`the underlying pathology that leads to
`the disease development. The mecha-
`nisms described are based on different
`hypotheses and have yet been inconclu-
`sive, lacking the desired scientific data to
`provide evidence towards the pathogene-
`sis of all the different forms of the dis-
`ease. Microorganisms have been mainly
`implicated in the papulopustular form of
`rosacea. The question that arises is
`whether the disease is indeed multifacto-
`rial; a single pathophysiological theory
`could not therefore explain all the differ-
`ent disease manifestations. The possible
`role of microbes has been thoroughly
`discussed over many years, since the
`identification of the possible association
`of Demodex folliculorum and rosacea.
` Although we cannot draw any conclu-
`sions about the degree of Demodex
` contribution to the disease development,
`the rosacea population has
`indeed
`greater density of the mite on their skin
`while its prevalence is described as higher
`in many studies and equal to the general
`population in others [1, 5, 6, 28, 29].
`An association between H. pylori infec-
`tion and rosacea development has not
`been proven, despite many studies been
`performed in different populations. The
`controversial results previously described
`are not easy to interpret. Based on our
`study, where a higher prevalence of
`H. pylori in rosacea patients was not
`found [6], we conclude that this bac-
`terium is unlikely to play a role in rosacea.
`Although S. epidermidis, C. pneumoniae,
`intestinal bacteria and proteolytic imbal-
`ance caused by microbial pathogens have
`been implicated in the disease develop-
`ment, they have not been connected def-
`initely to the pathogenesis of rosacea in
`the pilot studies. Further research is re-
`quired in this direction.
`In their clinicopathological study Aroni
`et al. observed that there is no histologi-
`cal pattern unique to rosacea and sug-
`gested that this reaction pattern reflects
`the fact that a variety of pathogenetic
`routes may be involved [7].
`Since only selected antibiotics are
` effective in rosacea, a bacterium sensi-
`tive to these agents could be involved in
`the pathogenesis of the disease [32].
` Although investigators have not been
`able to identify any new microbial
`strains that could be deemed responsible
`for rosacea, the dramatic improvement
`seen after therapy with antibiotics
` supports the theory that microbes could
`
`be implicated [33]. The fact though that
`sub- antimicrobial
`anti-inflammatory
`doses of doxycycline demonstrated
`clinical efficacy in the papulopustular
`form of the disease suggests that
` microbes alone cannot explain the
` disease manifestations [42]. Moreover,
`photodynamic therapy using methy-
`lated 5-aminolevunate MAL-PDT that
`demonstrated a similar effect to long-
`term antibiotics in rosacea patients
`did not seem to significantly affect the
`skin flora [43].
`In conclusion, the role of microorgan-
`isms in the development of rosacea has
`not been clearly defined. The data avail-
`able to date suggest that they may have a
`potential role, which seems to be rather
`synergistic with other factors, unless the
`real causative microorganism has not
`been identified yet.
`<<<
`
`Conflict of interest
`None.
`
`Correspondence to
`Dr. Elizabeth Lazaridou
`133 Tsimiski street
`GR-54621 Thessaloniki, Greece
`Tel.: +30-2310242433
`Fax: +30-2310271749
`E-mail: bethlaz@med.auth.gr
`
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`JDDG | 1˙2011 (Band 9)
`
`© The Authors (cid:129) Journal compilation © Blackwell Verlag GmbH, Berlin (cid:129) JDDG (cid:129) 1610-0379/2011/0901
`
`Galderma Laboratories, Inc. Ex 2011
`Dr. Reddy's Labs v. Galderma Labs., Inc.
`IPR2015-01777
`
`

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`The role of microorganisms in rosacea
`
`Review Article
`
`25
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