G ITAL DERMATOL VENEREOL 2009;144:663-71
`
`The pathophysiology of rosacea
`
`M. A. Mc ALEER, N. LACEY, F. C. POWELL
`
`Rosacea is thought to be a common skin disorder in the gene-
`ral population, presenting with many different clinical featu-
`res and unknown causes. Theories of pathogenesis have been
`extrapolated from clinical observation of factors, leading to a
`definition of the etiology of rosacea which was very limited
`until recently. A recent upsurge in translational research in
`rosacea has significantly advanced the insight into this disea-
`se. In this review the authors discuss the pathogenesis of this
`disease, which could be determined by the following factors: 1)
`exposure to UV radiation; 2) reactive oxygen species (inclu-
`ding superoxide and hydroxyl radicals, hydrogen peroxide and
`singlet oxygen); 3) vascular hyperreactivity; 4) neuropeptides;
`5) exacerbation of innate immune response; 6) microbes, in
`particular Fl. pylori and environmental aggressors, such as
`Demodex mite. Even if the recent investigations have signifi-
`cantly improved the understanding of its pathogenesis, the
`authors conclude that the histopathology of rosacea remains to
`be clarified according to subtype and age of development of
`individual lesions.
`
`Kev worms: Rosacea, etiology - Pathogenesis UV radiation -
`Innate immunity - Demodex.
`
`R osacea is a disease that in many ways is a conun-
`
`drum. It is thought to be a common skin disorder
`in the general population, but how common is unclear.
`All clinicians are agreed that facial erythema is a pri-
`mary feature of the disorder, but thereafter the clinical
`features are disputed. Some investigators include
`patients with transient facial erythema (due to frequent
`and profound flushing) in the clinical spectrum of
`rosacea and refer to these individuals as having a con-
`
`Corresponding author: F. C. Powell, Regional Centre of Dermatology,
`Mater Misericordiae Hospital, Dublin, Ireland.
`E-mail: fpowell@eircom.net
`
`Department of Dermatology
`Mater Misericonliae University Hospital, Dublin, Ireland
`
`dition called "pre-rosacea". At the other end of the
`spectrum reports of patients (usually female) who have
`deep cystic lesions with a propensity to scarring, pre-
`viously classified as having a variant of acne vulgaris,
`have been labelled as having "rosacea profunda".
`Between these polar extremes, many rosacea "experts"
`include those fair-skinned patients with a history of
`ultraviolet light exposure and who have fixed facial
`erythema and teliangiectasias in the category of ery-
`thematotelangiectatic rosacea (ETTR, also called sub-
`type 1 rosacea), even though the clinical features are
`indistinguishable from heliodermatitis (the effects of sun
`exposure and "weathering" on sun sensitive individu-
`als). Rhinophyma (enlargement of the nose due to seba-
`ceous gland hyperplasia) is referred to as "subtype 3
`rosacea" although such morphological nasal changes
`can be seen in some patients with longstanding acne vul-
`garis, following years of actinic damage to the nose in
`persons with skin type 3, or as a consequent of the
`development of telangiectatic vessels (neovasculari-
`sation) of the skin around the alae nasi and distal nose
`causing increased blood flow to the area. Another dis-
`order that can result from acne vulgaris is "called sol-
`id facial oedema". Some patients with this type of facial
`swelling accompanied by erythema have been classi-
`fied as having "edematous rosacea". Without the pres-
`ence of preceding or concomitant inflammatory lesions
`(papules and pustules) the link between solid facial
`
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`Mc ALEER (cid:9)
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`THE PATHOPHYSIOLOGY OF ROSACEA
`
`TABLE 1.—Clinical features of rosucea.
`
`Subtype
`
`Features
`
`Erythernatotelangeetat lc rosacea
`2. Papulopustular rosacea
`3. Phymatous rosacca
`4. Ocular rosacea
`
`— Flushing, persistent central facial erythema, telangectatic vessels, easily irritated skin
`— Persistent facial erytherna, erythematous papules surmounted by pustule , . oedema.
`— Distorted thickened skin with prominent pores, surface nodules
`— Itch, irritation, burning, stinging. watering, dryness, blurred vision; telaiipectasia and erythema of the lid
`margins, conjunctival injection, cbala/ion, hordeolum; interstitial keiatitis, opiscleritis, scleritis, iritis
`
`oedema and rosacea is tenuous to say the least. Mor-
`bihans disease is another term sometimes used to
`describe such patients with persistent non-pitting cen-
`trofacial oedema and erythema without preceding facial
`inflammatory lesions. A striking feature of thc clinical
`presentation of rosacea is the frequent occurrence of
`mild ocular inflammation (such as dryness or con-
`junctivitis) in association with the skin changes in some
`patients. This association distinguishes rosacea from the
`many other facial dermatoses. However, such ocular
`changes, while characteristic of rosacea, arc non-spe-
`cific and can be seen in otherwise healthy individuals.
`This fact has not prevented publication of several series
`of patients with such ocular changes being labelled as
`having "ocular rosacea7 even in the absence of pre-
`ceding or accompanying cutaneous lesions. While it
`is generally agreed that rosacea is a disorder with peak
`onset in middle age (30 to 60 years), there are many
`reports of children with varying degrees of facial ery-
`thema and inflammatory lesions as having "childhood
`rosacea" and others with the non specific eye changes
`described above as having "ocular rosacea of child-
`hood". A rare disorder which has been described under
`various titles such as Lupus miliaris disseminata faciei
`and Lewandowski's disorder is characterised clinical-
`ly by firm, non-tender, persistent, erythematous facial
`papules and histologically by the presence of granulo-
`matous inflammatory changes in the dermis has been
`classified by many investigators as "granulomatous
`rosacea". Other commentators have suggested that
`rosacea evolves in stages, beginning with transient
`facial erythema (as seen in patients who flush fre-
`quently) and terminating in the sebaceous hyperplasia
`of rhinophyma and edema, even though clinical expe-
`rience does not support such an evolution in individual
`patients with disorders of flushing and many patients
`with inflammatory rosacea and rhinophyma deny a
`tendency to frequent flushing preceding the onset of
`their skin lesions. From the preceding discussion it is
`likely that several different disorders have been
`
`"lumped" together under the broad rubric of rosacea,
`having in common (in most instances) the presence of
`facial erythema but diverse other manifestations which
`are unlikely to constitute a single disease entity.
`Bccause of the diverse clinical entities that have
`received the label of "rosacea" it is not surprising that
`there are confusing and alien conflicting reports regard-
`ing its prevalence in thc general population, the evo-
`lution of the clinical disorder, the typical histopatho-
`logical changes that arc found in lesional skin biopsies
`and the possible etiological factors at vvork in this dis-
`order.
`An attempt to give clarity to some of the issues was
`the publication of the expert group of the National
`Rosacea Society in 2002 which suggested dividing
`rosacea into four different independent subgroups
`without implying that one subgroup evolved into anoth-
`er in a progressive or staged manner.' This consensus
`document was intended to help clinicians and investi-
`gators to identify and classify the particular clinical fea-
`tures in the patients being treated or investigated in
`order to facilitate comparison of results of therapy or
`investigative studies across different groups (Table I).
`Using this classification it becomes clear that studies
`of patients in Subtype I (called ETTR) are likely to
`yield quite different results than investigative reports
`of patients in subgroup 3 (called phymatous rosacea).
`By comparing studies within fairly well-defined groups
`(or subtypes) of paticnts, the clinician/investigator is
`more likely to be comparing "like with like" rather
`than potentially different clinical entities being treat-
`ed/investigated. In the classification of subtypes, sub-
`type 2 (called papulopustular rosacea [PPR]) corre-
`sponds most closely to the original descriptions of this
`disorder (when it was referred to as "acne rosacea").
`It is the opinion of these authors that the patients in this
`subgroup represent the "epicentre" of this condition,
`and it is likely that study of individuals afflicted with
`papulopustular rosacea will yield most information
`regarding the pathophysiology of this disorder.
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`THE PATHORHYSIOLOGY OF ROSACLA (cid:9)
`
`Mc ALEER
`
`Rosacca is estimated to affect over 14 million Amer-
`icans.= Berg and Linden investigated 809 Swedish
`office employees and reported prevalence of roscaea
`of 10%. 3 Their study predated the standard classifi-
`cation of rosacea. We investigated a random selection
`of 1 000 Irish individuals and, as defined by the stan-
`dard elassification,l demonstrated a prevalence of
`papulopustular rosacea of 2.7%. 4
`The cause of rosacea is unknown. Until recently
`theories of pathogenesis were extrapolated from clin-
`ical observation of factors that precipitated or exacer-
`bated the condition and from treatments that improved
`the disease. Thus, our understanding of the etiology of
`this condition was limited. There has been a recent
`upsurge in translational research in rosacea that has
`significantly advanced our insight into this disease.
`
`Iiistopathology of rosacea
`
`Despite being a common condition, the histopatho-
`logical changes have still to be clearly defined. The
`most comprehensive and frequently quoted study of the
`histopathology of rosacca was that of Marks and Har-
`court-Webster in 1968. 5 They examined histological
`sections of skin biopsies taken from 108 patients with
`"rosacea". They defined "rosacea" as a "disease of
`the skin mostly affecting the cheeks and often thc chin,
`nose, and forehead characterized by persistent ery-
`thema and often telangiectasias with acute episodes
`of edema, papules and pustules in some cases". They
`recorded that biopsies of papules or papulopustules
`were taken from 74 of the 108 patients. They observed
`acute folliculitis in 25% of specimens, an inflamma-
`tory reaction at the hair follicle in 19%, and in 7% of
`cases there was total destruction of the follicle with an
`intensc granulomatous inflammatory reaction. They
`also recorded that in a further 37 specimens the inflam-
`matory infiltrate was partially distributed at the hair fol-
`licle. However, in spite of these findings they con-
`cluded in their abstract that rosacea was not a condi-
`tion related to the follicular apparatus, a conclusion
`that has been echoed since by may other authors. Bas-
`ta-Juzbasic et al. found Demodexfolliculorum in 43 of
`50 biopsy specimens from rosacea patients, and record-
`ed the presence of perifollicular abscesses and granu-
`lomas in some of these patients. 6 Roth took biopsies of
`eyelid skin from rosacea patients and showed perifol-
`liculitis around 42% of follicles in which there were
`Demodwc mites. 7 The histolopathology of rosacea has
`
`also been shown to vary with the stage of the condition
`biopsied 8 but morc study is required to clarify this
`important aspect of the progress of the condition.
`Inflammatory changes are noted to be focused main-
`ly around the follicle in papulopustular rosacea,
`although perivascular infiltrates arc also prominent as
`are the histological changes of actinic damage in sun-
`sensitive middle aged individuals (solar elastosis with
`a varying degree of tclangicctasias). In thc early stages,
`the superficial perivascular lymphocytic infiltrate
`appears marked. In well established lesions a mixed
`lymphocyte/neutrophilic infiltrate is evident around
`the follicular infundibulum. Forton and Seys demon-
`strated a statistically significant relationship between
`Demodex infestation and this follicular orientated
`inflammation. 9 As the condition advances, neutrophils
`are found in the follicular walls as well as within the
`follicular canals with histiocytes, epitheliod cells and
`lymphocytes surrounding the follicle. As mentioned
`above, telangiectases and actinic elastosis are often
`very prominent histologically irrespective of the stage
`of the lesion studied. 8, 10 Granulomatous inflamma-
`tion appears to be closely associated with follicular
`rupture suggesting a dermal foreign-body reaction to
`the discharged contents (keratin, sebum, mites, etc)
`of the disrupted follicular walls. 10
`Both a cell mediated and/or humoral immune
`responses are indicated in the inflammation reaction of
`rosacca. A study by Rufli and Buchner demonstrated
`that the perifollicular infiltrate in rosacea lesions con-
`sisted largely of T-helper lymphocytes. 11 More recent
`reports also confirm this finding. Georgala et al. indi-
`cated a delayed hypersensitivity reaction (type IV) in
`subjects with papulopustular rosacea, possibly trig-
`gered by antigens of follicular origin, most likely relat-
`ed to Demodexfolliculorum. 12 They demonstrated that
`CD, helper T cells predominated in dermal infiltrates
`from inflamed Demodex infested follicles, with an
`increase in macrophages and Langerhans cells also
`being noted. 12 Grosshans et al. indicates a humoral
`response for the inflammatory reaction, showing that
`patients with rosacea have Demodex-specific anti-
`bodies to D. caprae, by assuming cross-antigenicity
`between Demodex species of man and animals. 13
`
`Ultraviolet light
`Rosacea most commonly occurs in fair skinned, sun
`sensitive individuals and ultraviolet radiation (UVR)
`and sun exposure can exacerbate the symptoms of
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`Mc ALEER
`
`THE PATHOPHYSIOLOGY OF ROSACEA
`
`rosacea. 14 Furthermore, solar elastosis is a frequent
`histological finding in the biopsies of facial skin of
`rosacea patients. 5 These observations suggested that
`UV radiation may be involved it in the pathogenesis of
`the disease. It had been postulated that UV radiation
`causes a loss of dermal connective tissue integrity
`resulting in inadequate dermal vascular support and
`subsequent telangcctasias and erythema. 8 We studied
`I 000 Irish individuals investigating the prevalence of
`papulopustular rosacea and its relationship to UV radi-
`ation exposure and cutaneous photodamage. No asso-
`ciation between UV exposure and papulopustular
`rosacea was demonstrated. 4 The other subtypes of
`rosacea were also investigated in the course of the
`study. ETTR was significantly associated with UV
`exposure. 16 As previously discussed, the features of
`erythematotelangectatic rosacea and heliodermatitis
`are indistinguishable and this may have contributed
`to the significant association between UVR and EITR
`observed in our study. These disparate findings in the
`two subtypes of rosacca (ETTR and PPR) also suggest
`that these are separate entities and that an evolution
`from erythematotelangiectatic to papulopustular
`rosacea does not occur.
`Some laboratory studies suggest that UV radiation
`could induce erythema and telangectasias seen in rosacea
`by increasing angiogenic factors and degrading the
`extracellular matrix. Vascular endothelial growth factor
`(VEGF) and UVB are capable of stimulating endothe-
`lial proliferation. In the skin epidermal keratinoctyes
`are a major source of these angiogenic factors. UV-B
`radiation increases VEGF and Fibroblast Growth Fac-
`tor 2 (FGF2) secretion from human keratinocytes in
`vitro and stimulates cutaneous angiogenesis leading to
`telangectasia and new blood vessels in mice. 16
`Fimmel et al. investigated the influence of UV irra-
`diation on the synthesis of the angiogenic factor VEGF
`and corticotrophin releasing hormone (CRH) in human
`dermal micrvascular endothelial cells, keratinocytes,
`fibroblast and a sebaceous gland cell line SZ95. They
`reported that following exposure to a physiological
`dose of UVB radiation CRH synthesis significantly
`increased in keratinocytes, fibroblasts and moderate-
`ly in the sebocytes while CRH levels decreased in the
`endothelial cells. They suggest that epithelial skin
`cells respond to environmental stress by increased
`CRH production and this has direct effects on vessel
`wall function and, hence, could be involved in rosacea
`pathogenesis. 7
`
`UV radiation also induces an increase in oxidative
`stress, excellerating vascular and dermal matrix dam-
`age, which will be further discussed below. 18
`UVR may play a role in the pathogenesis of the ery-
`thematotelangiectatic subtype of roscea. Alternative-
`ly UVR may be a coincidental factor in the sunsensi-
`tive rosacea population resulting in findings (erythe-
`ma, telangectasias etc and histological evidence ot'
`solar elastosis in the dermis) that form a background
`of actinic damage on which the other clinical features
`evolve. Further studies investigating the role of UVR,
`using the defined criteria to strictly isolate the vari-
`ous rosacea subtypes, are required to dissect out its
`possible role in this disorder. In addition, consideration
`and research into the differences, if any, between ery-
`thematotelangectatic rosacea and actinic damage will
`aid to clarify aspects of this disease and its relationship
`to UVR.
`
`Reactive oxygen species
`Reactive oxygen species (ROS) may contribute to
`the pathophysiology of rosacea. ROS include superox-
`ide and hydroxyl radicals and other inactivated forms of
`oxygen such as hydrogen peroxide and singlet oxygen.
`ROS are the key mediators of UV induced biological
`effects in the skin, and the skin is more susceptible than
`other tissucs to damage caused by ROS. 19 ROS acti-
`vates cellular signalling, mediates cytokine induction and
`chemokine production, stimulates fibroblasts and alters
`MIVIPs. Therefore, upregulated ROS activity in the skin
`could result in the inflammation, vascular changes, and
`collagen degeneration observed in rosacea. 20
`Oztas et al. found decreased activity of superoxide
`dismutase (oxygen radical quenching enzyme) and
`increased malondialdehydc levels (lipid peroxidation
`product as a result of free radical activity) in patients
`with severe rosacea compared with controls. 21 Anoth-
`er study investigated plasma ROS activity and the
`antioxidant status and their relationship with H pylori
`infection in 29 patients with rosacea. They found high-
`cr malondialdehyde levels and reduced antioxidant
`potential levels in rosacea patients compared with con-
`trols, but no correlation with H pylori seropositivity. 22
`The role of ROS in rosacea aetiopathogenesis has been
`supported by the fact that effective treatments for
`rosacea inhibit ROS generation in neutrophils. 20 Fur-
`thermore, a decrease of ROS in rosacea skin was
`observed after azithromycin treatnnent. 23 These stud-
`ies imply a antioxidant system dysfunction in rosacea,
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`THE PATHOPHYSIOLOGV OF ROSACEA (cid:9)
`
`Mc ALEER
`
`however, whether this is a cause or as a result of inflam-
`mation requires more comprehensive investigation.
`
`Vascular changes
`
`Many patients with rosacea complain of frequent
`and more persistent flushing. Laser-Doppler flowom-
`etry demonstrated that lesional blood flow in patients
`with rosacea was 3-4 timcs that of control subjects. 24
`Guzman-Sanchez et al. investigated 16 individuals
`with rosacea (8 ETTR, 8 PPR) and 8 controls to assess
`burning perception, hcat pain threshold, skin blood
`flow, and skin temperature. Quantative thermal sensor
`testing and laser doppler imaging were used. They
`demonstrated that individuals with rosacea had
`increased sensitivity to noxious hcat stimuli and that
`PPR affected skin had increased blood flow compared
`with unaffected skin. There was no significant
`increased blood flow in ETT lesional skin compared
`with unaffected skin. 25 Further supporting the role of
`vascular hyperrcactivity in rosacca, application of a
`topical alpha-adrenergic receptor agonist resulted in
`resolution of erythema and flushing in individuals
`with rosacea. 26 The skin of rosacea patients has been
`shown to have increased expression of vascular
`endothelial growth factor (VEGF), that causes prolif-
`eration of vascular endothelial cells and increases per-
`meability of vessels, as well as the lymphatic endothe-
`I ium marker D2-40. 27 These findings suggest that
`rosacea skins have stimulants for vascular and lym-
`phatic endothelial cells. As previously discussed, UVR
`induces VEGF in keratinocytes and may explain the
`photodistribution and reported photoaggrevation of
`rosacea. Yamanaski et al. postulate that the antimi-
`crobial peptide cathelicidin could be a trigger for the
`observed increased vascularity in rosacea, and unifies
`the innate immune system dysregulation (discussed
`later) and increased vascularity in roscaea. Catheli-
`cidin induces endothelial cell changes through various
`pathways, including angiogenesis via formyl peptide
`receptor like l(FPRL 1 ) and transactivation of epider-
`mal growth factor receptor (EGRF) that induces VEGF
`in keratinocytes. 20
`
`Neuropeptides
`
`The rapid responses of tlushing, stinging and itch
`experienced by many rosacea patients have suggested
`to some investigators that the cutaneous neurovascu-
`lar system plays a role in the condition. 28, 29 The tern-
`
`poral relationship between thc onset and exacerbation
`of inflammatory skin conditions and psychological
`stress also has provided support for a connection
`betwecn the central nervous systcm and the peripher-
`al cutaneous neuroimmune systems. It has becn report-
`ed 60-91% of individuals with rosacea associated the
`onset or flares of thcir condition with emotional stress
`3 (4 31 and hypnosis of patients was found to be helpful
`for the treatment of established rosacea 32 providing cir-
`cumstantial evidence of a link between the psyche and
`cutancous inflammatory changes.
`Individuals with rosacea have been shown to have
`increased serum substance P (SP) compared with a
`control group. When the SP level was measured in 23
`rosacea patients, 9 had elevated levels, compared with
`none of the control group. 33 In another study, SP
`immunoreactive neurons were increased around the
`blood vessels of lesional skin in 9 rosacea patients,
`compared with non-lesional skin in the same individ-
`uals. 34 Lonne-Rahm et al. investigated the effects of
`pulsed dye laser treatment on 31 patients with erythe-
`matotelangectatic rosacea with regards to skin sensi-
`tivity, nerve density, contacts between nerves and ves-
`sels, and the expression of the ncuropeptides SP, Cal-
`citonin-Gene related peptide (CGRP), and Vasoactive
`Intestinal Peptide (VIP). 28 Three months after pulsed
`dye laser treatment was completed, a significant num-
`ber of patients had decreased facial skin sensitivity
`and a significant reduction in superficial nerve fibre
`density with a reduced number of neurons immunore-
`active to SP.
`Vasoactive intestinal peptide (VIP) has also been
`shown to be increased in the skin of some patients
`with rosacea. Five patients with rhinophyma were
`shown to have a more dense distribution of VIP recep-
`tor (VIP-R) positive cells within the endothelium and
`perivascular large cells compared with the control
`group. 35
`Calcitonin gene related peptide (CGRP) is one of the
`most prominent neuropeptides in the skin. 36 Lonne-
`Rahn et al. found vascular related CGRP positive fibres
`in the dermis of rosacea patients. Following the pulsed
`dye laser treatment there was a no significant decrease
`in the numbers of CGRP positive fibres compared
`with before treatment. 28
`Somatostatin (SST) activity has been demonstrated
`in Merkel cells associated with sweat glands, in ker-
`atinocytes, Langerhan cells, suprabasal cells of the
`epidermis and in dendritic cells and neurons. 37 Four
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`Mc ALEER
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`THE PATHOPHYSIOLOGY OF ROSACEA
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`patients with PPR that responded to octreotide, a long
`acting somatoslatin analogue have been reported. It
`was poAulatecl that the inhibitory effects of SSM on the
`granuloma tous response and on neurogenic inflam-
`mation helped treat the papulopustular rosacca. 38
`In contrast to the above studies Murphy et a/. inves-
`tigated facial vasomotor instability and the release of
`neuropeptides in 27 patients with untreated rosacea
`(1 6 PPR, 9 ETTR) and 27 age, sex and socioeconom-
`ic matched psoriasis control patients. There was more
`postprandial flushing in rosacea patients, but no cor-
`relation between neuropeptide release and rosacea or
`post-prandial flushing. 39
`Neuropeptides appear to be dysregulated in rosacea
`and may be contributing to the inflammation, vascu-
`lar reactivity and sensitivity seen in this condition.
`Observed neuropeptide abnormalities may be induced
`by the exacerbatcd innate immune system in this dis-
`ease.
`
`Innate immune system
`
`Despite being under constant assault from environ-
`mental aggressors, such as microbes, UVR, and phys-
`ical and chemical trauma, the skin respond to these
`stimuli and maintains its intcgrity because of the barri-
`cr function of the outer horny layer and its ability to
`mount an immune response. Cutaneous immunity is
`achieved by both a rapid innate immune response and
`a morc specific adaptive immune reaction. In innate
`immunity the pattern recognition system, that involves
`toll like receptors (TLR) and neucleotidc binding domain
`and leucine-rich repeat-containing (NRL) families,
`respond to stimuli and cause an increase in cytokines and
`anti-microbial peptides (AMP) such as cathelicidins
`and defensins. These peptides are a first-line defense
`in the skin against the various pathogens it encounters
`and have been described as early warning peptides or
``alarmins', reflecting their ability to kill microbes and
`trigger host-tissue immune responses. AMPs have been
`shown to affect leukocyte chemotaxis, angiogenesis,
`expression of extracellular matrix components, and
`inflammation. 40 Some forms of cathelicidins, includ-
`ing the LL-37 form, can be both proinflammtory and
`vasoactive. Yamasaki et al dcmonstrated that patients
`with rosacea express high levels of the cathelicidin in the
`LL-37 peptide form. 41 This AMP can promote and reg-
`ulate leukocyte chemotaxis, angiogenesis and expression
`of extracellular matrix components. They also demon-
`strated that in rosacea skin the proteolytically processed
`
`forms of cathelicidin were found to be different from
`those in normal subjects; there was an abundance of
`LL-37 in addition to peptides of unique mass that were
`absent in normal skin. Rosacea skin had highly expressed
`stratum corneum tryptic enzyme (SCTE or kallikrein 5)
`co-localised with cathelicin expression. When serine
`protease inhibitor depleted mice (Spink5 deficient) were
`injected with the cathelicidin peptides isolated from
`rosacea subjects, in addition to SCTE, marked inflam-
`mation and vascular dilatation in the mouse skin
`ensued. 4 This landmark study provided new insights
`into the pathogenesis of rosacea and suggested that an
`exacerbated innate immune response is central in the
`pathogenesis of this disease.
`
`Microbes
`The role of Helicobacter pylori in the pathogenesis of
`rosacea is controversial. H. pylori colonisation occurs in
`childhood and persists throughout life, causing disease
`mainly in adults. Despie the fact that about half the
`world's population carries H. pylori only a small pro-
`portion develops ulcers or gastric cancer. 42 There have
`been reports of eradication therapy for H. pylori associ-
`ated with improvement in rosacea. 43, 44 Whether these
`improvements were coincidental, as a result of antibiotic
`therapy used to eradicate H. pylori, or related to the H.
`pylori eradication is unclear. Subsequent studies inves-
`tigating anti-H. pylori antibodies in rosacea patients
`wcrc conflicting, showing both an increase in sero-
`prevalence of H. pylori infection 45-47 and no significant
`difference in seroprevalence in rosacea patients com-
`pared with healthy controls. 48 Furthermore, a double-
`blind, placebo controlled study showing that treating
`and eradicating H. pylori in patients with both rosacea and
`H.pylori infection had no beneficial effect on the symp-
`toms of rosacea. 49 H pylori produces ROS and individ-
`uals with rosacea have been shown to have higher ROS,
`including nitric oxide, compared with controls. 22, 50 H.
`pylori induces cytokine release in gastric epithelial cells
`via toll-like receptors. 51 It has been suggested that ROS
`and cytokines released by toll like receptors stimuli in the
`gastric epithelium in H pylori colonisation could exac-
`erbate rosacea. 20 These various laboratory and clinical
`studies have not demonstrated any clear association
`between H pylori infection and rosacea and its relevance,
`if any, remains to be seen.
`Demodex folliculorum and D. brevis are often seen
`in skin biopsies taken from patients with rosacea. Both
`Demodex species are ubiquitous in the human adult
`
`668 (cid:9)
`
`GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA (cid:9)
`
`December 2009
`
`6
`
`Galderma Laboratories, Inc. Ex 2009
`Dr. Reddy's Labs v. Galderma Labs., Inc.
`IPR2015-01778
`
`(cid:9)
`

`
`THE l'ATHOPHYSIOLOGY OF ROSACEA
`
`Mc ALEER
`
`population. Demoder arc considered to be commensal
`organisms in human skin. In most individuals thcy
`produce no clinical signs or symptoms of inflamma-
`tion. The mite is usually not present in neonatcs, its
`population is sparse in children and adolescents, with
`numbers increasing with the host's age. 51-54 Mites are
`thought to be transmitted by direct contact from adults
`to children, and predominantly occupy areas rich in
`sebaceous glands, such as facial skin, thc neck, scalp,
`eyelids and upper chest.
`Demo(lex mites arc complex organisms that have
`received little attention form biologists or other
`researchers in the past. The generic mite body can be
`characterised for both species into three clear regions:
`the gnathosoma (mouth parts), podosoma (legs attach)
`and striated opisthosoma (abdominal region). The
`exoskeleton of these mitcs is composed of three lay-
`ers; the epicuticle, exocuticle and cndocuticle. This
`protective covering is colourless and transparent. 55
`The course of thc lifecycle of both species of Demod-
`ex mite is predominantly referred to as lasting 14.5
`days throughout the literature. This estimation has
`been based on the behavioural studies pertained by
`Spickctt in 1961 which remains (to our knowledge)
`thc only published attempt to define the duration of the
`life stages and full cycle of human Democlex. 56
`Spickett suggested the following lifecycle ofDemod-
`ex.f)Iliculorum mites: The males roam the skin surface
`and copulates with a gravid female in the opening of
`a pi losebaceous follicle, usually on the face. After 12
`hours the female deposits a number of eggs deep in thc
`follicle close to the sebaceous gland. These hatch into
`larvae after 60 hours. This larval stage feeds constantly
`on sebocytes for 40 hours, and then is moved up the
`pilosebaceous canal by the flow of sebum and moults
`to the protonymphal stage. After 72 hours the
`protonymph gives rise to the deutonyrnph which crawls
`in a random fashion to a new follicle and goes through
`the final moult to become an adult after 60 hours. The
`female mites live for 120 hours and the males for
`approximately 59 hours. Spickett emphasises that all
`these figures could deviate from in vivo.
`The tendency for rosacea to develop after the age of
`30 years of age is parallelled by an increase in Dernod-
`ex numbers in human facial skin at that age. Demod-
`ex numbers also tend to increase in spring and summer
`months, when rosacea may bc exacerbated. 57, 58
`Demodex infe