Rosacea: I. Etiology, pathogenesis, and subtype classification

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CONTINUING
MEDICAL EDUCATION
Rosacea: I. Etiology, pathogenesis, and subtype
classification
Glen H. Crawford, MD,a Michelle T. Pelle, MD,b and William D. James, MDa
Philadelphia, Pennsylvania, and Boston, Massachusetts
Rosacea is one of the most common conditions dermatologists treat. Rosacea is most often characterized by
transient or persistent central facial erythema, visible blood vessels, and often papules and pustules. Based
on patterns of physical findings, rosacea can be classified into 4 broad subtypes: erythematotelangiectatic,
papulopustular, phymatous, and ocular. The cause of rosacea remains somewhat of a mystery. Several
hypotheses have been documented in the literature and include potential roles for vascular abnormalities,
dermal matrix degeneration, environmental factors, and microorganisms such as Demodex folliculorum
and Helicobacter pylori. This article reviews the current literature on rosacea with emphasis placed on the
new classification system and the main pathogenic theories. ( J Am Acad Dermatol 2004;51:327-41.)
Learning objective: At the conclusion of this learning activity, participants should be acquainted with
rosacea’s defining characteristics, the new subtype classification system, and the main theories on
pathogenesis.
R
osacea is a common condition characterized
by transient or persistent central facial erythema, visible blood vessels, and often
papules and pustules. Because the facial skin is the
predominant site of involvement, many patients
sense that rosacea alters their social and professional
interactions, leading to problems on the job, in their
marriage, or in meeting new people. These common
issues have led to the formation of a large active
patient advocacy group, the National Rosacea
Society, which produces newsletters, encourages
research by offering grants, and distributes educational and supportive materials to professionals and
patients.
While therapeutic interventions are expanding
with new light-producing devices and topical remedies, our understanding of the pathophysiology of
rosacea has not progressed substantially. New treatments target empirically the signs and symptoms
From the Department of Dermatology, University of Pennsylvania
Medical Center,a and the Department of Dermatology, Boston
University Medical Center.b
Initial support for the clinical-educator fellowship program from
which this study resulted was provided by a generous grant
from Ronald Krancer to the Dermatology Section of the
Pennsylvania Hospital, Philadelphia, in honor of his dermatologist, Paul R. Gross, MD.
Conflict of interest: None identified.
Reprints not available from the authors.
0190-9622/$30.00
ª 2004 by the American Academy of Dermatology, Inc.
doi:10.1016/j.jaad.2004.03.030
without understanding the mechanism by which
these pathologic processes take place. It is possible
that with renewed interest, funding sources, and
advanced technology, more and better studies to
discover the pathogenesis of rosacea will follow.
However, research into a disease state requires precise definitions and exclusion, and many of the
studies performed so far have been hampered by
a lack of such disease-defining terms. Complicating
the acceptance of any comprehensive set of diagnostic criteria is the fact that there is no benchmark
laboratory test and that patients with rosacea demonstrate a broad spectrum of possible findings. There
has been recognition that some patients’ clinical
pictures are dominated by a certain set of findings,
such as redness and flushing (erythematotelangiectatic rosacea [ETR]), and others’ by papules
and pustules (papulopustular rosacea [PPR]). A few
studies segregate their patients into these 2 subtypes
and have shown divergent results of the factors
investigated. A recent article has helped to better
define and subclassify rosacea into 4 main nosologic
subtypes.1 What follows is a review of the literature
about the pathophysiology of and the treatment
options for rosacea in the context of these recently
designated subtypes.
DEFINITION AND SUBTYPES
The April 2002 issue of this Journal contained an
important article in which members of an expert
committee assembled by the National Rosacea
327
328 Crawford, Pelle, and James
Society reported their conclusions of a meeting designed to standardize diagnostic criteria for rosacea.1
The defining characteristics are a loosely associated
series of signs and symptoms. The presence of
flushing, persistent erythema, telangiectasia, papules,
and pustules in a central facial distribution is certainly
enough to allow even dermatologic neophytes to
recognize the common classic cases; however, this
imprecise clustering of findings does not adequately
set a standard on which future studies of rosacea
should be based. One reason for a lack of precision
may be the desire to account for those patients
whose condition lies apart from the center of the
classic disease spectrum, of which there are a wide
variety of examples.
Rosacea is a disease, however, for which there is
no laboratory benchmark test and for which we are
many years from understanding the basic pathophysiology and etiopathogenesis. Therefore we currently need to explicitly and meticulously define the
condition on the basis of recognizable morphologic
characteristics. The difficulty in interpreting data
from the large body of literature amassed to date is
to some degree a result of such lack of precision in
the past.
The expert panel recognized 4 subtypes of
rosacea. The concept that patients present with
a preponderance of one or a clustering of signs is
most useful. Dermatologists know that some patients
have only persistent erythematous cheeks without
papules and pustules. These patients often are the
same ones who have dramatic histories of flushing to
a wide variety of stimuli, who bitterly complain of
burning and stinging, and who often are intolerant of
topically applied products. Contrast such patients
with the sebaceous-skinned man with many papules,
pustules, and even nodular erythematous lesions,
and a background of central facial erythema. Patients
like him are often not ‘‘flushers and blushers,’’ have
fewer, if any, symptoms of burning and stinging, and
tolerate topical medications better than patients
with ETR.2
These 2 classic subtypes require different therapeutic approaches. Findings of studies of the
pilosebaceous apparatus, cutaneous sensitivity,
sun-induced inflammatory processes, or many other
variables would also be predicted to be quite diverse
between such groups. In experimental studies, the
lumping of patients with various clinical presentations may mask insights into rosacea.
Finally, rosacea has been historically divided into
stages. It is often stated or implied that stages of the
disease evolve from one to another.3-6 The committee did not discuss stages and recognized only one
variant.1 This advance in the classification and def-
J AM ACAD DERMATOL
SEPTEMBER 2004
inition of disease will certainly aid in lessening the
confusion in future research and publications about
this subject.
DISEASE DEFINITION
The expert committee stated that the diagnosis of
rosacea requires the presence of one or more of the
following primary features concentrated on the
convex areas of the face: flushing (transient erythema), nontransient erythema, papules and
pustules, and telangiectasia.1 While we agree with
the basic diagnostic criteria presented, we believe
that additional refinements are needed. For instance,
is a history of flushing in a central facial distribution
enough to define rosacea? How long is the transient
erythema of the flush? Are facial papules and
pustules in a central facial distribution characteristic
enough to define rosacea? How long does the nontransient erythema persist? We believe that the most
important finding is persistent erythema of the
central portion of the face lasting for at least 3
months. There is a marked tendency to spare the
periocular skin. We propose this type of erythema to
be the sole requisite criterion for the diagnosis of
rosacea. Flushing, papules, pustules, and telangiectases on the convex surfaces are supportive characteristic findings, but not necessary for diagnosis.
Secondary features include burning or stinging,
edema, plaques, a dry appearance, ocular manifestations, perpheral locations, and phymatous
changes.1 When present, the relative abundance of
these associated findings will dictate the subtype of
disease the patient manifests. As will be discussed in
the next section, subtype designation is of paramount importance because the therapeutic implications are quite different among the subtypes.
Several diseases must not be present: polycythemia vera, connective tissue diseases (lupus
erythematosus, dermatomyositis, and mixed connective tissue disease), carcinoid, and mastocytosis.
Patients who have applied topical steroids to the
central facial convexities over a long period are also
excluded. Rosacea primarily affects the face, so the
presence of extrafacial erythema is generally an
exclusionary sign, with the exception of sites described under each subtype.
A myriad of diseases that cause a red facial
appearance usually are not difficult to discern from
rosacea. Most will fall aside when limitation to specific
sites of the face and chronicity are specified. Patients
with polycythemia vera, connective tissue disease,
carcinoid, or mastocytosis will generally manifest
a variety of systemic symptoms and extrafacial signs
that will lead to the appropriate diagnosis. These
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VOLUME 51, NUMBER 3
conditions also have specific laboratory markers that
will confirm the clinical suspicion.
Finally, photosensitivity and allergic contact dermatitis will at times be considerations. The former
will usually affect other sun-exposed sites, such as the
dorsal part of the hands, ears, and neck; phototesting
is the diagnostic test. Allergic contact dermatitis is
itchy, scaly when present for a long period, and often
present either intermittently or at other sites as well.
Patch testing should be employed as a diagnostic test
when itch is a prominent symptom or when allergy to
a topical product occurs as a complication of rosacea
treatment.
ROSACEA SUBTYPES
It is of paramount importance to indicate the
subtype of rosacea that is diagnosed, as there is
a wide spectrum of patients for whom the umbrella
term rosacea is commonly rendered. The classic
patient at the midpoint of the spectrum—Wilkin’s
typological center—is easily recognized.5 It is likely
that this epicenter was what originally separated
rosacea most easily from other diseases. However,
manifestations of rosacea are protean, involve
multiple associated signs and symptoms, and are
often modified by therapeutic intervention. Consequently, the red-faced patients who present to the
dermatologist with manifestations outside this ‘‘nodal
center’’ comprise a large portion of the patients
currently being studied and designated as having
rosacea.
The simple diagnosis of rosacea without the
appended subtype may be viewed as akin to the
diagnosis of alopecia without the appropriate designator. Certainly alopecia areata differs in presentation,
pathophysiology, and therapeutic options from androgenetic alopecia. Likewise, the patient with sebaceous, thickened skin whose face is dull red and
studded with papules, pustules, and nodulocystic
lesions is quite different from the thin-skinned bright
pink-faced patient who complains bitterly of burning
and stinging. We believe the difference is likely to be
reflective of varying pathophysiologic mechanisms
also. Certainly these divergent conditions require
alternate therapeutic approaches, as suggested by
Dahl in the differential treatment recommendations
for pustules versus telangiectases.7
Some authors have theorized that rosacea progresses from one stage to another.3-6 The expert
committee’s recent report did not include this notion.1 A progression from one subtype to another
probably does not take place, except perhaps in the
cases of severe papulopustular or glandular rosacea
that eventuate into phymatous forms.
Crawford, Pelle, and James 329
Erythematotelangiectatic type (ETR)
The flushing that rosacea patients experience is
prolonged. Many people without rosacea experience
evanescent flushing in response to embarrassment,
exercise, or hot environments.8 The flushing of
rosacea, however, is not the evanescent several
seconds to few minutes of pinkness that is commonly
experienced. Usually rosacea patients describe their
flushing to last longer than 10 minutes. Such a prolonged vasomotor reaction may help in differentiating physiologic flushing from that seen in rosacea
patients. The central portion of the face is generally
the site of the most intense color,9 but the redness
may also involve the peripheral portion of the face,
the ears, the neck, or the upper part of the chest.10
There is characteristic sparing of the periocular skin.
The stimuli that bring on such flushing may be
acutely felt emotional stress, hot drinks,11 alcohol,12
spicy foods,8 exercise, cold or hot weather, or
hot baths or showers.13 At times the episodes are
without known stimuli. Often a burning or stinging
sensation accompanies the flush of rosacea; however, sweating, light-headedness, or palpitations
do not.
Patients with ETR (Fig 1) have a lower threshold
for irritation from topically applied substances.2
They experience stinging and burning that can
be quite severe. Topically applied products may
exacerbate these symptoms. They describe itch in
response to sunscreens, cosmetics, and medicaments
meant to alleviate the redness. Patients in whom itch
is a prominent symptom deserve patch testing. Those
who complain of acute sun-induced symptoms likewise deserve phototesting and photopatch testing;
however, results usually prove negative. The skin is
usually fine in texture without a sebaceous quality or
oiliness that better characterizes the other subtypes.
At times roughness and scaling are seen in the
affected sites, probably reflecting a chronic, lowgrade dermatitis.7 There is usually no history of
acne.4
Papulopustular rosacea (PPR)
Patients with PPR (also known as classic rosacea,
pink papular rosacea, and typologic center disease)
present with a strikingly red central portion of the
face but have persistent or episodic inflammation
characterized by small papules that may be
surmounted by pinpoint pustules (Fig 2). Edema
may accompany such episodes but is frequently
subtle in its expression.14,15 There is almost universal
sparing of the periocular skin, which contrasts strikingly with the intense redness at adjacent sites. A
history of flushing is often present; however, this
symptom is usually milder than that experienced in
330 Crawford, Pelle, and James
Fig 1. Erythematotelangiectatic subtype. (From Plewig G,
Kligman AM. Acne and rosacea, 3rd ed. Berlin: SpringerVerlag, 2000. p. 471; used with permission.)
patients with ETR. Irritation from external stimuli is
also not as constant a feature2; thus scaling and
roughness are often absent. These patients are most
often women in midlife.4 Telangiectases are often
subtly present but may be obscured by the generally
erythematous background.
The episodes of inflammation may lead to chronic
edema. The presence of the more dramatic manifestation of solid facial edema and phymatous changes
can occur in men with this subtype of disease but are
distinctly rare in women.16,17 The reasons these
problems tend to be less common in women are
unknown but may relate to hormonal influences,
earlier therapy that prevents repeated insults, or
other, unknown factors.
Phymatous rosacea
The expert committee designated phymatous
rosacea as one of the 4 rosacea subtypes.1 Phymata
include marked skin thickening and irregular surface
nodularities, and can occur on the nose
(rhinophyma; Fig 3), chin (gnathophyma), forehead
(metophyma), one or both ears (otophyma), and
eyelids (blepharophyma).18 Four variants of
rhinophyma (glandular, fibrous, fibroangiomatous,
actinic) can be recognized clinically and have distinct
histopathologic features.18
J AM ACAD DERMATOL
SEPTEMBER 2004
Fig 2. Papulopustular subtype. Central facial redness,
circumoral and circumocular sparing, and small erythematous papules, some of which are topped with a small
pustule. (From Plewig G, Kligman AM. Acne and rosacea.
3rd ed. Berlin: Springer-Verlag; 2000. p. 469. Reprinted
with permission.)
The discussion of phymata in the context of
writings about rosacea is not preceded by suppositions that it is a vascularly based or a sun-induced condition, as other manifestations of rosacea are.7,18-20
In parallel with different subtype-targeted therapies,
phymata are approached in a dramatically different
fashion from the other subtypes of rosacea. The
mainstays of therapy are isotretinoin and surgical
correction.18,20-25
Ocular rosacea
Blepharitis and conjunctivitis are the most common findings in rosacea patients with ocular manifestations (Fig 4).14,26-28 Inflammation of the lids
with recurrent chalazion and inflammation of the
meibomian glands may be present. Interpalpebral
conjunctival hyperemia, conjunctival telangiectases,
and watery or dry, irritated eyes can occur. Burning
or stinging, itching, light sensitivity, and a foreign
body sensation are frequent symptoms in the patient
with ocular rosacea. Keratitis, scleritis, iritis, and
complications of such involvement are infrequent
but can occur.14,26,27,29-35
Ocular rosacea may precede the cutaneous signs
by many years36; however, in most dermatology
J AM ACAD DERMATOL
VOLUME 51, NUMBER 3
Fig 3. Phymatous rosacea. Thick sebaceous skin, papules
and pustules, marked skin thickening, and irregular surface nodularities most prominent on the nose. (From
Plewig G, Kligman AM. Acne and rosacea. 3rd ed. Berlin:
Springer-Verlag; 2000. p. 475. Reprinted with permission.)
practices, concurrent presentation or eye findings
following the skin signs are more often observed.26,27
As discussed below, distinct therapies for ocular
manifestations make it extremely important for
dermatologists to actively pursue a history of eye
complaints and to conduct a thorough examination
of the lid margins and conjunctiva.
OTHER CLINICAL CONSIDERATIONS
Glandular rosacea
One phenotype displayed in certain rosacea
patients is quite different from the other 4 classic
subtypes recognized above. We propose the term
glandular rosacea (GR) to describe this phenotype,
which is commonly seen and illustrated in textbooks
(Figs 5 and 6) but has not previously been clearly
separated into a distinct nosologic subtype. GR is
most common in men who have thick, sebaceous
skin. Edematous papules and independent pustules
are often of large size, and nodulocystic lesions may
be present. These lesions often will cluster in the
central and inner aspects of the cheeks but may be
seen in any sites that show erythema. In women
with this subtype, the chin is often a more favored
location. Frequently such patients will have a history
of adolescent acne with the typical scars. Unlike ETR
Crawford, Pelle, and James 331
Fig 4. Ocular rosacea. Erythema of the nose is most
prominent. Associated conjunctivitis and blepharitis are
demonstrated. (From Plewig G, Kligman AM. Acne and
rosacea. 3rd ed. Berlin: Springer-Verlag; 2000. p. 481.
Reprinted with permission.)
and PPR, there is usually an absence of sensitivity to
and complaints of burning and stinging from topical
agents. Therapeutic options, then, are extended
to include benzoyl peroxide and benzoyl peroxidee
antibiotic combinations, which are frequently dramatically effective.
The marked periocular sparing is again notable.
Flushing is less frequently present than in the other
subtypes. The background redness is less dramatically pink but instead will frequently have shades of
rust. The hue surrounding the raised inflammatory
lesions, however, will be brightly erythematous, and
the edema surrounding them is often dramatic. The
dermal effects of chronic sun damage and the dilated
vasculature may be less visible because of the overlying hypertrophied sebaceous glands. The patient
may exhibit chronic central facial edema if the process has been allowed to continue untreated or if
particularly dramatic episodes of nodulocystic disease have occurred. A predisposition to the development of rhinophyma is present.
Extrafacial lesions
When discussing rosacea, many experts will relate
that extrafacial lesions are sometimes seen.10,37,38 In
the erythematotelangiectatic form, one may observe
332 Crawford, Pelle, and James
Fig 5. Glandular subtype. Central facial erythema, papules and pustules associated with large-pored seborrheic
skin. (From Plewig G, Kligman AM. Acne and rosacea. 3rd
ed. Berlin: Springer-Verlag; 2000. p. 471. Reprinted with
permission.)
macular redness of the ears, lateral facial contours,
neck, upper portion of the chest, and scalp. These
extrafacial manifestations in ETR patients are uncommon and are usually seen only in areas affected
by flushing and chronic sun damage.39 Acneiform
lesions have been reported to occur on the central
part of the chest, the scalp, the neck, and occasionally the limbs.4,10,38,40,41 Further characterization of
the erythematous papules and pustules and
nodulocystic lesions in these patients should lend
insight into the nature of these uncommon extrafacial
lesions. Finally, the red scrotum syndrome—characterized by intense redness, burning, and
stinging42—has been hypothesized by some to be
a manifestation of rosacea. In the many patients with
the red scrotum syndrome seen by the authors, none
had recurrent flushing of the scrotum, only occasionally has facial rosacea been present, and in none
did therapy utilized in the treatment of rosacea result
in improvement of the scrotal manifestations.
Conversely, after questioning hundreds of patients
who presented for treatment of rosacea, the authors
have not found anyone with burning and stinging of
the scrotum. This finding is in contrast to the frequent
discovery of unrevealed eye symptoms on specific
questioning. In our opinion, the red scrotum syndrome is the result of chronic irritation, long-term
J AM ACAD DERMATOL
SEPTEMBER 2004
Fig 6. Glandular subtype. Central facial erythema, diffuse
sebaceous gland hyperplasia and prominent pores. (From
Plewig G, Kligman AM. Acne and rosacea. 3rd ed. Berlin:
Springer-Verlag; 2000. p. 475. Reprinted with permission.)
steroid use, or atopic dermatitis (personal observations, W. D. J., M. T. P., G. H. C.).
Sun damage
Sun damage is a mildly inflammatory process and
can produce variably conspicuous telangiectases and
erythema. These findings are present on the entire
sun-exposed surfaces; hence, while they spare the
periocular skin as in rosacea, they also affect the
periphery of the face, the neck (sparing the area below
the chin), the upper part of the chest (particularly in
women), and the dorsal portions of the ears (in
patients with short hair). In addition, dyspigmentation
is present to some degree in most patients.
It is not uncommon for patients who present for
treatment of rosacea to have only severe sun damage.
These same patients may have joined national societies for the condition, be avoiding triggers publicized to induce flushing (even without episodes of
flushing), and be concerned about the eventual
development of a ‘‘W. C. Fields nose.’’ It is important
to differentiate such patients from those with
rosacea. Patients with solely actinic changes should
be directed to appropriate preventive and corrective
strategies, such as the daily use of sunscreens and
sun-avoidance measures. While some overlapping of
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treatment strategies exists, there is of course no need
to incur lifestyle changes in diet and exercise or to
fear the enlarged, bulbous nose of rosacea in the
patient with solely sun-damaged skin.
Topical steroid use
The prolonged use of topical steroids may
reproduce many of the signs and symptoms
characteristic of PPR.43,44 It is thought that anyone
may develop this complication; however, it may be
that rosacea-prone persons are more susceptible.45,46
The condition is not necessarily limited to the central
part of the face but rather occurs in the facial sites
where the steroids are applied. It is not considered to
be a subtype of disease but rather an adverse drug
effect that mimics rosacea. The best treatment for this
steroid-induced rosacea-like eruption requires not
only stopping the medication but also intervening
with antibiotics and topical tacrolimus.47,48 This latter
agent is not known to be effective in rosacea but may
help calm the symptomatic dermatitis seen in ETR
(personal observations, W. D. J., G. H. C., M. T. P.).
Perioral dermatitis
Perioral dermatitis has often been classified within
the umbrella of rosacea variants. However, the
distribution, signs, and symptoms vary from the
definitions presented. Consequently, despite responding to agents normally effective for rosacea, it
is not included as a subtype of rosacea.1
Granulomatous lesions
Granulomatous rosacea was classified by the
expert committee as a disease variant characterized
by periorificial yellow, brown, or red monomorphic
papules or nodules that, when severe, can lead to
scarring.1 While it is true that most experienced
physicians may accurately predict clinical lesions
that will at biopsy show granulomatous inflammation, the term granuloma is a histologically, not
clinically, defined term. Patients with ‘‘granulomatous rosacea’’ often do not have persistent facial
erythema, may not have disease limited to the
convexities of the face, often have periocular lesions,
usually do not flush as rosacea patients do, and may
have unilateral disease. It is thus difficult to consider
this condition to be nosologically or pathophysiologically within the rosacea spectrum.
While we recognize the difficulty of proposing
new names for disease states deeply ingrained in the
literature, we suggest granulomatous facial dermatitis as a diagnostic category for this condition. Other
variants of granulomatous facial dermatitis have
been described and have not always been placed
Crawford, Pelle, and James 333
under the umbrella of rosacea. Examples include the
more recently described facial Afro-Caribbean childhood eruption (FACE),49 granulomatous perioral
dermatitis,50 and the older lupus miliaris disseminatus faciei.51
Implications of rosacea subtypes
Most investigations to date do not specify the
defining characteristics of their patient population
and have not subcategorized patients. In 1989 Marks
opined that one reason for a lack of progress in
understanding the pathogenesis of rosacea was that
rosacea may represent more than one disease
entity.52 Some studies do state that erythematotelangiectatic or papulopustular subtypes
were studied and often the findings are quite variable. In a study by Lonne-Rahm et al,2 it was
discovered that 7 of 7 ETR patients experienced
stinging when 5% lactic acid solution was applied to
the cheek. However, only 68% of the PPR patients
and 17% of control subjects reacted with the perception of stinging. When the role of the adnexal
structures, vascular reactivity, and other potential
etiologic factors in rosacea are being investigated, it
is essential that the patient population be clearly
defined as to the basic definition of rosacea and the
particular subtype studied.
The use of these subtypes also allows
better education of patients. Not all are at risk for
the development of the large bulbous nose; not
everyone needs to make lifestyle changes or avoid
irritants. Also, there is clearly the expectation
that varying therapeutic interventions will be necessary, that responses will not be uniform, and that
adverse reactions may be prominent in one subtype
but nearly absent in another.
PATHOPHYSIOLOGY
The cause of rosacea remains unknown. Several
factors have been implicated in its pathogenesis,
some based on the evidence of scientific investigation, others on anecdotal observation. Proposed
etiologic mechanisms can be grouped into the following categories: vasculature, climatic exposures,
matrix degeneration, chemicals and ingested agents,
pilosebaceous unit abnormalities, and microbial
organisms. However, a central paradox remains;
how does one explain the varied clinical expressions
of rosacea through one isolated mechanistic theory?
It is likely that rosacea’s distinct nosologic subtypes
(erythematotelangiectatic, papulopustular, phymatous, and ocular) represent heterogeneous
responses to a combination of these purported
334 Crawford, Pelle, and James
factors. In addition, all of these implicated triggers
are experienced by healthy persons who never go
on to develop the symptoms or signs of rosacea.
Consequently, rosacea-prone persons must have an
inherent sensitivity to these ubiquitous triggers.
Vasculature
Perhaps the most-cited pathogenic theories about
rosacea center on inherent abnormalities in cutaneous vascular homeostasis. Most of these theories are
based on the prominent facial flushing seen in many
rosacea patients.4,5,53 Flushing, or transient, erythema is controlled by 2 vasodilatory mechanisms:
humoral substances and neural stimuli.54 Wilkin
demonstrated that proportional increases in cutaneous blood flow were the same in both the forearm
and the face after neurally mediated (oral thermal
challenge) and direct smooth muscleemediated
(nicotinic acid test) signals.9 That flushing in ETR
and PPR is visibly concentrated on the face can be
explained by the fact that baseline blood flow is
increased in the face55-57 and that facial vessels are
larger, more numerous, and nearer to the surface
than in other areas of the body.58 Consequently, both
neural mechanisms and circulating humoral agents
produce flushing reactions that may be visibly limited to the face.9,11
Dysregulation of thermal mechanisms has been
proposed by some to cause the vasodilation in
rosacea.13,59-61 The normal physiologic response to
hyperthermia is an increased flow of blood from the
face to the brain, presumably to aid in intracranial
cooling. In one small study, this response to hyperthermia was absent in 4 rosacea patients (measured
in the angular veins near the orbit) as compared with
2 control subjects.13 Studies have also shown that
when challenged with thermal stimuli, rosacea
patients flush more easily and in a more pronounced
fashion than control subjects.13,59-61 In a study of 24
patients with ETR, Wilkin demonstrated that it was
the temperature rather than the caffeine of coffee that
generated flushing responses.11 Theoretically, increased oral temperature leads to a heat exchange
mechanism in the carotid arteries that signals the
hypothalamus to trigger vasodilation.11 Albeit interesting, this theory has not yet facilitated the treatment
of facial flushing in rosacea patients, except for the
suggested use of ice chips in the mouth during such
thermal stimuli as warm showers or hot weather.
Interest in the role of substance P—the mediator
now thought to induce flushing in carcinoid62—has
waned owing to a lack of substantial evidence in
previous studies.63-65 Other proposed mediators
have included vasoactive intestinal peptide,66 gas-
J AM ACAD DERMATOL
SEPTEMBER 2004
trin,6,67,68 serotonin, histamine, and prostaglandins.69,70 Robust experimental support for any of
these soluble mediators is lacking.
Climatic exposures
Many authors have endorsed the notion that
rosacea results from the caustic effects of climatic
exposures that damage both cutaneous blood vessels
and dermal connective tissue.3,5,17,71-77 Several
authors have observed that rosacea is often found
in persons occupationally exposed to heat.6,73
The pivotal role of sunlight is supported by the
distribution of erythema and telangiectases on the
facial convexities. Sun-protected areas, such as
the supraorbital and submental areas, are typically
spared. The association with fair skin and light
eyes,73 the predilection for disease flares in early
spring,73 and the tendency to spare the young are all
consistent with a pathogenic role for solar radiation.
In addition, actinic elastosis is prominent in skin
biopsy specimens from rosacea patients.74
In contrast, epidemiologic studies demonstrate
that only 17% to 31% of rosacea patients report
worsening of symptoms by sunlight.78,79 Several
photoprovocation studies in rosacea patients have
failed to show heightened skin sensitivity to the acute
effects of ultraviolet radiation.73,79-82 Despite the
increased prevalence in those with fair complexion,
rosacea does occur in black patients.83,84 However,
these findings should be considered cautiously. Even
patients with proved photoinduced disorders, such
as tumid lupus, are often unaware of the sun’s effect
on their skin, especially when the effect is slow to
appear.85 In addition, subacute and chronic changes
that are most relevant to rosacea are much more
difficult to identify without ample population sizes
and adequate control subjects matched for age, skin
type, and history of sun exposure.
Dermal matrix degeneration
Much interest has surrounded the dermal connective tissue and its role in the pathogenesis of rosacea.
Histopathologic studies have demonstrated both
endothelial damage and matrix degeneration in skin
specimens of affected patients.73,74,86-89 It is clear
from other research fields that cutaneous vascular
damage can precede matrix degeneration. In a study
of ultraviolet light effects on rats, dilated and tortuous
vessels were detected well before matrix abnormalities became apparent.90 In persons with diabetes,
microangiopathy can lead to alterations in perivascular connective tissue.91 The common premise
is that abnormal vascular homeostasis leads to leaky
vessels and delayed clearance of serum proteins,
J AM ACAD DERMATOL
VOLUME 51, NUMBER 3
inflammatory mediators, and metabolic waste, all of
which may lead to matrix degeneration.
Alternatively, some authors support a primary role
for damaged connective tissue in inducing vascular
pathology.58,74,86,88 Solar radiation may alter lymphatic and blood vessel function via damage to the
dermal support network of elastic and collagen
fibers.58,72 This matrix-centered theory holds that
telangiectasia, persistent erythema, profound
flushing, and edema are all caused by poor connective tissue support for cutaneous vessels, resulting in
the pooling of serum, inflammatory mediators, and
metabolic waste.52 Despite prominent ectasia,
vessels in rosacea maintain the ability to dilate and
to constrict in response to local (ethylnicotinate
privine and dimethyl sulfoxide)6 and systemic
(adrenaline, noradrenaline, histamine, and acetylcholine)60,61 vasoactive agents. These findings provide some support for the central role of matrix
degeneration, since vessel reactivity remains intact.
Soybe described the benefit of massage therapy in
cases with prominent edema, and he theorized that
lymphatic abnormalities might play a role in pathogenesis.73 Delayed clearance of inflammatory cells,
soluble mediators, and cellular degradation products
result in prolonged inflammation and tissue damage.
As in the lower extremities, lymphedema in the
central part of the face could result in connective
tissue hypertrophy and fibroplasia. This mechanism
has been theorized to produce some of the findings
in rhinophyma.
Chemicals and ingested agents
Dietary factors and gastrointestinal diseases have
historically been theorized to influence rosacea.
Although spicy foods, alcohol, and hot beverages
are known to trigger flushing reactions in rosacea
patients,11,79 the prevailing evidence at present does
not support a primary role for diet or other gastrointestinal factors in the pathogenesis of rosacea.
Through misrepresented media imagery, the ‘‘plethoric facies’’ and ‘‘drinker’s noses’’ of phymatous
rosacea are often presumed to result from excessive
alcohol consumption. However, medical support for
this theory is lacking. Epidemiologic studies that
have focused on the relationship between rosacea
and alcohol have been confounded by barriers to
medical access, by poor patient compliance, by
inaccuracies in alcohol-consumption history provided by alcoholic persons, and by inadequate
control populations.12,73,92 Alcoholism can manifest
itself in the skin in a variety of ways, many of which
are likely the result of cirrhosis rather than the direct
effect of alcohol.12
Crawford, Pelle, and James 335
Certain medications can induce flares in rosacea
or produce rosacea-like dermatoses. Amiodarone
has been reported to induce rosacea and multiple
chalazia.93 Topical steroids have most often been
considered triggers or causal agents in rosacea-like
eruptions.43,94-97 Occasionally, rosacea patients have
been reported to have dramatic flares even after
using nasal steroids for allergic rhinitis.98 Nicotinic
acid is also known to stimulate flushing reactions in
rosacea patients.9 Acneiform eruptions that resemble
rosacea have also been reported in association with
supplements that contain high doses of vitamins B6
and B12.99,100
Pilosebaceous unit abnormalities
Controversy exists as to whether the papules and
pustules of rosacea are follicularly based. In a study
of 108 biopsy specimens, including 74 from patients
with PPR and 24 from patients with ETR, Marks and
Harcourt-Webster found abnormalities of the hair
follicle in only 20% of the 74 papules or papulopustules subjected to biopsy.74 In addition,
perifollicular inflammatory infiltrates were found in
only 51% of these specimens. Ramelet and Perroulaz
conducted a similar study of French patients with
rosacea.86 All 75 specimens contained perivascular
infiltrates, while only 13 (17%) were judged to be
predominantly periadnexal in nature. In a histologic
study of 12 patients with ETR, Motley, Barton, and
Marks described common lymphohistiocytic infiltrates that were predominantly in a perivascular,
not perifollicular, location.88
It is, however, documented that the glandular type
of rhinophyma is a follicularly based inflammatory
process.19 Therapies such as topical and oral antibiotics, which may be targeting follicularly based
organisms such as Propionibacterium acnes, are
effective in rosacea. These medications include benzoyl peroxide, which is well tolerated and effective in
PPR and GR patients but has no inherent antiinflammatory action. In addition, the role of
Demodex, a follicularly based organism, has been
the subject of repeated investigation as a possible
causative factor in rosacea.
Additional studies are warranted to investigate the
role of a follicular-based inflammatory process in
rosacea. Future studies should subdivide patients
into the appropriate rosacea subtypes. In the histopathologic studies of Marks and Harcourt-Webster74
and Ramelet and Perroulaz,86 only a minority of
patients underwent investigation with serial sectioning. It is our experience that horizontal sections are
best able to reveal follicular-based disease in nonscalp skin. When further studies are undertaken in
336 Crawford, Pelle, and James
the various subtypes of rosacea, it would be of
interest to document whether the lesions subjected
to biopsy are early or late in evolution, what the
frequency and density of P acnes is, especially in
therapeutic protocols with antibiotics, and how the
sebaceous gland size and secretion rates are characterized. While Burton et al101 and Pye, Meyrick, and
Burton102 found normal secretion rates and lipid
composition in affected rosacea skin sites, we believe
that subdividing the patients into subtypes may
reveal variable results.
Microbial organisms
Demodex. Demodex is a common inhabitant of
normal human skin, and its role in human disease is
a matter of controversy. Several authors have proposed that Demodex plays a pathogenic role in
rosacea.3,17,75,76,103-112 Historical support derives
from observations that Demodex prefers skin regions
most often affected by rosacea, such as the nose and
cheeks.41,113 The tendency for clinical manifestations
of rosacea to appear later in life parallels the increase
in Demodex mite density that occurs with age.114-117
In addition, studies have demonstrated immune
responses in rosacea patients that may be directed
against Demodex antigens.80,118,119 Grosshans et al
reported that in 22% of 31 rosacea patients,
Demodex-specific antibodies were found in the
serum.118 Another study showed a predominance
of helper-inducer T cells in infiltrates that surrounded
Demodex mites.119
Numerous studies have been performed to report prevalence rates for Demodex infestation in
rosacea patients.3,16,17,75,76,105,106,120 However, the
sampling methods employed have been extremely
variable (eg, adhesive bands, skin scrapings, skin
impressions, comedo extraction, hair epilation, cyanoacrylate skin surface biopsies, and punch biopsies), making little value of any interstudy
comparison. Demodex is also known to vary with
patient age and the skin site sampled. In addition,
Demodex is found in a large number of healthy
persons. In fact, with more modern and sensitive
techniques, the prevalence in healthy adults
approaches 100%.76,116,117,121,122 Consequently, the
simple identification of Demodex is by no means
proof of pathogenesis. It is the density of
mites76,106,113 or their extrafollicular location103,111,123-125
that is of greater importance in the assessment of
pathogenesis.
Techniques that employ cyanoacrylate surface
biopsies are extremely sensitive.76,106,110 Studies by
Forton and Seys and by Erbagci and Ozgoztasi both
independently demonstrated that the density of
J AM ACAD DERMATOL
SEPTEMBER 2004
Demodex was significantly higher in patients with
papulopustular rosacea than in age-matched control
subjects.106,126 In contrast, both studies failed to
demonstrate statistically significant increased mite
densities in patients with ETR. This lack of statistical
power could represent a true lack of difference in
mean mite counts, or could be the result of a much
smaller sample size of patients with ETR than that of
patients with PPR investigated in both studies.
Another limitation is that skin surface biopsies can
show D folliculorum residing only superficially in
the follicle. Thus this technique misses mites deeper
in the follicle and D brevis mites that reside in the
sebaceous glands.
After having observed mites or fragments in
extrafollicular inflammatory infiltrates, some investigators believe that Demodex mites are responsible for some of the skin lesions in rosacea.107,127-129
Forton demonstrated a statistically significant relationship between the presence of Demodex and
perifollicular, lymphohistiocytic inflammation in 69
biopsy specimens from rosacea patients.129 Other
studies have not supported these findings.74,86,124 In
both Ramelet and Perroulaz’s and Marks and
Harcourt-Webster’s large histopathologic studies of
rosacea, there was no correlation between perifollicular inflammation and the presence of
Demodex.74,86 However, these results can be
questioned by the fact that Demodex is not easily
detected on histologic preparations. Only 19% of 108
specimens were found to contain Demodex mites in
the study by Marks and Harcourt-Webster, and only
3% of 75 specimens in that of Ramelet and Perroulaz.
With a more exhaustive approach, one would expect
higher densities of Demodex.
Lastly, it has been hypothesized that the beneficial
effects of metronidazole on rosacea may be related to
an antiparasitic effect toward Demodex. Mites, however, can survive high concentrations of the drug.130
Others claim that oral and topical metronidazole
formulations are effective via an immunologic pathway or by a metabolite with activity against
Demodex.6,131,132 However, studies have shown that
clinical resolution of rosacea after treatment with
tetracycline76 or topical 3% sulfur ointment133 did not
affect the Demodex population. Whether Demodex is
truly pathogenic or simply an inhabitant of follicles in
rosacea-prone skin remains the subject for future
study.
Helicobacter pylori. Some controversy has
also persisted concerning the possible role of H
pylori in rosacea.134-139 Interest emerged from statistically unsupported, yet historically ingrained,
associations between rosacea and gastrointestinal
diseases, such as hypochlorhydria, gastritis, and
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VOLUME 51, NUMBER 3
abnormal jejunal mucosa.53 Others have observed
that the seasonal fluctuations of rosacea mimic those
of peptic ulcer disease, a condition that is now
known in most cases to be caused by H pylori
infection. In addition, metronidazole, a common
treatment for rosacea, is an effective agent against
H pylori.
H pylori is the most common infection in human
beings.140 Hampering the study of this organism’s
role in rosacea is its ubiquitous presence and its
benign nature in most people.141 Robust support for
a causal association between H pylori and rosacea
does not exist. Several studies have demonstrated
high prevalence rates of H pylori in rosacea
patients,142-145 some even in comparison with ageand sex-matched controls.146 Other studies, however, did not corroborate these data.134, 147-151 In
addition, several studies have demonstrated either
clinical improvement in rosacea134 or a lack
thereof151,152 at the conclusion of therapeutic regimens aimed at the eradication of H pylori. None of
these studies, however, was fully controlled for all
the confounding variables known to influence H
pylori prevalence, such as sex, age, socioeconomic
status, and medications, or was statistically powered
to account for the ubiquitous nature of H pylori
infection in the general population.
With all these data generated from prior studies,
we can conclude with some certainty that the following statements are reasonable:
H pylori is commonly found in patients with
rosacea and in the general population; and
treatments aimed at eradicating H pylori may also
influence the clinical outcome of rosacea.
Despite inconclusive studies, interesting hypotheses concerning the possible pathogenic role of
H pylori have recently been generated. It is known
that H pylori infection increases several vasoactive
substances such as histamines, prostaglandins and
leukotrienes, and various cytokines. However, these
vascular mediators are found only with H pylori
strains that produce a specific cytotoxin, CagA
(cytotoxin-associated gene A) or VacA (vacuolatingassociated gene A). Szlachcic et al compared 60
rosacea patients with age- and gender-matched nonulcer dyspepsia control subjects.146 They found that
when infected with H pylori, 67% of rosacea patients,
versus only 32% of controls, had positive findings
for CagA. In addition, these patients had elevated
systemic levels of tumor necrosis factor a and interleukin 8. After eradication of H pylori infection,
symptoms of rosacea disappeared in almost all
patients (51 of 53) and tumor necrosis factor a
and interleukin 8 levels normalized.146 Despite
Crawford, Pelle, and James 337
these interesting findings, robust support for the
role of H pylori in the pathogenesis of rosacea is
lacking.
FUTURE STUDIES
Many aspects of rosacea require further investigation. It is our hope that this manuscript will stimulate
some of these efforts. One area to approach in
regard to pathophysiology is the possible follicular
nature of the papules and pustules. Researchers
should also investigate the role of P acnes in the
formation of these inflammatory lesions. Concerning investigation into Demodex and H pylori,
we suggest that future efforts be directed elsewhere. Despite exhaustive efforts in numerous studies, clear evidence for a pathogenic role in rosacea
has not been demonstrated for either of these
organisms.
The role of hormones in producing the flush
responses, the oiliness of facial skin in glandular
rosacea, and the utility of spironolactone in papulopustular rosacea or glandular rosacea are yet to be
defined. In addition, further investigations of the
potential extrafacial symptoms of rosacea, the inherent sun sensitivity of rosacea skin, and possible
circulating vasoactive mediators are warranted. The
contribution of a genetic predisposition to sun damage, responses to other climatic conditions, and
flushing responses should be studied. It is clear that
certain populations are more susceptible and that
many patients with rosacea have similarly affected
relatives. What genetic factors are important and
why?
Potentially bridging the divergent hypotheses of
ultraviolet light exposure and vascular dysregulation
on rosacea pathogenesis, Kosmadaki et al demonstrated an increased expression of vascular endothelial growth factor messenger RNA levels after in vitro
irradiation of cultured keratinocytes, an effect that
appeared to be independent of tumor necrosis factor
a.153 Certainly, this remains an area ripe for future
investigation, as the complex interplay between
matrix degeneration and vascular homeostasis in
rosacea has yet to be clearly defined.
As we theorize that the pathogenesis of rosacea
varies with the phenotypic subtype, we emphasize
the importance of clearly defined criteria and subtype inclusion in future studies. Additionally, control
populations should be properly matched in terms of
factors known to influence rosacea phenotype, such
as age, sex, and cumulative sun exposure. Certainly
many more questions than these remain. It is hoped
that curiosity has been stimulated, the need for
continued research highlighted, and progress in
338 Crawford, Pelle, and James
understanding this common and important condition will follow.
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