A NOVEL METHOD FOR INDUCING REMISSION IN ROSACEA AND A NEW HYPOTHESIS TO
ACCOUNT FOR ITS AETIOLOGY

S Kendall


ABSTRACT

Rosacea is a chronic facial dermatosis characterized by hypersensitivity
of the facial vasculature, presenting with intense flushing eventually
leading to permanent erythema and telangiectasia. Its aetiology is unknown.
Symptoms often respond to oral antibiotics and frequent associations with
inflammatory digestive disorders have been reported. Substance
P-immunoreactive neurons occur in considerably greater numbers in tissue
surrounding affected blood vessels suggesting the involvement of neurogenic
inflammation. Plasma kallikrein-kinin activation is consistently found in
patients. It is suggested that inflammatory digestive disorders chronically
activate the kallikrein-kinin system and that symptoms result from
bradykinin induced sensitization of afferent neurons. A patient without
digestive disease is described, who experienced complete remission of
rosacea symptoms following the ingestion of a material intended to sweep
through the digestive tract and reduce transit time below 30 hours. It is
proposed that ordinary intestinal bacteria are capable of kallikrein-kinin
activation. The implications for fibromyalgia and related syndromes are
discussed.


INTRODUCTION

Rosacea is a common facial dermatosis found to affect 10% of the working
population [1]. It is a chronic, incurable disease that tends to develop in
individuals aged between 30-50 years, although it can occur at any age. It
is primarily characterized by a hypersensitivity of the facial vasculature.
Sufferers frequently experience episodes of intense facial flushing provoked
by stimuli that would usually not be expected to cause vasodilation.
Symptoms can affect the cheeks, chin, nose, forehead, neck and occasionally
the upper chest.

The condition is generally progressive and the frequent facial flushing
often gives way to a permanent erythema across affected areas and the
development of telangiectasia. In some individuals the disease can progress
to a papulo-pustular phase, where papules and pustules develop across
afflicted regions and finally, in the most severe cases a condition called
rhinophyma can occur, in which hypertrophy of the sebaceous glands and
connective tissue of the nose occurs leading to considerable disfigurement.
Rhinophyma tends to afflict males more often than females and generally
occurs in patients that have not sought medical intervention at an earlier
stage and have not adapted their lifestyle to halt the progression of
symptoms.

Ocular involvement in rosacea is found to occur in as much as 50% of
patients [2]. Symptoms include sties, chalazia, iritis and frequently
blepharitis and conjunctival hyperaemia.


GASTROINTESTINAL DISORDERS IN ROSACEA

The aetiology of rosacea remains a mystery. A variety of oral antibiotics
have been found to produce symptomatic improvement in many patients,
occasionally resulting in a temporary remission of symptoms upon first use.
However, the disease tends to relapse and the long-term effectiveness of
antibiotics is less reliable. Amongst the many antibiotics that have been
found to be active in treating rosacea symptoms, metronidazole has been
found to be particularly effective, followed by tetracyclines [3].
Clarithromycin has also been found to be beneficial in rosacea treatment
[4]. It is currently not known how antibiotics influence the pathogenesis of
rosacea.

Throughout the literature there has been a consistent thread of reports
describing a variety of digestive disorders in association with rosacea.
Rosacea has been reported in association with ulcerative colitis [5,6],
Crohn’s disease [7,8], gastritis [9,10], coeliac disease [11], food
allergies [12], hypochlorhydria [13,14], chronic constipation [15,16],
abnormalities in jejunal mucosa [11,17], reduced lipase secretion [18] and
Helicobacter pylori infection [19,20]. Correlations between the severity of
rosacea symptoms and the severity of digestive disease have also been
reported [8]. This author has also observed a high incidence of irritable
bowel syndrome in rosacea patients.

Early investigations into the involvement of hypochlorhydria in rosacea
found that symptoms can be considerably improved with hydrochloric acid
supplementation with food and this has been confirmed in later studies [21].
Such improvement has also been observed by this author.

H. pylori infection is the most recent hypothesis put forward in the
search for an underlying cause for rosacea. The appeal of H. pylori is that
it could simultaneously explain the frequent occurrence of gastritic
symptoms in rosacea patients and the efficacy of metronidazole and other
antibiotics. This has had a mixed response, with some studies finding a
higher incidence of infection among rosacea patients versus controls whilst
others have not. There have been a small number of “cures” reported
following H. pylori eradication. However, with over eight years of
investigation, eradication therapy seldom produces long-term improvement in
rosacea symptoms and no studies have demonstrated H. pylori infection in all
rosacea patients, so it would seem unlikely that H. pylori could be
responsible for causing rosacea in the majority of cases.

The frequent occurrence of multifarious digestive ailments continue to be
reported in rosacea patients, but as yet no satisfactory explanation has
been given to account for their occurrence. Furthermore, a large subset of
rosacea patients appear not to suffer any digestive symptoms at all.


NEUROGENIC INFLAMMATION AND INVOLVEMENT OF THE KALLIKREIN-KININ SYSTEM

The vascular symptoms in rosacea patients appear to involve neurogenic
inflammation. It has been found that substance P-immunoreactive neurons are
increased considerably around blood vessels in the papillary dermis in
lesional skin in rosacea patients compared with normal skin from similar
locations [22]. This is also consistent with the vascular hypersensitivity
observed in rosacea patients. Neurogenic inflammation can be triggered by a
variety of stimuli including noxious substances, heat, mechanical
stimulation etc. These same stimuli are also well known to produce acute
exacerbation of rosacea symptoms.

Particular mention is often made of the severe worsening of rosacea
symptoms following consumption of very spicy foods. Capsaicin, a vanilloid
found in hot peppers, is a substance that has a potent capacity to stimulate
afferent neurons and to induce neurogenic inflammation [23]. It would seem
likely that the pronounced worsening of rosacea symptoms following ingestion
of spicy foods is due to stimulation of afferent neurons by capsaicin or
similar substances.

Rosacea associates very significantly with migraine. In one study, 44% of
rosacea patients suffered migraine compared with 13.1% of controls (P <
0.0005) [24]. Another study found 27% of rosacea patients suffered migraine
compared to 13% in controls (P < 0.001) [1]. This suggests that rosacea is
part of a more general underlying vascular disorder. This also further
supports the involvement of neurogenic inflammation in producing vascular
symptoms, since neurogenic inflammation has been widely implicated in the
pathogenesis of migraine [25,26].

Supposing rosacea symptoms are a consequence of neurogenic inflammation
originating from facial afferent neurons, what could cause these neurons to
become hypersensitive in rosacea patients?
It is well known that bradykinin, a vasoactive nonapeptide, is capable of
stimulating neurogenic inflammation in afferent neurons. More importantly,
it has the capacity to sensitize afferent neurons, thereby reducing the
stimulatory threshold for firing and increasing responses to suprathreshold
stimuli.

Three studies have investigated the kallikrein-kinin system in rosacea
patients. In two studies, it was found that plasma concentrations of
pre-kallikrein and kallikrein inhibitors were significantly reduced in
rosacea patients versus controls (P < 0.01) [27,28] indicating activation of
the plasma kallikrein-kinin system. In another study, plasma bradykinin
concentrations were directly measured before and during a flushing episode
induced by the consumption of beer. It was found that bradykinin levels
increased in all patients during the flushing episode on average by 60% (P <
0.01) [29].

These studies support the involvement of the kallikrein-kinin system in
the pathogenesis of rosacea. However, given the increased numbers of
substance P-immunoreactive neurons and the vascular hypersensitivity
observed in rosacea skin, it would seem more likely that it is not the
direct vasoactivity of bradykinin (as suggested in these studies) that is
responsible for rosacea symptoms, but that bradykinin is stimulating and
sensitizing afferent neurons and that the resulting neurogenic inflammation
is responsible for the expression of rosacea symptoms.

The manner by which bradykinin induces hypersensitivity in afferent
neurons offers further evidence supporting its role in the pathogenesis of
rosacea. An increased plasma concentration of bradykinin is not in itself
likely to induce widespread neurogenic inflammation. Instead, it appears
that local inflammation and the presence of other inflammatory mediators, in
particular prostaglandin E2 (PGE2), are necessary for afferent neurons to
undergo sensitization to bradykinin.

PGE2 is capable of sensitizing neurons to bradykinin and moreover,
recruiting other neurons that express substance P which are normally
unresponsive to bradykinin [30]. It has also been demonstrated that neurons
that do not normally express substance P, can begin to express substance P
following chronic inflammation [31]. This could account for the observed
increase in substance P-immunoreactive neurons in the surrounding tissue of
the papillary dermal vasculature in rosacea.

The requirement for an initiating phase of inflammation to induce rosacea
symptoms is consistent with many case histories. There have been a number of
reports describing the development of rosacea following PUVA therapy for
psoriasis [32] as well as frequent reports of acute overexposure to UV
inducing rosacea [9].

UV-induced inflammation is primarily mediated by PGE2 and both
inflammation and PGE2 concentrations are further augmented by prior
administration of methoxypsoralen and moreover, inflammation is completely
inhibited by the application of indomethacin [33].

A number of accounts of irritating facial cosmetics and topical acne
medications inducing rosacea are also known to this author. However, it
also seems that frequently the initiation of rosacea is not distinguished by
a single event and the emergence of symptoms is gradual, although UV
exposure probably remains an important factor in its eventual development
given the considerably higher incidence of rosacea in individuals with fair
skin.

The potential for PGE2 to sensitize afferent neurons to bradykinin is
attenuated by inhibition of adenylyl cyclase. This suggests that the
effects of PGE2 are mediated by activation of the cyclic AMP transduction
cascade [34]. Other substances that are capable of activating the cAMP
pathway are also capable of sensitizing afferent neurons to bradykinin [35].

It is well known that long-term use of topical cortisone preparations
frequently precipitate the development of rosacea [36]. It has been found
that incubation of skin in hydrocortisone for more than 6 hours, causes a
marked increase in cAMP accumulations versus controls after exposure to
adrenaline [37]. It is possible that long-term application of topical
corticosteroid preparations increase activation of the cAMP pathway in
facial skin, thereby sensitizing afferent neurons to bradykinin leading to
the development of rosacea symptoms.


DIGESTIVE DISORDERS AND ACTIVATION OF THE KALLIKREIN-KININ SYSTEM

Given that activation of the plasma kallikrein-kinin system has been
consistently observed in rosacea patients and also given the frequent
occurrence of inflammatory digestive disorders in patients, it seems
plausible to speculate that these distinct observations may be related.

Inflammatory digestive disorders are frequently accompanied by activation
of the plasma kallikrein-kinin system. It has been found that
kallikrein-kinin activation frequently occurs in patients with gastritis and
related symptoms including H. pylori induced gastritis [38,39]. Similarly
it has been found that the plasma kallikrein-kinin system is frequently
activated in patients with inflammatory bowel disorders (IBD) [40,41] .

However, many rosacea patients do not apparently suffer any detectable
gastrointestinal disease, although this group of patients still exhibit
significant activation of the plasma kallikrein-kinin system versus controls
(P < 0.01) [28] and the majority of these patients still exhibit a similar
response to antibiotic therapy.
The same antibiotics that have proven effective in treating rosacea, and
particularly metronidazole, have also been demonstrated to be effective in
treating inflammatory digestive disorders, in particular Crohn’s disease
[42,43] , but also colitis [44] and even irritable bowel syndrome [45].

Considerable evidence exists indicating that the activity of antibiotics
in treating IBD symptoms is due to their activity against ordinary resident
bacteria in the intestines. It is becoming increasingly accepted that
luminal bacteria within the intestines play a primary role in the
pathogenesis of IBD and are capable of both inducing and perpetuating
chronic intestinal inflammation [46, 47].

Crohn's disease preferentially localises in areas of highest bacterial
concentrations and areas of relative stasis. Not only can broad spectrum and
anaerobic specific antibiotics significantly improve inflammation, but so
can bowel rest with total parenteral nutrition, elemental diets and surgical
bypass [48], all of which would decrease bacterial populations.

Furthermore, IBD patients demonstrate evidence of both humoral and
cell-mediated immune responses to normal indigenous microflora [49].

Experimental animal models give the clearest evidence that resident
luminal bacteria play a crucial role in the development and perpetuation of
IBD. Interleukin (IL)-10 deficient (knockout) mice develop aggressive small
intestinal and colonic inflammation in a conventional laboratory environment
[50]. However, in mice that are reared in a germ-free (sterile) environment,
there is no evidence of any intestinal inflammation by sensitive
histological or immunological parameters [51]. Furthermore, existing
colitis in IL-10 deficient mice can be attenuated by administration of
neomycin and metronidazole [52].

The development of aggressive intestinal inflammation is likely to involve
a complex interaction between genetic factors and environmental conditions,
but resident microflora in the lumen of the intestine appear to be the
constant antigenic stimulus driving the inflammatory reaction.

Similarly, exposure to luminal bacteria also appears capable of activating
the plasma kallikrein-kinin system. The plasma kallikrein-kinin system can
be activated in genetically susceptible Lewis rats following intestinal
intramural injection of peptidoglycan-polysaccharide polymers (PGPS), which
are the primary structural components of cell walls in nearly all bacteria
[53,54]. Furthermore, specific inhibition of plasma kallikrein modulates
inflammatory symptoms in experimental IBD induced by intramural injection of
PGPS [55], indicating involvement of the plasma kallikrein-kinin system in
the pathogenesis of IBD.

Given the likely role that luminal bacteria play in driving the
inflammatory response in IBD and in activating the plasma kallikrein-kinin
system in such conditions, and given the fact that both IBD and rosacea
symptoms respond to the same profile of antibiotics and that rosacea
patients consistently exhibit plasma kallikrein-kinin activation with or
without the presence of IBD symptoms, it was decided to investigate whether
luminal bacteria could play a role in the pathogenesis of rosacea in
patients without IBD symptoms.

PATIENT AND METHODS
A 24-year-old male rosacea patient who had suffered moderate erythematous
rosacea for 6 years was investigated. The patient did not suffer any
detectable digestive disease, except possibly mild abdominal bloating.
Apart from rosacea, the patient also suffered Raynaud’s syndrome, infrequent
migraine and occasional episodes of cluster headaches. The patient also
suffered as a child from asthma, severe migraine and suspected, but
undiagnosed attention deficit hyperactivity disorder. Various oral
antibiotic treatments had been employed during the course of the patient’s
rosacea with varying success, but symptoms relapsed on all occasions. The
patient was not taking any medication at the time of the investigation.

It was decided that in order to investigate the involvement of luminal
bacteria in the pathogenesis of rosacea an entirely new method would be
employed to reduce bacterial populations in the intestines. 30g of coarse
wheat bran was mixed with warm water and a small amount of sugar to improve
the taste. This mixture was consumed 30 minutes to 1 hour after each of the
three major meals of the day. Fluid consumption was also increased.

The wheat bran was intended to sweep through the digestive tract and to
significantly reduce the transit time of food through the intestines. This
would inhibit stasis of digesta in the intestines, thereby inhibiting
excessive fermentation of food by bacteria and ultimately reducing bacterial
populations within the intestines.

RESULTS
Whole gut transit time (WGTT) was measured to be >70 hours prior to
treatment.

After 7 days of treatment, WGTT was measured to be 28 hours. Stool
frequency and size was significantly increased. Rosacea symptoms were
markedly improved with reduced erythema and reduced sensitivity of the
facial skin.

After 14 days of treatment, there were no apparent symptoms of rosacea.
The facial skin appeared normal and without detectable erythema. All
vascular hypersensitivity was abolished and the patient no longer
demonstrated a tendency to flush. The patient’s Raynaud’s symptoms were
also eliminated and although not measured the patient’s abdominal bloating
was visibly reduced.

The treatment was continued for a further 5 weeks and the full remission
of symptoms was maintained during this period. The patient also reported
remission from migraine and cluster headaches during this period. However,
during the 6th week the patient reported an acute burning sensation
emanating from the duodenal region. After a further day, the burning
symptoms worsened and the patient’s rosacea symptoms returned with great
severity. The patient’s cheeks and nose were profoundly erythematous with
considerable oedema. Ocular involvement was also present with severe
conjunctival hyperaemia and blepharitis. The patient also reported
persistent migraine symptoms and episodes of bronchoconstriction.

Ingestion of further wheat bran was discontinued and the patient’s
symptoms rapidly attenuated within 4 days. Although, not in full remission,
the patient’s rosacea symptoms remained considerably improved from prior to
treatment.

It was considered that the patient may have developed an intolerance to
wheat bran, so after symptoms had fully stabilized and all burning symptoms
had resolved, the wheat bran was re-administered. Within 2 days the burning
symptoms returned and rosacea symptoms rapidly worsened again. Wheat bran
was discontinued and two months later the patient was tested for coeliac
disease, which proved negative. The patient continued to experience
worsening of rosacea symptoms following the consumption of wheat products
for the following 6 months. After 12 months and considerable avoidance of
wheat the patient was able to resume moderate consumption of wheat products
without detectable worsening of rosacea symptoms.

DISCUSSION
It is difficult explain the positive influence of wheat bran on the
symptoms of rosacea, except in terms of its effects on the contents and
function of the digestive tract. The wheat bran diet will have considerably
reduced luminal bacterial populations in the intestines and given the
similar response of symptoms that can result from antibiotic treatment in
rosacea patients and the evidence supporting the involvement of intestinal
bacteria in the pathogenesis of IBD which frequently coexists in rosacea
patients, it would seem likely that the wheat bran diet also induced
remission of rosacea symptoms in this patient without IBD, by decreasing
luminal bacterial populations.

The acute worsening of rosacea symptoms following prolonged consumption of
wheat bran and the simultaneous development of burning symptoms emanating
from the duodenal region suggest that the wheat bran itself was also capable
of provoking rosacea symptoms, but that this relapse was unlikely to involve
intestinal bacteria. This is further evidenced by the rapid resolution of
symptoms following discontinuation of wheat bran and that after resolution
symptoms remained improved from prior to treatment. As stated earlier, both
food allergies [12] and coeliac disease [11] have been reported in
association with rosacea.

Therefore, it would seem unlikely that rosacea symptoms are mediated by
substances released directly by bacteria in the digestive tract as has been
hypothesized in earlier studies[19], but that rosacea symptoms are mediated
by substances released by the digestive tract in response to
inflammation/exposure to aggravating material. Given the involvement of the
plasma kallikrein-kinin system in rosacea patients, it would appear that in
the investigated patient, rosacea symptoms resulted from chronic activation
of the plasma kallikrein-kinin system due to chronic exposure to intestinal
bacteria.

Larger studies should be conducted on rosacea patients to investigate the
possible involvement of intestinal luminal bacteria in the pathogenesis of
rosacea.


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