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A new explanation for rosacea

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  • S K
    Message 1 of 3 , Feb 28, 2003

      S Kendall


      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


      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

      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.


      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

      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.


      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

      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

      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.


      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.

      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.

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

      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

      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.

      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

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


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    • joerg p
      hello S Kendall, thanks for sharing your study. ... Wouldn t it be helpful to have a questionary in the net? Something like: Do you ever had symptoms with
      Message 2 of 3 , Mar 1, 2003
        hello S Kendall,

        thanks for sharing your study.

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

        Wouldn't it be helpful to have a questionary in the net?

        Something like:
        Do you ever had symptoms with wheat? y/n
        How do you react on antibiotics? y/n

        I think somebody who researched a lot like you, should know a lot of
        important questions to ask rosacea sufferers...

        I actually always had a problem with yeast until I was 25. I got skin
        problems in my face like burning skin at the eyes and bleeding lips. I took
        Nystatin and the problems disappeared.
        Now I am 30 and have rosacea since 3 years.

      • madamzara <PBVAssociates@aol.com>
        very interesting read!! I have long since thought that my rosacea was linked with my digestive system. This was confirmed when i was eating very little after
        Message 3 of 3 , Mar 1, 2003
          very interesting read!! I have long since thought that my rosacea
          was linked with my digestive system. This was confirmed when i was
          eating very little after a traumatic personal situation and my
          flushing disappeared.

          At the moment i am eating a mainly alkaline diet and find that the
          few spots i had have now gone and my skin looks so much better. The
          flushing is still evident unfortunately.

          It is my belief that a breakthrough in understanding what causes
          rosacea will come about through a sufferer, as we have more reason to
          put in the time to research. So i would like to thankyou very much
          for all the work you have obviously put in and look forward to
          hearing more in the future.

          --- In rosacea-support@yahoogroups.com, joerg p <superbla3000@g...>
          > hello S Kendall,
          > thanks for sharing your study.
          > > Larger studies should be conducted on rosacea patients to
          investigate the
          > > possible involvement of intestinal luminal bacteria in the
          pathogenesis of
          > > rosacea.
          > Wouldn't it be helpful to have a questionary in the net?
          > Something like:
          > Do you ever had symptoms with wheat? y/n
          > How do you react on antibiotics? y/n
          > I think somebody who researched a lot like you, should know a lot of
          > important questions to ask rosacea sufferers...
          > I actually always had a problem with yeast until I was 25. I got
          > problems in my face like burning skin at the eyes and bleeding
          lips. I took
          > Nystatin and the problems disappeared.
          > Now I am 30 and have rosacea since 3 years.
          > joerg
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