JOURNAL OF PHYSIOLOGY AND PIIARI\IACOLOGY 1999, 50, 5, 777-786
`
`A. SZLACHCIC, Z. SLIWOWSKI, E. KARCZEWSKA, W. BIELANSKI,
`J. PYTKO-POLONCZYK *, S.J. KONTUREK
`
`HELICOBACTER PYLORI AND ITS ERADICATION IN ROSACEA
`
`Department of Physiology and *Department of Conservative Dentistry, University School of
`Medicine, Cracow, Poland.
`
`Rosacea is a common condition of unknown etiology usually accompanied by
`to
`the
`treatment with
`gastrointestinal symptoms and favorably responding
`antibiotics. This study was designed
`to examine
`the prevalence of gastric
`lle/icobacter pylori (Hp) infection verified by 13C-UTB-test, CLO, Hp culture and
`serology (IgG) in patients with rosacea. Gastroduodenoscopy was combined with
`pentagastrin secretory test and antral and fundic biopsy samples were taken for
`histological evaluation (the Sydney system). Blood samples were also taken for the
`determination of plasma gastrin using RIA and plasma interleukin (IL)-8 and tumor
`necrosis factor alpha (TNFa) using ELISA. This study was performed in 60 patients,
`31-72 year old, with visible papules and pustules associated with erythema and
`flushing on the face and on 60 age- and gender-matched patients without any skin
`diseases but with similar as in rosacea gastrointestinal symptoms but without
`endoscopic changes in gastroduodenal mucosa (non-ulcer dyspepsia - NUD). The
`Hp prevalence in rosacea patients was about 88 % as compared to 65% in control
`NUD patients. Among rosacea patients, 67% were cytotoxin associated gene
`A (CagA) positive, while in NUD patients .only 32% were CagA positive. Rosacea
`patients showed gastritis with activity of about 2.1 in antrum and 0.9 in the corpus of
`the stomach while those with NUD only mild gastritis with activity of -1.0)
`confined to the antrum only. Following initial examination, typical 1 wk anti-Hp
`therapy including omeprazole (20 mg bd.), clarithromycin (500 mg bd.) and
`metronidazol (500 mg bd.) was carried out. After eradication, 51 out of 53 treated
`rosacea patients became Hp negative. Within 2~ weeks, the symptoms of rosacea
`disappeared in 51 patients, markedly declined in 1 and remained unchanged in
`1 other subject. A dramatic reduction in activity of gastritis (to 0.3 in antrum and to
`0.1 in corpus) was observed. Basal plasma gastrin decreased from 48 ± 5 pM before to
`17 ± 3 pM after eradication, while pentagastrin-induced maximal (MAO) declined,
`respectively, from about 16.6 ± 4.2 to 8.5 ± 1.8 mmoljh. Plasma TNFa: and IL-8
`were reduced after the therapy by 72% and 65%, respectively. We conclude that: 1)
`Rosacea is a disorder with various gastrointestinal symptoms closely related to
`gastritis, especially involving the alllrum mucosa, with Hp expressing cagA in the
`majority of cases and elevated plasma levels of TN Fa and IL-8; 2) The eradication of
`Hp leads to a dramatic improvement of symptoms of rosacea and reduction in
`related gastrointestinal symptoms, gastritis, hypergastrinemia and gastric acid
`secretion; and 3) Rosacea could be considered as one of the major extragastric
`symptoms of Hp infection probably mediated by Hp-rclated cytotoxins and
`cytokines.
`
`Key words: Rosacea, llelicobacter pylori, cytotoxins, /L-8, TNFet, gastric mucosa, gastrin
`
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`Journal of Physiology and Pharmacology
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`INTRODUCTION
`
`Rosacea belongs to the group of chronic skin diseases involving about 2%
`of the population and most often appears in adults usually in their thirties and
`older (1). Although more frequent in women, the symptoms are more intensive
`in men (2). The skin changes are symmetrical and located mainly in the middle
`area of the face. Still, they can also appear on the neck and legs. At first, they
`are characterized as erythematous changes, which with
`time
`lead
`to
`teleangiectasia, papular and pustular eruption, an overgrowth of connective
`tissue and sebaceous glands, especially in men (rhinophyma (3, 4, 5). Except for
`the classic rosacea, there are also atypical forms: circumscribed, diffuse,
`extra-facial, conglobata, fulminant or granulomatous (3, 5).
`The course of rosacea is chronic with periodic improvement or aggravation.
`It was noted that the worsening of skin changes can occur after excessive
`exposure to ultraviolet light and stress, after alcohol intake, strong coffee or hot
`food etc. Additionally, a connection between intensified rosacea and hormonal
`changes during menstruation period or menopause in women has been noticed
`(3-5).
`Except for the skin, eye changes occur with the characteristics of eyelid
`inflammation, conjunctivitis,
`iritis. Besides, gastric disorders such as
`hypochlorhydria, gastritis and peptic ulcer disease (3, 4, 5) have also been noted.
`Despite numerous studies, the pathogenesis of rosacea remains unknown. It
`is assumed that the development of skin changes is caused by many, unrelated
`factors. It is believed that, dependent on emotional factors or resulting from
`excessive vessels' sensitivity to endogenous opiates or its excessive secretion,
`vasomotor disorders play a marked role (6, 7). Moreover, it has been observed
`in patients with rosacea an increased concentration of substance P, which has
`an influence on vasodilation and a local inflammatory reaction (8).
`No relation between the degree of the development in skin changes and
`seborrhea has been noted despite the location of the skin symptoms in so called
`seborrheic areas (9).
`Intensified skin changes during menstruation and their aggravation in
`women during menopause suggest hormonal factors in the pathogenesis of
`rosacea (4).
`The occurrence of Demodex folliculorum in hair follicles and sebaceous
`glands located within the skin changes could indicate their participation in the
`pathomechanism of rosacea. Although can be found more often in the affected
`areas, it can be also found in skin appendages in healthy patients (10-12).
`In patients with rosacea, digestive dosorders such as achlorhydria, gastritis
`or even chronic peptic ulcer disease are very often observed (3-5, 13-16). At
`present it is known that Helicobacter pylori {Hp) plays the key role in the
`development of gastritis, peptic ulcer, MALT lymphoma or even gastric cancer
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`strongly suggesting an involvement of the bacterium also in the mechanisms
`of certain skin changes diseases. Hp is a spiral bacterium which, is linked
`to B-form of gastritis, and the release of various noxious substances including
`platelet activating factor (PAF), lipopolysaccharides (LPS), cytotoxins such
`as CagA and VacA proteins and numerous cytokines originating from the
`host cells such as interleukin (IL)-8, ILl p, TNFrt, ammonia due to high
`to
`the
`urease activity and others. These substances may contribute
`inflammation of gastric mucosa, alterations in gastric acid secretion ranging
`from achlorhydria in acute phase of infection with pangastritis to gastric
`hyperchlorhydria in chronically infected patients with typical chronic active
`antritis and high plasma gastrin levels. In addition, there is an increase in
`production of IgG and lgA antibodies to Hp in gastric juices and in the
`plasma (17-20).
`This study was designed: 1) to establish the prevalence of Hp infection in
`the stomach of patients with rosacea symptoms as based on standard Hp
`detection tests, 2) to assess the relation between the colonization of the gastric
`mucosa with Hp and the symptoms of rosacea, and 3) to compare the
`co-existence of the Hp infection in the stomach and skin disorders before and
`after the application of one-week triple therapy (omeprazol + clarythromycin
`+ metronidazol).
`
`MATERIAL AND METHODS
`
`The studies were performed on 60 control subjects without any demonstrable endoscopic
`gastroduodenal changes but with various subjective gastrointestinal symptoms of non-ulcer
`dyspepsia (NUD) similar to those recorded in rosacea patients and on 60 patients with rosacea, all
`aged between 30 and 70 years. Skin symptoms were evaluated on a three grade scale;
`I -
`erythematous alone, erythematous and papular; II -
`papular, papulo-pustular and
`teleangiectasias; III -· inflammatory infiltration, nodulous changes, rhinophyma (5).
`The tests were conducted before and after four weeks of anti-Hp therapy. Patients had no
`ailments in other organs and took no antibiotics for at least four weeks prior to the tests. All
`patients underwent gastroscopy during which mucosal biopsy samples were taken from the
`stomach (from amrum and from corpus) to perform a rapid urease CLO-test (Jartox-H.p.-test,
`Procter and Gamble, Pharmaceutical, Wcitcrstradt, Germany) and bacterial culture from biopsy
`samples on special agar plates with the addition of 5% of horse serum and antibiotics blocking the
`growth of bacteria others than Hp. Furthermore, the biopsy samples of antral and fundic mucosa
`were taken for histological evaluation using Sydney classification. To confirm the Hp infection in
`
`the stomach, the 13C-urca breath test e3C-UBT) was performed as described before (21).
`
`Additionally, the level.of lgG anti-Hp and anti-CagA antibodies were measured in plasma by
`ELISA as described before (21). Blood samples were withdrawn under basal conditions for
`determination of plasma gastrin by radioimmunoassay and TNFa: and intcrlcukin-8 (IL-8) using
`· ELISA as described before (21). Finally, gastric secretory test was performed during the endoscopy
`using single dose (2 Jlg/kg) of pentagastrin (Pcptavlon, Zcncca, Macclesfield, Cheshire, UK) injected
`i.m. 10 min before the start of the start of endoscopy. The gastric juice present in the stomach was
`removed and then aspirated during 10 min of gastric endoscopy as described before (22). The
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`volume of collected juice was mutliplied by H+ concentration and again multiplied by 6 to express
`the H + output in mmolfh.
`All patients with a diagnosed Hp infection underwent a one-week triple therapy (23, 24)
`including omeprazol 2x20 mg, clarytromycin 2x500 mg and metronidazol 2x500 mg. Despite
`symptoms no other dermatological treatment was applied 10 days before and during anti-Hp
`therapy.
`Four weeks after the completion of the therapy, all laboratory tests were repeated to establish
`the effectiveness of the applied therapy. The results were statistically analysed by means of the chi
`2 test, with a significance degree of p<0.05.
`
`RESULTS
`
`In the group of 60 patients with rosacea, 53 (88.3%), while in 60 age-and
`gender-matched NUD controls only 69 (65%) had the Hp infection as
`least
`two of Hp
`confirmed by at
`(Fig. 1). The largest number of the infected patients were between 41-50 years
`of age (20 patients -
`37.7%) and the smallest number aged between 31-60
`5.6%) (Fig. 2). The Hp positivity was detected in 88% of
`years (3 patients -
`rosacea patients and in 65% in NUD controls was largely observed in
`
`tests e3C-UBT, CLO, culture
`
`100
`
`c 80
`CJ)
`0
`c
`... 60
`11'1
`--~
`0
`.c
`- 40
`
`11'1
`c:
`Q)
`:;:
`c
`0.
`0 20
`~ 0
`
`0
`
`CLO
`Gastric culture
`UBT
`
`Hp (+)
`(+)
`(+)
`
`Hp (-)
`(-)
`(-)
`
`N =60
`
`100
`
`c 80
`::::>
`z
`.c
`:= 60
`~
`
`11'1 -
`-
`
`c:
`Q)
`:40
`c
`0.
`0
`a-!! 20
`
`0
`
`Hp (+)
`(+)
`(+)
`
`Hp (-)
`(-)
`(-)
`
`Fig. 1. The Hp positivity measured by CLO, culture and UBT in rosacea and NUD controls
`Asterisk indicates significant decrease below the value obtained in rosacea patients.
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`patients between 31 and 60 years of age. The overall difference
`Hp
`prevalence between rosacea patients and NUD comrols was statistically
`significant (Fig. 1),
`
`781
`
`N=53
`("rolal number of patlents N=60)
`
`41-:-50
`years old
`
`51+60
`years old
`
`6 +70
`years old
`
`Fig. 2. Th~ age distribution of Hp positive patients with rosacea.
`
`Fig. 3 shows the occurrence of gastrointestinal symptoms in patients with
`rosacea and the presence of Hp in their stomach. Among 52 rosacea patients
`reporting a variety of gastrointestinal symptoms, e.g., heartburn, flatulence,
`the group
`belching, light pain, diarrhea, etc., 47 were Hp-positive,
`without symptoms (8 patients) the presence of the bacterium was found
`6 patients. Among NUD controls
`patients showed gastrointestinal
`symptoms irrespective whether they were Hp positive or
`negative.
`Ba.sed on the histological examination of biopsy specimens taken from
`gastric mucosa, it was established (based on the classification of inflammatory
`changes according to the Sydney system) that the largest proportion of rosacea
`patients,
`i.e. 72%, exhibited
`the histologically chronic active gastritis,
`predominantly involving the antral portion of the stomach (antritis). In about
`0%
`patients chronic active multifocal inflammation of the stomach
`(gastritis mult{/ocalis), and in remaining 18% antritis and chronic inflammation
`of the body of the stomach (corpusitis) were found (Fig. 4). In NUD controls,
`only antral chronic active gastritis without involvement of the fundic gland
`area was found in histology.
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`',,,, Without gastric
`symptoms
`
`Hp (+)
`
`Hp (-)
`
`Fig. 3. The occtirrencc of g«strointestinal symptoms in Hp positive and
`patients.
`
`negative rosocea
`
`Gastritis
`, - - - - -
`multifocalis
`
`Corpusitis
`
`Fig. 4. Histology findings in the antrum and corpus of the stomach in rosucea patients.
`
`patients with Hp infection in
`Based on serological tests, it turned out that
`the stomach, the plasma anti-Hp antibodies of lgG class were present in about
`88%
`infected patients and antibodies to CagA in about 67'% of these
`patients (Fig. 5). These seroprevalence of anti-Hp and anti-CagA antibodies
`between rosacea patients and NUD controls was statistically significant
`of 53 Hp-positive patients with typical for rosacea skin changes, the
`anti-Hp therapy resulted in Hp eradication in all treated patients as confirmed
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`detecting tests. The cutaneous rosacea ~ymptoms
`by at least two of the
`disappeared or fully receded
`51 patients, markedly declined
`one but
`remained unchanged in one other patients (Fig.
`
`783
`
`'100
`
`I
`
`80
`
`(j)
`>
`:;:::
`·;;; 60
`0
`0..
`l!J
`Ol
`0 40
`~~
`
`20
`
`0
`
`Rosacec
`
`NUD
`
`Fig. 5. Serum levels of lgG anti-Hp and anti-CagA antibodies to Hp in patients with rosacea and in
`'KUD controis. Asterisk indicates significant decrease below the value obtained in rosacea patients.
`
`II) -t:
`
`.!!!
`0
`a.
`0
`~
`
`Fig. 6. Dermatological effects of Hp eradication.
`
`triple therapy
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`Serum levels of TNFa. and IL-8 were reduced after anti-Hp therapy by 72
`and 65%, respectively. Serum gastrin level that under basal conditions
`amounted to about 48 ± 5 pM was reduced after Hp therapy by 35%.
`Maximal gastric acid secretion induced by pentagastrin that averaged about
`16.6 ± 4.2 mmol/h in rosacea patients before the anti-Hp therapy was
`significantly reduced to about 8.5 ± 1.8 mmol/h 4 weeks upon the completion
`of this therapy.
`
`DISCUSSION
`
`Hp is an undoubtly the most common cause of infection of the world
`dimention and is usually accompanied by gastritis and various gastrointestinal
`symptoms that favorably respond to antibiotic therapy (25). The major interest
`in Hp-related diseases has so far been focused on local gastro-duodenal disorders
`induced by the inoculation of gastro-duodenal mucosa by Hp and resulting in
`gastritis, peptic ulcerations, gastric cancer and MALT lymphoma (25).
`More recently numerous publications described an association, mostly
`based on epidemiological studies, between the gastric Hp infection and certain
`extragastric symptoms of this infection including cardio-vascular system (26),
`extragastric MALT lymphoma (26), food allergy (27), certain skin diseases (28)
`and others described, in part, in this issue of this Journal.
`Our present results provide an evidence that rosacea could be considered as
`one of major extragastric manifestations of Hp infection in the stomach. We
`found that the prevalence of Hp infection in rosacea patients was significantly
`higher than in age- and gender-matched controls as documented by 13C-UBT,
`CLO, culture and serology. Also the expression of Hp-related CagA cytotoxin
`was significantly higher in rosacea patients (about 67%) than in age- and
`gender-matched controls (32%). The seropositivity of CagA and significantly
`elevated serum levels of proinflammatory cytokins such as TNFa. and IL-8,
`were probably the major factors in the pathogenesis of rosacea symptoms.
`These factors could also explain the presence of chronic active gastritis in all
`subjects tested and confined predominantly to the antrum (antritis) and less
`often to the corpus (cmpusitis) in our rosacea patients.
`The major support for the notion that Hp infection is strongly associated
`with rosacea
`is provided by our finding
`that
`the successful anti-Hp
`therapy, including antibiotics (clarythromycin +metronidazole) combined with
`omeprazole, was followed by the disappearance of the rosacea symptoms in
`almost all patients and also caused a marked reduction in gastrointestinal
`symptoms. Also, the serum levels of proinflammatory cytokines such as TN A a.
`and IL-8, were dramatically reduced (by 72% and 65%, respectively) following
`such anti-Hp therapy.
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`As critically discussed in present issue of this journal by \Vedi and Kapp
`(27), various skin diseases have been linked to Hp infection with best
`evidence for such association found with urticaria and rosacea. The major
`problems with clear cut documentation of this linkage are various confounding
`factors, especially properly selected control group, which have to be taken
`under consideration in epidemiological studies related to this linkage. So
`far only Bamford et a/. (28), conducted the double-blind placebo control
`randomized study but, while in their study no difference was found in the
`Hp prevalence between rosacea and their double-blind controls, they also
`showed marked improvement of the rosacea symptoms thought it was
`irrespective to the presence of Hp infection. Authors concluded, therefore,
`that Hp is not the major determinant of the presence, severity and extent
`of rosacea.
`Our results confirms, in part, these finding by showing that: 1) the Hp
`prevalence is significantly higher in the rosacea patients than in age- and
`gender, and 2) the anti-Hp therapy is highly efficient in the reduction in the
`rosacea symptoms. Our conclusions differ, however, from those of Bamford et
`a/. (28), as we demonstrated for the nrst time that not Hp alone. but the
`Hp-related virulence factors (CagA) and cytokines (TNFet, IL-8) are probably
`the major pathogenic factor in the Hp-infected rosacea patients and that the
`eradication of Hp in the rosacea patients abolish both the cutaneous and
`gastrointestinal symptoms. Furthermore, the anti-Hp therapy dramatically
`improved the histology of the gastric mucosa and restored highly elevated
`plasma gastrin level and elevated gastric acid secretion. Thus, it is reasonable
`to accept that CagA positive Hp and various Hp-related cytokines contribute
`to the pathogenesis of rosacea and accompanying gastrointestinal symptoms.
`
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`
`Received: October 28, 1999
`Accept c d: November 24, 1999
`
`Author's address: A. Szlachcic, Department of Physiology Univ. Med. School, Cracow,
`Poland.
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