Int. J. Med. Sci. 2015, Vol.

12 387

Ivyspring
International Publisher International Journal of Medical Sciences
2015; 12(5): 387-396. doi: 10.7150/ijms.10608
Review

Major Pathophysiological Correlations of Rosacea: A

Complete Clinical Appraisal
Ravi Chandra Vemuri1, Rohit Gundamaraju1, Shamala Devi Sekaran1, Rishya Manikam2
1. Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia
2. Department of Trauma and Emergency, University Malaya Medical Center, 59100 Kuala Lumpur, Malaysia.

Corresponding author: Ravi Chandra Vemuri, Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala
Lumpur 50603, Malaysia. Email: [email protected]; [email protected]. Prof. Dr. Shamala Devi Sekaran, Department
of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia. Email: [email protected]; sha-
[email protected]

2015 Ivyspring International Publisher. Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited.
See http://ivyspring.com/terms for terms and conditions.

Received: 2014.09.22; Accepted: 2015.01.08; Published: 2015.05.05

Abstract
Background: Rosacea is a characteristic cutaneous disorder with a diverse clinical manifestations
ranging from facial vascular hyper-reactivity to sebaceous gland hyperplasia. Many theories on
pathophysiology of rosacea were proposed over the past decade, however the pathogenicity is
poorly understood.
Aim: To review the evidence on different pathophysiological correlations of rosacea.
Methods: A literature search was conducted for studies published between 1990 to March 2014.
The inclusion criteria was pathophysiology, randomized controlled trials, controlled trials on
rosacea.
Results: Out of 5141 articles, 14 high quality studies met all the selection criteria. Of 14 articles,
5 are randomized control trials (RCTs), 2 are controlled trial, 3 comparative trials, 2 observational
trials, 1 prospective and 1 diagnostic trial. The studies were categorized into two groups: the
trigger factors and sub-types & symptoms. Of 7 high quality studies, 4 provided strong evidence
that immune responses causing disease triggered by external/internal factors such as sunlight, food
and chemical agents, 3 trials provided significant evidence of microorganisms as causative agents.
The remaining trials did not provide significant evidences on pathophysiology.
Conclusion: Vasculature, chronic inflammatory responses, environmental triggers, food and
chemicals ingested and microorganisms either alone or in combination are responsible for rosacea.
Many promising drugs are under various phases of clinical trials and interestingly, probiotics could
also possibly be used as one of the treatment option.
Key words: Rosacea; pathophysiology; vasculature; Chronic Inflammation; randomized control trials.

Introduction
Rosacea is a characteristic condition affecting cause burning sensation and soreness in the eyes [1-2].
skin by causing facial erythema or redness. Around 1 In more severe cases, the skin can become thicker and
in 10 people in the world are affected by rosacea. It is a enlarge on or around the nose and small blood vessels
chronic, inflammatory disease which is poorly un- in the facial skin become visible [3]. The disease can be
derstood due to its intricate reason of cause and onset triggered by certain psychological factors like stress
[1]. The disease affects the convexities of central face, and exposure to certain environment or allergens
firstly by triggering the redness on your nose, fol- [4-5]. Rosacea has resemblances with acne and other
lowed by cheeks, chin, and forehead, by causing skin disorders [2]. As with acne, there are some mi-
swelling and skin sores that look like acne. It can also croorganisms that seem to play a role in symptoms.

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Int. J. Med. Sci. 2015, Vol. 12 388

However, it is important to realize that rosacea is not are removed and total articles screened are 2680. Ap-
infectious, and cannot be transmitted from one plying inclusion and exclusion criteria, 2627 articles
person to another. From the recent studies it is re- were excluded, leaving 53 full-text articles under eli-
vealed that people with fair-skin are more prone to gibility criterion. 35 full-text articles were excluded
rosacea [6]. It is more common in women, but the from selected 53, as they do not fit for the literature. 14
symptoms are often more severe in men. The symp- full-text research articles were included for high
toms tend to recur, usually intermittent but can pro- quality synthesis. Figure 1 depicts the flow diagram of
gressively lead to permanently flushed or red (colour) selection process. Out of 14 articles, 5 are randomized
skin [7], as the skin may fail to return to its normal control trials (RCTs), 2 are controlled trial, 3 compar-
colour and the enlarged blood vessels and pimples ative trials, 2 observational trials, 1 prospective and 1
arrive in time. The latter may be described as high diagnostic trial. The 14 studies selected are conducted
colour and is associated with the development of all over the world, 5 trials are from USA, U.K (with 1
permanent telangiectasia [8]. Additionally, there are multicenter) and 3 trials are from France, and one
individual reports of facial edemas and gritty eyes. each from Ireland, Germany, Croatia, Georgia, Italy
Rosacea may rarely reverse itself and generally lasts and Libya. The sample size from all the studies rang-
for years, and, if untreated, it tends to gradually ing from n= 20 to n= 504. Included trials have got
worsen [9]. subjects from young to middle age, which helped us
The onset of the disease could be from childhood to correlate the occurrence of the disease in different
or early teen and exacerbates in adulthood due to age groups. Table 1 describes the detailed description
change in lifestyles, food, psychological factors. The of trials included.
symptoms of rosacea were also reported after excess Studies were grouped into two key intervention
intake of alcohol but not specific [10]. The exact cause areas: pathophysiology based on various trigger fac-
and mechanism of pathogenicity is still unknown, all tors (Sunlight, microorganisms, chemical and food
the proposed mechanisms were based on sheer ob- ingested, immune responses) and other based on
servations or correlations. specific symptoms & sub-types. Within these groups,
the quality synthesis of evidence is provided by using
Methods a narrative approach. Out of 14 trials, 6 RCTs inves-
A systematic literature review was conducted of tigated on various trigger factors and the rest of them
peer-reviewed articles published between 1990 and are based on the symptoms and sub-types. The study
March 2014 in the following databases: EMBASE, period among selected studies varied from 4 weeks to
PubMed and the Cochrane Central Register of Con- 12 months. Among all the studies, only one was mul-
trolled Trials (CENTRAL). The following search terms ticenter study by Casas et al. [25] conducted across the
were entered: rosacea or pathophysiology or ran- USA (n= 98) on Demodex, immune responses in
domized controlled trials or controlled trials. Refer- rosacea condition. 3 studies used the surgical proce-
ence lists within individual studies and review papers dures, blood samples of the patient to measure the
were screened to retrieve relevant studies. The fol- T-cell responses, peroxidase levels and inflammation
lowing general inclusion criteria were applied: (i) levels [19, 32, 48]. Only one study was an observa-
Types of study design: RCTs and other (ii) experi- tional, cross-sectional survey conducted on clinical
mental studies. Comparison groups included no association and disease progression between rosacea
treatment or other interventions. We excluded ab- sub-types [46]. The adherence rate in all studies was
stracts, dissertations, studies involving trials with measured, an average of 88% (range: 60 100%) of
post-test only design, trials including pathophysiol- participants were examined till the end of the trials.
ogy intervention as a small component of health The studies used different measurement parameters
promotion programmes, animal studies, studies like biopsy specimens immuno-staining, T-cell re-
lacking outcomes related to the objectives of this re- sponse from blood samples of patients and HCs,
view as well as non-English articles. cross-sectional surveys, reactive oxygen species (ROS)
measurement by superoxide dismutase (SOD) & glu-
Results tathione peroxidase (GPX), ferritin levels were meas-
The literature search yielded 5141(n) articles ured by serum peroxidases and ant oxidative levels
from various databases with 2461 articles from Pub- from blood samples [36, 39, 48]. For measuring the
Med, 1461 articles from EMBASE, 1000 articles from presence of the gut bacteria, the patients are lactulose
MEDLINE. Cochrane CENTRAL was also used for and glucose breath tests [67]. In some of the studies,
the search of literature, which yielded 209 completed the investigators used the overall assessment of in-
and on-going articles. 10 articles were considered flammatory lesion severity was expressed as a 7-point
from other sources. The articles left after duplicates static score, ranging from 0 (clear) to 7 (severe), ac-

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cording to an investigator's global assessment (GA) eration of dermal matrix, chemicals and ingested
[39, 48, 68]. agents, microbial organisms, ferritin levels in body,
The statistical analysis of the results from all the influence of reactive oxidative species. However, the
studies were performed using various versions of main reason causing the disease is still unknown. Also
SPSS (11-22), Graph pad prism by analysis of vari- the disease progression among the subtypes (ery-
ance (ANOVA), independent t-test, student t-test etc. themato-telangiectatic, papulopustular (PPR),
phymatous, and ocular) could be either by a single
Effects of various trigger factors factor or combination of factors [4, 15]. Consequently,
Proposed trigger factors are grouped into the rosacea-prone persons must have an inherent sensi-
following categories based on the various trials per- tivity to these ubiquitous triggers [12].
formed [11]: vasculature, climatic exposures, degen-

Table 1: Detailed description of trials

Author Trial type Sample size & description Length Outcome/Result
Jarmuda et al Controlled trial on Demodex n= 127, R= 75, HC= 52 15 weeks Demodex in patients
(Ireland) levels on face of patients (P=0.0001)
[25]
Sherif et al Randomized controlled trial on n= 36, Mean age SD = 37.8 6.6 years 21 weeks Sun exposure and H. Pylori
(Libya) H. pylori have possibly have role in
[27] Rosacea. (P= 0.005)
Brown et al Comparative analysis (Rosacea n= 57, R= 27; LE=30 6 months T-Cell mediated responses
(USA) (R) & Cutaneous Lupuserythem- Average age= have significant role in R and
[48] atous (LE)) (55.5 vs 42.3 years LE.
P = .0029)
Tisma et al. Randomized controlled trial on n= 71, R= 60; HC= 11 6 months Serum peroxides & serum
(Croatia) serum peroxides & ferritin levels Mean age= 30 to 70 years total anti-oxidative potential
[36] levels in R vs HC (P= .05)
Bakar et al. Controlled trials on ROS levels n= 42, R= 17, HC= 25 6 weeks ROS levels in rosacea pa-
(Turkey) Mean SD age 50.3 19, 15.1 years. tients than in HC
[39]
Cribier et al. Diagnostic trial on Pathophysi- n= 86 3 months Vasculature and Inflamma-
(France) ology of Rosacea mean age= 25 to 49 years tion primary factors in
[19] Rosacea
LE Heuzey et al. Randomized controlled trial on n= 504, CI = 95% 12 months HR = 0.80; 95%
(France) Amiodarone on skin (red- Middle-aged patients CI 0.60-1.07; P = 0.129
[21] ness/flush) Redness
Tsiskarishvili Observational trial on early stage n= 50, R= 25, HC= 25, 12 months Beta-blockers and Rozaliak
et al. treatment mean age= 25 to 49 years effective for treatment
(Georgia)
[49]
Tan J et al. Observational cross-sectional n (R) = 135 3 months Disease progression amongst
(Germany) survey on clinical association & associated sub-types. (P =
[46] progression b/w sub-types 0.005)
Guzman-Sanchez Comparative trial to assess heat n= 24, R= 16; 5 weeks Enhanced sensitivity to
et al. pain thresholds and skin blood HC= 8 noxious heat stimuli/blood
(USA) flow flow in rosacea-affected skin.
[18] P < .05.
Casas et al. Prospective/multicenter trial on n= 98, R= 50 12 months D. folliculorum density was
(France) Demodex, Rosacea & immune HC= 48 5.7 times in rosacea patients
[24] responses. than in healthy volunteers.
P < 0.05.
Smith et al. Controlled trial on vascular n= 20 (R) 4 weeks VEGF-ligand binding in
(USA) endothelial receptor (VEGF) Mean age= 25 35 years rosacea could contribute
[50] expression in rosacea vascular & cellular changes
Coda et al. Randomized multicenter on role n= 60 (R= 55) 16 weeks Cathelicidin & serine pro-
(USA, U.K) of cathelicidin in rosacea HC= 5 tease activity in rosacea
[32] age= 18-40 years patients.
Parodi et al. Randomized Controlled trial on n= 113 (R= 53), mean age, 52 15 years. 9 months Gut bacteria in rosacea
(Italy) gut bacteria HC= 60 mean age, 49 11 years; 82 patients when compared to
[66] women, 31 men. HCs. Rifaximin drug therapy
was given to rosacea patients
and disease
N= Total number of patients; R= Rosacea; HC= Healthy control; HR= hazard ratio; P= Significance; CI = confidence interval; = High; = Low.

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Figure 1: Flow diagram for selection process.

[15-17] and followed by vascular leakage and delayed

Climatic Exposure clearance of serum proteins, inflammatory mediators,
Exposure to harsh climatic conditions damages and metabolic waste, thus resulting in matrix degen-
cutaneous blood vessels and dermal connective tissue eration [17].
[13, 14]. Facial convexities and flare during rosacea
could possibly occur due to exposure to solar irradia- Perivascular inflammation
tion [14]. Relation to heat stimuli due to sunlight ex- An inflammatory penetrate could exist in a
posure and rosacea was shown in the study con- perivascular location. The evidence is however con-
ducted by Guzman-Sanchez et al [18]. flicting regarding which location predominates [19].
For understanding the perivascular inflammation
Vasculature phenomena, more studies need to be designed to
Flushing associated with rosacea is possibly categorize subtypes of rosacea depending on the
caused by increased blood flow to blood vessels sub-classification.
which are closer to the surface of the face [18]. And
also, hyperthermia by vasodilation is thought to be Foods, therapeutics and other chemical agents
exaggerated in rosacea patients [12]. The excessive intake of processed and ready to
use food and hot beverages are traditionally thought
Degeneration of dermal layers to trigger flushing in patients with rosacea [19].
Rosacea involves in the damage of endothelium However, most of the evidence does not support that
and degeneration of the dermal matrix [16]. But the the dietary factors play a central role in the patho-
facts little known are whether the initial damage is in genesis. And also, specific medications such as an-
the dermal matrix and leads to poor tissue support of ti-arrhythmic drugs (amiodarone) have proven to
cutaneous vessels. After which the pooling of serum play a vital role in the disease pathogenicity [21].
occurs, possibly giving rise to the inflammatory me- Apart the drugs, any high intake of useful vitamins
diators, and metabolic waste. It could also be like the such as B-6 and B-12 may cause reddish flares for pa-
initial abnormality exists in the cutaneous vasculature tients with rosacea [10, 20-21].

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Int. J. Med. Sci. 2015, Vol. 12 391

Microorganism borne presence of human cathelicidins, specifically, human

Demodex Folliculorum (Demodex) mites that cationic antimicrobial protein, hCAP-18/LL-37 has
normally inhabit human hair follicles may play a vital been found in high numbers in rosacea patients. The
role in the pathogenesis of rosacea. Some studies cathelicidin, hCAP/LL-37 is not only expressed in
suggest that Demodex invades the skin regions that are leukocytes, lymphocytes but also effects vascular en-
affected in rosacea, such as the nose and cheeks [22]. dothelial layer by modulating the vascular endothelial
Research also suggests that an immune response of growth factor (VEGF) [31-32]. The researchers in-
T-cell occurs at the site of Demodex antigens in pa- duced LL-37 and its novel peptides into mice, which
tients with rosacea [23]. However, the conflicting ev- gave rise to inflammatory responses, telangiectasia
idence indicates that Demodex does not induce an in- and erythema. This output led researchers postulate
flammatory response in patients with rosacea, as it is that an excess of cathelicidins combining with ab-
also found in large numbers of healthy individuals normal processing caused disease [34].
without rosacea [24, 25]. And also, inconclusive evi- Influence of Reactive Oxygen species
dence suggests that there is a possible association of
The process of neutrophils releasing the reactive
Helicobacter pylori with the aetiology of rosacea [26].
oxygen species (ROS) as an early inflammatory re-
However, many of the studies have not controlled for
sponse is postulated to have important role in rosacea
confounding variables that influence H. pylo-
[35]. ROS leading to oxidative tissue damage is ex-
ri prevalence, such as age, socioeconomic status, sex
plained by the free radicals such as superoxide anions
and certain medications [27, 66]. Furthermore, these
and hydroxyl radicals, in addition to other reactive
studies were not statistically significant to account for
molecules, such as molecular oxygen, hydrogen per-
the ubiquitous nature of H pylori and also demodex
oxide [39, 40]. The following are several mechanisms
infection.
which state how ROS result in skin inflammation
Role of Antimicrobial peptides (Figure 2) [40-43]:
Antimicrobial peptides (AMPs) have an im- Inactivation of natural defenses caused by oxi-
portant role in rosacea pathogenicity. Being the small dant stress from ROS.
molecular weight proteins, they are the face of innate Change of the lipid balance in rosacea patients,
immunity. AMPs are proven to show a wide variety which in normal proportions would suppress the
of antimicrobial activity against bacteria and virus [28, creation of ROS.
45]. They have been inducted in the pathogenesis of The production of cytokines and other inflam-
many inflammatory skin diseases as the first line of matory mediators by keratinocytes, fibroblasts.
defence upon injury or infection of the skin [46-47]. The endothelial cells damaged by ROS and,
The most common types of AMPs are cathelicidins The generation of ROS by cathelicidins which
and -defensins. The evidence based on the recent are found in greater amounts in the facial skin of
research shows the high level expression of cathelici- affected patients.
dins in individuals affected by rosacea [29-30]. The

Figure 2: Mechanism of ROS resulting in inflammation [40-43].

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Int. J. Med. Sci. 2015, Vol. 12 392

Table 2: List of drugs under trials

Type Investigational Drug Intended Actions Clinical trial phase Dosage form Refer-
ences
Erythematotelangi- Laropiprant Human prostaglandin D2 receptor-1 Early phase Topical [52]
ectatic rosacea
(On hold)
Aganirsen Antisense oligonucleotide Early phase Topical [53]
Papulopustular Omiganan pentahydrochlo- Disruption of the cytoplasmic membranes Phase III Topical [60, 61]
rosacea ride
Ivermectin 1% cream -n/a- Phase III completed Topical [55]
Carbamide peroxide Inhibiting inflammatory mediators Phase III completed Topical [62]
SGT-VD-54 -n/a- Phase II Topical [62]
Sarecycline hydrochloride Down regulates inflammatory cytokine Phase II Oral [63]
production
Apremilast Modulates multiple anti-inflammatory Phase II completed Oral [56]
pathways
Azelaic acid foam Phase III ongoing Topical Author [57]
et. al
Incobotulinumtoxin A -n/a- Phase II I.V [58, 64]
Phymatous Rosacea No specific drug under trials -n/a
Ocular Rosacea No specific drug under trials -n/a-
-n/a- = Not available; I.V= Intravenous.

pies that are specifically designed to address the

Ferritin levels and Oxidative damage problem of redness. In addition, other agents in the
The Iron levels in body specifically at cellular pipeline should further improve the arsenal of treat-
level should be maintained, as it catalyzes the con- ments for the papules and pustules of rosacea.
version of hydrogen peroxide to free radicals leading In the year 2013, many new therapies are cur-
to tissue injury by damaging cellular membranes, rently in various clinical evaluation phases (Table 2)
more specifically the proteins and DNA. Iron that is for the treatment of patients with rosacea and a few
not metabolized is stored as ferritin at the cellular more are in preclinical and laboratory testing stage.
level [35]. In a recent study, the biopsy specimens of The novel compounds are expected to provide clini-
skin from patients with rosacea were im- cally improvements in the treatment of patients with
mune-histo-chemically analyzed, and the number of rosacea the papulopustular, erythemato-telangiectatic
ferritin-positive cells was significantly higher in af- types, thereby bridging the gap by addressing the
fected individuals compared with control subjects erythema component of rosacea, where current ap-
[36]. Moreover, the higher ferritin positivity in cells is proaches fall short.
linked with advanced subtypes of rosacea. And so, we Furthermore, American academy of Dermatolo-
can say that pathogenesis of rosacea is interdependent gists (AAD) in 2013 proposed the use of probiotics in
on free iron release (proteolysis) of ferritin resulting in treating rosacea [66]. The hypothesis was based on
oxidative damage to the skin [37]. Bacterial interferences. The probiotics, with living
microorganisms are known for their positive effects.
What are the ongoing drug trials on Rosacea?
When applied topically on rosacea or acne prone area
In August 2013, the topical form of the alpha-2 of skin (site), the immune system recognizes them as
agonist brimonidine [44] became the first Food and foreign particle and acts at site, thus reducing in-
Drug Association (FDA)-approved topical treatment flammation, redness, or bumps. And also, a couple of
developed and indicated specifically for small-scale trials one conducted in Korea and other in
rosacea-associated facial erythema. The medication, Italy, showed promising results in effective clearing of
which was approved for adults aged 18 years or older, rosacea and acne symptoms [67-68].
was assessed using 2 phase 3 clinical studies
(short-term), involving a total of 550 patients, as well Discussion
as a long-term study (up to 12 months) in 276 subjects
This review identified 14 key studies (Table 1)
[44]. The most common adverse events (i.e., those
on different pathophysiologies of rosacea. Apart from
affecting at least 4% of patients) in the long-term trial
randomized control trials, there were comparative,
included flushing (10%), erythema (8%), rosacea (5%),
observational, diagnostic trials were included. No
nasopharyngitis (5%), skin burning sensation (4%),
adverse events were reported from any of the study;
increased intraocular pressure (4%), and headache
however confirmation of specific or exact single cause
(4%).
for the disease was a limitation of the review. Each
Furthermore, the treatment gap will soon be
cause identified here could possibly act as precursors,
narrowed, thanks to the development of novel thera-

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Int. J. Med. Sci. 2015, Vol. 12 393

a bridge between and amongst all the caused. The RCT was conducted (n= 71, HC= 11) using the
Firstly, exposure to sunlight could trigger the blood samples and measuring the serum peroxidases
disease to the people whose skin is too sensitive and and serum antioxidative potential levels. The serum
prone to rosacea. Guzman-Sanchez et al [18] in a peroxidase levels were significantly higher in the
comparative (n= 24), multicenter, cross-sectional trial rosacea patients, which helps in release free iron ions
conducted in USA for over a year to assess the heat and increase the oxidative stress and ferritin expres-
pain threshold and dermal vascularity with 8 healthy sion.
controls (HCs) and 16 rosacea patients. This study Cathelicidin levels in rosacea patients were
showed enhanced sensitivity to noxious heat stimuli higher than HCs in study conducted by Coda et al
in rosacea-affected skin, which was more prominent [32]. The study (n= 55, HC= 5) measured the serine
in the PPR group (P < .05). By this study, it can be said protease activity and correlated the levels of the
that there is a correlation between heat and vascular- cathelicidin levels. Rosacea can be averted in the early
ity in rosacea. stages was shown in the trial conducted by Tsis-
Cribier et al. [19] conducted a diagnostic trial in karishvili et al [49]. The observational study (n= 50)
France among patients & HCs (n= 86), on relation conducted on beta-blockers and rozaliak in early stage
vascularity and inflammation. The study revealed rosacea condition. Both beta-blockers and rozaliak
that vasculature and inflammatory responses are in- had a positive effect in rosacea treatment during the
terrelated and aiding in pathology of rosacea. The early stage diagnosis.
result of excess of blood supply leads to hy- The potential role of microorganisms in patho-
per-erythema. physiology of rosacea is still a debate. However, the
In 2006, Smith et al. [50] conducted a trial to various studies conducted on possible role of Demo-
study the vascular endothelial growth factor (VEGF) dex and H. Pylori in rosacea were scientifically sig-
expression levels in rosacea patients (vascular endo- nificant. Jarmuda et al. [25] conducted a controlled
thelium and mononuclear blood cells). All the pa- trial (n= 127) to measure the level of demodex mites
tients (n= 20) were diagnosed with rosacea, the biopsy on facial skin. All the skin samples were collected
specimens were collected and immuno-stained to from patients, HCs and checked the presence of de-
identify the expressions of VEGF, VEGF-R1, VEGF-R2 modex. The percentage of demodex mites in rosacea
using indirect method using antigen retrieval. The patients was much higher when compared to HCs. A
VEGF-R1, R2 receptors frequently stained positive but similar result was obtained in another study con-
infrequently in case of VEGF. And in case of lym- ducted by Casas et al [24]. The demodex levels in
phocytes, macrophages and plasma cells, all three rosacea patients (n= 98) in correlation to their immune
receptors are very well expressed (P= 0.005). VEGF responses were measured. The density of demodex in
receptors-binding-ligands may contribute in vascular rosacea patients was 5.7 times higher than HCs (P=
and cellular changes in the rosacea patients. In com- 0.05).
parison with the studies conducted by Guz- With regards to H. Pylori, many studies were
man-Sanchez et al [18] and Cribier et al. [19] with conducted to assess the role in rosacea. All the studies
Smith et al, there is surely a connection between vas- were nor inconclusive nor affirming the role of H.
culature, inflammation, immune responses and Pylori in rosacea. Sherif et al [28] conducted a RCT (n=
rosacea. 36) on relation of sunlight on H. Pylori in rosacea.
In a study conducted by LE Heuzey et al. [21] to Here, exposure to sunlight, vasculature and inflam-
assess the effects of chemical agents on skin red- matory response acts as a trigger point to gut bacteria
ness/flush, it was evident that external agents have a stimulating rosacea. The role of bacteria is still un-
role in pathophysiology of rosacea. Here, droneda- known. However, in another study randomized trial
rone and amiodarone (antiarrhythmic agents) were conducted by Parodi et al. [66] demonstrated that
checked on rosacea patients/HCs. There was a sig- there is highly significant number of H. Pylori in the
nificant rise in the redness/flush (n=504, P= 0.129) on gut of the rosacea patients (n= 53) when compared to
the skin and thus it contributes to rosacea. Though HCs (n= 60) (P< 0.001). Eradication of small intestinal
there is no significant evidence that food items aid in bacterial overgrowth state and normalization of the
disease, however it cannot be ruled out. intestinal flora via the antibiotic rifaximin led to im-
The potential role of ROS was measured by Ba- provement of rosacea.
kar et al [39]. The study is an unprecedented ex vivo Brown et al. [48] conducted a comparative trial
study (n= 42) to support the role of ROS in rosacea. (n= 57) between rosacea and cutaneous Lupus ery-
The ROS levels when compared to HCs were much thematosus (LE) to measure the chronic immune ac-
higher in rosacea patients. Ferritin levels, oxidative tivation phenomena. Chronic immune activation
damage in rosacea were measured by Tisma et al [36]. leads to mild-severe inflammations giving rise to se-

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Int. J. Med. Sci. 2015, Vol. 12 394

vere skin disorders. In this study the role of T-cells whole pathophysiology, how each factor singly or
(acquired immune subsets) was assessed. Interest- cumulatively responsible for disease.
ingly, the T-cell mediated responses have a significant Demodex mites presence stimulates the inflam-
role in rosacea and LE conditions. Thus, we can say matory response with help of bacteria degradation in
immune responses are responsible for disease with the body. Any alteration or abnormality in vascular
vasculature. system, leads to dilation of blood vessels which hap-
The rosacea progression was also associated pens to be a favorable conditions for demodex to
with sub-types. Tan J et al. [46] conducted an obser- colonize and thrive. The presence of high number
vational, cross sectional survey amongst patients (n= demodex mites leads to activation of various inflam-
135) who are diagnosed with different types of matory responses resulting in appearing of initial
rosacea. The clinical association and progression of symptoms of the disease. The chronic inflammatory
rosacea amongst the various sub-types was evident responses in turn help in release of oxygen free radi-
(P= 0.005). cals leading to dermal matrix damage and blood ves-
Rosacea, the most intricate disease, has multiple sel damage. The release of oxygen free radicals, blood
pathologies involving prominent vascular and in- vessel damage and additional inflammatory respons-
flammatory response factors. Characteristic small es can possibly result in over expression of
blood vessels, mononuclear blood cells, perivascular pro-inflammatory peptides such as cathelicidins.
inflammation come into account of histology. Various Apart from the mentioned factors, psychological fac-
environmental triggers involving exposure to sun- tors such as stress, anxiety and depression can also be
light, temperature change have a prominent role in responsible for rosacea. The psychological factors ei-
the disease. The role of microorganisms was ex- ther alone or in combination with the consumption of
plained with weight of evidence. Figure 3 explains the processed comfort foods alters the gastrointestinal
flora, which in turn leads to
increased intestinal permeabil-
ity.

Figure 3: The presumed pathophysiology of

rosacea in correlation with specific molecular,
immunological, neuronal and clinical triggers.
(A) Recurrent exposure to extreme sunlight
(environmental changes) causes the dermal
matrix degeneration, which in turn may trigger
genetic predisposition leading to hypersensi-
tivity and flush on the skin. (B) As a part of
hypersensitivity, it triggers the innate immune
response. (C) Effect of microorganisms like
Demodex and Helicobacter pylori gives rise to
the several inflammatory responses in the
body. (D) Chemical and food agents would also
trigger inflammatory responses. (E) Vasodila-
tion of blood vessels by immune responses that
may lead to Telangiectasia, Erythema. (F)
Neural activation results in vasodilatation,
edema and burning sensation (G) Chronic
neurogenic inflammation may lead to persis-
tent erythema, followed by angiogenesis. (H)
Imbalance in lymphatic system leads to
lymphedema followed (I) Glandular hyperplasia
and fibrosis (J) leading to inflammatory re-
sponses like vasodilation, extravasation and
plasma leakage (severe case) giving rise to (K)
erythema, edema and papules.

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Int. J. Med. Sci. 2015, Vol. 12 395

Conclusion Allergy. Acad press: Food science and Technology series, Elsevier Science &
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In conclusion, we can say that there are multiple Randomized, DoubleBlind, ParallelGroup Study to Evaluate the Efficacy and
factors responsible for the disease. All the present Safety of Dronedarone versus Amiodarone in Patients with Persistent Atrial
Fibrillation: The DIONYSOS Study. J Cardiovasc Electrophysiol. 2010; 21:
treatment options and forthcoming therapies are 597-605. doi:10.1111/j.1540-8167.2010.01764.x.
based on symptoms. There is still need for high qual- 22. Bonnar E, Eustace P, Powell FC. The Demodex mite population in rosacea. J
Am Acad Dermatol. 1993; 28: 443-8.
ity RCTs targeting clinical, cellular and molecular 23. Rather PA, Hassan I. Human demodex mite: The versatile mite of dermato-
pathophysiological relations to rosacea. Future trials logical importance. Indian J Dermatol. 2014; 59: 60-6. doi:
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