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| Pathophysiology of Rosacea from Ref 2 via-Noncommercial 4.0 International (CC BY-NC 4) 0) |
This post is part of my apparent never-ending quest to get
complex illnesses and blog about them.
About 15 years ago, I saw my primary care physician and described some
dermatology problems that I was having.
I won’t get too deep into the weeds about my symptoms, but somewhere
along the line I also recalled that my father had similar symptoms. In those
days back in the 1950s and 1960s he really did not get any formal
diagnosis. He was told instead that the
somewhat matted lesions he had on his face should be “drained” and his
physician cut into them with a scalpel. Eventually
they cleared up on their own. In my case I was given some topical metronidazole
that seemed to work for local outbreaks and have been using it ever since. It
seems good for focal lesions but it does not seem to do much for more global
symptoms such as a burning and stinging sensation of the more recently
discovered ocular symptoms of rosacea.
I first started to diagnose it and refer it for treatment
when I was seeing patients in acute care psychiatric units. I acquired a text that was considered
state-of-the art in the late 20th century (1) to assist me in
describing rashes and diagnosing dermatology diseases. The definition of rosacea was: “Papules and
papulopustules occur in the center of the face against livid erythematous background
with telangiectasias. There is also quite often diffuse connective tissue and
sebaceous gland hyperplasia and sometimes hypertrophy of the nose (rhinophyma)”
(p. 730). The disease was described as
progressive stages rather than discrete phenotypes and the pathology of each
stage was described and as a chronic inflammatory condition.
Little was known about the pathophysiology at the time but
the usual suspects of genetic predisposition and relationships to diet and
other potential irritants. The mite Demodex folliculorum was suspected. Various irritants like sun, mechanical
irritation, heat, cold, hot drinks, alcohol, and caffeine increased the
erythema (redness). The authors
described progressive stages rather than distinct phenotypes. Eye involvement
was known at the time including complications like blepharitis, conjunctivitis,
iritis, and in some cases keratitis of the cornea leading to blindness. Associated symptoms were eye pain and
photophobia. The main treatment
described was systemic and topical antibiotics, sunscreen and avoiding other
irritants.
Today like many diseases there are clearer diagnostic criteria and there is also accumulated knowledge on possible pathophysiology. The American Rosacea Society proposed the criteria listed in the following table. Currently 2 or more major features are diagnostic. The criteria are controversial because they include a number of features with low predictive value. A subsequent update by the Global ROSacea COnsensus Panel (ROSCO) modified the criteria and expanded to 6 phenotypes. Note that there are no formal biomarkers for the phenotypes just very approximate clinical descriptions.
|
Primary Features |
Central distribution of:
Transient erythema
(flushing) Permanent erythema Papules/pustules Telangiectasia
|
|
Secondary Features |
Burning or stinging sensation Ocular involvement Edema Dryness Plaque formation Peripheral location Phymatous changes
|
|
Phenotypes |
Subtypes:
Erythematotelangiectatic Papulopustular Phymatous Ocular
Variant: Granulomatous
|
|
ROSCO
Phenotypes |
|
Flushing |
|
Persistent Erythema |
|
Telangiectasia |
|
Papules/pustules |
|
Phymatous changes |
|
Ocular manifestations |
This post is not about how to make the diagnosis or treat
this disorder, although every physician including psychiatrists should be able
to recognize the condition. I am hoping to convey some diagnostic imperatives
and discuss disease complexity that underlies fairly basic diagnostic
categories. It will also be apparent that basic science research has added
quite a lot in terms of the treatment or this disorder, but that a lot of
uncertainty remains.
Let me start with pathophysiology. There is always plenty
of controversy about pathophysiology despite the fact that not much is known
about it – even in common complex diseases.
That includes psychiatric diseases and yet people seem to suspend their
critical thinking when it comes to psychiatry – and claim that the lack of
pathophysiological mechanisms and medications specific for that pathophysiology
represents something unique. In the case of rosacea since it is considered a
complex inflammatory disease there are a couple of approaches to looking at
pathophysiology. The first is to consider the two main types of immunity and
how they are modified. The first general
type in innate immunity basically comprised of various barriers to
pathogens like skin and mucous membranes, non-specific immune cells, and
inflammatory proteins like interferons.
Local chemical environments can also produce a number of physical and
chemical conditions that can kill potential pathogens. Adaptive immunity is more specific and
it depends on recognitions on antigens on pathogens and the resulting reactions
with antibodies and immune cells. In the case of rosacea there are different
theories involving both types of immunity.
One theory suggests that there is increased production of
cathelicidin antimicrobial peptide (CAMP) – a component of innate immunity that
leads to the inflammatory process associated with rosacea. CAMP gene expression is regulated by VDR (a
Vitamin D dependent transcription factor) and C/EBPα (a
Vitamin D independent transcription factor). During winter months there is not
enough UV light to produce CAMP by the Vitamin D dependent process. This theory
suggests there is a mutation that allows for C/EBPα activation leading to
toll-like (TLR) receptor mediated immune responses and upregulation of
endoplasmic reticulum (ER) stress responses.
Although this sequence of events leads to increased inflammation due to
a number of end products [sphingosine-1-phosphate (S1P), LL-37 the active
cleavage product of CAMP, interleukin-1β (IL-1β),
IL-17, IL-18, as well as associated T-helper (Th) cells and chemokines. This process is depicted in the graphic at
the top of this post (click on it to enlarge).
The activation of this inflammatory reaction can be verified by
measuring end products in both the epithelium and the ocular surface. Dry eye clinics have the capacity to check
for tear osmolarity and inflammatory markers like matrix metalloproteinase-9 (MMP-9) – an enzyme. MMP-9
can be done as a point-of-care test so that the results are available within
minutes.
A logical question to ask is whether widespread activation
of the inflammatory response associated with rosacea can affect organ systems
other than skin. The degree of inflammation is also a factor. It is common to
see patients with diverse findings ranging from mild erythema on the cheeks to
intense erythema of the eyelids and central facial areas. The question of other
organ systems has been examined with interesting findings. Cardiac,
neurological, and psychiatric conditions are all more likely in patients with
rosacea (6-15). In terms of cardiac
conditions that includes a modest increased risk for atherosclerotic heart
disease. There is less evidence of
increased risk for arrhythmias but that increased risk has been demonstrated
for other inflammatory dermatological conditions like atopic dermatitis and
psoriasis (14). In the papers where the authors comment on possible
pathophysiology the suggested mechanisms are innate immunity, adaptive
immunity, or both.
Rosacea is a complex inflammatory disease that can lead to significant
ocular and dermatological complications. According to one theory the
pathophysiology of the illness may have been caused by an adaptive mutation in
Nordic populations that preserved innate immunity when Vitamin D dependent
factors were not available due to decreased photoperiod and UV light. The
general consensus is that there is no agreed up theory to explain the
underlying pathophysiology and like the immunological literature in psychiatry
different authors have differing hypotheses.
Psychiatrists need to be aware of the condition because
about 5% of the population has it, it is readily diagnosed based on visual
inspection but the ocular phenotype may require referral to a specialized dry
eye clinic. The dry eye disease untreated can lead to significant eye
complications. From a theoretical perspective there are direct parallels with
the psychiatric process including the categorial diagnoses, theoretical
pathophysiology, and a number of treatments that may or may not address that
pathophysiology. Current clinical and
future research questions include:
1: Are there immunological
mechanisms common to both rosacea and common psychiatric disorders? Immune etiopathophysiological hypotheses for
psychiatric disorders have been proposed since 1985 (16) and their complexity
and the number of disorders covered have only increased since that time. Over the same time frame much more has been
discovered about the basic science of immunology. Do the proposed immune
mechanisms of rosacea affect other organ systems in the same way that the skin
is affected? Are these mechanisms
responsible for some of the early observations about PET imaging of the brain
(15) in rosacea?
2: What about the
immunological products of rosacea? Is it
possible that they are contributing to what are considered symptoms of general
disorders like anxiety and depression?
Cytokines like IL-17 can lead to flu-like symptoms and a general feeling
of malaise – could this lead to the appearance of a treatment resistant anxiety
or depressive disorder? Could it lead to
the misdiagnosis of a psychiatric disorder?
3: Even if there is
no direct physiological connection between rosacea and anxiety and depression
can pathophysiological processes lead to psychiatric complications especially
with pre-existing anxiety and depression. For example- rosacea leads to neurovascular
hyperactivity in the form of facial flushing and skin sensitivity to a variety
of physical and chemical irritants. If you have a pre-existing concern about
embarrassment, humiliation, and obvious physical signs of anxiety rosacea
compounds that. It also can lead to
sleep problems due to skin sensitivity that will compound any associated
psychiatric disorder.
4: Dealing with the
stress of a chronic disorder activates additional processes that can either
exacerbate or precipitate anxiety or depression. There is an inherent bias to
see conditions like rosacea as a minor problem rather than a potentially very
stressful problem with considerable morbidity that can actually lead to
physical disability.
That is what I have found to be interesting about rosacea
and dealing with it at an individual level. I hope there is more research focused on it in
the future from the combined perspectives of psychiatry, dermatology, and
immunology. There is much more to be
learned.
George Dawson, MD, DFAPA
References:
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Plewig G. Wolff HH, Winkelmann RK.
Dermatology. Springer-Verlag,
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approach to pathogenesis through translational research. ACTA Derm Venerol 2016; 96: 147-156.
3: Ratajczak MZ, Pedziwiatr D, Cymer M,
Kucia M, Kucharska-Mazur J, Samochowiec J. Sterile inflammation of brain, due
to activation of innate immunity, as a culprit in psychiatric disorders.
Frontiers in psychiatry. 2018 Feb 28;9:60.
4: Salam AP, Borsini A, Zunszain PA. Trained
innate immunity: A salient factor in the pathogenesis of neuroimmune
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