Rosacea Is A Complex Illness – And Here Is Why That Is Important

 

Pathophysiology of Rosacea from Ref 2 via-Noncommercial 4.0 International (CC BY-NC 4) 0)

    (click to enlarge)

 

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 20^th 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:

1:  Braun-Flaco O, Plewig G. Wolff HH, Winkelmann RK.  Dermatology.  Springer-Verlag, Berlin 1991: 730-731.

2:  Melnik BC.  Rosacea: the blessing of the Celts – an 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 psychiatric disorders. Molecular Psychiatry. 2018 Feb;23(2):170-6.

5:  Zengeler KE, Lukens JR. Innate immunity at the crossroads of healthy brain maturation and neurodevelopmental disorders. Nature Reviews Immunology. 2021 Jul;21(7):454-68.

6:  Garrett ME, Qin XJ, Mehta D, Dennis MF, Marx CE, Grant GA, VA Mid-Atlantic MIRECC Workgroup, PTSD Initiative, Injury and Traumatic Stress (INTRuST) Clinical Consortium, Psychiatric Genomics Consortium PTSD Group, Stein MB. Gene expression analysis in three posttraumatic stress disorder cohorts implicates inflammation and innate immunity pathways and uncovers shared genetic risk with major depressive disorder. Frontiers in Neuroscience. 2021 Jul 29;15:678548.

7:  Pape K, Tamouza R, Leboyer M, Zipp F. Immunoneuropsychiatry—novel perspectives on brain disorders. Nature Reviews Neurology. 2019 Jun;15(6):317-28.

8:  Bekkering S, Domínguez-Andrés J, Joosten LA, Riksen NP, Netea MG. Trained immunity: reprogramming innate immunity in health and disease. Annual review of immunology. 2021 Apr 26;39:667-93.

9:  Dounousi E, Duni A, Naka KK, Vartholomatos G, Zoccali C. The innate immune system and cardiovascular disease in ESKD: monocytes and natural killer cells. Current Vascular Pharmacology. 2021 Jan 1;19(1):63-76.

10:  Scott Jr L, Li N, Dobrev D. Role of inflammatory signaling in atrial fibrillation. International journal of cardiology. 2019 Jul 15;287:195-200.

11:  Zhou X, Dudley Jr SC. Evidence for inflammation as a driver of atrial fibrillation. Frontiers in cardiovascular medicine. 2020 Apr 29;7:62.

12:  Bellocchi C, Carandina A, Montinaro B, Targetti E, Furlan L, Rodrigues GD, Tobaldini E, Montano N. The Interplay between Autonomic Nervous System and Inflammation across Systemic Autoimmune Diseases. International Journal of Molecular Sciences. 2022 Feb 23;23(5):2449.

13:  Choi D, Choi S, Choi S, Park SM, Yoon HS. Association of Rosacea With Cardiovascular Disease: A Retrospective Cohort Study. J Am Heart Assoc. 2021 Oct 5;10(19):e020671. doi: 10.1161/JAHA.120.020671. Epub 2021 Sep 24. PMID: 34558290; PMCID: PMC8649155.

14:  Schmidt SAJ, Olsen M, Schmidt M, Vestergaard C, Langan SM, Deleuran MS, Riis JL. Atopic dermatitis and risk of atrial fibrillation or flutter: A 35-year follow-up study. J Am Acad Dermatol. 2020 Dec;83(6):1616-1624. doi: 10.1016/j.jaad.2019.08.039. Epub 2019 Aug 20. PMID: 31442537; PMCID: PMC7704103.

15:  Liu Y, Xu Y, Guo Z, Wang X, Xu Y, Tang L. Identifying the neural basis for rosacea using positron emission tomography-computed tomography cerebral functional imaging analysis: A cross-sectional study. Skin Res Technol. 2022 May 29. doi: 10.1111/srt.13171. Epub ahead of print. PMID: 35644027.

16:  Knight JG.  Possible autoimmune mechanisms in schizophrenia.  Integrative Psychiatry 1985; 3: 134-143.