Considering Rosacea as a Systemic Disease

Consultant dermatologist Dr Firas Al-Niaimi discusses how rosacea can be linked to organ systems and co-morbidities in patients

Rosacea is a common inflammatory skin condition with a high prevalence among the Western population.1 Whilst the signs and symptoms predominantly affect the centrofacial part of the skin, there has been increasing interest and emerging evidence linking it with other organ systems and co-morbidities. The question posed is whether rosacea is a cutaneouslimited disease or one with systemic involvement, or perhaps a manifestation of a wider systemic inflammation.

Causes of rosacea During the present time, the exact pathophysiology of rosacea remains unclear. It involves an aberrant neurovascular signalling and a dysregulation of the immune system, in particular the innate system.2 High levels of cathelicidins – anti-microbial peptides expressed by leukocytes and epithelial cells – have often been found in rosacea patients; in addition to kallikrein-5, matrix metalloproteinases 2 and 9, and increased mast cell infiltration.1,2 It is well established that kallikrein-5 cleaves cathelicidin to its more active form of LL-37 which is pro-inflammatory and angiogenic. High expression of cathelicidin has also been found in colonic mucosa of inflammatory bowel disease patients.3 The gut-brain-skin axis is a term that has been existent in medical literature for some time, linking certain inflammatory skin conditions with stress and gut-related pathology.4 In recent years, a better understanding has shed light on rosacea and its systemic links. Several large case-control observational studies have shown an association between rosacea, several systemic diseases and co-morbidities including gastrointestinal, cardiovascular, respiratory, autoimmune, and neurological disorders.5,6 Furthermore, chronic inflammation is a feature of both rosacea and several systemic co-morbidities, notably cardiometabolic disease.5,6 In addition, a genome-wide association study identified loci for rosacea, which was associated with several autoimmune diseases such as diabetes mellitus, coeliac disease, and rheumatoid arthritis.7

Gut dysbiosis and rosacea Association studies linking rosacea to the gastrointestinal system have shown a connection with inflammatory bowel disease and an overgrowth of gut bacteria. These include both helicobacter pylori (H. pylori) and small intestinal bowel overgrowth.8 The microenvironment in the gut is increasingly linked to skin inflammation with gut dysbiosis – an alteration in the harmonious composition of the gut microbiome – playing an important role. This can either be through the mediation of inflammation or through mucosal barrier compromise.9 Gut dysbiosis is based on the influence of age, food consumption, stress, and antibiotics (in anti-microbial doses). Intestinal inflammation and gut dysbiosis have shown to activate plasma kallikrein-kinin system pathway – an inflammatory cascade triggered by an unhealthy gut – which is pro-inflammatory in rosacea.10 In addition, gut dysbiosis leads to mucosal barrier compromise with pro-inflammatory substances circulating in the bloodstream. Control of the harmonious gut microbial, as well as the inflammation, can have a positive effect on the control of rosacea symptoms and is increasingly being recognised as part of the overall management of rosacea.10,11 This is controlled through dietary modification, consumption of probiotics, as well as control and eradication of potential pathogenic microbes such as H. pylori and small intestinal bowel overgrowth.11 Gastrin-induced flushing has also been linked to the presence of H. pylori.8

The skin microbiome The skin microbiome too has increasingly been recognised as an important key player in several inflammatory cutaneous diseases including rosacea.12 The skin microbiome refers to the diverse microbial population unique to every individual, comprising bacteria, viruses, fungi, and mites. Some are skin resident and act as symbiont, while others are invaders and often pathogenic. Advances in genomic sequencing research, as opposed to outdated culture-based techniques, has enabled for a better understanding of the microbiome’s composition.13 The skin microbiome is in a delicate environment affected by several factors such as the skin’s acidity, temperature, lipid composition, humidity, stress, pollution, dehydration, and local skin changes such as dry or moist skin.13 These factors can alter the harmony and composition of the delicate microbiome leading in some cases to a pro-inflammatory state. In rosacea, the presence of the mite Demodex folliculorum and the bacteria Bacillus oleronius elicit a proinflammatory state through the activation of pattern-recognition toll-like receptors 2 (TLR2) – expressed on keratinocytes and dendritic cells – as well as interleukin-8 and TNF-alpha, as consequential downstream activation of inflammatory pathways.14 This link is strengthened by the observation of improvement in rosacea symptoms with antiparasitic drugs (targeting the mites) and tetracycline-based antibiotics (primarily targeting Bacillus oleronius). TLR2 are further activated by stress and ultraviolet radiation; the latter increases the production of the antimicrobial peptide cathelicidin, mostly secondary to UV-induced vitamin D3 production. A possible explanation to the low prevalence of rosacea among higher Fitzpatrick skin type individuals is that they tend to have lower levels of vitamin D3, which as a consequence, means there is possibly less cathelicidin present.15

Chronic inflammation Chronic inflammation in rosacea has also been linked to cardiometabolic risks with case-controlled studies linking rosacea to a high incidence of hypertension, dyslipidaemia, obesity, and an elevated fasting glucose level.16 Both rosacea and dyslipidaemia patients express low levels of a protective highdensity lipoprotein-associated antioxidant called paraoxonase-1 (PON-1), as well as a relatively high inflammatory baseline level of C-reactive protein (CRP), found in most cardiometabolic diseases.17 Interestingly, current smokers have a somewhat protective effect on their rosacea symptoms. This could possibly be due to the vasoconstrictive effects of smoking and the worsening of

rosacea symptoms has been observed in past smokers.18 Currently, it remains unclear if strict control of all cardiometabolic factors and diseases can positively correlate to rosacea severity and symptoms, although this association is being observed and clinicians may want to consider this in patients with severe rosacea or those resistant to treatment. Neuropsychiatric associations with rosacea have found links with depression, anxiety, migraines, and Parkinson’s disease.19,20 As mentioned previously, stress can worsen rosacea through stressmediated inflammation as well as through alteration of the gut microbiome, leading to gut dysbiosis.

Conclusion Increasing evidence is linking rosacea to a wider systemic state of chronic inflammation and its associations with the gastrointestinal and cardiovascular systems. This may warrant some adjustments in the approach and management of rosacea patients, particularly in the presence of systemic symptoms. Clinicians should be aware of the systemic associations and co-morbidities of rosacea when treating patients.

Dr Firas Al-Niaimi is an award-winning consultant dermatologist, as well as Mohs and laser surgeon based in London. He has published more than 200 publications, 10 book chapters and his own book on preparation for dermatology specialist examination. Dr Al-Niaimi is also a researcher at Aalborg University, Denmark, and is involved in clinical and translational research in the field of lasers and spectrophotometry. Qual: MD, MSc, MRCP, MRCP (Dermatology), EBDV

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