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A Neural Link to Understanding Rosacea: Focusing on Flushing Triggers

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A Neural Link to Understanding Rosacea: Focusing on Flushing Triggers A Neural Link to Understanding Rosacea: Focusing on Flushing Triggers B.D. Gray, DO,* K. Metzler-Wilson, PT, PhD,** K.W. Dawes, MD,*** T.E. Wilson, PhD**** *Intern, OhioHealth O’Bleness Hospital, Athens, OH **Assistant Professor of Neuroscience & Pharmacology, Marian University College of Osteopathic Medicine, Indianapolis, IN ***Dermatologist, Dawes Fretzin Clinical Research Group & Dawes Fretzin Dermatology Group, Indianapolis, IN ****Professor of Physiology, Marian University College of Osteopathic Medicine, Indianapolis, IN Abstract Facial erythema in rosacea can be triggered by events that do not normally cause sustained flushing. This review discusses why flushing was evolutionarily conserved, how facial blood flow increases, and how the process can go awry in rosacea. Known mechanisms of increased facial-skin blood flow associated with thermal/environmental, social/emotional, pharmaceutical/topicals, dietary, and physical-exercise trigger events are explored. Flushing triggers begin with neural (sympathetic, cranial nerve, axon reflex, or sensory afferent) responses inducing vasodilation (active vasodilation and/or reduced tonic vasoconstriction), fluid extravascularization, and increased vascular volume. Local inflammatory mediators can augment responses, but it is neural responses that initiate the process. We theorize that mechanistically understanding erythema will allow rosacea to be better tolerated and controlled. Introduction are important, it is the neural events (sympathetic, which decrease inflammation associated with Rosacea is a chronic skin disorder most cranial nerve, axon reflex, and sensory afferent) rosacea but do not generally improve the that initiate the trigger. We refer the reader erythema. In contrast, neural (ganglionic, commonly characterized by erythema and α inflammatory lesions in the central face region, to a number of excellent reviews and source cholinergic, and -adrenergic) antagonism which affects many people worldwide, including material that cover general information about strategies have been reported to reduce rosacea rosacea, inflammatory and pathological changes erythema.13-15 One interesting approach is the an estimated 16 million people in the United 6-12 α States.1 Disease classification often includes associated with it, and its potential treatment. use of an 2-adrenergic agonist (brimonidine gel), both subtypes and variants. Subtypes include Although etiology is unknown, current FDA- which has recently been approved for treatment of approved treatments in the United States include rosacea erythema. This class of drug can directly erythematotelangiectatic, papulopustular, α phymatous, and ocular rosacea; variants include metronidazole, azelaic acid gel, and doxycycline, cause some vasoconstriction via post-synaptic 2- granulomatous and neurogenic rosacea.2,3 Regardless of classification or whether all patients Table 1. Common rosacea triggers can be adequately classified, most patients present Category Examples Stimulus/Mechanism at some point with induced or permanent facial Sun UV,* local and whole-body heating flushing.4 Hot weather Local and whole-body heating Rosacea erythema, especially in the erythematotelangiectatic subtype, can change Wind Local heating and cooling, irritation, in intensity and is activated by trigger events. AVAs,** blood-pressure effect Erythema triggers vary among patients but can Thermal/ Hot bath, sauna Local and whole-body heating be grouped into categories related to thermal/ Environmental environmental, social/emotional, pharmaceutical/ Cold Local and whole-body cooling, AVAs, topicals, dietary, and exercise (Table 1). In a recent blood-pressure effect National Rosacea Society survey, more than 50% Indoor heat Local and whole-body heating of North American participants reported that Humidity Whole-body heating hot weather and baths, sun and wind exposure, emotional stress, alcohol consumption, and Embarrassment Mental stress exercise all trigger flushing and associated Psychological stress Arousal, blood-pressure effect symptomatology.5 Besides acute erythema, these Social/Emotional Anxiety Mental stress, blood-pressure effect episodes can cause local inflammation, edema, and painful burning or stinging sensations. Sexual arousal Arousal, whole-body heating Chronic and repeated bouts of flushing and Medications Variable associated inflammation can induce structural Skin-care products Irritation, allergic changes in the vasculature (e.g., telangiectasias) Pharmaceutical/Topical and connective tissue, which add to disease signs Cosmetics Irritation, allergic and symptoms. Alcohol Direct effect, gustatory reflex This review addresses what is known about Spicy food Gustatory reflex the neural mechanisms underlying rosacea Heated foods and beverages Gustatory reflex erythema trigger events. We discuss why flushing Dietary was evolutionarily conserved, how blood flow Certain fruits and vegetables Variable, unknown mechanistically increases in facial skin, and how it Dairy Unknown can go awry in disorders such as rosacea. A review Aerobic exercise Whole-body heating with this particular focus, neural mechanisms of Exercise rosacea erythema triggers, has not been previously Resistance exercise Arousal, blood-pressure effect completed. Most mechanistic evaluations of * UV - ultraviolet rosacea have almost exclusively focused on the **AVA - arteriovenous anastomosis inflammatory aspects of the disease; while these GRAY, METZLER-WILSON, DAWES, WILSON Page 11 adrenergic receptors on vascular smooth muscle face during an embarrassing task corresponds to which includes neurovascular dysregulation but also reduces the release of neurotransmitters an increase in an index of skin blood flow in that and inflammation.12 The subsequent sections α 22 and modulators from these nerves via 2- area. It is thought that embarrassment, and in of the review discuss the neural origins of these adrenergic receptors located presynaptically part blushing, may be a remnant of appeasement erythema triggers based on patient-frequency on the adrenergic axon terminals. Our central display that is observed in some social animals.23 data and trigger categorization. theory is that if rosacea erythema triggers are In sum, flushing should be considered a normal mechanistically understood, better avoidance and physiological response that can aid in providing treatment plans as well as prevention strategies social cues and conveying emotion. Rosacea Erythema Trigger for those more susceptible to this disease state Facial flushing can also participate to a minor Mechanisms can evolve. In rosacea, no erythema trigger is universal.5 In extent in heat dissipation. Humans can lose heat the current review, we refer to triggers as having from the face and head but primarily rely on hairy major (>50% of survey respondents), moderate skin of the rest of the body for heat dissipation. Skin Blood Flow (25%-50%), and minor (<25%) incidence rates To understand the erythema associated with Both in glabrous skin (e.g., nose, ears) and other and will discuss only the major and moderate rosacea, an understanding of the physiology facial areas (e.g., forehead, cheek), blood flow can triggers.5 Rosacea erythema triggers can be of skin blood flow and its measurement is increase during times in which heat dissipation is roughly categorized into five groups (Table 1), required. The advent of many noninvasive necessary, but because of hairy skin’s sheer surface with varied mechanisms of induction of facial indices of skin blood flow (e.g., laser-Doppler area and large blood flow capacity (up to 8 L/min), flushing and associated symptomatology. The flowmetry with both fixed probes and scanners, there is a much greater potential to offload heat 24-26 study of facial blood flow is made more difficult transcutaneous tissue oxygenation, in vivo video in hairy skin. In addition to differences in skin because certain mechanistic pharmacological microscopy, photoplethysmography) has allowed blood flow, there are also neural, anatomical, and 16- procedures (e.g., intradermal microdialysis) measurements of indices of facial blood flow. functional differences between the types of skin 18 cannot be completed in the human face for safety The ease of use of these devices has allowed (Table 2). Notably, there is vasomotor cranial- and ethical reasons. Glabrous skin also suffers for increased utilization, but most dermatology- nerve involvement in facial mucosa and skin but 27 transcutaneous drug delivery difficulties due focused studies do not appropriately control for not in peripheral glabrous and hairy skin. Thus, to its thick epidermal layer. Thus, the majority factors that affect skin blood flow independent for primary heat dissipation, humans rely not on of mechanistic in vivo studies are completed of their treatment paradigm. For instance, not facial flushing but on blood-flow changes in non- in the hairy skin of the forearm, calf, or thigh. expressing laser-Doppler measures as cutaneous facial hairy skin. Nonetheless, a discussion of erythema triggers as vascular conductance (flux/mean arterial blood If facial flushing is normal during embarrassment they relate to forearm, leg, and palm skin with the pressure) is problematic because blood pressure and heat-stress conditions, what constitutes a inclusion of face skin when available provides a increases flow independent of changes in luminal flushing disorder? There are a number of factors framework to investigate flushing mechanisms in diameter of the blood
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