In 1994, I described rosacea as a cutaneous and ocular vascular disease,1 which was based on premises the most compelling of which was that patients with severe flushing due to systemic disease often had rapidly progressive rosacea, including ocular rosacea, facial telangiectasia, and phymatous changes. The earliest stages of rosacea were proposed to have an inflamed superficial vasculature and low-grade sterile superficial dermal cellulitis due to recognized provocative factors, such as local irritants, temperature extremes, wind, and flushing reactions. Subsequently, I have sought articles adding molecular details to my mental picture of this vascular pathogenesis of rosacea, and the evidentiary harvest has been abundant. Steinhoff et al2,3 demonstrated that (1) transient receptor potential vanilloid subfamily (TRPV) receptors are activated by typical rosacea trigger factors, such as heat, capsaicin, and inflammatory mediators, suggesting that flushing from these trigger factors may be via TRPV-positive blood vessels and mast cells; (2) erythematotelangiectatic rosacea (ETR), papulopustular rosacea (PPR) and phymatous rosacea may have different TRPV subtype profiles, with intergrades between ETR and PPR suggesting the possibility of a “march” in some patients with ETR toward PPR; and (3) pituitary adenylate cyclase–activating polypeptide, a potent vasodilator, is upregulated 20 to 30 times in early ETR. Clearly, inflammatory rosacea cannot stand as a synonym exclusively for PPR, given this evidence for inflammatory events in ETR. Another factor postulated to possibly contribute to the vascular pathogenesis of rosacea was actinic damage,1 especially to the elastin network as a low-resistance pathway through the interstitium along which macromolecules pass to the lymphatic system.4,5 Actinic damage here might lead to low-grade superficial dermal lymphatic failure in the rosacea distribution.1 Moreover, photodistributed, mostly vasodilator drug–related telangiectasia underscores the potential role for actinic exposure in the pathogenesis of telangiectasia.6 Yano et al7 and Kajiya et al,8 in exploring the mechanisms of acute UV-B–induced angiogenesis and photodamage in human skin, demonstrated the consequent epidermal hyperplasia, infiltration of elastin-producing neutrophils, and elastin fiber damage, along with a significant increase in both vascular density and vessel size, features consistent with the proposed pathogenesis of ETR1 as well as the cutaneous signs of telangiectatic photoaging (TP), as described by Helfrich et al.9 There are now plausible molecular links for clinically well-recognized rosacea triggers, including actinic damage, with the proposed inflammatory vascular pathogenesis of rosacea, beginning with ETR.1 However, not everyone agrees that rosacea begins with ETR or that ETR is even a subtype of rosacea. Helfrich et al9 remind us that ETR is probably the most disputed subtype of rosacea, with some authors arguing that it is merely photodamage or, at least, difficult to distinguish from photodamage. This is a curious twist given that rosacea was first recognized as a distinct facial dermatosis separate from common acne (acne vulgaris) by virtue of its rosy hue (acne rosacea).10 Helfrich et al find that ETR is, in fact, distinguishable from TP. This study by Helfrich et al9 is pharmacotherapeutically timely, given the current state of drug product development for ETR. Perhaps their distinction between ETR and TP will enable the physician to better pair treatments with specific dermatoses. Even in the era before the approval of drug products for ETR, identification of erythema and telangiectasia had a role. The occasional patient would have dramatic reduction in facial erythema when given systemic antibiotic and anti-flushing therapy. Among this minority, fewer still would experience PERT (posterythema-revealed telangiectasia),1 the emergence of preexisting telangiectasia from a receding intense erythema. When assessing the potential for PERT for a patient with rosacea presenting with intense facial erythema, I have sought to roughly apportion the intensity of redness among background skin color, ETR, and photodamage. It is important to be very close to the patient for this examination because many fine telangiectases are perceived as simple erythema if the dermatologist is not close. The retro-auricular skin where neither photodamage nor rosacea is expected provides the assessment of background skin redness. Next, the skin overlying the sternocleidomastoid is examined for the sum of background skin redness and photodamage. The cheek is then examined for the sum of all 3 factors, and the contribution attributable to rosacea is often pink, actually rosy, with or without fine wispy telangiectases. This calculus of rough apportionment of erythema might now be reconsidered, and possibly simplified, in light of the observation by Helfrich et al9 that ETR is more centrally facial, and telangiectatic photoaging more laterally facial. Such an apportionment of erythema and finer definition of ETR, if confirmed, may favorably affect regulatory criteria for approval of drug products for rosacea or its subgroup(s) by providing a more rational basis for the clinical descriptions within the investigator’s global assessment (IGA) for efficacy end points and also for inclusion and exclusion criteria for pivotal clinical trials. The US Food and Drug Administration (FDA) has recommended the following 2 primary efficacy end points for demonstrating efficacy in the treatment of rosacea: (1) inflammatory lesion counts (papules, pustules, and nodules) and (2) the static IGA. The FDA has also recommended that clinical signs (erythema and telangiectasia) be incorporated into the static IGA. For a product intended to treat only a specific subgroup of rosacea, it would be rational for the FDA to recommend that the IGA for that subgroup need contain only the signs or symptoms specific to that subgroup. For example, it would be important to assess whether a drug product intended to treat only PPR led to worsening of erythema and/or telangiectasia, but this could be assessed specifically and separately from the IGA for the efficacy end point, which should not include erythema and telangiectasia. The potential for this article by Helfrich et al9 to provide an improved understanding and clinical recognition of ETR depends on how well ETR and TP were distinguished from each other. Excluding subjects with both photodamage and flushing was a necessity. All enrolled subjects had to have a diagnosis of either TP or ETR, which were mutually exclusive using their diagnostic criteria. Patients with TP had to have facial telangiectases and prominent feature(s) of photoaging and could not have any more than very minor flushing. Those with ETR had to have prominent flushing and were permitted but not required to have facial telangiectases. Since clinical evidence of photodamage was essential for a diagnosis of TP and not for ETR, it would have been rather surprising if Helfrich et al had not found significantly more photodamage in TP than in ETR by clinical examination and in facial cutaneous biopsy specimens by light microscopic histologic analysis and immunohistologic analysis and by transmission electron microscopy. Likewise, we are comforted by their findings that flushing was significantly greater in ETR than in TP, since this was the only diagnostic point they used that mutually separated enrolled subjects between ETR and TP. The observation of Helfrich et al9 that the dilated vessels in ETR did not exhibit the same degree of surrounding collagen damage as those in TP does not exclude an important actinic contribution to the pathogenesis of ETR. It is obvious, but important to state for completeness, that it also does not follow from the identification of facial telangiectasia associated with prominent photodamage in the absence of prominent flushing that prominent flushing could not have driven the development of facial telangiectasia. The finding of facial telangiectases in a patient with prominent photodamage who has not had prominent flushing in over 6 months could be consistent with successful surgery for carcinoid syndrome in an outdoor worker with much sun exposure. Since the key exclusion criterion separating ETR from TP is prominent flushing, the findings of Helfrich et al9 of greater inflammation, greater mast cell activation, and elevation of selected neuropeptides in ETR than in TP may be evidence of the provocation and progression of rosacea, especially ETR, by frequent and intense flushing episodes. However, the necessary inclusion criterion for a diagnosis of TP, but not ETR, of prominent feature(s) of photodamage does not exclude the possibility that extensive, chronic, and prominent photodamage may reduce or eliminate the ability of the skin to sustain such inflammation, mast cell activation, and elevation of selected neuropeptides. Photodamage might “burn out” inflammatory rosacea, especially ETR. Helfrich et al note that “the typical patient with ETR is a younger to middle-aged woman, while the typical patient with TP is an older man,”9 which could be consistent with a progression from ETR to TP with cumulative photodamage. Longitudinal studies could address this hypothesis, which might also have been preliminarily explored had there been a second ETR group who were not only strong flushers but also had prominent feature(s) of photodamage. This study by Helfrich et al9 may be an important step toward understanding ETR, including some issues identified 21 years ago, such as whether “prerosacea” might be recognized; how, or whether, ETR can lead to PPR; and, how effective might avoidance of trigger factors be in prevention of progression.1 Back to top Article Information Corresponding Author: Jonathan K. Wilkin, MD, 300 W Spring St, Ste 802, Columbus, OH 43215 (email@example.com). Published Online: March 23, 2015. doi:10.1001/jamadermatol.2014.4999. Conflict of Interest Disclosure: Dr Wilkin served as consultant to Abbott Laboratories, Aciex Therapeutics, Aclairo Pharmaceutical Development, Aclaris, Actavis, Actelion Clinical Research, ADOCIA, Adolor Corporation, Advancing Innovation in Dermatology (AID), Aisling Capital LLC, Allergan Sales LLC, Almirall SA, Amgen Inc, Anacor Pharmaceuticals, Angion Biomedica Corp, Anterios Inc, Apogee Clinical Inc, Aponia Laboratories Inc, Aqua Pharmaceuticals LLC, Argyle Therapeutics Inc, Arkin Communications Ltd, Array BioPharma, Artielle Immunotherapeutics, Astellas Pharma Global, Astellas Pharma Global, AstraZeneca, Asubio Pharmaceuticals, Auxilium Pharmaceuticals Inc, Basilea Pharmaceutical Ltd, Bayer HealthCare, Berg Pharma, BioMas Ltd, Biosynexus, Braintree Laboratories Inc, Brickell Biotech, Buzzz Pharmaceuticals Ltd, CanFite, CapGenesis LLC, Chemo SA, Chromaderm Inc, Cipher Pharmaceuticals Inc, Clementia Pharmaceuticals Inc, CODA Therapeutics Inc, Cosmo Dermatos srl, Cowen and Company, Creabilis, Cutanea Life Sciences Inc, DEB Group Ltd, Decheng Capital LLC, Dermex Pharmaceutical Inc, Dermira Inc, Dermtreat ApS, Dial Corporation, Dipexium Pharmaceuticals, Dow Pharmaceutical Sciences, Drais Pharmaceuticals Inc, DUSA Pharmaceuticals, Ecolab Inc, Edimer Pharmaceuticals Inc, Eisai Medical Research, Ervin Epstein, Excaliard Pharmaceuticals, Exeltis France, Fidia Farmaceutici SpA, Fluence Therapeutics, Foamix, Follica Incorporation, Foresight Biotherapeutics, Fougera Pharmaceuticals Inc, Galderma Laboratories US, Galderma Research & Development FR, Genentech Inc, GlaxoSmithKline LLC, Halozyme Inc, Hatchtech Pty Ltd, Heal-Or Ltd, Healiance Pharmaceuticals Corp, Heal-Or Ltd, Healthpoint, Ltd, Hill Dermaceuticals Inc, Histogen Inc, Hyman, Phelps & McNamara, Idera Pharmaceuticals Inc, INC Research LLC, Insight Medical Writing, Intendis GmbH, Intendis Inc, Intermune Inc, Isdin SA, Investor Growth Capital AB, Investor Growth Capital Inc, Juventio LLC, Kendle International Inc, Kings College London, Kythera Biopharmaceuticals, LEO Pharma, Lithera Inc, LivSo LLC, Lotus Tissue Repair, Macrocure Ltd, M Arkin (1999) Ltd, Mayne Pharma Group, MC2 Biotek, Medicis Global Services, Medimetriks Pharmaceuticals, MediWound Ltd, Merz Pharmaceuticals LLC, Mitsubishi Tanabe Pharma, Moberg Derma, Mylan Pharmaceuticals Inc, NanoBio Corporation, NeoStrata Company, Neothetics, Neuroquest Inc, Nitric Biotherapeutics Inc, Novabiotics Ltd, Novan Inc, NovaQuest, Novartis Pharmaceuticals Corp, Nuron Biotech Inc, Nuvo Research Inc, Orenova Development Co, Otsuka Pharmaceutical Co, Patagonia Pharmaceuticals LLC, PellaPharm Inc, Pernix Therapeutics LLC, Perrigo Pharmaceuticals, Pfizer Inc, Photocure ASA, Pierre Fabre Dermatologie, Polichem SA, PreCision Dermatology, PRISM Pharma Co, Promius Pharma LLC, Provectus Pharmaceuticals, Quadex Pharmaceuticals, Reata Pharmaceuticals, Revance Therapeutics, Rhythm Pharmaceuticals Inc, Sancilio & Company Inc, Sanofi Aventis Recherche, Sciaderm LLC, Scibase AB, Scioderm Inc, Sebacia Inc, Sinclair IS Pharma PLC, Slayback Pharma, Smith & Nephew, Sofinnova Ventures Inc, Sol-Gel Technologies, Squarex LLC, Stiefel Laboratories Inc, Symbiomix Therapeutics LLC, SynAgile Corporation, Taro Pharmaceuticals, Teva Branded Pharmaceutical Products, Therapeutics Inc, Thesan Pharmaceuticals, Three D Communications, Tigercat Pharma Inc, Tioga Research Inc, Tolmar Inc, Trevi Therapeutics Inc, Ulthera Inc, Valeant Pharmaceuticals North America, Velius LLC, Velocity Pharmaceutical Development, Verrica Pharmaceuticals Inc, Vical Incorporated, ViDAC Pharma Ltd, Vitae Pharmaceuticals Inc, Vivo Ventures LLC, Warner Chilcott US, Water Street Healthcare Partners, Watson Pharmaceuticals, XenoPort Inc, XOMA, and Zogenix Inc. No other disclosures are reported. Previous Presentation: This research was presented at the Annual Meeting of the American Academy of Dermatology; March 23, 2015; San Francisco, California. References 1. Wilkin JK. Rosacea: pathophysiology and treatment. Arch Dermatol. 1994;130(3):359-362.PubMedGoogle ScholarCrossref 2. Steinhoff M, Buddenkotte J, Aubert J, et al. Clinical, cellular, and molecular aspects in the pathophysiology of rosacea. J Investig Dermatol Symp Proc. 2011;15(1):2-11.PubMedGoogle ScholarCrossref 3. Steinhoff M, Ständer S, Seeliger S, Ansel JC, Schmelz M, Luger T. Modern aspects of cutaneous neurogenic inflammation. Arch Dermatol. 2003;139(11):1479-1488.PubMedGoogle ScholarCrossref 4. Ryan TJ. Biochemical consequences of mechanical forces generated by distention and distortion. J Am Acad Dermatol. 1989;21(1):115-130.PubMedGoogle ScholarCrossref 5. Ryan TJ. Structure and function of lymphatics. 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JAMA Dermatology – American Medical Association
Published: Aug 1, 2015