Due to substantial advances in the understanding of rosacea discovered over the past 15 years, an updated standard classification system was recently published that allows clinicians to identify rosacea’s signs and symptoms on an individual basis. Additionally, it aids clinicians in selecting treatment targeted to the specific needs of individual patients.1

The updated standard classification and pathophysiology of rosacea was published by the National Rosacea Society (NRS) as an update to the original NRS standard classification of rosacea, published in 2002.2 The new system was developed by a consensus committee and review panel of 28 rosacea experts to reflect current scientific knowledge establishing a consistent multivariate disease process that underlies the various clinical manifestations of the disorder. The intent is to provide a more precise, evidence-based framework for research, diagnosis, and patient care.

Because the pathogenesis and pathophysiology of rosacea were then unknown, the original system was based on morphological characteristics alone and designated the most common groupings of primary and secondary features as subtypes. Unfortunately, the subtype descriptions were interpreted by many as distinct entities, failing to consider the frequent occurrence of more than one subtype at the same time or the evolution from one subtype to another.

The committee noted that, because rosacea appears to encompass a consistent inflammatory continuum, it seemed appropriate to focus on individual phenotypic characteristics (“phenotypes”) that may result from this disease process to provide a means of assessing and treating rosacea in a manner consistent with each individual patient’s expression of disease. Observing the respective phenotypes in clinical practice will encourage consideration of the full range of potential signs and symptoms that may occur in any individual patient, and assessment of severity and the selection of treatment may be more precisely tailored to each individual.

Although rosacea’s potential phenotypes may appear in various combinations and at various times, research suggests that all may be part of the same underlying disease process, and rosacea may progress both in severity and to encompass additional phenotypes. Recent studies now suggest a multivariate set of pathogenic pathways that include the innate and adaptive immune systems, mast cells and related biochemical mechanisms, as well as the neurovascular system.

Updated Classification

The new standard system identifies “Diagnostic Phenotypes,” “Major Phenotypes,” and “Secondary Phenotypes.”1 It is proposed that the presence of one of the diagnostic phenotypes—fixed centrofacial erythema in a characteristic pattern that may periodically intensify or, less commonly, phymatous changes, often around the nose—is sufficient to allow consideration of a diagnosis of rosacea. Physicians must rule out other possible causes of rosacea-like symptoms, such as lupus, steroid-induced rosacea, or seborrheic dermatitis, before confirming the diagnosis of rosacea. In the absence of a diagnostic phenotype, two or more major phenotypes—flushing; papules and pustules; telangiectasia; and ocular manifestations including lid margin telangiectasia, interpalpebral conjunctival injection, spade-shaped infiltrates in the cornea, and scleritis and sclerokeratitis—may be considered diagnostic. These findings also often appear along with the diagnostic features.

Secondary phenotypes, which may appear with one or more diagnostic or major phenotypes, include a burning sensation or stinging sensation, edema, and dry appearance.1

Ocular rosacea can be present with cutaneous rosacea but may also occur in the absence of skin disease.1 Signs and symptoms of ocular rosacea include telangiectases on the eyelid margin, conjunctival injection, corneal infiltrates, scleritis, or sclerokeratitis. Burning, stinging, light sensitivity, and the sensation of a foreign object may also occur, as well as conjunctivitis, blepharitis, chalazia, and crusty accumulations at the base of the eyelashes, in addition to others. Secondary ocular features include “honey crust” and collarette accumulation at the base of the lashes, irregularity of the lid margin, and evaporative tear dysfunction (rapid tear breakup time).

The committee also noted that recent evidence suggests clinicians may expect to find rosacea in individuals with darker skin types and may use the updated standard criteria to determine its presence in individuals with entire range of skin pigmentation.1

Pathophysiology and Progression

Although the cause of rosacea remains unknown, researchers have now identified major elements of the disease process that may lead to significant advances in its treatment.

Recent studies (reviewed in reference 1) have shown that the initial erythema is likely to be the beginning of an inflammatory process initiated by a combination of neurovascular dysregulation and the innate immune system. The role of the innate immune system in rosacea has been the focus of breakthrough studies, including the discovery of irregularities of antimicrobial peptides known as cathelicidins. Further research has now demonstrated that a marked increase in mast cells, located at the interface between the nervous system and vascular system, is a common element in all major presentations of the disorder, indicating a link between the neurovascular, inflammatory, phymatous, and ocular presentations. Other studies have documented a possible genetic component, as well as the potential role of the human microbiome, including Demodex mites and certain bacteria.3-5

Initial erythema and vascular manifestations, such as telangiectasia, may be in a continuum triggered by a combination of neurovascular dysregulation and innate immune responses that include increased LL37 and serine proteases (reviewed in reference 1). Papules involve an increase in Th1 and Th17 cells, plasma cells, mast cells and macrophages, while pustules are accompanied by an increase in neutrophil-recruiting chemokines (reviewed in reference 1).

Although immune response gene expression levels are highest in rosacea with papules and pustules (reviewed in reference 1), neurovascular and phymatous presentations of rosacea also include a marked inflammatory infiltrate and upregulation of genes involved in innate and adaptive immune responses, suggesting a continuum of inflammation through different cellular activities and molecular pathways that are reflected in the various clinical signs and symptoms.1

Because some inflammatory pathways may be more operative in some clinical presentations than in others, more studies are needed for clarification. For example, while phymatous changes may present without erythema in some patients, biopsies show an inflammatory infiltrate, and transcriptome analysis indicates the presence of inflammatory mediators, suggesting the occurance of subclinical inflammation (reviewed in reference 1).

A current hypothesis is that early phymatous rosacea in the absence of clinical erythema may be associated with subclinical neuroinflammation and innate or adaptive immune responses, which may be followed by the development of fibrosis and glandular hyperplasia. This is consistent with the fact that patients with phymatous rosacea have shown increased expression levels of genes associated with inflammation and immune responses (reviewed in reference 1). Thus, while not all patients may experience phymatous changes, subclinical fibrotic changes may be present before they can be seen clinically, suggesting that fibrosis in rosacea may begin at a much earlier stage than might be expected through clinical observation.1,6

Quality of Life

The consensus committee also emphasized that clinicians should factor the psychosocial effects of rosacea on their patients into their treatment, as multiple patient surveys have documented rosacea’s substantial adverse impact on emotional, social, and occupational well-being.

In an NRS survey of rosacea patients, 90 percent said that rosacea’s effect on their personal appearance had lowered their self-esteem and self-confidence, and 52 percent said they had avoided face-to-face contact because of the disorder.7 Rosacea’s overall emotional impact on patients appears to increase as symptoms progress. While 68 percent of those who described their rosacea as mild reported a negative impact on their general outlook on life, the adverse impact rose to 87 percent for those with moderate symptoms and 95 percent of those with severe symptoms.

More than 74 percent of rosacea patients in a survey on social interactions said they have received questions or comments about the appearance of their face, and 87 percent felt people had misconceptions about their appearance.8 Approximately 76 percent of respondents said they sometimes attracted stares, and 44 percent felt that people purposely avoided looking at their face. In a separate survey, 41 percent of respondents reported that their condition had caused them to avoid public contact or cancel social engagements.9

In another survey by the NRS, more than 75 percent of all respondents—and 92 percent of those reporting severe symptoms—said their rosacea had affected interactions with others in the workplace.10 More than 66 percent said rosacea had negatively impacted interactions with co-workers or customers, and 29 percent of patients reporting mild symptoms and 43 percent with severe symptoms said they had missed work because of the condition.

Comorbidities

The consensus committee published an accompanying commentary summarizing the growing number of recent studies that have found associations between rosacea and an increased risk for an expanding range of potentially serious systemic disorders.11 Although further research is needed to determine any causal relationships, this might substantially raise the clinical significance of rosacea as evidence mounts that it might be an outcome of systemic inflammation. In addition, current scientific knowledge has pointed to a variety of promising research avenues that might help further illuminate rosacea’s etiology, pathophysiology, and clinical implications.

In various studies, researchers found an increased incidence in rosacea patients of cardiovascular disorders including dyslipidemia, hypertension, and coronary artery disease; gastrointestinal disorders including celiac disease, Crohn’s disease, irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis, and gastroesophageal reflux disease (GERD); urogenital diseases; and type II diabetes (reviewed in reference 11).

In large retrospective studies in Denmark and the US, rosacea patients were found to be at significantly greater risk of developing Parkinson’s disease, as well as at a slightly elevated risk for dementia and Alzheimer’s disease (reviewed in reference 11). Studies have also found a potential association between rosacea and increased risk of thyroid cancer, basal cell carcinoma, and glioma. Female rosacea patients may be at increased risk for multiple sclerosis, rheumatoid arthritis, celiac disease, type 1 diabetes, and migraines (reviewed in reference 11).

In addition, recent research has found other elements that may affect rosacea. Genetic factors appear to be an influence, and data show that a microbial contribution to rosacea suggests the skin microbiome may be significant.3-5 In addition, while the involvement of the innate immune system is well established, it now seems clear the adaptive immune system may also be involved.

Conclusion

Growing knowledge of rosacea’s pathophysiology has increasingly found that a consistent multivariate disease process appears to underlie the various potential manifestations of the disorder, and its clinical significance may increase substantially as more is understood about the many comorbidities that have been reported. Meanwhile, the new phenotype-based standard classification of rosacea encourages dermatologists to consider the full range of potential manifestations of the disorder when diagnosing individual patients, resulting in more targeted care and significant improvements in the quality of their lives.

Samuel Huff founded the National Rosacea Society in 1992 and has more than 35 years’ experience in medical communications and organizational management. He is President of NRS.

Richard D. Granstein, MD is Chairman of Dermatology and George W. Hambrick, Jr. Professor of Dermatology at Weill Cornell Medical College, Cornell University, in New York City.

1. Gallo RL, Granstein RD, Kang S, et al. Standard classification and pathophysiology of rosacea: The 2017 update by the National Rosacea Society Expert Committee. J Am Acad Dermatol 2018 Jan;78(1):148-155. doi: 10.1016/j.jaad.2017.08.037. Epub 2017 Oct 28.

2. Wilkin J, Dahl M, Detmar M, et al. Standard classification of rosacea: Report of the National Rosacea Society Expert Committee on the Classification and Staging of Rosacea. J Am Acad Dermatol 2002;46:584-587.

3. Rainer BM, Kang S, Chien AL. Rosacea: Epidemiology, pathogenesis, and treatment. Dermatoendocrinol 2017 Oct 4;9(1):e1361574. doi: 10.1080/19381980.2017.1361574

4. Zaidi AK, Spaunhurst K, Sprockett D, Thomason Y, Mann MW, Fu P, Ammons C, Gerstenblith M, Tuttle MS, Popkin DL. Characterization of the facial microbiome in twins discordant for rosacea. Exp Dermatol 2018;27:295-298.

5. Murillo N, Aubert J, Raoult D. Microbiota of Demodex mites from rosacea patients and controls. Microb Pathog 2014;71-72:37-40.

6. Schwab VD, Sulk M, Seeliger S, Nowak P, Aubert J, Mess C, Rivier M, Carlavan I, Rossio P, Metze D, Buddenkotte J, Cevikbas F, Voegel JJ, Steinhoff M. Neurovascular and neuroimmune aspects in the pathophysiology of rosacea. J Investig Dermatol Symp Proc 2011;15:53-62.

7. Emotional toll of facial redness equal to bumps, pimples: survey. Rosacea Review. Available at: 2013;fall:2 https://www.rosacea.org/rr/2013/fall/article_3.php. Accessed April 10, 2018.

8. New survey defines impact of rosacea in social situations. Rosacea Review. Available at: 2017;winter:1 https://www.rosacea.org/rr/2017/winter/new-survey-defines-impact-rosacea-social-situations. Accessed April 10, 2018.

9. Successful treatment improves social life, according to survey. Rosacea Review. Available at: 1999;fall:2 https://www.rosacea.org/rr/1999/fall/article_3.php. Accessed April 10, 2018.

10. Rosacea can affect workplace interactions, survey reveals. Rosacea Review. Available at: 2015;fall:2 https://www.rosacea.org/rr/2015/fall/article_3.php. Accessed April 10, 2018.

11. Gallo RL, Granstein RD, Kang S, et al. Rosacea comorbidities and future research: The 2017 update by the National Rosacea Society Expert Committee. J Am Acad Dermatol 2018 Jan;78(1):167-170. doi: 10.1016/j.jaad.2017.06.150. Epub 2017 Nov 1.