In a recent study published in Scientific Reports, researchers investigated if rosacea, a common skin condition widely considered to be only a cosmetic issue, could be associated with several comorbidities, including melanomas.
Study: Rosacea is strongly associated with melanoma in Caucasians. Image Credit: Andrey_Popov/Shutterstock.com
Background
They used a large age- and sex-matched cohort derived from the TriNetX platform (n = 244,888) for the study comprising Caucasian, Black, Asian, Alaskan, and Pacific Islander ethnicities.
Their findings elucidate that, contrary to previous research, rosacea is significantly associated with a heightened risk of visual disturbances, metabolic disorders, joint problems, and type 2 diabetes (T2D).
Notably, the Caucasian sub-cohort depicted a substantially increased risk of melanoma, a finding absent in the Asian cohort. This ethnicity-associated outcome may explain conflicting comorbidity reports from previous studies.
While the present study has notable limitations in its retrospective design, it helps justify further research into the pathology of this common yet poorly understood disease.
What is rosacea, and why has it slipped under the epidemiological radar for so long?
Rosacea is a chronic skin condition predominantly causing redness and rashes on affected individuals' cheeks, chin, nose, and forehead. The condition is most prevalent in females between the ages of 30-50, though it can occur in individuals irrespective of age or sex.
Global reports suggest that individuals of Celtic descent and fair-skinned northern Europeans are more vulnerable to the disease, with prevalence in these ethnicities assumed to be between 5-10% compared to the global estimate of 1-7%.
Despite having been described in Geoffrey Chaucer's "The Canterbury Tales" in the late 1300s and possibly in 200 BC by Theocritus, alarmingly, rosea remains poorly understood.
While numerous causes for the condition have been proposed, including ultra-violet exposure, smoking, alcohol, heat, exercise, psychological stress, and most commonly genetics, these have never been scientifically validated.
Recent research has associated Demodex species infections with manifestations of rosacea, resulting in oral antibiotics being the clinical intervention of choice when symptoms manifest. However, these interventions provide only temporary relief, and there is currently no long-term cure for the disease.
A possible explanation for why such a common disease has been left understudies for so long could be that, until recently, rosacea was assumed to be solely a cosmetic problem.
Recent research has challenged this widespread notion, with a growing body of literature suggesting that rosacea is associated with inflammatory bowel disease, autoimmune disorders, coronary artery disease, and similar chronic inflammatory conditions.
Since imbalanced inflammatory and immune responses are often observed as carcinogens, particularly in skin cancers, few studies have investigated the associations between rosacea and cancer. Unfortunately, the outcomes of these investigations remain confounding and inconclusive.
Despite representing only 4% of skin cancers globally, malignant melanomas are responsible for more than 50% of skin cancer-related deaths annually, making them the most lethal and aggressive forms of these diseases.
Given that the prevalence of skin cancer, already the most common cancer subtype in the world, is increasing rapidly, it is imperative to identify at-risk populations and risk factors early to reduce the healthcare burden of this potential terminal ailment.
About the study
The present study aimed to retrospectively use data from an extensive "real-world" database (the TriNetX platform) to elucidate potential correlations between rosacea and several systemic diseases, including malignant carcinomas.
The dataset was derived from the 21,913,235 TriNetX enrolled patients between June and July 2023 and included both demographics (particularly age, sex, and ethnicity) and medical health records (diagnoses, medications, laboratory observations, and genomic information).
Study inclusion criteria comprised patients with a diagnosis of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) code L71 (rosacea) and an equal number of age- and sex-matched non-rosacea patients included as controls.
"A subset analysis was carried out on April 2nd, 2024 for rosacea patient with ICD-10 codes C43 [malignant melanoma of the skin] and C44 [other and unspecified malignant neoplasm of the skin] separately. 86% of the data is derived from US patients and ethnicity is routinely queried upon inclusion in the database."
Statistical analyses comprised propensity score matching, the Kaplan-Meier survival analysis (excluded for melanomas), and compare outcome analysis, all conducted using TriNetX analytics tools.
Additionally, Risk Difference, Odds Ratios (ORs), and Risk Ratios (RRs) of observed comorbidities were calculated during an independent sub-cohort analysis.
Study findings and conclusions
Of the 132,388 patients diagnosed with ICD-10 code L71 (rosacea), 122,444 (69.2% female) had age- and sex-match non-rosacea-diagnoses counterparts and were included in the present analyses. Of these, 82% were Caucasian, 3% Black, 1.6% Asian, 10% unknown, and the remaining Alaskan, Indian, Hawaiian, or Pacific Islanders.
"While the risk of being diagnosed with a vascular disease was at 0.185 in patients without rosacea, this risk increased to 0.336 in patients with rosacea [OR 2.234 (2.192, 2.276)]."
Contrasting previous reports, rosacea was found to be associated with significant increases in the risks of heart disease (OR = 1.649), type 2 diabetes (T2D; OR = 1.618), metabolic diseases (OR = 3.165), and ophthalmologic or joint diseases (OR = 4.164-4.801).
Alarmingly, the comorbidities most strongly associated with rosacea were skin neoplasms (including malignant melanomas; OR = 6.031).
"In a subset analysis of rosacea patients with neoplasms of the skin, we were able to determine not only an increased risk of non-melanoma skin cancer [C44; OR 5.550 (5.345, 5.763)], but of malignant melanoma (C43) as well [OR 4.468 (4.144, 4.818)]. With the starkly increased risk for malignant melanoma in our rosacea population, we performed a Kaplan–Meier analysis of this subset of patients. The survival probability at the end of the time window was 92.51% and 97.71% for the cohort with or without rosacea, respectively. At an HR of 3.286 (95% CI 3.101, 3.481), the mortality of malignant melanoma patients was higher if they also suffered from rosacea (p = 0.059)."
In summary, this study is the first to conclusively correlate rosacea with many comorbidities, some of which (melanomas and heart diseases) are life-threatening.
Despite its noteworthy limitations of only using retrospective data and ICD-10 codes, it highlights the importance of rosacea and the need for further research into this deceptively harmless disease.
Gene editing restores treatment sensitivity in melanoma