Despite recent advances in rosacea therapy and an ongoing shift toward phenotype-driven treatment, experts told Medscape Medical News that addressing the multifaceted mechanisms of rosacea remains challenging. With research into novel therapeutic approaches largely in early stages, dermatologists must optimize an existing armamentarium that leaves room for improvement, particularly regarding symptoms beyond inflammation.

‘Major Unmet Need’

Dermatologists excel at recognizing rosacea and maximizing use of available therapies, said Christopher G. Bunick, MD, PhD, associate professor of dermatology and faculty member with the Program in Translational Biomedicine at Yale University, New Haven, Connecticut. “But there’s still a major unmet need for more effective therapies, partly because we’re still not entirely certain of the root causes of rosacea. There are ideas, but there’s still a lot of research to be done in understanding the root causes and developing new therapies.”

Benjamin Ungar, MD, assistant professor of dermatology and director of the Rosacea & Seborrheic Dermatitis Clinic at the Icahn School of Medicine at Mount Sinai in New York City, added that rosacea treatments have advanced to the point where several options can provide benefit. But generally, he told Medscape Medical News, these options work best on rosacea’s inflammatory phenotype.

Medications approved by the FDA since 2020, all for inflammatory rosacea, include minocycline foam 1.5% (Zilxi), microencapsulated benzoyl peroxide 5% (Epsolay), and, in November 2024, low-dose oral extended-release minocycline 40 mg (Emrosi).

In the MVOR-1 and MVOR-2 phase 3 trials of adults with moderate-to-severe rosacea, 62.4% of those treated with extended-release minocycline achieved Investigator Global Assessment (IGA) success (defined as IGA 0/1 with at least a 2-point reduction from baseline) at week 16 vs 38.6% among those on extended-release doxycycline and 29% for placebo (P ≤ .01 for all analyses). Corresponding reductions in absolute inflammatory lesion counts were 19.65, 15.35, and 11.6, respectively (P < .001 for all analyses).

Ungar said that although extended-release minocycline has only been commercially available since March, he finds it encouraging that his patients with rosacea tolerate it well, and it generally has been helpful clinically. Compared with topical therapies, he added, having an oral agent will simplify consistent use for many patients.

Understanding how well extended-release minocycline helps particular symptoms or patients will be an ongoing process, Ungar said, as will monitoring for postmarketing side effects. “But so far, it seems to be going well.” 

Topical Bias?

Whether extended-release minocycline will alter physicians’ prescribing habits remains to be seen, Ungar told Medscape Medical News. “For many dermatologists, and likely primary care physicians as well,” he explained, “there is often a bias toward topical medications that are seen as less likely to have side effects or as generally safer.” Despite extended-release minocycline’s low total dose of 40 mg, he added, concerns over long-term antibiotic safety also may hinder uptake. Because the product is a specialty formulation, Ungar added, many insurers may not cover it, or high out-of-pocket costs could slow sales.

Neal Bhatia, MD, director of clinical dermatology at Therapeutics Clinical Research in San Diego, said that extended-release minocycline represents the future for treating ocular rosacea in particular. Bhatia, who was co-primary investigator in the phase 3 trials, explained that minocycline uses the same molecular mechanism as doxycycline to enter the vasculature, reduce cathelicidin biology and cytokine interactions, and address other promoters of rosacea inflammation such as matrix metalloproteinases and neutrophils.

Nondrug therapies being explored for rosacea’s inflammatory component include transcutaneous auricular vagus nerve stimulation (taVNS). A randomized clinical trial of patients with erythematotelangiectatic rosacea published in October showed that taVNS provided lasting improvements in both erythema scores and systemic comorbidities, including anxiety and depression.

Based on prior research, the study authors wrote, taVNS synergistically modulates the cholinergic anti-inflammatory reflex and rebalances cytokine networks, specifically suppressing pathogenic cytokines including interleukin (IL) 1 beta, IL-6, high-mobility group box 1 protein, and TNF-alpha. Additionally, vagus nerve stimulation has been shown to produce antidepressant effects, partly by modulating monoaminergic neurotransmission, including altering serotonin and norepinephrine levels, in limbic circuits, while also upregulating neurotrophic factors that enhance synaptic plasticity and suppress neuroinflammation via the cholinergic anti-inflammatory pathway, according to a review published in 2023.

Early-Stage Research

To a large extent, Ungar said, recent advances in treating rosacea’s inflammatory component have highlighted the need for better treatments for other manifestations of rosacea. Although many treatments are under investigation, he said, none are advanced enough to warrant a deep dive. “Different mechanistic approaches are being looked at, at least in principle,” Ungar said. “But it’s hard to know if and when we’ll actually see what’s happening.”

The complexity of rosacea etiology likely will require multiple treatment approaches, he said, to address the inflammatory, neurogenic, vascular proliferative, and oxidative stress response components. “I tend to wait to see published phase 2 studies, let alone phase 3, before getting too excited about an individual treatment,” Ungar added.

Phenotypic Shift

The shift from subtype-driven diagnosis and treatment to a phenotype-based approach recommended by organizations including the National Rosacea Society, the American Acne & Rosacea Society, and the global Rosacea Consensus (ROSCO) panel remains a relatively recent development, said Ungar. Rather than targeting the previously recommended erythematotelangiectatic, papulopustular, and/or ocular subtypes, updated ROSCO guidelines recommend choosing treatments based on each patient’s presentation.

For dermatologists who have been practicing for many years, Ungar said, the phenotype-driven model of diagnosis and treatment may not be as top-of-mind as it could be. Although there is likely no “silver bullet” for raising such providers’ awareness, he said that as the dermatology community continues to discuss rosacea, adoption of this approach will expand.

Increasingly, Ungar said, clinicians intuitively recognize that rosacea, which stems from multiple recognized pathways and creates diverse symptoms that rarely fit neatly into a single subtype, demands an individualized strategy. “There is movement in the right direction,” he told Medscape Medical News, adding that he would not be surprised if the phenotypic strategy becomes the primary way of conceptualizing rosacea over the next few years. Development of additional treatments that target specific rosacea components will further fuel the shift, he said.

Bunick said he doubts that dermatologists consciously consider whether they are using a phenotype- or subtype-driven strategy when addressing rosacea. Rather, he said, diagnosing and treating rosacea effectively requires combining both approaches. Dermatologists’ use of visual cues to recognize rosacea subtypes is consistent with the phenotypic strategy, he added. “You look at a patient and generally know that they either have phymatous changes on the nose, or papules and pustules, or they don’t,” he said.

Where the phenotypic approach becomes more challenging, and where it is important for dermatologists to pay attention, Bunick told Medscape Medical News, is in addressing possible vascular and/or neurogenic rosacea. Identifying these phenotypes can be trickier, he said, depending on patient presentation. “ How do you distinguish redness from skin inflammation from the redness caused by vasomotor instability and dilated blood vessels? Are there symptoms — burning, stinging, pain, itch, swelling?” Swelling can signify vascular rosacea, he explained, while burning, stinging, pain, and itch may indicate neurogenic origins. 

The 2011 publication in which Tiffany C. Scharschmidt, MD, and colleagues first characterized neurogenic rosacea identified with burning, stinging, and erythema symptoms — key clues for the clinician to look for — in 100% of cases, Bunick told Medscape Medical News. “Dysesthesia out of proportion to flushing or inflammation was also common,” he added, “whereas papules and pustules are less common in neurogenic rosacea. Telangiectasias, the dilated blood vessels seen in vascular rosacea, are not as frequently associated with such dysesthesia, and the blood vessels can often be visualized on dermatoscopy distinct from any inflammatory erythema.”

Patients with rosacea should be screened for concomitant neurologic or neuropsychiatric conditions, which are more prominent in neurogenic rosacea, Bunick added.

To better understand neuroimmune dysregulation and systemic inflammation in rosacea at the molecular level, authors of a recent study used serum proteomic signatures to identify molecular rosacea endotypes. Specifically, quantitative proteomic profiling on plasma samples from 27 patients with rosacea and 25 healthy control participants showed that the former group had 431 upregulated proteins implicating inflammatory, metabolic, and neuroregulatory pathways, and 59 downregulated proteins linked to complement pathways. Further analysis uncovered both inflammatory-predominant and neurogenic-metabolic subtypes in 22 and five patients, respectively.

Ungar said that this paper reinforces much of the current understanding of rosacea pathophysiology, highlighting systemic inflammatory and neurogenic components and the clinical heterogeneity of disease presentation. Additionally, he told Medscape Medical News, the paper could provide a springboard for future research.

Bunick reported having no relevant financial relationships. Ungar reported being a consultant, researcher, and/or speaker for AbbVie, Arcutis Biotherapeutics, Bristol Myers Squibb, Botanix Pharmaceuticals, Castle Biosciences, Fresenius Kabi, Galderma, Incyte, Johnson & Johnson, LEO Pharma, Eli Lilly, Pfizer, Primus Pharmaceuticals, RAPT Therapeutics, Sanofi, Sun Pharma, UCB, Veradermics, and VRG Therapeutics. Bhatia reported having affiliations with AbbVie, Advanced Derm Solutions, Almirall, Arcutis, Beiersdorf, Galderma, Journey, La Roche-Posay, LEO, Ortho Dermatologics, Sagimet Biosciences, Skinfix, and Sun Pharma.

John Jesitus is a Denver-based freelance medical writer and editor.