Rosacea

Number: 0547

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

 Scope of Policy

This Clinical Policy Bulletin addresses rosacea.

1. Medical Necessity

   1. Aetna considers medical treatment of rosacea medically necessary. However, surgical treatment of disfigurement from rosacea (e.g., scarring and telangiectasias) is considered cosmetic.
   2. Aetna considers excision or shaving of rhinophyma medically necessary for the treatment of bleeding or infection refractory to medical therapy (i.e., the need for repeated cautery of bleeding telangiectasias or frequent courses of antibiotics for pustular eruptions).

2. Experimental, Investigational, or Unproven

   1. Aetna considers the following procedures experimental, investigational, or unproven because their effectiveness has not been established:

      • Evaluation of the gastro-intestinal microbiome
      • Measurement of hematological parameters (e.g., (platelet crit, platelet volume, and red blood cell distribution width) as biomarkers for diagnosis and monitoring of rosacea
      • Measurement of interferons (e.g., IFN-γ) as biomarkers for diagnosis and monitoring of rosacea
      • Measurement of interleukins (e.g., IL-1β, IL-1α, IL-4R, IL-6, IL-12β, IL-13, IL-17A, IL-17F, IL-18, IL-23, and IL-31) as biomarkers for diagnosis and monitoring of rosacea
      • Measurement of matrix metalloproteases (e.g., MMP-9) as biomarkers for diagnosis and monitoring of rosacea
      • Measurement of serum bilirubin, uric acid and zonulin levels in rosacea
      • Measurements of serum chemokines (including CCL2, CCL3, CCL20, CXCL1, CXCL8, CXCL9, CXCL10, and CXCL12) as indicators of rosacea and for evaluation of severity of disease
      • Measurement of serum endocan (previously known as endothelial cell-specific molecule 1) as a marker for disease progression in rosacea
      • Measurement of transcription factors (e.g., FOS, GATA3, and JUN) as biomarkers for diagnosis and monitoring of rosacea
      • Measurement of transforming growth factor (e.g., TGF-β) as biomarkers for diagnosis and monitoring of rosacea
      • Measurement of tumor necrosis factor (e.g., TNF-α) as biomarkers for diagnosis and monitoring of rosacea
      • Reflectance confocal microscopy and spectrometry for rosacea assessment and monitoring of therapy.

   2. Aetna considers the following treatments of rosacea experimental, investigational, or unproven because their effectiveness for this condition has not been established:

      • Intense pulsed light (for ocular rosacea)
      • Photodynamic therapy
      • Platelet-rich plasma injection, alone or in combination with, pulsed light therapy or botulinum toxin injection.

3. Cosmetic

   Surgical treatment of disfigurement from rosacea (e.g., scarring and telangiectasias) is considered cosmetic.

   Note: Cosmetic surgery is excluded from coverage under Aetna standard benefit plans. Please check benefit plan descriptions for details. 

4. Related Policies

   Note: See member’s pharmacy benefit plan for self-administered medications that apply under the pharmacy benefit.

   See also:

   • CPB 0031 - Cosmetic Surgery and Procedures
   • CPB 0113 - Botulinum Toxin
   • CPB 0251 - Dermabrasion, Chemical Peels, and Acne Surgery
   • CPB 0559 - Pulsed Dye Laser Treatment.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
CPT codes covered if selection criteria are met:
10040	Acne surgery (e.g., marsupialization, opening or removal of multiple milia, comedones, cysts, pustules) [for acute rosacea]
30120	Excision or surgical planing of skin of nose for rhinophyma [for the treatment of bleeding or infection refractory to medical therapy (i.e., the need for repeated cautery of bleeding telangiectasias or frequent courses of antibiotics for pustular eruptions)]
CPT codes not covered for indications listed in the CPB:
Measurement of serum zonulin levels, gastro-Intestinal microbiome, measurements of serum chemokines, measurements of serum endocan, photodynamic therapy, interferons, transcription factors, platelet crit, platelet volume, and red blood cell distribution width, Interleukins, Matrix metalloproteases, transforming growth factors, tumor necrosis factor - no specific code
0232T	Injection(s), platelet rich plasma, any site, including image guidance, harvesting and preparation when performed
15780	Dermabrasion; total face (e.g., for acne scarring, fine wrinkling, rhytids, general keratosis)
15781	segmental, face
15782	regional other than face
15783	superficial, any site (e.g., tattoo removal )
15788	Chemical peel, facial; epidermal
15789	dermal
15792	Chemical peel, nonfacial; epidermal
15793	dermal
17000	Destruction (e.g., laser surgery, electrosurgery, cryosurgery, chemosurgery, surgical curettement), premalignant lesions (e.g., actinic keratoses); first lesion
+17003	second through 14 lesions, each (List separately in addition to code for first lesion)
17004	Destruction (e.g., laser surgery, electrosurgery, cryosurgery, chemosurgery, surgical curettement), pre-malignant lesions (e.g., actinic keratoses); 15 or more lesions
17106	Destruction of cutaneous vascular proliferative lesions (e.g., laser techniques); less than 10 sq cm
17107	10.0 to 50.0 sq cm
17108	over 50.0 sq cm
17110	Destruction (eg, laser surgery, electrosurgery, cryosurgery, chemosurgery, surgical curettement), of benign lesions other than skin tags or cutaneous vascular proliferative lesions; up to 14 lesions
17111	Destruction (eg, laser surgery, electrosurgery, cryosurgery, chemosurgery, surgical curettement), of benign lesions other than skin tags or cutaneous vascular proliferative lesions; 15 or more lesions
17340	Cryotherapy (CO2 slush, liquid N2) for acne
17360	Chemical exfoliation for acne (e.g., acne paste, acid )
82247	Bilirubin; total
82248	Bilirubin; direct
84550	Uric acid; blood
96931	Reflectance confocal microscopy (RCM) for cellular and sub-cellular imaging of skin; image acquisition and interpretation and report, first lesion
96932	image acquisition only, first lesion
96933	interpretation and report only, first lesion
+96934	image acquisition and interpretation and report, each additional lesion (List separately in addition to code for primary procedure)
+96935	image acquisition only, each additional lesion (List separately in addition to code for primary procedure)
+96936	interpretation and report only, each additional lesion (List separately in addition to code for primary procedure)
ICD-10 codes covered if selection criteria are met:
L53.9	Erythematous condition, unspecified [persistent facial erythema]
L71.0 - L71.9	Rosacea
ICD-10 codes not covered for indications listed in the CPB:
I78.0 - I78.9	Disease of capillaries [telangiectasias and scarring from rosacea]
L90.5	Scar conditions and fibrosis of skin [from rosacea]

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Background

Rosacea, also called acne rosacea, is a multi-factorial skin disorder that usually affects middle-aged individuals and is characterized by persistent erythema, telangiectasias and acute episodes of edema, papules, and pustules. Patients may have a tendency to flush easily. Chronic inflammation is involves especially the skin of the nose, forehead, and cheeks that is characterized by congestion, flushing, telangiectasia and marked nodular swelling of tissues especially of the nose. Treatment is difficult and is dependent on the severity of disease. Avoidance of excessive sunlight and extreme temperatures is typically recommended. Medical management is aimed only at the inflammatory papules and pustules and the erythema that surrounds them. Topical preparations of metronidazole, clindamycin and erythromycin have been shown to be helpful for mild cases. Oral tetracycline and erythromycin are often prescribed for moderate cases, and Accutane (isotretinoin) has been found to be effective in severe refractory cases. Oral metronidazole has also been used in severe refractory cases.

Laser, dermabrasion and chemical peels are used to eliminate erythema, telangiectasias and other cosmetic effects of rosacea. Laser skin resurfacing involves removal of the upper layer of skin that triggers the body’s natural production of new collagen and skin cells. Chemical peels involve the controlled removal of the outer layer of facial skin with specific chemicals such as phenol and trichloroacetic acid (TCA) to smooth out the skin. Dermabrasion is a procedure that abrades the facial skin to remove the upper layer resulting in smoother skin. 

Accepted guidelines indicate that laser surgery and electrocautery are the only satisfactory treatments for the telangiectasias. Treatment is directed toward obliteration of ectatic vessels. Rhinophyma (soft tissue and sebaceous hyperplasia of the nose) is considered the culmination of acne rosacea. Rhinophyma responds to electrosurgery, laser excision, and surgical debulking. Because telangiectasias and rhinophyma do not cause functional limitations, their treatment is considered cosmetic. 

Goldberg (2005) stated that pharmacological agents remain the mainstay for initial and maintenance treatment of rosacea. However, monochromatic (i.e., laser) and polychromatic light-based therapies are increasingly being used for the treatment of certain signs of rosacea. The author noted that despite the increased use of lasers and other light-based therapies, few well-controlled studies have been conducted on their use for the treatment of rosacea. Furthermore, a Cochrane review on interventions for rosacea (van Zuuren et al., 2005) concluded that the quality of studies evaluating rosacea treatments was generally poor. There is evidence that topical metronidazole and azelaic acid are effective. There is some evidence that oral metronidazole and tetracycline are effective. There is insufficient evidence concerning the effectiveness of other treatments. Good randomized controlled trials looking at these treatments are urgently needed.

Sadick et al. (2011) rhinophyma is a benign dermatological disease of the nose that affects primarily Caucasian men in their 5h decade of life. Its main characteristic is a slowly progressive hyperplasia of the sebaceous glands and the adjacent tissue with irregular thickening of the nasal skin and nodular deformation. It is defined as the end stage of acne rosacea. The main reasons for patients to seek medical help are cosmetic problems and functional impairments (e.g., nasal airway obstruction, difficulty in eating). Surgery is indisputably the treatment of choice for rhinophyma.

Macdonald and Nguyen (2012) presented the case of a 42-year old man with a 10-year history of rosacea, and who exhibited impaired nasal breathing and a mass on the tip of his nose that began growing 9 months earlier. Examination revealed a multi-lobulated sebaceous nodule (4 cm by 3 cm) protruding from the nasal tip. The histopathological findings of marked sebaceous hyperplasia, follicular rupture, an absence of granulomas, and prominent fibrosis confirmed the clinical suspicion of rhinophyma. A biopsy specimen was obtained, and staining did not reveal infectious organisms. Phyma is the result of hyperplasia and fibrosis of the sebaceous glands in the presence of rosacea. Although rhinophyma is by far the most common pattern in cases of phyma, metophyma (swelling of the forehead), otophyma (swelling of the ear), and gnathophyma (swelling of the chin) can also be observed. The lesions can become large, causing significant social stigmatization and posing a challenge in the management of patient care. Re-contouring with the use of electrosurgery or CO2 laser resurfacing is common. This patient underwent staged procedures, with shave-debulking surgery followed by contouring with electrosurgery. His breathing was restored to normal.

Little et al. (2012) stated that rhinophyma is a cosmetically disfiguring disease of the external nose that most frequently affects elderly Caucasian males. Frequently, there is associated derangement of nasal airway patency. Although the true incidence of rhinophyma and its exact etiology remain unknown, it is widely believed to represent the final stage in a continuum of acne rosacea. Medical therapy has not been effective in reversing the disease process, and surgery remains the most accepted method of treating rhinophyma. A wide variety of surgical techniques have been developed and modified over the years in an effort to treat this disorder safely and without significant sequelae. Despite many advances in fundamental understanding, surgical techniques, and related technologies, no single method has been universally embraced and employed as the "gold standard". These investigators described the most commonly employed modern surgical techniques and methods used throughout the world to treat rhinophyma. There was special emphasis on the authors' preferred method of excision and post-operative management (tumescent anesthesia, Weck blade excision, and argon beam coagulation), which has been demonstrated to be effective and expeditious.

Husein-Elahmed and Armijo-Lozano (2013) noted that early stages of rhinophyma can be managed with medical treatment using isotretinoin or oral antibiotics (metronidazole). However, severe cases usually are refractory to medical approaches. Surgical therapies to treat these severe refractory cases have been described. These investigators described a simple, safe, efficient, and cost-effective approach to the treatment of severe rhinophyma using a scalpel and the electroscalpel, instruments readily available in every operating room.

In a Cochrane review, van Zuuren et al. (2015) evaluated the safety and effectiveness of treatments for rosacea. The authors concluded that there was low quality evidence for low dose minocycline, laser and intense pulsed light therapy and cyclosporine ophthalmic emulsion for ocular rosacea. Time needed to response and response duration should be addressed more completely, with more rigorous reporting of adverse events. They stated that further studies on treatment of ocular rosacea are needed.

Intense Pulsed Light (for Ocular Rosacea)

In a review on "Topical, systemic and light-based therapies”, Kennedy Carney and colleagues (2009) reported that rosacea is a common chronic inflammatory disorder of the facial skin characterized by periods of exacerbation, remission and possible progression. The principle subtypes include erythematotelangiectatic rosacea, papulopustular rosacea, phymatous rosacea and ocular rosacea. Although the pathogenesis is unknown, rosacea is largely recognized as an inflammatory disorder. Individual subtypes are likely a result of different pathogenic factors and respond best to different therapeutic regimens. The non-pharmacologic approach to therapy is adequate skin care, trigger avoidance and photo-protection; in addition, there are several topical, herbal, systemic and light based therapies available. Standard Food and Drug Administration

(FDA)-approved treatments included topical sodium sulfacetamide, metronidazole, and azelaic acid. Anti-inflammatory dose doxycycline, a controlled-release 40-mg formulation offered a non-antibiotic, anti-inflammatory therapeutic option. Combination of azelaic acid or topical metronidazole with anti-inflammatory doxycycline appeared to have a synergistic effect. Oral isotretinoin may be effective for phymatous rosacea and treatment resistant rosacea. Light based therapies with pulsed dye laser and intense pulsed light (IPL) are effective in treatment of erythema and telangiectasias.

In a systematic review, Wat and associates (2014) reported that the FDA has approved IPL devices for the treatment of a variety of benign pigmentary and vascular lesions, but the range of disease amenable to IPL treatment continues to expand, and there are no evidence-based clinical guidelines for its use in FDA-approved and off-label indications. These investigators provided evidence-based recommendations to guide physicians in the application of IPL for the treatment of dermatologic disease. They performed a literature search of the CENTRAL (1991 to May 6, 2013), Embase (1974 to May 6, 2013), and Medline in-process and non-indexed citations and Medline (1964 to present) databases. Studies that examined the role of IPL in primary dermatologic disease were identified, and multiple independent investigators extracted and synthesized data. Recommendations were based on the highest level of evidence available. Level 1 evidence was found for the use of IPL for the treatment of melasma, acne vulgaris, and telangiectasia. Level 2 evidence was found for the treatment of lentiginous disease, rosacea, capillary malformations, actinic keratoses, and sebaceous gland hyperplasia. Level 3 or lower evidence was found for the treatment of poikiloderma of Civatte, venous malformations, infantile hemangioma, hypertrophic scars, superficial basal cell carcinoma, and Bowen's disease. The authors concluded that IPL is an effective treatment modality for a growing range of dermatologic disease and in some cases may represent a treatment of choice. It is typically well-tolerated; further high-quality studies are needed.

Measurement of Serum Bilirubin, Uric Acid and Zonulin Levels in Rosacea

Karaosmanoglu and colleagues (2020) noted that rosacea is an inflammatory skin disease with a chronic course. Although the pathogenesis of rosacea is not completely understood, it is regarded as an inflammatory process. These investigators examined serum uric acid (UA) levels in patients with rosacea and investigated the correlation of UA levels with disease activity. A total of 61 patients with rosacea and 64 sex- and age-matched controls were included in the study. Demographic characteristics, medical history, and dermatological examination of the patient and control groups were recorded. Concentrations of serum UA and C-reactive protein (CRP) were evaluated and compared in both groups. This study included 61 patients with rosacea (39 females, 22 males, median age = 30 years) and 64 age- and sex-matched controls. Metabolic syndrome was significantly more common in patients with rosacea than in the control group. Patients with rosacea had significantly higher body mass index (BMI) values compared with those of controls. Serum UA and CRP values were significantly higher in the rosacea group than values in the control group. There was no statistically significant correlation between serum UA level and clinical rosacea severity. The authors concluded that the findings of this study suggested that rosacea is not only a skin-related disease but also an inflammatory disease that could be related to higher UA levels, BMI values, and metabolic syndrome. These researchers stated that it may be recommended that clinicians pay careful attention to the clinical follow-up of these patients to avoid missed associated co-morbidities.

Turkmen (2020) stated that rosacea is a common chronic inflammatory skin disease that the pathogenesis is not fully understood. Although the significant role of oxidative stress in rosacea pathophysiology has been shown in recent studies, there is no study addressing the potential roles of bilirubin and UA in rosacea. In this study, serum bilirubin and UA antioxidant levels were measured in rosacea patients. A total of 87 rosacea patients and 81 healthy controls (HCs) of similar age and gender were included in this trial. From all subjects, blood samples were drawn and the values of total bilirubin (Tbil), direct bilirubin (Dbil), indirect bilirubin (Ibil), and UA were analyzed. The type of rosacea was erythemato-telangiectatic in 51.7% of the patients, papulo-pustular in 43.7%, and phymatous in 4.6%. In rosacea group serum, Tbil, Dbil, Ibil, and UA values were found to be significantly lower than in the HCs. Male rosacea patients were found to have lower Tbil, Dbil, Ibil, and UA levels when compared with the males in the HCs. There was also the same significant difference in female patients. The authors concluded that the principal finding of this study was that when compared with the control group, serum bilirubin and UA levels were significantly lower in rosacea patients. These levels sustained the hypothesis that antioxidant status and oxidative stress are important in the pathogenesis of rosacea.

Yuksel and Ulfer (2022) noted that although the etiopathogenesis of acne rosacea has not yet been clearly elucidated, it has been discussed over the years that autoimmunity may play a role. Genetic and environmental factors are known to have combined effects in the background of autoimmunity, but it has recently been emphasized that an impaired intestinal barrier system is also involved in the development of the disease. Zonulin is a protein that reversibly increases intestinal permeability. These researchers examined serum zonulin levels in acne rosacea. A total of 61 subjects (30 diagnosed with acne rosacea and 31 healthy controls) were included in this trial. There was no difference between the 2 groups in terms of age, gender, and BMI. Serum zonulin was examined using the enzyme-linked immunosorbent assay (ELISA). Serum zonulin levels were found to be significantly higher in the patient group than in the control group (18.5 ± 2.9 ng/ml versus 13.2 ± 2.7 ng/ml, respectively; p < 0.001). The authors concluded that this was the 1st study in the literature to show that the serum zonulin levels were increased in patients with acne rosacea. This was a small (n = 30 for acne rosacea); these preliminary findings need to be validated by well-designed studies.

Reflectance Confocal Microscopy / Spectrometry for Assessment and Monitoring of Therapy

Logger and associates (2022) stated that reflectance confocal microscopy (RCM) enables non-invasive Demodex mite detection in rosacea. Objective scoring of rosacea severity is currently lacking. These researchers examined the value of RCM for monitoring Demodex, inflammation and vascular parameters in rosacea during treatment. In 20 rosacea patients, clinical and RCM examination were performed before, during, and 12 weeks after a 16-week treatment course with topical ivermectin. Using RCM, number of mites and inflammatory cells, epidermal thickness, and vascular density and diameter were measured; RCM features were correlated with clinical assessment. Treatment resulted in clinical reduction of inflammatory lesions. Mites were detected in 80% of patients at baseline, 30% at week 16, and 63% at week 28. The number of mites reduced significantly during treatment, but no changes in inflammatory cells, epidermal thickness or vascular parameters were observed. Correlation between number of inflammatory lesions and mites was low. None of the RCM variables was significant predictors for clinical success. The authors concluded that RCM enabled anti-inflammatory effect monitoring of topical ivermectin by determining mite presence. Quantifying exact mite number, and inflammatory and vascular characteristics is challenging due to device limitations. These researchers stated that in its current form, RCM appeared to be of limited value for non-invasive follow-up of rosacea in clinical practice.

Logger and colleagues (2020) noted that rosacea assessment and therapy monitoring can be challenging to standardize, as most clinical evaluation systems are prone to inter-observer variability and not always validated. Thus, objective, reliable and preferably non-invasive measurement tools are needed. In a systematic review, these investigators examined available non-invasive imaging techniques and biophysical methods in rosacea. PubMed, Embase, Cochrane and Web of Science databases were searched until September 1, 2018 in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, to identify studies providing original data about objective non-invasive imaging and/or biophysical skin measurement techniques for diagnosis, assessing severity or therapy monitoring of adult patients with cutaneous facial rosacea. Risk of bias of included articles was assessed with the Cochrane Risk of Bias tool, Quality in Prognosis Studies tool, and the Newcastle-Ottawa Scale. A total of 78 studies were included, describing 14 imaging and biophysical methods. Widespread information about (sub)surface cutaneous morphology and functionality was obtained. Methodological study quality was relatively low and inter-study outcome variability was large. Several tools showed promising value in research settings: for treatment follow-up Demodex mites are countable with RCM, spectrometry can quantify erythema, and rosacea severity could be objectified with skin hydration- and trans-epidermal water loss measurements. The authors concluded that the findings of this systematic review described the spectrum of non-invasive imaging and biophysical methods in rosacea assessment, giving multi-faceted information regarding structure and properties of rosacea skin, especially useful for research purposes. These researchers stated that larger studies with good methodological quality are needed to create validated protocols for further implementation into research. They noted that RCM and spectrometry are especially promising in therapy monitoring and skin barrier measurements for rosacea severity assessment; larger studies with better methodological quality are needed to create validated protocols for implementation into research.

Evaluation of the Gastro-Intestinal Microbiome

Searle and associates (2020) noted that increasing evidence suggested that the gut-skin axis is implicated in the pathogenesis of rosacea. Sufficient evidence exists to support the notion that the gastro-intestinal (GI) microbiome plays a role in the inflammatory cutaneous response and there appears to be associations with small intestinal bacterial overgrowth and Helicobacter pylori (H pylori) infection. A dysbiotic microbiome and an innate immune system dysregulation contribute to the pathophysiology of rosacea, and further examination of their roles is needed. The authors concluded that greater understanding of this condition and the effect of the gut-skin axis could allow for more effective and timely treatment.

Daou and colleagues (2021) stated that although a long-recognized entity, the exact pathophysiology of rosacea is still debated. Current theories highlight the role of the cutaneous microbiome and its associated inflammatory effects in rosacea's pathogenesis. However, microbiological reverberations are not limited to the skin, as recent studies have described the potential cutaneous effects of alterations in the GI microbiome. Associations with additional GI pathologies, including small intestinal bacterial overgrowth (SIBO), inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), have been examined, as well as H pylori infection. To better understand and characterize these relationships, as well as current therapeutic options, these researchers carried out a systematic review of the literature in PubMed, Cochrane, and Embase from their inception to August 6, 2020. They synthesized the literature findings within 3 sections of this manuscript: the cutaneous microbiome, the gut microbiome, and therapeutic strategies. These investigators stated that future studies should examine the role of the GI microbiome in the pathogenesis of rosacea and the role of enteral drugs in mitigating cutaneous symptoms as intra-luminal agents such as rifaximin have already been shown to have beneficial effects.

Wang and co-workers (2021) noted that rosacea is a chronic inflammatory disease with complicated pathophysiology that involves genetic and environmental elements and dysregulation of innate and adaptive immunity, neurovascular responses, microbiome colonization or infection, resulting in recurrent inflammation. Rosacea has been reported to be associated with various GI diseases including, celiac disease, IBD, IBS, gastro-esophageal reflux disease (GERD), H pylori infection, and SIBO. The link may involve common predisposing genetic, microbiota, and immunological factors, comprising the theory of the gut-skin axis. These researchers stated that although the evidence is still equivocal, medication for eradicating SIBO and HP appeared to provide an effective and prolonged therapeutic response for rosacea in some studies. Not only do these associations remind investigators of these GI co-morbidities among patients with rosacea but also provide an innovate direction for treating rosacea.

Measurements of Serum Chemokines (including CCL2, CCL3, CCL20, CXCL1, CXCL8, CXCL9, CXCL10, and CXCL12) as Indicators of Rosacea and for Evaluation of Severity of Disease

Liu et al. (2022) noted that rosacea is a common chronic inflammatory skin disease involving millions of patients worldwide. Previous studies have highlighted the up-regulation of a variety of chemokines in the skin lesions of both rosacea patient and rosacea-like mouse model; however, the serum levels of these chemokines and their clinical significance have not been examined. These researchers examined the serum levels of a series of chemokines (including CCL2, CCL3, CCL20, CXCL1, CXCL8, CXCL9, CXCL10, and CXCL12) implicated in rosacea and their correlation with disease severity. Bio-Plex Pro Human Chemokine Assays were used to measure the serum levels of these chemokines. Investigator's Global Assessment (IGA) was used for evaluating the papules/pustules of rosacea patients, while persistent erythema was examined by the Clinician's Erythema Assessment (CEA). The findings revealed that the serum concentration of CCL3, CXCL8, CXCL9, and CXCL10 were markedly elevated in rosacea patients compared to healthy controls. Among them, the levels of CCL3, CXCL8, and CXCL9 were positively correlated with the IGA score, while serum CXCL9 and CXCL10 were positively related with the CEA score of rosacea patients. Furthermore, the expression of the corresponding receptors of CCL3 (Ccr1), CXCL8 (Cxcr1 and Cxcr2), CXCL9, and CXCL10 (Cxcr3) were all significantly increased in the skin lesions of rosacea-like mouse model with CXCR2 and CXCR3 highly expressed in rosacea patient skins. The authors concluded that these findings indicated that CCL3, CXCL8, CXCL9, and CXCL10 might potentially serve as serum indicators for rosacea and could aid in evaluating the severity of disease. Moreover, these researchers noted that findings in this study would also potentially help to develop new targeted therapies for rosacea in the future.

Measurements of Serum Endocan as a Marker for Disease Progression in Rosacea

Kilic et al. (2021) noted that previous studies have shown a relationship between certain inflammatory disorders and serum endocan levels. Endocan (previously known as endothelial cell-specific molecule 1) might play a role in the pathogenesis of various inflammatory diseases. These researchers measured serum endocan levels in patients with rosacea to examine the association of endocan with the demographic data. They recruited individuals aged greater than or equal to 18 years of age who voluntarily agreed to participate in the study. Subjects included 37 women (mean age of 48.29 ± 12.08 years) and 13 men (mean age of 52.23 ± 13.34 years) diagnosed with rosacea, and 37 women (mean age of 49.18 ± 16.6 years) and 13 men (mean age of 53.69 ± 11.30 years) selected as controls. Both groups were matched according to age and sex. The diagnosis of rosacea was based on clinical examination findings, and serum endocan levels were measured using the method of ELISA. The statistical significance of the data was determined by the Mann-Whitney U test, and a value of p < 0.05 was deemed statistically significant. Serum endocan levels differed significantly between the patients with rosacea and the control group (p < 0.05). The authors concluded that circulating endocan might be a new marker related to disease progression in patients with rosacea. Moreover, these researcher s stated that further investigation is needed to examine if endocan levels could become a new therapeutic target in rosacea.

The authors stated that this study did not have an adequate sample size to evaluate all subtypes of rosacea. In particular, the number of patients in the phymatous rosacea group, which is one of the subtypes of rosacea, was very low. These researchers stated that future, multi-center clinical and laboratory studies with larger sample sizes and extended follow-up evaluations are needed to better understand the relationship between rosacea and its subtypes with serum endocan levels.

Photodynamic Therapy

In a systematic review, Li et al. (2022) examined the effectiveness of photodynamic therapy (PDT) in the treatment of rosacea. PubMed, Embase, and Cochrane Library databases were searched for studies published by February 5, 2022, using "photodynamic therapy" and "rosacea" as the keywords. A total of 9 studies were included in the review. The number of patients varied from 1 to 30 in each study, with ages ranging from 18 to 76 years. Methyl amino-levulinate (MAL) and amino-levulinic acid (ALA) were used as the photosensitizer, and red light, blue light, intense pulsed light (IPL), long-pulsed dye laser (LPDL), pulsed dye laser (PDL), and tungsten lamp were used as the light or laser source. The follow-up time ranged from 1 month to 25 months. Most of the studies showed a satisfactory clinical response, and the side effects were tolerant and temporary. The authors concluded that current studies have provided preliminary evidence that PDT is a safe and efficient therapy in the treatment of rosacea. Moreover, these researchers stated that rigorous RCTs with a larger sample size and longer follow-up time are needed to verify the curative effects of PDT in the treatment of rosacea and examine the most appropriate treatment schedule.

Biomarkers of Rosacea

Geng et al. (2024) stated that rosacea is a chronic and psychologically ladened disease affecting 1% to 3% of people globally. The identification and validation of biomarkers in rosacea patients has the potential to improve disease progression, support diagnosis, provide objective measures for clinical trials and aid in management. In a systematic review, these investigators identified all rosacea biomarkers, categorize them by type and identify trends to improve disease expression. Eligibility criteria for this review included RCTs, case-control studies, cohort studies, and other observational studies. No restrictions were placed on patient demographics (age, sex, ethnicity) or language of publication until February 2023. Quality of studies was assessed using the National Institute of Health (NIH) quality assessment tool. The literature search was carried out according to the PRISMA guidelines. A total of 805 unique studies were screened based on the applied inclusion and exclusion criteria. After the studies were screened based on title/abstract and full-text, a total of 38 studies were included, reporting on a total of 119 unique biomarkers. The results of this review and current rosacea pathogenic mechanisms provided the greatest support for the innate cathelicidin and inflammasome, Th 1 and Th 17 pathways. The most commonly reported biomarkers include IL-1β, TNF-α, IL-37, IFN-γ and MMP-9. The authors concluded that biomarkers identified in this study supported current theories of rosacea pathogenesis and provided direction for research to further the knowledge. Moreover, these researchers stated that further investigations are needed to identify biomarkers panels that can provide diagnostic utility; they noted that this may be difficult due to the heterogeneity of the disease and potential differences between rosacea subtypes.

The authors stated that drawbacks of this review included small sample sizes of individual studies, use of different laboratory assays to measure various markers, and heterogeneous patient populations. These investigators noted that they were unable to pool estimates together; more research is needed to identify a panel of biomarkers that could provide diagnostic and disease monitoring utility.

Liang et al. (2024) stated that rosacea is a chronic inflammatory skin disease. Systemic inflammation plays a vital role in the pathogenesis of rosacea. Many studies have reported hematological parameters as biomarkers for diseases with inflammatory processes; however, the diagnostic value of hematological parameters in rosacea remains a puzzle. This study involved 462 patients with rosacea, including erythemato-telangiectatic rosacea (ETR, n = 179), papulo-pustular rosacea (PPR, n = 250), and phymatous rosacea (PhR, n = 33), and 924 HCs. Demographic, clinical, and laboratory information was collected and compared between rosacea subtypes. The hematological parameters of patients and HCs were compared retrospectively. The platelet volume (MPV) and platelet crit (PCT) were significantly up-regulated, and the lower red blood cell distribution width (RDW) was significantly down-regulated in rosacea compared to HCs, and they were identified as the diagnostic biomarkers for rosacea with area under the curve (AUC) values of 0.828, 0.742, and 0.787, respectively. Comparing the hematological parameters among the 3 rosacea subtypes, these investigators found that platelet-to-lymphocyte ratio and platelet-to-neutrophil ratio values in the ETR group were significantly higher than those in the PPR and PhR groups. The correlation between hematological parameters and clinical scores showed that RDW was negatively correlated with the CEA score. However, there was no significant correlation between the IGA score and hematological parameters. The authors concluded that PCT, MPV, and RDW have diagnostic value for rosacea, and RDW is correlated with the severity of rosacea erythema, implying the potential applications of PCT, MPV, and RDW in the diagnosis and monitoring of rosacea.

Platelet-Rich Plasma Injection

Pang et al. (2025) noted that platelet-rich plasma (PRP) has been employed for the treatment of various inflammatory diseases due to its potent anti-inflammatory and anti-bacterial properties. Considering its therapeutic potential, PRP is emerging as a promising option for the treatment of rosacea. These researchers examined the safety and effectiveness of PRP injection in the treatment of distinct clinical presentations of rosacea and assessed its potential as an alternative to systemic treatments, especially in cases where conventional therapies are contraindicated. A total of 5 patients of rosacea with distinct presentations were treated with PRP therapy. The treatment outcomes were analyzed, and a brief review of relevant literature was carried out to contextualize the findings. Clinical effectiveness was evaluated using clinical photographs captured at 0 and 30 days after baseline according to the National Rosacea Society Standard (NRSS) grading system. Furthermore, the effectiveness of combining PRP injections with delicate pulsed light therapy or BTX injections was assessed. PRP therapy showed significant safety and effectiveness in treating rosacea, offering a viable alternative to systemic treatments. The combination of PRP with delicate pulsed light therapy or BTX injections demonstrated enhanced therapeutic outcomes, not only alleviating rosacea symptoms but also reducing or eliminating patients' dependence on oral medications. The authors concluded that PRP therapy, both as a stand-alone treatment and in combination with pulsed light therapy or BTX injections, represents a promising approach for the treatment of rosacea. These findings highlighted the potential of PRP to address the limitations of conventional therapies and improve patient outcomes. Moreover, these researchers stated that the drawbacks of this study included the small sample size (n = 5) and the lack of male patients, which may affect the stability and representativeness of the results. In addition, in Patient 2, PRP was combined with delicate pulsed light, and in Patient 4, PRP was combined with BTX and delicate pulsed light L; thus, the improvement may not be entirely attributed to PRP. The authors stated that further investigations (studies with large number of patients, including male participants, and the establishment of a control group with longer period of follow‐up) are needed to validate these preliminary findings and optimize treatment protocols.

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References