Biophotonic Therapy with Fluorescent Light Energy Decreases Facial Erythema, Improves Signs and Symptoms of Rosacea, and Increases Patient Satisfaction: A Postmarket Study

J Clin Aesthet Dermatol. 2021;14(7):16–21

by Martin Wade, BMed Sci, MBBS, FACD; Vanessa Charest, BSc; Bruno Ballardin, B. Eng, MBA; Deirdre Edge, PhD; and Michael Canova Engelbrecht Nielsen, PhD

Dr. Wade, Ms. Charest, and Mr. Ballardin are with the London Skin and Hair Clinic in London, England. Drs. Edge and Nielsen are with Guangdong Klox Biomedical Group Co., Ltd., in Guangzhou, China.

FUNDING: No funding was provided for this article.

DISCLOSURES: Drs. Edge and Nielsen are employees of Guangdong Klox Biomedical Group Co., Ltd. The other authors report no conflicts of interest relevant to the content of this article.

ABSTRACT: Background. Rosacea is a difficult-to-manage chronic inflammatory skin condition reported to have a negative psychosocial impact on patients. Novel approaches are sought to target the many signs and symptoms of the condition while also improving the quality of life of patients.

Objective. We assessed the efficacy of the Kleresca® biophotonic platform (KLOX Technologies Inc., Laval, Canada), which creates fluorescent light energy (FLE), to induce a novel form of photobiomodulation for treating rosacea. We also assessed patient satisfaction with their facial appearance and concerns about perceptions of others before and after treatment.

Methods. Nine patients were treated once a week for four weeks with FLE. Patients and the treating clinician completed questionnaires throughout and after the treatment to grade the rosacea signs and symptoms and capture patients’ perceptions of the treatment and their condition.

Results. FLE significantly reduced the inflammatory erythematous reaction of the face, improved flushing and erythema associated with rosacea, and had a positive impact on patients’ self-perception and emotional wellbeing.

Conclusion. Our results support FLE as an effective, noninvasive treatment modality for rosacea.

Keywords: Rosacea, erythema, flushing, questionnaire, biophotonics, chromophore, fluorescent light energy, inflammatory skin conditions, FLE, photobiomodulation, skin quality, patient perception, quality of life

Rosacea is a chronic inflammatory skin condition affecting both men and women, with high incidence rates in those with Fitzpatrick Skin Types I and II.¹ Often underdiagnosed, it is estimated to affect approximately 5.5 percent of the population worldwide.² While the etiology of rosacea is evolving, it is understood that an aberrant immune response, altered neurovascular signalling, and colonization of the skin with microorganisms (i.e., Demodex folliculorum) all play a role.¹ Common features of rosacea include flushing, nontransient erythema, papules, pustules, telangiectasia, burning or stinging, and skin sensitivity.³ Rosacea has typically been classified into four main subtypes, erythematotelangiectatic (ETR), papulopustular (PPR), phymatous, and ocular, depending on the presentation.³ However, with updates to this classification system, it has emerged that patients often present with a variety of clinical features characteristic of more than one subtype.⁴ Further, major fixed centrofacial erythema is a main diagnostic feature⁵ and common among all presentations of rosacea.^6,7 

Effectively targeting erythema has posed a challenge in treating rosacea.⁸ Since a single patient with rosacea can have a variety of clinical features, a combined treatment approach is often prescribed. Current treatment options often include topical creams, systemic treatments, and laser and light therapy to target the broad spectrum of phenotypes of the condition.⁹ However, results are varied, with either low adherence or limited patient satisfaction.^10,11 

In addition to the physical aspects of rosacea, there is a significant psychosocial burden associated with the condition. Patients report low self-esteem, embarrassment, frustration, and affected professional interactions.^10,12 Furthermore, rosacea is linked to depression and has significant effects on patients’ quality of life (QoL).^12,13 There is currently no cure for rosacea; therefore, treatment options that can manage the signs and symptoms, halt progression, and improve the patient’s QoL are required. 

Previous reports with the Kleresca® biophotonic platform (KBP; KLOX Technologies Inc., Laval, Canada) have been promising in not only treating rosacea signs and symptoms in rosacea subtypes 1, 2, and 3, but also in improving the visible appearance of the skin.^14,15 This postmarket study sought to assess the therapeutic efficacy of the KBP while also capturing the patient and clinician perceptions of the condition and the effect of the treatment. 

Methods

Patients with rosacea subtype 1 (ETR) and subtype 2 (PPR) were recruited by the treating clinic to receive the treatment. At the initial consultation, the treating practitioner completed a patient information and first assessment form. The treatment procedure was conducted as per the manufacturer’s instructions for use. Briefly, a 2-mm layer of the proprietary chromophore-containing gel was applied to the cleansed face and illuminated with a multi-light-emitting diode lamp for nine minutes, once per week for four consecutive weeks (note: one patient had a three-week break between the first and second treatments due to work commitments). Patients were brought back to the clinic for a follow-up visual assessment at between eight and 12 weeks from initiation of the treatment (mean±standard error of the mean time: 9.5±0.6 weeks).

Patients had their photo taken (VISIA® System; Canfield Scientific, Fairfield, New Jersey) and both the patients and the treating practitioner completed a questionnaire before every treatment and at the follow-up session. Patient questions were partly adapted from research by Zeichner et al¹⁰ addressing the severity of rosacea signs and symptoms (intensity: graded as 0=absent, 1=mild, 2=moderate, or 3=severe). The skin’s appearance was graded from 0 to 10, where 0=very bad and 10=excellent. An initial assessment specifically investigating patients’ satisfaction with their facial appearance and concerns about others’ perceptions was evaluated using a five-point Likert scale (1=strongly disagree, 2=disagree, 3=neither agree nor disagree, 4=agree, 5=strongly agree) and was completed before the first treatment and repeated after the four treatments. All patients participated on a voluntary basis and provided informed consent before the initiation of the study. Clinician questions focused on grading the rosacea signs and symptoms as well as the overall appearance of the skin. 

Participants. The demographics of the study participants are outlined in Table 1. Nine patients completed the four treatment sessions to the follow-up phase. The mean age was 36±3 years and, of the nine patients, 78 percent were female and 22 percent male, diagnosed 31±13 months ago. PPR was the predominant rosacea subtype, with 80 percent of patients presenting, while 20 percent had ETR. Participants had previously tried a variety of treatments, including topical creams (e.g., ivermectin, metronidazole, and elidel) and antibiotics. Participants were not undergoing any treatment that would interfere with results during the study.

Data analysis. Questionnaire data were coded and manually entered into Microsoft Excel (Microsoft Corporation, Redmond, Washington). Frequency and percentages were used to summarize data where relevant. Otherwise, per question, data were averaged for all participants in each session (i.e., Week 1, Week 4, etc.) and compared across sessions. Nonresponsive data (left blank) were treated in the same as “neither,” where applicable. Data were compared using a repeated-measures one-way analysis of variance with Tukey’s multiple comparison or paired Student’s t-test as necessary (GraphPad version 8; GraphPad Software Inc., San Diego, CA, USA). Data are expressed as mean±standard error of the mean values and p<0.05 was considered to be statistically significant.

For patient image analysis, a standardized area of all (baseline, Week 4, and follow-up) patient VISIA® photos (red, green, and blue; RGB) was selected in a uniform manner and cropped using ImageJ (v.1.51u; National Institutes of Health, Bethesda, Maryland). In the cropped part of the photo, the blue and green channels were removed from the RGB and the remaining red channel was converted into a graphic interchange format (GIF), allowing for a frequency distribution of the redness of the pixels to be calculated (0–256 bins of red pixels) (Figure 1A).

Subsequently, the frequency distribution was analyzed to determine the change in the redness. This was assessed by a shift in the pixel bin frequency, whereby a shift towards a higher distribution in lower bins represented a reduction in facial redness and vice versa. Images were compared using repeated-measures two-way analysis of variance using the Greenhouse-Gaisser correction for an overall change in the distribution (intensity) of red pixels among the three time points (baseline, during treatment, and follow-up). 

Results

Facial redness. There was a significant overall decrease in facial redness both during the treatment period and in the follow-up period relative to at baseline for all patients combined (n=9) (p<0.001). This was represented by a leftward shift in the frequency distribution of the intensity of red pixels (decreased intensity) for both, in treatment (four-week time point) and the follow-up period for each patient (Figure 1B). Baseline pixel distribution pattern was comparable for all patients at each sampling point.

Rosacea signs and symptoms questionnaire data. Patient self-assessment reported that the intensity of flushing and redness were significantly decreased following treatment (p=0.029 and p=0.022, respectively, one-way analysis of variance) (Figure 2A) at the four-week time point compared to at Week 1 (baseline, just before treatment commenced for flushing) (p=0.017) and at both the four-week and follow-up time points compared to at Week 1 for redness (p=0.022 and p=0.021, respectively) (Figure 2A). There was a reduction in the sensation of burning and stinging in the follow-up period (p=0.032) and, although the intensity of telangiectasia, papules/pustules, or itching was not statistically different, patients did report a decrease in each of these features at both the Week 4 and the follow-up phase (Figure 2B). 

The treating practitioner reported an improvement in all signs and symptoms of rosacea, with significant effects noted in redness, telangiectasia, burning and stinging, and papules and pustules (Figure 2C). The treating practitioner also assessed additional rosacea signs and symptoms. Treatment did not significantly affect the presence of plaques, ocular manifestations, edema, or the presence of enlarged pores; however, it significantly improved the appearance of dry skin (p=0.048) (Figure 2C).

Skin quality. Patients reported significant improvements in all manners of the skin’s appearance. The presence of enlarged pores, the overall skin texture, and the overall skin appearance were all significantly improved (p=0.004, p<0.0001, and p=0.0007, respectively) (Figure 3A). These improvements were reported at both the four-week and follow-up time points (Figure 3A). However, the treating practitioner only noted improvements in the skin’s appearance in the follow-up period (p=0.024 for skin texture and p=0.049 for overall skin appearance) (Figure 3A). 

Effects of rosacea on participants. In response to the question, “how is your rosacea affecting you?,” there was a significant improvement noted in the effect of rosacea among the participants (p=0.0006) (Figure 3B). This was observed at both the four-week time point (p=0.019), and the follow-up session relative to at Week 1 (p=0.0005) (Figure 3B). There was no difference in the effect of rosacea between Week 4 and the follow-up period (Figure 3B).

Patients’ satisfaction and concerns about perceptions of others. Specific questions addressed how the patients were feeling about their condition before and after the four treatments. Patients were more satisfied with the appearance of their face in relation to rosacea and less worried that people will jump to conclusions (i.e., alcoholic or shy) based on their facial redness (p=0.040 and p=0.002, respectively) (Table 2). The treatment also affected the patients’ concerns about the perceptions of others; patients disagreed more with the statements that they were less likely to be happy following treatment (p=0.023) (Table 2), that they were less likely to have a romantic partner (p=0.030), that they were less likely to be confident (p=0.022), and that they were more likely to be unhealthy (p=0.040) (Table 2).

Having completed the treatment, 80 percent of patients either agreed or strongly agreed that they would recommend the treatment to others and 60 percent of patients said they would repeat the treatment. 

Discussion

This study sought to evaluate the clinical efficacy along with the patient’s and treating practitioner’s perceptions of the biophotonic treatment. Questionnaires specifically addressed the impact of rosacea and its signs and symptoms on the patients and evaluated the effects of treatment. The key findings were: 1) there was a significant reduction in the overall facial redness, most notable in the follow-up phase of the study; 2) the treatment had a positive effect on the impact of rosacea on the patients; 3) the treatment improved most signs and symptoms of rosacea, with notable effects in both flushing and redness; and 4) the overall appearance of the skin was improved during and maintained following treatment. 

Rosacea is a complex condition; in addition to it having a multifactorial etiology, affected patients suffer from chronic cyclical episodes, including periods of exacerbation and remission, making it difficult to treat.¹⁶ Here, we report a significant improvement in the redness of the skin during and following treatment. There is a lack of effective treatment options for this bothersome feature, described in the literature as an unmet need.^7,8 Indeed, patients had previously tried a range of topical and systemic therapies (e.g., ivermectin, azelaic acid, elidel cream, metronidazole, and doxycycline), with limited success. The clinical efficacy of the KBP inducing FLE has been reported in numerous clinical studies. This approach reduces inflammation and associated lesions in acne vulgaris^17,18; targets the inflammatory and erythematous reaction common to rosacea subtypes 1, 2, and 3^14,15; targets inflammation in granulomatous rosacea¹⁹ and erlotinib-induced acneiform eruptions²⁰; and improves the overall texture of the skin.^15,21,22 This study addressed the effect of a rosacea-specific chromophore-containing gel on the erythematous and inflammatory reactions of rosacea. The ability of FLE to successfully decrease the facial redness response, common across the continuum of rosacea subtypes,¹¹ offers a new therapeutic approach. 

Recent work has focused on elucidating some of the key mechanisms underpinning the therapeutic effect of FLE. In-vitro work reports the capacity to modulate the inflammatory signature of key cutaneous cells and induce angiogenesis.²³ A consistent outcome of many photobiomodulation-inducing devices is the ability to modulate inflammation,²⁴ a known characteristic of many dermatological indications,²⁵ including rosacea.^26,27 The release of both interleukin-6 and tumour necrosis factor-alpha, two key proinflammatory cytokines, was reduced from human dermal fibroblasts and epidermal keratinocytes exposed to M1-like conditioned media and treated with FLE.²³ The ability of FLE to tune down this response might play a part in the resolution of redness observed in our patients, since an exaggerated immune response, including the production of proinflammatory cytokines and chemokines, plays a role in rosacea pathogenesis.^16,27 Additionally, in noninflamed conditions, FLE has been shown to encourage angiogenesis, an effect that might be considered as counterintuitive in rosacea at first. However, following the resolution of inflammation, the ability of FLE to induce healthy neovasculature, we reason, might assist in the distribution of blood, destress the skin, and help in the treatment of facial erythema. 

In addition to the physical symptoms of rosacea, the condition poses a significant psychosocial burden for patients and has a negative impact on their QoL.^10,28 We sought to capture the impact of rosacea signs and symptoms on patients’ emotional wellbeing, self-perceptions, and satisfaction before and following treatment. 

Our questionnaires were designed so patients and the treating practitioner could rate the intensity of the common rosacea features and report how the treatment affected them. Improvements were reported in all rosacea signs and symptoms, with significant effects noted in flushing and redness from the patients’ perspective, while the treating practitioner noted significant improvements not only in nontransient erythema, but also telangiectasias, burning and stinging, and the appearance of papules and pustules. Facial erythema is known to have a major negative impact on patients’ self-perception, irrespective of whether they are suffering from ETR or PPR.¹⁰ Interestingly, Moustafa et al²⁹ noted that new treatment options that can effectively target facial erythema might help to mitigate the negative psychological impact of rosacea. In addition to erythema, flushing has been noted as one of the key symptoms of rosacea linked to social anxiety common among patients with rosacea.³⁰ A very promising outcome of this study is the significant improvement in both flushing and redness self-reported by the participants after only three treatment sessions, which was maintained in the follow-up period. 

Our patients’ satisfaction with the treatment is most evident from the response to the question, “how is your rosacea affecting you?,” which significantly improved during and following treatment.

Rosacea has a substantial negative impact on participants in many aspects of QoL, including: emotional well-being, self-perception, and functional limitations due to emotional problems.¹⁰ From the assessment of participants’ concerns about others’ perceptions, at least 50 percent of patients agreed or strongly agreed that their happiness, relationships, health, confidence, and shyness were all affected by rosacea. The treatment significantly improved their concerns about happiness, relationships, and health. FLE significantly improved the patients’ satisfaction with their facial appearance and decreased their concerns about other people jumping to conclusions about their facial redness. 

In addition to the therapeutic portfolio of FLE in treating inflammatory skin conditions such as acne and rosacea,^{14,15,17–20} it also has an aesthetic application, rejuvenating the skin and improving its overall appearance.^15,21 In typically healthy skin, FLE increased collagen production, reduced the appearance of visible pores, fine lines, and wrinkles.²¹ Moreover, in a case report of PPR, along with a marked reduction in the inflammatory reaction of the skin, the KBP also improved the overall texture of the patient’s large pore skin type.¹⁵ Hence, in addition to its therapeutic efficacy, FLE offers an additional aesthetic benefit to patients. In the current study, this was captured by both the patients and the treating practitioner who assessed and rated the appearance of the skin. The patients noted significant improvements in all manners of their skin’s appearance, including the presence of enlarged pores and the texture and overall appearance of the skin. Patients noted these improvements at both the four-week time point and follow-up assessment. While the treating practitioner also noted improvements in the skin’s texture and overall appearance, these were significant in the follow-up session. It is noteworthy that the treating practitioner’s initial assessment of the skin was more positive than the patient’s assessment. However, both reported similar final endpoints. This divergence highlights the negative perception patients have about their own skin before any treatment and, for clinicians, the importance of speaking to patients and gaining their feedback throughout a treatment regimen.⁸

A minor limitation of the study is the single time point for the follow-up assessment. While this ranged from 8 to 12 weeks across participants, it would be beneficial to have a longer follow-up period with several assessments due to the chronic relapsing and remitting features of the condition. It is noteworthy that, in a recent case study reporting the beneficial effects of FLE in the PPR and ETR components of granulomatous rosacea, there was no relapse in the condition at six months following treatment.¹⁹ 

Conclusion

We have shown the capability of the KBP to significantly reduce the inflammatory erythematous reaction, a major debilitating feature of rosacea. Further, patients and the treating practitioner reported an improvement in the many signs and symptoms of the condition and an improvement in the overall appearance and texture of the skin. Significant improvements were also noted in the patients’ satisfaction with their skin and concerns about others’ perceptions. Finally, following only three treatments, patients reported a significant improvement in how the condition was affecting them. The KBP utilising FLE can be considered a new treatment approach to rosacea, targeting the inflammatory erythematous reaction of the condition, improving the overall appearance of the skin, and positively affecting patients’ psychological wellbeing.

References

1. Tan J, Berg M. Rosacea: current state of epidemiology. J Am Acad Dermatol. 2013;69(6 Suppl 1):S27–S35. 
2. Gether L, Overgaard LK, Egeberg A, Thyssen JP. Incidence and prevalence of rosacea: a systematic review and meta-analysis. Br J Dermatol. 2018;179(2):282–289. 
3. 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(4):584–587.
4. Tan J, Almeida LMC, Bewley A, et al. Updating the diagnosis, classification and assessment of rosacea: recommendations from the global ROSacea COnsensus (ROSCO) panel. Br J Dermatol. 2017;176(2):431–438. 
5. 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;78(1):148–155.
6. Del Rosso JQ. Advances in understanding and managing rosacea: Part 1 – Connecting the dots between pathophysiological mechanisms and common clinical features of rosacea with emphasis on vascular changes and facial erythema. J Clin Aesthet Dermatol. 2012;5(3):16–25.
7. Del Rosso JQ. Advances in understanding and managing rosacea: Part 2 – The central role, evaluation, and medical management of diffuse and persistent facial erythema of rosacea. J Clin Aesthet Dermatol. 2012;5(3):26–36. 
8. Huynh TT. Burden of disease: The psychosocial impact of rosacea on a patient’s quality of life. Am Heal Drug Benefits. 2013;6(6):348–354. 
9. Abokwidir M, Feldman SR. Rosacea management. Ski Appendage Disord. 2016;2(1–2):26–34. 
10. Zeichner JA, Eichenfield LF, Feldman SR, et al. Quality of life in individuals with erythematotelangiectatic and papulopustular rosacea: findings from a web-based survey. J Clin Aesthet Dermatol. 2018;11(2):47–52.
11. Del Rosso JQ, Faocd F de, Tanghetti EA, et al. The burden of illness of erythematotelangiectatic rosacea and papulopustular rosacea: findings from a web-based survey. J Clin Aesthet Dermatol. 2017;10(6):17–31.
12. Harper J, Del Rosso JQ, Ferrusi IL. Cross-sectional survey of the burden of illness of rosacea by erythema severity. J Drugs Dermatol. 2018;17(2):150–158.
13. Kini SP, Nicholson K, DeLong LK, et al. A pilot study in discrepancies in quality of life among three cutaneous types of rosacea. J Am Acad Dermatol. 2010;62(6):1069–1071. 
14. Sannino M, Lodi G, Dethlefsen MW, et al. Fluorescent light energy: treating rosacea subtypes 1, 2, and 3. Clin Case Reports. 2018;6(12): 2385–2390.
15. Braun SA, Gerber PA. A photoconverter gel-assisted blue light therapy for the treatment of rosacea. Int J Dermatol. 2017;56(12): 1489–1490.
16. Rainer BM, Kang S, Chien AL. Rosacea: epidemiology, pathogenesis, and treatment. Dermatoendocrinol. 2017;9(1):e1361574. 
17. Antoniou C, Dessinioti C, Sotiriadis D, et al. A multicenter, randomized, split-face clinical trial evaluating the efficacy and safety of chromophore gel-assisted blue light phototherapy for the treatment of acne. Int J Dermatol. 2016;55(12):1321–1328. 
18. Nikolis A, Fauverghe S, Scapagnini G, et al. An extension of a multicenter, randomized, split-face clinical trial evaluating the efficacy and safety of chromophore gel-assisted blue light phototherapy for the treatment of acne. Int J Dermatol. 2018;57(1):94–103. 
19. Liu RC, Makhija M, Wong XL, Sebaratnam DF. Treatment of granulomatous rosacea with chromophore gel-assisted phototherapy. Photodermatol Photoimmunol Photomed. 2019;35(4):280–281. 
20. Mahendran A, Wong XL, Kao S, Sebaratnam DF. Treatment of erlotinib-induced acneiform eruption with chromophore gel-assisted phototherapy. Photodermatol Photoimmunol Photomed. 2019;35(3):190–192.
21. Nikolis A, Bernstein S, Kinney B, et al. A randomized, placebo-controlled, single-blinded, split-faced clinical trial evaluating the efficacy and safety of KLOX-001 gel formulation with KLOX light-emitting diode light on facial rejuvenation. Clin Cosmet Investig Dermatol. 2016;9:115–125. 
22. Scarcella G, Dethlefsen M, Nielsen M. Treatment of solar lentigines using a combination of picosecond laser and biophotonic treatment. Clin Case Reports. 2018;6(9):1868–1870.
23. Edge D, Mellergaard M, Dam-Hansen C, et al. Fluorescent light energy: the future for treatment of inflammatory skin conditions? J Clin Aesthet Dermatol. 2019;12(5):E61–E68.
24. Hamblin MR, R Hamblin M. Mechanisms and applications of the anti-inflammatory effects of photobiomodulation. AIMS Biophys. 2017;4(3):337–361. 
25. Houh YK, Kim KE, Park HJ, Cho D. Roles of erythroid differentiation regulator 1 (Erdr1) on inflammatory skin diseases. Int J Mol Sci. 2016;17(12):1–10. 
26. Steinhoff M, Schauber J. New insights into rosacea pathophysiology: a review of recent findings. J Am Acad Dermatol. 2013;69(6): S15–S26. 
27. Holmes AD, Steinhoff M. Integrative concepts of rosacea pathophysiology, clinical presentation and new therapeutics. Exp Dermatol. 2017;26(8): 659–667. 
28. National Rosacea Society. Managing psychological and social aspects of rosacea. Available at: https://www.rosacea.org/patients/materials/coping-with-rosacea/managing-psychological-and-social-aspects-of-rosacea. Accessed June 22, 2021. 
29. Moustafa F, Lewallen RS, Feldman SR. The psychological impact of rosacea and the influence of current management options. J Am Acad Dermatol. 2014;71(5):973–980. 
30. Heisig M, Reich A. Psychosocial aspects of rosacea with a focus on anxiety and depression. Clin Cosmet Investig Dermatol. 2018;11: 103–107.