Visible light in photodermatology

Abstract

Until recently, visible light (VL) had been regarded to be without significant photobiologic effect on the skin. Updated research suggests that this is not the case and the measurable effect of visible light on the skin is being documented in all skin types. Recent studies have demonstrated that in dark-skinned individuals, visible light can induce more intense and longer lasting pigmentation of the skin compared to UVA1. This effect was potentiated when VL was combined with a small percentage of ultraviolet A1 radiation (UVA1). Further, the combination of VL + UVA1 was also able to induce erythema in light-skinned individuals, a novel finding since the erythemogenic spectrum of sunlight had primarily been attributed to ultraviolet B (UVB) and short wavelength UVA (320–340 nm). Based on these findings, VL and UVA1 may also potentially play a role in conditions aggravated by sun exposure such as phototoxicity in light-skinned patients and post-inflammatory hyperpigmentation and melasma, especially in dark-skinned individuals. Currently available organic (chemical) UV filters are not sufficient to protect the skin from the effect of VL. VL is emerging as a key player in photodermatology and additional research is needed on the cutaneous effects of VL, as well as the development of filters and other means of photoprotection against the harmful effects of the VL spectrum. The aim of this manuscript is to review the literature on the cutaneous effects of VL as well as to highlight areas of dermatology where VL may play an important role.

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Introduction

In 1903, Niels Ryberg Finsen (1860–1904) received the Nobel Prize in Medicine in recognition of his work on the treatment of diseases, especially the treatment of lupus vulgaris, using concentrated light rays. What began as an effort to improve his own illness (which would later be diagnosed as Niemann–Pick disease) became the foundation for photodermatology.¹ Since Finsen's development of electric carbon arc-based lamp (later known as the Finsen light) more than a century ago, a significant amount of research has been conducted on the effects of ultraviolet A (UVA) and ultraviolet B (UVB) radiation. Recently, visible light (VL) has also begun to emerge as playing an important role in photodermatology. This article will review the most recent literature on the cutaneous effects of visible light and its potential harmful effects.

Cutaneous effect of visible light

The visible spectrum is defined as the portion of electromagnetic radiation visible to the human eye, corresponding to wavelengths of 400 to 700 nm,² and comprising 44% of the solar energy at sea level.³ Visible light has been used in laser therapy, intense pulse light therapy, and photodynamic therapy for quite some time. However, up until now, few studies have been performed to examine the effect of visible light on the skin.^4–8 One of the main reasons for this could be the lack of a readily available broad-spectrum light source that emits only in the visible spectrum without ultraviolet or infrared (IR) components. In 2010, Mahmoud et al. was able to design a light source and conduct a study that emitted 98.3% visible light with 0.19% UVA1 (340–400 nm) and 1.5% IR. Since the highest dose of visible light used in the study was 480 J cm⁻², there was less than 1 J cm⁻² of UVA1 emitted. Twenty-two healthy volunteers (20, skin types IV–VI, 2, skin types II) were irradiated with UVA1 and, at separate sites, with visible light. Results showed that although both UVA1 and visible light could induce pigmentation in skin types IV–VI, the pigmentation induced by VL was darker and more sustained until the end of the study period, which was 2 weeks. In addition, the pigmentation induced by UVA1 was initially gray in color and turned brown after 24 hours and was not surrounded by erythema at any point of time, whereas the pigmentation induced by visible light was dark brown from the beginning and erythema appeared immediately following irradiation. Clinically, the erythema started to fade after thirty minutes and completely disappeared after 2 hours. In contrast, no pigmentation or erythema was observed in skin type II individuals.⁹ A potential explanation for the erythema only seen in skin types IV–VI was that heat is produced in melanocompetent skin due to the absorption of VL by the melanin pigment. Heat can then cause dilation of deep thermal vessels leading to clinical erythema which would be why no response was seen in subjects with skin type II. The implication of the results of this study was that VL could possibly have a role in producing darker and longer lasting pigmentation in populations with skin types IV–VI⁹ and currently, there is no effective organic filter in sunscreens that protects against VL. Further, these findings indicate that VL could potentially exacerbate photoaggravated dermatoses such as melasma and post inflammatory hyperpigmentation.

Visible light: blue light and opsin 3

Following the results of the above study, Duteil et al. hypothesized that specific wavelengths of VL must be responsible for the photobiological effects on pigmentation,¹⁰ given that previous in vitro experiments showed that various wavelengths of VL or IR could have opposite biological effects in human fibroblasts.¹¹ An experiment using healthy human subjects was conducted using LED light. The blue/violet LED emitted at λ = 415 ± 5 nm with 30 mW cm⁻² light intensity output whereas the red LED emitted at λ = 630 ± 5 nm with 55 mW cm⁻² light intensity output. Results showed a clear dose effect with the 415 nm irradiation, whereas 630 nm did not induce hyperpigmentation.¹⁰

A follow-up study by Regazzetti et al. was performed on normal human melanocytes (NHMs) to understand the mechanisms of blue light induced hyperpigmentation. It was demonstrated that blue light stimulates melanogenesis by acting on microphthalmia associated transcription factor (Mitf), the master gene of pigmentation. To determine if radical species were involved in blue-light induced melanogenesis, the effect of adding an antioxidant, N-acetylcysteine, was evaluated; however, N-acetylcysteine showed no effect on the activation of the melanogenesis pathway.¹²

Photons are absorbed and converted into a cellular response through a class of light-activated G protein-coupled receptors called opsins. Traditionally, opsins are well known for their role in photoreception of the eye. However, recent studies have demonstrated that rhodopsin (OPN2), short-wavelength cone opsins (OPN1-SW), encephalopsin/opsin-3 (OPN3), and neuropsin (OPN5) are expressed in both human melanocytes and keratinocytes. Notably, OPN2 and OPN3 mRNA were found to be significantly more abundant than the other opsins.¹³ OPN1-SW, OPN2, OPN3, OPN4, and OPN5 have an absorption spectrum in the shorter wavelengths of VL. In Regazzetti's study, after irradiating normal human melanocytes with blue light, OPN3 was the only opsin significantly expressed. To investigate whether OPN3 could mediate the effects of blue light melanogenesis, OPN3 was knocked down using small interfering RNA (siRNA). In NHMs with siRNA directed against OPN3, blue light irradiation no longer had any effect on Mitf phosphorylation. Thus, it was determined that opsin-3 is a key sensor in melanocytes and is responsible for the hyperpigmentation induced by the shorter wavelengths of visible light. The induction of opsin-3 ultimately leads to the phosphorylation of micropthalmia associated transcription factor (Mitf) resulting in the increase of melanogenesis enzymes, tyrosinase and dopachrome tautomerase. This multimeric tyrosinase/tyrosinase-related protein complex is mainly formed in dark-skinned melanocytes and induces a sustained tyrosinase activity which explains the hyperpigmentation seen in skin types III or higher after irradiation with blue light.¹²

The synergistic effect of visible light and UVA1

As the effects of visible light were elucidated, its impact in real life multispectral environments were further characterized. The effects of UVA and VL on pigmentation were further delineated by Kohli et al. in 2018. Assessments were made by investigator's global assessment (IGA), colorimetry, and diffuse reflectance spectroscopy (DRS). Ten subjects with Fitzpatrick skin phototypes IV–VI were irradiated on their backs with visible light dose of 480 J cm⁻² in the absence or presence of UVA1 (340–400 nm, less than 0.5%) with irradiances of 250 mW cm⁻² (32 minutes (min)), 200 mW cm⁻² (40 min), 150 mW cm⁻² (54 min), and 100 mW cm⁻² (80 min). The rule of reciprocity states that a response is directly proportionally to the dose, a product of the irradiance and exposure time. The results showed that the pigmentary responses to pure VL were irradiance-independent, conforming to the expected pattern of reciprocity. However, at the VL + UVA1-irradiated sites, more intense pigmentation was seen with higher irradiance levels. Immediate pigment darkening and persistent pigment darkening are thought to be a result from the oxidation of existing melanin; consequently, one would predict a stronger response at a lower irradiance level because it allows for a greater amount of time for the oxidation reaction to take place. The unanticipated behavior of the VL + UVA1 sites clearly needs to be further investigated; it may be a result of the synergic interactions between long-wavelength VL and UVA1.¹⁴

In another study, ten subjects with Fitzpatrick skin phototypes I–III were irradiated with VL + UVA1 (2% UVA1) at a dose of 480 J cm⁻². Similar assessment methods were used. A statistically significant increase in erythema was seen immediately after irradiation compared to the subject's baseline nonirradiated skin; the erythema resolved in 24 h. This was a novel finding since the erythemogenic spectrum of sunlight was thought to be primarily UVB and UVA2 (320–400 nm), further highlighting the need for better sunscreen protection against VL + UVA1.¹⁵ This data also suggests that trace amounts of UVA1 in previous studies,^9,10 thought to be negligible, may have played an important role in pigmentation and erythema.

Photoprotection against visible light

Current available organic (chemical) UV filters are not sufficient to protect the skin from the effect of visible light. Organic UV filters work by allowing for high energy UV rays to be absorbed. Inorganic (physical) UV filters, i.e., zinc oxide and titanium dioxide, modulate the penetration of UV photons into the skin by reflection, scattering and absorption. Reflection and scattering of VL photons by metal oxides make them appear white when applied to the skin. This can be cosmetically unappealing, especially in individuals of darker skin types. Decreasing the particle size into micronized range (10–50 nm) would also improve cosmesis; however, it results in less scattering of long wave UV and VL photons, and shifts protection towards shorter wavelengths. Iron oxide, which is not categorized as UV filters and has a reddish color, can be added to sunscreens to make inorganic sunscreens more cosmetically pleasing and to improve UVA and visible light protection.¹⁶ A randomized controlled trial conducted by Boukari et al. in patients with melasma demonstrated that tinted sunscreens with iron oxides could potentially provide protection against VL wavelengths by decreasing the relapse of melasma.¹⁷ At the International Union of Photobiology Conference in Barcelona, Spain (August 25–30, 2019), Bacqueville et al. presented information on the development of a new filter, phenylene bis-diphenyltriazine (TriAsorB), that covers both long UVA and the visible light region. It has a wide absorption spectrum in UVB and UVA (λ_max = 355 nm, λ_c = 384 nm, ε = 52 492 L mol⁻¹ cm⁻¹) and is not light sensitive (greater than 98% according ICH Topic Q1B). Spectrophotometric experiments have also shown that TriAsorB provides a protection in both the visible and the infrared spectral range, suggesting that TriAsorB is a full spectrum sunfilter.¹⁸ TriAsorB has been deemed safe for use as a UV-filter in sunscreen products up to a concentration of 5% by the European Scientific Committee on Consumer Safety.¹⁹

Liebel et al. have shown that irradiation of human epidermal skin equivalents in vitro with VL induced production of reactive oxygen species (ROS) which are a primary factor in skin damage and contribute to premature photoaging. Of note, the VL source used in this study did have 0.14% UVA1 (350–400 nm) in the spectral output. The highest VL dose investigated was 240 J cm⁻² which would include approximately 0.34 J cm⁻² of UVA1. Skin surface temperature of skin equivalents and media temperature exposed to either UV or VL sources were measured during exposure periods; it did not increase by >1 °C.³ ROS mediates the release of proinflammatory cytokines and matrix metalloproteinases (MMP) which breakdown collagen, inhibits new collagen synthesis, and promotes general skin inflammation. Also in the study, the effects of antioxidants were tested to determine if they could reduce the damage caused by VL. The antioxidant combination consisted of Feverfew (Tanacetum parthenium) extract, Soy (Glycine soja) extract, and gamma tocopherol. All of these ingredients were combined into a UVA/UVB sunscreen and applied to the human epidermal skin equivalents. The addition of antioxidants into the UVA/UVB sunscreen resulted in a significant reduction in the effects of VL, leading to the downregulation of the generation of reactive oxygen species, interleukin-1a, and matrix metalloproteinases by 78%, 82%, and 87% respectively. The direct effect of the antioxidants without the sunscreen was also tested and similarly mitigated the ROS, cytokine, and MMP release induced by VL. The in vitro ROS results were further confirmed in human subjects with a 54% reduction in the formation of free radicals.³

Recently, in vivo studies have been conducted to determine the efficacy of an antioxidant complex in reducing the biologic effects of VL + UVA1 for all skin phototypes. In a study conducted by Kohli et al., twenty subjects, 10 with skin phototypes (SPT) I–III, and 10 with SPT IV–VI, were treated with three concentrations of a topical antioxidant complex (ingredients proprietary property of Beiersdorf) and were compared to an untreated control. The areas were irradiated with VL + UVA1 480 J cm⁻² for SPT I–III and 320 J cm⁻² for SPT IV–VI. The lower dose of VL in SPT IV–VI subjects was selected as intense pigmentary response can already be detected at this dose. All 10 SPT I–III subjects had erythema at all sites immediately following irradiation (treated and untreated). Colorimetry measurements demonstrated that the site treated with the highest concentration of the antioxidant complex had significantly lower erythema (p = 0.007) compared to untreated controls. In comparison, all 10 of the SPT IV–VI subjects had an immediate pigment darkening response. IGA did not show a statistical difference; however, colorimetry measurements demonstrated that the site that was treated with the highest concentration of the antioxidant complex was significantly lighter immediately after irradiation (p = 0.005), and this trend continued at day 7 although significance was not reached (p = 0.07).²⁰

Recently, in vivo study of subjects with SPT IV–VI conducted by Mohammad and Kohli et al. indicates that a 28 days course of Polypodium leucotomos (PLE) (at 240 mg twice daily) may suppress VL + UVA1-induced persistent pigment darkening and delayed tanning, suggesting that PLE may be used as an adjuvant therapy in visible light photoprotection.²¹

Photosensitivity and photoaggrevated diseases

There are two types of photodermatoses with action spectrum in the visible light range. Solar urticaria (SU) is a mast cell-mediated disease that presents with sensitivity to UV or VL which triggers urticaria. Several case reports have also demonstrated significant improvement in solar urticaria, including VL-induced SU, with the use of omalizumab, an anti-IgE antibody.^22–25

A second visible light-induced disorder that has been difficult to treat is erythropoietic protoporphyria (EPP). Briefly, EPP is a severe photodermatosis that is associated with acute phototoxicity. The phototoxicity results from accumulated protoporphyrin in red blood cells and tissues because of decreased activity of an enzyme in biosynthesis of heme, ferrocheletase. When the skin is exposed to sun or VL, the accumulated protoporphyrin in blood vessels is activated by blue light (400–410 nm) producing free radical reactions that lead to severe pain, erythema, and edema.²⁶

In 2015, results from multicenter, randomized, double-blinded, placebo-controlled phase III trials done in the United States and in the European Union were published, evaluating subcutaneous implant of afamelanotide for the treatment of erythropoietic protoporphyria. The mechanism of action of afamelanotide in the treatment of EPP was postulated due to increased production of eumelanin which would serve as a scavenger of the free radicals induced by visible light, and would also provide photoprotection by absorbing and scattering VL and UV light.²⁷ The duration of pain-free time following sun exposure was longer in the group treated with afamelanotide and an improved quality of life was noted. Adverse events were mild, and no serious adverse events related to the drug occurred.²⁸ In 2014, afamelanotide was approved by the European Medicines Agency for the prevention of phototoxicity in adult patients with EPP. No late effects were reported in volunteers 25 years after the first exposure or after continuous long-term application of up to 8 years in EPP patients, and an immunogenic potential has been excluded.²⁹ Concern has been raised regarding the potential of afamelanotide promoting the development of melanoma. However, several in vivo and in vitro studies have found no correlation and have actually shown inhibition of melanocyte proliferation.²⁷ In October 2019, it was approved for use by the US Food and Drug Administration for treatment of EPP.

Afamelanotide is an alpha melanocyte stimulating (α-MSH) hormone analogue. It is 13 amino acids long and exists in a linear shape. Afamelanotide, like α-MSH, binds to the melanocortin 1 receptor (MC1R) in dermal cells and in melanocytes, thereby stimulating melanocyte production of eumelanin as well as melanocyte proliferation (MC1R is critical in the survival, proliferation, and pigmentation of melanocytes). Eumelanin plays numerous roles, including photoprotection against UV light and scavenging of free radicals while also filtering out longer wavelengths of VL.²⁹ Therefore, afamelanotide could potentially also be photoprotective against the effects of visible light in VL-induced dermatoses and thus is not only an effective treatment option for EPP but could also be used for solar urticaria.³⁰ In an open-label, phase II investigator-initiated study, five patients with solar urticaria received a single dose of 16 mg subcutaneous afamelanotide implant in wintertime. Mean melanin density increased by day 7, peaked at day 15, and remained elevated at day 60. A significant fall in wheal area occurred across responding wavelengths from 300 to 600 nm at 60 days postimplant (P = 0.049) along with a greater than twofold overall increase in minimal urticarial dose (P = 0.0580).³¹

Further, a study performed by Martini et al. tested different sunscreens and their effects on hyperpigmentation. The percentage of hyperpigmented area of the volunteers using sunscreens containing pigments that protected against both UV and VL demonstrated a significant decrease after 60 days compared to the volunteers using sunscreens that contain only UV filters, who showed no significant difference after 30 or 60 days.³² Melasma is an acquired hyperpigmentation on sun-exposed areas that is common in women of darker skin types. A potential mechanism for melasma could be due to VL induced generation of reactive oxygen species leading to release of inflammatory cytokines and matrix degrading enzymes in the skin. In 2013, a study was conducted comparing the depigmenting efficacy of hydroquinone plus either a sunscreen that had both UV and VL protection (i.e., containing iron oxide) or a sunscreen that has only UV protection. Sixty-one patients concluded the study. At 8 weeks, the group that received the UV-VL sunscreen showed a 15%, 28%, and 4% greater improvement in the melasma area and severity index scores, colorimetric values and melanin assessments, respectively, in comparison to the UV only sunscreen group, illustrating that visible light may play a role in the pathogenesis of melasma.³³ As mentioned previously in the article, iron oxide-containing sunscreen was more effective in preventing the relapse of melasma compared to sunscreen that did not have iron oxide in it.¹⁷

Conclusion

Until recently, VL had been regarded to be without significant photobiologic effects on the skin. However, the results from studies reviewed in this article highlight the significant photobiologic effects of VL and its effect on dermatoses such as melasma, post-inflammatory hyperpigmentation, solar urticaria, and erythropoietic protoporphyria. Currently available UV filters, either organic (chemical) or inorganic (physical) filters, do not provide protection against VL. As such, additional research is needed to fully elucidate the effects of VL and to develop better photoprotection against the VL spectrum.

Abbreviations

UVA	Ultraviolet A radiation
UVB	Ultraviolet B radiation
PLE	Polypodium leucotomos extract
VL	Visible light
SU	Solar urticaria
EPP	Erythropoietic protoporphyria
IR	Infrared
ROS	Reactive oxygen species
SPT	Skin phototype
MMP	matrix metalloproteinase
α-MSH	Alpha melanocyte stimulating hormone
MC1R	Melanocortin 1 receptor
NHMs	Normal human melanocytes
OPN2	Rhodopsin
OPN1-SW	Short-wavelength cone opsins
OPN3	Encephalopsin/opsin-3
OPN5	Neuropsin
siRNA	Small interfering RNA
min	Minutes
Mitf	microphthalmia associated transcription factor

Conflicts of interest

HWL is an investigator for PCORI, L'Oréal, Estée Lauder, Ferndale, Unigen, Incyte, and Beiersdorf, consultant for Pierre Fabre, ISDIN, Galderma, and Ferndale, and has served as a speaker in general educational sessions sponsored by Pierre Fabre, Eli Lilly, and Ra Medical System. SN is a sub-investigator for Loreal, GE, PCORI, Incyte, and Pfizer. IHH is an Investigator for AbbVie, Clinuvel, Janssen, Estée Lauder, L'Oréal, Ferndale, Unigen, GE, PCORI, Johnson and Johnson, Beiersdorf, Allergan, and Incyte, and is a consultant for Pfizer, Johnson and Johnson and Beiersdorf. IK is an Investigator for Ferndale, L'Oréal, Estée Lauder, Unigen, Johnson and Johnson, Allergan and Beiersdorf, and is a Consultant for Pfizer, Johnson and Johnson, and Beiersdorf.

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