Alternative modality in the treatment of acne vulgaris ...

J Gen Proced Dermatol Venereol Indones. 2021;5(2);121-129

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Review Article Alternative modality in the treatment of acne vulgaris: Low level laser

therapy

Rudi Chandra1, Nelva K. Jusuf2

1 Department of Dermatology & Venereology, Medical Faculty of Universitas Prima Indonesia,

Medan, North Sumatera, Indonesia 2Department of Dermatology & Venereology, Faculty of Medicine Universitas Sumatera Utara, H. Adam

Malik General Hospital, Medan, North Sumatera, Indonesia

Email: [email protected]

Abstract

Acne vulgaris is a chronic inflammatory disease of the pilosebaceous unit with polymorphic manifestations. The four key elements leading to the formation of acne lesions are alteration of follicular keratinization that leads to comedones, increased and altered sebum production under androgen control, follicular colonization by Propionibacterium acnes, and complex inflammatory mechanisms that involve both innate and acquired immunity. Phototherapy (light, lasers, and photodynamic therapy) has been proposed as an alternative therapeutic modality to treat acne vulgaris and is proposed to have less side effects compared to other treatment options. Recently, low-level laser (light) therapy (LLLT) which refers to the use of red-beam or near-infrared laser with a wave-length between 600 and 1000 nanometers and power from 5 to 500 milliwatts, starts to be used in the treatment of acne. Mechanism of action of LLLT for acne is through photochemical reaction that produces reactive free radicals and singlet oxygen species which in turn lead to bacterial destruction by blue light. Meanwhile, red light can affect the sebum secretion of sebaceous glands, change keratinocytes behavior, and modulate cytokines from macrophages and other cells that reduce inflammation. LLLT is proposed to be effective as an alternative modality for inflammatory type lesions in acne vulgaris. Keywords: acne vulgaris, blue light, low level laser therapy, red light. Background Acne vulgaris is a chronic inflammatory disease of the pilosebaceous unit with polymorphic manifestations. Clinically, it is diagnosed by the presence of comedones (its pathognomonic feature), papules, pustules, nodules, and cysts.1,2 In 2010, acne was reported to affect approximately 9.4% of the population. Acne affects about 90% of people during their teenage years and sometimes in adulthood. About 20% of people have moderate and severe cases.3 Acne is a complex disease with multifactorial pathogenesis and considerable variation in severity. Thus, it is important to understand the

underlying basis for acne and the mechanisms of action of the multitude of therapeutic options in treating acne that will assure better therapeutic results. The pathogenesis of acne is multifaceted, but four basic steps have been identified.4 Four key elements that lead to the formation of acne lesions are alteration of follicular keratinization that leads to comedones, increased and altered sebum production under androgen control, follicular colonization by Propionibacterium acnes, and complex inflammatory mechanisms that involve both innate and acquired immunity.5 The American Academy of Dermatology Acne Consensus Conference (ACC) developed a


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classification of acne severity based on the number and types of lesions present, which was adopted by The South-East Asia Study Alliance (SASA) group, included Indonesia, Malaysia, the Philippines, Singapore, Thailand, and Vietnam. These evidence-based grading criteria were based on dermatologists’ recognition of acne severity and inflammatory eruption counts; the latter were divided into mild (0–5), moderate (6–20), severe (21–50), and very severe (>50).1 Current therapeutic options for acne vulgaris include benzoyl peroxide, topical retinoids (e.g., tretinoin and adapalene), topical antibiotics (e.g., clindamycin and erythromycin), topical dapsone, alpha hydroxy acids (AHA), salicylic acid, and azelaic acid. In severe cases, administration of antibiotics (e.g., tetracycline, doxycycline), oral retinoids, and certain hormonal treatments are recommended. Most medications work by counteracting microcomedone formation, sebum production, P. acnes, and inflammation. Despite the many treatment options currently available, several patients still show an inadequate response to the treatment, while others suffer from actual adverse effects.4,6 Phototherapy (light, lasers, and photodynamic therapy) has been proposed as an alternative therapeutic modality to treat acne vulgaris and was proposed to have fewer side effects compared to other treatment options.6 Recently, low-level laser (light) therapy (LLLT) which is referred to the use of a red-beam or near-infrared laser with a wavelength between 600 and 1000 nanometers and power from 5 to 500 milliwatts, started being used in the treatment of many aesthetic conditions, such as hair loss, acne, scars, aging, pigmentation, and fat reduction.7 Porphyrins that produced by P. acnes as a part of its normal metabolism, will be a target for phototherapy (specifically blue light) and cause a photochemical reaction and forms reactive free radicals and singlet oxygen species which in turn lead to bacterial destruction. Red light can affect the sebum secretion of sebaceous gland, change keratinocytes’ behavior, and reduce inflammation.6,7 Although the light-based treatments are beneficial in that they avoid some of the side effects of the oral medications, the cost of these light and laser treatments tends to be prohibitive and inferior; however comprehensive literature reports covering the utility of LLLT are scarce and thus the need for coverage arises to escalate the usage of this alternative modality in the treatment of acne.6

Definition & type of wavelength Low-level laser therapy (LLLT) refers to the use of a red-beam or near-infrared laser with a wavelength between 600 and 1000 nanometers and power from 5 to 500 milliwatts.7 LLLT, phototherapy, or photobiomodulation refers to the use of photons at a non-thermal irradiance to alter biological activity. LLLT uses either coherent light sources (lasers) or non-coherent light sources consisting of filtered lamps or light-emitting diodes (LED) or, on occasion, a combination of both.6

Laser radiation or noncoherent light has a wavelength– and radiant exposure–dependent capability to alter cellular behavior in the absence of significant heating.6,8 Phototherapy uses light with wavelengths between 390 and 1100 nm and can be continuous wave or pulsed. In normal circumstances, it uses relatively low fluences (0.04-50 J/cm2) and power densities (<100 mW/cm2).6,9 Wavelengths in the range of 390-600 nm are used to treat superficial tissue, and longer wavelengths in the range of 600-1100 nm, which penetrate further, are used to treat deeper-seated tissues (Fig. 1).6,10 Wavelengths in the range of 700-750 nm have been found to have limited biochemical activity and are therefore not often used.8 Various light sources used in LLLT include inert gas lasers and semiconductor laser diodes such as helium neon (HeNe; 633 nm), ruby (694 nm), argon (488 and 514 nm), krypton (521, 530, 568, 647 nm), gallium arsenide (GaAs; 760 nm, with a common example of 904 nm), and gallium aluminum arsenide (GaAlAs; 612-870 nm).11 Indication LLLT is mainly applied for repairing and promoting regeneration of tissues and nerves, reducing inflammation and pain. In the last few decades, LLLT has been used increasingly for many dermatologic conditions including wound healing, photoaged skin, scars, herpes simplex, wrinkles, vitiligo, and psoriasis. More recently, it has also been used for acne.6,7

Controversion Although LLLT is now used to treat a wide variety of ailments, it remains somewhat controversial as a therapy for 2 principal reasons: First, there are


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uncertainties about the fundamental molecular and cellular mechanisms responsible for transducing signals from the photons incident on the cells to the biological effects that take place in the irradiated tissue. Second, there are significant variations in terms of dosimetry parameters: wavelength, irradiance or power density, pulse structure, coherence, polarization, energy, fluence, irradiation time, contact versus noncontact application, and repetition regimen. Lower dosimetric parameters can result in reduced effectiveness of the treatment, and higher ones can lead to tissue damage.12 This illustrates the concept of the biphasic dose-response that has been reported to operate in LLLT.6,12-14 Many of the published studies on LLLT include negative results. It is possibly because of an inappropriate choice of light source and dosage. It may also be due to inappropriate preparation of the patient’s skin before application of LLLT, such as lack of removal of makeup and oily debris, which can interfere with the penetration of the light source, and failure to account for skin pigmentation.6,11 Inappropriate maintenance of the LLLT equipment can reduce its performance and interfere with clinical results as well. It is important to consider that there is an optimal dose of light for any particular application.6

Mechanism of action The mechanism of action of LLLT is exposing cells or tissue to low levels of red and near-infrared (NIR) light. This process is termed as ‘low-level’ because the optimum levels of energy or power densities employed are low compared to other forms of laser therapy such as ablation, cutting, and thermally coagulating tissue.7 Their biological effect is not thermal. LLLT also know as cold laser, soft laser, biostimulation laser or photobiomodulation laser, and therapeutic laser. Biomodulation is defined as changing the natural biochemical response of cells or tissue within the normal range of its function.6 The mechanism associated with the cellular photobiostimulation by LLLT is not yet fully understood. From observation, it appears that LLLT has a wide range of effects at the molecular,

cellular, and tissue levels. The basic biological mechanism behind the effects of LLLT is thought to be through absorption of red and (nearly infra-red) NIR light by mitochondrial chromophores, in particular, cytochrome-c-oxidase (CCO), which is contained in the respiratory chain located within the mitochondria,6,15-17 and perhaps also by photoacceptors in the plasma membrane of cells. Consequently, a cascade of events occurs in the mitochondria, leading to biostimulation of various processes (Fig. 2).6,18 Absorption spectra obtained for CCO in different oxidation states were recorded and found to be very similar to the action spectra for biological responses to the light.6,15 It is hypothesized that this absorption of light energy may cause photodissociation of inhibitory nitric oxide from CCO,6,19 leading to enhancement of enzyme activity,6,20 electron transport,6,21 mitochondrial respiration, and adenosine triphosphate production (Fig. 1).22-24 In turn, LLLT alters the cellular redox state, which induces the activation of numerous intracellular signaling pathways, and alters the affinity of transcription factors concerned with cell proliferation, survival, tissue repair, and regeneration.6,15,16, 25,26

In the treatment of acne, phototherapy, such as light, lasers, and photodynamic therapy, has been proposed as an alternative therapeutic modality to treat acne vulgaris with fewer side effects compared with other treatment options.6,27 One mechanism of action of LLLT for acne is through the absorption of light (specifically blue light) by porphyrins that have been produced by P. acnes as a part of its normal metabolism, and that act as endogenous photosensitizers. This process causes a photochemical reaction and forms reactive free radicals and singlet oxygen species which in turn lead to bacterial destruction (Figure 3). Red light is known to penetrate deeper in tissues when compared to blue light. It has been demonstrated that red light can affect the sebum secretion of sebaceous glands and change keratinocyte behavior. Furthermore, red light might also exert its effects by modulating cytokines from macrophages and other cells, which in turn could reduce inflammation.6,7 When used in combination, red light and blue light have synergistic effects in the treatment of acne.28


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Figure 1. Tissue penetration depths of various wavelengths. (Figure courtesy of Wellman Center for Photomedicine.)

Figure 2. Mechanism of action of LLLT. (Figure courtesy of Wellman Center for Photomedicine.)


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Figure 3. Illustration of acne treatment with red and blue light. (Figure courtesy of Wellman Center for Photomedicine.)


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Table 1. Studies of LLLT in the treatment of acne vulgaris

Studies Subjects Wavelength (nm)

Power Density

(mW/cm2)

Standard Dose

(J/cm2)

Procedure Result Level of Evidence

Papageorgiou et al. (2000)30

107 patients with mild to moderate acne vulgaris. Randomized into four treatment groups: blue light, mixed blue and red light, cool white light and 5% benzoyl peroxide cream.

§ Blue light 415 nm

§ Red light 660 nm

§ 4,23 mW/cm2

§ 2,67 mW/cm2

§ 320 J/cm2

§ 202

J/cm2

Irradiation was carried out daily for 15 min; Assessments were performed every 4 weeks.

• After 12 weeks: mean improvement of 76% in inflammatory lesions was achieved by the combined blue±red light better than others.

• The final mean improvement in comedones by using blue±red light was 58%, better than other but not significant.

1+

Goldberg et al . (2006)31

24 subjects, Fitzpatrick skin types II–V, with mild to severe symmetric facial acne vulgaris.

• Blue light 415 nm

• Red light 633 nm

• 40 mW/cm2

• 80 mW/cm2

• 48 J/cm2

• 96 J/cm2

• Treated 8 sessions, two per week 3 days apart.

• Patients received mild microdermabrasion before each session.

• Acne was assessed at baseline and at weeks 2, 4, 8 and 12.

• Mean lesion count reduction 46% after 4 weeks, after 12 weeks 81%

• Severe acne showed a marginally better response than mild acne

• Comedones did not respond as well as inflammatory lesions

2+

Lee et al. (2007)28

24 patients with mild to moderately severe facial acne.

• Blue light 415±5 nm

• Red light 633±6 nm

• 40 mW/cm2

• 80 mW/cm2

• 48 J/cm2

• 96 J/cm2

• Treatment was performed twice a week for 4 weeks.

• Objective assays of the skin condition were carried out before and after treatment at each treatment session.

• Clinical assessments were conducted

• Final mean improvements in non-inflammatory and inflammatory lesions were 34.28% and 77.93%, respectively

• Instrumental measurements indicated that the melanin levels significantly decreased after treatment

2+


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before treatment, after the 2nd, 4th, and 6th sessions and at 2, 4, and 8 weeks after the final treatment by grading and lesion counting.

• Brightened skin tone and improved skin texture were spontaneously reported by 14 patients.

Sadick (2008)32

21 patients with Burton grades 3 to 4 of acne vulgaris.

• Blue light 415 nm


• 40 mW/cm2

• 70 mW/cm2

• 48 J/cm2

• 126 J/cm2

• Each subject was given 1 of 6 locations on the face to treat: left or right forehead, cheek, nose or chin.

• Each week, the subject administered 2 alternate exposures: blue light for 20-minute duration and red light for a 30-minute duration.

• A 2 to 3 day interval was instructed between blue and red light treatments. (total of 8 treatments)

• Final average reduction of 69% seen at the week 12 assessment.

• The majority graded the light treatment as having moderate or marked improvement 68% in comparison to 32% of subject who only rated their improvement as mild.

• Of those 6 subjects who reported only mild improvement, 3 (50%) had clearances of >70% when compared to baseline.

2+

Aziz-Jalali et al. (2012)33

28 patients with mild to moderate acne vulgaris.


• Infrared LLLT 890 nm

• 10 mW/cm2

• 12 J/cm2

• 12 J/cm2

• Treated on the right and left sides of the face respectively, twice in a week for 12 sessions, and clinically assessed at baseline and weeks 2, 4, 6, and 8.

• All patients were treated by topical clindamycine 2% on both sides.

• 10 weeks after treatment, acne lesion were significantly decreased in the side treated by 630 nm (27.7±12.7 to 6.3±1.9), but not significant in the site treated by 890 nm (26.9±12.4 to 22.2±8.5).

• Red wavelength is safe and effective to be used to treat acne vulgaris by LLLT compared to infrared wavelength.

2+

* levels of evidence based on British Association of Dermatologists guidelines.


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Conclusion LLLT appears to have a wide range of applications of use in dermatology, especially in acne vulgaris. Mechanism of action of LLLT for acne is photochemical reaction that produces reactive free radicals and singlet oxygen species which in turn lead to bacterial destruction by blue light. Whereas red light can affect the sebum secretion of sebaceous glands, change keratinocytes behavior, modulating cytokines from macrophages and other cells that reduce inflammation. LLLT was effective as an alternative modality for inflammatory type lesions in acne vulgaris. Acknowledgements We wish to thank Wellman Center for Photomedicine for generously making available every figure in our review. References 1. Goh CL, Abad-Casintahan F, AW DCW, et

al. South-East Asia study alliance guidelines on the management of acne vulgaris in South-East Asian patients. Journal of Dermatology 2015; 42: 945–953. doi: 10.1111/1346-8138.12993

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