Therapeutic Photomedicine

1

What is phototherapy?

Phototherapy is the use of nonionizing electromagnetic radiation (usually in the ultraviolet [UV] range, but also extending into the visible light range) to treat cutaneous disease ( Fig. 54.1 ).

• Broadband ultraviolet B (BBUVB): 290 to 320 nm

• Narrowband ultraviolet B (NBUVB): 311 nm

• Xenon chloride (excimer) laser: 308 nm

• Ultraviolet A (UVA): 320 to 400 nm

• UVA-1: 340 to 400 nm

• Psoralen plus UVA light (PUVA): 320 to 400 nm

• Blue light in Soret band: Approximately 400 to 410 nm

• Intense pulsed light and broadband light: 300 to > 2000 nm

2

What diseases can be treated with phototherapy?

See Table 54.1 .

Gambichler T, Breuckmann F, Boms S, Altmeyer P, Kreutzer A. Narrowband UVB phototherapy in skin conditions beyond psoriasis. J Am Acad Dermatol. 2005;52:660–670.

3

How does traditional phototherapy work?

Immunomodulation locally, and possibly systemically, is the primary mechanism of action of phototherapy. Effects on keratinocyte proliferation and differentiation are likely secondary to the immunomodulatory effects, which include:

• T-cell apoptosis (CD8 ⁺ in epidermis, CD4 ⁺ in dermis)

• Inhibition and depletion of antigen-presenting cells (Langerhans cells in epidermis, dermal dendritic cells in dermis)

• Release of immunosuppressive cytokines (interleukin [IL]-10 and IL-4); reduced expression of tumor necrosis factor-α, interferon-γ, IL-12, IL-23, IL-17, IL-22 locally

• Photoisomerization of trans-urocanic acid to cis-urocanic acid (which suppresses cellular immune responses, such as antigen presentation by Langerhans cells)

• Upregulation of CD95L (Fas ligand that binds to the Fas receptor on T cells inducing apoptosis).

As a result, the T-helper cell 1 and 17 (Th1/Th17) inflammatory pathways are suppressed, shifting the immune response toward the Th2 profile. IL-18, IL-8, IL-1β, and IL-6 are additional inflammatory mediators that may be suppressed.

Walters IB, Ozawa M, Cardinale I, et al. Narrowband (312-nm) UV-B suppresses interferon gamma and interleukin (IL) 12 and increases IL-4 transcripts: differential regulation of cytokines at the single-cell level. Arch Dermatol. 2003;139:155–161.

Johnson-Huang LM, Suárez-Fariñas M, Sullivan-Whalen M, Gilleaudeau P, Krueger JG, Lowes MA. Effective narrow-band UVB radiation therapy suppresses the IL-23/IL-17 axis in normalized psoriasis plaques. J Invest Dermatol. 2010;130:2654–2663.

4

How is phototherapy administered?

It is usually administered in a physician's office or treatment center, or patients may purchase certain phototherapy units (usually ultraviolet B [UVB]) and treat themselves at home. Distance from the treatment center may lead to poor adherence due to time and inconvenience of travel, so patients should be appropriately selected for in-office or home treatment. Home- and office-based phototherapy appears to be similar in both effectiveness and cost, while patients prefer home treatment. Patients receive a controlled dose of UV light while standing in a booth lined with high-output UV light bulbs ( Fig. 54.2 ). The initial UV light exposure is determined by assessing the patient's skin type and history of burning or by establishing the minimal erythema dose (MED). Phototherapy can also be combined with other treatments, as in oral retinoids with PUVA (RePUVA), which can lower the necessary dose of both treatments, or combining low-dose NBUVB, with tofacitinib which has been shown to repigment vitiligo. Phototherapy combined with etanercept or adalimumab may result in better clearance than either treatment alone.

Weng QY, Buzney E, Joyce C, Mostaghimi A. Distance of travel to phototherapy is associated with early nonadherence: a retrospective cohort study . J Am Acad Dermatol . 2016;74(6):1256–1259.

Koek MB, Buskens E, van Weelden H, Steegmans PH, Bruijnzeel-Koomen CA, Sigurdsson V. Home versus outpatient ultraviolet B phototherapy for mild to severe psoriasis: pragmatic multicentre randomised controlled non-inferiority trial (PLUTO study). BMJ . 2009;338:b1542.

Kim SR, Heaton H, Liu LY, King BA. Rapid repigmentation of vitiligo using tofacitinib plus low-dose, narrowband UV-B phototherapy. JAMA Dermatol . 2018;154(3):370–371.

Armstrong AW, Bagel J, Van Voorhees AS, Robertson AD, Yamauchi PS. Combining biologic therapies with other systemic treatments in psoriasis: evidence-based, best-practice recommendations from the Medical Board of the National Psoriasis Foundation. JAMA Dermatol . 2015;151(4):432–438.

5

Compare the induction phase, maintenance phase, and tapering phase for various forms of phototherapy.

• Induction phase :

  • BBUVB: Daily or three times weekly treatments, increasing approximately 10% each treatment until pink or therapeutic level reached.

  • NBUVB: Three times weekly, increasing approximately 10%–20% each treatment until pink or therapeutic level reached.

  • UVA-1: Daily or three times weekly, usually set at a standard dose depending on condition being treated. High-dose regimens (130 J/cm ² ), medium-dose regimens (30 to 50 J/cm ² ), and low-dose regimens (20 J/cm ² ) can used.

  • PUVA: Two to three times weekly, increasing 0.5 to 1 J/cm ² each treatment until pink or therapeutic level reached.

The induction phase is continued until clearing of skin lesions is noted, the patient has burning, or the end point is reached. Periods of remission with NBUVB and PUVA may last for weeks to months even after treatment is stopped.

• Maintenance phase :

  • BBUVB: Ranges from three times weekly to once every other week.

  • NBUVB: Taper to between once weekly to once every other week.

  • UVA-1: Once weekly to once every other week.

  • PUVA: Once every other week to once monthly.

• Tapering phase :

Decreasing frequency of treatments over a period of 1 to 2 months until the patient is completely tapered off therapy or enters maintenance therapy. If flaring of disease occurs after discontinuing therapy or during maintenance therapy, the frequency can be increased or the induction phase restarted. Long-duration treatment is often required for vitiligo, where the most benefit can be expected on the head and neck.

Note: The tanning effect may significantly decrease after 2 weeks, and the potential for burning patients with treatments spaced greater than every 2 weeks is much higher. Therefore, exercise caution and consider decreasing dose if greater than 2 weeks have elapsed since the last treatment.

Bae JM, Jung HM, Hong BY, et al. Phototherapy for vitiligo: a systematic review and meta-analysis. JAMA Dermatol . 2017;153(7):666–674.

6

What advantages does narrowband UVB have over broadband UVB?

NBUVB utilizes a TL-01 light source emitting UV light almost exclusively at 311 to 312 nm, which is near the most effective action spectrum for induction of T-cell apoptosis and suppression of dendritic antigen presenting cells in inflammatory skin diseases such as psoriasis. The absence of other wavelengths of UV light decreases side effects (erythema, carcinogenesis, photoaging) without sacrificing efficacy. Unlike BBUVB, suberythemogenic doses are effective.

7

What advantages does narrowband UVB have over PUVA? PUVA or UVB?

Oral psoralens have many potential side effects, including:

• Gastrointestinal : nausea, vomiting

• Neurological : dizziness, headache, insomnia, depression and anxiety

• Systemic : hepatotoxicity, drug interactions, allergic reactions, narrow window of phototherapy treatment after taking medication (1 to 2 hours), variability of tissue response depending on medication absorption and distribution (which is time sensitive)

• Cutaneous : photoallergic reactions, PUVA keratoses, PUVA lentigines, PUVA pain, transient nail pigmentation, photo-onycholysis, facial hypertrichosis, lichenoid eruptions, photosensitivity for 24 hours (even through windows), substantially increased risk of melanoma and other skin cancers including genital skin cancer

• Ophthalmologic : risk of cataracts, need for special glasses and avoid natural sunlight after taking medication for 24 hours.

PUVA can be provided with the psoralens applied topically, either as a cream or in a bath. This process may reduce the risks of some systemic side effects but is often impractical for routine use. PUVA has been shown more likely to induce complete remission in cutaneous T-cell lymphoma (CTCL) (mycosis fungoides) compared to UVB (73.8% vs. 62.2%).

Patients in all types of phototherapy should wear appropriate eye protection and cover their genitals, as phototherapy is a known risk factor for genital squamous cell carcinoma.

NBUVB does not carry most of these side effects and has not demonstrated increased carcinogenicity thus far in humans, and the efficacy is similar. However, increased carcinogenicity has been noted in rats with NBUVB, and long-term follow-up is not yet available.

Laube S, George SA. Adverse effects with PUVA and UVB phototherapy. J Dermatol Treat. 2001;12:101–105.

Phan K, Ramachandran V, Fassihi H, Sebaratnam DF. Comparison of narrowband UV-B with psoralen-UV-A phototherapy for patients with early-stage mycosis fungoides: a systematic review and meta-analysis. JAMA Dermatol . 2019;55:335–341.

Weischer M, Blum A, Eberhard F, Röcken M, Berneburg M. No evidence for increased skin cancer risk in psoriasis patients treated with broadband or narrowband UVB phototherapy: a first retrospective study. Acta Derm Venereol. 2004;84(5):370–374.

Douglawi A, Masterson TA. Penile cancer epidemiology and risk factors: a contemporary review. Curr Opin Urol . 2019;29(2):145–149.

8

What is targeted laser phototherapy?

An excimer (XeCl) laser, which emits a wavelength of 308 nm (near the NBUVB wavelength of 311 nm), is effective in treating individual psoriatic plaques and patches of vitiligo ( Fig. 54.3 ). Supererythemogenic doses, from 6 to 8 MEDs, are used on individual psoriasis plaques for 8 to 12 treatments and may induce months of remission. It is advantageous in that it avoids irradiating healthy, nonlesional skin. It more effectively induces T-cell apoptosis, as well. In psoriasis, it targets individual plaques with higher fluences and reaches deeper T cells and dendritic cells within the dermis. The pulsed dye laser at 585 to 595 nm has also been shown to be efficacious in treating individual psoriatic plaques but appears less effective than the 308-nm excimer laser.

Nicolaidou E, Antoniou C, Stratigos A, Katsambas AD. Narrowband ultraviolet B phototherapy and 308-nm excimer laser in the treatment of vitiligo: a review. J Am Acad Dermatol. 2009;60:470–477.

Zakarian K, Nguyen A, Letsinger J, Koo J. Excimer laser for psoriasis: a review of theories regarding enhanced efficacy over traditional UVB phototherapy. J Drugs Dermatol. 2007;6:794–798.