Phototherapy

Introduction

Clinical improvement and short-term control of acute symptoms can be achieved in most patients with mild atopic dermatitis (AD) through the combination of topical emollients, anti-inflammatory agents and trigger avoidance (e.g., excess heat, irritants). However, these are typically insufficient for inducing remission in more severe AD. In moderate to severe AD, additional treatment options consist of phototherapy and systemic immunosuppressive agents. Systemic corticosteroids and immunosuppressants have variable efficacy and tolerability and major adverse effects that limit their long-term use. Phototherapy demonstrated consistent efficacy in the treatment of AD. Due to its efficacy and low side-effect profile, phototherapy is considered by the American Academy of Dermatology (AAD) as second-line treatment in children and adults with AD who fail first-line treatment. The primary mechanism of action behind UV irradiation in AD and other inflammatory skin diseases is hypothesized to be via photo-immunosuppression and immunomodulation. Additional mechanisms include increased vitamin D production, reduction of skin surface bacteria and suppression of superantigen production from Staphylococcus aureus.

This module will discuss the multiple forms of light therapy reported to be beneficial for AD symptom and disease control, including broad-band ultraviolet B (BBUVB), narrow-band ultraviolet B (NBUVB), Goeckerman therapy, monochromatic excimer laser, ultraviolet light A (UVA), psoralens and UVA (PUVA) and combination UVA/UVB therapy.

Ultraviolet B Radiation (UVB)

Broad-band UVB (BBUVB)

In the 1920s, it was observed that AD improved in sea-air climates during the summer months; however, it was not until 1948 that the efficacy of BBUVB using carbon arc lamps was found to be effective for the treatment of AD. Since then, phototherapy with BBUVB light in the wavelength range of 290 to 320 nm has been used for the treatment of AD. Broadband UVB with a dosing of 0.5 to 1.0 minimal erythema dose (a minimal threshold dose that may result in erythema/redness) was found in one study to be significantly more effective in AD treatment than visible light. No significant differences in efficacy between BBUVB doses of 0.4 and 0.8 MED were reported, supporting a BBUVB regimen in which therapy is initiated at a lower dose and incrementally increased in refractory AD.

Narrow-band UVB (NBUVB)

Phototherapy with narrowband UVB light (in the wavelength range of 311-313 nm) offers several advantages over BBUVB, including having longer lasting efficacy, being less erythemogenic and causing less photo-damage and carcinogenesis. It has been shown to be equally or more effective than visible light, UVA, medium-dose UVA-1 and PUVA. Because of its efficacy, ease of administration and limited side effects, NBUVB is commonly considered by providers to be the first-line phototherapy modality. Overheating and perspiration are common adverse effects from NBUVB and other phototherapy treatments and should be mitigated by use of air conditioning during treatments.

Narrowband UVB has also been demonstrated to be effective in combination with other therapies. In a trial of seven adults aged 28 to 40 years, an 8-week neoadjuvant course of oral cyclosporine A followed by a wash-out phase of 4 to 6 weeks and consecutive NBUVB therapy 3 times weekly for 2 to 3 months demonstrated a sustained improvement in scoring of atopic dermatitis (SCORAD) index of ≥50%, relative to baseline. The use of NBUVB in pediatric AD patients can be beneficial, but is limited by age, maturity and adherence.

A trial in adult AD patients has shed some light on the mechanism of NBUVB, showing that NBUVB treatment 3 times per week until clearance or 12 weeks was able to reverse immune activation and epidermal defects, suppressing Th2 and Th22 axes, eliminating inflammatory leukocytes and normalizing epidermal hyperplasia and differentiation.

UVB and Crude Coal Tar (Goeckerman Regimen)

The Goeckerman regimen was the first method to use phototherapy in the treatment of dermatologic disease. Named after the American dermatologist William Goeckerman who formulated it in 1925, this regimen consists of the application of crude coal tar followed by exposure to BBUVB. The Goeckerman regimen is still used for the treatment of AD, often in combination with topical corticosteroids, emollient baths, oral antihistamines, or systemic agents. The safety and efficacy of the Goeckerman regimen in AD has only been shown in a limited number of retrospective studies. Factors such as higher cost of inpatient care, availability of newer modalities of phototherapy and concerns about tar carcinogenicity make the Goeckerman regimen a relatively rare form of phototherapy in AD treatment.

Excimer Laser (308 nm)

Phototherapy using a monochromatic excimer laser (308 nm in wavelength) started to be used in the late 1990s. It offers two main advantages over other phototherapy modalities. First, it requires sessions only every 7 to 15 days, which may reduce treatment burden, increase adherence and improve quality of life. Second, it allows for targeted treatment of only the affected areas, reducing the risk of potential adverse effects. This approach might be useful in patients with severe refractory lesions that are limited in extent. While excimer laser was shown to be more effective than NBUVB in psoriasis, only a limited number of small studies demonstrated the efficacy of excimer laser in AD. The American Academy of Dermatology guidelines therefore do not currently recommend excimer laser for AD treatment.

Ultraviolet A Radiation (UVA)

UVA-1

UVA-1 (340-400 nm) therapy was developed to avoid the risk of sunburn associated with higher-energy, lower wavelength irritation of UVA-2 (320-340 nm) and UVB (290-320 nm). Unlike most other phototherapies, UVA-1 has shown efficacy in the treatment of acute AD flares. In two dose-comparison studies, no significant difference was observed between high-dose (130 J/cm²) and medium-dose (65 J/cm²) UVA-1 at improving AD, but low-dose (20 J/cm²) was less effective than medium-dose UVA-1. Medium-dose UVA-1 appears to have efficacy similar to NBUVB and topical tacrolimus in the treatment of AD. Medium-dose UVA-1 was better tolerated than high-dose UVA-1. Treatment with high-dose UVA-1 may be limited by intolerance to heat and intense sweating in patients. In response, UVA-1 cold light therapy was developed from lamps that filter infrared rays and has been found to have greater efficacy than conventional UVA-1 or combination UVA/UVB. While UVA-1 therapy has been shown to effective in AD, it is a relatively rare form of phototherapy owing to limited availability.

Psoralens and UVA

In 1978, a landmark study was published by Dr. Morison and colleagues following the observation that symptoms of patients with refractory AD improved in sunny climates. Since psoralen makes the skin more sensitive to UV, they treated such patients with 8-methoxypsoralen (an oral psoralen), followed by exposure to long-wave UVA (PUVA). Their success helped fuel the study of phototherapy as a treatment for AD.

PUVA is still utilized today, with systemic and topical regimens available. In systemic PUVA, the psoralen is taken orally, whereas topical regimens involve creams or baths (balneophototherapy). In cream therapy, psoralen-containing ointment is applied to areas 30 to 60 minutes prior to UV therapy. Balneophototherapy is used in some European centers and can involve UVA with or without UVB exposure; if UVB is not used, then the psoralen is often substituted with salt water. During balneophototherapy, phototherapy and topical therapy can occur concurrently or in tandem. Typically, bath-PUVA consists of UVA exposure following 20 to 30 minutes of bathing in warm water containing 0.5 to 1.0 mg/L of a psoralen. Unlike other phototherapies, PUVA should not be used for long-term treatment, since it has been associated with an increased risk of melanoma.

Combination UVA/UVB

Combination UVA/UVB (280-400 nm) has been shown to be more effective than BBUVB therapy, and has also shown efficacy in children. Combination treatment is achieved by either using UV lights with an emission spectrum that includes both wavelengths or combining UVA and UVB lights, simultaneously or in tandem. A downside of combined spectrum UV lights is being unable to dose UVA and UVB separately, and increase photo-aging and potential carcinogenicity.

Combination Therapy with Phototherapy

Phototherapy is safe as either monotherapy or combination therapy with moisturizers and topical corticosteroids. However, use with topical calcineurin inhibitors is cautioned, since the labels for pimecrolimus and tacrolimus recommend limiting exposure to natural and artificial sunlight sources while using these medications. The implementation of phototherapy may ultimately decrease or obviate the need for topical corticosteroids and immunomodulators. Some patients with moderate to severe AD who had an inadequate response to topical therapy may achieve disease clearance and discontinue topical corticosteroids. In such scenarios, decreasing the frequency of or discontinuing phototherapy treatments should be considered. If the patient then flares, the risks and benefits of the following treatment approaches should be considered: 1) resuming phototherapy to manage the acute flare; 2) utilizing once weekly maintenance phototherapy for prevention of flares; 3) start an oral systemic or biologic treatment for treatment and prevention of flares; or 4) reverting back to monotherapy with topical anti-inflammatory agents.

AAD Guidelines on Phototherapy

The AAD guidelines for phototherapy in AD do not recognize one or more forms of phototherapy as being superior to all others, as there are limited head-to-head trials and a lack of comprehensive comparative studies. As such, there are no recommendations to differentiate between the different forms regarding efficacy. However, NBUVB is typically most commonly recommended by providers, due to its relatively low-risk profile, relative efficacy, availability, insurance coverage and level of provider comfort with the modality. The AAD guidelines for phototherapy are shown in Table 8-1.

Many physicians initiate phototherapy in AD based on dosing protocols outlined in the AAD psoriasis guidelines, due to familiarity. In general, patients should be dosed according to minimal erythema dose (MED) and/or Fitzpatrick skin type. Dosing guidelines for PUVA are shown in Table 8-2. Dosing protocols for BBUVB (Table 8-3) and NBUVB (Table 8-4) differ and are not interchangeable. Phototherapy can be administered on an intermittent basis (typically scheduled 2 or 3 times weekly) for management of acute flares. Maintenance phototherapy can also be used (typically scheduled once weekly) for those patients with chronic persistent or frequently recurrent disease.

Ultimately, a variety of variables will determine which phototherapy is most appropriate for a given patient, including local availability, transportation, insurance cost, out-of-pocket cost, patient skin type, skin cancer history and concurrent medications.

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Pediatric Considerations

UVA and UVB have been shown to be safe and effective in children in several studies; however, long-term consequences of phototherapy use in children have not been assessed. Treatment with PUVA has been shown to be associated with an increased risk of non-melanoma skin cancer in children with psoriasis. NBUVB (311-313 nm) is often considered the first choice phototherapy modality in children since it is easy to administer, has a favorable safety profile with less carcinogenesis compared to PUVA and is safe and effective for a number of photo-responsive dermatoses.

Limitations of Phototherapy

Limitations of phototherapy include out-of-pocket expense, logistical requirements with respect to transportation, work- and school-schedule, caregiver responsibilities, special equipment, trained staff and limited efficacy in difficult-to-treat areas, including skin folds and hairy skin. Since dose-escalating regimens for UVB therapy typically take several weeks before an anti-inflammatory dose is achieved, it is recommended that patients undergoing NBUVB or BBUVB be treated with topical and/or systemic agents during the first few weeks of UV therapy. Even with proper dosing, phototherapy is often not effective enough in patients with severe AD. Additional psychosocial factors need to be considered in children, including overcoming intimidating equipment and addressing caregiver concerns.

Side Effects of Phototherapy

The true incidence of adverse effects in patients undergoing phototherapy is unknown, but it is believed to be low. Several common adverse effects of phototherapy include actinic damage, local erythema and tenderness, pruritus, burning and stinging and even AD flares triggered by increased heat and sweating in phototherapy units without proper temperature control and ventilation. Less common adverse effects include non-melanoma skin cancer, melanoma, lentigines, photosensitive eruptions, folliculitis, photoonycholysis, herpes simplex virus reactivation and facial hypertrichosis. Certain adverse effects are specific to the type of phototherapy, such as cataract formation in UVA therapy. The addition of oral psoralen to UVA treatment is associated with a higher risk of headache, nausea, vomiting and in rare cases hepatotoxicity. Oral psoralen also increases ocular and cutaneous photosensitivity for several hours following ingestion. Although melanoma is a possible adverse effect of all phototherapy modalities, patients undergoing PUVA appear to be at greatest risk.

Home Phototherapy and Tanning Beds

No studies investigated the efficacy of tanning beds in the treatment of AD. Although tanning beds may be convenient and cost effective for patients who find in-office phototherapy to be inconvenient or expensive, there are several concerns regarding their use. The light used in tanning beds is poorly defined, with variable and often distorted UV spectral distribution. Their use is associated with dramatically higher rates of melanoma and nonmelanoma skin cancer. Since the risk of skin cancer outweighs any potential benefit of using tanning beds, the use of this modality is not recommended.

Frequent trips to a provider of phototherapy and insurance coverage are the greatest barriers to more widespread use. As such, at-home therapy represents a promising alternative. Unfortunately, there are no studies assessing the efficacy of home light therapy in patients with AD. However, studies do exist for the use of home UVB treatment in the treatment of psoriasis. The PLUTO study demonstrated that home NBUVB phototherapy increased satisfaction vs in-office treatment and decreased the burden of treatment in patients with psoriasis. PASI score reduction, cumulative doses and incidence of short-term (up to 46 irradiations) adverse effects were no different compared to in-office treatment. Since comparable results could be expected in patients with AD, home phototherapy under the direction of a physician can be considered for patients unable to receive phototherapy in an office setting.

Conclusions

Phototherapy is an effective and relatively safe second-line treatment modality for patients with moderate to severe AD and an inadequate response to topical therapy. NBUVB is the most commonly employed type of phototherapy for the management of chronic AD, with relatively good long-term safety. UVA-1 has shown similar efficacy as NBUVB in the management of chronic AD, and may also be effective in acute flares. Despite the relatively good safety and efficacy, phototherapy may not be feasible for many patients owing to the delayed onset of efficacy and limited access.