INTRODUCTION — Ultraviolet A1 (UVA1) is a form of phototherapy that uses only the longer, nonerythemogenic UV wavelengths (340 to 400 nm), thus reducing the risk of sunburn reactions associated with the shorter-wavelength UVA2 (320 to 340 nm) and UVB (290 to 320 nm). It is important to note that the UVA1 light sources are not equivalent to the light sources used for cosmetic purposes in tanning parlors and home units, which emit UVA2 wavelengths and often some UVB as well in addition to UVA1. The therapeutic effect of UVA1 is due to its ability to penetrate into the dermis deeper than UVB and target cells that reside in or infiltrate the dermis, including dendritic cells, fibroblasts, mast cells, and T and B lymphocytes [1].
This topic reviews the mechanism of action, clinical indications, and adverse effects of UVA1 phototherapy. PUVA therapy and broadband and narrowband UVB phototherapy are discussed separately. (See "Psoralen plus ultraviolet A (PUVA) photochemotherapy" and "UVB therapy (broadband and narrowband)".)
MECHANISM OF ACTION AND BIOLOGIC EFFECTS — The long-wavelength ultraviolet A1 (UVA1) radiation (340 to 400 nm) is able to penetrate into the dermis deeper than short-wavelength UVA2 (320 to 340 nm) and UVB (290 to 320 nm). UVA1 exerts its biologic effects on a variety of cells, including T and B lymphocytes, fibroblasts, dendritic cells, and immature mast cells [2-4].
UVA1-induced apoptosis — The ability of UVA1 to induce apoptosis of infiltrating T cells is thought to underlie its therapeutic efficacy for the treatment of T cell-mediated inflammatory and neoplastic skin diseases, such as atopic dermatitis and mycosis fungoides. Malignant CD4+ T cells appear to be more sensitive to UVA1 radiation-induced apoptosis than normal CD4+ T cells [5].
In vitro, UVA1 has been shown to induce immediate and delayed cell apoptosis through at least two different mechanisms. In the first, UVA1 induces the generation of singlet oxygen species, which depolarize mitochondrial membranes and trigger immediate cell apoptosis through the activation of the FAS/FAS ligand system [2]. This mechanism is termed preprogrammed cell death and appears to be specific of UVA1 phototherapy, since it is not observed with UVB or PUVA phototherapy. The second mechanism involves the production of superoxide anions, which damage the mitochondrial membrane resulting in the release of cytochrome C and activation of a caspase-dependent apoptotic pathway [3].
Cytokine modulation — UVA1 radiation has been shown to suppress proinflammatory cytokines, such as IL-12 and tumor necrosis factor (TNF)-alpha, and downregulate transforming growth factor (TGF)-beta in human skin [6]. In addition, UVA1 decreases the levels of interferon-gamma and ICAM-1, which are involved in lymphocyte activation and trafficking.
Effects on fibroblasts — UVA1-induced singlet oxygen species and hydrogen peroxide upregulate matrix metalloproteinases such as collagenase-1 produced by dermal fibroblasts [7,8]. The resulting increased collagen breakdown is thought to be the mechanism underlying the efficacy of UVA1 in the treatment of morphea and other sclerotic skin diseases [9,10]. (See "Morphea (localized scleroderma) in adults: Management", section on 'Phototherapy'.)
LIGHT SOURCES — Ultraviolet A1 (UVA1) is generated by fluorescent tubes or filtered metal halide lamps that filter out the erythemogenic UVA2. Treatment units equipped with fluorescent lamps deliver mean patient irradiance of 20 mW⁄cm2 and are suitable for low-dose UVA1 [11]. The delivery of medium and high doses of UVA1 requires the higher irradiance (approximately 60 mW⁄cm2) of metal-halide units [11]. Because of the high amount of heat generated, metal-halide lamp units require the installation of large fans or other heat-removal systems. Although metal-halide lamps are commonly used as a light source for UVA1 therapy due to their high intensity, they are not efficient because of their broad spectrum (200 to 500 nm) and need of three filters to remove the unnecessary wavelengths.
Light-emitting diodes (LEDs) are being investigated as an alternative UVA1 light source for UVA1 phototherapy. Preliminary in vitro studies of the wavelength characteristics of aluminium gallium nitride (AlGaN)-based and indium gallium nitride (InGaN)-based LED systems suggest that UV-LED devices emitting a peak wavelength of 365 nm may be an effective UVA1 delivery system [12,13].
DOSIMETRY — Ultraviolet A1 (UVA1) dosimetry is categorized into low (10 to 29 J/cm2), medium (30 to 59 J/cm2), and high (>60 J/cm2) dose regimens. Low-dose UVA1 is generated by fluorescent lamps, whereas medium and high doses require high-intensity emitting metal-halide lamps. (See 'Light sources' above.)
Before initiating treatment, a half-dose of UVA1 is used as a provocation challenge to assess the patient's sensitivity to UVA1. If erythema does not develop, treatment with the required dose of UVA1 can be administered. Treatment times can range from 10 minutes to one hour per treatment session, depending upon the irradiance of the UVA1 phototherapy unit; sessions are typically repeated three to five times per week. In contrast with UVB or PUVA therapy, which uses incremental radiation doses, the dose of UVA1 is held constant throughout the treatment.
The therapeutic efficacy of UVA1 therapy is dose-dependent. In studies of patients with atopic dermatitis, a medium UVA1 dose (50 J/cm2) was superior to a low-dose UVA1 regimen (10 J/cm2), but no significant difference was noted between medium- and high-dose regimens [14,15]. Moreover, low-dose UVA1 (30 J/cm2) was less effective than UVA/UVB therapy, whereas high-dose UVA1 therapy (130 J/cm2) was superior to UVA/UVB phototherapy [16,17].
INDICATIONS — Ultraviolet A1 (UVA1) phototherapy was first used for the treatment of atopic dermatitis. In an open study of patients with acute severe exacerbation of atopic dermatitis, high-dose UVA1 (130 J/cm2) given daily for 15 consecutive days rapidly induced clinical improvement and reduced the levels of serum eosinophil cationic protein [17]. Subsequently, the indications for UVA1 phototherapy have extended to several other skin diseases, including mycosis fungoides, urticaria pigmentosa, and localized and systemic scleroderma [18].
Atopic dermatitis — The role of UVA1 phototherapy in the treatment of severe atopic dermatitis is well established. A systematic review of nine randomized trials found that in adult patients with acute, severe atopic dermatitis phototherapy with UVA1 was faster than conventional UVA/UVB in inducing clinical improvement, with a peak response after 10 treatments [19]. A subsequent systematic review of 19 randomized trials including 905 adult patients with atopic dermatitis, showed that medium-dose UVA1 phototherapy was as effective as narrowband UVB phototherapy in improving the clinical signs and symptoms of dermatitis, as measured with several scoring systems [20].
The use of UVA1 and other forms of phototherapy for the treatment of severe atopic dermatitis is discussed in greater detail separately. (See "Evaluation and management of severe refractory atopic dermatitis (eczema) in adults", section on 'Phototherapy' and "Management of severe atopic dermatitis (eczema) in children", section on 'Phototherapy'.)
Localized scleroderma (morphea) — UVA1 has been used for the treatment of morphea (localized scleroderma) and other sclerotic skin diseases [21]. Morphea is characterized by the presence of an inflammatory infiltrate predominantly composed of T helper cells and dysregulated matrix metabolism leading to excessive collagen deposition [22]. Patients with morphea have increased levels of circulating intercellular adhesion molecule (ICAM)-1 and fibrogenic T-helper 2 cytokines, such as interleukin-4 and transforming growth factor (TGF)-beta. These cytokines recruit eosinophils and other inflammatory cells, and induce fibroblasts to synthesize excessive collagen and connective-tissue growth factor. (See "Pathogenesis, clinical manifestations, and diagnosis of morphea (localized scleroderma) in adults".)
UVA1 irradiation disturbs the cellular responsiveness to TGF-beta-1 through the induction of nonfunctional latent TGF-beta binding protein and the downregulation of TGF-beta receptors. In addition, UVA1 depletes skin-infiltrating T cells by inducing T cell apoptosis; inhibits T cell activation and cytokine production; and upregulates the expression of matrix metalloproteinase-1 (collagenase-1) in dermal fibroblasts [8]. The ultrastructural changes observed in clinically softened skin of scleroderma patients treated with UVA1 include a decrease in the diameter of the broad collagen fibrils in the reticular dermis and de novo synthesis of type I collagen and new thin fibrils [23].
Phototherapy for localized scleroderma is discussed in detail separately. (See "Morphea (localized scleroderma) in adults: Management", section on 'Phototherapy'.)
Systemic sclerosis — UVA1 may be helpful for the treatment of acral cutaneous sclerosis in patients with systemic sclerosis [24-26]. In a small study of four patients with systemic sclerosis, UVA1 phototherapy induced marked softening of the forearm skin after 9 to 29 exposures, with increase in joint passive range of motion and skin temperature and elasticity [24]. Histologic examination of skin specimens obtained before and after UVA1 phototherapy revealed loosening of collagen bundles and the appearance of small collagen fibers.
Urticaria pigmentosa — Several studies have suggested that UVA1 phototherapy reduces pruritus and urtication in patients with urticaria pigmentosa. (See "Mastocytosis (cutaneous and systemic) in children: Epidemiology, clinical manifestations, evaluation, and diagnosis", section on 'Skin' and "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis", section on 'Mastocytosis in the skin'.)
In an open study, four adult patients with severe generalized urticaria pigmentosa were treated with high-dose UVA1 phototherapy administered as monotherapy once daily five times per week for two consecutive weeks [27]. The initial dose of 60 J/cm2 UVA1 was subsequently increased to 130 J/cm2 UVA1. High-dose UVA1 therapy reduced pruritus and urtication from stroking (Darier's sign) after three exposures, but little or no effect was noted on the hyperpigmented skin lesions. In two patients with systemic manifestations of urticaria pigmentosa, relief from systemic symptoms (eg, migraine, diarrhea) and reduction of elevated serum serotonin to normal levels was observed after 10 exposures. No relapses occurred more than two years after cessation of high-dose UVA1 therapy.
Another study including 12 patients with urticaria pigmentosa found that high-dose (130 J/cm2) and medium-dose (60 J/cm2) UVA1 given for 15 days were equally effective in reducing pruritus for six months after the completion of treatment [28]. Although the number of lesions was not reduced after treatment, the number of mast cells in the lesions decreased after treatment and remained low after a follow-up of six months. (See "Cutaneous mastocytosis: Treatment, monitoring, and prognosis".)
Cutaneous T cell lymphoma — In a few small studies, UVA1 phototherapy has been successfully used for the treatment of patients with cutaneous T cell lymphoma [29-32]. In one study, three patients with early-stage mycosis fungoides were treated with high- or medium-dose UVA1 regimen [29]. Complete clinical and histologic clearance of lesions was observed after 16 to 20 exposures. In another study, 11 of 13 patients with widespread plaque-type, nodular, and erythrodermic mycosis fungoides showed complete clinical and histologic response with a high-dose UVA1 regimen [30].
Although PUVA is a widely accepted therapeutic option for early-stage mycosis fungoides, UVA1 phototherapy may be a valuable alternative to PUVA, without the undesirable side effects of oral psoralens (eg, nausea, long-lasting skin photosensitivity, requirement for eye protection). Along the same lines, narrowband UVB phototherapy is used for the treatment of early stages of mycosis fungoides [33]. (See "Treatment of early stage (IA to IIA) mycosis fungoides".)
Dyshidrotic eczema — Localized UVA1 phototherapy appears to be effective for the management of chronic dyshidrotic hand eczema [34-36]. In a small study, 10 of 12 patients with acute exacerbation of dyshidrotic eczema reported a marked improvement after 15 treatments with 40 J/cm2 per day administered over a period of three weeks [34]. In a small randomized trial involving 28 patients, medium dose UVA1 (40 J/cm2) was more effective than placebo in improving the symptoms of dyshidrotic eczema, as measured by the dyshidrotic eczema area and severity index (DASI) score [35]. In a right-left comparison study involving 27 patients, localized high-dose UVA1 (maximum dose 130 J/cm2) was as effective as cream PUVA in reducing the DASI score by nearly 50 percent after 15 treatments administered over three weeks [36]. (See "Acute palmoplantar eczema (dyshidrotic eczema)".)
Other diseases — UVA1 phototherapy has also been used for the treatment of a variety of skin conditions, including:
●Pityriasis rubra pilaris [37] (see "Pityriasis rubra pilaris: Prognosis and management", section on 'Phototherapy')
●Hypereosinophilic syndromes with cutaneous involvement [38] (see "Hypereosinophilic syndromes: Treatment")
●Pityriasis rosea [39] (see "Pityriasis rosea", section on 'Phototherapy')
●Pityriasis lichenoides et varioliformis acuta and pityriasis lichenoides chronica [40] (see "Pityriasis lichenoides et varioliformis acuta (PLEVA)", section on 'Phototherapy' and "Pityriasis lichenoides chronica", section on 'Phototherapy')
●Scleredema [41] (see "Scleredema", section on 'Phototherapy')
CONTRAINDICATIONS — Ultraviolet A1 (UVA1) phototherapy is contraindicated in patients with the following:
●Xeroderma pigmentosum
●Porphyria
●Melanoma and nonmelanoma skin cancer
●Long-term immunosuppressive therapy (eg, after organ transplantation)
Moreover, UVA1 phototherapy should not be used for patients with UVA-sensitive photodermatoses or photosensitive atopic dermatitis or patients taking photosensitizing drugs. The efficacy and long-term safety of UVA1 therapy has not been evaluated and therefore should be used with caution in patients younger than 18 years [42]. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment".)
ADVERSE EFFECTS — Severe acute adverse effects of ultraviolet A1 (UVA1) phototherapy have not been reported. Mild adverse effects are common and include hyperpigmentation, erythema, xerosis, and pruritus. Skin darkening may occur after a single high-dose UVA1 treatment and may limit the efficacy of subsequent UVA1 phototherapy [43]. Although UVA1 is not highly erythemogenic, episodes of phototoxicity may occur, especially among light-skinned individuals [44,45].
Long-term adverse effects of UVA1 phototherapy include photoaging and photocarcinogenesis. Although the carcinogenic potential of UVA1 has not been determined in humans, it is now accepted that UVA1 causes DNA damage with formation of cyclobutane pyrimidine dimers, which are the most relevant lesions for UV-induced mutagenesis [46,47].
The actual contribution of UVA radiation to the development of malignant melanoma in humans is still under debate but cannot be excluded. There is a single case report of melanoma in a patient with mastocytosis who received long-term UVA1 and bath PUVA therapy [48]. Two cases of Merkel cell carcinoma have been reported in immunocompromised patients receiving high-dose UVA1 therapy [49].
MONITORING — Patients receiving ultraviolet A1 (UVA1) phototherapy should be monitored with lifelong regular skin examinations [42]. A complete skin examination for skin cancer, premalignant lesions, and actinic damage should be performed before starting treatment and annually thereafter.
SUMMARY AND RECOMMENDATIONS
●Ultraviolet A1 (UVA1) is a form of phototherapy that uses only the longer UV wavelengths (340 to 400 nm). The UVA1 therapeutic effect is due to its ability to penetrate into the dermis and target a variety of cells, including T and B lymphocytes, fibroblasts, mast cells, and dendritic cells. (See 'Introduction' above and 'Mechanism of action and biologic effects' above.)
●UVA1 dosimetry is categorized into low (10 to 29 J/cm2), medium (30 to 59 J/cm2), and high (>60 J/cm2) dose regimens. Low-dose UVA1 is generated by fluorescent lamps, whereas medium and high doses require high-intensity emitting metal-halide lamps. (See 'Light sources' above and 'Dosimetry' above.)
●Indications for UVA1 phototherapy include severe atopic dermatitis, localized scleroderma, urticaria pigmentosa, and early stage mycosis fungoides. (See 'Indications' above.)
●Short-term adverse effects of UVA1 phototherapy include hyperpigmentation, erythema, xerosis, and pruritus. Long-term adverse effects include photoaging and photocarcinogenesis, although the carcinogenic potential of UVA1 has not been determined. (See 'Adverse effects' above.)
