Soodabeh Zandi, MD1,2,3; Sunil Kalia, MD, FRCPC1,2; Harvey Lui, MD, FRCPC1,2
1Psoriasis and Phototherapy Clinic, Vancouver General Hospital, Vancouver, BC, Canada
2Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
3Department of Dermatology, Kerman University of Medical Sciences, Kerman, Iran
High intensity long-wavelength ultraviolet A (340-400 nm; UVA1) lamps were initially developed as skin research tools; over time they have proven to be useful for treating a number of chronic dermatoses. UVA1 units and dosimetry are strikingly different from conventional UV phototherapy. The therapeutic effect of UVA1 is related to the fact that its long wavelength penetrates the dermis more deeply than UVB. UVA1 radiation induces collagenase (matrix metalloproteinase-1) expression, T-cell apoptosis, and depletes Langerhans and mast cells in the dermis. UVA1 exposure stimulates endothelial cells to undergo neovascularization. Ultraviolet A1 exerts significant therapeutic effects in atopic dermatitis and morphea; there is also evidence for its use in other skin diseases, including cutaneous T-cell lymphoma and mastocytosis.
phototherapy, skin diseases, ultraviolet A1, UVA1
The roots of ultraviolet A1 (UVA1) phototherapy can be traced to the development of a relatively “pure”, high-intensity UVA light source that was originally meant to be used for studying the physiologic cutaneous effects of UVA alone. UVA photons are approximately 1000 times less potent than UVB photons in eliciting photobiological responses, and thus, the technological challenge was to develop an artificial lamp that could deliver a biologically relevant UVA dose within a practical time frame and a sufficiently large irradiation field.1 Using a specially filtered metal halide lamp, the spectral output was weighted towards longer, more penetrating UVA wavelengths (340-400 nm), and was distinctly different from that of fluorescent UVA tubes used for psoralen + UVA (PUVA) therapy. Over time UVA1 came to be used diagnostically for photoprovocation of conditions such as polymorphous light eruption and then as a novel treatment modality for certain inflammatory dermatoses.
UVA1 induces T-cell apoptosis, which is one of its proposed mechanisms for improving atopic dermatitis (AD), mycosis fungoides (MF), and localized scleroderma.2 Consistent efficacious results with UVA1 have been observed with a variety of inflammatory, sclerosing, and neoplastic skin diseases that are characterized by dermal infiltrates rich in T lymphocytes.3 UVA1 is one of the most recent advances in phototherapy for localized scleroderma and systemic sclerosis, and has been used more extensively in Europe than North America or Asia.
UVA1 Phototherapy in Practice
UVA1 treatment units typically consist of metal halide lamps equipped with a series of special optical filters. Smaller units provide localized therapy, whereas whole-body treatment is best carried out using lie-down or standing UVA1 cabinets. Standing cabinets are more practical for whole-body treatment since liedown units can only expose one side of the body (i.e., anterior or posterior) at a time. Fluorescent tubes emitting predominantly in the UVA1 range have also been used for long wave UVA therapy, but these are not as powerful and efficient as filtered metal halide lamps. In North America UVA1 availability is limited, perhaps due to the relatively high equipment costs; UVA1 units are usually two to three times more expensive than conventional whole body UV treatment units.
UVA1 dosimetry has been categorized into low (≤40 J/cm2), medium (40-80 J/cm2), and high (80-130 J/cm2) dose regimens,4 and depending on the desired fluence and the irradiance of the UVA1 phototherapy unit, treatment times can range between 10 minutes and 1 hour per treatment session. Like other forms of UV phototherapy UVA1 requires a series of repeated exposures. However, with UVA1 the treatment fluence is usually held constant for a given course of therapy in contrast to UVB and PUVA, where the dosing is increased incrementally with each successive exposure. Prior to initiating treatment it may be appropriate to phototest the patient’s normal skin to screen for unusual UVA1 reactivity (e.g., occult polymorphous light eruption or UVA photosensitivity). The number of treatment sessions recommended for atopic dermatitis is usually 15 and for morphea or systemic scleroderma 20-40 treatments are given. Patients are treated daily with a break on the weekends. Continued improvement is often observed for up to several months after a treatment course; therefore, therapy is usually limited to 1-2 courses per year. In addition, since there is no data on the remission potential of UVA1, maintenance phototherapy is not routinely recommended. As the long-term side-effects of UVA1 are not well established, patients younger than 18 years should be treated judiciously.
Biologic and Mechanistic Effects of UVA1
UVA1 induces immediate tanning through oxidation of preexisting melanin and also causes delayed pigment darkening by an increase in melanin content.
Studies have shown that the mechanism of apoptosis with UVA1 differs from UVB and PUVA.5 UVA1 induces early apoptosis or preprogrammed cell death through two apoptotic pathways in lymphocytes and immature proliferating mast cells.6 The first pathway involves the production of superoxide anions and the second apoptotic pathway produces singlet oxygen species, which depolarize mitochondrial membranes.5 Apoptosis of T-cells underlies UVA1’s therapeutic effects in atopic dermatitis, mycosis fungoides (MF), and inflammatory scleroderma. Studies have been shown that UVA1 suppresses TNF-α, IL-12, IFN-γ, and ICAM-1.7-10 IL-6 and IL-8, cytokines with pivotal importance in sclerotic skin diseases, are down regulated by UVA1 in localized scleroderma lesions.11
Irradiation with UVA1 increases collagenase synthesis, as demonstrated by increased levels of collagenase mRNA and protein in cultured fibroblasts from morphea patients.12 Recently, it has been revealed that UVA1 radiation suppresses calcineurin activity, both in vivo and in vitro. This loss in activity is due to singlet oxygen and superoxide generated by photosensitization. These findings provide a mechanistic basis for the hypothesis that UVA1 and calcineurin inhibitors both affect the same signal transduction pathway in the skin.13
Although the use of UVA1 has been reported in a range of conditions, the main indications of UVA1 phototherapy are atopic dermatitis, cutaneous T-cell lymphoma, sclerosing skin diseases, and mastocytosis (Table 1).
|Indication||Strength of Evidence||Recommended Dosing Regimen*||Treatment Course (# of exposures)|
|Atopic dermatitis||Randomized controlled trials||Medium-dose||15|
|Sclerosing skin diseases||Randomized controlled trials||Medium- and/or high-dose||20-40|
|Mycosis fungoides||Open studies||Medium- and/or high-dose||10-35|
|Urticaria pigmentosa||Open studies||Medium- and/or high-dose||10-15|
|Table 1. Main indications and recommendations for UVA1 phototherapy|
* Medium-dose = 40-80 J/cm2, high dose = 80-130 J/cm2
In 1992 Krutmann et al showed that UVA1 improved patients with atopic dermatitis, thus becoming the first skin disease to be effectively treated by UVA1.2 The main mechanisms by which UVA1 phototherapy induces remission in atopic dermatitis involves a range of immunomodulating effects that include apoptosis of infiltrating T-cells, suppression of cytokine levels, and reduction in Langerhans cell numbers.
UVA1 has been proved to be superior to combined UVA/ UVB therapy in several studies.14 Narrowband (NB) UVB and medium-dose UVA1 are equally effective in the treatment of patients with moderate to severe AD.15 Tzaneva et al showed that high-dose and medium-dose UVA1 therapies have comparable efficacy in severe atopic dermatitis. Both high- and medium-dose regimens achieved comparable results as demonstrated by similar reductions in clinical scores.16 Low-dose UVA1 phototherapy did not reduce severity of atopic dermatitis.17 Several controlled studies indicate that UVA1 is effective in acute, severe AD and superior to broadband UV regimens, and that a course of medium-dose UVA1 may be a safer modality than low-dose UVA1. Due to practical considerations (i.e., availability, exposure times, and clinical experience) conventional UV therapy remains the first treatment of choice for phototherapy in atopic dermatitis, with UVA1 being reserved for acute severe exacerbations.
Sclerotic Skin Diseases
Phototherapy is an effective therapeutic option in scleroderma and should be considered among the first approaches in the management of localized scleroderma or morphea. Collagen metabolism disturbance, autoimmune activity, and vascular dysregulation are the main pathways that lead to the development of scleroderma.18 UVA1 photons are the most deeply penetrating form of UV therapy and they appear to exhibit their effects in all three of the above pathways by induction of collagenase messenger RNA expression, depletion of skin T-cells and cytokines (IL-1, IL-6), and neovascularization.19-21
High-dose UVA1 treatment for scleroderma was first conducted by Stege et al in 1997, who revealed that high-dose UVA1 phototherapy reduced sclerotic plaque thickness while increasing their elasticity.22 Andres et al in 2010 also showed that UVA1 phototherapy had a significant effect on collagen metabolism by reducing sclerotic plaque and lesional skin thickness, and improving skin elasticity.23
Kreuter et al in a comparative study demonstrated that mediumdose UVA1 was superior to both low-dose UVA1 therapy and NBUVB therapy with no significant difference between low-dose UVA1 and NB-UVB.21 UVA1 phototherapy has also been used for patients with limited and diffuse systemic sclerosis. Morita et al treated sclerotic skin on the forearms of four patients with systemic sclerosis. Sclerotic skin lesions were softened after 10-30 exposures of medium-dose (60 J/cm2) UVA1 therapy, resulting in increased passive joint mobility and cutaneous elasticity in patients with sclerosis.24 A case report documented UVA1’s effectiveness in softening sclerotic perioral skin and improving symptoms related to microstomia in systemic sclerosis.25
Cutaneous T-cell Lymphoma (Mycosis Fungoides)
UVA1 phototherapy was used by Plettenber et al in three patients with stage IA and IB mycosis fungoides (MF). Complete clearance was achieved after 16 to 20 exposures, with a high- or mediumdose regimen.26 In another study, 13 patients with widespread plaque-type, nodular and erythrodermic MF were given 100 J/cm2 UVA1 phototherapy 5 times/week. Eleven patients showed complete response and partial improvement was observed in two patients. Circulating CD4+/CD45RO+ and CD4+/CD95+ lymphocytes were significantly reduced with therapy.27 Suh et al treated 15 MF patients with UVA1, with 13 and 2 patients showing complete and partial remissions, respectively. This study reported that UVA1 therapy induced excellent therapeutic efficacy in patients with MF, delivering a quick response, and is safe in early and advanced stages of MF.28
UVA1 phototherapy reduces the density of dermal mast cells and has been reported to be effective for patients with urticaria pigmentosa. Four adult patients with generalized urticaria pigmentosa were treated with 130 J/cm2 UVA1 for 2 weeks. Pruritus improved after three treatment sessions, and two patients with diarrhea and migraine experienced relief of these symptoms as well. None of these patients had relapsed after at least 10 months follow-up, although the authors did not specifically report on the response of the skin lesions to UVA1.29 Gobello et al treated patients suffering from cutaneous mastocytosis with high- and medium-dose UVA1. In the majority of patients, the number of visible skin lesions was not significantly reduced; however, the number of mast cells in lesional skin decreased markedly in most patients. Pruritus and quality of life improved by the end of treatment and during the 6-month follow-up. No significant differences were observed between patients receiving high- or medium-dose UVA1.30
Other Skin Conditions
Other diseases treated with UVA1 with varying degrees of response include lichen sclerosus et atrophicus, dyshydrotic hand eczema, scleredema, necrobiosis lipoidica, granuloma annulare, pityriasis lichenoides chronica, systemic lupus erythematosus, sarcoidosis, granulomatous slack skin, and graft-versus-host disease. There are no controlled clinical trials investigating the efficacy of UVA1 on psoriasis. Because of its cost, longer exposure time, and limited availability, UVA1 is not used for psoriasis.
Side-effects of UVA1
Side-effects of UVA1 are usually fewer than with other types of phototherapy and most studies have reported no serious adverse effects. Most notably, the frequency of UV-induced burning seems to be lower for UVA1 than for conventional UVB or PUVA. In our experience, the minimal erythema dose for UVA1 is typically greater than 130 J/cm2. Side-effects with UVA1 phototherapy have been classified as acute or chronic. The most common acute sideeffects are hyperpigmentation, redness, dryness, and pruritus. Hyperpigmentation or tanning are virtually universal side-effects and can be striking, particularly within the active affected skin sites. Other observed side-effects include herpes simplex virus reactivation and polymorphic light eruption induction.31 Chronic side-effects in patients who receive UVA1 phototherapy include photoaging and possible photocarcinogenesis. Reports of skin cancer in patients treated with UVA1 are usually confounded with the use of other therapies known to also increase the risk of cutaneous malignancies. For instance, a case of melanoma was reported in a patient with mastocytosis after receiving UVA1 treatment, however, this individual had also received PUVA bath therapy in the past.32 As well, there are two cases of Merkel cell carcinoma after UVA1 phototherapy, but both patients had blood dyscrasias and were treated with immunosuppressants.33
Contraindications to UVA1 therapy include photosensitivity disorders such as xeroderma pigmentosum and porphyria disorders. Relative contraindications also include a history of melanoma or nonmelanoma skin cancers, immunosuppressed individuals following organ transplant, and patients who have received prior radiation treatment, which potentially predisposes them to skin tumor development.4
UVA1 is a relatively new, unique, and possibly underutilized therapeutic modality available in photodermatology that has shown relatively good evidence for treating atopic dermatitis and sclerotic skin diseases. Overall, the side-effects from therapy are well tolerated by patients, with the long-term adverse effects and relative utility for other dermatoses still remaining to be better elucidated.
- Mutzhas MF, Holzle E, Hofmann C, et al. A new apparatus with high radiation energy between 320-460 nm: physical description and dermatological applications. J Invest Dermatol 1981 Jan;76(1):42-7.
- Krutmann J, Czech W, Diepgen T, et al. High-dose UVA1 therapy in the treatment of patients with atopic dermatitis. J Am Acad Dermatol 1992 Feb;26(2 Pt 1):225-30.
- Dawe RS. Ultraviolet A1 phototherapy. Br J Dermatol 2003 Apr;148(4):626-37.
- York NR, Jacobe HT. UVA1 phototherapy: a review of mechanism and therapeutic application. Int J Dermatol 2010 Jun;49(6):623-30.
- Guhl S, Hartmann K, Tapkenhinrichs S, et al. Ultraviolet irradiation induces apoptosis in human immature, but not in skin mast cells. J Invest Dermatol 2003 Oct;121(4):837-44.
- Godar DE. UVA1 radiation triggers two different final apoptotic pathways. J Invest Dermatol 1999 Jan;112(1):3-12.
- Godar DE. UVA1 radiation triggers two different final apoptotic pathways. J Invest Dermatol 1999 Jan;112(1):3-12.
- Gambichler T, Skrygan M, Tomi NS, et al. Significant downregulation of transforming growth factor-beta signal transducers in human skin following ultraviolet-A1 irradiation. Br J Dermatol 2007 May;156(5):951-6.
- Skov L, Hansen H, Allen M, et al. Contrasting effects of ultraviolet A1 and ultraviolet B exposure on the induction of tumour necrosis factor-alpha in human skin. Br J Dermatol 1998 Feb;138(2):216-20.
- Krutmann J, Grewe M. Involvement of cytokines, DNA damage, and reactive oxygen intermediates in ultraviolet radiation-induced modulation of intercellular adhesion molecule-1 expression. J Invest Dermatol 1995 Jul;105(1 Suppl):67S-70S.
- Szegedi A, Simics E, Aleksza M, et al. Ultraviolet-A1 phototherapy modulates Th1/Th2 and Tc1/Tc2 balance in patients with systemic lupus erythematosus. Rheumatology (Oxford) 2005 Jul;44(7):925-31.
- Kreuter A, Hyun J, Skrygan M, et al. Ultraviolet A1-induced downregulation of human beta-defensins and interleukin-6 and interleukin-8 correlates with clinical improvement in localized scleroderma. Br J Dermatol 2006 Sep;155(3):600-7.
- Gruss C, Reed JA, Altmeyer P, et al. Induction of interstitial collagenase (MMP-1) by UVA-1 phototherapy in morphea fibroblasts. Lancet 1997 Nov 1;350(9087):1295-6.
- Musson RE, Hensbergen PJ, Westphal AH, et al. UVA1 radiation inhibits calcineurin through oxidative damage mediated by photosensitization. Free Radic Biol Med 2011 May 15;50(10):1392-9.
- de Kort WJ, van Weelden H. Bath psoralen-ultraviolet A therapy in atopic eczema. J Eur Acad Dermatol Venereol 2000 May;14(3):172-4.
- Majoie IM, Oldhoff JM, van Weelden H, et al. Narrowband ultraviolet B and medium-dose ultraviolet A1 are equally effective in the treatment of moderate to severe atopic dermatitis. J Am Acad Dermatol 2009 Jan;60(1):77-84.
- Tzaneva S, Seeber A, Schwaiger M, et al. High-dose versus medium-dose UVA1 phototherapy for patients with severe generalized atopic dermatitis. J Am Acad Dermatol 2001 Oct;45(4):503-7.
- Kowalzick L, Kleinheinz A, Weichenthal M, et al. Low dose versus medium dose UV-A1 treatment in severe atopic eczema. Acta Derm Venereol 1995 Jan;75(1):43-5.
- Breuckmann F, Stuecker M, Altmeyer P, et al. Modulation of endothelial dysfunction and apoptosis: UVA1-mediated skin improvement in systemic sclerosis. Arch Dermatol Res 2004 Oct;296(5):235-9.
- Camacho NR, Sanchez JE, Martin RF, et al. Medium-dose UVA1 phototherapy in localized scleroderma and its effect in CD34-positive dendritic cells. J Am Acad Dermatol 2001 Nov;45(5):697-9.
- Kerscher M, Volkenandt M, Gruss C, et al. Low-dose UVA phototherapy for treatment of localized scleroderma. J Am Acad Dermatol 1998 Jan;38(1):21-6.
- Kreuter A, Hyun J, Stucker M, et al. A randomized controlled study of low-dose UVA1, medium-dose UVA1, and narrowband UVB phototherapy in the treatment of localized scleroderma. J Am Acad Dermatol 2006 Mar;54(3):440-7.
- Stege H, Berneburg M, Humke S, et al. High-dose UVA1 radiation therapy for localized scleroderma. J Am Acad Dermatol 1997 Jun;36(6 Pt 1):938-44.
- Andres C, Kollmar A, Mempel M, et al. Successful ultraviolet A1 phototherapy in the treatment of localized scleroderma: a retrospective and prospective study. Br J Dermatol 2010 Feb 1;162(2):445-7.
- Morita A, Kobayashi K, Isomura I, et al. Ultraviolet A1 (340-400 nm) phototherapy for scleroderma in systemic sclerosis. J Am Acad Dermatol 2000 Oct;43(4):670-4.
- Tewari A, Garibaldinos T, Lai-Cheong J, et al. Successful treatment of microstomia with UVA1 phototherapy in systemic sclerosis. Photodermatol Photoimmunol Photomed 2011 Apr;27(2):113-4.
- Plettenberg H, Stege H, Megahed M, et al. Ultraviolet A1 (340-400 nm) phototherapy for cutaneous T-cell lymphoma. J Am Acad Dermatol 1999 Jul;41(1):47-50.
- Zane C, Leali C, Airo P, et al. “High-dose” UVA1 therapy of widespread plaquetype, nodular, and erythrodermic mycosis fungoides. J Am Acad Dermatol 2001 Apr;44(4):629-33.
- Suh KS, Kang JS, Baek JW, et al. Efficacy of ultraviolet A1 phototherapy in recalcitrant skin diseases. Ann Dermatol 2010 Feb;22(1):1-8.
- Stege H, Schopf E, Ruzicka T, et al. High-dose UVA1 for urticaria pigmentosa. Lancet 1996 Jan 6;347(8993):64.
- Gobello T, Mazzanti C, Sordi D, et al. Medium- versus high-dose ultraviolet A1 therapy for urticaria pigmentosa: a pilot study. J Am Acad Dermatol 2003 Oct;49(4):679-84.
- McGrath H, Jr. Ultraviolet A1 (340-400 nm) irradiation and systemic lupus erythematosus. J Investig Dermatol Symp Proc 1999 Sep;4(1):79-84.
- Wallenfang K, Stadler R. [Association between UVA1 and PUVA bath therapy and development of malignant melanoma]. Hautarzt 2001 Aug;52(8):705-7.
- Calzavara-Pinton P, Monari P, Manganoni AM, et al. Merkel cell carcinoma arising in immunosuppressed patients treated with high-dose ultraviolet A1 (320-400 nm) phototherapy: a report of two cases. Photodermatol Photoimmunol Photomed 2010 Oct;26(5):263-5.