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Rheumatology Advance Access originally published online on March 7, 2006
Rheumatology 2006 45(6):653-655; doi:10.1093/rheumatology/kel063
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

EDITORIAL

Light therapy (with UVA-1) for SLE patients: is it a good or bad idea?

S. Pavel

Department of Dermatology, Leiden University Medical Centre, Leiden, The Netherlands

Correspondence to: S.Pavel{at}lumc.nl

The development of skin rash—an unusual reaction to sunlight—is one of the criteria used in the diagnosis of systemic lupus erythematosus (SLE). In addition, exposure to sunlight is a risk factor for the induction or exacerbation of the disease. Patients with SLE who regularly protect themselves against sunlight appear to have significantly less renal involvement, thrombocytopenia, hospitalization and requirement for cyclophosphamide treatment [1]. All these facts support the importance of photoprotection in patients with SLE and suggest that light therapy in SLE patients may be more detrimental than beneficial.

However, in 1987 McGrath and co-workers [2] reported that long-wave ultraviolet (UV) radiation had a favourable effect on disease activity in SLE model mice. These rather unexpected results were later confirmed in a group of SLE patients [3]. Until now, there have been only a few clinical trials investigating this new therapeutic approach. They have all shown, however, that repeated whole-body exposure to the long-wave UV (UVA-1) can reduce disease activity in SLE patients [4–6]. In our recent work we suggested that UVA-1 could be used as an adjuvant therapy for SLE [7]. Thus, it appears that light therapy does not have to be a bad idea at all if the patients are exposed to selected wavelengths of the solar spectrum.

The biological effects of light on living cells are the consequence of the absorption of light photons by various molecules. The absorbed light energy briefly increases the vibration of the absorbing molecules, and this is followed by its rapid dispersion as heat. Higher irradiance can overcome the heat-dispersing capacity of the molecules, which can cause disruption of molecular structures. Such changes in the structure of molecules can lead to the formation of functionally active photoproducts (such as during UV-induced vitamin D3 synthesis), but in the majority of cases it results in damage and loss of normal molecular function. There are some compounds that are capable of channelling light energy for the conversion of oxygen into reactive oxygen species (ROS): singlet oxygen (1O2) and superoxide radical (Formula). Such compounds are called photosensitizers. Due to the high reactivity and very short lifetime of the ROS, these reactive species can cause damage only in the direct neighbourhood of the irradiated photosensitizers. However, the superoxide radical can be converted enzymatically to hydrogen peroxide. This relatively stable compound can diffuse and cause oxidative damage even in surrounding cells after being in contact with some transition metals.

Although UV radiation forms only about 5–7% of the solar spectrum, this radiation is responsible for the majority of the photobiological effects of sunlight. This can be explained by the fact that UV radiation is much better absorbed by cells and tissues than other sunlight components.

The UV radiation that reaches the earth consists of two parts: UVB (290–320 nm) and UVA (320–400 nm). The most important UVB-absorbing compounds in the skin are the pigment melanin, proteins, nucleic acids, urocanic acid and 7-dehydrocholecalcipherol (a vitamin D3 precursor). Relatively high concentrations of these compounds in epidermal cells result in almost complete absorption in the epidermis, and only a small proportion (around 10%) reaches the superficial parts of dermis.

The absorption of high UVB doses by the skin leads to an inflammatory skin reaction (sunburn). In sunburn, some epidermal cells are irreversibly damaged and die through an apoptotic process. Under normal circumstances, apoptotic cells are rapidly cleared. However, disturbed clearance of UV-induced apoptotic cells has been suggested to be an important pathogenic factor that may induce antibody production, and therefore responsible for the initiation or exacerbation of autoimmune reactions [8]. Another possible cause of antibody production, which has recently been demonstrated in irradiated keratinocytes, involves the presence of multiple UVB-induced cross-linked RNA–protein complexes [9]. From these data it has become clear that exposure to this radiation can cause the formation of neo-antigens in the skin, and this can induce the production of antibodies against autoantigenic nuclear material.

The ability of UVA radiation to cause skin erythema is approximately 103 to 104 times lower than that of UVB. The much lower concentrations of UVA-absorbing compounds in the skin account for this difference. Symptoms of photosensitivity may occur in SLE patients when irradiated with UVA doses higher than 20 J/cm2 [10]. UVA radiation is the oxidizing component of sunlight and exerts its biological effects mainly by producing ROS [11, 12]. Because of its limited epidermal absorption, UVA can reach deeper layers of the skin. This holds especially true for UVA-1, a long-wave (340–400 nm) component of UVA radiation. As UVA-1 is even less erythematogenic than UVA, much higher doses can be tolerated by patients. Since the introduction of high-output UVA-1 sources allowing high-dose delivery, this therapy has been used successfully to treat different dermatological conditions [13]. The doses used for the treatment of various skin diseases are generally much higher than those used to treat SLE.

The cells in the skin contain only a small number of compounds capable of absorbing UVA-1 irradiation (Table 1) [14]. Two of them, namely porphyrins and riboflavins, are well known for their photosensitizing properties. The concentration of UVA-1-absorbing photosensitizers is highest in the mitochondria. Therefore, one can expect that these organelles will be particularly sensitive to UVA-1 radiation and damage to them might initiate the apoptotic process. It has been shown that singlet oxygen is able to open mitochondrial megachannels, releasing apoptosis-initiating factor (AIF) and cytochrome c [15].


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  		TABLE 1. UVA-1-absorbing compounds

 
Their relatively lower propensity to apoptosis is a natural feature of epidermal cells (keratinocytes and melanocytes). This resistance is probably necessary for maintaining the protective function of the skin. Nevertheless, high doses of UVB or simulated solar radiation lead to the formation of apoptotic (sunburn) cells in the epidermis, whilst the ability of UVA-1 to cause apoptosis of epidermal cells is very low [16]. Clinical experience with UVA-1 radiation shows that skin-infiltrating white blood cells are much more sensitive to UVA-1 than the epidermal cells. The UV-induced reduction in the number of infiltrating cells forms the basis of the therapeutic effect of UVA-1 in different dermatological conditions [11, 17]. The light sensitivity of T cells has repeatedly been shown during the treatment of cutaneous T-cell lymphomas [18, 19].

We have recently determined that approximately 40% of UVA-1 can penetrate through the epidermis. This portion of UV radiation can reach the cells present in the capillary network of the skin [20]. At rest, the total skin blood flow is estimated to be between 200 and 500 ml/min [21]. This means that, during 10 min of total body exposure, 2–5 l of blood can be irradiated. Obviously, the irradiation dose in the subepidermal capillary network will be higher than that in the more deeply localized arterial and venous vessels. Nevertheless, by significantly influencing circulating blood components, a systemic effect of UVA-1 radiation can be brought about.

In a recent publication, a Hungarian group reported some immunological parameters in SLE patients who were successfully treated with UVA-1 [22]. They observed that after 9 weeks of low-dose (6 J/cm2) UVA-1 therapy, the proportion of IFN-{gamma}-producing CD4+ Th1 cells and CD8+ Tc1 cells in the peripheral blood was significantly reduced compared with the situation before the therapy, and became significantly lower than control values. The percentage of IL-4-secreting Th2 cells increased significantly, whereas the proportion of Tc2 cells decreased, so both became comparable to control cell numbers. Due to these changes in lymphocyte subsets, there was a prominent decrease in the Th1/Th2 and Tc1/Tc2 ratios. The authors propose that since IFN-{gamma} plays an important role in the pathogenesis of SLE, this mechanism may be one of the beneficial effects of UVA-1 treatment in lupus patients.

McGrath [3] was the first to report a decrease in circulating antibodies in some of his patients treated with UVA-1 radiation. Similar observations have been made by us [6, 7]. These discoveries obviously turn attention to the function of B cells. SLE is one of the autoimmune diseases in which increased numbers of plasma cells are present in the peripheral blood. Jacobi et al. [23] have tested the hypothesis that the degree of abnormality of circulating B-cell subsets correlates with disease activity. With the use of flow cytometric analysis of B cells they were able to identify characteristic changes in peripheral B-cell homeostasis that were significantly correlated with disease activity in SLE patients. They reported that anti-DNA antibodies, mucocutaneous manifestations and B-cell abnormalities (especially increased frequencies of CD27high plasma cells) distinguished patients with active disease from those with low disease activity. Moreover, an expansion of CD27high plasma cells was found to be associated with the serological presence of particular autoantibodies and the duration of disease. We suggest that these abnormal cells may be one of the targets of UVA-1 therapy and that the irradiation might be able to suppress B-cell activity or induce the apoptosis of circulating activated B lymphocytes in the dermal blood vessels. In an in vitro model, we have recently shown a dose-related inhibition of immunoglobulin production and apoptosis of B cells by UVA-1 radiation [20].

From this experimental evidence it can be concluded that the systemic effect of UVA-1 therapy in SLE patients can be (at least in part) ascribed to the effects of the irradiation on the function of the peripheral T and B lymphocytes. It is of interest to point out that, in addition, many clinical symptoms were improved after the 3-week course of treatment. Using a daily dose of 12 J/cm2 UVA-1 for the treatment of 12 patients with moderately active SLE, the frequently improved symptoms were: arthritis (6/9), myalgia/myositis (5/7), dyspnoea (4/4), fatigue (4/11), headache (4/4), leucocyturia/erythrocyturia (4/7), and blood pressure (4/4) [7]. Molina and MacGrath [5] regarded the sustained relief of fatigue as the most gratifying feature for the patient, since many patients reported returning to work, increasing their workloads and experiencing marked improvement of their quality of life. An interesting example of the systemic effect of UVA-1 therapy was described by Menon et al. [24]. UVA-1 treatment of a patient with neuropsychiatric SLE led to the reversal of symptoms of brain dysfunction; this was confirmed by positron emission tomography, which showed complete clearing of the brain abnormalities observed earlier. A similar case of a SLE patient with progressive cognitive dysfunction and high levels of anticardiolipin antibodies successfully treated with UVA-1 radiation has been reported very recently [25].

Whereas 6–12 J/cm2 of short-wavelength UV light (UVB) would cause serious burns with many apoptotic (sunburn) cells in the superficial skin, UVA-1 at the same dose level does not generate any macroscopic or microscopic changes in the epidermis or dermis. The only short-term side-effects of UVA-1 therapy are minimal redness and dryness of the skin and a very slight increase in pigmentation.

Experiments on albino mice showed that the highest effectiveness for skin cancer induction occurs in the UVB range (maximum at 293 nm), with a steep decrease into the UVA region [26]. The striking difference in carcinogenicity between the short- and long-wave UV radiation has been confirmed in humans. Burren et al. [27] found much lower p53 expression in human epidermis after 2 and 3 minimal erythemal doses (MED) of UVA-1 compared with 2 and 3 MED of solar-simulated irradiation or 3 MED of so-called narrowband UVB. Furthermore, only an occasional sunburn cell was observed in human epidermis after repeated exposure to 35 J/cm2 UVA-1 [28]. These findings were recently confirmed by Beattie and co-workers [16], who showed that 3 MED of UVA-1 produced negligible numbers of sunburn cells in the epidermis of volunteers, in contrast to 3 MED of narrowband UVB and 3 MED of simulated solar radiation.

The difference in the extent and type of carcinogenic outcome between UVA and UVB can be explained by their different wavelength-specific effects. UVB acts mainly through direct damage to DNA bases, leading to the formation of pyrimidine dimers, which are potential sources of mutations. DNA, on the other hand, does not absorb UVA-1 irradiation. The most important mechanism of DNA damage is based on the fact that ROS, formed during the exposure of endogenous photosensitizers, may cause oxidative damage of DNA molecules [29]. However, the doses of UVA-1 used in the treatment of SLE patients are quite low, which minimizes the carcinogenic risk of this phototherapy.

Sunlight consists of a spectrum of different wavelengths that can positively or negatively influence disease activity in SLE patients. The detrimental effect of UVB radiation contrasts with the beneficial effect of UVA-1 radiation. This has consequences for the requirement for irradiation equipment of appropriate quality. It is absolutely essential that the irradiation apparatus used for the treatment of SLE patients does not emit short-wave (up to 340 nm) UV radiation. As mentioned before, UVB photons are much more biologically effective and even a low dose of UVB could cause epidermal damage that could lead to the induction of antibody production. With appropriate apparatus, UVA-1 therapy can become a valuable adjuvant therapy for SLE patients without detrimental side-effects.

The author would like to thank Prof. P. A. Riley (London) for critical reading of the manuscript.
Figure 1

The author declares that there was no funding for this paper and no conflict of interest.

References

  1. Vila LM, Mayor AM, Valentin AH et al. Association of sunlight exposure and photoprotection measures with clinical outcome in systemic lupus erythematosus. P R Health Sci J 1999;18:89–94.[Medline]
  2. McGrath H Jr, Bak E, Michalski JP. Ultraviolet-A light prolongs survival and improves immune function in (New Zealand black x New Zealand white) F1 hybrid mice. Arthritis Rheum 1987;30:557–61.[ISI][Medline]
  3. McGrath H Jr. Ultraviolet-A1 irradiation decreases clinical disease activity and autoantibodies in patients with systemic lupus erythematosus. Clin Exp Rheumatol 1994;12:129–35.[ISI][Medline]
  4. McGrath H Jr, Martinez-Osuna P, Lee FA. Ultraviolet-A1 (340–400 nm) irradiation therapy in systemic lupus erythematosus. Lupus 1996;5:269–74.[Abstract/Free Full Text]
  5. Molina JF, McGrath H Jr. Longterm ultraviolet-A1 irradiation therapy in systemic lupus erythematosus. J Rheumatol 1997;24:1072–4.[ISI][Medline]
  6. Polderman MCA, Huizinga TWJ, Le Cessie S, Pavel S. UVA-1 cold light treatment of SLE: a double blind, placebo controlled crossover trial. Ann Rheum 2001;60:112–5.
  7. Polderman MCA, Le Cessie S, Huizinga TWJ, Pavel S. Efficacy of UVA-1 cold light as an adjuvant therapy for systemic lupus erythematosus. Rheumatology 2004;43:1402–4.[Abstract/Free Full Text]
  8. Andrade F, Casciola-Rosen A, Rosen A. Apoptosis in systemic lupus erythematosus: clinical implications. Rheum Dis Clin North Am 2000;26:215–7.[CrossRef][ISI][Medline]
  9. Andrade F, Casciola-Rosen LA, Rosen A. Generation of novel covalent RNA–protein complexes in cells by ultraviolet B irradiation. Arthritis Rheum 2005;52:1160–70.[CrossRef][ISI][Medline]
  10. Hasan T, Nyberg F, Stephansson E et al. Photosensitivity in lupus erythematosus, UV provocation results compared with history of photosensitivity and clinical findings. Br J Dermatol 1997;136:699–705.[CrossRef][ISI][Medline]
  11. Morita A, Werfel T, Stege H et al. Evidence that singlet oxygen-induced human T helper cell apoptosis is the basic mechanism of ultraviolet-A radiation phototherapy. J Exp Med 1997;186:1763–8.[Abstract/Free Full Text]
  12. Godar DE. UVA1 radiation triggers two different final apoptotic pathways. J Invest Dermatol 1999;112:3–12.[CrossRef][ISI][Medline]
  13. Mang R, Krutman J. UVA-1 phototherapy. Photodermatol Photoimmunol Photomed 2005;21:103–8.[CrossRef][Medline]
  14. Young AR. Chromophores in human skin. Phys Med Biol 1997; 42:789–802.[CrossRef][ISI][Medline]
  15. Godar DE, Miller SA, Thomas DP. Immediate and delayed apoptotic cell death mechanisms: UVA versus UVB and UVC irradiation. Cell Death Differ 1994;1:59–66.[Medline]
  16. Beattie PE, Finlan LE, Kernohan NM, Thomson G, Hupp TR, Ibbotson SH. The effect of ultraviolet (UV) A1, UVB and solar-simulated radiation on p53 activation and p21Waf1/Cip1. Br J Dermatol 2005;152:1001–8.[CrossRef][Medline]
  17. Polderman MCA, Wintzen M, Van Leeuwen RL, De Winter S, Pavel S. Ultraviolet A1 in the treatment of generalized lichen planus: a report of 4 cases. J Am Acad Dermatol 2004;50:646–7.[Medline]
  18. von Kobyletzki G, Dirschka T, Freitag M, Hoffman K, Altmeyer P. Ultraviolet-A1 phototherapy improves the status of the skin in cutaneous T-cell lymphoma. Br J Dermatol 1999;140:768–9.[Medline]
  19. Zane C, Leali C, Airo P, Panfilis G, Pinton PC. High-dose UVA1 therapy of widespread plaque type, nodular, and erythrodermic mycosis fungoides. J Am Acad Dermatol 2001;44:629–33.[Medline]
  20. Polderman MCA, Van Kooten C, Smit NPM, Kamerling SWA, Pavel S. UVA-1 radiation suppresses immunoglobulin production of activated B lymphocytes in vitro. Clin Exp Immunol 2006 (in press).
  21. Rowell LB. Human cardiovascular control. New York: Oxford University Press, 1993:219.
  22. Szegedi A, Simicx, AM, Horkay I et al. Ultraviolet-A1 phototherapy modulates Th1/Th2 and Tc1/Tc2 balance in patients with systemic lupus erythematosus. Rheumatology 2005;44:925–31.[Abstract/Free Full Text]
  23. Jacobi AM, Odendahl M, Reiter K et al. Correlation between circulating CD27high plasma cells and disease activity in patients with systemic lupus erythematosus. Arthritis Rheum 2003;48:1332–42.[CrossRef][ISI][Medline]
  24. Menon Y, McCarthy K, McGrath H Jr. Reversal of brain dysfunction with UV-A1 irradiation in a patient with systemic lupus. Lupus 2003;12:479–82.[Abstract/Free Full Text]
  25. McGrath H Jr. Elimination of anticardiolipin antibodies and cessation of cognitive decline in a UV-A-1-irradiated systemic lupus erythematosus patient. Lupus 2005;14:859–61.[Abstract/Free Full Text]
  26. De Gruijl FR, Sterenborg HJ, Forbes PD et al. Wavelength dependence of skin cancer induction by ultraviolet irradiation of albino hairless mice. Cancer Res 1993;53:53–60.[Abstract/Free Full Text]
  27. Burren R, Scaletta C, Frenk E, Panizzon RG, Applegate LA. Sunlight and carcinogenesis: expression of p53 and pyrimidine dimers in human skin following UVA I, UVA I + II and solar simulating radiations. Int J Cancer 1998;76:201–6.[CrossRef][ISI][Medline]
  28. Lavker R, Kaidbey K. The spectral dependence for UVA-induced cumulative damage in human skin. J Invest Dermatol 1997;108:17–21.[CrossRef][ISI][Medline]
  29. Kielbassa C, Roza L, Epe B. Wavelength dependence of oxidative DNA damage induced by UV and visible light. Carcinogenesis 1997;18:811–6.[Abstract/Free Full Text]

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