Rheumatology 2006;45:653–655
1093/rheumatology/kel063
Advance Access publication 7 March 2006
Editorial
Light therapy (with UVA-1) for SLE patients:
is it a good or bad idea?
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 (O
2 ). 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 con-
verted 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
653
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doi:10.
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
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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].
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
654 Editorial

TABLE 1. UVA-1-absorbing compounds to point out that, in addition, many clinical symptoms were
improved after the 3-week course of treatment. Using a daily
Pyridine nucleotides (NAD, NADP) dose of 12 J/cm2 UVA-1 for the treatment of 12 patients with
Riboflavin (FAD, FMN)
moderately active SLE, the frequently improved symptoms were:
Porphyrin
Pteridine arthritis (6/9), myalgia/myositis (5/7), dyspnoea (4/4), fatigue (4/11),
Urocanic acid headache (4/4), leucocyturia/erythrocyturia (4/7), and blood
Cobalamin (vitamin B12) pressure (4/4) [7]. Molina and MacGrath [5] regarded the sustained
-Carotene
Bilirubin
[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-
- at 293 nm), with a steep decrease into the UVA region [26]. The
producing CD4þ Th1 cells and CD8þ 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-
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 character-
istic changes in peripheral B-cell homeostasis that were signifi-
cantly correlated with disease activity in SLE patients. They
reported that anti-DNA antibodies, mucocutaneous manifesta-
tions 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
relief of fatigue as the most gratifying feature for the patient, since
many patients reported returning to work, increasing their work-
loads 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 radia-
tion has been reported very recently [25].
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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 effective-
ness for skin cancer induction occurs in the UVB range (maximum
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.
 Editorial
Rheumatology Key message
 Long-wave UV therapy (>340 nm) can be
beneficial and safe for SLE patients.
The author declares that there was no funding for this paper and
no conflict of interest.
S. PAVEL
Department of Dermatology, Leiden University Medical Centre,
Leiden, The Netherlands
Correspondence to: S.Pavel@lumc.nl
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