Light therapy (with UVA-1) for SLE patients: is it a good or bad idea?
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Autoimmunity↗
Biomedical subjects
S Pavel
Publications and source records attributed to S Pavel.
Ultraviolet-A (UVA-1) radiation suppresses immunoglobulin production of activated B lymphocytes in vitro.
Previous studies have shown that low-dose ultraviolet-A (UVA-1) total body irradiations were capable of improving disease activity in patients with systemic lupus erythematosus (SLE). We hypothesized that UVA-1-induced suppression of immunoglobulin production by activated B cells in the dermal capillaries could be (partly) responsible for this effect. Our experiments with donor skin demonstrated that approximately 40% of UVA-1 could penetrate through the epidermis. Irradiation of peripheral blood mononuclear cells (PBMCs) with 2 J/cm(2) of UVA-1 resulted in 20% cell death. This toxic effect could be prevented totally by preincubation of the cell cultures with catalase. This indicates that the generation of hydrogen peroxide plays a role in UVA-1 cytotoxicity. T cells and B cells appeared to be less susceptible to UVA-1 cytotoxicity than monocytes. With the use of a CD40-CD40L B cell activation method we measured immunoglobulin production after various doses of UVA-1 irradiation (0-2 J/cm(2)). The doses of 2 J/cm(2) caused a significant decrease of IgM, IgG, IgA and IgE production under the conditions of interleukin (IL)-10 or IL-4 (IgE) stimulation. Although UVA-1 can cause apoptosis of B lymphocytes, we show that relatively low doses of UVA-1 radiation also affect the function of these cells. Both effects may be responsible for the observed improvement of disease activity in SLE patients.
B-Lymphocytes↗
Normalized ultraviolet (UV) induction of Langerhans cell depletion and neutrophil infiltrates after artificial UVB hardening of patients with polymorphic light eruption.
BACKGROUND: Ultraviolet (UV) B hardening has been widely used as a prophylactic treatment in patients with polymorphic light eruption (PLE). Recent investigations have shown that in patients with PLE Langerhans cells (LCs) and neutrophils display less migration from and to the epidermis after an intense UVB irradiation compared with controls. OBJECTIVES: To investigate the effect of UVB hardening of patients with PLE on their cell migratory responses after intense UVB exposure. METHODS: Thirteen patients with PLE were recruited and UVB provocation testing was performed before entering the study. Among these patients, seven developed PLE rash upon UVB provocation ('UVB-P') and the other six did not respond ('UVB-NP'). Eleven age/sex-matched controls were included. Buttock skin of all included individuals was exposed to 6 minimal erythema doses (MED) of UVB (TL-12 lamps). Biopsies were taken after 24 h and 48 h, together with one control biopsy of unirradiated skin. Patients received total-body UVB hardening therapy consisting of 12 irradiations, on average rising from 10% to 140% of the initial MED in 6 weeks. Subsequently, MEDs were reassessed and biopsies were taken from newly irradiated (6 MED UVB) and unirradiated buttock skin. Skin sections were stained for the presence of LCs, macrophages and neutrophils. The cross-sectional area (in percentage) of positively stained cells within the epidermis was assessed from patients before and after hardening and compared with controls. RESULTS: Before therapy, epidermal LC depletion and neutrophil influx at 48 h after 6 MED were most significantly reduced in 'UVB-P' patients (P = 0.025 and P =0.006, respectively) when compared with controls. 'UVB-NP' patients did not differ significantly from controls. After therapy, there were no longer any significant differences in the cell numbers among these three groups. CONCLUSIONS: UVB hardening significantly improves UV-induced cell migratory responses in patients with PLE. UVB provokability of PLE appears to be most strongly linked to reduced UVB-induced trafficking of LCs and neutrophils, and 'UVB-P' patients show normalization of these responses after UVB hardening.
Adult↗
Cutaneous side-effects of transdermal iontophoresis with and without surfactant pretreatment: a single-blinded, randomized controlled trial.
BACKGROUND: Iontophoresis, a method that facilitates drug transport across skin by an external electrical field, offers the possibility for long-term transdermal delivery of compounds in a well-controlled manner. In general, the literature supports the contention that iontophoresis is a safe procedure. However, there are important medical issues concerning the epidermal and dermal effects of iontophoresis that have not been extensively investigated. Specific and strictly controlled studies on the dermal effect of iontophoresis are scarce. OBJECTIVES: The aim of this study was to investigate the cutaneous side-effects of transdermal iontophoresis application in healthy human volunteers. METHODS: This was a single-blinded, randomized and parallel design study. In one group (n=12) subjects were treated nonocclusively with a surfactant formulation followed by iontophoresis (3-h application at a current density of 250 microA cm(-2)). In another group (n=12) iontophoresis alone was performed. No drug was included in these studies. The corresponding passive treatments served as controls. Noninvasive methods including sensation record, transepidermal water loss (TEWL), skin colour and the visual scoring were used to assess cutaneous effects. RESULTS: Tingling and itching were commonly experienced in the first 30 min of the current application. Iontophoresis in combination with the pretreatment induced significant increases in TEWL values and in skin redness, and resulted in slight to mild erythema and oedema compared with the control. Compared with the iontophoresis alone, the presence of surfactant pretreatment caused slightly more skin irritation (erythema and oedema) but did not further disturb the skin barrier function. CONCLUSIONS: The transdermal iontophoresis challenges the skin barrier function and induces transient mild skin irritation, but does not cause any permanent damage to the skin when applied for 3 h at a current density of 0.25 mA cm(-2).
Adult↗
[Risk factors for skin melanoma: genetic factors probably more important than exposure to sunlight].
Pigmented naevi (moles) are increasingly regarded as risk factors for the development of melanoma. The probability of melanoma developing from congenital naevi is proportional to the volume of the naevi. The risk of melanoma development from large naevi (diameter > 20 cm) is already present in the early years of childhood. The most important risk factor is the higher number of acquired naevi. This applies particularly to dysplastic (also called clinically atypical) naevi that not only represent the highest risk group but are also considered potential melanoma precursors. The development of acquired naevi (including dysplastic naevi) is dependant on the degree of skin pigmentation. The role of sunlight (ultraviolet radiation) in the development of melanoma is less significant than is generally assumed. The indirect effect of sunlight on melanoma development is to stimulate naevogenesis. One of the risk-modifying genes is the gene coding for melanocortin-1-receptor (MC1R). The presence of some gene variants has been found to lead to changes in melanin synthesis and is associated with a higher risk of melanoma. Recent research has shown that dysplastic naevi synthesise more phaeomelanin. There are also strong indications that dysplastic naevus cells suffer from chronic oxidative stress. This situation can lead to hypermutability and genetical instability.
Humans↗
Efficacy of UVA-1 cold light as an adjuvant therapy for systemic lupus erythematosus.
OBJECTIVE: The assessment of the efficacy of therapy of patients with moderately active systemic lupus erythematosus (SLE) with low doses of UVA-1 cold light. METHODS: A double blind, placebo-controlled, cross-over study design was used for the examination of the efficacy of low doses of UVA-1 radiation (12 J/cm2/day for 15 days) in 12 patients. RESULTS: UVA-1 treatment resulted in a significant decrease of well-validated disease activity indexes [the SLE Activity Measure (SLAM) (P < 0.001) and the SLE Disease Activity Index (SLEDAI) (P = 0.007)], whereas neither score improved significantly during placebo treatment. Furthermore, UVA-1 therapy proved to be more effective [mean decrease 4.8 points) than placebo (mean decrease -1.7 points (i.e. an increase)] when measured by the SLAM (P = 0.001, 95% CI -7.56 to -2.28), but not by the SLEDAI. Two patients had transient skin reactions at the beginning of treatment. CONCLUSION: UVA-1 therapy appears to be a useful adjuvant treatment modality for patients suffering from moderately active SLE. Its effect could possibly be explained by reduction of B-cell function or apoptosis of plasma cells.
Adult↗
A double-blind placebo-controlled trial of UVA-1 in the treatment of dyshidrotic eczema.
We carried out a randomized, double-blind, placebo-controlled study to examine the therapeutic effect of UVA-1 irradiation on dyshidrotic hand eczema. Twenty-eight patients were randomised to receive UVA-1 irradiation (40 J/cm2) or placebo, five times a week for 3 weeks. Evaluated by the DASI and the VAS, UVA-1 was significantly more effective after 2 and 3 weeks. Also, desquamation and area of affected skin improved significantly more after UVA-1. We did not find any difference regarding the response of patients with increased IgE blood levels (>100 IU/mL) compared with those having normal IgE levels. No side effects were observed. This study indicates that UVA-1 can cause a significant improvement of both objective and subjective signs of dyshidrotic eczema.
Adolescent↗
[Photo dermatology].
Photodermatology has become an important part of the dermatologist's area of focus. This subspeciality is not only involved with studying basic biological processes such as the effects of ultraviolet (UV) irradiation on the skin's immune system (photo-immunology), melanocytes or DNA (carcinogenesis), but also with clinical issues such as photoprotection, photosensitive skin diseases (photodermatoses) and phototherapy. Increasing knowledge about the effects of UV irradiation on the skin, with or without photosensitising agents, has led to the development of new forms of photo(chemo)therapy. These allow good therapeutic results to be achieved in the treatment of not only psoriasis, but also other chronic inflammatory skin diseases, with minimal side effects. DNA can absorb UV irradiation. This can lead to irreversible DNA damage and mutations in genes responsible for cell cycle control. These events can lead to skin cancer. The presence of pheomelanin, which is an inferior type of UV light-absorbing melanin, can add to this process of DNA damage. The three most important types of skin cancer are basal cell carcinoma (more than 30,000 new patients per year in the Netherlands), squamous cell carcinoma and melanoma.
Basal Cell Carcinoma↗
Topical calcipotriol plus oral fumaric acid is more effective and faster acting than oral fumaric acid monotherapy in the treatment of severe chronic plaque psoriasis vulgaris.
BACKGROUND: Calcipotriol is an established topical therapy for psoriasis vulgaris. OBJECTIVE: This study aimed to investigate whether the addition of calcipotriol to fumaric acid ester (FAE) monotherapy had an additive efficacy and an FAE-sparing effect in patients with severe plaque psoriasis. METHODS: This multicentre, randomised, double-blind, vehicle-controlled study included 143 patients for up to 13 weeks treatment. Group A received FAE tablets (Fumaderm) with an increasing daily dosage from 105 to 1,075 mg + ointment vehicle. Group B received FAE tablets + calcipotriol ointment (50 microg/g). Ointments were applied twice daily. Clinical response was assessed using percentage changes in the Psoriasis Area and Severity Index (PASI), from baseline to treatment end. RESULTS: The mean percentage change in the PASI was -76.1% in group B and -51.9% in group A, the difference between treatments was -24.2% (95% CI from -34.2 to -14.2%; p < 0.001). Group B responded more rapidly to treatment. Investigators' and patients' overall efficacy assessments were significantly more favourable for group B (p < or = 0.001). Group B was prescribed less FAE than group A. This difference was greatest at the last visit (mean daily dose 529 and 685 mg, respectively; p = 0.006). Overall adverse events in the two groups were similar. CONCLUSION: This study shows that the combination of calcipotriol and FAEs is significantly more effective and faster acting than FAE monotherapy in the treatment of severe plaque psoriasis. The combination has a slight FEA-sparing effect and therefore a superior benefit/risk ratio.
Administration, Oral↗
Melanin content of cultured human melanocytes and UV-induced cytotoxicity.
Cultured melanocytes originating from persons with different skin phototypes were utilized for measurement of endonuclease sensitive sites induced by UVB and the determination of cell survival after UVA or UVB irradiation. During culture, the melanocytes largely maintained their phenotypic characteristics according to their original skin phototype. Total melanin concentrations were 4.9 times higher in the darker skin phototype (IV-VI) melanocytes when compared to the cells from lighter skin phototypes (I-III). Also phaeomelanin contents were higher (2.5 times) in the skin phototype (IV-VI) melanocytes which implies that the cells from light skin types contain less melanin, but a relatively high proportion of phaeomelanin. After UVB irradiation a stronger induction of endonuclease sensitive sites was found for melanocytes with a lower level of total melanin and a high content of pheomelanin. By measuring the clone forming ability in different melanocyte cultures after UVB irradiation, significant better survival was found in case of the cells with the higher melanin content. Despite the large variations in melanin content, no significant difference in survival after UVA irradiation could be demonstrated in this way. Our results suggest a protective effect of melanin for UVB and indicate the importance of the measurements of melanin content and composition when different parameters of UV-induced damage are studied in melanin producing cells.
3T3 Cells↗
Melanocortin-1 receptor variant R151C modifies melanoma risk in Dutch families with melanoma.
Germline mutations of the cell-cycle regulator p16 (also called "CDKN2A") in kindreds with melanoma implicate this gene in susceptibility to malignant melanoma. Most families with familial atypical multiple-mole melanoma (FAMMM) who are registered at the Leiden dermatology clinic share the same p16-inactivating deletion (p16-Leiden). Incomplete penetrance and variable clinical expression suggest risk modification by other genetic and/or environmental factors. Variants of the melanocortin-1 receptor (MC1R) gene have been shown to be associated with red hair, fair skin, and melanoma in humans. Carriers of the p16-Leiden deletion in Dutch families with FAMMM show an increased risk of melanoma when they also carry MC1R variant alleles. The R151C variant is overrepresented in patients with melanoma who are from families with the p16-Leiden mutation. Although some of the effect of the R151C variant on melanoma risk may be attributable to its effect on skin type, our analyses indicate that the R151C variant contributes an increased melanoma risk even after statistical correction for its effect on skin type. These findings suggest that the R151C variant may be involved in melanoma tumorigenesis in a dual manner, both as a determinant of fair skin and as a component in an independent additional pathway.
Adult↗
Aberrant lipid organization in stratum corneum of patients with atopic dermatitis and lamellar ichthyosis.
There are several skin diseases in which the lipid composition in the intercellular matrix of the stratum corneum is different from that of healthy human skin. It has been shown that patients suffering from atopic dermatitis have a reduced ceramide content in the stratum corneum, whereas in the stratum corneum of lamellar ichthyosis patients, the amount of free fatty acids is decreased and the ceramide profile is altered. Both patient groups also show elevated levels of transepidermal water loss indicative of an impaired barrier function. As ceramides and free fatty acids are essential for a proper barrier function, we hypothesized that changes in the composition of these lipids would be reflected in the lipid organization in stratum corneum of atopic dermatitis and lamellar ichthyosis patients. We investigated the lateral lipid packing using electron diffraction and the lamellar organization using freeze fracture electron microscopy. In atopic dermatitis stratum corneum, we found that, in comparison with healthy stratum corneum, the presence of the hexagonal lattice (gel phase) is increased with respect to the orthorhombic packing (crystalline phase). In lamellar ichthyosis stratum corneum, the hexagonal packing was predominantly present, whereas the orthorhombic packing was observed only occasionally. This is in good agreement with studies on stratum corneum lipid models that show that the presence of long-chain free fatty acids is involved in the formation of the orthorhombic packing. The results of this study also suggest that the ceramide composition is important for the lateral lipid packing. Finally, using freeze fracture electron microscopy, changes in the lamellar organization in stratum corneum of both patient groups could be observed.
Dermatitis, Atopic↗
Solar-simulated skin adaptation and its effect on subsequent UV-induced epidermal DNA damage.
Repeated skin exposure to ultraviolet radiation leads to increased tolerance for erythema. Whether this tolerance is accompanied by a significant protection against epidermal DNA injury has never been thoroughly investigated. In a first set of experiments we irradiated 25 healthy volunteers three times a week for 3 wk using solar-simulating tanning lamps. In addition, all individuals were exposed to a (challenge) dose of three times the initial minimal erythema dose on a small area of skin before the first and after the final exposure. On both occasions, cyclobutane pyrimidine dimers were quantified in biopsies. As expected, repeated ultraviolet exposures resulted in increased epidermal pigmentation and thickness. The ultraviolet sensitivity for erythema decreased on average by 75%. The cyclobutane pyrimidine dimer formation was reduced on average by 60%. In a second set of experiments, with a group of 13 subjects, DNA repair kinetics were assessed. Within a period of 5 d after a single, slightly erythemal dose (1.2 minimal erythema dose), levels of cyclobutane pyrimidine dimer and p53-expressing cells were determined in skin biopsies. Both markers of DNA damage were elevated upon the single ultraviolet exposure and returned to background levels after 3-4 d. This information is important when trying to minimize the risk of DNA damage accumulation after repeated exposures during a tanning course.
Adaptation, Physiological↗
UVA-1 cold light treatment of SLE: a double blind, placebo controlled crossover trial.
OBJECTIVE: Treatment of patients with systemic lupus erythematosus (SLE) often implies strong drugs with possibly serious side effects. Thus there is a need for new immunosuppressive treatments. Long wave ultraviolet A (UVA-1) cold light therapy is an anti-inflammatory, immunomodulatory treatment with a possible systemic effect and few side effects. In the current study low dose UVA-1 cold light treatment was tested to determine whether it reduces disease activity in SLE. METHODS: Eleven patients with SLE were treated with UVA-1 cold light treatment and a placebo light treatment in a double blind, placebo controlled, crossover study. In two consecutive 12 week periods the patients were treated in the first three weeks with UVA-1 and placebo treatment or vice versa. The primary variables were the SLE Disease Activity Index (SLEDAI) and SLE Activity Measure (SLAM). RESULTS: The mean SLAM and SLEDAI showed a significant decrease of 30.4% (p=0.0005) and 37.9% (p=0.016) respectively after three weeks of UVA-1 and a non-significant decline of 9.3% (p=0.43) and 12.2% (p=0.54) respectively after three weeks of placebo treatment. In this small trial the difference in reduction of the disease activity indices during UVA-1 compared with during placebo treatment failed to reach the conventional border of significance (p=0.07). The total score of quality of life measure RAND-36 did not improve significantly, but the subscore for vitality did improve. CONCLUSION: Low dose UVA-1 cold light treatment was strongly suggestive of lowering disease activity in this double blind placebo controlled study, and no side effects occurred.
Adolescent↗
SPRR4, a novel cornified envelope precursor: UV-dependent epidermal expression and selective incorporation into fragile envelopes.
The cornified cell envelope (CE), a structure formed in the outermost layers of stratified squamous epithelia, provides a physical barrier against environmental insults. It is composed of several structural proteins, which are irreversibly crosslinked by calcium-activated transglutaminases. The small proline rich proteins (SPRRs) are one set of CE precursors. SPRR4, a novel member of this gene family, displayed very low or undetectable expression levels in normal human skin or other stratified squamous epithelia, but was clearly induced by UV light both in vivo and in vitro. High epidermal expression of SPRR4 was monitored only after chronic UV exposure and was concomitant with a thickening of the stratum corneum, which is believed to provide protection against subsequent damage. The calcium-dependent translocation of an SPRR4-GFP fusion protein to the cell periphery in living keratinocytes and its integration into both rigid and fragile cornified envelopes proved that SPRR4 is a novel CE precursor. Interestingly, after UV irradiation, SPRR4 was selectively incorporated into fragile CEs. Our results show for the first time that UV-induced cornification is accompanied by qualitative changes in CE precursor assembly. SPRR4 is part of an adaptive tissue response to environmental stress, which is likely to compensate for UV induced impairment of the epidermal barrier function.
3T3 Cells↗
Melanin offers protection against induction of cyclobutane pyrimidine dimers and 6-4 photoproducts by UVB in cultured human melanocytes.
The goal of this investigation was to correlate the melanin content in human pigmentary cells with the generation of UVB-induced photoproducts and to examine the relationship between the melanin content and the removal of the photoproducts. Cultured melanocytes from light-skinned individuals synthesized less melanin and produced more cyclobutane pyrimidine dimers and 6-4 photoproducts upon UVB exposure than did melanocytes from black skin. Tyrosine-stimulated melanogenesis provided protection against DNA damage in both cell types. In another set of pigmented cell lines a ratio between eumelanin and pheomelanin was determined. The assessment of association between DNA damage induction and the quantity and quality of melanin revealed that eumelanin concentration correlated better with DNA protection than pheomelanin. Skin type-I and skin type-VI melanocytes, congenital nevus (CN)-derived cells and skin type-II melanocytes from a multiple-melanoma patient were grown in media with low or high L-tyrosine concentration. The cells were irradiated with 200 J/m2 UVB, and the levels of the photoproducts were determined immediately and after 6 and 24 h. Once again the induction of the photoproducts was mitigated by increased melanogenesis, and it was inversely correlated with the skin type. No significant differences were found for the removal of photoproducts in the cultures of skin types I and VI and CN cells. No indications of a delay in the removal of photoproducts in the melanocytes from the multiple-melanoma patient were found either.
Cells, Cultured↗
[Protection from sunlight, particularly for children].
Excessive exposure to ultraviolet radiation (UVR) in childhood has been recognized as an extrinsic risk factor for the development of skin cancer later in life. The risk of squamous cell carcinoma is clearly related to the lifetime accumulated UVR dose, while the risk of melanoma and basal cell carcinoma is increased by intermittent UVR exposure, which is frequently responsible for sunburn. Besides UVR exposure, several intrinsic factors increase the risk of skin cancer, especially the risk of melanoma, such as skin type, the number of normal and dysplastic melanocytic naevi and family history. Responsible sun behaviour in childhood is most important to prevent skin cancer: stay in the shade, especially between 12:00 and 3:00 p.m., wear protective clothing, including a hat and sunglasses, try to build-up natural adaptation of the skin to UVR and apply a sunscreen to UVR exposed skin. There are strong indications that the possible preventive effect of sunscreens on the development of skin cancer is abolished in case of prolonged and intensive UVR exposure, because of a false feeling of safety. The most important measure to prevent the development of melanomas and basal cell carcinomas is probably the prevention of sunburn in childhood.
Child↗
Effect of the microsomal system on interconversions between hydroquinone, benzoquinone, oxygen activation, and lipid peroxidation.
Our previous results indicated that cytochrome P450 destruction by benzene metabolites was caused mainly by benzoquinone (Soucek et al., Biochem. Pharmacol. 47 (1994) 2233-2242). The aim of this study was to investigate the interconversions between hydroquinone, semiquinone, and benzoquinone with regard to both spontaneous and enzymatic processes in order to test the above hypothesis. We have also studied the participation of hydroquinone and benzoquinone in OH radicals formation and lipid peroxidation as well as the role of ascorbate and transition metals. In buffered aqueous solution, hydroquinone was slowly oxidized to benzoquinone via a semiquinone radical. This conversion was slowed down by the addition of NADPH and completely stopped by microsomes in the presence of NADPH. Benzoquinone was reduced to semiquinone radical at a significantly higher rate and this conversion was stimulated by NADPH and more effectively by microsomes plus NADPH while semiquinone radical was quenched there. In microsomes with NADPH. both hydroquinone and benzoquinone stimulated the formation of OH radicals but inhibited peroxidation of lipids. Ascorbate at 0.5-5 mM concentration also produced significant generation of OH radicals in microsomes. Neither hydroquinone nor benzoquinone did change this ascorbate effect. On the contrary, 0.1-1.0 mM ascorbate stimulated peroxidation of lipids in microsomes whereas presence of hydroquinone or benzoquinone completely inhibited this deleterious effect of ascorbate. Iron-Fe2+ apparently played an important role in lipid peroxidation as shown by EDTA inhibition, but it did not influence OH radical production. In contrast, Fe3+ did not influence lipid peroxidation, but stimulated OH radical production. Thus, our results indicate that iron influenced the above processes depending on its oxidation state, but it did not influence hydroquinone/benzoquinone redox processes including the formation of semiquinone. It can be concluded that interconversions between hydroquinone and benzoquinone are influenced by NADPH and more effectively by the complete microsomal system. Ascorbate, well-known antioxidant produces OH radicals and peroxidation of lipids. On the other hand, both hydroquinone and benzoquinone appear to be very efficient inhibitors of lipid peroxidation.
Animals↗