narrow-band uvb and medium-dose uva1 are equally effective ... · (eg2) and neutrophils (elastase)...

Narrow-band UVB and medium-dose UVA1 are equally effective in the treatment of moderate to severe atopic dermatitis

I.M.L. Majoie*, J.M. Oldhoff*, H. van Weelden, M. Laaper-Ertmann, M.T. Bousema1, V. Sigurdsson, E.F. Knol, C.A.F.M. Bruijnzeel-Koomen, M.S. de Bruin-Weller * These authors contributed equally to this study Department of Dermatology and Allergology, University Medical Centre Utrecht 1Department of Dermatology, Meander Medical Centrum, Amersfoort

Submitted

Abstract Background Patients with atopic dermatitis (AD) may improve after phototherapy, such as narrow‐band (NB) UVB. Recently, medium‐dose (MD) UVA1, a specific form of UVA phototherapy, was introduced for the treatment of AD. Objectives To study both clinical and histological effects of NB UVB and MD UVA1 treatment in patients with AD Methods Thirteen adult patients with moderate to severe AD were included in this randomized investigator‐blinded half‐side comparison study. Half‐side irradiation with threshold erythematic doses of NB UVB and MD UVA1 was performed three times weekly over a period of eight weeks with a follow up period of 4 weeks. Non irradiated body sides were covered with a half‐sided overall. The severity of disease was assessed separately for both sides of the patients’ body by the Leicester Sign Score and visual analog scoring for pruritus. Skin biopsies were taken from both body sides before and after phototherapy. Results All patients completed the trial. Both NB UVB and MD UVA1 phototherapy significantly decreased the severity of AD measured by the Leicester Sign Score and the visual analogue scale for pruritus (P < 0.01). Both types of phototherapy significantly decreased the total number of T‐lymphocytes (CD3), eosinophils (EG2) and neutrophils (elastase) in the dermis. No significant differences between NB UVB and MD UVA1 were observed. Conclusions NB UVB and MD UVA1 are equally effective in the treatment of patients with moderate to severe AD. This is supported by a decrease in inflammatory cell infiltrate in both treatment groups.

Narrow‐band UVB versus medium‐dose UVA1

Introduction Atopic dermatitis (AD) is an inflammatory skin disease with a chronic relapsing course. Phototherapy may be effective in AD. Ultraviolet (UV) lamps that have been studied include broad‐band UVB (280‐315 nm), narrow‐band (NB) UVB (311 nm), UVA (315‐400 nm), UVA1 (340‐400 nm), photo‐chemotherapy (PUVA), bath‐PUVA, combinations of UVA and UVB (UVAB), and extra‐corporal photo‐chemotherapy1;2.

NB UVB phototherapy for AD was first applied in 1993 by George et all.3 Since then, several open‐design studies have been published, which show its efficacy in AD4‐8. Clinical assessment of this mode of phototherapy in psoriasis suggested a number of advantages over conventional broad‐band UVB. These include a reduced incidence of burning episodes, increased efficacy, and longer remission periods. Furthermore, NB UVB seems to be less photo‐carcinogenic than conventional UVB9. A study performed by Jekler et al. shows that UVAB is superior to conventional broad‐band UVB or UVA in the management of AD10. Another study comparing UVAB with NB UVB showed a preference for NB UVB11.

The therapeutic effectiveness of UVA1 radiation in AD was first studied by Krutmann et al.12 in an open study in which 15 patients with acute, severe AD were exposed to high‐dose UVA1 (130 J/cm²) and compared to 10 patients receiving UVAB phototherapy. In comparison to UVAB therapy, significant improvement in clinical score was found in favour of high‐dose UVA113. Within the following years, these observations have been confirmed by several reports, which mainly represent uncontrolled, open, and sometimes even non‐comparative studies13‐15. Because of concerns about possible long‐term side effects of high‐dose UVA1 therapy, for example, photo‐damage and carcinogenesis, the effect of lower doses UVA1 was studied16. The results of this study demonstrated that both high‐dose UVA1 (max. 130J/cm²) and medium‐dose (MD) UVA1 (max. 65J/cm²) are effective, whereas low‐dose UVA1 (max. 20J/cm²) is not16. The clinical effect of MD UVA1 phototherapy in AD has been studied by several authors17;18. In a bilateral comparison study in 10 patients with AD, Tzaneva et al. showed that MD UVA1 is as effective as high‐dose UVA119. In a comparative study by von Kobyletzki et al. MD UVA1 showed a significantly better improvement of the clinical score for AD than UVAB17.

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The biological effect of phototherapy has been studied extensively in vitro, in mouse models and in vivo, mainly in psoriasis patients20. To our knowledge there are no studies comparing the histological effects of the different modalities of phototherapy currently available. NB UVB is the first choice of phototherapy to treat AD patients in the Netherlands and MD UVA1 is a rather new phototherapeutic modality. Therefore we investigated the effectiveness of MD UVA1 compared with NB UVB in AD patients by clinical and immunohistological evaluation. Patients and methods Study design The study was done in a randomized, investigator‐blinded and half side comparison design. Figure 1 shows the trial flow chart. Half‐side irradiation with threshold erythematic doses of NB UVB and MD UVA1 was performed three times weekly over a period of eight weeks with a follow up period of 4 weeks. Figure 1

Wash out periodWash out period Treatment periodTreatment period Follow up periodFollow up period

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Trial flow chart: LSS = Leicester Sign Score, VAS = visual analogue scale. During the treatment period phototherapy was applied 3 times per week; patients were randomly assigned to receive NB UVB to one body side and MD UVA1 to the other side. Patients Thirteen patients with AD were enrolled, of which 8 female, median age 25 years (range 20‐56). All patients fulfilled the criteria of Hanifin and Rajka21 and all had symmetrical distribution of their eczema. Exclusion criteria included local treatment with corticosteroids or other medical topical agents within the last 2 weeks or systemic treatment with antibiotics, corticosteroids or oral immunosuppressive drugs within the last 4 weeks.

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Clinical scoring Severity of the eczema was evaluated by the Leicester Sign Score (LSS; range 0‐108) by a blinded investigator. Severity is scored by 6 clinical features (erythema, purulence, excoriation or crusting, dryness or scaling, cracking or fissuring, and lichenification) graded at 6 defined body sites on a scale of 0 (none) to 3 (severe)22. Patients were asked to complete a visual analogue scale (VAS) for pruritus, where the level of their itch is reflected on a scale of 0‐10 (0 = ‘no itch’ and 10 = ‘most intense itch imaginable’). Both LSS and VAS‐pruritus scoring were performed before, during and after the treatment period (Figure 1). Each scoring was performed just before the next phototherapy session, so that erythema caused by phototherapy could not influence scoring. Before the treatment period, at the moment of inclusion, the median LSS for MD UVA1 was 20 (range 8–31). The median LSS for NB UVB was 19 (range 9–29). The baseline characteristics are shown in table 1. All participants in this study gave their informed consent. This study was approved by the local medical ethical committee, which follows the declaration of Helsinki’s protocol.

Table 1 Baseline characteristics AD patients n = 13 Age, yr 25 (20‐56) Sex, M : F 5 : 8

Half‐side phototherapy MD UVA1 NB UVB

LSS 20 (8‐31) 19 (9‐29) VAS ‐pruritus 7.5 (3.5‐10) 7.5 (3.5‐10)

Baseline characteristics of atopic dermatitis patients with symmetrical distribution of disease: LSS = Leicester Sign Score, VAS = visual analogue scale, MD UVA1 = medium‐dose UVA1, NB UVB = narrow‐band UVB. The baseline characteristics were the same for both body sides before half‐sided phototherapy. Data are expressed as median values (minimum‐maximum values). Phototherapy and dosimetry The NB UVB phototherapy‐unit consisted of a Waldmann light cabinet with 20 Philips TL‐01 lamps (311 nm). The ‘minimal erythemal dose’ for NB‐UVB (MED‐UVB) for each patient was determined before treatment. UVB treatment was started with an initial dose of 70% of the MED. Subsequent dose increments were given on the basis of erythema reactions of the skin. The MD UVA1 phototherapy‐unit consisted of a Waldmann light cabinet with 40 Philips TL‐10R lamps emitting wavelengths of 350 to 400 nm only, with a maximum of ± 370 nm. The average dose of UVA1 was 45 J/cm2.

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Phototherapy took place 3 times a week during 8 weeks, with a follow up period of 4 weeks. Patients were randomly assigned to receive NB UVB to one body side and MD UVA1 to the other body side. The non‐exposed body sides were covered with a half‐sided overall. During the treatment period no topical treatment apart from emollients was allowed. During the follow up period topical corticosteroids were allowed if needed. The face was excluded from half sided comparison and analysis. It was only treated with MD UVA1 and if needed mild topical corticosteroids (European class I or II). Biopsy specimens Biopsies from lesional skin of all patients were performed from both body sides before and after 8 weeks of phototherapy (48 h after the treatment). Skin biopsies (4mm) were performed under local anesthesia (xylocaine), snap‐frozen in liquid nitrogen, embedded in Tissuetek® (Sakura, Torrance, CA, USA) and stored at ‐70°C until further handling. Sections (5μm) were cut from the tissuetek‐embedded skin tissue and mounted on 3‐aminopropyl tri‐ethoxy silane‐coated (Sigma) glass slides. Immunohistochemistry Antibodies The mouse antibodies recognizing the following antigens were used as markers for immunohistohemical staining of the frozen sections: CD3 (Leu‐4, clone SK7, Becton Dickinson); eosinophilic cationic protein (clone EG2, Pharmacia & Upjohn, Sweden); mast cell tryptase (clone AA1, DAKO, Denmark); neutrophil elastase (clone NP57, DAKO) and CD1a (FITC‐conjugated, clone NA 1/34, DAKO).

Immunostaining Staining for CD3, mast cell tryptase, eosinophilic cationic protein and neutrophil elastase was combined with a biotinylated horse anti mouse IgG (Vector Laboratories, Inc. Burlingame, CA 94010) as described before by Thepen et al23. The FITC‐conjugated CD1a antibodies sections were fixed with dry aceton, air dried, and pre‐incubated for 20 min in 10% Normal Human Serum (NHuS) in PBS. Primary antibodies were diluted in 1% NHuS and incubated with the sections for 60 min. Slides were washed three times for 5 min with PBS + 0.05% Tween 20 (Sigma P‐1379) and were subsequently incubated with alkaline phosphatase (AP) conjugated sheep anti‐fluorescein (Fab fragments, Boehringer Mannheim, Germany) in PBS for 30 min. After incubation slides were washed with Tris‐HCl (0.1 M, pH 8.5). AP reactivity was demonstrated as previously described23.

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Quantification of staining Skin sections were examined by light microscopy at x400 magnification by a blinded observer. Before evaluation, sections were compared with either the isotype‐control‐stained counter sections or were compared with the non‐stained counter sections. Positive cells in the dermis were counted in three different sections of 1‐1.5 mm2 per section and calculated as cells per mm2. In fields containing sweat ducts and hair shafts, only the intervening dermal regions were counted. For EG2, CD3, elastase and CD1a, dermal and epidermal compartments were examined separately. The number of epidermal CD1a positive cells was graded as: no, or hardly any positive cells present (0), presence of scattered positive cells (1), abundant presence of positive cells (2), closed maze of positive cells (3). A second independent observer controlled one out of every 5 analyses. The mean inter‐observer coefficient of variation was within 10%. Statistical analysis Statistical analysis was performed using the program SPSS for Windows (version 10.0.5, 1999). The Wilcoxon signed rank test was used for all paired comparisons. P‐value of ≤ 0.05 was considered significant. Results Clinical improvement Thirteen patients fulfilled the entry criteria and were randomly assigned to phototherapy as described in the section above. All patients completed the trial. Only data obtained from the phototherapy period (0 to 8 weeks) were used for statistical analysis because during this period, all patients exclusively received phototherapy with no other treatment. During the follow up period (8 to 12 weeks) patients were allowed to use local corticosteroids, which most patients did.

Patients received median cumulative doses of 10.5 J/cm2 NB UVB (range 9.9‐11.5) to one body side and 930.6 J/cm2 MD UVA1 (range 717.1‐1067.4) to the other body side. Figure 2 shows the clinical results assessed for both body sides separately. The LSS was significantly decreased after both NB UVB and MD UVA1 treated side: mean reduction for NB UVB from 19.2 to 9.2 points (P < 0.01); for MD UVA1 from 19.5 to 11.7 points (P < 0.01). The patients’ self‐assessment, measured by the VAS‐pruritus, was also significantly decreased after both treatment modalities: mean reduction for NB UVB from 7.3 to 2.9 points (P < 0.01); for MD UVA1 from 7.3 to 3.6 points (P < 0.01). The improvement of the NB UVB treated side was compared with the improvement of the MD UVA1 treated

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side; no significant difference was observed (measured by SCORAD and VAS‐pruritus). Figure 2 A B

LSS mean n =13

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Clinical results MD UVA1 = medium‐dose ultraviolet A1, NB UVB = narrow‐band ultraviolet B.

A. Mean reduction in LSS (Leicester Sign Score). No significance difference in favour of NB UVB. x‐axes: time in weeks, y‐axes: Mean LSS score. Vertical lines display the standard deviation.

B. Mean reduction in VAS (Visual Analogue Scale) pruritus. No significance difference in favour of NB UVB. x‐axes: time in weeks, y‐axes: Mean VAS‐pruritus score. Vertical lines display the standard deviation.

Cellular infiltrate reduction Biopsy material of nine patients was suitable for evaluation. Material of four patients was lost due to technical reasons. The cellular infiltrate was scored for CD3 (T cell), EG2 (eosinophil), CD1a (dendritic cell), AA1 (mast cell) and elastase (neutrophil) counts. No significant differences in these cellular counts were found between body sides before phototherapy.

Figure 3 shows the immunohistological results. After phototherapy both MD UVA1 and NB UVB–treated skin showed a significant decrease in number of dermal T cells (P < 0.01), eosinophils (P < 0.01), and neutrophils (P < 0.05). The number of dermal dendritic cells was significantly decreased after NB UVB (P < 0.05), but not after MD UVA1. The number of mast cells was not significantly changed after both treatments. The epidermal number of T cells, dendritic cells and neutrophils were significantly decreased after both treatment modalities. No

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change was observed in epidermal eosinophils (data not shown). Between treatments comparison did not show significant differences in dermal or epidermal cell infiltrate. Discussion We show that both NB UVB and MD UVA1 have equal clinical effect in atopic dermatitis patients. This is supported by a comparable decrease in inflammatory cell infiltrate after both treatments.

Our data are in accordance with the results found in a recent study by Legat et al. In this study, with a similar design, NB UVB was compared with MD UVA1 in AD patients using half‐side irradiations. Although clinical benefit of NB UVB over MD UVA1 was suggested, there was no significant difference between the two treatment groups24.

In a controlled study of 73 patients with AD treated with either NB UVB, broad‐band UVA or visible light (placebo), Reynolds et al. reported more reduction of total disease activity and extent of disease after NB UVB than placebo. They also found that NB UVB was more effective than broad‐band UVA in reducing the extent of AD25.

The design of our study, which utilised half‐side irradiation, allows within‐patient comparisons. The possibility of systemic effects from phototherapy in half‐side irradiation studies is a matter of discussion in the literature. However, a recent study by Dawe et al. demonstrated that NB UVB improved chronic plaque psoriasis through local effects26.

The amount of irradiance needed for effective phototherapy is less for NB UVB than for MD UVA1. Due to this, the exposure time is short and less heat is produced during NB UVB treatment compared with MD UVA1. This aspect makes NB UVB more comfortable for the patient.

The clinical comparable effect of NB UVB and MD UVA1 is supported by a similar cellular infiltrate reduction. We show that both types of phototherapy result in a significant decrease of not only epidermal T cells, neutrophils and Langerhans cells, but also in a significant decrease in dermal T cells, eosinophils and neutrophils. This is in contrast to the expected penetration of UVB, which is thought to be mainly restricted to the epidermis20. Dermal dendritic cells were significantly decreased after NB UVB, but not after MD UVA1. Dermal dendritic cell numbers were however, not significantly different after the two treatment modalities. Neutrophilic granulocytes were present in three patients before start of therapy, which is of interest since patients with clinical signs of bacterial skin infection were excluded.

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Figure 3 Dermal infiltrate before and after phototherapy

CD3 Elastase NB UVB UVA1 NB UVB UVA1

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0 8 Immunohistochemical results (n = 9). Cellular infiltrate before (t = 0) and after phototherapy (t = 8) in patients with AD. Treatment of one body side was with narrow‐band UVB (NB UVB) and the other body side with medium‐dose UVA1 (MD UVA1) x‐axes: time: 0 = lesional skin, 8 = after 8 weeks of phototherapy. y‐axes: cells/mm2. CD3 = T cell; EG2 = eosinophil; CD1a = dendritic cell; AA1 = mast cell and elastase = neutrophil staining. * Indicates a significant different decrease in cells compared with t = 0. No significant differences were observed between the NB UVB side and MD UVA1 side.

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Furthermore, the number of mast cells did not decrease after MD UVA1 or after NB UVB. This in contrast to the reduced effect of dermal mast cells found in urticaria pigmentosa patients following high‐dose or MD UVA1 treatment27 and supports the previous published data of Breuckmann et al. also demonstrating that there was no effect of MD UVA1 on mast cells in AD patients28. UVB phototherapy penetrates human skin less than UVA and therefore the effect of UVB is hypothesized to be mainly via modulation of epidermal cells20;29. Histological studies of NB UVB in AD are lacking. Previously published data of BB UVB in AD showed a significant reduction in epidermal and dermal dendritic cells and T cells30. NB UVB therapy was studied in psoriasis vulgaris patients; a decrease of epidermal dendritic cells and T cells was found29;31. Furthermore, NB UVB therapy showed a more effective depletion of dermal T cells cells than BB UVB32. Our results indicate that NB UVB also reduces the dermal infiltrate in AD patients.

High‐dose UVA1 phototherapy in AD is known to result in a decrease of dermal T cells,33;34 dermal dendritic cells and dermal mast cells35. MD UVA1 decreases dermal T cells, dendritic cells and eosinophils in AD36;37. This is in accordance with our results. The influence of MD UVA1 on epidermal cells in AD has not been studied before and our results indicate that MD UVA1 also reduces the number of inflammatory cells in the epidermis. Since UVB phototherapy is assumed to penetrate less in human skin than UVA phototherapy, it can be expected that MD UVA1 would be superior at reducing the dermal cellular infiltrate than NB UVB. Our results show that NB UVB has at least the same capacity of influencing dermal inflammatory cells as MD UVA1. This effect can be a direct apoptotic effect on dermal cells or it might be via indirect effects on epidermal keratinocytes or Langerhans cells20. We found no significant difference in clinical and immunohistological efficacy between NB UVB and MD UVA1. In view of these results as well as the advantages of NB UVB (less heat load, shorter duration of phototherapy) we suggest NB UVB is the preferred choice of phototherapy when treating patients with chronic AD. We thank dr. M. Naunton, Groningen, for critically reading the manuscript.

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narrow-band uvb and medium-dose uva1 are equally effective ... · (eg2) and neutrophils (elastase)...

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