Climatotherapy at the Dead Sea is a remittive therapy for psoriasis: Combined effects on epidermal and immunologic activation

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1 Climatotherapy at the Dead Sea is a remittive therapy for psoriasis: Combined effects on epidermal and immunologic activation Emmilia Hodak, MD, a Alice B. Gottlieb, MD, PhD, c Tsvi Segal, MD, a Yael Politi, MD, a Lea Maron, BSc, a Jaqueline Sulkes, PhD, b and Michael David, MD a Tel Aviv, Israel, and New Brunswick, New Jersey Background: The beneficial effect of climatotherapy at the Dead Sea (CDS) for psoriasis has been established clinically but there is a striking lack of studies assessing its in vivo effect at the molecular and cellular levels. Objective: We sought to study the response of activated immunologic cells and keratinocytes in psoriatic lesions to CDS. Methods: A total of 27 patients with chronic, stable, plaque-type psoriasis treated with CDS for 28 consecutive days were evaluated with the Psoriasis Area and Severity Index score and quantitative histologic measures. Results: After 4 weeks of treatment, the overall Psoriasis Area and Severity Index score decreased by 81.5%. Complete clearance was achieved in 48% of the patients, and moderate to marked improvement in 41%. The average duration of remission was 3.3 months. Histologically, there was an overall reduction in malpighian layer thickness by 63.4%, and keratinocyte hyperplasia, assessed by Ki-67 cell cycle antigen expression, decreased by 78%; residual cell proliferation was confined mainly to the basal layer. These changes were accompanied by normalization of keratin 16 expression in 90% of the patients. T lymphocytes were almost totally eliminated from the epidermis (depletion of 90% of CD3 and CD25 cells), with only a low number remaining in the dermis (depletion of 69.4% of CD3 cells and 77.4% of CD25 cells). This reduction in activated T cells was accompanied by a marked reduction in HLA-DR expression by epidermal keratinocytes. Conclusions: CDS is a highly effective and remittive treatment for moderate to severe plaque-type psoriasis, leading to a reversal of both pathologic epidermal and immunologic activation. (J Am Acad Dermatol 2003;49:451-7.) Climatotherapy at the Dead Sea (CDS) has been used successfully for more than 25 years for the treatment of moderate to severe psoriasis. 1-8 In a retrospective study of 1340 patients from 18 countries, 58% achieved complete remission and 30% had marked improvement. The patients from abroad responded considerably better than the patients from Israel owing to their longer stay (4 vs 2 weeks). 6 In 740 patients from Germany evaluated in another study, 4 weeks of CDS led to a 70% rate of complete clearance. 7 CDS has also been shown to confer long remission. In a recent prospective study of 100 patients with psoriasis, 75% achieved clearance after 4 weeks at the From the Department of Dermatology a and Epidemiology Unit, b Rabin Medical Center, Beilinson Campus, Petah Tiqva and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; and University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, New Jersey. c Supported by The Dead Sea Medical Research Center, Dead Sea, Israel. Conflicts of interest: None identified. Accepted for publication December 1, Presented in poster form at the annual meeting of the European Academy of Dermatology and Venereology, Geneva, Switzerland, October 11-15, Reprint requests: Emmilia Hodak, MD, Department of Dermatology, Rabin Medical Center, Beilinson Campus, Petah Tiqva , Israel. ehodak@clalit.org.il. Copyright 2003 by the American Academy of Dermatology, Inc /2003/$ doi: /s (03)

2 452 Hodak et al JAM ACAD DERMATOL SEPTEMBER 2003 Fig 1. Patient before (A) and 4 weeks after (B) climatotherapy at Dead Sea, showing complete remission. Dead Sea. Of these, 68% were still in remission after 4 months, 43% after 6 months, and 10% after 8 months. 8 CDS is associated with rare and negligible shortterm side effects. The treatment is enjoyed by the patients and is associated with psychologic relaxation. Recent publications have shown that it is the sun exposure, and not the bathing in Dead Sea water, that is the main contributory factor to the beneficial results. 9 There is a surprising lack of studies assessing the effect of CDS on the immunopathologic features of psoriatic skin. The aim of this study was to evaluate the in vivo effect of CDS at the molecular and cellular levels. METHODS The study protocol was approved by the ethics committee of Rabin Medical Center, Tel Aviv, Israel. The study group comprised 27 patients (18 men, 9 women; age years) with chronic, stable, plaque-type psoriasis of more than 4 years duration (range: 4 to 30 years). All patients provided written informed consent to participate. Patients who were using photosensitizing medications or had a preexisting photosensitive disease were excluded. All patients stopped any topical treatment (except emollients) and intake of systemic antipsoriatic drugs 2 and 4 weeks, respectively, before climatotherapy. In all, 14 patients had skin type III, 9 patients had type IV, and 4 patients had type II. All patients had moderate to severe disease affecting a mean body surface area of 28% (range: 10% to 60%). Treatment protocol Treatment was carried out at the central solarium in the Ein Bokek area in Israel, and included daily bathing in Dead Sea water and sunlight exposure. Bathing sessions lasted 30 minutes. Sunlight exposure was increased gradually from 15 minutes to a maximum of 3 hours daily, divided into morning and afternoon sessions. The required time for sun acclimatization was 5 days for skin types III and IV, and 6 days for skin type II. During the study period, patients were allowed to use emollients before and after treatment, and tar shampoo. In the first 2 to 3 days, most of the patients used salicylic acid (2%-5%) ointment. Clinical evaluation Clinical assessment was done at baseline and at the end of the 4-week treatment period. Those who achieved complete remission were followed up monthly until relapse. The severity of the eruption was measured with the Psoriasis Area and Severity Index (PASI) score, 10 which takes into account the degree of erythema, scaling, and thickness in 4 anatomic regions: head; trunk; and upper and lower extremities. The area affected in each anatomic region is fractioned into the overall score. The maximum score is 72. Response to treatment was defined according to the rate of improvement in PASI score, as follows: complete response, more than 95% improvement; good or marked, 75% to 94%; moderate, 50% to 74%; slight, 25% to 49%; and none, less than 25%. Relapse was defined as a deterioration of 25% or more in the pretreatment PASI score. Pathologic and immunopathologic analysis A punch biopsy specimen was obtained from a psoriatic plaque before initiation of treatment and a second biopsy specimen, from an area adjacent to the first one, at the end of the study. Each biopsy specimen was embedded in optimal cryogenic temperature compound, snap-frozen in methanol, cooled with dry ice, and stored at 70 C until use. Epidermal thickness was measured directly on the cryostat-cut sections using a calibrated microscope ocular micrometer. The thickness of the malpighian layer (from the top of the granular layer to

3 J AM ACAD DERMATOL VOLUME 49, NUMBER 3 Hodak et al 453 Fig 2. Reversal of psoriatic epidermal features after climatotherapy at Dead Sea. Pretreatment frozen sections (A, C, E) are compared with posttreatment frozen sections (B, D, F). Hematoxylin-eosin stained sections (A, B) and reaction with antibodies to Ki-67 (C, D) and to K-16 (E, F) are shown; original magnification 100. the bottom of the basal layer) was calculated in 4 separate areas of each sample and averaged. Immunoperoxidase studies were done using an avidin-biotin peroxidase complex immunoperoxidase staining system (Vectastain, Vector Laboratories Inc, Burlingame, Calif) with 3-amino-9-ethylcarbazole as the developing agent. In all, 5 monoclonal antibodies were used: CD3; CD25, an antibody to IL-2 receptor; HLA-DR (Dako, Glostrup, Denmark); Ki-67, clone MIB1, a marker for cycling keratinocytes (Biosource International, Camarillo, Calif); and Ks 8.12, an antibody to hyperproliferative keratin 16 (Sigma Chemical Co, St Louis, Mo). The mean number of CD3 lymphocytes, CD25 lymphocytes, and Ki-67 keratinocytes in the epidermis were calculated in each specimen by counting the positively stained cells in the whole epidermis and dividing by the length of the epidermis. CD3 and CD25 lymphocytes in the papillary dermis were quantitated by averaging the number of positively stained cells in fields. Keratin 16 staining was described as absent, focal suprabasal, or diffuse suprabasal. HLA-DR expression of the surface of epidermal keratinocytes was determined semiquantitatively relative to the pretreatment findings. Statistical analysis Results are shown as mean SD. To analyze statistically significant differences in mean continuous parameters before and after treatment, paired t test was done (Wilcoxon signed t test was also performed). P values.05 were considered statistically significant.

4 454 Hodak et al JAM ACAD DERMATOL SEPTEMBER 2003 Fig 3. Quantitative analysis of thickness of malpighian layer (A) and of epidermal (Ki-67 ) cells (B) before and at end of climatotherapy at Dead Sea. RESULTS Clinical response All 27 patients completed the 4 weeks of treatment at the Dead Sea. Overall, there was an 81.5% reduction in PASI score, from a mean of (median 16) before treatment to (median 2.05) after. Response to treatment was complete in 13 patients (48%) (Fig 1, A and B), marked in 5 (19%), moderate in 6 (22%), and slight in 2 (7%). Only 1 patient failed to respond at all. The average remission period for the patients who achieved complete clearance was 3.3 months (range: 1 to 5.5 months). Side effects No side effects were recorded during the treatment period apart from mild and transient pruritus after bathing in the sea in 2 patients, which did not necessitate any systemic therapy and responded well to emollients. Effect on epidermal pathology At completion of CDS, the cornified and malpighian layers showed considerable thinning, with restoration of the granular layer and orthokeratosis (Fig 2, A and B). The average reduction in the malpighian layer was 63.4% (P.001 compared with before treatment) (Fig 3, A). Ki-67 is a nuclear proliferation-associated antigen that is synthesized by cells after proliferative activation and has been shown to be a useful marker for assessing keratinocyte proliferation in psoriasis. 11 The pretreatment and posttreatment psoriatic lesional reactions with Ki-67 antibodies are represented in Fig 2, C and D. At baseline, reaction with numerous basal and immediately suprabasal keratinocytes was noted, whereas at the end of week 4, there was a reduction in the density of Ki-67 nuclei, with residual positive cells, mainly in the basal cell layer. As shown in Fig 3, B, the mean number of Ki-67 cells in the epidermis per millimeter length of epidermal surface decreased by 78% (P.001). Suprabasal staining with Ks 8,12 is a result of expression of K-16, a hyperproliferative keratin and a marker for epidermal growth activation along the alternate or regenerative pathway. 12 Before therapy, K-16 was expressed by suprabasal keratinocytes in all psoriatic lesions (diffuse staining in 25, focal staining in 2). On completion of climatotherapy, K-16 expression was totally eliminated from the suprabasal layers in 24 of the 27 patients (90%), (Fig 2, E and F). Effect on immunologic activation Fig 4, A to D, are representative micrographs of CD3 lymphocytes and CD25 lymphocytes (IL-2 receptor) in psoriatic lesions before and after CDS. At the end of therapy, both types of lymphocytes were almost totally eliminated from the epidermis, with only residual cells in the dermis. The quantitative analysis of the CD3 and CD25 T cells in the epidermis is shown in Fig 5, A and B. The total number of epidermal CD3 T cells was reduced by an average of 94.3%, and the CD25 cells, by 97.7% (P.001 for both compared with pretreatment levels). The reduction in dermal T lymphocytes averaged 69.4% for CD3, and 77.4% for CD25 (P.001 for both). Marked reductions in HLA expression by epidermal keratinocytes were also observed in 24 of the 27 patients (90%) (Fig 4, E and F). DISCUSSION This is the first prospective study to evaluate both the clinical response of patients with psoriasis to CDS and also the objective immunopathologic response. Our results confirm previous reports that CDS is highly effective for moderate to severe plaque-type psoriasis, leading to sustained remis-

5 J AM ACAD DERMATOL VOLUME 49, NUMBER 3 Hodak et al 455 Fig 4. Reversal of immunologic activation in psoriatic skin lesions after climatotherapy at Dead Sea. Pretreatment frozen sections (A, C, E) are compared with posttreatment frozen sections (B, D, F). Reactions with antibodies to CD3 (A, B), CD25 (C, D), and HLA-DR (E, F) are shown; original magnification 100. sion. Of our patients, 48% achieved complete remission and 41% showed a moderate to marked response. However, the rate of complete remission and the average duration of remission (3.3 months) were lower than in other studies. 6-8 This difference could be a result of the inclusion of patients with lower severity scores and the use of different criteria to define these parameters. The results of our immunopathologic evaluation clearly showed that 4 weeks of CDS almost completely reversed the psoriatic features. The main epidermal pathology, namely, parakeratosis, absence of granular layer, and acanthosis, had almost normalized. These changes were accompanied by a profound reduction in the number of cycling keratinocytes, with restoration of keratinocyte proliferation to the basal layer and reversal of regenerative epidermal growth, as indicated by the elimination of K-16 expression from the suprabasal layers. In addition, CDS led to a reversal of the immunologic alterations observed in lesional psoriatic skin, namely infiltration of the epidermis and dermis by T lymphocytes, many expressing IL-2 receptors, and induced expression of HLD-DR on the surface of the epidermal keratinocytes. There was almost total depletion of activated T lymphocytes from the epidermis and their considerable diminution in the dermis. This reduction in activated T cells was accompanied by a marked reduction of HLA-DR expression by epidermal keratinocytes. These data provide the immunopathologic basis for the efficacy of CDS in treating psoriasis and in inducing a durable clinical remission. Interestingly, psoralen with UVA (PUVA) bath, another antipsoriatic therapy known for its high efficacy and long remission, was found to be associated with a similar depletion in epidermal and

6 456 Hodak et al JAM ACAD DERMATOL SEPTEMBER 2003 Fig 5. Quantitative analysis of CD3 and CD25 T cells in epidermis (A) and dermis (B). dermal T cells, and a reversal in epidermal activation. 11,13 The marked effect of CDS on the dermal T cells is probably attributable to the UVA component of Dead Sea sunlight. Broadband UVB rays have been shown to selectively deplete intraepidermal T cells, with minimal effect on dermal lymphocytes. 14 This finding parallels the known inability of UVB to penetrate the dermis. 14 Accordingly, the longer periods of clinical remission obtained with PUVA compared with UVB might be explained by the greater ability of PUVA to deplete dermal lymphocytes from the psoriatic skin. 14 Recently, another study reported that narrowband UVB rays deplete epidermal and dermal T lymphocytes to a greater extent than broadband UVB rays. However, the dermis still showed half the amount of T-cell depletion than the epidermis. 15 As for CDS, there are no studies comparing its efficacy with other standard psoriasis treatments. CDS is associated with infrequent side effects that are usually minor and easily corrected. Mild sunburn, photosensitivity, and infections such as herpes simplex and folliculitis have been previously reported. 16 Nevertheless, concern remains regarding the potential long-term hazards of skin aging and increased risk of skin cancer. The risk of long-term side effects might be lower at the Dead Sea owing to a weakening of the UV radiation, especially in the UVB spectrum. 17 It was recently reported that patients from Denmark with psoriasis subjected to CDS constituted a high-risk group for nonmelanoma skin cancer, 18 but the study design precluded any conclusions regarding the specific role of CDS in this risk. 18 This year a multicenter cross-sectional study was done in Israel to evaluate the prevalence of photodamage and skin cancer among patients with psoriasis after repeated treatments at the Dead Sea. 19 Actinic damage such as solar elastosis, solar lentigines, and face wrinkles were more common among the psoriatic group than the control group. There was no difference in the rate of nonmelanoma skin cancer between the groups. 19 On the basis of these results, it seems that in contrast to PUVA, 20 CDS is not associated with an increased risk of skin cancer in patients from Israel. In addition, CDS may be the most cost-effective modality for psoriasis (the calculated annual cost for 4 weeks of CDS is US $2300.) 8 In conclusion, CDS appears to be an effective remittive treatment for moderate to severe plaquetype psoriasis. Our study provides the immunopathologic basis for the clinical efficacy of CDS. We thank Gloria Ginzach and Hanni Penn for their editorial and secretarial assistance. REFERENCES 1. Dostrovsky A, Sagher E. Preliminary report: the therapeutic effects of the hot springs of Zohar on some skin diseases. Harefuah 1959;57: Goldberg LH, Sagher E. Psoriasis treatment at the Dead Sea. Cutis 1975;16: Avrach WW. Climatotherapy at the Dead Sea. In: Farber EM, editor. Psoriasis proceedings of the second international symposium New York: Yorke Medical Books; p Abels DJ, Kattan-Byron J. Psoriasis treatment at the Dead Sea: a natural selective ultraviolet phototherapy. J Am Acad Dermatol 1985;12: Even-Paz Z, Shani J. The Dead Sea and psoriasis: historical and geographic background. Int J Dermatol 1989;28: Abels DJ, Rose T, Bearman J. Psoriasis at a Dead Sea dermatology clinic. Int J Dermatol 1995;34: Harari M, Shani J. Demographic evaluation of successful antipsoriatic climatotherapy at the Dead Sea (Israel) DMZ clinic. Int J Dermatol 1997;36: Shani J, Harari M, Hristakieva E, Seidl V, Bar-Giyora J. Dead Sea climatotherapy versus other modalities of treatment for psoriasis: comparative cost effectiveness. Int J Dermatol 1999;38:

7 J AM ACAD DERMATOL VOLUME 49, NUMBER 3 Hodak et al Even-Paz Z, Guman R, Kipnis V, Abels DJ, Efron D. Dead Sea sun versus Dead Sea water in the treatment of psoriasis. J Dermatol Treat 1996;7: Fredriksson T, Pettersson U. Severe psoriasis: oral therapy with new retinoid. Dermatologica 1978;157: Vallat VP, Gilleaudeau P, Battat L, Wolfe J, Nabeya R, Heftler N, et al. PUVA bath therapy strongly suppresses immunological and epidermal activation in psoriasis: a possible cellular basis for remittive therapy. J Exp Med 1994;180: Mansbridge JN, Knapp AM. Changes in keratinocyte maturation during wound healing. J Invest Dermatol 1987;89: Coven TR, Murphy FP, Gilleaudeau P, Cardinale I, Krueger JG. Trimethylpsoralen bath PUVA is a remittive treatment for psoriasis vulgaris. Arch Dermatol 1998;134: Krueger JG, Wolf TJ, Nabeya R, Vallat VP, Gilleaudeau P, Heftler N, et al. Successful ultraviolet B treatment of psoriasis is accompanied by a reversal of keratinocyte pathology and by selective depletion of intraepidermal T cells. J Exp Med 1995;182: Ozawa M, Ferenczi K, Kikuchi T, Cardinale I, Austin LM, Coven TR, et al. 312 nanometer ultraviolet B light (narrowband UVB) induces apoptosis in T cells within psoriatic lesions. J Exp Med 1999;189: Even-Paz Z. Dermatology at the Dead Sea spas. Isr J Med Sci 1996;32: Kushelevsky AP, Slifkin MA. Ultraviolet measurements at the Dead Sea and Beer Sheva. Isr J Med Sci 1975;11: Frentz G, Olsen JH, Avrach WW. Malignant tumours and psoriasis: climatotherapy at the Dead Sea. Br J Dermatol 1999;141: David M, Adder B, Zucrov B, Segal Z, Pavloski F, Hershko K, et al. Actinic damage among psoriatic patients who were treated at the Dead Sea. Presented at: 26th Annual Meeting of the Israel Society of Dermatology and Venereology; June 6, 2002; Ein Bokek, Dead Sea, Israel. 20. Stern RS, Lunder EJ. Risk of squamous cell carcinoma and methoxsalen (psoralen) and UV-A radiation (PUVA): a meta-analysis. Arch Dermatol 1998;134: