Abstract
Background: A beneficial effect was observed in patients with psoriasis vulgaris following balneotherapy with Dead Sea bath salt.
Objectives: To evaluate the possible role of trace elements in the effectiveness of balneotherapy.
Methods: Serum levels of 11 trace elements were
analyzed in 23 patients with psoriasis vulgaris who participated in a double-blind controlled study of balneotherapy with either Dead Sea bath salt (12 patients) or common salt (11 patients). Thirteen healthy volunteers served as controls.
Results: The mean pre-treatment serum levels of boron, cadmium, lithium and rubidium were significantly lower in patients compared to controls, whereas the mean pre-treatment serum level of manganese was significantly higher in patients compared to controls. Balneotherapy with Dead Sea bath salt resulted in a significant decrease (P = 0.0051) in the mean serum level of manganese from 0.10 + 0.05 mol/L to 0.05 + 0.02 mmol/L. The mean reduction in the serum level of manganese differed significantly (P = 0.002) between responders (% Psoriasis Area and Severity Index score reduction 5 25) and non-responders (% PASI score reduction <25). Following balneotherapy with Dead Sea bath salt the mean serum level of lithium decreased in responders by 0.01 +0.02 mmol/L, whereas its level in non-responders increased by 0.03 + 0.03 mmol/L. (P = 0.015).
Conclusions: Manganese and lithium may play a role in the effectiveness of balneotherapy with Dead Sea bath salt for psoriasis.
Spa therapy modalities employed at the Dead Sea area include heliotherapy (sun exposure), thalassotherapy (bathing in the Dead Sea water), balneotherapy (immersion in baths and pools of thermomineral water), pelotherapy (heated Dead Sea mud pack therapy) and climatotherapy (a type of treatment utilizing the atmosphere, temperature, humidity, barometric pressure, and light [1,2]. It has been shown that sun exposure was the main factor producing beneficial results for psoriasis (plaque
type) in Dead Sea spa therapy. [3] A beneficial effect has been attributed to bathing in Dead Sea water (which has a high content of minerals) and to immersion in baths and pools of Thermo mineral water in
dermatology [1,2] and rheumatology [4,5], although the mechanisms involved have not been fully elucidated. Such mechanisms probably incorporate mechanical, thermal, chemical and immunomodulatory effects [6±9]. Elution of proinflammatory mediators from the affected skin [10] may be induced by spa therapy as well. The chemical effects of the Dead Sea spa therapy in psoriasis
were demonstrated by Shani et al. [11±17] by in vitro and in vivo studies involving humans and animals, which revealed increased levels of minerals. The possibility that Dead Sea minerals penetrate psoriatic skin has been suggested in view of significant elevations of four ions, Br, Rb, Ca, and Zn, in the
serum of psoriatic patients following daily bathing in the Dead Sea for 4 weeks [11]. It has been shown that Dead Sea minerals penetrate psoriatic skin more than healthy skin, and that this penetration may occur even if diluted Dead Sea water is used [11]. Psoriatic keratinocytes obtained from patients treated with Dead Sea salt solution and mud revealed elevated mineral content while retaining normal structure [14,15]. Furthermore, it has been shown that the Dead Sea minerals (magnesium and potassium ions) have a specific inhibitory capacity on the uncontrolled proliferation of psoriatic dermis grown in tissue
culture [17]. These data suggest that the therapeutic effect observed in psoriatic patients following Dead Sea spa therapy may be attributable, at least in part, to Dead Sea minerals, which may play a role in cell proliferation and differentiation [18]. A recent study that we conducted in patients with psoriasis
vulgaris revealed a beneficial effect of balneotherapy with Dead Sea bath salt as compared to common salt [19]. The percent reduction in the Psoriasis Area and Severity Index score following balneotherapy with Dead Sea bath salt at the end of treatment (3 weeks) and 1 month later (34.8%and 43.6%, respectively) was higher than that recorded following balneotherapy with common salt(27.5%and24%, respectively). We suggested that balneotherapywithDeadSea bath saltmay serveasanadjuvant therapy in psoriasis vulgaris. The exact mechanism responsible for the therapeutic effect observed in this type of balneotherapy is unknown. It has been proposed that minerals and trace elements (i.e., bromine, magnesium, lithium and rubidium)in the Dead Sea bath salt may play a role [11,12,18]. The aim of the present study was to clarify the possible role of trace elements in balance therapy with Dead Sea bath salt for psoriasis.
Materials and Methods
The study group comprised 23 of 25 patients (15 males and females, agerange20±73years,meanage45.8+14.7years) who participated in the previously reported double-blind
controlled clinical study of balneotherapy for psoriasis [19]. The patients suffered from psoriasis vulgaris involving more than15%bodyarea. None of the patients had is chemic heart disease, severe hypertension or any other disease that disqualified them from bathing in accordance with the treatment protocol. None of the patient was being treated with lithium,beta-blocking agents,anti-malarial drug sornon steroidal anti-inflammatory drugs, all of which are known to aggravate psoriasis. The patients were allocated randomly to two treatments,with baths of either Dead Sea bath salt (12patients)or common salt (11 patients). The two types of salts were supplied in identical packets(one packet per bath),
and neither the physician north epatientsk newwhich bath salt was being administered. DeadSeabathsaltwassuppliedinpacketsof5kgperbath, while common salt was supplied in packets of 3kg per bath, in an attempt to achieve a similar osmolalityofabout3%inboth groups. The Dead Sea bath salt and the common software composed of minerals(ofwhichMgCl2, KCl, CaCl2, NaCl, were the major ones), trace elements and water, in varying concentrations[19].Thecontentof traceelementsintheDead
Seabathsalt and the common salt, measured by inductively coupled plasma spectrometer (ICP-MS), is presented in Table 1. The treatment protocol involved once-daily immersion of 20 minutes duration over 3weeks of the whole body(except for the head) inthesaltbathsthatwereheatedto358C. Immediately
after the salt baths the patients washed themselves with tap water and lubricated their skin twice daily with white soft paraffin. In order to assess effect of balneotherapy, the patients were instructed to stop topical and systemic anti-psoriatic therapy,2and4weekspriortostartingthetreatment protocol, respectively. During the treatment period,the patients were advised to avoid sun exposure.All patients were assessed by one dermatologist(H.G.)before commencing treatment and at its conclusion(end of week 3). Clinical evaluation was based on thePsoriasisAreaandSeverity Index score. The percentage
reduction of the PASI score after treatment was calculated according to the formula:
(PASIscore before treatment±PASIscore at the end of treatment)x100/PASI score before treatment
In view of the results of the former clinical study[19](34.8%and 27.5%,mean percentage reduction in the PASI score following balneotherapy with Dead Sea bath salt or common salt, respectively), the response to balneotherapy was defined as follows:
responders=%PASI reduction525;non-responders=%PASI reduction<25.
Analysis of trace elements
Determination of serum trace element concentrations was performed in 23 psoriatic patients before and after balneotherapy,as well as in 13 healthy volunteers who served as controls (6 males and 7 females; age range 30±55 years, manage 46.5 +7.1 years).
Seven milliliters of blood were drawn from the patients and the controls, after cleansing of the skin with distilled water followed by 70% ethanol. Blood samples were left to clot at room temperature and then centrifuged at 1,500 rpm for 10 minutes. The separated serum was collected and stored in
sterile plastic tubes at-708Cuntilused. Determination of serum concentrations of 11 elements was performed using the inductively coupled plasma mass spectrometer (ICP-MS). The laboratory technician was blinded to the study-group affiliation for each serum sample. The traceelements tested forwere:
aluminium(Al),boron(B),bromine(Br),cadmium(Cd),cobalt (Co),copper(Cu), lithium(Li),manganese(Mn),rubidium(Rb), strontium(Sr)andzinc(Zn). The main out come measure was the serum levels of trace elements in the two treatment groups and their association with clinical response.Statistical analysis was done using parametric or non-parametric methods, as appropriate.
Results
The mean age did not differ significantly between the 23 psoriatic patients and the 13 controls (45.8+14.7 and 46.5+ 7.1 years, respectively).Furthermore,the mean age(42.7+16.1 and 49.1+13.1 years, respectively), or pre-treatment PASI score(18.9+9.3and14.4+6.0, respectively)did not differ significantly between the two study groups (12 psoriatic patients treated with sea bath salt and 11 psoriatic patients treated with common salt).The number of responders (%PASI reduction525)was higher inpatients treated with
DeadSeabathsalt(7/12,58%)as compared to patients treated with common salt (4/11,36%), although the difference was not statistically significant (P>0.05). Similarly, themean+SD percentage reduction in the PASI score calculated for psoriatic patients treated with Dead Sea bath salt and common salt(25.6
+33.7and28.2+9.1, respectively)did not differ significantly (P>0.05, Mann-Whitney test). The mean serum levels of the11trace elements analyzed in psoriatic patients before and after balneotherapy with Dead Sea
bath salt or common salt,and in healthy controls,are presented in Table 2. Themeanpre-treatment serum levels of boron, cadmium, lithium and rubidium were significantly lower (P= 0.012, P=0.0049, P=0.018, andP<0.001, respectively) in psoriatic patients compared to controls, whereas the mean
serum level of manganese was significantly higher inpsoriatic patients compared to controls (0.09+0.05vs. 0.01+0.003 mmol/L, respectively,P<0.001). Following balneotherapy with Dead Sea bath salt, the mean
serum level of manganese decreased significantly from0.10+ 0.05mol/L to.05+0.02mmol/L (P=0.0051, Wilcoxon test). The mean reduction in these rum levels of manganese in patients treated with Dead Sea bath salt differed significantly(P=0.002) between responders(0.02+0.02mmol/L)and non-responders
(0.08+0.02mmol/L).The mean serum level of manganese was not affected significantly by balneotherapy with common salt. Following balneotherapy with Dead Sea bath salt, the mean serum level of lithium in responders decreased by 0.01 + 0.02 mmol/L (from 0.09 + 0.03 to 0.08 + 0.03 mmol/L), whereas its
level in non-responders increased by 0.03 + 0.03 mmol/L (from 0.07 + 0.03 to 0.1 + 0.03 mmol/L) (P = 0.015). The mean serum level of lithium was not affected significantly by balneotherapy
with common salt. The mean serum levels of the other nine trace elements were not affected significantly by balneotherapy with either Dead Sea bath salt or common salt.
Discussion
Analysis of Dead Sea spa therapy modalities for psoriasis revealed that the mean percentage reduction in the PASI score was 28.4% in patients who only bathed in the Dead Sea water, 72.8% in those only sunbathing, and 83.4% in those doing both, i.e., bathing in Dead Sea water enhanced the effect of solar
radiation [3]. The mean percentage reduction in the PASI score observed by us in psoriatic patients following balneotherapy with Dead Sea bath salt [19] was similar to the improvement observed in psoriatic patients who only bathed in the Dead Sea water [3]. The present study aimed to evaluate the possible role of trace elements in the effectiveness of balneotherapy with Dead Sea bath salt for psoriasis. The mean serum levels of the 11 trace elements studied in healthy controls were similar to reported levels for the general adult population [20]. Decreased mean pre-treatment levels of boron, cadmium and rubidium were recorded in psoriatic patients compared to controls. The role of boron in psoriasis is obscure. Cadmium, a carcinogenic metal that is involved in gene regulation and cellular signaling
pathways, may play a role in the pathogenesis of psoriasis. The decreased mean serum levels of rubidium recorded in patients suffering from psoriasis, a proliferative disorder of keratinocytes, may be analogous to decreased levels of rubidium recorded in the whole blood of 13 patients with colorectal cancer as compared to 10 normal controls [21]. The significant increase in the mean pre-treatment serum level of manganese, recorded by us in 23 psoriatic patients compared to 13 healthy controls, has been reported previously by Fidarov [22] in 30 psoriatic patients compared to 40 healthy controls. The mean serum level of manganese decreased in our psoriatic patients following balneotherapy with Dead Sea bath salt, but not following balneotherapy with common salt. Furthermore, the mean reduction in the serum level of
manganese in patients treated with Dead Sea bath salt differed significantly between responders and non-responders. The mechanism responsible for the decreased serum manganese level in psoriatic patients following balneotherapy with Dead Sea bath salt is not clear. This trend is consistent with the low
content of manganese in Dead Sea bath salt (2.3 parts per million) as compared to common salt (38 ppm). Previous reports revealed decreased serum or blood manganese levels in psoriatic patients whose condition improved or achieved clinical remission following treatment [22]. Significantly diminished manganese levels were found also in psoriatic skin (involved and uninvolved) compared to normal skin [23]. Serum manganese levels in psoriatic patients may reflect the activity of manganese superoxide dismutase in psoriatic skin, an enzyme postulated to have a role in cell differentiation and proliferation. Accordingly, the decreased mean serum manganese levels recorded in psoriatic patients following balneotherapy with Dead Sea bath salt may merely represent an epiphenomenon, related to the enhanced clinical improvement induced by Dead Sea bath salt (58% responders) as compared to common salt (36% responders). The trend towards increased serum levels of lithium in nonresponders as compared to decreased serum levels of lithium in responders following balneotherapy with Dead Sea bath salt is consistent with the role of lithium in the induction of new-onset psoriasis or exacerbation of pre-existing psoriasis [24]. This role involves molecular mechanisms such as the adenylate cyclase
system, the inositol pathway, and release of inflammatory cytokines. Increased serum levels of lithium following bal neotherapy with Dead Sea bath salt may imply the possibility of transcutaneous absorption of lithium from the salt. This possibility is consistent with the high concentration of lithium in Dead Sea bath salt (1.0 ppm) compared to common salt (< 0.2 ppm). Yet, transcutaneous absorption of lithium-ion from spa water containing lithium-ion (40 + 5 ppm) did not occur in healthy subjects [25]. Although the exact components of the Dead Sea bath salt, which are responsible for its therapeutic effects, are still obscure, the present study implies that elution of lithium from the salt may enhance its therapeutic properties. The low mean pre-treatment serum level of lithium recorded in psoriatic patients compared to healthy controls is not clear and may reflect homeostatic compensatory responses. It may be argued that alterations in trace elements may merely reflect the influence of dietary intake [20], and that controlled dietary conditions are necessary. However, the average basal or normative requirements for manganese could not be established. Furthermore, the overall manganese balance was not significantly affected by differences in dietary fiber, which is believed to have the greatest negative effect on manganese bioavailability [20]. A major source of dietary intake of lithium-ion is drinking water. Accordingly, dietary influences on the serum levels of lithium are not expected in patients included in our study who, being residents of the same area, were drinking from the same water sources [25]. In conclusion, alterations in manganese and lithium may play a role in the effectiveness of balneotherapy with Dead Sea bath salt for psoriasis. In view of the small sample size, further investigation is needed. Analysis of the concentrations of trace elements in the skin itself may further clarify the role of trace elements in the pathogenesis of psoriasis and in the effectiveness of Dead Sea spa therapy.
Acknowledgements. We thank Mrs. Lea Bouhnik and Mrs. Rina Ben Zeev, from the Department of Dermatology, Soroka University Medical Center, for their excellent technical assistance. This study was supported by a grant from Dead Sea Works, Ltd. This paper was presented in part at: The 24th Annual Meeting of the Israel Dermatological Society, 14±15 June 2000, Jerusalem, and Psoriasis 2000 at the Dead Sea, an International Symposium, 7±10 September 2000, Dead Sea, Israel.
