Actinic damage among patients with psoriasis treated by climatotherapy at the Dead Sea

Actinic damage among patients with psoriasis treated by climatotherapy at the Dead Sea Michael David, MD,a Boris Tsukrov, MD,a Bella Adler, MPH,c Klilah Hershko, MD,d Felix Pavlotski, MD,b Dganit Rozenman, MD,e Emmilia Hodak, MD,a and Ora Paltiel, MDCM, MScc Petah Tiqva and Jerusalem, Israel Background: Dead Sea climatotherapy is highly effective in the treatment of psoriasis. However, its potential side effects, especially the risk of skin cancer, are unclear. Objective: We sought to determine the prevalence of solar damage and skin cancer among patients with psoriasis who underwent Dead Sea climatotherapy compared with control patients. Methods: This multicenter controlled cross-sectional study was carried out at the Dead Sea Solarium Clinic and outpatient clinics of the participating centers. A total of 1198 participants (460 patients with psoriasis and 738 control patients) aged 20 to 70 years were included. A standard questionnaire including demographic parameters and sun exposure habits was administered to all participants. Patients were questioned about previous psoriatic treatments and climatotherapy at the Dead Sea. All participants underwent a structured physical examination of the skin. We compared the prevalence of solar damage for patients with psoriasis and control patients and assessed the extent of photodamage among patients with psoriasis according to exposure time at the Dead Sea in univariate and multivariate analyses. Results: Elastosis (P \ .001), solar lentigines (P = .03), poikiloderma (P \ .001), and facial wrinkles (P \ .001) were significantly more common among patients with psoriasis compared with control patients and showed a dose response with increased Dead Sea exposure time. Self-reported previous skin cancers were more common in control patients compared with patients with psoriasis (8.2% vs 3.5%, P = .002), however, the prevalence of nonmelanoma skin cancer on examination did not differ between the two groups. No cases of malignant melanoma were detected in either group. Conclusions: Dead Sea climatotherapy is not associated with an increased risk of malignant melanoma or nonmelanoma skin cancer for patients with psoriasis in Israel. However, UV exposure at the Dead Sea may play a role in the development of solar damage. ( J Am Acad Dermatol 2005;52:445-50.)

T

he beneficial effect of Dead Sea climatotherapy (DSC) on thousands of patients with psoriasis has been reported in several pub-

From the Departments of Dermatology, Rabin Medical Centera and Sheba Medical Center,b Tel Hashomer, Sackler School of Medicine, Tel Aviv University; Braun School of Public Healthc and Department of Dermatology,d Hadassah-Hebrew University; and Department of Dermatology, Haemek Medical Center, Afula.e Supported in part by the Dead Sea Research Center, Neve-Zohar, Dead Sea Post 86910. Conflicts of interest: None identified. Accepted for publication November 2, 2004. Reprint requests: Michael David, MD, Department of Dermatology, Rabin Medical Center, Petah Tiqva 49100, Israel. E-mail: [email protected]. 0190-9622/$30.00 ª 2005 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2004.11.019

Abbreviations used: BCC: DSC: NMSC: PUVA: SCC:

basal cell carcinoma Dead Sea climatotherapy nonmelanoma skin cancer psoralen plus ultraviolet A squamous cell carcinoma

lications.1-5 Recently, it has been shown that DSC is a remittive therapy leading to a reversal of the immunopathologic abnormalities of psoriasis in involved epidermis and dermis.6 Frentz et al7 assessed the risk of skin cancer among 1738 Danish patients with psoriasis who underwent DSC during 1972 to 1993. They found that patients subjected to DSC constitute a high-risk group for nonmelanoma skin cancer (NMSC), squamous cell carcinoma (SCC) in particular. However, 445

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Table I. Study population: Distribution of demographic characteristics

Table II. Clinical characteristics of patients with psoriasis

Patients with Control patients psoriasis (N = 460) (N = 738) P value

Male sex (%) Median age, y Origin (%) Israel Europe/United States Other Current smokers (%)

261 (57) 48

296 (40) 47

266 (59) 138 (31)

459 (64) 158 (22)

48 (11)

104 (14)

155 (34)

200 (27)

\.001 .019 .002

.009

the authors noted that their study design precluded conclusions on whether climatotherapy plays a specific part in skin carcinogenesis because Danish patients sent to the DSC were a selected group. In view of the above, we carried out a multicenter Israeli controlled cross-sectional study, the purpose of which was to determine whether there is an increased risk of melanoma, NMSC, or other sune related skin damage among patients with psoriasis who have been exposed to UV radiation at the Dead Sea compared with control patients. Because the Israel Cancer Registry does not include data on NMSC, it was important to establish the prevalence of SCC and basal cell carcinoma (BCC) in control patients without psoriasis.

Characteristic

Duration

Age of onset of disease, y Range Median

1-68 24

Duration of disease, y Range Median

7-68 20

Treatments for psoriasis (%) UV, undefined UVA UVB PUVA UV-tar-anthralin Any UV Retinoids Methotrexate Cyclosporine Steroids Fumaric Creams Tar/anthralin Calcipotriol Alternatives Others Climatotherapy at the Dead Sea Yes Mean stay at Dead Sea

26 20 109 49 37 187 41 59 10 50 21 286 109 198 67 29

(6) (5) (26) (12) (9) (40.6) (10) (14) (2.4) (12) (5) (69) (26) (48) (16) (7)

397 (87%) 224 days (6245), median 140 days

PUVA, Psoralen plus ultraviolet A.

METHODS Eligible patients included those with plaque-type psoriasis, aged 20 to 70 years, whose disease duration was at least 7 years. Patients with psoriasis were recruited from among members of the Israel Psoriasis Association or were patients attending dermatology clinics at one of the study hospitals. Control patients were those aged 20 to 70 years who were referred to outpatient dermatology clinics for benign skin conditions including contact dermatitis and seborrhea. Patients with psoriasis and control patients who were deemed to be immunecompromised, those with photosensitivity, and those with skin type V or VI were excluded. Details of recruitment and methods have also been reported in a companion study.8 All participants provided signed informed consent. The protocol was approved by the institutional review boards at all participating hospitals. A standard questionnaire was administered to both patients with psoriasis and control patients regarding demographic parameters, habits, and recreational and occupational sun exposure. Patients

with psoriasis were questioned extensively regarding previous antipsoriatic treatments and climatotherapy at the Dead Sea. Patients with psoriasis and control patients were asked about recreational and occupational sun exposure. Finally, a structured physical examination was performed by a qualified dermatologist in which the number and location of skin lesions, benign and malignant, were noted on an anatomic chart. Suggested malignant lesions were confirmed several months after the initial visit by a telephone inquiry to the patients or treating physician. Statistical analysis There are no data regarding NMSC in the Israel Cancer Registry. For melanoma we calculated the expected number of cases using known rates as reported in the Israel Cancer Registry based on age, sex, and ethnicity.9 We compared characteristics of patients with psoriasis and control patients using chi-square test for categorical variables and the Mann-Whitney test for

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Table III. Morbidity comparing patients with psoriasis and control patients Minimum N

Suggested neoplasm on examination Removal benign neoplasm Underwent biopsy in the past Skin cancer by self-report

Patients with psoriasis (460)

Control patients (738)

9 (2.0%)

14 (1.6%)

Table IV. Morbidity among patients with psoriasis according to exposure to Dead Sea Exposure to Dead Sea P value

NS

49 (11.3%)

138 (20.3%) \.001

54 (12.4%)

117 (16.9%)

.041

14 (3.5%)

51 (8.2%)

.002

NS, Not significant.

Suggested neoplasm on examination Removal benign neoplasm Underwent biopsy in the past Skin cancer by self-report

Light (0-150 days)

Heavy (>150 days)

P value

2* (0.9%)

6 (2.9%)

.16

22 (10.5)

24 (12.4%)

.6

22 (10.5)

27 (13.6%)

.36

4 (2.1)

9 (4.9%)

.16

*One case with no information on Dead Sea exposure.

comparing medians of continuous variables. Finally, a logistic regression analysis was performed to assess predictors of malignant or premalignant lesions by self-report or by skin examination. The goodnessof-fit of the logistic models was tested using the Hosmer-Lemeshow test. For all statistical analyses a 2-sided P value of .05 was considered statistically significant.

RESULTS A total of 1282 patients with psoriasis and control patients participated in the study. We excluded 48 participants (3.7%) whose age was unknown or who did not fulfill the age criteria, 7 patients with psoriasis whose duration of illness was unknown, two patients with psoriasis because of known malignancy or immunosuppression, and two control patients with vitiligo. The final study population consisted of 460 patients with psoriasis and 738 control patients (N = 1198). The vast majority of control patients (656; 89%) were examined in one of the participating hospitals (Rabin Medical Center-Beilinson Campus), with only a minority examined in the remaining centers. Demographic characteristics of the patients and control patients are shown in Table I. There were more men (57% vs 40%) and more smokers (34% vs 27%) among patients with psoriasis than among control patients. There were also more patients with psoriasis of European/United States origin than control patients (31% vs 22%). The patients with psoriasis had a median disease duration of 20 years (Table II). The median age at disease onset was 24 years. Of the 457 ([99%) who responded to the study question, 87% had been treated at the Dead Sea, and 45% had been treated with some form of UV irradiation including UVA, UVB, and psoralen-UVA (PUVA). Other treatments included retinoids, steroids, methotrexate, cyclo-

sporine, fumaric acid ester, creams, tar-anthralin, calcipotriol, and alternative treatments. Based on the distribution of age, sex, and ethnic origin, 0.096 cases of melanoma were expected among the patients with psoriasis and none were observed. There were also no cases among control patients (0.131 expected). In all, 6 cases of BCC and 3 cases of SCC were suggested on examination of the patients with psoriasis. One BCC and one SCC were confirmed histologically. Other lesions were biopsied and found to be solar keratosis. The corresponding numbers in control patients were 11 (two confirmed) and 3 (one confirmed). Comparing patients with psoriasis and control patients there were significantly more self-reported malignant neoplasms (P = .002), benign neoplasms (P \.001), and biopsies in the past (P\.041) among control patients (Table III). On the other hand, among patients with psoriasis (Table IV), suggested neoplasms on examination or by history were more common among those with heavy Dead Sea exposure but in none of the comparisons were the differences statistically significant. We compared nonmalignant photodamage between patients with psoriasis and control patients and according to exposure to the Dead Sea (Tables V and VI). Elastosis, solar lentigines, poikiloderma, and facial wrinkles were significantly more common among patients with psoriasis compared with control patients. Solar keratosis was more prevalent among control patients (P = .001). When restricting the analysis to patients with psoriasis alone, greater exposure to the Dead Sea was significantly associated with benign forms of photodamage except telangiectasia, solar keratosis, and cheilitis (Table VI). We repeated the above analyses for the 218 patients with psoriasis and 346 control patients aged 50 to 70 years at the examination. All of the

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Table V. Photodamage comparing patients with psoriasis and control patients Lesion

Elastosis Telangiectasia Solar keratosis Solar lentigo Cheilitis Poikiloderma Wrinkles of face

Patients with psoriasis (%)

181 101 51 293 86 217 262

(39.6) (21.9) (10.9) (64.1) (18.8) (47.5) (57.5)

Table VI. Photodamage in patients with psoriasis according to Dead Sea exposure Exposure to Dead Sea

Control patients (%)

200 183 200 425 167 215 214

(27.1) (24.8) (26.9) (57.7) (22.7) (29.2) (29.1)

P value

\.001 NS \.001 .029 NS \.001 \.001

Lesion

Elastosis Telangiectasia Solar keratosis Solar lentigo Cheilitis Poikiloderma Wrinkles of face

NS, Not significant.

NS, Not significant.

confirmed BCC and SCC among patients with psoriasis and control patients occurred in this age category. Sex distribution and prevalence of smoking was similar to that observed for the entire population. The proportion of participants born in Europe and the United States (42% among patients with psoriasis and 30% among control patients) was higher than in the entire study population. A history of removal of benign (P \ .001) or malignant (P = .001) neoplasm was significantly more common among control patients than patients with psoriasis in this age group. As noted in the overall population, elastosis (P = .02), poikiloderma (P \ .001), and wrinkles (P \.001) were more common among the patients with psoriasis whereas solar keratoses (P = \ .001) were more common among the control patients. Once again, in this age group, among patients with psoriasis, a dose response was noted between light and heavy exposure to the Dead Sea and an increased prevalence of elastosis, solar lentigo, poikiloderma, and facial wrinkles. We repeated this analysis according to time from first exposure to the Dead sea, finding an increased prevalence of elastosis (P = .05), solar lentigo (P = .008), poikiloderma (P = .02), and wrinkles (P = .004) among the patients with psoriasis whose first exposure to DSC was at least 10 years previously. In a logistic regression analysis (Table VII) that included only patients with psoriasis, adjusting for age ( per year entered as a continuous variable), sex, smoking, and treatment with any UV irradiation, heavy exposure to DSC ([150 days) was not associated with suggested skin malignancies on examination or with a history of skin biopsy of benign or malignant neoplasm. Furthermore, on multivariate analysis, solar keratosis among patients with psoriasis was not associated with exposure to DSC after controlling for age, sex, smoking, or previous UV therapy.

DISCUSSION

Light (0-150 days) Heavy (>150 days) P value

75 51 22 118 36 95 106

(34%) (23%) (10%) (54%) (16%) (43%) (48%)

96 43 26 152 47 111 140

(47%) (21%) (13%) (74%) (23%) (54%) (68%)

.008 NS NS \.001 NS .032 \.001

Our results show that DSC is associated with an increased rate of chronic sun damage, and there was a dose response with increasing Dead Sea exposure time (Table VI). Solar elastosis, solar lentigines, poikilodermic changes, and wrinkles of face were all significantly more prevalent among patients with psoriasis compared with control patients. Our results also indicate that DSC is not associated with a higher risk of NMSC. Interestingly the prevalence of solar keratosis, a precancerous lesion, was significantly lower among the study group compared with control patients. This is an unexpected finding because patients with psoriasis may have more malignant skin tumors compared with the general population.10 Brooke et al11 have reported on the discordance between the presence of BCC and facial wrinkling. They suggested that mechanisms responsible for the development of facial wrinkles may mitigate against the appearance of BCC on the face. It is possible that solar keratosis and SCC may also occur less commonly on wrinkled sun-exposed compared with nonwrinkled skin. Another possible explanation is that our control patients without psoriasis may not represent the general population. We have examined this finding in greater detail in a separate publication and concluded that psoriasis may confer protection against actinic keratosis.8 Our results do not confirm the findings of Frentz et al,7 who reported that the risk of NMSC among Danish patients with psoriasis treated at the Dead Sea is increased almost 5-fold compared with the Danish general population. It should be stressed that the authors were unable to delineate why patients undergoing DSC develop skin cancer, because of the design of their study. Danish patients sent to the Dead Sea are a selected group. The climate therapy cohort excluded patients addicted to drugs or alcohol, but included patients who showed benefit from sunlight or artificial UV light and who enjoyed

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Table VII. Logistic regression: Suggested and self-reported neoplasms among patients with psoriasis

Outcome

N*

Variable Age (/y continuous) P

Suggested malignancy on examination, OR (95% CI)

Self-reported malignancy

Benign tumor removed

Biopsy

Solar keratosis

1.00 (0.93-1.06) NS

1.06 (1.00-1.12) .06

1.02 (0.99-1.04) NS

1.03 (1.00-1.06) .05

1.10 (1.06-1.14) \.001

Sex Male Female P

217 166

1.81 (0.33-9.81) 1 NS

0.82 (0.25-2.68) 1 NS

0.50 (0.25-0.98) 1 .045

0.64 (0.33-1.22) 1 NS

0.69 (0.34-1.39) 1 NS

Dead Sea exposure Heavy Light P

195 184

0.38 (0.07-2.08) 1 NS

0.54 (0.16-1.91) 1 NS

1.02 (0.51-2.02) 1 NS

0.80 (0.41-1.53) 1 NS

1.06 (0.52-2.15) 1 NS

Smoking Yes No P

134 245

2.09 (0.45-9.69) 1 NS

0.95 (0.27-3.29) 1 NS

1.13 (0.56-2.27) 1 NS

1.02 (0.52-1.98) 1 NS

0.56 (0.25-1.25) 1 NS

UV treatment Yes No P

208 171

0.37 (0.07-2.02) 1 NS

1.11 (0.34-3.66) 1 NS

1.10 (0.55-2.18) 1 NS

1.31 (0.68-2.52) 1 NS

1.02 (0.51-2.07) 1 NS

.66

.54

.99

.62

.87

P for goodness-of-fity

CI, Confidence interval; NS, not significant; OR, odds ratio. *Maximal numbers entered into the model. Some models had up to 5% missing values. y Hosmer-Lemeshow test; the closer the P value to 1, the better the fit of the model.

exposure to sun radiation. Thus, even before their arrival at the Dead Sea, they could be considered at high risk for skin cancer.12 Furthermore, the Israeli population is more chronically exposed to the sun, unlike the Danish population. The sudden intense sun exposure at the Dead Sea may be particularly harmful for unprepared skin. Various modalities of UV phototherapy are effective and popular in the treatment of moderate to severe psoriasis. The long-term side effects of UVB and PUVA resemble those of chronic sun exposure and are similar to those associated with DSC. Obviously the major concern is the potential of skin carcinogenesis. Broadband UVB has been shown to be associated with skin cancer of the genitalia,13 indeed, most UVB protocols require covering the genitalia. Narrowband UVB seems to be safer than PUVA.14 However, because narrowband UVB has been in use only since the late 1980s its long-term side effects are still undetermined. In longitudinal studies it has been reported that patients with psoriasis who have had long-term exposure to PUVA are at increased risk of developing NMSC15 and melanoma.16 No single case of malignant melanoma was detected in our study cohort possibly because of the limited sample size. The possible

explanation for the difference in the rate of skin cancer associated with photo(chemo)therapy versus DSC is in the quality and intensity of UV radiation at the Dead Sea. Because of the Dead Sea’s unique geographic location the UV radiation that reaches the ground has fewer short UVB rays and a high ratio of UVA to UVB.17 In a recent study UV radiation received by patients with psoriasis treated at the Dead Sea was compared with that given at phototherapy clinics in various countries. The mean UVB exposure given at the Dead Sea was among the lowest reported for the clearance of psoriasis.18 Recently, Paul et al19 have reported that treatment of psoriasis with cyclosporine is associated with an increased risk of NMSC. Previous exposure to PUVA, methotrexate and immunosuppressants also contributed to an increased risk. In our study, only a small percentage of patients with psoriasis were exposed to PUVA, methotrexate, or cyclosporine (Table II). There are several limitations to this study. First, we have no population-based estimates of the incidence of NMSC in Israel. Thus, we cannot be sure that the control patients without psoriasis represent the general population. Second, they were not fully matched to the psoriatic population in terms of demographic characteristics. Third, the power to

450 David et al

perform comparison in subgroups was small. Finally, the study groups were too small to detect an increased prevalence of melanoma. In summary, our study shows that patients with psoriasis in Israel who underwent repeated treatments at the Dead Sea had an increased rate of chronic solar damage. Nevertheless, DSC is not associated with an increased prevalence of skin cancer among Israeli patients. It must be stressed, however, that our results should not be interpreted to say that there is no increased risk. Patients treated at the Dead Sea should be encouraged to use total sun block for the face, chest, and other sun-exposed, uninvolved areas to minimize sun damage. A longitudinal, prospective study is needed to confirm our results, and to estimate the risk of melanoma and NMSC according to exposure time. REFERENCES 1. Goldberg LH, Sagher E. Psoriasis treatment at the Dead Sea. Cutis 1975;16:61-2. 2. Abels DJ, Kattan-Byron J. Psoriasis treatment at the Dead Sea: a natural selective ultraviolet phototherapy. J Am Acad Dermatol 1985;12:639-43. 3. Even-Paz Z, Shani J. The Dead Sea and psoriasis: historical and geographic background. Int J Dermatol 1989;28:1-9. 4. Abels DJ, Rose T, Bearman J. Treatment of psoriasis at the Dead Sea dermatologic clinic. Dermatology 1995;34:134-7. 5. Harari M, Shani J. Demographic evaluation of successful antipsoriatic climatotherapy at the Dead Sea (Israel) DMZ clinic. Int J Dermatol 1997;36:304-8. 6. Hodak E, Gottlieb A, Segal T, Politi Y, Maron L, Sulkes J, et al. Climatotherapy at the Dead Sea is a remittive therapy for psoriasis: combined effects on epidermal and immunological activation. J Am Acad Dermatol 2003;49:451-7.

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7. Frentz G, Olsen JH, Avruch WW. Malignant tumors and psoriasis: climatotherapy at the Dead Sea. Br J Dermatol 1999;141:1808-91. 8. Paltiel O, Adler B, Herschko K, Tsukrov B, David M. Are psoriatic patients susceptible to the classic risk factors for actinic keratoses? Arch Dermatol 2004;140:805-10. 9. Israel National Cancer Registry World Wide Web Site. Melanoma. Available from: URL:http://www.health.govi.il/icr. Accessed November 5, 2004. 10. Margolis D, Bilker W, Hennessy S, Vittorio C, Santanna J, Strom BL. The risk of malignancy associated with psoriasis. Arch Dermatol 2001;137:778-83. 11. Brooke RCC, Newbold SA, Telfer NR, Griffiths CEM. Discordance between facial wrinkling and the present of basal cell carcinoma. Arch Dermatol 2001;137:751-4. 12. Murphy GM. Skin cancer in patients with psoriasis—many intertwined risk factors. Br J Dermatol 1999;141:1001-3. 13. Stern RS. Genital tumors among men with psoriasis and ultraviolet A radiation (PUVA) and ultraviolet B radiation. N Engl J Med 1990;332:1093-7. 14. Barbagallo J, Span CT, Tutrone WD, Weinberg JM. Narrowband UVB phototherapy for the treatment of psoriasis: a review and update. Cutis 2001;68:345-7. 15. Stern RS, Lunder EJ. Risk of squamous cell carcinoma and methoxsalen ( psoralen) and UVA radiation (PUVA). Arch Dermatol 1998;134:1582-5. 16. Stern RS, Nichols KT, Vakeva LH. Malignant melanoma in patients treated for psoriasis with methoxalen (psoralen) and ultraviolet A radiation (PUVA): the PUVA follow-up study. N Engl J Med 1997;336:1041-5. 17. Kudish AI, Evseev E, Kushelevsky AP. The analysis of ultraviolet radiation in the Dead Sea basin. Int J Climat 1997;17:1697-704. 18. Kushelevsky AP, Harari M, Kudish AL, Hristakieva E, Ingber A, Shani J. Safety of solar phototherapy at the Dead Sea. J Am Acad Dermatol 1998;38:447-52. 19. Paul CF, Hove VC, McGeown C, Christophers E, Schmidtmann B, Guillaume JC, et al. Risk of malignancies in psoriasis patients treated with cyclosporine: a 5-year cohort study. J Invest Dermatol 2003;120:211-6.