STUDY Are Patients With Susceptible to the Classic Risk Factors for Actinic Keratoses?

Ora Paltiel, MDCM, MSc; Bella Adler, MPH; Klilah Herschko, MD; Boris Tsukrov, MD; Michael David, MD

Background: Anincreasedprevalenceofbenignsolardam- , hair, and eye color and propensity or history of - age (eg, facial wrinkles) but not neoplastic lesions was ob- adjusted for age, ethnicity, and sun exposure. served among patients with psoriasis who were exposed to Dead Sea climatotherapy compared with controls. Results: Actinic keratoses were observed in 200 con- trols (27%) and 51 subjects (11%) (PϽ.001). This in- Objectives: To compare the prevalence of actinic kera- creased prevalence occurred in both sexes, participants tosis in psoriatic patients and controls and to assess whether aged 35 years or older, all ethnic groups, smokers, and known risk factors behave similarly in both groups. nonsmokers. The anatomical distribution of lesions did not substantially differ between subjects and controls. In Design: Multicenter cross-sectional study. multivariate analysis, psoriasis conferred a protective effect (odds ratio, Ͻ1), as did , dark eyes, and a his- Setting: clinics in 4 participating Israeli tory of severe in childhood. However, signifi- hospitals and at a Dead Sea clinic. cant interactions were observed between psoriasis and hair color as well as psoriasis and propensity to sun- Participants: Adult subjects (n=460) with plaque- burn, whereby a linear association was observed for con- type psoriasis were recruited from the Israel Psoriasis As- trols but not for patients with psoriasis. sociation (volunteer sample) and from dermatology clin- ics (convenience sample). The control group (n=738) Conclusions: Psoriasis confers protection against ac- consisted of nonimmunosuppressed patients attending tinic . Hair color and propensity to sunburn these clinics for benign conditions unrelated to sun ex- exert differential effects among psoriatic patients and posure, such as atopic or . controls.

Main Outcome Measures: Prevalence and distribu- tion of actinic keratoses and odds ratios associated with Arch Dermatol. 2004;140:805-810

HERE IS A CONSENSUS AMONG (NMSC) (espe- the scientific community cially SCC) has been reported in that the 3 major types of individuals with psoriasis who are ex- skin cancer—squamous posed to high cumulative doses of psor- (SCC), basal cell alen–UV-A.8-11 In one study, climato- From the School of Public (Dr Paltiel and Ms carcinoma (BCC), and malignant mela- therapy at the Dead Sea among Danish T 1,2 Adler) and the Department noma—are caused by sun exposure. Fur- of Hematology (Dr Paltiel), thermore, inherited characteristics, such as For editorial comment Hadassah-Hebrew University skin type and propensity to sunburn, may Medical Center, Jerusalem, have a marked effect on the risk of skin can- see page 873 Israel; and the Departments cer.3 It is not known whether the presence of Dermatology, of other dermatologic conditions modi- patients was found to be associated with Hadassah-Hebrew University fies the association between sun expo- an increased risk of NMSC.12 The study re- Medical Center (Dr Herschko), sure, skin type, and actinic damage. sults, however, were possibly con- Rabin Medical Center, Petah Psoriasis is a chronic founded by the fact that patients selected Tikva, Israel (Drs Tsukrov and 4 David), and Tel-Aviv that affects approximately 2% of the popu- for Dead Sea climatotherapy were those University, Tel-Aviv, Israel lation, but with considerable ethnic and whose psoriasis was improved by sun ex- 5 (Drs Tsukrov and David). The geographic variation. Manifestations of the posure. Treatment with UV-B may also be authors have no relevant disease are often ameliorated by sun ex- associated with a mild increase (2% per financial interest in this article. posure.6,7 An increased incidence of non- year) of NMSC.13 High-dose –

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 demographic characteristics, sun exposure, propensity to sun- Table 1. Prevalence of Actinic Keratoses Among Patients burn, and previously diagnosed benign and malignant neo- With Psoriasis and Controls by Sociodemographic Factors plasms. A structured physical examination was performed by a qualified dermatologist who noted skin type, hair color, eye No. (%) color, and the presence and location of suspected malignant skin lesions as well as solar keratosis and other signs of pho- Patients With todamage. Controls Psoriasis (n = 738) (n = 460) P Value STATISTICAL ANALYSIS Sex M 79 (27) 28 (11) .001 We compared characteristics of subjects with psoriasis and con- F 121 (28) 23 (12) .001 trols using the ␹2 test for categorical variables and the Mann- Prevalence by age, y Whitney test for comparing medians of continuous variables. 20-34 8 (4) 1 (1) .45 Variables included in the analysis were group (patients with 35-49 33 (18) 8 (5) Ͻ.001 psoriasis or controls); skin type (I-IV reclassified into light or 50-59 76 (39) 15 (12) Ͻ.001 Ն60 83 (56) 27 (30) Ͻ.001 dark); eye color (black/brown or blue/green); hair color (black, Ethnic origin brown, or blonde/red); propensity to sunburn (often/always, Asia-Africa 30 (29) 7 (15) .07 sometimes, or never), and history of severe sunburn in child- Europe/America 63 (40) 14 (10) Ͻ.001 hood (yes or no). We also constructed a summary variable of Israel 106 (23) 28 (11) Ͻ.001 “fairness,” which took into account eye color, hair color, and Smoking complexion. We constructed logistic regression models for the Yes 38 (19) 10 (6) Ͻ.001 presence of solar keratosis on examination, controlling for age No 161 (30) 41 (14) Ͻ.001 (continuous variable), country of origin (Israel, Asia, North Africa, or other), yearly hours of sun exposure (recreational and occupational categorized into quartiles), and smoking his- tory (current smoker: yes or no). To these models we added UV-A therapy (1000 J/cm2) has also been reported to be psoriasis/control status and individual measures of sun sensi- associated with an increased risk of .14 tivity, such as skin color, hair color, eye color, and propensity A cross-sectional study was previously performed to sunburn. The models were slightly modified in terms of the in Israel that compared actinic damage among patients covariates entered according to goodness-of-fit criteria (Hosmer- with psoriasis (87% of whom had undergone climato- Lemeshow test). therapy at the Dead Sea Solarium Clinic, Ein Bokek, Is- We then tested whether there were significant interac- tions between psoriasis/control status and these variables. We rael) and controls (individuals without psoriasis) (M.D., also tested whether solar elastosis and solar keratosis ap- B. T., B. A., et al, unpublished data, 2000). In that study, peared together in the same anatomical locations and mea- the control subjects had higher self-reported rates of pre- sured agreement using the ␬ statistic. All analyses were per- vious skin , removal of benign growth, or pre- formed using SPSS software (Version 10; SPSS Inc, Chicago, vious malignant . There was an association be- III). For all tests of significance, a 2-sided P value of .05 was tween extent of exposure to the Dead Sea and benign considered statistically significant. photodamage, such as facial wrinkles, elastosis, solar len- tigo, and poikiloderma. However, solar keratosis was more RESULTS prevalent among controls than among patients with pso- riasis and showed no association with days of exposure at the Dead Sea. This surprising finding prompted a de- UNIVARIATE ANALYSIS tailed analysis of factors associated with the presence of solar keratoses, with a comparison of persons with and The study population consisted of 460 subjects with pso- without psoriasis. riasis and 738 controls (N=1198). Patients with psoria- sis were more likely to be current smokers (34% vs 27%), male (57% vs 40%), and of European origin (31% vs 22%) METHODS than the controls. Of the patients with psoriasis, 49 (12%) had received psoralen–UV-A therapy and 109 (26%) had STUDY POPULATION been treated with UV-B. Very few malignant neoplasms Subjects were patients with plaque-type psoriasis aged 20 to were noted on examination. Six cases of BCC and 3 of 70 years with a disease duration of at least 7 years. They were SCC were suspected among the patients with psoriasis, recruited from among members of the Israel Psoriasis Associa- whereas among the controls the corresponding num- tion at a Dead Sea psoriasis clinic or attended dermatology clin- bers were 11 and 3. Only 5 cases (2 SCCs [1 each among ics at 1 of the 4 participating hospitals. Controls were patients patients with psoriasis and controls] and 3 BCCs [1 among aged 20 to 70 years who were attending dermatology clinics patients with psoriasis and 2 among controls]) were con- for benign skin conditions, eg, contact dermatitis and atopic firmed histologically. Solar keratoses were present among dermatitis. Patients with , , auto- 200 controls (27%) and 51 patients with psoriasis (11%) immunity, or suspected as the reason for the clinic (P=.001). In both psoriatic patients and controls, the visit were excluded as controls. We also excluded controls with skin types V or VI. prevalence of solar keratosis increased with age. At all All participants provided signed informed consent, and the ages, in both sexes, and in all ethnic groups, the preva- study protocol was approved by the institutional review boards lence of solar keratosis was higher among controls than of all participating hospitals. A questionnaire was adminis- among psoriatic patients (Table 1). Among the con- tered to subjects and controls and included items concerning trols, European-American origin was more common in

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 those with solar keratoses, but this pattern was not seen among the psoriatic patients. Table 2. Distribution of Actinic Keratoses Among those with solar keratosis, the number of le- Among Patients With Psoriasis and Controls sions per subject varied from 1 to 105, with 26% of pso- riatic patients and 38% of controls having 6 or more le- No. (%) sions. Table 2 shows the comparison of the distribution Patients of actinic keratosis in patients with psoriasis and con- Controls With Psoriasis All Subjects trols. In both groups, lesions were most commonly seen (n = 738) (n = 460) (N = 1198) in the head, neck, and face areas. Solar keratoses and so- Subjects with any 200 (27) 51 (11) 251 (21) lar elastosis were found simultaneously in the face re- actinic keratoses* ␬ Ͻ No. of lesions† gion in 92 cases ( =0.34; P 001, indicating fair 1 43 (22) 15 (29) 58 (23) agreement). 2-3 45 (23) 14 (28) 59 (24) Table 3 shows the associations between sun sen- 4-5 37 (19) 9 (18) 46 (18) sitivity and the presence of any solar keratosis in psori- Ն6 75 (38) 13 (26) 88 (35) atic patients and controls. Of note, blue or green eye color Distribution‡ was associated with a higher frequency of solar kerato- Head, neck, face 165 (82) 36 (71) 201 (80) Arms 101 (50) 17 (33) 118 (47) sis in both psoriatic patients and controls. was Hands 87 (44) 17 (33) 104 (41) associated with this lesion in controls but not in psori- Chest, back, trunk 69 (34) 8 (16) 77 (31) atic patients. With regard to hair color, no association Legs 37 (19) 6 (12) 43 (17) was noted among the psoriatic patients, whereas this char- acteristic was highly associated with the presence of kera- *PϽ.001. tosis amongthe controls. The composite variable fair- †Proportion of population with any lesion P = .36. ‡Number of individuals with any lesion in these areas. ness, which combined hair, skin, and eye color into a single profile, was associated with the presence of solar kera- tosis in both psoriatic patients and controls. Finally, a monotonic relationship was noted between propensity odds of solar keratosis with lighter hair color and with to sunburn and keratoses among the controls but not increased propensity for sunburn in the controls, whereas among the psoriatic patients. Similarly, a weak associa- the relationship was flat among the patients with pso- tion between a history of severe sunburn in childhood riasis. and solar keratosis was noted in the psoriatic patients, whereas the association was strong in the controls. COMMENT We assessed the prevalence of solar keratosis ac- cording to quartiles of sun exposure, and no association Traditional and well-established risk factors for NMSC was noted among the psoriatic patients, whereas this le- and photodamage have included skin and hair charac- sion was associated with degree of sun exposure in the teristics as well as occupational and recreational sun ex- controls. Of note, the association was nonmonotonic, with posure.1 These factors,2,15,16 as well as a history of severe a positive relationship noted across the first, second, and sunburn before the age of 20 years,17 are also important third quartiles and a decrease observed for the fourth in determining susceptibility to actinic keratoses. To our (heaviest exposure) quartile. knowledge, there has not been a systematic comparison of the relative effects of these risk factors in psoriatic and MULTIVARIATE ANALYSIS nonpsoriatic patients. Solar or actinic keratoses are generally considered The logistic regression analyses are shown in Table 4. to be premalignant lesions,15,16,18 but some authors19,20 con- In this multivariate analysis, we show the association be- sider them to be established SCCs. In the present cross- tween solar keratosis, patient characteristics (eg, skin color sectional study, their prevalence was lower among pso- and eye color), group (patients with psoriasis or con- riatic than nonpsoriatic patients attending dermatology trols), and the interactions between them. The reported clinics for problems unrelated to photodamage. Some of odds ratio are adjusted for covariates such as ethnic ori- these differences may be explained by differential distri- gin (ie, Asia-Africa, Europe-America, and Israel), sex, age, bution of age, ethnicity, and sun exposure between sub- and degree of sun exposure. Smoking was removed be- jects and controls. However, on multivariate analysis, even cause it did not contribute to the models. In these analy- after these factors and characteristics related to sun sen- ses, psoriasis exerted a protective effect (odds ratio, Ͻ1) sitivity, such as skin color, eye color and hair color, were on the presence of solar keratosis. Furthermore, dark skin, controlled for, the odds of solar keratosis was strikingly dark eyes, and black hair were also protective against the lower for the patients with psoriasis than for the con- presence of solar keratosis. Significant interactions were trols. Furthermore, in some instances (eg, hair color and noted between black vs blonde hair color and psoriasis propensity to sunburn), the classic risk factors ap- when the presence of solar keratosis was analyzed, and peared to have a differential effect in psoriatic patients between propensity to sunburn and psoriasis, meaning compared with nonpsoriatic patients. This analysis pro- that the relationship between these patient characteris- vides preliminary data that demonstrate a modifying effect tics and solar keratosis have differential effects in psori- of psoriasis on the classic factors that have been shown atic patients and in nonpsoriatic patients (Figure 1 and to affect susceptibility to neoplastic or preneoplastic pho- Figure 2). This analysis shows a clear increase in the todamage.

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Table 3. Prevalence of Any Solar Keratosis Among Patients With Psoriasis and Controls by Personal Characteristics and Sun Exposure

Controls, No. (%) P Value Patients With Psoriasis, No. (%) P Value Eye color Black/brown 106 (21) 18 (6) Ͻ.001 .001 Blue/green 92 (40) 32 (18) Skin color Light 121 (35) 24 (16) Ͻ.001 .06 Dark 76 (20) 26 (9) Hair color Black 34 (11) 12 (8) Brown 127 (36)Ͻ.001 30 (12) .24 Blonde 37 (51) 8 (15) “Fairness” Fair 28 (48) 5 (13) Somewhat 102 (34)Ͻ.001 22 (17) .03 Dark 68 (18) 23 (8) Propensity to sunburn Often/always 87 (41) 17 (13) Sometimes 87 (28)Ͻ.001 24 (10) .66 Never 25 (14) 9 (12) Severe sunburn in childhood Yes 97 (41) 24 (15) Ͻ.001 .06 No 97 (21) 26 (9) Yearly hours of sun exposure Quartile I, 0-39 30 (18) 12 (10) Quartile II, 40-182 48 (30) 8 (7) .003 .27 Quartile II, 183-481 64 (34) 11 (11) Quartile IV, Ն482 48 (26) 15 (16)

The first question that should be asked is whether type (and not hair or eye color) predicted skin cancer risk our findings were the result of chance. Although the in- in psoriatic patients who were treated with psoralen– teractions we observed were statistically significant, we UV-A, providing additional evidence for a possible dif- did not perform the study with this hypothesis in mind. ferential or inconsistent effect of the classic risk factors Selection bias may have played a role, as neither the pso- for NMSC among patients with psoriasis. riatic group nor the control group was population based. Apart from malignant changes ascribed to the treat- However, given the high degree of sun exposure among ment of psoriasis, little is known about actinic damage the patients with psoriasis, it would have been expected in this disease. Two studies performed in the 1980s sug- that they would be at greater risk for the development gested that persons with psoriasis have a similar risk of of skin neoplasms and preneoplastic conditions than a developing SCC compared with several other popula- population of patients with and other dermato- tions of patients.23,24 In a Danish cohort, the risk of NMSC logic complaints. Since NMSC is not reported to the Is- among patients with psoriasis was 2.5 times that of the rael Cancer Registry, we have no population-based esti- general population.25 A more recent cohort study26 re- mate of actinic keratoses or NMSC in Israel; therefore, it ported a 2- to 4-fold risk of NMSC developing among per- is difficult for us to measure the degree of bias in the se- sons with psoriasis compared with hypertensive con- lection of the study population. Our analysis took into trols, with the risk varying with the severity of psoriasis. account confounders such as country of origin, age, sex, It is difficult to separate the risks associated with anti- and smoking. Indeed, the results were weakened when psoriatic treatment from those inherently associated with we adjusted for these factors, but some of the interac- the disease. Certain skin diseases, such as atopic derma- tions remained. Unmeasured confounders may have titis and urticaria, are substantially rarer among psori- played a role in these results. atic patients than among controls.27 In 1977, Kocsard28 Therefore, while these findings may be spurious, the reported that actinic keratoses are rare in patients with observation that actinic keratosis is more prevalent among psoriasis compared with controls. His study, which was nonpsoriatic patients is consistent in all subgroups, and carried out among Australian military personnel, found there is a suggestion that hair color and propensity to sun- relatively few cases of actinic keratosis, even among fair- burn played a differential role in contributing to solar kera- skinned and blue-eyed persons with psoriasis, whereas tosis in the 2 groups. Is there biological plausibility for 88% of the persons without psoriasis who were exam- this finding? A survey of psoriatic patients21 showed that ined had evidence of these lesions. skin type (based on ability to tan and susceptibility to The prevalence of psoriasis appears to vary by coun- sunburn) showed higher correlations with minimal ery- try and skin type,29 with a higher frequency noted in Eu- thema dose after UV irradiation than did hair or eye color. ropean populations compared with African or Asian popu- Interestingly, in 1984, Stern and Momtaz22 found that skin lations and with specific HLA types.4 Furthermore, while

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Table 4. Logistic Regression Analysis of the Relationship 8 Between Solar Keratosis, Personal Characteristics, Psoriatic Patients Controls Psoriasis, and Interactions 6

OR (95% CI) P Value 4 Skin color*

Light 2.60 (1.74-3.88) Ͻ.001 Odds Ratio Dark† 2 Group Psoriasis 0.31 (0.18-0.54) Ͻ.001 Control† 0 Interaction Black Brown Blond/Red Skin color ϫ psoriasis 0.63 (0.29-1.40) .25 (Hosmer-Lemeshow test = 0.80) Figure 1. Adjusted odds ratios for solar keratosis by hair color comparing psoriatic patients and controls. Eye color‡ Black/brown 1.90 (1.3-2.8) .001 Blue/green† 5 Group Psoriatic Patients Psoriasis 0.20 (0.12-0.35) Ͻ.001 Controls Control† 4 Interaction Eye color ϫ psoriasis 1.28 (0.6-2.71) .52 3 (Hosmer-Lemeshow test = 0.58) 2 Hair color* Odds Ratio Black 3.74 (2.27-6.15) Ͻ.001 Brown 7.70 (3.89-15.26) Ͻ.001 1 Blond† Group 0 Psoriasis 0.38 (0.17-0.87) .02 Never Sometimes Often/Always Control† Interaction Figure 2. Adjusted odds ratios for solar keratosis by propensity to sunburn comparing psoriatic patients and controls. Blonde ϫ psoriasis 0.23 (0.06-0.88) .03 Brown ϫ psoriasis 0.54 (0.21-1.38) .16 (Hosmer-Lemeshow test = 0.35) herent (as opposed to treatment-related) risk of malig- Severe sunburn in childhood§ nant and premalignant skin disorders in persons with pso- Yes 2.24 (1.52-3.31) Ͻ.001 riasis. No† On a genetic level, the GSTM1 null phenotype32 has Group Psoriasis 0.28 (0.17-0.46) Ͻ.001 been shown to be a risk factor for solar keratosis in a white Control† population, after skin type and ability to tan were con- Interaction trolled for. On the other hand, a recent study33 has shown Sunburn ϫ psoriasis 0.85 (0.40-1.81) .67 that GSTM1 variant alleles are associated with psoriasis. (Hosmer-Lemeshow test = 0.76) Thus, alleles associated with an increased incidence of Propensity to sunburn* psoriasis may be associated with a decreased risk of ac- Often/always 4.80 (2.60-8.90) .02 tinic skin damage. Sometimes 2.02 (1.12-3.70) Furthermore, recent studies have shown that pso- Never† riatic patients with skin cancer (BCC) have evidence of Group Psoriasis 0.48 (0.19-1.22) .12 increased DNA damage and defective DNA repair com- 34,35 Control† pared with those without BCC. Interestingly, Dyb- Interaction dahl et al35 reported that psoriatic patients without BCC Propensity ϫ psoriasis 0.25 (0.08-0.77) .02 had marginally higher repair than controls (although the Propensity ϫ psoriasis 0.56 (0.19-1.64) .29 results were not statistically significant), suggesting that (Hosmer-Lemeshow test = 0.77) skin cancers occur in a subgroup of psoriatic patients, while others may be protected. It is conceivable that in Abbreviations: CI, confidence interval; OR, odds ratio. *Adjusted for ethnic origin, sex, age, and degree of sun exposure. some patients with psoriasis, hyperproliferation of ke- †Reference group. ratinocytes may protect against the effects of sun dam- ‡Adjusted for ethnic origin, sex, and age. age when DNA repair mechanisms are intact, explain- §Adjusted for sex, age, and degree of sun exposure. ing the interactions we found in our study. Indeed, the occurrence of SCC within psoriatic plaques is exceed- actinic keratoses are thought to be a “dose meter of chronic ingly rare.36 Our findings may serve as a foundation for sun damage,”16 this does not seem to be the case in all future studies specifically designed to answer these ques- populations.30 To our knowledge, there is only 1 case re- tions. Notwithstanding the results of our study, it should port of multiple actinic keratoses that developed in sun- be stressed that cutaneous neoplasia occurs in patients protected areas in a psoriatic patient who received a dose with psoriasis and that efforts to prevent skin cancer in of 883 J/cm2 of UV-A,31 but little is known about the in- this population are still required.

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Accepted for publication December 29, 2003. squamous cell to solar keratoses. Arch Dermatol. 1988;124:1039- This study was supported in part by the Dead Sea Medi- 1042. 16. Salasche SJ. Epidemiology of actinic keratoses and . cal Research and Development Center, Dead Sea, Israel. J Am Acad Dermatol. 2000;42:4-7. Participating hospitals were Rabin Medical Center, Pe- 17. Kennedy C, Bajdik CD, Willemze R, De Gruijl FR, Bouwes Bavinck JN; Leiden Skin tah Tikva; Hadassah-Hebrew University Hospital, Ein- Cancer Study. The influence of painful and lifetime sun exposure on Karem, Jerusalem; Ha’emek Medical Center, Afula; Sheba- the risk of actinic keratoses, seborrheic , melanocytic nevi, atypical nevi, Tel-Hashomer Medical Center, Tel-Aviv; all in Israel. and skin cancer. J Invest Dermatol. 2003;120:1087-1093. 18. Kocsard E. Solar keratoses and their relationship to non-melanoma skin can- Correspondence: Ora Paltiel, MDCM, MSc, School of cers. Australas J Dermatol. 1997;38(suppl 1):S30. Public Health, Hadassah-Hebrew University, POB 12000, 19. Ackerman BA. Opposing views of 2 academies about the nature of solar kerato- Jerusalem, Israel 91120 ([email protected]). sis. Cutis. 2003;71:391-395. 20. Fu W, Cockerell CJ. The actinic (solar) keratosis: a 21st-century perspective. Arch Dermatol. 2003;139:66-70. REFERENCES 21. Weinstock MA. Assessment of sun sensitivity by questionnaire: validity of items and formulation of a prediction rule. J Clin Epidemiol. 1992;45:547-552. 1. Armstrong BK, Kricker A. The epidemiology of UV-induced skin cancer. J Pho- 22. Stern RS, Momtaz K. Skin typing for assessment of skin cancer risk and acute tochem Photobiol B. 2001;63:8-18. response to UV-B and oral methoxsalen photochemotherapy. Arch Dermatol. 1984; 2. Vitasa BC, Taylor HR, Strickland PT, et al. 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