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

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1 STUDY Are Patients With Psoriasis 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: Anincreasedprevalenceofbenignsolardamage (eg, facial wrinkles) but not neoplastic lesions was observed among patients with psoriasis who were exposed to Dead Sea climatotherapy compared with controls. Objectives: To compare the prevalence of actinic keratosis in psoriatic patients and controls and to assess whether known risk factors behave similarly in both groups. Design: Multicenter cross-sectional study. Setting: Dermatology clinics in 4 participating Israeli hospitals and at a Dead Sea clinic. Participants: Adult subjects (n=460) with plaquetype psoriasis were recruited from the Israel Psoriasis Association (volunteer sample) and from dermatology clinics (convenience sample). The control group (n=738) consisted of nonimmunosuppressed patients attending these clinics for benign conditions unrelated to sun exposure, such as atopic or contact dermatitis. Main Outcome Measures: Prevalence and distribution of actinic keratoses and odds ratios associated with skin, hair, and eye color and propensity or history of sunburn adjusted for age, ethnicity, and sun exposure. Results: Actinic keratoses were observed in 200 controls (27%) and 51 subjects (11%) (P.001). This increased prevalence occurred in both sexes, participants aged 35 years or older, all ethnic groups, smokers, and nonsmokers. The anatomical distribution of lesions did not substantially differ between subjects and controls. In multivariate analysis, psoriasis conferred a protective effect (odds ratio, 1), as did dark skin, dark eyes, and a history of severe sunburn in childhood. However, significant interactions were observed between psoriasis and hair color as well as psoriasis and propensity to sunburn, whereby a linear association was observed for controls but not for patients with psoriasis. Conclusions: Psoriasis confers protection against actinic keratosis. Hair color and propensity to sunburn exert differential effects among psoriatic patients and controls. Arch Dermatol. 2004;140: From the School of Public Health (Dr Paltiel and Ms Adler) and the Department of Hematology (Dr Paltiel), Hadassah-Hebrew University Medical Center, Jerusalem, Israel; and the Departments of Dermatology, Hadassah-Hebrew University Medical Center (Dr Herschko), Rabin Medical Center, Petah Tikva, Israel (Drs Tsukrov and David), and Tel-Aviv University, Tel-Aviv, Israel (Drs Tsukrov and David). The authors have no relevant financial interest in this article. THERE IS A CONSENSUS AMONG the scientific community that the 3 major types of skin cancer squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and malignant melanoma are caused by sun exposure. 1,2 Furthermore, inherited characteristics, such as skin type and propensity to sunburn, may have a marked effect on the risk of skin cancer. 3 It is not known whether the presence of other dermatologic conditions modifies the association between sun exposure, skin type, and actinic damage. Psoriasis is a chronic skin condition that affects approximately 2% 4 of the population, but with considerable ethnic and geographic variation. 5 Manifestations of the disease are often ameliorated by sun exposure. 6,7 An increased incidence of nonmelanoma skin cancer (NMSC) (especially SCC) has been reported in individuals with psoriasis who are exposed to high cumulative doses of psoralen UV-A In one study, climatotherapy at the Dead Sea among Danish For editorial comment see page 873 patients was found to be associated with an increased risk of NMSC. 12 The study results, however, were possibly confounded by the fact that patients selected for Dead Sea climatotherapy were those whose psoriasis was improved by sun exposure. Treatment with UV-B may also be associated with a mild increase (2% per year) of NMSC. 13 High-dose psoralen 805

2 Table 1. Prevalence of Actinic Keratoses Among Patients With Psoriasis and by Sociodemographic Factors (n = 738) No. (%) UV-A therapy (1000 J/cm 2 ) has also been reported to be associated with an increased risk of actinic keratosis. 14 A cross-sectional study was previously performed in Israel that compared actinic damage among patients with psoriasis (87% of whom had undergone climatotherapy at the Dead Sea Solarium Clinic, Ein Bokek, Israel) and controls (individuals without psoriasis) (M.D., B. T., B. A., et al, unpublished data, 2000). In that study, the control subjects had higher self-reported rates of previous skin biopsies, removal of benign growth, or previous malignant neoplasms. There was an association between extent of exposure to the Dead Sea and benign photodamage, such as facial wrinkles, elastosis, solar lentigo, and poikiloderma. However, solar keratosis was more prevalent among controls than among patients with psoriasis and showed no association with days of exposure at the Dead Sea. This surprising finding prompted a detailed analysis of factors associated with the presence of solar keratoses, with a comparison of persons with and without psoriasis. METHODS Patients With Psoriasis (n = 460) STUDY POPULATION P Value Sex M 79 (27) 28 (11).001 F 121 (28) 23 (12).001 Prevalence by age, y (4) 1 (1) (18) 8 (5) (39) 15 (12) (56) 27 (30).001 Ethnic origin Asia-Africa 30 (29) 7 (15).07 Europe/America 63 (40) 14 (10).001 Israel 106 (23) 28 (11).001 Smoking Yes 38 (19) 10 (6).001 No 161 (30) 41 (14).001 Subjects were patients with plaque-type psoriasis aged 20 to 70 years with a disease duration of at least 7 years. They were recruited from among members of the Israel Psoriasis Association at a Dead Sea psoriasis clinic or attended dermatology clinics at 1 of the 4 participating hospitals. were patients aged 20 to 70 years who were attending dermatology clinics for benign skin conditions, eg, contact dermatitis and atopic dermatitis. Patients with vitiligo, immunosuppression, autoimmunity, or suspected malignancy as the reason for the clinic visit were excluded as controls. We also excluded controls with skin types V or VI. All participants provided signed informed consent, and the study protocol was approved by the institutional review boards of all participating hospitals. A questionnaire was administered to subjects and controls and included items concerning demographic characteristics, sun exposure, propensity to sunburn, and previously diagnosed benign and malignant neoplasms. A structured physical examination was performed by a qualified dermatologist who noted skin type, hair color, eye color, and the presence and location of suspected malignant skin lesions as well as solar keratosis and other signs of photodamage. STATISTICAL ANALYSIS We compared characteristics of subjects with psoriasis and controls using the 2 test for categorical variables and the Mann- Whitney test for comparing medians of continuous variables. Variables included in the analysis were group (patients with psoriasis or controls); skin type (I-IV reclassified into light or dark); eye color (black/brown or blue/green); hair color (black, brown, or blonde/red); propensity to sunburn (often/always, sometimes, or never), and history of severe sunburn in childhood (yes or no). We also constructed a summary variable of fairness, which took into account eye color, hair color, and complexion. We constructed logistic regression models for the presence of solar keratosis on examination, controlling for age (continuous variable), country of origin (Israel, Asia, North Africa, or other), yearly hours of sun exposure (recreational and occupational categorized into quartiles), and smoking history (current smoker: yes or no). To these models we added psoriasis/control status and individual measures of sun sensitivity, such as skin color, hair color, eye color, and propensity to sunburn. The models were slightly modified in terms of the covariates entered according to goodness-of-fit criteria (Hosmer- Lemeshow test). We then tested whether there were significant interactions between psoriasis/control status and these variables. We also tested whether solar elastosis and solar keratosis appeared together in the same anatomical locations and measured agreement using the statistic. All analyses were performed using SPSS software (Version 10; SPSS Inc, Chicago, III). For all tests of significance, a 2-sided P value of.05 was considered statistically significant. RESULTS UNIVARIATE ANALYSIS The study population consisted of 460 subjects with psoriasis and 738 controls (N=1198). Patients with psoriasis were more likely to be current smokers (34% vs 27%), male (57% vs 40%), and of European origin (31% vs 22%) than the controls. Of the patients with psoriasis, 49 (12%) had received psoralen UV-A therapy and 109 (26%) had been treated with UV-B. Very few malignant neoplasms were noted on examination. Six cases of BCC and 3 of SCC were suspected among the patients with psoriasis, whereas among the controls the corresponding numbers were 11 and 3. Only 5 cases (2 SCCs [1 each among patients with psoriasis and controls] and 3 BCCs [1 among patients with psoriasis and 2 among controls]) were confirmed histologically. Solar keratoses were present among 200 controls (27%) and 51 patients with psoriasis (11%) (P=.001). In both psoriatic patients and controls, the prevalence of solar keratosis increased with age. At all ages, in both sexes, and in all ethnic groups, the prevalence of solar keratosis was higher among controls than among psoriatic patients (Table 1). Among the controls, European-American origin was more common in 806

3 those with solar keratoses, but this pattern was not seen among the psoriatic patients. Among those with solar keratosis, the number of lesions per subject varied from 1 to 105, with 26% of psoriatic patients and 38% of controls having 6 or more lesions. Table 2 shows the comparison of the distribution of actinic keratosis in patients with psoriasis and controls. In both groups, lesions were most commonly seen in the head, neck, and face areas. Solar keratoses and solar elastosis were found simultaneously in the face region in 92 cases ( =0.34; P 001, indicating fair agreement). Table 3 shows the associations between sun sensitivity and the presence of any solar keratosis in psoriatic patients and controls. Of note, blue or green eye color was associated with a higher frequency of solar keratosis in both psoriatic patients and controls. Light skin was associated with this lesion in controls but not in psoriatic patients. With regard to hair color, no association was noted among the psoriatic patients, whereas this characteristic was highly associated with the presence of keratosis amongthe controls. The composite variable fairness, which combined hair, skin, and eye color into a single profile, was associated with the presence of solar keratosis in both psoriatic patients and controls. Finally, a monotonic relationship was noted between propensity to sunburn and keratoses among the controls but not among the psoriatic patients. Similarly, a weak association between a history of severe sunburn in childhood and solar keratosis was noted in the psoriatic patients, whereas the association was strong in the controls. We assessed the prevalence of solar keratosis according to quartiles of sun exposure, and no association was noted among the psoriatic patients, whereas this lesion was associated with degree of sun exposure in the controls. Of note, the association was nonmonotonic, with a positive relationship noted across the first, second, and third quartiles and a decrease observed for the fourth (heaviest exposure) quartile. MULTIVARIATE ANALYSIS The logistic regression analyses are shown in Table 4. In this multivariate analysis, we show the association between solar keratosis, patient characteristics (eg, skin color and eye color), group (patients with psoriasis or controls), and the interactions between them. The reported odds ratio are adjusted for covariates such as ethnic origin (ie, Asia-Africa, Europe-America, and Israel), sex, age, and degree of sun exposure. Smoking was removed because it did not contribute to the models. In these analyses, psoriasis exerted a protective effect (odds ratio, 1) on the presence of solar keratosis. Furthermore, dark skin, dark eyes, and black hair were also protective against the presence of solar keratosis. Significant interactions were noted between black vs blonde hair color and psoriasis when the presence of solar keratosis was analyzed, and between propensity to sunburn and psoriasis, meaning that the relationship between these patient characteristics and solar keratosis have differential effects in psoriatic patients and in nonpsoriatic patients (Figure 1 and Figure 2). This analysis shows a clear increase in the Table 2. Distribution of Actinic Keratoses Among Patients With Psoriasis and (n = 738) odds of solar keratosis with lighter hair color and with increased propensity for sunburn in the controls, whereas the relationship was flat among the patients with psoriasis. COMMENT No. (%) Patients With Psoriasis (n = 460) All Subjects (N = 1198) Subjects with any 200 (27) 51 (11) 251 (21) actinic keratoses* No. of lesions 1 43 (22) 15 (29) 58 (23) (23) 14 (28) 59 (24) (19) 9 (18) 46 (18) 6 75 (38) 13 (26) 88 (35) Distribution Head, neck, face 165 (82) 36 (71) 201 (80) Arms 101 (50) 17 (33) 118 (47) Hands 87 (44) 17 (33) 104 (41) Chest, back, trunk 69 (34) 8 (16) 77 (31) Legs 37 (19) 6 (12) 43 (17) *P.001. Proportion of population with any lesion P =.36. Number of individuals with any lesion in these areas. Traditional and well-established risk factors for NMSC and photodamage have included skin and hair characteristics as well as occupational and recreational sun exposure. 1 These factors, 2,15,16 as well as a history of severe sunburn before the age of 20 years, 17 are also important in determining susceptibility to actinic keratoses. To our knowledge, there has not been a systematic comparison of the relative effects of these risk factors in psoriatic and nonpsoriatic patients. Solar or actinic keratoses are generally considered to be premalignant lesions, 15,16,18 but some authors 19,20 consider them to be established SCCs. In the present crosssectional study, their prevalence was lower among psoriatic than nonpsoriatic patients attending dermatology clinics for problems unrelated to photodamage. Some of these differences may be explained by differential distribution of age, ethnicity, and sun exposure between subjects and controls. However, on multivariate analysis, even after these factors and characteristics related to sun sensitivity, such as skin color, eye color and hair color, were controlled for, the odds of solar keratosis was strikingly lower for the patients with psoriasis than for the controls. Furthermore, in some instances (eg, hair color and propensity to sunburn), the classic risk factors appeared to have a differential effect in psoriatic patients compared with nonpsoriatic patients. This analysis provides preliminary data that demonstrate a modifying effect of psoriasis on the classic factors that have been shown to affect susceptibility to neoplastic or preneoplastic photodamage. 807

4 Table 3. Prevalence of Any Solar Keratosis Among Patients With Psoriasis and by Personal Characteristics and Sun Exposure, No. (%) P Value Patients With Psoriasis, No. (%) P Value Eye color Black/brown 106 (21) 18 (6).001 Blue/green 92 (40) 32 (18).001 Skin color Light 121 (35) 24 (16).001 Dark 76 (20) 26 (9).06 Hair color Black 34 (11) 12 (8) Brown 127 (36) (12).24 Blonde 37 (51) 8 (15) Fairness Fair 28 (48) 5 (13) Somewhat 102 (34) (17).03 Dark 68 (18) 23 (8) Propensity to sunburn Often/always 87 (41) 17 (13) Sometimes 87 (28) (10).66 Never 25 (14) 9 (12) Severe sunburn in childhood Yes 97 (41) 24 (15).001 No 97 (21) 26 (9).06 Yearly hours of sun exposure Quartile I, (18) 12 (10) Quartile II, (30) 8 (7).003 Quartile II, (34) 11 (11).27 Quartile IV, (26) 15 (16) The first question that should be asked is whether our findings were the result of chance. Although the interactions we observed were statistically significant, we did not perform the study with this hypothesis in mind. Selection bias may have played a role, as neither the psoriatic group nor the control group was population based. However, given the high degree of sun exposure among the patients with psoriasis, it would have been expected that they would be at greater risk for the development of skin neoplasms and preneoplastic conditions than a population of patients with rashes and other dermatologic complaints. Since NMSC is not reported to the Israel Cancer Registry, we have no population-based estimate of actinic keratoses or NMSC in Israel; therefore, it is difficult for us to measure the degree of bias in the selection of the study population. Our analysis took into account confounders such as country of origin, age, sex, and smoking. Indeed, the results were weakened when we adjusted for these factors, but some of the interactions remained. Unmeasured confounders may have played a role in these results. Therefore, while these findings may be spurious, the observation that actinic keratosis is more prevalent among nonpsoriatic patients is consistent in all subgroups, and there is a suggestion that hair color and propensity to sunburn played a differential role in contributing to solar keratosis in the 2 groups. Is there biological plausibility for this finding? A survey of psoriatic patients 21 showed that skin type (based on ability to tan and susceptibility to sunburn) showed higher correlations with minimal erythema dose after UV irradiation than did hair or eye color. Interestingly, in 1984, Stern and Momtaz 22 found that skin type (and not hair or eye color) predicted skin cancer risk in psoriatic patients who were treated with psoralen UV-A, providing additional evidence for a possible differential or inconsistent effect of the classic risk factors for NMSC among patients with psoriasis. Apart from malignant changes ascribed to the treatment of psoriasis, little is known about actinic damage in this disease. Two studies performed in the 1980s suggested that persons with psoriasis have a similar risk of developing SCC compared with several other populations of patients. 23,24 In a Danish cohort, the risk of NMSC among patients with psoriasis was 2.5 times that of the general population. 25 A more recent cohort study 26 reported a 2- to 4-fold risk of NMSC developing among persons with psoriasis compared with hypertensive controls, with the risk varying with the severity of psoriasis. It is difficult to separate the risks associated with antipsoriatic treatment from those inherently associated with the disease. Certain skin diseases, such as atopic dermatitis and urticaria, are substantially rarer among psoriatic patients than among controls. 27 In 1977, Kocsard 28 reported that actinic keratoses are rare in patients with psoriasis compared with controls. His study, which was carried out among Australian military personnel, found relatively few cases of actinic keratosis, even among fairskinned and blue-eyed persons with psoriasis, whereas 88% of the persons without psoriasis who were examined had evidence of these lesions. The prevalence of psoriasis appears to vary by country and skin type, 29 with a higher frequency noted in European populations compared with African or Asian populations and with specific HLA types. 4 Furthermore, while 808

5 Table 4. Logistic Regression Analysis of the Relationship Between Solar Keratosis, Personal Characteristics, Psoriasis, and s 8 6 Psoriatic Patients OR (95% CI) P Value Skin color* Light 2.60 ( ).001 Dark Psoriasis 0.31 ( ).001 Skin color psoriasis 0.63 ( ).25 (Hosmer-Lemeshow test = 0.80) Eye color Black/brown 1.90 ( ).001 Blue/green Psoriasis 0.20 ( ).001 Eye color psoriasis 1.28 ( ).52 (Hosmer-Lemeshow test = 0.58) Hair color* Black 3.74 ( ).001 Brown 7.70 ( ).001 Blond Psoriasis 0.38 ( ).02 Blonde psoriasis 0.23 ( ).03 Brown psoriasis 0.54 ( ).16 (Hosmer-Lemeshow test = 0.35) Severe sunburn in childhood Yes 2.24 ( ).001 No Psoriasis 0.28 ( ).001 Sunburn psoriasis 0.85 ( ).67 (Hosmer-Lemeshow test = 0.76) Propensity to sunburn* Often/always 4.80 ( ).02 Sometimes 2.02 ( ) Never Psoriasis 0.48 ( ).12 Propensity psoriasis 0.25 ( ).02 Propensity psoriasis 0.56 ( ).29 (Hosmer-Lemeshow test = 0.77) Abbreviations: CI, confidence interval; OR, odds ratio. *Adjusted for ethnic origin, sex, age, and degree of sun exposure. Reference group. Adjusted for ethnic origin, sex, and age. Adjusted for sex, age, and degree of sun exposure. Odds Ratio Black Brown Blond/Red Figure 1. Adjusted odds ratios for solar keratosis by hair color comparing psoriatic patients and controls. Odds Ratio Psoriatic Patients Never Sometimes Often/Always Figure 2. Adjusted odds ratios for solar keratosis by propensity to sunburn comparing psoriatic patients and controls. actinic keratoses are thought to be a dose meter of chronic sun damage, 16 this does not seem to be the case in all populations. 30 To our knowledge, there is only 1 case report of multiple actinic keratoses that developed in sunprotected areas in a psoriatic patient who received a dose of 883 J/cm 2 of UV-A, 31 but little is known about the inherent (as opposed to treatment-related) risk of malignant and premalignant skin disorders in persons with psoriasis. On a genetic level, the GSTM1 null phenotype 32 has been shown to be a risk factor for solar keratosis in a white population, after skin type and ability to tan were controlled for. On the other hand, a recent study 33 has shown that GSTM1 variant alleles are associated with psoriasis. Thus, alleles associated with an increased incidence of psoriasis may be associated with a decreased risk of actinic skin damage. Furthermore, recent studies have shown that psoriatic patients with skin cancer (BCC) have evidence of increased DNA damage and defective DNA repair compared with those without BCC. 34,35 Interestingly, Dybdahl et al 35 reported that psoriatic patients without BCC had marginally higher repair than controls (although the results were not statistically significant), suggesting that skin cancers occur in a subgroup of psoriatic patients, while others may be protected. It is conceivable that in some patients with psoriasis, hyperproliferation of keratinocytes may protect against the effects of sun damage when DNA repair mechanisms are intact, explaining the interactions we found in our study. Indeed, the occurrence of SCC within psoriatic plaques is exceedingly rare. 36 Our findings may serve as a foundation for future studies specifically designed to answer these questions. Notwithstanding the results of our study, it should be stressed that cutaneous neoplasia occurs in patients with psoriasis and that efforts to prevent skin cancer in this population are still required. 809

6 Accepted for publication December 29, This study was supported in part by the Dead Sea Medical Research and Development Center, Dead Sea, Israel. Participating hospitals were Rabin Medical Center, Petah Tikva; Hadassah-Hebrew University Hospital, Ein- Karem, Jerusalem; Ha emek Medical Center, Afula; Sheba- Tel-Hashomer Medical Center, Tel-Aviv; all in Israel. Correspondence: Ora Paltiel, MDCM, MSc, School of Public Health, Hadassah-Hebrew University, POB 12000, Jerusalem, Israel REFERENCES 1. Armstrong BK, Kricker A. The epidemiology of UV-induced skin cancer. J Photochem Photobiol B. 2001;63: Vitasa BC, Taylor HR, Strickland PT, et al. Association of nonmelanoma skin cancer and actinic keratosis with cumulative solar ultraviolet exposure in Maryland watermen. Cancer. 1990;65: Hogan DJ, To T, Gran L, Wong D, Lane PR. Risk factors for basal cell carcinoma. Int J Dermatol. 1989;28: Christophers E. Psoriasis: epidemiology and clinical spectrum. 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