Actinic prurigo: a case-control study of risk factors

Report

Actinic prurigo: a case–control study of risk factors

Diana Sugey Vera Izaguirre1, MD, Soraya Zuloaga Salcedo2, MD,Pablo C�esar Gonz�alez S�anchez3, MD, Karla S�anchez Lara4, MD, Norberto Ch�avez Tapia4, MD,Maria Teresa Hojyo Tomoka1, MD, Luciano Dom�ınguez Soto1, MD, Juan Carlos CuevasGonz�alez1,5, DDS, Erika Rodr�ıguez Lobato1, MD, and Maria Elisa Vega Memije1, MD

1Department of Dermatology, Dr Manuel

Gea Gonz�alez General Hospital, Mexico

City, Mexico, 2Department of Dermatology,

M�edica Tec 100 Hospital, Quer�etaro,

Mexico, 3Private Dermatology Practice, City

La piedad Michoacan, Mexico, 4M�edica Sur

Hospital, Mexico City, Mexico, and 5Student

of the master and doctorate program in

medical, dental and health sciences

(PMDCMOS), National Autonomous

University of Mexico, Mexico City, Mexico

Correspondence

M. Elisa Vega Memije, MD

Department of Dermatology

Hospital General Dr Manuel Gea Gonz�alez

Calzada de Tlalpan 4800

Secci�on XVI Delegaci�on Tlalpan, DF CP

14080

Mexico

E-mail: [email protected]

Funding: None.

Conflicts of interest: None.

Abstract

Background Actinic prurigo (AP) is an idiopathic photodermatosis that usually onsets

during childhood and predominates in women. It is characterized by the symmetrical

involvement of sun-exposed areas of the skin, lips, and conjunctiva.

Objectives This study aimed to analyze the risk factors associated with AP using a case–

control design.

Methods All patients diagnosed with AP during 1990–2006 at Dr. Manuel Gea Gonz�alez

General Hospital in Mexico City were included. Respective controls were recruited. Race,

demographic, geographic, socioeconomic, environmental, clinical, and nutritional risk

factors were assessed.

Results A total of 132 persons were enrolled. These included 44 cases and two control

groups comprising, respectively, dermatology and non-dermatology outpatients without AP

or any autoimmune disease. Distribution by gender, age, place of birth, place of residence,

and economic status did not differ significantly among the three groups. A total of 256

variables were analyzed. Only 19 variables were found to be statistically significant

(P < 0.05). These were: use of a boiler; use of firewood; car ownership; use of

earthenware; mixed material housing; socioeconomic level 1; sun exposure; use of soap;

lemon consumption; use of moisturizing hair cream; living with pets in the house; living with

farm animals; age; having a family member with AP; having had surgery; having had

trauma; having been hospitalized; use of oral medication; and use of herbal medication. Of

40 macro- and micronutrients analyzed, 11 were found to have statistically significant

effects (P < 0.05).

Conclusions Multiple epidemiologic, geographic, clinical, and immunologic factors are

involved in the etiology of AP. This study proposes a clear line for research directed at

specific risk factors that refer to an individual’s clinical, allergic, health, and socioeconomic

status. Further study should also investigate the etiologic role of diet in AP and the

molecular mechanisms behind the development of AP to establish whether AP is caused

by exposure to polycyclic aromatic hydrocarbons.

Introduction

Actinic prurigo (AP) is an idiopathic family photoderma-tosis that particularly tends to affect mixed-race popula-tions with skin types IV and V in countries in theAmericas.1–6 It has been related to genetic susceptibility.In a Mexican population, Hojyo et al.2 reported findingsof a strong link to the human leukocyte antigen (HLA),particularly to allele HLA-DR4, which varies within pop-ulations. In Mexico, 90.0–92.8% of patients with APhave this allele, the most common subtype of which isHLA-DRB1*0407, which occurs as frequently as in60–80% of the population.

Actinic prurigo usually onsets during childhood, ataround 6–8 years of age, and predominates in women (atratios that vary from 2 : 1 to 4 : 1). It runs a chroniccourse and tends to exacerbate after sun exposure. Actinicprurigo is characterized by the symmetrical involvementof sun-exposed areas of the skin, lips, and conjunctiva.Pruritus is always present; it is usually severe and, insome cases, almost unbearable. The skin lesions are poly-morphic and include maculae, papules that may merge toform plaques, crusts, hyperpigmentation, and lichenifica-tion.1,7,8

Lip involvement has been reported in 84% of patients;the affected vermilion may show swelling, scaling,

International Journal of Dermatology 2014, 53, 1080–1085 ª 2013 The International Society of Dermatology

1080

fissures, hyperpigmentation, and serohematic crusts thatare usually accompanied by intense pruritus, tingling, orpain.1,9 Eye involvement is reported in 45% ofpatients.1,8 Ocular changes begin with hyperemia, photo-phobia, and lacrimation; later, there is brown pigmenta-tion, hypertrophy of the papillae, and pseudopterygiumformation. Cheilitis is the sole manifestation of AP in27.6% of patients.1,8,9

Not all patients show the same signs. Why somepatients show mild forms and others show more persis-tent and more severe forms of dermatosis remainsunknown. It has been suggested that the age of onset ofAP is the most important factor in determining the typeof eruption and the patient’s prognosis.10 No studies haveelucidated factors related to AP. The aim of this studywas to analyze the risk factors associated with AP using acase–control study design.

Materials and methods

A case–control study was conducted at the Departments of

Dermatology and Internal Medicine at Dr. Manuel Gea

Gonz�alez General Hospital in Mexico City.

Clinical files were reviewed. All patients diagnosed with AP

from 1990 to 2006 were included, reviewed, and their data

entered into a database. The sample was calculated to support

a power of 95% and precision of 2%. Forty-four cases were

identified; respective controls were recruited in a consecutive

manner.

Case selection

Patients with clinical and histopathologic diagnoses of AP, who

attended the outpatient dermatology clinic, were included in the

study.

Control selection

Control group 1 included dermatology outpatients not diagnosed

with AP or any autoimmune disease.

Control group 2 included outpatients attending the

Department of Internal Medicine and not diagnosed with AP or

any autoimmune disease.

The local research ethics committee approved the study.

Informed consent was obtained from all patients.

Evaluation of risk factors

Race, demographic, geographic, socioeconomic, environmental,

clinical, and nutritional risk factors were assessed. The groups

were evaluated by direct interview using a structured

questionnaire based on previously validated surveys. Data on

demographic, geographic, and socioeconomic variables were

obtained through the National Health Interview Surveys

(NHIS).11 Data on environmental variables were obtained using

a structured questionnaire approved by the Research

Committee of the Department of Coordination of Community

Health and the specialty hospital Centro M�edico Nacional Siglo

XXI.12 Data on nutritional variables were obtained using the

Frequency of Consumption Questionnaire (SNUT) from the

National Institute of Public Health (Public Health Research

Center).13

Statistical analysis

Means and standard deviations (SDs) were used to describe

the distribution of continuous variables in comparisons between

AP patients and controls. The non-parametric Mann–Whitney

U-test was applied because some of these variables showed a

non-normal distribution.

The risks associated with the probability of developing AP

were calculated by means of cross-tabulation. Odds ratios

(ORs) were calculated with the independent variables coded in

a binary form. Statistical significance was determined using

Fisher’s exact test (two-tailed) and 95% confidence intervals

(CIs). To derive the adjusted OR associated with the probability

of being a case, multivariate unconditional logistic regression

analyses were conducted. Multicollinearity in the adjusted

models was tested by deriving the covariance matrix. All

statistical analyses were carried out using SPSS Version 10.0

(SPSS, Inc., Chicago, IL, USA).

Results

A total of 132 persons were included in this study. Theseincluded 44 cases and two control groups (group 1:Department of Dermatology outpatients [n = 44]; group2: Department of Internal Medicine outpatients [n = 44]).Distribution by gender, age, place of birth, place of resi-dence, and economic status did not differ significantlyamong the three groups. People who use the hospital atwhich the study was conducted are usually born andreside in Mexico City or its surroundings, where livingconditions are very similar.The study population included 85 female (64%) and

47 male (36%) subjects. The AP group, specifically, com-prised 29 female (66%) and 15 male (34%) subjects.Ages ranged from 11 years to 86 years. Mean � SD agewas 32.18 � 15.73 years in the case group,41.20 � 20.57 years in control group 1, and45.65 � 17.08 years in control group 2. Actinic prurigopatients reported having had the first manifestations ofdisease in childhood but were not usually diagnosed untillate in adulthood when symptoms were exacerbated bysun exposure.A total of 256 variables were analyzed. When data for

the three groups were compared, only 19 variables werefound to be statistically significant (P < 0.05). Thesewere: use of a boiler; use of firewood; ownership of acar; use of earthenware; mixed material housing;

ª 2013 The International Society of Dermatology International Journal of Dermatology 2014, 53, 1080–1085

Vera Izaguirre et al. Risk factors for actinic prurigo Report 1081

socioeconomic level 1; sun exposure (time); use of soap;lemon consumption; use of moisturizing hair cream; liv-ing with pets in the house; living with farm animals;age; having a family member with AP; having had sur-gery; having had trauma; having been hospitalized; useof oral medication, and use of herbal medication.The health behavior variables analyzed included nutri-

tional condition and body mass index (BMI: weight inkilograms divided by height in meters squared). TheSNUT survey evaluated 12 food sections and 104different types of food. The BMI of each subject wascalculated, and scores were grouped into standard catego-ries of underweight (< 18.5 kg/m2), normal weight (18.5–24.9 kg/m2), overweight (25.0–29.9 kg/m2), and obese(� 30.0 kg/m2). Of the 40 macronutrients and micronu-trients analyzed (Table 1), 11 were found to have statisti-cally significant effects (P < 0.05). High rates ofconsumption of all statistically significant nutrients wereobserved among AP patients (Table 2) but not amongcontrol subjects; therefore, nutritional status should beconsidered to represent a risk factor for AP.The 19 potential risk factors for developing AP were

primarily analyzed separately in univariate logistic regres-sion analyses. In order to determine the independenteffect of each risk factor, a multivariate analysis, includ-ing all 11 factors found to be statistically significant inthe univariate analysis, was subsequently performed(Table 3). Any potential confounding or mediating effect

introduced by correlations between the risk factors wastested and excluded beforehand.The multivariate analysis showed that among subjects

without AP, the use of firewood increased the risk fordeveloping AP (OR = 8.1, 95% CI 1.2–53.9). Subjects

Table 1 Macro- and micronutrients subjected to nutrition-related evaluation of factors implicated in the developmentof actinic prurigo

Macronutrients Micronutrients

Kilocalories Vitamin B12

Protein, g Vitamin K

Lipids, g Retinol

Carbohydrates, g Carotene

Calcium a-Carotene

Iron b-Carotene

Magnesium Lutein

Sodium Vitamin D

Zinc Vitamin E

Copper a-Tocopherol

Manganese b-Tocopherol

Iodine c-Tocopherol

Selenium d-Tocopherol

Vitamin C h-Tocopherol

Vitamin B1 Cholesterol

Vitamin B2 Alcohol

Vitamin B3 Animal fat

Vitamin B5 Vegetable fat

Vitamin B6 Saturated fat

Folate Mono-unsaturated fat

Table 2 Statistically significant nutrition-related variables

Nutrient

Cases

(n = 44)

Mean � SD

Control

group 1

(n = 44)

Mean � SD

Control

group 2

(n = 44)

Mean � SD P-valuea

Energy, kcal 2568 � 1322 2098 � 1025 1880 � 1169 0.01

Proteins, g 89 � 53 72 � 42 65 � 33 0.02

Carbohydrates,

g

348 � 180 275 � 134 247 � 163 0.007

Magnesium, mg 395 � 202 318 � 171 292 � 104 0.01

Sodium, mg 2212 � 1415 1709 � 1185 1602 � 1080 0.02

Selenium, lg 46 � 53 29 � 17 28 � 21 0.04

Vitamin B1, mg 1.9 � 1.2 1.5 � 1.1 1.2 � 1.0 0.01

Vitamin B6, mg 2.3 � 1.3 1.7 � 0.9 1.7 � 1.3 0.01

Retinol, IU 4841 � 632 2838 � 2435 2761 � 3282 0.03

Cholesterol, mg 300 � 229 223 � 147 203 � 135 0.02

Animal fat, g 54 � 37 41 � 39 39 � 26 0.03

SD, standard deviation.aMann–Whitney U-test, P < 0.05.

Table 3 Risk factors associated with the development ofactinic prurigo (AP)

Variable ORa (95% CI)

Demographic, geographic, socioeconomic

Firewood use 9.5 (1.9–47.0)

Car ownership 0.3 (0.1–0.8)

Environmental

Soap use 3.1 (2.4–4.0)

Moisturizing hair cream use 0.6 (0.5–0.7)

Living with pets in the house 3.6 (1.6–7.9)

Living with farm animals 6.9 (2.2–21.1)

Clinical

Age < 38 years 2.12 (1.0–4.5)

Family member with AP 3.6 (2.7–4.9)

Record of surgery 0.2 (0.1–0.6)

Record of hospitalization 0.1 (0.1–0.4)

Use of oral medication 0.3 (0.2–0.7)

aLogistic regression odds ratio adjusted by firewood use,owning/not owning a car, use of soap, use of moisturizinghair cream, living with pets in the house, living with farmanimals, age, family member with AP, surgery records, hospi-talization records, oral medication.Reference: firewood use: unexposed; car: not owned; soap:not used; moisturizing hair cream: not used; living with petsin the house: unexposed; living with farm animals: unex-posed.


Report Risk factors for actinic prurigo Vera Izaguirre et al.1082

who shared their homes with pets had a risk for develop-ing AP three times greater (95% CI 1.0–9.1) than that ofsubjects who did not live with pets in the house. Subjectswith records of hospitalization had a risk for developingAP five times lower (95% CI 1.4–2.0) than that of sub-jects without records of hospitalization (Fig. 1).

Discussion

Although many studies have assessed the clinical featuresand diagnosis of AP and methods of treating it, this is, toour knowledge, the first study to analyze risk factors forAP. By contrast with other case report studies, this reportdescribes a case–control study in which variables, includ-ing demographic, geographic, socioeconomic, environ-mental, and behavioral variables, that had not beenevaluated previously were assessed using a broad struc-tured questionnaire. This evaluation was based on previ-ously validated surveys.Actinic prurigo is an idiopathic photodermatosis. There

are multiple factors involved in the etiology of AP, suchas epidemiologic factors (ethnic group, gender, age atonset, skin type), geographic factors (area of residence,altitude, seasonal variations), clinical factors (topographicdistribution, morphology of lesions, symptomatology,family history of disease, clinical course), and immuno-logic factors (histopathology, immunogenetic findings, theresponse of AP to thalidomide), which interact in geneti-cally susceptible hosts (with the HLA allele). Althoughthe presence of HLA-DR4 has been associated with auto-immune diseases, there are no studies that show anincreased risk for developing autoimmune diseases amongsubjects with AP.In almost all studies (case reports), the individuals

affected come from racially mixed populations.1–3,8,9,14–18

In the present study, all patients came from a non-mixedrace population: they were the offspring of Mexican par-ents for two generations of antecedents; therefore, racecan be considered as a risk factor for the development ofAP.With regard to the family history of the condition, Vega

et al. reported a clinicopathologic analysis of 116 patientsin which a positive family history of AP was identified inonly five (4.3%) instances.9 However, our study showedthat 25% of AP patients had a positive family history ofAP. This difference in rates suggests that genetic suscepti-bility may vary from one individual to another.Maga~na et al.17 suggested a possible etiologic role of

dieting in AP. These authors proposed that AP patientsdeveloped the disease as a result of, among other factors,a low protein diet.17 We found, by contrast, that the con-sumption of some macro- and micronutrients (kcal, pro-teins, carbohydrates, magnesium, sodium, selenium,vitamin B1, vitamin B3, vitamin B6, retinol, cholesterol,and animal fat) was higher in AP patients than in subjectsin the control groups. The etiologic role of diet in APshould be researched in future studies before these resultscan be assumed to be valid and a change in diet can besuggested as part of an AP treatment protocol.The multivariate analysis showed that among subjects

without AP, the use of firewood increased the risk fordeveloping AP (OR = 8.1, 95% CI 1.2–53.9). Subjectswho lived with pets in the house had a three times (95%CI 1.0–9.1) greater risk for developing AP compared withsubjects who did not. Subjects with records of hospital-ization had a five times (95% CI 1.4–2.0) decreased riskfor developing AP compared subjects without hospitaliza-tion records.Environmental factors and exposure to allergens have

been related to the severity of asthma and lupus syn-drome in sensitive individuals.11,13,19–24 However, nostudies have examined environmental factors and expo-sure to allergens in association with AP. This study pro-poses a clear line of research, which should be directed atspecific risk factors and should seek to establish relation-ships that refer to infection-related, allergy, health, andsocioeconomic status. The present study has limitations,but it is the only AP case–control study to have clinicalvalue.We suggest further study should investigate the molecu-

lar mechanisms behind the development of AP in order toidentify whether AP is caused by exposure to polycyclicaromatic hydrocarbons (PAHs), which are formed duringincomplete combustion because most of the AP patientsin the present study were exposed to firewood burning.Automobile exhaust, domestic wood burning, and indus-trial waste byproducts are all sources of PAHs. Recently,the US Environmental Protection Agency (EPA) listed

Protectivefactor

OR (95% CI)

Risk factorOR (95% CI)

Living with pets in the house3 (1.0–9.1)

5 (1.4–20) Hospitalization record

∞ ∞

8.1 (1.2–53.9)Firewood

FumesExposure

Figure 1 Independent risk factors associated with actinicprurigo in multivariate analysis. OR, odds ratio; CI,confidence interval



some PAHs as primary pollutants and reported them tobe photomutagenic. Much more attention should be paidto the phototoxicity of PAHs because they are usuallyexposed to sunlight in the environment.Although there has been great concern about the expo-

sure of PAHs in the environment to sunlight, the vastmajority of research has focused on the photomodifica-tion of compounds, such as their photodegradation andphotooxidation, and subsequent toxicities. The role ofPAHs as photosensitizers has received much less atten-tion; nevertheless, it has been known for more than a cen-tury that PAHs show significant toxicity in the presenceof ultraviolet (UV) light.Notably, PAHs have induced certain types of DNA

damage in the presence of UV light, which may contrib-ute to photomutagenesis and photocarcinogenesis. Onearea that demands further study is the arylhydrocarbonreceptor (AhR) pathway. Some symptoms pointingtowards a disruption of AhR-regulated keratinocyte pro-liferation and differentiation have been observed, and theAhR pathway has also been identified as a moleculareffector involved in the mechanism of the antiapoptoticeffect in some epithelial human cells. It is also known tobe involved in allergic inmunoregulation.25,26

Conclusions

The present study demonstrates that economic variablesare not important factors in the development of AP. Clin-ical factors and environmental exposures were stronglyassociated with a higher risk for developing AP. As manyenvironmental factors as possible should be examined infuture studies in order to improve our understanding ofAP and to facilitate the development of more effectivepreventive and treatment strategies.

References

1 Hojyo MT, Vega E, Granados J, et al. Actinic prurigo: anupdate. Int J Dermatol 1995; 34: 380–384.

2 Hojyo MT, Granados J, Vargas G, et al. Furtherevidence of the role of HLA-DR4 in the geneticsusceptibility to actinic prurigo. J Am Acad Dermatol

1997; 36: 935–937.3 Menag�e HP, Vaughan RW, Baker CS, et al. HLA-DR4

may determine expression of actinic prurigo in Britishpatients. J Invest Dermatol 1996; 106: 362–364.

4 Grabczynska SA, McGregor JM, Kondeatis E, et al.Actinic prurigo and polymorphic light eruption: commonpathogenesis and the importance of HLA-DR4/DRB1*0407. Br J Dermatol 1999; 140: 232–236.

5 Bernal JE, Duran de Rueda MM, De brigard D, et al.Human lymphocyte antigen in actinic prurigo. J Am Acad

Dermatol 1998; 18: 310–312.

6 Suarez A, Valbuena M, Rey M, et al. Association of HLAsubtype DRB1*0407 in Colombian patients with actinicprurigo. Photodermatol Photoimmunol Photomed 2006;22: 55–58.

7 Wiseman M, Orr P, Macdonald S, et al. Actinic prurigo:clinical features and HLA associations in a Canadian Inuitpopulation. J Am Acad Dermatol 2001; 44: 952–956.

8 Hojyo MT, Vega ME, Cort�es R, et al. Prurigo actinicocomo modelo de fotodermatosis cr�onica en Latinoam�erica.Med Cut Iber Lat Am 1996; 24: 265–277.

9 Vega ME, Mosqueda A, Irigoyen M, et al. Actinicprurigo cheilitis: clinicopathologic analysis andtherapeutic results in 116 cases. Oral Surg Oral Med

Oral Pathol Oral Radiol Endod 2002; 94: 83–91.10 Lane PR, Hogan DJ, Martel MJ, et al. Actinic prurigo:

clinical features and prognosis. J Am Acad Dermatol

1992; 26: 683–692.11 Rose D, Mannino D, Leaderer B, et al. Asthma

prevalence among US adults, 1998–2000: role of PuertoRican ethnicity and behavioral and geographic factors.Am J Public Health 2006; 96: 880–888.

12 Zonana A, Rodr�guez L, Jim�enez F, et al. Factores deriesgo relacionados con lupus eritematoso sist�emico enpoblaci�on mexicana. Salud Publica Mex 2002; 44: 213–218.

13 Hern�andez M, Romieu I, Parra S, et al. Validity andreproducibility of a food frequency questionnaire toassess dietary intake of women living in Mexico City.Salud Publica Mex 1998; 40: 133–140.

14 Arrese J, Dom�nguez L, Hojyo M, et al. Effector ofinflammation in actinic prurigo. J Am Acad Dermatol

2001; 44: 957–961.15 Estrada I, Garibay A, Nunez A, et al. Evidence that

thalidomide modifies the immune response of patientssuffering from actinic prurigo. Int J Dermatol 2004; 43:893–897.

16 Hojyo MT, Vega ME, Cortes R, et al. Diagnosis andtreatment of actinic prurigo. Dermatol Ther 2003; 16:40–44.

17 Maga~na-García M, Maga~na M. Actinic prurigo. Thepossible etiologic role of an amino acid in the diet. Med

Hypotheses 1993; 41: 52–54.18 Correa MC, Memije EV, Vargas G, et al. HLA-DR

association with the genetic susceptibility to develop ashydermatosis in Mexican Mestizo patients. J Am Acad

Dermatol 2007; 56: 617–620.19 Hees EV. Role of drugs and environmental agents in

lupus syndromes. Curr Opin Rheumatol 1992; 4: 688–692.

20 Salazar M, Rub�n RL, Garc�a J. Systemic lupuserythematosus induced by isoniazid. Ann Rheum Dis

1992; 51: 1085–1087.21 Fritzler MJ. Drug recently associated with lupus

syndromes. Lupus 1994; 3: 455–459.22 Freni LW, Kelley DB, Grow AG, et al. Connective tissue

disease in southeastern Georgia: a case–control study ofetiologic factors. Am J Epidemiol 1989; 130: 404–409.


Report Risk factors for actinic prurigo Vera Izaguirre et al.1084

23 Murray CS, Poletti G, Kebadze T, et al. Study ofmodifiable risk factors for asthma exacerbations: virusinfection and allergen exposure increase the risk ofasthma hospital admissions in children. Thorax 2006; 61:376–382.

24 Porsbjerg C, Von Linstow M, Suppli C, et al. Riskfactors for onset of asthma. A 12-year prospectivefollow-up study. Chest 2006; 129: 309–316.

25 Toyooka T, Ibuki Y. DNA damage induce by coexposureto PAHs and light. Environ Toxicol Pharmacol 2007; 23:256–263.

26 Chiba T, Uchi H, Tsuji G, et al. Arylhydrocarbonreceptor (AhR) activation in airway epithelial cellsinduces MUC5AC via reactive oxygen species(ROS) production. Pulm Pharmacol Ther 2011; 1:133–140.



Actinic prurigo: a case-control study of risk factors

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