Rosacea, a common chronic inflammatory facial skin

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1 RESEARCH ARTICLE Patients with Rosacea Have Increased Risk of Dementia Alexander Egeberg, MD, 1,2 Peter R. Hansen, MD, 2 Gunnar H. Gislason, MD, 2,3,4 and Jacob P. Thyssen, MD 1 Objective: Rosacea is a common chronic inflammatory skin disorder where upregulation of matrix metalloproteinases (MMPs) and antimicrobial peptides (AMPs) is observed. Notably, inflammation, MMPs, and AMPs are also involved in the etiopathogenesis of neurodegenerative disorders including certain forms of dementia such as Alzheimer disease (AD). Based on several clinical observations, we investigated the association between rosacea and dementia, including AD in Danish registers. Methods: All Danish citizens aged 18 years between January 1, 1997 and December 31, 2012 were linked at the individual level through administrative registers. Cox regression was used to calculate unadjusted and adjusted hazard ratios (HRs). Results: The study comprised a total of 5,591,718 individuals, including 82,439 patients with rosacea. A total of 99,040 individuals developed dementia (any form) in the study period, of whom 29,193 were diagnosed with AD. The adjusted HRs of dementia and AD were 1.07 (95% confidence interval [CI] ), and 1.25 (95% CI ), respectively, in patients with rosacea. Stratified by sex, the HRs of AD were 1.28 (95% CI ) and 1.16 (95% CI ) in women and men, respectively. When results were stratified by age at study entry, the risk of AD was only significantly increased in individuals 60 years old (adjusted HR , 95% CI ). When analyses were limited to patients with a hospital dermatologist diagnosis of rosacea only, the adjusted HRs of dementia and AD were 1.42 (95% CI ) and 1.92 (95% CI ), respectively. Interpretation: Rosacea is significantly associated with dementia, particularly AD. Increased focus on symptoms of cognitive dysfunction in older patients with rosacea may be relevant. ANN NEUROL 2016;00: Rosacea, a common chronic inflammatory facial skin condition in adults, is usually perceived as an umbrella term covering 4 distinct, but often overlapping, subtypes: (1) erythematotelangiectatic, (2) inflammatory papulopustular, (3) phymatous, and (4) ocular. 1 Interestingly, a subtype of patients have prominent neurological symptoms such as burning and stinging pain from the skin, migraine, and neuropsychiatric symptoms, suggesting a link between rosacea and neurological diseases. 2 The exact prevalence of rosacea in Denmark is unclear, and although reported worldwide prevalences of rosacea differ markedly between countries, a rosacea prevalence of 10% has been reported from Sweden. 3 Although the etiopathogenesis of rosacea is complex and poorly understood, both genetic and environmental risk factors have been reported. 1,4 Rosacea skin shows an upregulation of various inflammatory mediators, for example, cytokines, antimicrobial peptides (AMPs), chemokines, and matrix metalloproteinases (MMPs) 1, 3, and 9. 1,5 8 The increased MMP activity has mainly been associated with ocular and phymatous rosacea. 9 Notably, pharmacological drugs with MMP inhibitor function, for example, tetracycline, minocycline, or doxycycline given in subantimicrobial doses, are frequently used to treat rosacea. 1,5 Although several causes of Alzheimer disease (AD) have been proposed, chronic infections and neuroinflammation are thought to significantly contribute to the pathogenesis of AD. 10 Specifically, expression of certain AMPs are upregulated in brains of patients with AD, View this article online at wileyonlinelibrary.com. DOI: /ana Received Sep 24, 2015, and in revised form Mar 15, Accepted for publication Mar 16, Address correspondence to Dr Egeberg, Department of Dermato-Allergology, Herlev and Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark. alexander.egeberg@gmail.com From the 1 National Allergy Research Center, Department of Dermato-Allergology, Herlev and Gentofte University Hospital, University of Copenhagen, Hellerup; 2 Department of Cardiology, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup; 3 Danish Heart Foundation, Copenhagen; and 4 National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark VC 2016 American Neurological Association 1

2 ANNALS of Neurology elevated levels of MMP-9 are found in the cerebrospinal fluid of patients with AD and vascular dementia, and cognitive scores are inversely associated with MMP-9 activity Moreover, cerebrospinal fluid MMP-3 levels have been correlated with the duration of AD, and MMPs have been proposed as potential biomarkers for the diagnosis of AD. 14 We hypothesized that patients with rosacea may have increased risk of AD, because we have clinically observed a familial overrepresentation of AD in patients with rosacea, and because of the overlap of proinflammatory mediators between rosacea and AD. Furthermore, a 1955 single case report also suggested an association between rosacea and AD. 15 We therefore evaluated an association between rosacea and AD in a population-based cohort using nationwide registers. Subjects and Methods Data Sources and Study Population Study approval was obtained from the Danish Data Protection Agency (ref , int ref GEH , I-Suite 02736). Review of an ethics committee is not required for register studies in Denmark. Conduct of this study was in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology recommendations. 16 In brief, the Danish Civil Registration System assigns a permanent and unique 10-digit personal identification number to all citizens at birth or immigration, which allows for unambiguous linkage across nationwide registers. 17 Moreover, the Danish Civil Registration System contains information such as date of birth, sex, and vital status, and Statistics Denmark records information on tax reports of household income. 18 The Danish National Patient Register contains information on all inpatient and outpatient (ambulatory) hospital contacts according to the International Classification of Diseases (ICD; prior to 1994 according to the 8th revision [ICD-8] and thereafter ICD-10; for administrative reasons, ICD-9 was never used in Denmark), and hospital treatment interventions, surgical procedures, and hospital-administered pharmacotherapy are coded as treatment procedure (SKS) codes. 19 All pharmacy-dispensed prescriptions in Denmark have been accurately recorded in the Registry of Medicinal Product Statistics since 1994, and all drugs are classified according to the Anatomical Therapeutic Chemical (ATC) classification. 20 Drug expenses are partially reimbursed by Danish healthcare authorities, which ensures complete registration and minimal incentives to claim drugs through other sources. All Danish citizens aged 18 years or older were included in the cohort on January 1, 1997, or the subsequent day after they reached 18 years of age. Individuals were followed until December 31, 2012, migration, a diagnosis of dementia, or death from any cause, whichever came first. Rosacea was defined according to discharge diagnosis codes of rosacea (ICD and ICD-10 L71) identified in the Danish National Patient Register or by claimed prescription of topical metronidazole treatment (ATC D06BX01). The index date of rosacea was defined as whichever came first of either a hospital (inpatient or outpatient) diagnosis of rosacea, or when patients claimed their second prescription of topical metronidazole, which is the preferred first-line treatment for rosacea and infrequently used for other skin conditions in Denmark. We used the second such prescription to ensure persistent medical treatment for rosacea. Throughout the article, baseline refers to study start rather than time of rosacea diagnosis. At baseline, patients with prevalent dementia (any form; ICD-8 codes , , , , , and , and ICD-10 codes F00, F01, F03, and G30) were excluded to enable accurate examination of the temporal relationship between exposure (rosacea) and subsequent risk of dementia and AD, respectively. Endpoints The primary endpoint was a hospital neurologist diagnosis (inpatient or outpatient) of dementia (ICD-10 codes F00, F01, F03, and G30). Among these cases, we further identified patients with a neurologist diagnosis of AD (ICD-10 codes F00 and G30). Experienced neurologists and psychiatrists have previously validated the diagnostic coding of dementia and AD with an accuracy of 85.8% and 81.8%, respectively, in the Danish National Patient Register with use of medical chart reviews, investigator evaluations, and patient interviews. 21 Covariates We obtained information on the following covariates at baseline: cholesterol-lowering drugs (ATC code C10A), antidepressants (ATC code N06A), diabetes, hypertension, alcohol abuse, smoking history, and socioeconomic status. Diabetes was defined by either a hospital discharge (ICD-10 E10-E11) diagnosis, or use of glucose-lowering drugs (ATC A10). Hypertension was defined by either a hospital diagnosis, or a patient receiving treatment within 90 days with at least 2 of the following classes of antihypertensive drugs: a-adrenergic blockers, nonloop diuretics, vasodilators, b-blockers, calcium channel blockers, and renin angiotensin system inhibitors, as previously validated with a positive predictive value of 80% and a specificity of 95%. 22 Collection of data on smoking history and alcohol abuse has been described elsewhere. 23,24 We calculated an index of socioeconomic status between 0 and 4 based on the average gross annual income (standardized by age) during a 5- year period before study inclusion. Baseline medication was calculated up to 6 months, and information on comorbidity, smoking history, and alcohol abuse was collected up to 5 years prior to the index date, respectively. Statistical Analysis Baseline characteristics were presented as frequencies with percentages for categorical variables and means with standard deviations for continuous variables. Unadjusted event rates were summarized per 1,000 person-years at risk. Rosacea was included as a time-dependent variable so that patients were only considered at risk from the time they fulfilled the rosacea 2 Volume 00, No. 00

3 Egeberg et al: Rosacea and Risk of Dementia TABLE 1. Baseline Characteristics of Study Population Characteristic Reference Population, n 5 5,509,279 Rosacea, n 5 82,439 Age, mean yr (SD) 40.4 (19.7) 42.1 (17.0) Women, No. [%] 2,775,014 [50.4] 55,161 [66.9] Men, No. [%] 2,734,265 [49.6] 27,278 [33.1] Socioeconomic status, mean (SD) 2.0 (1.4) 2.5 (1.4) Smoking, No. [%] 553,210 [10.0] 8,194 [9.9] Comorbidity, No. [%] Alcohol abuse 77,196 [1.4] 949 [1.2] Diabetes 83,375 [1.5] 971 [1.2] Hypertension 180,094 [3.3] 2,747 [3.3] Medication, No. [%] Antidepressants 151,035 [2.7] 2,672 [3.2] Statins 29,287 [0.5] 521 [0.6] The reference population includes everyone who did not have a rosacea diagnosis during the study (baseline or during follow-up), and rosacea includes everyone with rosacea at any time during the study. SD 5 standard deviation. criteria. Therefore, outcomes and time at risk after study start, but prior to onset of rosacea, were assigned to the reference population. Similarly, outcomes and time at risk after onset of rosacea were assigned to the rosacea group to obtain a more accurate risk-time allocation. Patients with prevalent rosacea were included in the rosacea group from the time of study start. We used Cox regression models to calculate crude and adjusted hazard ratios (HRs). In adjusted analyses, HRs were adjusted for age at baseline, sex, socioeconomic status, statin and antidepressant use, diabetes, hypertension, alcohol abuse, and smoking. Two separate analyses were performed for adjusted HRs. The first analysis was adjusted for the abovementioned covariates at baseline, whereas the second analysis also included information on statin and antidepressant use, diabetes, hypertension, alcohol abuse, and smoking recorded during follow-up (as time-dependent covariates), Subjects lost to follow-up due to emigration from Denmark were censored at time of emigration. The proportional hazards assumption was tested and found to be valid. We performed sensitivity analyses, where we only included patients with a hospital (inpatient or outpatient) ICD diagnosis of rosacea (ICD and ICD-10 L71) in the rosacea group. Moreover, we performed a sensitivity analysis, where the outcome of interest was initiation of pharmacotherapy specifically used for dementia, that is, donepezil (ATC code N06DA02 and SKS code BRHDA02), rivastigmine (ATC code N06DA03 and SKS code BRHDA03), galantamine (ATC code N06DA04 and SKS code BRHDA04), or memantine (ATC code N06DX01 and SKS code BRHD4X01). Two-tailed probability values < 0.05 were considered statistically significant, and results were reported with 95% confidence intervals (CIs) where applicable. All analyses were performed using SAS statistical software version 9.2 (SAS Institute, Cary, NC) and STATA software version 11.2 (StataCorp, College Station, TX). Results From January 1, 1997 to December 31, 2012, the study population comprised 5,644,567 Danish citizens aged 18 years or older. After excluding 11,989 individuals with prevalent dementia (any form) and 40,860 individuals with incomplete information on migration, the final cohort comprised a total of 5,591,718 individuals, with a maximum follow-up of 16 years. Of these, 82,439 individuals had rosacea. The baseline characteristics of the study population are shown in Table 1. During the study period, a total of 97,846 and 1,194 cases with dementia were registered among the controls and patients with rosacea, respectively, including 28,728 and 465 cases of AD in the 2 groups, respectively. The incidence rates of dementia per 1,000 personyears were 1.47 (95% CI ) and 2.03 (95% CI ) in the reference population and in patients with rosacea, respectively, and the corresponding incidence rates of AD were 0.43 (95% CI ) and 0.79 (95% CI ), respectively (Table 2). The baseline- and follow-up adjusted HRs of dementia in patients with rosacea were 1.14 (95% CI ) and 1.07 (95% CI ), respectively, Month

4 ANNALS of Neurology TABLE 2. Incidence Rates of Dementia and Alzheimer Disease per 1,000 Person-Years in the Reference Population and Rosacea Population Reference Population Rosacea Any Women Men Any Women Men Any dementia Person-years 66,515,152 33,771,353 32,743, , , ,100.5 Number of events 97,846 59,534 38,312 1, Incidence rate/ ,000 person years 95% confidence interval Alzheimer disease Person-years 66,708,286 33,889,420 32,818, , , ,356.3 Number of events 28,728 18,200 10, Incidence rate/ ,000 person years 95% confidence interval Pharmacotherapy used for dementia Person-years 66,634,121 33,841,773 32,792, , , ,808.4 Number of events 48,826 30,576 18, Incidence rate/ ,000 person years 95% confidence interval and age- and sex-stratified results are shown in Table 3. The baseline- and follow-up adjusted HRs of AD were were 1.31 (95% CI ) and 1.25 (95% CI ), respectively. Sex stratification revealed followup adjusted HRs for AD of 1.28 (95% CI ) and 1.16 (95% CI ) in women and men with rosacea, respectively. When results were stratified for age at baseline, the risk of AD was only significantly increased in individuals 60 years old (see Table 3). Sensitivity Analyses When the study outcome was changed to initiation of pharmacotherapy specifically used for dementia, the baseline- and follow-up adjusted HRs were 1.28 (95% CI ) and 1.20 (95% CI ), respectively. Sex stratification revealed follow-up adjusted HRs of 1.21 (95% CI ) and 1.16 (95% CI ) in women and men with rosacea, respectively (see Table 3). Stratified based on age at baseline, the baseline- and follow-up adjusted HRs of pharmacotherapy for dementia were 2.08 (95% CI ) and 1.94 (95% CI ) in individuals <40 years old, 1.38 (95% CI ) and 1.26 (95% CI ) in individuals 40 to 59 years old, and 1.18 (95% CI ) and 1.13 (95% CI ) in individuals 60 years old. In sensitivity analyses where the exposure was a dermatologist hospital ICD diagnosis of rosacea, the baseline- and follow-up adjusted HRs of dementia were 1.51 (95% CI ) and 1.42 (95% CI ), respectively. Sex stratification revealed follow-up adjusted HRs for dementia of 1.41 (95% CI ) and 1.43 (95% CI ) in women and men with a hospital diagnosis of rosacea, respectively. Stratified based on age at baseline, the baseline- and follow-up adjusted HRs of dementia were 1.59 (95% CI ) and 1.37 (95% CI ) in individuals <40 years old, 1.26 (95% CI ) and 1.06 (95% CI ) in individuals 40 to 59 years old, and 1.54 (95% CI ) and 1.47 (95% CI Volume 00, No. 00

5 Egeberg et al: Rosacea and Risk of Dementia TABLE 3. Unadjusted and Adjusted HRs with 95% CIs of Dementia and Alzheimer Disease in Patients with Rosacea and Controls Obtained from Cox Regression Analyses Crude Adjusted, Baseline a Adjusted, Follow-up b HR 95% CI p HR 95% CI p HR 95% CI p Any dementia < < c Women Men < <40 years years years Alzheimer disease < < <0.001 c Women < <0.001 c Men < c <40 years years years < < <0.001 c Pharmacotherapy used for dementia < < <0.001 c Women < <0.001 c Men < < c <40 years years < < c 60 years < < c a Adjusted for baseline age, sex, socioeconomic status, and baseline presence of alcohol abuse, smoking, statin and antidepressant use, hypertension, and diabetes. b Adjusted for baseline age, sex, socioeconomic status, and presence (including during follow-up as time-dependent covariates) of alcohol abuse, smoking, statin and antidepressant use, hypertension, and diabetes. c Statistically significant. CI 5 confidence interval; HR 5 hazard ratio. 1.82) in individuals 60 years old. Additional analyses are available in Table 4. Similarly, for AD, patients with a hospital diagnosis of rosacea had baseline- and followup adjusted HRs of 2.01 (95% CI ) and 1.92 (95% CI ), respectively. Sex stratification revealed follow-up adjusted HRs for AD of 1.91 (95% CI ) and 1.89 (95% CI ), in women and men with a hospital diagnosis of rosacea, respectively. Stratified based on age at baseline, the risk of AD was only significantly increased in individuals 60 years old (follow-up adjusted HR ; 95% CI ). Discussion Primary Findings In this population-based study, we found a significant association with dementia, and especially AD, in patients with rosacea. The associations were strongest in individuals 60 years old at baseline, and the results remained consistent in a range of sensitivity analyses, and after adjustment for potential confounding factors. Strengths and Limitations Several strengths and limitations apply to the interpretation of the present results. The high accuracy of the Month

6 ANNALS of Neurology TABLE 4. Unadjusted and Adjusted HRs with 95% CIs of Dementia and Alzheimer Disease in Patients with Rosacea (Diagnosed by a Hospital Dermatologist) and Controls Obtained from Cox Regression Analyses Crude Adjusted, Baseline a Adjusted, Follow-up b HR 95% CI p HR 95% CI p HR 95% CI p Any dementia < < <0.001 c Women c Men < c <40 years years years < <0.001 c Alzheimer disease < < <0.001 c Women < c Men < c <40 years d years years < < <0.001 c Pharmacotherapy used for dementia < < c Women Men < < c <40 years d years years c a Adjusted for baseline age, sex, socioeconomic status, and baseline presence of alcohol abuse, smoking, statin and antidepressant use, hypertension, and diabetes. b Adjusted for baseline age, sex, socioeconomic status, and presence (including during follow-up as time-dependent covariates) of alcohol abuse, smoking, statin and antidepressant use, hypertension, and diabetes. c Statistically significant. d Not applicable; no events in the rosacea group <40 years old. CI 5 confidence interval; HR 5 hazard ratio. Danish registers, as well as the available information on socioeconomic status, medication, and comorbidities, allows for large-scale nationwide analyses, in which selection and recall bias are minimized. We used ICD codes and prescriptions of topical metronidazole for rosacea identification and severity classification. However, as the results of our sensitivity analyses (where rosacea was diagnosed by a hospital dermatologist) were generally in accordance with those of the primary analysis, the risk of bias due to misclassification of patients with rosacea is likely to be low. Finally, the Danish population is primarily of Northern European descent, which may limit extrapolation to other ethnicities, and the observational nature of our study does not allow for establishment of causation. Interpretation MMP-1, -3, and -9 appear to play important roles in the etiopathogenesis of rosacea. 6 Interestingly, patients with AD have increased levels of MMP-3 in their cerebrospinal fluid, and levels of MMP-3 correlate with the duration of AD. 14 Tetracycline, a commonly used oral therapy for rosacea, reduces kallikrein 5 serine protease activity through inhibition of MMP expression in endothelial cells and keratinocytes, which in turn blocks the proteolytic cleavage of cathelicidin into the AMP LL-37, 6 Volume 00, No. 00

7 Egeberg et al: Rosacea and Risk of Dementia which is thought to play a role in subtypes of rosacea. 7,25 In this regard, it is also notable that results from multiple studies have demonstrated suppressed b-amyloid and tau protein expression, as well as neuroprotective effects, following treatment with tetracycline This suggests that tetracycline may have therapeutic potential in patients with dementia, including AD, although this is hypothesis-generating and requires further study. Additionally, although involvement of AMPs is wellestablished in rosacea, b-amyloid (which itself is an AMP with proinflammatory abilities) is central to the pathology of AD. 1,10,29 The current sum of evidence suggests that certain forms of dementia, in particular AD, have prominent inflammatory components, and MMPs and AMPs may provide mechanistic links for the observed association between rosacea and dementia. 30 However, other proinflammatory mediators may also play a role, and a very recent study found substantial levels of T-cell involvement and increased gene expression levels for a range of cytokines, for example, interleukin (IL)-17 and tumor necrosis factor-a, in facial biopsies of patients with rosacea across all subtypes, and a considerable role for IL-17 in AD has also been suggested. 31,32 In potential further support of an inflammatory component in AD, studies have associated AD with diabetes, and AD is sometimes referred to as type 3 diabetes. 33,34 Moreover, numerous epidemiological studies have demonstrated a significant decreased risk of AD following treatment with nonsteroidal anti-inflammatory drugs. 35 In conclusion, we observed a significant association with dementia, including AD, in patients with rosacea. Increased focus on symptoms of cognitive dysfunction in patients with rosacea may be warranted. Author Contributions Conception and design of the study: A.E., P.R.H., G.H.G., J.P.T. Acquisition and analysis of data: A.E., P.R.H., G.H.G., J.P.T. Drafting the manuscript: A.E., P.R.H., J.P.T. Potential Conflicts of Interest Nothing to report. References 1. Two AM, Wu W, Gallo RL, Hata TR. Rosacea: Part I. Introduction, categorization, histology, pathogenesis, and risk factors. J Am Acad Dermatol 2015;72: Scharschmidt TC, Yost JM, Truong SV, et al. Neurogenic rosacea: a distinct clinical subtype requiring a modified approach to treatment. Arch Dermatol 2011;147: Berg M, Liden S. An epidemiological study of rosacea. Acta Derm Venereol 1989;69: Chang AL, Raber I, Xu J, et al. Assessment of the genetic basis of rosacea by genome-wide association study. J Invest Dermatol 2015;135: Two AM, Wu W, Gallo RL, Hata TR. Rosacea: Part II. Topical and systemic therapies in the treatment of rosacea. 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