Rosacea is associated with chronic systemic diseasesin a skin severityedependent manner:Results of a case-control study - PDF Document

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  1. Rosacea is associated with chronic systemic diseases in a skin severityedependent manner: Results of a case-control study Barbara M. Rainer, MD, Alexander H. Fischer, BS, Dimitre Luz Felipe da Silva, Sewon Kang, MD, and Anna L. Chien, MD Baltimore, Maryland Background: Rosacea is a common chronic inflammatory dermatosis of unclear origin. It has been associated with systemic comorbidities, but methodical studies addressing this association are lacking. Objective: We evaluated: (1) the association between rosacea and systemic comorbidities; and (2) if the severity of rosacea is impacted by comorbidities. Methods: This was a case-control study: patients with rosacea were matched (1:1) to rosacea-free control subjects by age, sex, and race. Relative risk estimates were calculated using logistic regression as odds ratios with 95% confidence intervals. Results: Among 130 participants (65 patients/65 control subjects), we observed a significant association between rosacea and allergies (airborne, food), respiratory diseases, gastroesophageal reflux disease, other gastrointestinal diseases, hypertension, metabolic and urogenital diseases, and female hormone imbalance. Compared with mild rosacea, moderate to severe rosacea was significantly associated with hyperlipidemia, hypertension, metabolic diseases, cardiovascular diseases, and gastroesophageal reflux disease. Limitations: This was a case-control study with moderate sample size. Associated medical conditions were self-reported and could not always be confirmed by medication use and medical records. Conclusions: Rosacea is associated with numerous systemic comorbid diseases in a skin severityede- pendent manner. Physicians should be aware of these associations to provide comprehensive care to patients with rosacea, especially to those with more severe disease. ( J Am Acad Dermatol 2015;73:604-8.) Key words: case-control study; comorbidity; rosacea; severity; systemic disease. R among adults ([30 years) of Northern European heritage with fair skin.1Symptoms present in various combinations and degrees of severity, often fluctu- ating between periods osacea is a chronic inflammatory disease of the skin. It affects up to 15% of the general population with the highest prevalence Abbreviations used: CI: CVD: GERD: GI: OR: confidence interval cardiovascular disease gastroesophageal reflux disease gastrointestinal odds ratio of exacerbation and Reprint requests: Barbara M. Rainer, MD, Department of Der- matology, Johns Hopkins University School of Medicine, 1550 Orleans St, Baltimore, MD 21231. E-mail: bm.rainer@gmail.com. Published online August 6, 2015. 0190-9622/$36.00 ? 2015 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2015.07.009 From the Department of Dermatology, Johns Hopkins University School of Medicine. Funding sources: None. Conflicts of interest: None declared. A portion of this work was presented at the Society for Investigative Dermatology Annual Meeting in Albuquerque, New Mexico, May 7-10, 2014. Accepted for publication July 6, 2015. 604

  2. J AM ACAD DERMATOL VOLUME 73, NUMBER 4 Rainer et al 605 remission. The complex network of the pathophys- iology of rosacea is still unclear, and existing thera- pies only temporarily improve cutaneous symptoms but are not curative. Traditionally,rosaceaisconsideredadiseasethatis limitedtotheskin.Afewstudieshaveobservedhigher risk of specific gastrointestinal (GI) symptoms and disorders,2-8 cardiovascular disease (CVD),9 depres- sion,10,11and migraine12in patients with rosacea. These previousanalyses,whichyiel- ded conflicting results, were primarily case series, case- control studies with small sample sizes, or retrospective database case-control studies investigating specific comor- bidities. Systematic studies to address the association of rosacea with extracutaneous diseases are lacking, and thereremainsacriticalknowl- edge gap regarding if and to what degree rosacea severity affects the prevalence of sys- temic comorbidities. We therefore enrolled patients with rosacea in a matched case-control study, and investigated the association between rosacea and comorbidities, and whether this association was altered by rosacea severity. We hypothesized that risk of rosacea, especially in patients with moderate to severe disease, would be associated with the presence of systemic comorbidities. Hopkins University Hospitals, Baltimore, MD, and through flyers. The study was conducted in accor- dancewith theethicalprinciples originatingfrom the Declaration of Helsinki and in compliance with local regulatory requirements. Written informed consent was obtained from all patients. Interview and clinical assessment A structured interviewer- administered collected detailed medical history and current comor- bidities, and information on demographics and lifestyle factors, including smoking habits, alcohol use, caffeine intake, and sun exposure. A single study dermatologist assessed rosacea characteris- tics and rosacea severity us- ing the National Rosacea Society’s standard grading system.13 Rosacea severity was grouped into mild and moderate to severe disease. CAPSULE SUMMARY questionnaire d Methodical studies addressing rosacea’s association with systemic comorbidities are scarce. d Rosacea is associated with systemic diseases. Moderate to severe rosacea is associated with hyperlipidemia, hypertension, metabolic and cardiovascular diseases, and gastroesophageal reflux disease. d Physicians should be aware of these associations to provide comprehensive care to patients with rosacea, especially to those with more severe disease. Medical conditions (lifetime) were self-reported and confirmed by medication use and medical records, where possible. Allergies were grouped as airborne, food, drug, and hymenoptera venom allergy. Respiratory disease chronic obstructive pulmonary disease, chronic bronchitis, and chronic rhinosinusitis ($8 weeks despite treatment). GI disease included gastritis, gastric/duodenal ulcers, malabsorption (lactose, fructose, sucrose, sorbitol), celiac disease, irritable bowel syndrome, small intestinal bacterial over- growth, colitis (ulcerative, infectious, lymphocytic), and Crohn’s disease. Metabolic disease included diabetes, hypertension, hyperlipidemia, and obesity defined by a body mass index [30 kg/m2. CVD included coronary heart disease, cerebrovascular disease, peripheral artery disease, and heart failure. Urogenital disease included chronic or recurrent urinary tract infections (2 in 6 months or 3 in 1 year), urolithiasis, polycystic kidney disease, nephritis, other unspecified kidney conditions, and urinary incontinence. Female hormone imbalance included premenstrual syndrome, infertility, female sexual dysfunction, endometriosis, ovarian syndrome (infertility, hirsutism, and oligo- menorrhea), ovarian cysts, fibrocystic breast and uterine fibroids, and hormone replacement therapy. Male hormone imbalance included erectile dysfunc- tion, benign prostate hyperplasia, hypogonadism, included asthma, METHODS Study design The study was a single-center case-control study with prospective recruitment of patients with rosa- cea and matched rosacea-free control subjects. The Johns Hopkins Institutional Review Board approved the study (NA_00078020/October 18, 2012). Study procedures were conducted at the Johns Hopkins Department of Dermatology in Baltimore, MD, between November 2012 and August 2013. polycystic Study cohort Eligible cases were patients 18 years of age or older with a diagnosis of rosacea. Rosacea-free control subjects were matched to each case by age within 5 years, sex, and race. Participants were recruited from the dermatology clinics at the Johns

  3. J AM ACAD DERMATOL OCTOBER 2015 606 Rainer et al and hormone replacement therapy (testosterone). Migraineand otherrecurrent headachesweregroup- ed together. Musculoskeletal disease included ar- thropathies, osteopathies, systemic connective tissue disorders. Hepatobiliary diseaseincluded hepatitis,cirrhosis, and liver failure. Thyroid disease included hyperthyroidism, hypo- thyroidism, thyroiditis, or other unspecified thyroid conditions. Neurologic disorders included epilepsy, neuropathy, degenerative disc disease, Parkinson disease, Alzheimer disease, brain tumors, and men- ingitis. Cancer was defined as any malignant tumor and grouped as ‘‘cancer including skin cancer’’ and ‘‘cancer other than skin cancer.’’ Table I. Demographics and lifestyle characteristics in rosacea cases and controls (n = 130) Cases n = 65 Controls n = 65 chondropathies, and Characteristic P value Sex, No. (%) Female Male Race, No. (%) White Asian African American Skin phototype, No. (%) 1 2 3 4 5 Age, y, mean (SD; range) BMI, kg/m2, mean (SD) Amount of sun, No. (%) No exposure Rare, 1 wk/y Medium, 2-4 wk/y Frequent, [4 wk/y Family history of rosacea, No. (%) Yes No Smoking status, No. (%) Nonsmoker Current smoker Alcohol, drinks/wk, mean (SD) Caffeine, 8-oz cups/d, mean (SD) 1.0* 43 (66.2) 22 (33.8) 43 (66.2) 22 (33.8) 1.0* 62 (95.4) 2 (3.1) 1 (1.5) 62 (95.4) 2 (3.1) 1 (1.5) .1y 15 (23.1) 42 (64.6) 5 (7.7) 2 (3.1) 1 (1.5) 50.6 (14.1; 23-92) 27.6 (5.8) 8 (12.3) 46 (70.8) 9 (13.9) 1 (1.5) 1 (1.5) 50.4 (14.8; 22-94) 26.0 (5.4) Statistical analysis Deidentified survey data were entered into a REDCap database, which is a secure World Wide Web application designed to support data capture for research studies.14We compared the distribution of rosacea cases and controls using paired t tests for continuous variables with appropriate transforma- tions, McNemar test for dichotomous and nominal variables, and Wilcoxon signed rank analyses for ordinal variables and continuous variables when transformation didnot achieve anormaldistribution. The associations between overall rosacea and co- morbid diseases were assessed using conditional logistic regression. Adjustment for history of smok- ing did not substantially change the association of rosacea with CVD, metabolic disease, hypertension, and hyperlipidemia (change in risk estimate\10%). We therefore reported estimates that were not adjusted for smoking. In a subgroup analysis, we investigated the asso- ciations between moderate to severe versus mild rosacea and comorbid diseases using unconditional logistic regression. We further performed sensitivity analyses, controlling the association between rosacea severity and comorbidities separately for age and sex. In analyses where comorbidity categories were spe- cific to a certain sex (for women: female hormone imbalance, hormonal contraception use; for men: male hormone imbalance), we limited analyses to include only members of that sex. All statistical analyses were performed using statistical software (SAS, Version 9.3, SAS Institute Inc, Cary, NC). For all analyses, P less than .05 was accepted as significant. .6z .1x .3y 0 (0.0) 10 (15.4) 20 (30.8) 35 (53.9) 1 (1.5) 18 (27.7) 11 (16.9) 35 (53.9) \.0001* 36 (55.4) 29 (44.6) 8 (12.3) 57 (87.7) [.99* 60 (92.3) 5 (7.7) 2.5 (2.5) 59 (90.8) 6 (9.2) 2.8 (4.9) .4y .2y 2.4 (2.0) 2.1 (1.6) BMI, Body mass index. *Calculated by McNemar test. yCalculated by Wilcoxon signed rank analysis. zCalculated by paired t test. xCalculated by paired t test after log transformation. (SD) age of cases was 50.6 (14.1) years, 43 (66.2%) were female, and 62 (95.4%) were Caucasian. Body mass index (P = .1), sun exposure (P = .3), smoking status (P = 1.0), alcohol intake (P = .5), and caffeine intake (P = .3) were comparable between cases and controls. Cases more frequently had a family history of rosacea (P \.0001). Table I provides the distri- bution of demographics and lifestyle characteristics. RESULTS Participant characteristics A total of 130 participants were recruited for the study, 65 patients and 65 control subjects. Each patient was matched to a control subject by age (P = .6), sex (P = 1.0), and race (P = 1.0). The mean Rosacea characteristics Of 65 patients with rosacea, 38 (58.4%) had mild and 27 (41.5%) had moderate to severe rosacea as

  4. J AM ACAD DERMATOL VOLUME 73, NUMBER 4 Rainer et al 607 Table II. Distribution of comorbidities in rosacea cases and controls (n = 130) Table III. Association between rosacea severity and comorbidities (n = 65) Cases n = 65 No. (%) Controls n = 65 No. (%) OR for rosacea (95% CI) Moderate to severe n = 27 No. (%) OR for moderate to severe rosacea (95% CI) P Mild n = 38 No. (%) value Comorbid disease Comorbid disease P value Allergy Airborne Food Respiratory diseases GERD Other GI diseases 23 (35.4) 11 (16.9) Hypertension Metabolic diseases Urogenital diseases Female hormone imbalance GERD Hyperlipidemia Hypertension Metabolic diseases Cardiovascular diseases 13 (34.2) 19 (70.4) 4.6 (1.6-13.2) 4 (10.5) 12 (44.4) 6.8 (1.9-24.6) 9 (23.7) 15 (55.6) 4.0 (1.4-11.7) 15 (39.5) 20 (74.1) 4.4 (1.5-12.9) .005 .003 .01 .007 44 (67.7) 26 (40.0) 11 (16.9) 18 (27.7) 4.6 (1.7-12.1) .002 10.0 (1.3-78.1) .03 4.0 (1.3-12.0) .01 2 (3.1) 6 (9.2) 32 (49.2) 13 (20.0) 4.2 (1.7-10.2) .002 3.0 (1.2-7.6) 2.8 (1.1-7.2) 2.4 (1.04-5.4) .04 12 (31.6) 18 (66.7) 4.3 (1.5-12.4) .006 .02 .03 24 (36.9) 13 (20.0) 35 (53.8) 24 (36.9) CI, Confidence interval; GERD, gastroesophageal reflux disease; OR, odds ratio. 15 (23.1) 2 (3.1) 7.5 (1.7-32.8) .007 21 (48.8) 10 (23.3) 3.2 (1.2-8.7) .02 the prevalence of comorbidities. Compared with mild rosacea, moderate to severe rosacea was strongly associated with hyperlipidemia (OR 6.8, 95% CI 1.9-24.6, P\.01), hypertension (OR 4.0, 95% CI 1.4-11.7, P = .01), metabolic diseases (OR 4.4, 95% CI 1.5-12.9, P\.01), CVD (OR 4.3, 95% CI 1.5-12.4, P\.01),andGERD(OR4.6,95%CI1.6-13.2,P\.01) (Table III). These results remained robust after separate adjustment for age and sex, with 1 notable exception for cancers including skin cancer; here rosacea severity was inversely associated with ‘‘can- cer including skin cancer’’ after adjusting for sex (OR 0.2, 95% CI 0.02-0.9, P\.05). CI, Confidence interval; GERD, gastroesophageal reflux disease; GI, gastrointestinal; OR, odds ratio. defined by a standard grading system for rosacea.13 Patients presented with erythematotelangiectatic (95.4%), papulopustular (36.9%), and phymatous (15.4%) changes, and nearly half (46.2%) had ocular involvement.Mean(SD)durationofdiseasewas11.8 (9.6) years. Rosacea and prevalence of comorbidities When analyzed by conditional logistic regression for matched case-control pairs, patients with rosacea were more likely to have allergies (airborne [odds ratio {OR} 4.6, 95% confidence interval {CI} 1.7-12.1, P \.01], food [OR 10.0, 95% CI 1.3-78.1, P \.05]), respiratory diseases (OR 4.0, 95% CI 1.3-12.0, P \ .05), gastroesophageal reflux disease (GERD) (OR 4.2, 95% CI 1.7-10.2, P\.01), other GI diseases (OR 3.0, 95% CI 1.2-7.6, P \.05), hypertension (OR 2.8, 95% CI 1.1-7.2, P\.05), metabolic diseases (OR 2.4, 95% CI 1.0-5.4, P\.05), urogenital diseases (OR 7.5, 95% CI 1.7-32.8, P \.01), and female hormone imbalance(OR3.2,95%CI1.2-8.7,P\.05)(TableII). Borderline significant associations were observed between rosacea and drug allergy (OR 2.2, 95% CI 1.0-5.2, P = .06), migraine (OR 2.3, 95% CI 0.9-5.6, P = .07), and musculoskeletal diseases (OR 2.2, 95% CI 1.0-5.2, P = .06). DISCUSSION Our case-control study reports significant associ- ations between rosacea and several systemic comor- bidities. Patients with rosacea have significantly higher odds of experiencing allergies (airborne and food), respiratory diseases, GERD/other GI diseases, hypertension, metabolic diseases, urogenital dis- eases, and female hormone imbalance compared with age-, sex-, and race-matched control subjects originating from the same population. Moderate to severe rosacea13is associated with hyperlipidemia, hypertension, metabolic diseases, CVD, and GERD. These associations remained robust after separate adjustment for age and sex. Interestingly, when we added sex into the regression model, the ORs of ‘‘cancer including skin cancer’’ were decreased in patients with moderate to severe rosacea compared with mild rosacea. Given that no association be- tween ‘‘cancer other than skin cancer’’ and rosacea severity was detected, skin cancer is likely driving the above-mentioned association. Considering that there was no difference in sun-exposing behaviors between groups, it is conceivable that patients with more severe rosacea may visit their dermatologists Rosacea severity and prevalence of comorbidities In a subgroup analysis that compared 27 (41.5%) patients with moderate to severe rosacea to 38 (58.4%) patients with mild rosacea, we detected a dose-response effect regarding rosacea severity and

  5. J AM ACAD DERMATOL OCTOBER 2015 608 Rainer et al more often; hence, skin cancer precursors might be detected and treated earlier. Previous studies suggested a link between rosa- cea and GI disorders such as malabsorption, celiac disease,2inflammatory bowel disease,3,4small intes- tinal bacterial overgrowth,6,7and Helicobacter pylori risk,7,8but these studies yielded conflicting results in some cases. Our study confirmed a significant asso- ciation of rosacea and GERD/other GI diseases. The risk of GERD was significantly higher in more severe rosacea (OR 4.6, 95% CI 1.6-13.2, P\.01) indepen- dent of doxycycline use. Another interesting finding is the strong associa- tion of rosacea with cardiovascular risk factors and CVD. Rosacea has been associated with biomarkers of CVD risk, such as total cholesterol, low-density lipoprotein, and C-reactive protein.9The current study indicates that rosacea disease activity matters, and demonstrates that moderate to severe rosacea is associated with hyperlipidemia, hypertension, meta- bolic diseases, and CVD. Thus, assessing cardiovas- cular risk factors and the overall CVD risk in patients with rosacea seems prudent. Although our study establishes associations be- tween rosacea and chronic systemic diseases, the pathophysiological connections are complex and remain unclear. It is likely that these connections involve mechanisms that underlie chronic inflamma- tory conditions including inflammatory cytokines, and metabolic, immune, and endocrine changes. The associations between rosacea and diseases involving barrier tissues such as the respiratory, GI, and urogenital tracts, which are constitutively colo- nized by a greatly diverse and site-specific flora, raisessuspicionthatdysbiosismightbeafactorinthe pathogenesis of rosacea, as well. Limitations that affect case-control studies need to be taken into account. These include recall and response bias in self-reported checklists, moderate sample sizes impacting the ability to analyze low- prevalence conditions, and the cross-sectional na- ture of the study, which precludes detection of cause-effect relationships and their directionality. Finally, we did not control for some potential confounders, such as physical activity, nutrition, or family history of disease, including atopy. Therefore, our results should be considered hypothesis gener- ating and require confirmation in prospective studies. The associations with several comorbid diseases in addition to the role of rosacea disease severity raise numerous new questions. To under- stand the link between comorbidities and rosacea, we need to investigate if pre-existing comorbidities affect the risk and phenotype of rosacea or if rosacea precedesthemanifestationof comorbiddiseases.Do comorbidities affect treatment response, and accord- ingly, should we use different treatment strategies in the presence of certain comorbidities? Lastly, given the involvement of tissues that interface with the microbial environment, such as the intestinal, respi- ratory, reproductive, and urinary tracts and the skin, future research needs to investigate how the tissue- environment interface is altered in patients with rosacea. In conclusion, our study provides evidence sup- porting the link between rosacea and systemic comorbidities. Moderate to severe rosacea is associ- ated with hyperlipidemia, hypertension, metabolic diseases, CVD, and GERD. Physicians should be aware of these associations to provide comprehen- sive care to patients with rosacea, especially to those presenting with more severe disease. REFERENCES 1. Spoendlin J, Voegel JJ, Jick SS, et al. A study on the epidemiology of rosacea in the U.K. Br J Dermatol. 2012;167: 598-605. 2. Watson WC, Paton E, Murray D. Small-bowel disease in rosacea. Lancet. 1965;1:47-50. 3. Walton S, Sheth M, Wyatt EH. Rosacea and ulcerative colitis: a possible association. J Clin Gastroenterol. 1990;12:513-515. 4. Romiti R, Jansen T, Heldwein W, et al. Rosacea fulminans in a patient with Crohn’s disease: a case report and review of the literature. Acta Derm Venereol. 2000;80:127-129. 5. Kendall SN. Remission of rosacea induced by reduction of gut transit time. Clin Exp Dermatol. 2004;29:297-299. 6. Parodi A, Paolino S, Greco A, et al. Small intestinal bacterial overgrowth in rosacea: clinical effectiveness of its eradication. Clin Gastroenterol Hepatol. 2008;6:759-764. 7. 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