Assessment of major comorbidities in adults with atopic dermatitis using the Charlson comorbidity index

ORIGINAL

ARTICLE

Assessment of major comorbidities in adults with atopic dermatitis using the Charlson comorbidity index Jacob P. Thyssen, MD, PhD, DMSc,a Lone Skov, MD, PhD, DMSc,a Carsten R. Hamann, MD,a Gunnar H. Gislason, MD, PhD,b,c,d and Alexander Egeberg, MD, PhDa Hellerup and Copenhagen, Denmark Background: There is a growing interest in comorbidities of adults with atopic dermatitis (AD). Objectives: To examine the burden of comorbidities in adult patients with AD using the Charlson comorbidity index (CCI) in nationwide registries. Methods: All Danish patients $18 years on January 1, 2012 with AD diagnosed by a hospital dermatologist were included. Patients were age-and sex-matched in a 1:4 ratio with general population controls. Severity was determined by systemic AD treatment and analyzed by conditional logistic regression. Results: In total, 10,738 adult patients with AD and 42,952 controls were analyzed. CCI score was significantly increased in smokers with AD compared with controls (0.41 vs 0.13, P \ .001). Nonsmokers with AD had a similar CCI score as controls (0.09 vs 0.08, P = .12). In analyses restricted to patients with severe AD, a stronger difference in CCI score was observed for smokers (0.48 vs 0.14, P \ .001) than for nonsmokers (0.10 vs 0.08, P = .01). Limitations: Observational studies do not establish cause and effect. Conclusion: On the basis of nationwide data, the risk for major comorbidities was significantly increased in adult patients with AD compared with controls. The risk difference was predominantly found in patients with severe disease and among smokers. ( J Am Acad Dermatol http://dx.doi.org/10.1016/ j.jaad.2017.01.030.) Key words: atopic dermatitis; comorbidity; epidemiology; risk; smoking.

topic dermatitis (AD) affects about one fifth of children,1 with many still having the disease in adulthood.2 Patients with AD not only have increased risk for atopic and psychiatric comorbidities3,4 but also certain autoimmune diseases.5-8 Recently, cardiovascular (CV) risk factors

A

and comorbidities were associated with AD,9-12 although lifestyle factors such as increased alcohol consumption and smoking might explain the increased risk of CV disease (CVD).13-15 The Charlson comorbidity index (CCI) allows for a comparison of comorbidities based on the International

From the Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmarka; Department of Cardiology, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmarkb; The Danish Heart Foundation, Copenhagen, Denmarkc; and The National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark.d Funding sources: None. Conflicts of interest: Dr Thyssen is supported by an unrestricted grant from the Lundbeck Foundation and has attended advisory board meetings for Roche and Sanofi-Genzyme. Dr Skov has received consultancy and speaker honoraria from Abbvie, Pfizer, Janssen-Cilag, Merck Sharp & Dohme, and Leo Pharma and is a member of the advisory boards of Abbvie, Pfizer, Janssen-Cilag, Merck Sharp & Dohme, Eli Lilly, Celgene, and Novartis. Dr Hamann has no relevant conflicts of interest to

declare. Dr Gislason is supported by an unrestricted research scholarship from the Novo Nordisk Foundation. Dr Egeberg has received research funding from Pfizer and Eli Lilly, and honoraria for consulting and speaking for Pfizer, Eli Lilly, Novartis, Galderma, and Janssen Pharmaceuticals. Accepted for publication January 20, 2017. Reprints not available from the authors. Correspondence to: Jacob P. Thyssen, MD, PhD, DMSc, Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark. E-mail: [email protected]. Published online April 6, 2017. 0190-9622/$36.00 Ó 2017 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2017.01.030

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Classification of Diseases (ICD) diagnostic codes. Based on adjusted risk for mortality or resource use,16 selected major systemic comorbidities have an associated weight from 1 to 6. The sum of all the weights results in a single comorbidity score for a patient, and a score of 0 indicates that no comorbidities exist. We compared the CCI in adults with AD and matched controls.

the CCI.22 Comorbidity for up to 5 years before December 31, 2012, was identified, and use of the CCI in the Danish National Patient Register has an overall positive predictive value of 98%.23

Statistical analysis Sample characteristics and CCI scores were summarized descriptively. Characteristics of individuals CAPSULE SUMMARY with or without AD were MATERIALS AND compared by using either METHODS Despite the growing literature on atopic the x2 for dichotomous variData sources and study dermatitis comorbidities, systematic ables and the Fisher’s exact population analyses of comorbidities remain scarce. test for continuous variables. Danish nationwide regisAdults with atopic dermatitis had an The associations between AD tries can be linked at the indioverall higher occurrence of and comorbid diseases were vidual level.17 The Danish comorbidities when nationwide data estimated by conditional loNational Patient Register18 were analyzed with the Charlson gistic regression, inherently contains information on incomorbidity index. The increased risk adjusting for the matched facand outpatient (ambulatory) was restricted to patients with severe tors, ie, age and sex. The hospital consultations accorddisease, and in particular smokers. Benjamini-Hochberg proceding to the ICD classification. ure was used to adjust for The Danish Registry of Sedentary lifestyle and modifiable risk multiple comparisons of the Medicinal Products Statistics19 factors should be targets for intervention examined outcomes, with difrecords information on all when assessing comorbidities in patients ferences considered signifipharmacy-dispensed medicawith atopic dermatitis. cant at P \ .05 in 2-sided tions according to the internatests. All analyses were pertional Anatomical Therapeutic formed with SAS v9.4 (SAS Chemical classification. Institute Inc, Cary, NC, USA) Medication dispensed durand STATA v13.0 (StataCorp, College Station, TX, ing hospitalization or given directly from ambulatory USA). The study was conducted in accordance with clinics is recorded in the Danish National Patient the Strengthening the Reporting of Observational Register. Tax-reported household income is reStudies in Epidemiology recommendations.24 corded by Statistics Denmark.20 The source population comprised all adults $18 years alive and resident in Denmark on December 31, 2012. We RESULTS identified all adults with an AD diagnosis (ICD-8 691 A total of 10,738 adult patients with AD and and ICD-10 L20) after their 18th birthday. To ensure 42,952 age- and sex-matched controls were analyzed accuracy of the AD diagnosis, we only included (Table I). Higher proportions of patients with AD diagnoses given by a hospital dermatologist. Each belonged to the highest socioeconomic class. About patient was matched on age and sex with 4 control half of patients with AD had severe disease. The subjects from the general population. Patients were proportion of smokers was significantly higher classified as outpatients (ie, seen in an ambulatory among AD patients than among controls (11.2% vs setting) unless they had been hospitalized at least 7.6%, P \.001). Tables II and III show the CCI scores once due to AD. Patients were classified with severe for patients with AD and controls. Overall, AD disease if they received systemic therapy for AD patients had a significantly higher CCI score than (methotrexate, azathioprine, mycophenolate mofecontrols (0.13 vs 0.09, P \ .001), but in subanalyses til, systemic corticosteroids, psoralen plus ultraviolet stratified by severity, we found that only severe AD A, or cyclosporine), and if not, they were classified as (0.17 vs 0.10, P \.001) and not mild AD (0.07 vs 0.07, mild. We calculated an age-standardized index of P = .98) was associated with higher CCI scores than socioeconomic status based on the mean gross controls. Stratification by hospitalization status annual income during the 5-year period before showed that both inpatients (0.16 vs 0.11, P \ .001) December 31, 2012. Smoking data was collected and outpatients (0.11 vs 0.08, P \ .001) had signifiusing a data retrieval algorithm, which has been cantly higher CCI scores than controls. The CCI score described extensively elsewhere.21 Major medical was only significantly increased in smokers with AD compared with control subjects (0.41 vs 0.13, comorbid disease burden was evaluated by means of d

d

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Abbreviations used:

Table I. Demographic characteristics of the study population

AD: CCI: CV: CVD: ICD:

Characteristic

atopic dermatitis Charlson comorbidity index cardiovascular cardiovascular disease International Classification of Disease

P \.001), whereas nonsmokers with AD had similar CCI scores as control subjects (0.09 vs 0.08, P = .12). A stronger difference in CCI score was observed for smokers who had severe AD (0.48 vs 0.14, P \.001) compared with nonsmokers who had AD (0.10 vs 0.08, P = .01), and the number of comorbidities did not significantly differ (P = .1) between AD nonsmokers and their respective control subjects (Table III). Table IV (available at http://www.jaad.org) shows the prevalence of specific comorbidities in patients with AD stratified by severity. Most but not all diseases were associated with severe AD.

DISCUSSION We found significantly higher concurrences of major comorbidities in AD patients, and in particular among those with severe AD (possibly owing to systemic anti-AD treatment) and a history of smoking tobacco. AD is associated with impaired quality of life and psychiatric comorbidity.3,4,25-27 The link with autoimmune disease might partly be explained by overlapping genetic predispositions,5 but the ADassociated risk for rheumatoid arthritis and inflammatory bowel disease also might owe to increased smoking.6 Indeed, we recently showed that the association between AD and autoimmune disease was stronger among smokers than among nonsmokers,28 and AD is strongly associated with tobacco smoking.29 Although it remains unresolved whether the increased risk for CVD is explained by systemic inflammation in AD or associated CV risk factors, stratified analyses showed that the risk was primarily restricted to smokers, including among patients with severe AD. Because causation cannot be established on the basis of observational data, it is possible that those affected by autoimmune diseases or other comorbidities begin to smoke or smoke more. Similarly, it is plausible that chronic systemic inflammation in AD could increase the risk for comorbidities, again resulting in secondary smoking. Dichotomous data on smoking was available, but we lacked quantitative data, which could have biased our estimates. Some patients in our study might have been misclassified as nonsmokers, thus attenuating the smoking-associated effect and, in turn, biasing our results toward the null.

Atopic dermatitis (n = 10,738)

Controls (n = 42,952)

Sex, n (%) Female 7055 (65.7) 28,220 Male 3683 (34.3) 14,732 Age, 42.9 (35.0-52.7) 42.9 median (IQR) Age group, n (%) 18-29 y 1.507 (14.0) 6208 30-39 y 2902 (27.0) 11,608 40-49 y 3039 (28.3) 12,156 50-59 y 1805 (16.8) 7220 60-69 y 917 (8.5) 3668 $70 y 568 (5.3) 2272 Socioeconomic status (income), n (%) Lowest 1948 (18.1) 8790 Below 2174 (20.3) 8564 average Average 2164 (20.2) 8574 Above 2100 (19.6) 8638 average Highest 2352 (21.9) 8386 Smoking, n (%) Smokers 1198 (11.2) 3273 Nonsmokers 9540 (88.8) 39,679 Atopic dermatitis severity, n (%) Mild 4885 (45.5) Severe 5853 (54.5) Inpatient vs Outpatient, n (%) Inpatient 3093 (28.8) Outpatient 7645 (71.2)

P value

(65.7) 1.000 (34.3) (35.0-52.7) 1.000

(14.0) (27.0) (28.3) (16.8) (8.5) (5.3)

1.000

(20.5) (19.9)

\.001

(20.0) (20.1) (19.5) (7.6) (92.4)

\.001

NA NA

NA NA

IQR, Interquartile range; NA, not applicable.

Table II. Number and percentage of patients and controls stratified by Charlson comorbidity index score Any AD Index score

0 1 2 3 $4 Mean index (SD)

AD patients, n (%) Controls, n (%) P value

10,037 329 235 74 63 0.13

(93.5) (3.1) (2.2) (0.7) (0.6) (0.60)

40,873 1025 717 198 129 0.09

(95.2) \.001 (2.4) (1.7) (0.5) (0.3) (0.47) \.001

AD, Atopic dermatitis; SD, standard deviation.

The possible iatrogenic effects of systemic therapy were unaccounted for, and use of medication might explain some of the increased observed comorbidities in patients with AD. The comorbidities in the CCI are generally considered hard endpoints and

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Table III. Number and percentage of patients and controls stratified by Charlson comorbidity index score and atopic dermatitis severity, hospitalization type, and smoking status By severity of atopic dermatitis CCI score

0 1 2 3 $4 Mean CCI score (SD)

Mild AD, n (%)

4700 79 73 15 18 0.07

(96.2) (1.6) (1.5) (0.3) (0.4) (0.45)

Controls, n (%)

18,743 416 250 71 60 0.07

(95.9) (2.1) (1.3) (0.4) (0.3) (0.45)

P value

Severe AD, n (%)

.123

5337 250 162 59 45 0.17

.983

(91.2) (4.3) (2.8) (1.0) (0.8) (0.69)

Controls, n (%)

P value

22,130 609 467 127 79 0.10

\.001

(94.5) (2.6) (2.0) (0.5) (0.3) (0.48)

\.001

By hospitalization type CCI score

0 1 2 3 $4 Mean CCI score (SD)

AD inpatients, n (%)

2822 135 86 32 18 0.16

(91.2) (4.4) (2.8) (1.0) (0.6) (0.64)

Controls, n (%)

P value

11,619 364 261 78 50 0.11

\.001

(93.9) (2.9) (2.1) (0.6) (0.4) (0.52)

AD outpatients, n (%)

7215 194 149 42 45 0.11

\.001

(94.4) (2.5) (2.0) (0.6) (0.6) (0.58)

Controls, n (%)

P value

29,254 661 456 120 89 0.08

(95.7) (2.2) (1.5) (0.4) (0.3) (0.44)

\.001

Controls, n (%)

P value

\.001

By smoking status CCI score

0 1 2 3 $4 Mean CCI score (SD)

AD smokers, n (%)

938 133 78 23 26 0.41

(78.3) (11.1) (6.5) (1.9) (2.2) (1.01)

Controls, n (%)

4445 170 120 34 23 0.13

(92.8) (3.6) (2.5) (0.7) (0.5) (0.55)

P value

AD nonsmokers, n (%)

\.001

9099 196 157 51 37 0.09

\.001

(95.4) (2.1) (1.7) (0.5) (0.4) (0.51)

36,428 855 597 164 116 0.08

(95.5) (2.2) (1.6) (0.4) (0.3) (0.45)

.281

.120

By smoking status in severe AD CCI score

0 1 2 3 $4 Mean CCI score (SD)

Severe AD smokers, n (%)

605 112 58 22 20 0.48

(74.1) (13.7) (7.1) (2.7) (2.5) (1.05)

Controls, n (%)

3017 117 92 25 17 0.14

(92.3) (3.6) (2.8) (0.8) (0.5) (0.56)

P value

Severe AD nonsmokers, n (%)

\.001

\.001

9432 217 177 52 43 0.10

(95.1) (2.2) (1.8) (0.5) (0.4) (0.53)

Controls, n (%)

37,856 908 625 173 122 0.08

(95.4) (2.3) (1.6) (0.4) (0.3) (0.46)

P value

.102

.010

AD, Atopic dermatitis; CCI, Charlson comorbidity index; SD, standard deviation.

thus less likely to suffer from surveillance bias. It was not possible to evaluate whether atopic or psychiatric comorbidity could explain some of the observed CCI differences. The adult AD population is heterogeneous in Denmark; the patients with AD belonged to high socioeconomic class. Moreover, we had no information about body constitution and physical activity, which might have confounded our analyses. However, adults in Scandinavia with AD had the same level of physical exercise as controls,30 and AD is not associated with being over-weight in Europe. Moreover, the risk for gallstones and type 2 diabetes was significantly lower in adults with AD compared with controls, supporting that AD patients in Denmark are normal weight.31 We determined disease severity based on the use of systemic treatment and cannot refute that medications might have been

prescribed for other conditions. Moreover, misclassification might have affected the results because patients with AD followed in primary or secondary clinics were not registered. However, such misclassification would arguably have biased the results towards the null, ie, no difference between mild and severe AD. Based on nationwide data, we showed that the risk for major comorbidities was significantly increased in adults with AD. Our observations suggest that besides AD severity, modifiable risk factors such as smoking are important in this relationship. REFERENCES 1. Weidinger S, Novak N. Atopic dermatitis. Lancet. 2016;387: 1109-1122.

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2. Vinding GR, Zarchi K, Ibler KS, Miller IM, Ellervik C, Jemec GB. Is adult atopic eczema more common than we think? A population-based study in Danish adults. Acta dermato-venereologica. 2014;94:480-482. 3. Cheng CM, Hsu JW, Huang KL, et al. Risk of developing major depressive disorder and anxiety disorders among adolescents and adults with atopic dermatitis: a nationwide longitudinal study. J Affect Disord. 2015;178:60-65. 4. Yu SH, Silverberg JI. Association between atopic dermatitis and depression in US adults. J Invest Dermatol. 2015;135: 3183-3186. 5. Mohan GC, Silverberg JI. Association of vitiligo and alopecia areata with atopic dermatitis: a systematic review and meta-analysis. JAMA dermatology. 2015;151:522-528. 6. Schmitt J, Schwarz K, Baurecht H, et al. Atopic dermatitis is associated with an increased risk for rheumatoid arthritis and inflammatory bowel disease, and a decreased risk for type 1 diabetes. JAllergy Clin Immunol. 2016;137:130-136. 7. Deckert S, Kopkow C, Schmitt J. Nonallergic comorbidities of atopic eczema: an overview of systematic reviews. Allergy. 2014;69:37-45. 8. Brunner PM, Silverberg JI, Guttman-Yassky E, et al. Increasing comorbidities suggest that atopic dermatitis is a systemic disorder. J Invest Dermatol. 2017;137:18-25. 9. Silverberg JI, Greenland P. Eczema and cardiovascular risk factors in 2 US adult population studies. J Allergy Clin Immunol. 2015;135:721-728.e6. 10. Silverberg JI. Association between adult atopic dermatitis, cardiovascular disease, and increased heart attacks in three population-based studies. Allergy. 2015;70:1300-1308. 11. Su VY, Chen TJ, Yeh CM, et al. Atopic dermatitis and risk of ischemic stroke: a nationwide population-based study. Ann Med. 2014;46:84-89. 12. Riis JL, Vestergaard C, Hjuler KF, et al. Hospital-diagnosed atopic dermatitis and long-term risk of myocardial infarction: a population-based follow-up study. BMJ Open. 2016;6:e011870. 13. Drucker AM, Li WQ, Cho E, et al. Atopic dermatitis is not independently associated with nonfatal myocardial infarction or stroke among US women. Allergy. 2016;71:1496-1500. 14. Andersen YM, Egeberg A, Gislason GH, Hansen PR, Skov L, Thyssen JP. Risk of myocardial infarction, ischemic stroke, and cardiovascular death in patients with atopic dermatitis. The Journal of allergy and clinical immunology. 2016;138:310-312. 15. Marshall VD, Moustafa F, Hawkins SD, Balkrishnan R, Feldman SR. Cardiovascular disease outcomes associated with three major inflammatory dermatologic diseases: a propensity-matched case control study. Dermatol Ther (Heidelb). 2016;6:649-658. 16. Yeung H, Takeshita J, Mehta NN, et al. Psoriasis severity and the prevalence of major medical comorbidity: a population-based study. JAMA dermatology. 2013;149: 1173-1179.

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17. Schmidt M, Pedersen L, Sorensen HT. The Danish Civil Registration System as a tool in epidemiology. Eur J Epidemiol. 2014;29:541-549. 18. Andersen TF, Madsen M, Jorgensen J, Mellemkjoer L, Olsen JH. The Danish National Hospital Register. A valuable source of data for modern health sciences. Dan Med Bull. 1999;46: 263-268. 19. Gaist D, Sorensen HT, Hallas J. The Danish prescription registries. Dan Med Bull. 1997;44:445-448. 20. Baadsgaard M, Quitzau J. Danish registers on personal income and transfer payments. Scand J Public Health. 2011;39:103-105. 21. Egeberg A, Mallbris L, Gislason GH, Skov L, Hansen PR. Risk of multiple sclerosis in patients with psoriasis: a Danish nationwide cohort study. The Journal of Investigative Dermatology. 2016;136:93-98. 22. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40:373-383. 23. Thygesen SK, Christiansen CF, Christensen S, Lash TL, Sorensen HT. The predictive value of ICD-10 diagnostic coding used to assess Charlson comorbidity index conditions in the population-based Danish national registry of patients. BMC Med Res Methodol. 2011;11:83. 24. von Elm E, Altman DG, Egger M, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet. 2007;370:1453-1457. 25. Simpson EL, Bieber T, Eckert L, et al. Patient burden of moderate to severe atopic dermatitis (AD): insights from a phase 2b clinical trial of dupilumab in adults. Journal of the American Academy of Dermatology. 2016;74:491-498. 26. Strom MA, Fishbein AB, Paller AS, Silverberg JI. Association between AD and attention deficit hyperactivity disorder in U.S. children and adults. Br J Dermatol. 2016;175:920-929. 27. Yu SH, Attarian H, Zee P, Silverberg JI. Burden of sleep and fatigue in US adults with atopic dermatitis. Dermatitis. 2016;27: 50-58. 28. Andersen YM, Egeberg A, Gislason GH, Skov L, Thyssen JP. Autoimmune diseases in adults with atopic dermatitis. J Am Acad Dermatol. 2016;76:274-280.e1. 29. Kantor R, Kim A, Thyssen J, Silverberg JI. Association of atopic dermatitis with smoking: a systematic review and meta-analysis. J Am Acad Dermatol. 2016;75:1119-1125.e1. 30. Lonne-Rahm SB, Sundstrom I, Nordlind K, Engstrom LM. Adult atopic dermatitis patients and physical exercise: a Swedish questionnaire study. Acta dermato-venereologica. 2014;94: 185-187. 31. Egeberg A, Andersen YM, Gislason G, Skov L, Thyssen JP. Gallstone risk in adult patients with atopic dermatitis and psoriasis: possible effect of overweight and obesity. Acta Derm Venereol. January 25, 2017. http://dx.doi.org/10.2340/ 00015555-2622.

Patients, n (%) Comorbid disease

131 55 63 155 51

(1.2) (0.5) (0.6) (1.4) (0.5)

Controls

452 116 146 454 184

(1.1) (0.3) (0.3) (1.1) (0.4)

OR AD overall (95% CI)

1.17 1.92 1.73 1.39 1.11

Adjusted* P value

OR mild AD (95% CI)

Adjusted* P value

OR severe AD (95% CI)

Adjusted* P value

(0.96-1.42) (1.39-2.65) (1.29-2.33) (1.15-1.67) (0.81-1.52)

.1970 .0005 .0010 .0017 .5584

0.93 1.47 1.09 0.95 0.63

(0.65-1.35) (0.86-2.52) (0.57-2.07) (0.66-1.36) (0.31-1.23)

.8682 .5148 .8682 .8682 .5148

1.29 2.27 2.02 1.63 1.36

(1.02-1.64) (1.50-3.41) (1.43-2.83) (1.30-2.04) (0.95-1.95)

.0384 .0003 .0003 .0003 .1099

105 (1.0) 34 (0.3)

312 (0.7) 122 (0.3)

1.35 (1.08-1.69) 1.12 (0.76-1.63)

.0163 .6002

1.23 (0.82-1.84) 0.71 (0.22-1.51)

.7353 .7897

1.42 (1.08-1.85) 1.35 (0.87-2.11)

.0257 .2059

133 (1.2) 5 (0.1)

252 (0.6) 9 (0.0)

2.16 (1.74-2.68) 2.22 (0.74-6.63)

.0005 .2061

0.49 (0.27-0.90) 2.00 (0.18-22.06)

.2541 .7897

3.22 (2.52-4.10) 2.29 (0.67-7.81)

.0003 .2059

3 (0.0) 10 (0.1)

9 (0.0) 15 (0.0)

1.33 (0.36-4.93) 2.67 (1.20-5.94)

.6610 .0312

1.60 (0.31-8.24) 2.50 (0.82-7.64)

.7897 .5148

1.00 (0.11-8.94) 2.86 (0.91-9.00)

1.0000 .0945

137 (1.3) 57 (0.5)

476 (1.1) 190 (0.4)

1.15 (0.95-1.40) 1.20 (0.89-1.62)

.2045 .2862

0.87 (0.62-1.24) 0.83 (0.48-1.45)

.7897 .7897

1.32 (1.05-1.68) 1.43 (1.00-2.05)

.0348 .0686

27 (0.3) 38 (0.4) 57 (0.5)

44 (0.1) 54 (0.1) 92 (0.2)

2.45 (1.52-3.96) 2.86 (1.88-4.35) 2.50 (1.79-3.48)

.0008 .0005 .0005

2.11 (0.98-4.53) 0.95 (0.35-2.57) 1.27 (0.66-2.45)

.4158 .9204 .7897

2.72 (1.47-5.04) 4.00 (2.47-6.48) 3.33 (2.24-4.95)

.0036 .0003 .0003

33 (0.3) 6 (0.1)

88 (0.2) 17 (0.0)

1.50 (1.01-2.24) 1.41 (0.56-3.58)

.0805 .5379

1.11 (0.55-2.24) 2.29 (0.67-7.81)

.8682 .5148

1.77 (1.08-2.89) 0.80 (0.18-3.65)

.0384 .8101

67 (0.6)

147 (0.3)

1.82 (1.37-2.44)

.0005

1.18 (0.70-2.01)

.7897

2.28 (1.60-3.24)

.0003

14 (0.1) 193 (1.8) 4 (0.0)

22 (0.1) 619 (1.4) 10 (0.0)

2.55 (1.30-4.97) 1.26 (1.07-1.49) 1.60 (0.50-5.10)

.0145 .0145 .5168

2.18 (0.81-5.90) 1.02 (0.76-1.37) Not applicable

.5148 .9204

2.91 (1.17-7.23) 1.40 (1.15-1.72) 4.00 (1.00-15.99)

.0384 .0024 .0686

39 (0.4)

108 (0.3)

1.44 (1.00-2.08)

.0805

0.31 (0.11-0.85)

.2541

2.50 (1.64-3.81)

.0003

AD, Atopic dermatitis; CI, confidence interval; OR, odds ratio. *P values are corrected for multiple comparisons with the Benjamini-Hochberg procedure.

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Myocardial Cardiac dysrythmia Cardiogenic shock Congestive heart failure Ischemic heart disease Myocardial infarction Vascular Cerebrovascular disease Peripheal vascular disease Pulmonary Chronic obstructive pulmonary disease Pulmonary edema Neurologic Dementia Hemiplegia Endocrine Diabetes Diabetes with complication Renal Acute renal failure Chronic renal failure Renal disease Liver Mild liver disease Severe liver disease Gastrointestinal Peptic ulcer disease Cancer/Immune AIDS Cancer Metastatic tumor Miscellaneous Rheumatological disease

AD

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Table IV. Association between atopic dermatitis severity and prevalent comorbid disease