Evidence-Based Complementary and Alternative Medicine
(543517.v2) Special Issue on
The Role of CAM in Public Health, Disease Prevention, and Health Promotion
Research Article
Traditional Chinese Medicines Decrease the Stroke Risk of Systemic Corticosteroid Treatment in Dermatitis: A Nationwide Population- based Study
Kao-Sung Tsai,1,2,3 Chia-Sung Yen,3 Po-Yuan Wu, 1,2 Jen-Huai Chiang,1,2 Jui-Lung Shen,4,5 Chung-Hsien Yang,1 Huey-Yi Chen,1,2 Yung-Hsiang Chen,1,2,6 Wen-Chi Chen1,2
1 Institute of Chinese Medicine, School of Chinese Medicine, Graduate Institute of Integrated Medicine, School of Post-Baccalaureate Chinese Medicine, Research Center for Chinese Medicine &
Acupuncture, Institute of Clinical Medical Science, College of Medicine, China Medical University, Taichung 40402, Taiwan
2 Departments of Dermatology, Medical Research, Obstetrics and Gynecology, and Urology, Management Office for Health Data, China Medical University Hospital, Taichung 40447, Taiwan
3 Department of Applied Cosmetology, Master Program of Cosmetic Science, Department of Cultural and Creative Industries, HUNGKUANG University, 43302, Taiwan
4 Center for General Education, Feng Chia University, Taichung 40724, Taiwan
5 Department of Dermatology, Taichung Veterans General Hospital, Taichung 40705, Taiwan
6 Department of Psychology, College of Medical and Health Science, Asia University, Taichung 41354, Taiwan
Correspondence should be addressed to Wen-Chi Chen and Yung-Hsiang Chen;
wgchen@mail.cmu.edu.tw and yhchen@mail.cmu.edu.tw
Abstract
Dermatitis is an allergic disease in which systemic inflammation involves more than just the skin. Epidemiological studies have shown a strong association between dermatitis and stroke. More evidences have shown that systemic inflammation can accelerate the progression of atherosclerosis and subsequently stroke. Systemic corticosteroid, the mainstay treatment for dermatitis, could enhance the atherosclerotic process. Traditional Chinese Medicine (TCM) has been therefore used as an alternative treatment for dermatitis to decrease the side effects of corticosteroid.
However, evidence of the different stroke risk in dermatitis patients treated with systemic corticosteroid or TCM remains unclear. This study identified 235,220 dermatitis patients and same comorbidity-matched subjects between 2000 and 2009 from claimed database of NHRI in Taiwan. The two cohorts were followed until December 31, 2011. The primary outcome of interest was new diagnosis of stroke.
The crude hazard ratio (HR) for future stroke among dermatitis patients treated with systemic corticosteroid was 1.40 (95% CI, 1.34-1.45; P < 0.0001) and TCM was 1.09 (95% CI, 1.05-1.13; P < 0.0001). The log-rank test showed a higher cumulative incidence of ischemic stroke in the patient treated with only systemic corticosteroid group than treated by systemic corticosteroid and TCM, only TCM and neither systemic corticosteroid nor TCM in the matched cohort during the follow-up period (P < 0.0001). We demonstrated that patients treated with systemic corticosteroid had an increased risk of stroke, and that the risk probably decreased by TCM treatment.
1. Introduction
Many complementary and alternative medicine (CAM) practices have
emphasized health promotion, however, this has not been the focus of the bulk of
CAM research. CAM practitioners could be seen as a public health resource to
increase the population’s access to certain clinical preventive services [1, 2].
Eczematous dermatoses account for a large proportion of all skin disease. Some
studies have suggested that dermatitis is an allergic disease in which systemic
inflammation involves more than just the skin [3-5]. More evidences have shown that
systemic inflammation can accelerate the progression of atherosclerosis and
thrombosis with resulting ischemic stroke [6]. Epidemiological studies have shown a
strong association between systemic inflammatory disease, particularly dermatoses
and cardiovascular diseases [7]. Furthermore, Su et al. demonstrated atopic dermatitis,
a chronically relapsing and constitutive skin disease, may be an independent risk
factor for ischemic stroke [8].
Contemporary medicines often used a combinations of topical steroid agents,
systemic antihistamine, corticosteroids and immune-modulating agents to control this
frustrating disease. The treatment of dermatitis, especially systemic corticosteroid
therapy, can influence the atherosclerotic process. It is believed that this treatment is
atherogenic for the long-term used, partially due to effects on plasma lipoproteins,
elevation of total cholesterol, triglycerides and for promoting an abnormal distribution
of high-density lipoprotein subclasses [9]. The systemic corticosteroid can also
indirectly accelerate the process by augmenting other traditional risk factors,
including hypertension and obesity [10]. On the other hand, inflammation is
associated with atherosclerosis, and therefore, corticosteroid therapy could have a
protective effect. Previous studies published in literature about this issue were
contradictory. The role of treatment with systemic corticosteroid or alterative
treatment in the evolution of stroke in dermatitis need to be further investigated.
The decision to use CAM is multifactorial, including dissatisfaction with
conventional treatment, and frustration with the chronic nature course of eczema. For
avoiding the potential adverse effects of systemic conventional dermatitis treatments
and also to attain better clinical outcomes, many patients and practitioners have tried
to seek alternative treatment [11]. Regarding the benefits, there is a raising trend of
CAM treatment and the use of CAM is actually associated with eczema prevalence
[12]. Traditional Chinese medicine (TCM) is one of the popular alternative treatments
for dermatitis in Asia and world [13, 14]. The aim of this study was to determine the
different risk of stroke in dermatitis patients treated with systemic corticosteroid or
TCM by using a nationwide database and proved a part of a structured initiative to
established evidenced-based clinical recommendation for management of
comorbidities in dermatitis.
2. Materials and methods
2.1. Data sources
Taiwan’s National Health Insurance (NHI) program, implemented by the
government in March 1995, provides comprehensive health care to almost all
Taiwanese citizens, with a coverage rate of more than 99% of Taiwan’s entire
population and contracted with 97% of hospitals and 92% of clinics. The National
Health Research Institute (NHRI) of Taiwan manages and publicly releases for
research purposes multiple NHI databases that include information about basic patient
characteristics, date of visit, diagnoses codes for the International Classification of
Diseases, Ninth Revision, Ninth Revision, Clinical Modification (ICD-9-CM) codes,
detailed claims data for examinations, disease management and drug prescriptions for
all admitted patients and outpatients [15, 16]. The NHRI created research data sets
including a random sample of 1,000,000 subjects from the registry of all NHI
enrollees in 2000, with the encryption of personal information that could identify any
individual patient. We obtained these data sets of NHRI from 2000 to 2011 for use as
our research database. This study was approved by the Institutional Review Board of
CMU-REC-101-012 from institutional review board approval of Public Health, Social
and Behavioral Science Committee Research Ethics Committee, China Medical
University and Hospital.
2.2. Study design and population
This population-based cohort study utilizing a nationwide database was
conducted of two groups. The population with dermatitis (aged 20 years) were
identified by code 690.X, 691.X, and 692.X in the ICD-9-CM and newly dermatitis
diagnosis (at least two medical visits) between 1 January 2000 and 31 December 2009
and followed up until December 31, 2011. Subjects who have a past history of stroke
before the enrollment date were excluded from the study group. Systemic
corticosteroid or TCM coding was obtained for medication variant control in
advanced step of analysis. We included the most common prescribed systemic
corticosteroids: Dexamethasone, Methylprednisolone and Prednisolone. Treatment
was divided into non-TCM and systemic steroid user, only TCM user, only systemic
steroid user, and use TCM and systemic steroid. The primary outcome of interest was
new diagnosis of stroke (ICD-9 code: 430-438). For stroke type analysis, we
separated hemorrhagic stroke (ICD-9-CM codes 430, 431 and 432) and compared the
ischemic stroke (ICD-9-CM codes 433-438) in further adjusted hazard ratio analysis.
The date for dermatitis diagnosis was defined as index date. All the subjects were
followed from the index date to occurrence of end point or until December 31, 2011,
whichever was first, and the observations on the last dates were considered as
censored observations.
2.3. Comparison group
Subjects without dermatitis were randomly selected from the same data set. Each
patient with newly diagnosed dermatitis in the NHRI database was pair-matched with
one subject of the same age, sex and index year. TCM or systemic corticosteroid
medications and comorbidities (allergic rhinitis, asthma, urticarial, diabetes mellitus,
hypertension, hyperlipidemia and atrial fibrillation) were not matched. We selected
comparison subjects using incidence density sampling by computer programming
[17]. In the comparison group, subjects who have past history of stroke before
enrollment were also excluded as the study group.
To determine stroke and survival analyses adjusting for age, sex, comorbidities,
and medications were carried out with Cox’s proportional hazards model. All
enrollees were followed from the date of enrollment until the first diagnosis of stroke
or censored date of death, withdrawal from the insurance, or until 31 December 2011.
2.4. Potential confounders
In the analysis of the effect of different treatment, systemic corticosteroid or
TCM, in patients with dermatitis on the outcome of stroke, we controlled for age and
sex and identified the following comorbidities as potential confounders: diabetes
mellitus (ICD-9 code: 250), hypertension (ICD-9 code: 401-405), hyperlipidemia
(ICD-9 code: 272.0, 272.1, 272.2, 272.3, and 272.4) atrial fibrillation (ICD-9 code
427.31).
2.5. Statistical analysis
Person-years of two populations were calculated from baseline to the occurrence
of stroke or closing date (December 31, 2011). All statistical analyses were performed
using SAS version 9.4 software (SAS Institute, Inc., Cary, NC).
All data are expressed as mean standard deviation or n (%) unless otherwise
stated. Comparisons between groups were performed using Student’s t-test for
continuous variables and Pearson’ s chi-square test, as appropriate, for categorical
variables. The Cox’s proportional hazards model was used to estimate the hazards
ratio for the progression of outcome. The probability of survival difference between
each group with dermatitis user and non-dermatitis users was tested with the log-rank
test. The Kaplan-Meier method was used to plot the cumulative incidence. Cox
proportional hazard model was used to calculate the hazard ratios and 95% confidence
interval of stroke for patients with dermatitis compared with non-dermatitis user. All
analyses were carried out with SAS statistical software. All statistical tests were
performed at the two-tailed significance level of 0.05. A P value < 0.05 was
considered statistically significant.
3. Results
Clinical characteristics of this study population identified patients newly
diagnosed with dermatitis between 1 January 2000 and 31 December 2009. After
excluding patients aged under 20 years or with antecedent stroke 235,220 patients
with dermatitis were included in the analyses. Another 235,220 patients without
dermatitis were selected by 1:1 matching by age, sex, and index year. The study
subjects were predominantly female (58.13%), and the median age was 41.9 ± 15.5
for dermatitis cohort group and 41.5 ± 15.9 years old for non-dermatitis cohort group.
Table 1 shows that basic characteristics and selected comorbidities were similar
between groups.
Predictors of difference stroke risk between systemic corticosteroid and TCM
treatment in patients with dermatitis were conducted in this study. During the follow-
up period, 206,402 (87.75%) patients with dermatitis were treated with systemic
corticosteroid and 160,541 (68.25%) were comparison subjects. 207,890 (88.38%)
patients with dermatitis treated with TCM and 183,949 (78.20%) were comparison
subjects. Also, subject with and without dermatitis had 78.47 and 57.22 percentage
who had used both TCM and systemic steroid. We also found that 13,079 (5.65%)
patients with dermatitis and 10,006 (4.25%) comparison subjects experienced stroke
attack. Analyzing different stroke type, 12,450 (5.29%) patients with dermatitis and
9,277 (3.94%) comparison subjects had Ischemic stroke attack. However, there was
no statistically difference in patients with dermatitis and comparison subjects that
experienced hemorrhagic stroke attack. The log-rank test showed a higher cumulative
incidence of stroke in the dermatitis group than in the matched cohort during the
follow-up period (P < 0.0001, Figure 1), suggesting that patients with dermatitis had
an increased risk of stroke in the long term.
After adjusting for age, gender, comorbidities and medications, we compared
with comparison subjects and stratified Cox’s proportional hazard regression
demonstrated that the crude hazard ratio (HR) for future stroke among patients with
dermatitis was 1.13 (95% confidence interval, (95% CI), 1.1-1.16; P < 0.0001) and
ischemic stroke among patients with dermatitis was 1.16 (95% CI, 1.12-1.19; P <
0.0001). Furthermore, compared with non-TCM and non-systemic steroid user, the
adjusted hazard ratio (HR) for future stroke among patients treated with only TCM
was 1.22 (95% CI, 1.13-1.32; P < 0.0001), only systemic steroid was 1.55 (95% CI,
1.43-1.67; P < 0.0001) and use TCM and systemic steroid was 1.64 (95% CI, 1.53-
1.76) (Table 2 and 3). These HR results suggested that dermatitis and patient treated
with systemic corticosteroid or TCM may be an independent risk factor for stroke.
The log-rank test showed a higher cumulative incidence of ischemic stroke in the
patient with dermatitis and treated with systemic corticosteroid group than treated by
systemic corticosteroid and TCM, only TCM and neither systemic corticosteroid nor
TCM in the matched cohort during the follow-up period (P < 0.0001, Figure 2).
We also identified the following independent factors determining the risk of
future stroke: The adjusted HRs of stroke was significantly lower in female than male
(HR, 0.81; 95% CI, 0.78-0.83; P < 0.0001), and increased with increasing age.
Significant adjusted HRs of stroke in Cox proportional hazard models were asthma
(HR, 1.07; 95% CI, 1.02-1.12; P = 0.0073), diabetes mellitus (HR, 1.37; 95% CI,
1.32-1.41; P < 0.0001), hypertension (HR, 1.87; 95% CI, 1.81-1.93; P < 0.0001) and
atrial fibrillation (HR, 1.70; 95% CI, 1.51-1.91; P < 0.0001).
4. Discussion
In this large population-based cohort study, we demonstrated that the patient
with dermatitis treated with systemic corticosteroid is a risk factor for stroke and the
patients treated with TCM may decrease incidence of this risk. Patients with
dermatitis treated with TCM had decreased incidence of ischemic stroke compared
with the corticosteroid group. These findings support the concept that dermatitis may
exert a systemic effect contributing to stroke and different treatments are important
confounders.
Corticosteroid is the mainstay treatment for dermatitis, with the route of
administration and dosage schedule dependent primarily on the severity. While
complications range in severity and frequency, which are generally considered to be
depended on the dosage and/or duration of corticosteroid. However, the adverse
effects result from not only the cumulative corticosteroid dose but also high-dose
corticosteroid treatment was significantly associated with development of stroke [18].
Obesity, diabetes mellitus, hypertension, atrial fibrillation and hyperlipidemia may be
worse as corticosteroid treated, furthermore these adverse effects may contribute to
the later development of atherosclerosis and ischemic stroke [19-21].
The atherosclerotic changes or stroke are associated with inflammatory processes
resulting from several dermatoses, such as atopic dermatitis [8], dermatitis
herpetifoprmis [22], systemic lupus erythematosus [23], bullous pemphigoid [24],
drug rash eosinophilia and systemic symptoms (DRESS) [25], and psoriasis [26].
Possible explanations for the high risk of stroke in patients with dermatitis are
atherosclerotic changes [4, 14, 23], oxidative stress [27], and activation of the
coagulation system related to chronic inflammation [28, 29]. Increasing evidence has
shown that systemic inflammation can promote the progression of atherosclerosis and
thrombosis to ischemic stroke [6]. There are several possible mechanisms of
dermatitis resulting in stroke: first, the elevation of platelet activation and reducing
fibrinolysis were founded in patients with chronic inflammatory allergic diseases such
as atopic dermatitis [30, 31]. Second, mast cell may participated in atherosclerosis by
releasing pro-inflammatory cytokines, chemokines and proteases to induced
inflammatory cell recruitment, cell apoptosis and angiogenesis [32, 33]. Third,
increased serum IgE levels in myocardial infarction patients and mast cell
accumulated in atherosclerotic lesions. [34]. Fourth, hypereosinophilia may play an
import role in some of these dermatoses, included dermatitis, bullous pemphigoid and
DRESS. Thrombosis may be related to eosinophilic hypothiocyanous acid
productions, which lead to a prothrombotic state [35]. Furthermore, Encephalopathy
may arise from small cerebral stroke or direct eosinophil toxicity [36]. Dermatitis is
an allergic disease, like asthma, it probably exerts systemic inflammatory effect in a
similar fashion, thereby contributing to cardiovascular or cerebrovascular
consequences. However, allergic rhinitis and urticarial seems to be milder and less
systemic inflammation than other atopic diseases.
A number of studies on TCM have been performed, with a collective result of
symptom improvement and decreased levels of inflammatory cytokines. Since
standard TCM prescribed of many herbs combined in different forms and dosed
differently depending on each individual patient, randomized control trial in this area
have been difficult to perform. It has been postulated that Zemaphyte might work as
an efficient antioxidant, capable of scavenging both superoxide and hydroxyl and
preventing peroxidation of biological membranes. Pentaherbs formulation, another
TCM prescription formula, was postulated that suppression of the low-affinity
receptors for IgE on antigen-presenting cell, modulated mast cells and inhibited the
the inflammatory mediators from mast cells [37], and possessed immunomodulatory
effects and inflammatory mediators [38]. Methodological advantages of the
interdisciplinary secondary data-base utilized include a high degree of
generalizability, completeness, absence of recall bias due to prospective input of
diagnoses and research questions and large sample size [39]. In this study, we
replicated the previous reported positive association between the major stroke risk
factors and found that atrial fibrillation, hypertension, diabetes and hyperlipidemia
seem very sensitive to change to multivariate models (Table 2). This may be due to
the low prevalence of those traditional risk factors for stroke in the dermatitis group.
We demonstrated dermatitis may be an independent risk factor for ischemic stroke. In
light of our limited understanding of the exact mechanisms explaining the adverse
stroke risk factors in dermatitis patients, it has been speculated that the established
association between stroke and different treatments might explain these finding.
Our study has several limitations. First, patients with dermatitis and stroke were
identified using a diagnostic code in a database, introducing the possibility of
misclassification because of coding errors or misdiagnosis. Second, some potential
risk factors, including obesity, smoking, alcohol use, and family history of
cardiovascular disease, were not included in our analyses because these data were not
available. Third, the follow-up period may not have been sufficiently long to detect
stroke development because atopic dermatitis always course in child to teenager but
stroke often attack in Middle-aged to elderly. Fourth, we could not directly evaluate
the severity of dermatitis stroke, the accumulated dosage of systemic corticosteroid,
ingredients of TCM and each comorbidity. Finally, because we did not have the
information of causes of death, stroke may be a cause of death but was not recorded
as an end-point. The role of inflammation biomarkers, ingredients of TCM and the
relationship between TCM, dermatitis and stroke are not clear. Further research is
needed to determine the possible pathogenic mechanisms between TCM prescribed in
dermatitis and stroke are necessary.
5. Conclusions
This large population-based study demonstrated that patients treated with
systemic corticosteroid had an increased risk of stroke, and that the risk probably
decreased by TCM treatment.
Conflict of Interests
The authors declare that they have no conflict of interests.
Acknowledgements
This study is supported in part by China Medical University (CMU103-S-47),
CMU under the Aim for Top University Plan of the Taiwan Ministry of Education,
Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of
Excellence (104-TDU-B-212-113002), Academia Sinica Taiwan Biobank, Stroke
Biosignature Project (BM104010096), NRPB Stroke Clinical Trial Consortium
(MOST 103-2325-B-039-006), Tseng-Lien Lin Foundation, Taichung, Taiwan Brain
Disease Foundation, and Katsuzo and Kiyo Aoshima Memorial Funds, Japan.
References
1. C. K. Kim, D. H. Kim, M. S. Lee, J. I. Kim, L. S. Wieland, and B. C. Shin.
"Randomized controlled trials on complementary and traditional medicine in the korean literature," Evidence-Based Complementary and Alternative Medicine, vol. 2014, p. 194047, 2014.
2. C. H. Wu, C. C. Wang, M. T. Tsai, W. T. Huang, and J. Kennedy. "Trend and pattern of herb and supplement use in the United States: results from the 2002, 2007, and 2012 national health interview surveys," Evidence-Based Complementary and Alternative Medicine, vol. 2014, p. 872320, 2014.
3. M. Steinhoff, A. Steinhoff, B. Homey, T. A. Luger, and S. W. Schneider. "Role of vasculature in atopic dermatitis," Journal of Allergy and Clinical Immunology, vol. 118, no. 1, pp. 190-197, 2006.
4. Y. Wang, H. Gao, C. M. Loyd, et al. "Chronic skin-specific inflammation promotes vascular inflammation and thrombosis," Journal of Investigative Dermatology, vol. 132, no. 8, pp. 2067-2075, 2012.
5. N. Shenoy, K. A. Shenoy, and P. R. U. "The perceptual preferences in learning among dental students in clinical subjects," J Clin Diagn Res, vol. 7, no. 8, pp.
1683-1685, 2013.
6. M. S. Elkind. "Inflammatory markers and stroke," Current Cardiology Reports, vol. 11, no. 1, pp. 12-20, 2009.
7. L. L. Husemoen, T. Skaaby, T. Jorgensen, et al. "No association between loss-of- function mutations in filaggrin and diabetes, cardiovascular disease, and all-cause mortality," PloS One, vol. 8, no. 12, p. e84293, 2013.
8. V. Y. Su, T. J. Chen, C. M. Yeh, et al. "Atopic dermatitis and risk of ischemic stroke: a nationwide population-based study," Annals of Medicine, vol. 46, no. 2, pp. 84-89, 2014.
9. F. Formiga, J. F. Meco, X. Pinto, J. Jacob, I. Moga, and R. Pujol. "Lipid and lipoprotein levels in premenopausal systemic lupus erythematosus patients,"
Lupus, vol. 10, no. 5, pp. 359-363, 2001.
10. B. F. Freire, R. C. da Silva, A. T. Fabro, and D. C. dos Santos. "Is systemic lupus erithematosus a new risk factor for atherosclerosis?," Arquivos Brasileiros de Cardiologia, vol. 87, no. 3, pp. 300-306, 2006.
11. K. L. Hon, T. F. Leung, H. C. Yau, and T. Chan. "Paradoxical use of oral and topical steroids in steroid-phobic patients resorting to traditional Chinese medicines," World Journal of Pediatrics, vol. 8, no. 3, pp. 263-267, 2012.
12. J. I. Silverberg, M. Lee-Wong, and N. B. Silverberg. "Complementary and alternative medicines and childhood eczema: a US population-based study,"
Dermatitis, vol. 25, no. 5, pp. 246-254, 2014.
13. K. S. Tsai, T. C. Lin, M. T. Wu, et al. "Irritant contact dermatitis risk of common topical traditional chinese medicines used for skin-lightening: a pilot clinical trial with 30 volunteers," Evidence-Based Complementary and Alternative Medicine, vol. 2014, p. 609064, 2014.
14. P. E. Harris, K. L. Cooper, C. Relton, and K. J. Thomas. "Prevalence of complementary and alternative medicine (CAM) use by the general population: a systematic review and update," International Journal of Clinical Practice, vol.
66, no. 10, pp. 924-939, 2012.
15. H. Y. Chen, Y. C. Chang, C. C. Lin, F. C. Sung, and W. C. Chen. "Obstructive sleep apnea patients having surgery are less associated with glaucoma," J Ophthalmol, vol. 2014, p. 838912, 2014.
16. H. Y. Chen, Y. C. Chang, I. J. Wang, and W. C. Chen. "Comparison of glaucoma diagnoses using Stratus and Cirrus optical coherence tomography in different glaucoma types in a Chinese population," Journal of Glaucoma, vol. 22, no. 8, pp. 638-646, 2013.
17. S. Wacholder, J. K. McLaughlin, D. T. Silverman, and J. S. Mandel. "Selection of controls in case-control studies. I. Principles," American Journal of Epidemiology, vol. 135, no. 9, pp. 1019-1028, 1992.
18. T. F. Leung, K. Y. Wong, C. K. Wong, et al. "In vitro and clinical immunomodulatory effects of a novel Pentaherbs concoction for atopic dermatitis," British Journal of Dermatology, vol. 158, no. 6, pp. 1216-1223, 2008.
19. A. Zonana-Nacach, S. G. Barr, L. S. Magder, and M. Petri. "Damage in systemic lupus erythematosus and its association with corticosteroids," Arthritis and Rheumatism, vol. 43, no. 8, pp. 1801-1808, 2000.
20. L. Wei, T. M. MacDonald, and B. R. Walker. "Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease," Annals of Internal Medicine, vol. 141, no. 10, pp. 764-770, 2004.
21. C. F. Christiansen, S. Christensen, F. Mehnert, S. R. Cummings, R. D. Chapurlat, and H. T. Sorensen. "Glucocorticoid use and risk of atrial fibrillation or flutter: a population-based, case-control study," Archives of Internal Medicine, vol. 169, no. 18, pp. 1677-1683, 2009.
22. J. T. Lear, R. H. Neary, P. Jones, D. A. Fitzgerald, and J. S. English. "Risk factors for ischaemic heart disease in patients with dermatitis herpetiformis,"
Journal of the Royal Society of Medicine, vol. 90, no. 5, pp. 247-249, 1997.
23. I. N. Bruce. "'Not only...but also': factors that contribute to accelerated atherosclerosis and premature coronary heart disease in systemic lupus
erythematosus," Rheumatology (Oxford, England), vol. 44, no. 12, pp. 1492- 1502, 2005.
24. Y. J. Chen, C. Y. Wu, M. W. Lin, et al. "Comorbidity profiles among patients with bullous pemphigoid: a nationwide population-based study," British Journal of Dermatology, vol. 165, no. 3, pp. 593-599, 2011.
25. R. Cahyanur, D. Oktavia, and S. Koesno. "DRESS and Ischemic Stroke," Acta Medica Indonesiana, vol. 44, no. 3, pp. 239-242, 2012.
26. C. H. Chiang, C. C. Huang, W. L. Chan, et al. "Psoriasis and increased risk of ischemic stroke in Taiwan: a nationwide study," Journal of Dermatology, vol. 39, no. 3, pp. 279-281, 2012.
27. N. Sivaranjani, S. V. Rao, and G. Rajeev. "Role of reactive oxygen species and antioxidants in atopic dermatitis," J Clin Diagn Res, vol. 7, no. 12, pp. 2683- 2685, 2013.
28. S. C. Pitchford, H. Yano, R. Lever, et al. "Platelets are essential for leukocyte recruitment in allergic inflammation," Journal of Allergy and Clinical Immunology, vol. 112, no. 1, pp. 109-118, 2003.
29. M. Gawaz, H. Langer, and A. E. May. "Platelets in inflammation and atherogenesis," Journal of Clinical Investigation, vol. 115, no. 12, pp. 3378-3384, 2005.
30. R. Tamagawa-Mineoka, N. Katoh, E. Ueda, K. Masuda, and S. Kishimoto.
"Platelet-derived microparticles and soluble P-selectin as platelet activation markers in patients with atopic dermatitis," Clinical Immunology, vol. 131, no. 3, pp. 495-500, 2009.
31. M. Nastalek, A. Wojas-Pelc, and A. Undas. "Plasma fibrin clot properties in atopic dermatitis: links between thrombosis and atopy," Journal of Thrombosis and Thrombolysis, vol. 30, no. 2, pp. 121-126, 2010.
32. J. Sun, G. K. Sukhova, P. J. Wolters, et al. "Mast cells promote atherosclerosis by releasing proinflammatory cytokines," Nature Medicine, vol. 13, no. 6, pp. 719- 724, 2007.
33. M. Ihara, H. Urata, A. Kinoshita, et al. "Increased chymase-dependent angiotensin II formation in human atherosclerotic aorta," Hypertension, vol. 33, no. 6, pp. 1399-1405, 1999.
34. M. Jeziorska, C. McCollum, and D. E. Woolley. "Mast cell distribution, activation, and phenotype in atherosclerotic lesions of human carotid arteries,"
Journal of Pathology, vol. 182, no. 1, pp. 115-122, 1997.
35. J. G. Wang, S. A. Mahmud, J. A. Thompson, J. G. Geng, N. S. Key, and A.
Slungaard. "The principal eosinophil peroxidase product, HOSCN, is a uniquely potent phagocyte oxidant inducer of endothelial cell tissue factor activity: a
potential mechanism for thrombosis in eosinophilic inflammatory states," Blood, vol. 107, no. 2, pp. 558-565, 2006.
36. P. W. Kaplan. "Central nervous system problems with eosinophilia," Archives of Neurology, vol. 68, no. 12, pp. 1613-1614; author reply 1614, 2011.
37. L. Y. Chung. "Antioxidant profiles of a prepared extract of Chinese herbs for the treatment of atopic eczema," Phytotherapy Research, vol. 22, no. 4, pp. 493-499, 2008.
38. B. C. Chan, K. L. Hon, P. C. Leung, et al. "Traditional Chinese medicine for atopic eczema: PentaHerbs formula suppresses inflammatory mediators release from mast cells," Journal of Ethnopharmacology, vol. 120, no. 1, pp. 85-91, 2008.
39. H. T. Sorensen, S. Sabroe, and J. Olsen. "A framework for evaluation of secondary data sources for epidemiological research," International Journal of Epidemiology, vol. 25, no. 2, pp. 435-442, 1996.
Figure Legends
Figure 1. The estimated cumulative incidence of stroke between the dermatitis cohort
and the non-dermatitis cohort by Kaplan-Meier analysis.
Figure 2. The estimated cumulative incidence of ischemic stroke between treated
with CTM or systemic corticosteroid in the patients of dermatitis cohort by Kaplan-
Meier analysis.
